CA1056685A

CA1056685A - Active agent dispenser and process for making same

Info

Publication number: CA1056685A
Application number: CA239,459A
Authority: CA
Inventors: Robert M. Gale; Richard W. Baker
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 1974-11-14
Filing date: 1975-11-12
Publication date: 1979-06-19
Also published as: DE2549856C2; SE7512744L; DE2549856A1; IT1050619B; MX158868A; JPS6059203B2; CH634226A5; JPS5170807A; MX158867A; GB1477813A; FR2290891A1; US3926188A; SE439432B; FR2290891B1

Abstract

ABSTRACT OF THE DISCLOSURE

A laminated active agent dispenser, such as a three layer laminate drug dispenser comprising a core lamina of a crystalline drug of low water solubility dispersed homogeneously in a polymer matrix of permeability, P, to the drug, the core lamina having a thickness, 2t, interposed between outer laminas made of a drug release rate controlling polymer of permea-bility, P', to the drug, each outer lamina having a thickness, t', such that the core lamina has an exposed surface area, A, and the outer laminas have a combined exposed surface area, A', and and

Description

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1~056685 BACKG~
Numerous sustained release dispensers, particularly ones for dispensing drugs, have been developed recently which comprise a drug which is confined withinc a polymer and which dispense the drug by a diffusion ; mechanism in which the drug permeates through the polymer. The aim of ~ ~
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these devices is to dispense the drug at a more or less constant rate for a prolonged period of time which results in improved therapy compared to drugs delivered by periodic ingestion of pills, injections or drops.
Basically such dispensers are of two types: monolithic and reservoir.
`~ 10 In a monolithic device the drug is dispensed in a polymer which is permeable to the drug. The time rate of release of the drug from such devices has been studied and reportedO It is proportional to time /20 A plot of ~,, release rate versus time for a monolithic device gives a curve which starts .
'`'! at a high rate and declines continuouslyO Notwithstanding this varying release rate~ monolithic devices ha~re the commer~ial attractiveness of being inexpensive to make.
, ~ In a reservoir device the drug is confined within a container ~-;~ formed of a polymer which is permeable to the drugO The drug may be neat or combined with a solid or liquid carrier. In copending~ commonly a~signed !
patent no. 942,667 issued February 26~ 1974 and applicati~n no. tS2~938 filed September 29, 1972 embodiments of reservoir devices in which the drug release is substantially constant are disclosed3 The two basic features of those embodiments which permit such release are~ fo~nulating the drug in a liquid carrier whose perm ability to the drug is greater than the permeability of the po1ymer defining the container to the drug; and ,.
. i lT. Higuchi~ ~ ~, 50, 874 (1961); To J. Roseman et al, ,~. Pharm.
sci.l 61, 46 (1972); and Ho K. Lonsdale, R. WO Baker~ "Controlled Release of Biologically Active Agents", Edo C~ Tanquery, Plenum Press, New ~ork ` ~1974~
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maintaining the concentration of the drug in the carrier at saturation for the effective dispensing lifetime of the device. For some drugs such reservoir embodiments are the only type of diffusion device for dispensing the drug at a practical controlled rate. $uch embodiments also provide the advantages of providing a substantially constant release of the drug~ I ;
which is an important factor as regards efficaGy and safety in many ther-apeutic regimensO The disadvantages of reservoir devices as compared to monolithic devices is economic the former being more complex and hence ; more costly to make ~han the latter.
STATEMENT 0~ THE INVENTION
One aspect of the invention is an active agent dispenser that dispenses an active agent of low water solubility by diffusion from a poly-mer matrix characterized in that the dispenser is a laminate of:
(a) a core lamina of crystalline particles of the active agent dis-persed in a polymer matrix having a permeability~ P, to the agent, the core lamina having a thickness, 2t, and being partly covered by;
(b) at least one outer lamina of an active agent release rate control-ling polymer having a permeability, P, to the agent and a thickness t~
such that the core lamina has an exposed surface area, A, from which the , agent may be dispensed and the outer lamina has an exposed surface area~ Al, from which the active agent may be dispensed, and the correlation Pt . P~
is geater than about 2 and the correlation kLA - ~ is at least 3 times the correlation -~ . pl ~wherein k is a constant whose value is dependent upon the geometrical shape of the laminate.
Another aspect of the in~ention ~ a process for making an active agent dispenser that dispenses an active agent of low water solubility by diffusion from a polymer matrix characterized by:

