CA1190060A - Composite materials - Google Patents

Abstract

Abstract of the Disclosure A composite material for the controlled release of an active substrate comprises a relatively insoluble, e.g. polymeric, matrix (11) in which a soluble particulate material (12) is dispersed. When the composite is place in an aqueous medium dissolution of the particulate material substantially increases the water permeability of the matrix. This effect may be used to provide for the controlled release of an active material into the aqueous medium.

Description

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COMPOSITE MATERIAI.S
This invention re]ates to arrangerments ancl methods for the controlled release of ac-tive materials :into solution.
There is a broad range o-f applications wherein it is necessary to pro-vide for the release of an active material at a controlled rate into an aqueous environment. In the biosciences, particularly, the potential for prolonging the action of numerous bioactive compo~mds is stimulating considerable interest.Since the early 1950's researchers have attempted to develop control-led release compounds able to store active materials ancl then release them at controlled rates into aqueous systems. This research has tended to concentrate on polymeric materials. Many polymers may be fabricated at relatively low temperatures to encapsulate effectively active materials thereby protecti.ng them from unwanted interaction with the environment. Subsequent release of the active material is effected by one of four general mechanisms, i.e. diffusion, swelling, ~bio) clremical action and magnetic processes. However, in most cases it has proved impractical *o engineer the required degree of control, especiallyover long periods, and in many instances toxicity of the special polymer itself has limited exploitation.
Controlled Release Glasses (CRG), such as those described in United States Patent 4,350,675, C.F. Drake,are inorganic glasses that may be formulated -to be non--toxic. Their solu-tion rates in aqueous media are chemical-ly contro:Lled and may be varied to give a high degree of precision, even over long periods. Unfortunately CRG may only be fabrica-ted at temperatures that would, on contact, destroy or degrade many of the active materials of interest. For this reason the development of CRG has tended to be concentrated on applica-tions requiring the release of inorganic materials.
The object of th:is inven-tion is to combine the most advant-ageous properties of both -the polymer and CRG approaches, without risk of toxicity. Thus the beneEits of low -temperature fabrication and re]ease control combine -to provide a new means of releasing a wide range of active materials.
According to the invention there is provided a coherent composite structure releasably incorporating an active material therein, said composite structure comprising a polymeric matrix material and a particula-te glass composition dispersed in said matrix material, said polymeric matrix material being essentially insoluble in aqueous medium and said particulate glass composition being sol-uble at a controlled dissolution rate in said aqueous medium whereby said composite structure shields said active material from release until contacted by said aqueous medium and when said composite struc-ture is contacted by said aqueous medium, said particulate glass composition dissolves at a controlled rate thereby increasing the aqueous permeability of said composite structure to release said active material incorporated therein at a controlled rate.
Typically the matrix material is a polymer.
When the composite comes into contact with an aqueous med-ium the particulate material dissolves to provide a series of pas-.~ - 2 -sageways -through the host matrix -thus permitting the ingress of water. Such a composi-te can be employecl for -the delayed and control-led release of an ac-tive material which, prior to the dissolution of the particulate material and the consequent significant increase in the water permeability of the eomposite, is proteeted by the eomposite i-tself.
Advantageously the partieula-te material is a soluble glass eomposition or a mixture of sueh glass eompositions. Water soluble glass eompositions have the 2a -. ~

important proRerty that th~ir dis~olution rate rnay be tailore~l to ~ desired value by composition adjustment t thu~ providin~ for the manufacture o:E composite mate~ials with a wide rang~ o release characteristics. Moreov~r, - 5 many of these glas~e~ are biGlogic:ally inert~
Etnbodimerlt~ of th~ invention will now b~
described with re~er~nce to the accompanying drawings i~
6Jhi G~:
Yigv 1 i~ a s~o~ section o~ a por'cion ~f a 10 cc:mpo~ite~ structur~
and ~ig. 2 illustr~tes the ~ffect clf an aqueou~
~edium on th~ compo~ite ~tructu~e ~hown ~n Fig. 1.
la~fer~ y to the dr~wings, th~ c:omposite shown mpri~e~ a ho~t matrix 11~ of a relatively low 15 soïubility or of ~ssentially insoluble materialO e-90 polymer, in which matrix a soluble particulate 7~at~rial 12 is dispersed. The loading of the partioulate mater~al 12 in the polym~r 11 is su~ficient to e~sure that eaeh p~rticl~ 12 is in contact with at lea~t two similar