~a) fo i ng a solid core lamina of thickness, 2t, fro~ a mixture of ;

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105~G85 crystalline particles of the agent and a polymer having a permeability P, ~ to the agent; and (b~ laminating at least one outer lamina of thickness~ tl, of an active agent release rate controlling polymer havi.ng a permeability~ P~
. to the agent to a portion of the exterior of the core, such that the core has an exposed surface area, A~ from which the agent may be dispensed and . the outer lamina has an exposed surface area, A~, from which the agent may be dispensed, and the correlation t ~ p~ is greater than about 2 ~ and the correlation k ~ is at least 3 times the correlation Pt . t~ , ;
- 10 wherein k is a constant whose value is dependent upon the geometrical . shape of the laminateO
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; BRIEF DESCRIPTION OF THE DRAWINGS
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`~ The drawings illustrate the structures and performances of pre-~ ferred embodiments of the active agent dispensers~ namely dispensers that ;~ dispense drugs. In the drawings like reference numerals refer to like parts~ and~

. Figure 1 is a cross-sectional view of a drug dispenser of this :

. invention;

Figure 2 is a graphical representation of the release rates of ~:

the devices described in Example 1~ infra; :~

Figure 3 is a graphical representation of the release rates of ` the devices described in Example 2~ infra;

-; Figure 4 is a graphical representation of the release rates of the devices described in Example 3~ infra; and ,. i .~ Figure 5 is an elevational perspective view of another drug dis-;
`~ penser of this invention.
~, ~ DESCRIPTION OF THE P _FERRED EMBODI~ENT6 ; Figure 1 illustrates a drug dispenser~ generally designated 10.
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i,6~5 Dispenser 10 is a three layer sand~ich-type laminate in the shape of a thin circular disc comprising a core Lamina 11 sandwiched between two outer laminas 12, 130 Core l~lmina 11 consists of solid particles of drug 14 dispersed within a polymer matrix 150 Matrix 15 has a permeability~ P~
to the drug and core L~mina 11 has a thickness, 2t. The edge 16 of core lamina 11 defines the surface area, A~ thereof which is exposed to the ~;~
environmentO ~ `
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Outer laminas 12, 13 each have a thickness~ t~ and a permeability pl, *o the drugO Surfaces 17,18 oP laminas 12,13 define a combined surface ;.,. ~.
10area, At, thereof which is exposed to the environment. (The area defined ~ .
by the axial edges of laminas 12~13 is also exposed but is negligible rel_ .:
ative to area Al.) ~ ~`
Dispenser 10 releases drug 14 at surfaces 16,17 and 18 by a diffu-sion mechanism. Drug molecules initially dissolve inc~atrix 15 and per-meate therethrough either to exposed surface 16 or to outer laminas 12~13 and therethrough to exposed surfaces 17~180 The molecules which reach :~.
~ exposed surfaces 16,17,18 are removed or cleared therefrom through contact ~
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with body fluids and/or body tissueO When the respective permeabilities -.; .
and thicknessesQfcore lamina 11 and outer laminas 12~13 are correlated as set forth above, that is -t o pl ~ is greater than about 2~ drug will be released from surfaces V,18 at a substantially constant rate as long as the polymer of matrix 15 is saturated with the drugO In contrast, drug is released from edge 16 at a constantly declining rate proportional to ;

3 time~1/2~
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~ However~ by correlating the permeabilities~ thicknesses~ and ~ ~
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exposed surface areas of core lamina 11 and outer laminas 12~13 as set ~;
forth above~ the amount of drug released from edge 16 is substantially less ~ than the amount of drug released from surfaces 17~180 AccordinglyJ the .`' :
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~sf~s overall release rate from dispenser 10 is dominated by the release rate of drug from surfaces 17,18 and thus the overall release rate approximates the substantially constant release rate from those surfacesO In this respect the greater the magnitude of t . pl~ and the greater the difference between the magnitude of the expression k ~ and the magnitude of the expre~sion t P~ , the closer is this approximation. If t . p~ is less than 2, the outer membranes do not control the drug release rate and the rate generally declines proportional to time /2. If k ~A ~2 ~ 3. t . p~ ~ the exposed area of the core is too high or the permeability of the core is too high and release of drug from the core edge predominates and again the release rate declines proportional to time 1/2. In the intermediate region, how-ever~ which is the subject of this invention, neither of these effects predominates and drug release rate is almost constant with time. The release rates of these laminates are, of course, not as constant as the release rates of comparable prior art reservoir devices in which the core is not exposed to the environmentO However~ for many therapies the degree of release rate constancy afforded by these laminates is acceptable. Thus they provide a viable~ less expensive alternative to the reservoir devices in such instances. Preferably Pt o p~ is greater than 3 and k ~ 2 is ~ 20 at least 10 times Pt . ptl .
; Figure 5 illustrates another drug dispenser, generally designated ` 19, of the invention. Dispenser 19 is a concentric-type lc~minate in the shape of a cylinder comprising a cylindrical core lamina 20 and an outer ~-concentric lamina 21 which covers the axial surface of core lamina 200 Core lamina 20, like core lamina 11, comprises particles of drug 14 dis-;~1 pensed within a polymer matrix lS. It is functionally equivalent to core ~ lamina 110 The ends 22,23 of core lamina 20 define the surface area~ A~
-~ thereof which is exposed to the environment. Core lamina 20 has a diameter~
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2t~ 0uter concentric lamina 21 has a permeability, P', to the durg and has a thickness, t'. Lamina 21 is f~ctionally identical to laminas 12, 13 and may be made from the same materials as the latter. The axial surface 24 of lamina 21 defines the surface area, A~, thereof which is exposed to the environment. lThe area defined by the radial edges of lamina 21 is also exposed but is negligible relative to area A'.) ;-Dispenser 19 releases drug 14 at surfaces 22, 23, 24 by a diffusion mechanism identical to that described above with respect to dispenser lOo - The correlations between the thicknessess~ permeabilities and exposed surface areas of laminas 20, 21 of dispenser 19 required to permit dispenser ~ ~-19 to release drug at a substantially constant rate are the same as those ; described above with respect to dispenser 10.
Drug 14 is solid ~crystalline) and should have a low water sol~
bility. Low water solubility is a requirement so that the drug does not function to any significant extent as an osmotic attractant to imbibe water from the use environment into core lamina 11. If substantial water is ~
` imbibed, the drug 14 may be released by an osmotic bursting mechanism rather ~ `
than a diffusion mechanism. This would affect the release rate of drug in ~ ;
an undesirable manner. The degree of water solubility will in many instan- ~ -ces depend on the permeability of matrix 15 to water. If matrix 15 has a high permeability to water, the water solubility of the drug should be "
correspondingly low and vice versa. Drugs which are 10ss than about 4 by weight soluble in water are desirable, and less than about 1% by weight ~
are preferred. ~ ' .; ;
e particle si~e of drug 14 is not criticalO Particle si~es in the range of 1~ to 20~ will normally be used since they are easy to handle and may be readily dispersed homogeneously in matrix 15 by conventional :,j l techniques. ~ ~
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l~ilS~5 The load:ing of drug 14 in core lamina ll is important because it may affect the permeability of core lamina 11 to the drug. At high drug loadings (greater than about 25% by weight) l~mina 11 has a tendency to become microporous over the device~s lifetime. This occurs because as ; drug particles t~ dissolve in matrix 15 and diffuse therefrom~ voids are ` left in the matrixO At such high drug loadings, the void v~lume is suf-ficient to make the portion of lamina 1l which has been depleted of drug -microporous. Such microporosity will cause the permeability of core lamina 11 to increase. Indeed, high drug loadings provide a means for mak-ing the permeabiliky of the core lamina 11 substantially greater than the permeability of the outer laminas even though the same polymer is used in bothO The drug loading of lamina 11 will depend upon the drug dosage regimen desired, with higher loadings providing greater dosages and/or more sustained release. Usually the loading will be in the range of 30%
to 75% by weight o~ the core lamina.
The nature of the drug will depend upon the therapy for which the device is intended. Drugs which produce a localized effect at the admin-istration site or a systemic effect at a site remote from the adminisration site may be used. Such drugs include inorganic and organic compounds~ for example~ hypnotics, sedatives, psychic energizers~ tranquilizers, anti-convulsants, muscle relaxants and anti-parkinson agents~ antipyretics and anti- mflammatory agents, local anesthetics, an~i-spasmodics and antiulcer agents, prostaglandins, anti-microbials, hormonal agents, estrogenic ster-oids, progestationaI steroids, such as for contraceptive purposes~ sympath-omimetic drugs~ cardiovascular drugs, diuretics, anti-parasitic agents, hypoglycemic drugs and ophthalmic drugs.
Matrix 15 may be made from a polymeric material which is homo-geneous and substantially imperforate (i.eO~ it has no man-made perforations) .
: . , , : ~ , ~L~56~35 ~- or it may be made from a po:Lymer which has been made m:icroporous by conven-tional techniquesO In either instance its permeability to the drug should be kno~n. Examples of substantially imperorate polymers which may be used are poly(butylmethacrylate), plasticized poly(vinylchloride), plasti-cized soft nylon, natural rubber, poly{isoprene)~ poly( isobutylene), - poly~butadiene), poly(ethylene), poly(vinylidenechloride)~ cross-linked poly(vinylpyrrolidone), chlorinated poly(ethylene), poly¦4~4~-isopropyl-idene diphenylene carbonate), ethylene~vinylacetate copolymer~ plasticized ethylene-vinylacetate copolymer, vinylidene chloride-acrylonitrile co-polymer, vinyl chloride-diethyl fumerate copolymer, silicone rubbers, ` especially the medical grade poly(dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonate copolymers and vinylidene chloride-vinyl chloride copolymer.
Microporous materials have pores which range in size from at least about 10 A to several hundred microns, but usually not more than about ~
100 micronsa Examples of materials from which microporous structures may ~;
be made are regenerated, insoluble, nonerodible cel1ulose~ acylated cellu-lose~ esterified cellulose, cell~lose acetate propionate~ cellulose acetate butyrate~ cellulose acetate phthalate, cellulose acetate diethyl-aminoace-tate~ poly (urethanes), poly Icarbonates), modified insoluble co:llagen~
cross-linked poly(vinyl alcohol), epoxy resins and poly(olefins) or :.-` poly(vinylchlorides). These materials may be made microporous by well knbwn procedures such as coprecipitatlon or leaching out incorporated salts~
~ soap micelles, starch or like materials. See~ for example~ J.D. Ferry, -, Chemical Reviews, 187 373 (1935)~ and "Synthetic Polymer Membranes~', by `
3 R.E. Xesting McGraw-Hill, 1971. ~ ;
Outer laminas 12,13,21 may be made from the same polymers as are 3 listed above for making matrix 15. The particular polymer selected from ~ -8-,,,,~, ~s~
said list for making matrix 15 may be the same or different than the part-icular polymer selected for making laminas 12,13~210 It is preferred that the permeability, P~ of matric 15 to the drug be substantially greater than the permeability, P', of the outer laminas 12,13,21 to the drug either because of the degree of drug loading mentioned above and/or by making the outer laminas 12,13,21 from a polymer that inheren~ly has a lower perme- -ability to drug than does the polymer from which matrix 15 is made. It will be appreciated that either of outer laminas 12,13 may be made from a drug-impermeable material. In such an instance, the effective thickness ~the maximum thickness through which the drug must permeate to reach a permeable outer lamina) of core lamina 11 will be twice that of an embodi-ment in which both laminas 12,13 are drug permeable and the exposed outer lamina surface area from which drug is released will be half that of an embodiment in which both laminas 12,13 are drug permeableO It is also ; within the scope of this invention to make laminas 12~13 from different polymeric materials of different drug permeability and to make them of ,~
different thicknessesO
The shape and size of the dispenser will depend upon the environ- -ment in which it is intended to be used. If the dispenser is intended to be implanted or inserted~ its size and shape will be compatible with the size and shape of the implantation or insertion site. For instance~ if it is intended to be used as an ocular insert, it will be sized and ~iaped .. ~ . ~ .
~ for insertion and retention in the eye. Likewise, if intended for inser-:, . .
.-3 tion in other body cavities, such as the vagina, uterus~ mouth and gastro- ~
.:j `~ intestinal tract, it will be sized and shaped accordinglyO In most instances it will be acceptable to employ regular shapes. As indicated above, the value of k in the expression k~ 2 will depend on the geomet-rical shape of the dispenserO For three-layered sandwich elliptical shaped , ~ ' , ; -:~ ~