2~ particleg. Wh~n the structure is placed in water or an ~: a~ueous medium tbe particul~te material 12 dis~olv~s to pro~ade an array o~ passageway~i 13 IPig~ 2) through th~
~: polymeric ma~rix thus si~nificantly i~creaslng th~ water permeability o~ tbe compositeO
The composi~e Ma~ be employed to provide for the c~ntrolled relea~e of an active material that i~ eith~r dispersed within ~t or i8 coat~d with it or cover~d by it.
The p~lymeric matrix 11 may comprise a wide ariety of materials. For biological and medical ~; 3~ applications we prefer to employ cellulo~ic materials, but other l~aterials may of course also be employed.
Typical of ~uch polymers, thGugh by no means li~iting, are polyene/ polye~ers, polyamides~ polysaccharides, natural gums and latexes, and mixtures and copolymers 3s thereof. Advantag~ously, in ~ome applications, the polymer matrix m~y be the~mosetting or thermoplastic thus permitting low cost bulk fabrication by any of the known techniques, e.g. pressing or extruding. Equally the polymer may be cross-linked by any of the known techniques.
The particulate material is preferably a substance having a controll-able dissolution rate in an aqueous medium, i.e. the material is of such a nature thatJ by suitable adjustment of its composition, a predeterminable dis-solution rate can be obtained. The best known examples of such materials are the controlled release glasses. These are water soluble glass compositions whose dissolution rate in an aqueous medium is determined by the relative pro-portions of the various glass forming and glass modifying constituents.
We prefer to employ phosphate or borate glasses for this purpose as SUCil materials are relatively non-toxic and also simple to prepare. Further-more, the techniques for controlling the dissolution rate of these glass systems are well ~mderstood. The glasses generally comprise phosphorous pent-oxide~ boric oxide or mixtures thereof, as the glass forming oxide of the glass together with one or more further oxides which provide the glass modifying con-stituents of the composition. The dissolution rate, and the pll of solutions of such compositions are determined by the nature and proportion of the g~lass modi-fying oxide or oxides and by the overall molar ratio of glass modifier to glass former.
We have also found that the presence of certain metal oxides, for example *he oxides of most two or three valent metals, reduces the dissolution rate of a glass composition whilst the presence of other metal oxides, in part-icular alkali metal oxides, increases the dissolution rate. Thus, by suitable adjustment of the ratio of glass-formers to glass modifiers and proportions of these two types of oxides a wide range of dissolution rates can be obtained.
The techniques of glass dissolution rate and solution pH control are more fully described in our United States Patent ~,350,675, C.F. Drake.