1~5~
dispensers such as dispenser 10, k has a value of 4. Its ralue for other sandwich-type dispensers of regular geometrical shape may be calculated (e.g., for a circle it is 8). For cylindrical concentric laminate dispensers such as dispenser 19~ k has a value o~ 1/8. The value of k for other concen--~ tric laminates of other cross-sectional shapes (e.g., hexagonal, square, elliptical) may be calculated.
The sandwich-type laminates of this invention may be manufactured according to well-known techniques. Depending upon the particular polymers constituting the core lamina and outer laminas, the laminate may be bonded together with or without binders. Various binders are well-known in the art.
See for instance the ~ clopedia of Polymer S~ience and Technology, John Wiley ~ Sons, Vol. 8, 1968. If a binder is used, it, of course, should be compatible with the polymers that constitute the laminas and should not affect or interfere with the drug permeation through the laminas or alter the drug deleteriously in any mannerO Conventional laminating machines and 9 techniques may be used, with the particular temperatures and pressures ;~
, employed varying with the polymers involved. ~he laminates may be formed as continuous sheets and the dispensers of this invention cut or punched therefrom by known techniques. The concentric-type laminates of the inven-tion may also be formed by well-known techniques such as coextrusion.
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While the dispensers have hereinabove been described as dispensers for releasing drugs for human or animal therapy, it will also be appreciated ~;
that they may be used to release other active agents in other environments, provided such agents are solid and have low water solubilityas described above. Such active agents incl~de, for example, pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides5 insecticides, ~ A
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anti-oxidants, plc~nt growth promoters and inhibitors, preservatives, surfac-tants, disinfectants, catalysts, fermentation agents, nutrients, plant :1 .'' .

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minerals, sex sterilants, plant hormones~ air purifiers and micro-organism attenuatorsO
EXAMPLES
The following examples illustrate the dispensers of this invent-ion and their performance relative to dispensers outside the scope of the invention.
Example l .~
A. A physostigmine dispenser~ such as might be inserted in the eye to dispense physostigmine thereto~ was made as follows. Fifty p~rts phy~
~ sostigmine ~particle size approximately 5 microns)~ and 50 parts of ethy-- 10 lene-vinylacetate copolymer (brand name~ Elvax 40) were mixed homogeneously on a rubber millO The resulting mixture was melt pressed into a 200 micron thick film. This film was then placed in a vacuum/heat laminator and a 150 micron thick sheet of ethylene-vinylacetate copolymer (brand name~
Elvax 40) was laminated to each side of ito Duplicate 5.8 mm x 13.5 mm ellipses were punched from the resulting three layer laminate. p~ pl3 `:
A and At, for these elliptical dispensers were determined and the values :~ for the expressions Pt . ptl and k ~ ~ 2 were calculated therefrom and ~ ;~
are reported in Table l below.
Duplicate physostigmine dispensers were made in accordance with part A above except that the outer laminas were each 75 microns thick.
The data for these dispensers are also reported in Table 1 belowO
C. For comparison, duplicate physostigmine dispensers were made in accordance with part A above except that the outer laminas were each 13 microns thick. The data for these dispansers are also reparted in Table 1 below~ ~
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Table 1 A A' P . t' A 1 ~ P P' (cm2) (cm2~ t P' k A J2 `~ 1 A 230 70 000650 1.23 4O93 1,430 1 B 230 70 0.0650 1.23 2.46 1,430 ; 1 C 230 70 000650 1 23 0.43 1,430 ~ ~
m e release rates of the dispensers of A, B and C were determined by placing ~ ;
~ individual devices in polymer mesh bags and suspencling the bags from a'!'1 vertically reciprocating bar into vessels containing 50 ml buffer stirred a~c 37 C. The physostig0ine concentration in the buffer was measured at regular intervals by UV analysis, the buffer being changed after each ;
measurementO Physostigmine release rates were calculated from the measure- `
i ments. Figure 2 is a plot of these release rates versus time. As indicated by the plots of Figure 2, the release rate of the dispensers of B is substan- ;
tially more constant than that of the dispensers of C and that of A is even more constant than Bo mis is a reflection of the increasing value of the expression _ 0 _ , as reported in Table 1.