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TypiGal of suitable gla~s co3rlpo~itions, but by no me~ns :Limiting/ are alkali m~'cal/phosphate glasses an~l alkali meta3 /bo~ate gla~
~he composite material may be manu~actured by a . nu~aber of techniqu~ according to th~ ultimate appli~atiorl o the material. Thus the particulate ~aterial l~ay b~ mixed with t~le! solid or li~uid polymer L and c2st:, press*d oe moulded t:o form monolithic blocks or ~he two ~ay h~ ~x~ruded toget~er into rods, tubes~ or f ibr~. Th~ particulate mater~al may al~ be , ~ incorpora~d in a film of the polysDe~ to form eith~r a el~ suplporting lay~r or a sultface coating to be app.lied ;. . ~o a sol id body ~, O~h~r technique~ include ~pray gr~nulations o~ mixt~re~ of the particulate material with lS the polym~rs.
In ~11 these processes, exc~pt those in which the composite i~ ir, the ~orm of a f ilm~ th~ volum~
p~oportion and/or lEorm o~ distributio~ of the par~iculat~
mat~rial in t~e compo~ite structure should be suff icient 2~ to *n~ure that ea~h particle is in contact with at least two similar particles, Typically 'chis requires ~ volume proportion oi~ at least 5~% of the total volum~ and preferably at le~st 67~6. In some applic~tions th~
composite may contain as much as 90 volume 9~ of the 25 particulat~ mat~rial" this high concentra~iorA being chieved by the lncorporation o a mixtur~ of la~e and small pa r t ic le~ i nto ~h~ polyme r .
th~ oase o:E the ilm-type composite it may only be necessary th t there should be a plurality of 30 patallel path~ through the 'chickness o~ the film, each path consi~ting of a ~ingle particle or a chain of contacting ~particle~O
~h~ body of m~terials described her~in may be used in a variety of applications as str~ctures whereby 35 an active mat~rial is stored and then subsequently released int:o an aqueous medium at a cor~trolled and predetermined rate. In many applications it may be ~ ~i deisirabl~ to minimi~ the~ Watl~Y permea~bilit~ of the ~ompo~it~ pr~or to di~solut:ion o~ th~ glass. Thi-~rei~uires that the glais~ bie w~tted by the polymerO Sirlce the ~las~e~ ~3escrib~ herein a~e ~ypicall~ hydrophylic we ~reer, i~ ~uch ~pplication~r to select polymers tha ate not non -pol~ .
~ h~re the body i~ in the form of a monoli~hic block or granuïe~ c:on~aining on~ oY ~ore active m~t~rial~
~it,her homogen~ou31y or hel:e ogeneously disper~ed through4ut it and i6 subsequently immersed in an aqueou~
mediu2a~ ~h~ par~iculate ma~Prial dis~o~ves thus providing ~ .~
passag~way~ throug1s th~ po1ym~r ., This signif icarltly in~rea~e~ 'che water pernleabi1ity of th~ compo~ite and allows the activ~ mat~ria1 to dis~o1v~ out. Such ~n arrarl~em~nt i~ ~ui~alble for bu1k distribu~ion of an ac~ive material whi~h materia1 may coinpris~ e . 9 ~ a ferti11~er, ~ se1ective nr non~e1~ctive herbicide7 an insecticid~, a pheroMorl~, a mo1u&cicide~ a nematicide, a fungicide, an a1gicid2~ a s1imici~2, a rodenticid~, or mi.xtures thereo. Th~ applicat~oll~ of such a structure includet bu~ ar~ no~ lim~ed to, ~il and C:EOp trea~cment, b10cida1 puriPic:~tiorl of water courses, corro~ion protact~on and th~ inhibition of bacteria1 gr~wth in w~ter sy~tem~., In ~ further app1ication a medic~mer~t or drug may b~ ~n;::orporat~d in ~he st~ucture whicll may ~e admir~isterQ~ to a hu~a~l or anima1 patient either interna11y t in th2 for~ o~ a tablet, impla~t or suppo~i~ory ~or ~ bolu~ for ruminarl~ animals) t or externall~ a~ a percutaneous device. The medicsment or drug may com~ri~ a nutrient, a prophy1actic a~ent, a ther~peutic ag~nt, an antibiotic~ an an'ciseptis agent; a para~iticide, a hormone or c:ontraceptive.
The monolithic body may be formed into a singl~
or mu1ti-cavity st~uctur~ the cavities of which contain a liquid or -~o1id drug or medicament. A single c~vity structure of. this kind, when contacted by an aqueous medium, provides a contro11e~ delay prior to re1ease of