Example 2 Two sets of chloramphenicol dispensers were made by the general procedure of Example lAo The core lamina was made from 66 parts chloramph-nicol (particle si~e approximately 5 microns) and 34 parts copolymer and ;
~1 and was 125 microns thicko me outer lami~as were 50 microns thick and ~`
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~ 17.5 microns thick, respectively. me data for these two sets, designated ~ ~
, ~ i `,A'" 2A and 2B, are reported in Table 2 below. ~;~
Table 2 ( 2) (cm2) t P
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2A 90 16 0.1 1023 4 5 605 2B 90 16 Ool 1.23 1.6 605 -:,.~ ..
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1~5t~6~35 The release rates o~` d:ispensers 2A and 2B were determined by the procedure : described in Example to Figure 3 is a plot of these release rates versus time~
Example 3 Two sets of hydrocortisone dispensers were prepared by the gen-eral procedure of Ex~mple 1~. The core lamina was made from 60 parts hydrocortisone (par*icle size approximately 2 microns) and 40 parts cop-olymer and was 150 microns thicko The outer laminas were 50 microns thick and 1705 microns thickg respectively. The data for these two sets, des- ~
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;~ 10 ignated 3A and 3B, are reported in Table 3 belowO

Table 3 r (cm2) ! n ~cm ) P . ptl k LA ¦

. 3A 72 1.9 0.1 1.23 25.3 605 3~ 72 lo9 Oo 1 1023 8.8 . 605 ~-The release rates of dispensers 3A and 3B were determined by the procedure . r `r described in Example lo Figure 4 is a plot of these release rates versus timeO
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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An active agent dispenser that dispenses an active agent of low water solubility by diffusion from a polymer matrix characterized in that the dispenser is a laminate of:
(a) a core lamina of crystalline particles of the active agent dis-persed in a polymer matrix having a permeability, P, to the agent, the core lamina having a thickness, 2t, and being partly covered by;
(b) at least one outer lamina of an active agent release rate con-trolling polymer having a permeability, P1, to the agent and a thickness t1, such that the core lamina has an exposed surface area, A, from which the agent may be dispensed and the outer lamina has an exposed surface area, A1, from which the active agent may be dispensed, and the correlation is greater than about 2 and the correlation 2 is at least 3 times the correlation , wherein k is a constant whose value is dependent upon the geometrical shape of the laminate.

2. An active agent dispenser as claimed in claim 1 further char-acterized in that the agent is a drug.

3. An active agent dispenser as claimed in claim 2 characterized in that the drug is chloramphenicol, physostigmine or hydrocortisone, and the dispenser is sized and shaped for insertion in the cul-de-sac of a human eye.

4. An active agent dispenser as claimed in claim 1 further characterized in that , is greater than 3 and is at least 10 times .

5. An active agent dispenser as claimed in claim 4 further characterized in that P is substanitally greater than P1.

6. An active agent dispenser as claimed in claim 5 characterized in that P is substantially greater than P1 because of the porosity of the core lamina caused by the quantity of active agent therein.

7. An active agent dispenser as claimed in claim 1 characterized in that the active agent initially comprises 30% to 75% by weight of the core lamina.

8. An active agent dispenser as claimed in claim 1 characterized in that the dispenser is a three layer sandwich-type laminate, said core lamina being sandwiched between a pair of said outer lamina.

9. An active agent dispenser as claimed in claim 8 wherein the laminate has the geometrical shape of a thin circular disc and k is 8.

10. An active agent dispenser as claimed in claim 8 wherein the laminate has the geometrical shape of a thin elliptical disc and k is 4.

11. An active agent dispenser as claimed in claim 1 wherein the dispenser is a concentric-type laminate, said outer lamina being outerly concentric to said core lamina and covering the axial surface of said core lamina.

12. An active agent dispenser as claimed in claim 11 wherein the laminate is cylindrical in shape and k has a value of 1/8.

13. A process for making an active agent dispenser that dispenses an active agent of low water solubility by diffusion from a polymer matrix characterized by:
(a) forming a solid lamina of thickness, 2t, from a mixture of crystalline particles of the agent and a polymer having a permeability, P, to the agent; and (b) laminating at least one outer lamina of thickness, t1, of an active agent release rate controlling polymer having a permeability, P1 to the agent to a portion of the exterior of the core, such that the core has an exposed surface area, A, from which the agent may be dispensed and the outer lamina has an exposed surface area, A1, from which the agent may be dispensed, and the correlation , is greater than about 2 and the correlation 2 is at least 3 times the correlation , wherein K is a constant whose value is dependent upon the geometrical shape of the laminate.

14. A process for making an active agent dispenser as claimed in claim 13 characterized in that the agent is a drug.