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~h~ active corl~es~. Where a ~ul~icav:ity ~evice i5 ~mploye~i, a pr~det.ermlned c~r programme~ release rate prof 11~ m~y Ib~ ob~ainQd .
It i~ ~ten ad~ant~ou~ ~o ~mploy a polyrneric ms~Qrial ~hat has arl appreciable but very low ~is~olution f ~ate ol: that i~ bio~legradable. This en~ures ~ha~c ul~mat.~lx no ~al id ~*~idue i~ lef~.
Ploreov~r ~ in ~he case~ dher~s ~he ac~ive ma~rial is di~per~ed within th~ poly~eric Tna~rix the r~leas~ rat~
prafil~ i~ d~t:erm~n~d t~y tl~Q re!lativ~ rat~ ~3f dissolution h of the partlcu~ate mat~rial to tbe dis~;olution, d~grada~ion, or ero~ion rate o~ the polymer. :~ c~n b~
shown that i th~ ~orme~ dissolution ra~e is si~;nifical ~ly gr~a~el: than the lat~er ~h~n the rate of transfeY: o~ the astive material to solu~ion ~ollows app~oxima~ly a ~quar~ root law, whereas if the two ra~es ~r~ similar then the rate o~ trans~ approxirr~ates to a ~t`;` line~r law.
I~ a particularly advant~geous ar rangem~nt ~he activ¢ material i~ granlllar anld i~ formed into a body ~ wherein th~ granule~ are c~m@nted together by a compc~site 1~ ~ompri 3ing a polymer and a powdered water soluble gla~s.
The gla~s p~rticle~ ate significantly smaller than the ac~i~e material granules so that the compo~ite acts a~ a 'mortar ~ ~etwees~ the gras~ules thuJ3 providing ~ coh~ren body. Th~ body may be ~ormed e,g. ~y peessirlg~ extru~ion s~n~, In ~ ~u~th~r embo~im~nt the comE~o~ite str~cture . may be produced as a ilm either by ilm casting 0 techniques or b~ pr~ssing. The fil~ ma~ be self suppor~ing OE it may be employed in the form of a -~urfas~
coatin~ on a solid substrate~
The f ilm may be employed as an ~ncapsules~t which is applied, e.y. b~r heat ~hrinking, to a body containing 3~ an active material. When such an encap~ulated body is placed ir~ an aqueous medium ~he encapsulent coating protects the body ~rom dissolution for a predetermined I' .
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E~r od or until par~icular condi~o~ e. a de~ired ~olution p~ ar~ ~atisied.
The encapsulated body may comprise a pill OE
tablet for oral ~dml~i~tration to a human or animal t 5 patient ~ the coatln~ provldtn9 a pr~d~t~rmined delay i; pr~or to relea~ o ~:he active! ~ub~t~nce~ conta:ln~d in the pill or t~b~et~ In a particularly advani:ageou~
arrangem~ne a plurali~y o~ s~s:h device~, e~ch wi~h a di~er~nt dis~olution rat~ or differen~ thickne~
coating, are sealed in a 8~91~ solubl~ ~.g. gelatin, ca~ing. Wh~n ~his ~evice is adminis~ered to a patierlt ¦~ th~ casing di~ol~J~3~r~l~asing the indiv~idual cap~ul~
eacb of which th2n r~le~ses it~ a~tlve content after ~
~if~erent pred~termirled d~lay~ This provides the pati~nt with regular ~0~8 of the active material over a perivd of several hour~ or days.
. ~n a ~ th~r eDnbodiment tlle active material i~
in granul~r ~orDI and the ir~dividual. gr~nule~ are each coa~d wi~h the film 'co produce a granular prodllc'c in whichf ~fter coming into contact; with an aqueou~ ~ned~u~n7 there is a delay beor~ l:he active mat~rial ~tarl:s ~o di~so:Lve in th~ aqueou~ mediu~nO
; The composit~ materia~ ~oay be applied a~ a ~urface eoating on a ~oli~3 ~ubskrat~? rom a ~lurry o~ th~
particulat~ mat~rial in a th~rmosettin~ polym~r. Th~
. slurry is applied to ~he ~urface by bru~hirlg, spreading or sprayinq and is then cured to a coheren~ mat~rial by healting, chemical cro~s-linking, phy~ic21 crs7ss linking, ~olverlt evaporatioIlV or by applying energy in the form of light or other ~le~trom~gnetic radiation. In such an arrangement an active n~atcrial is incorporated in the composite, ~he actiY~ matcrial being released wh~n dis~olution of th~ particle material ailows water to diffuse into the composi'ce~ The active snaterial for such 3S applications mas!r be an anlti-foulant~ e.g. ~or mari~e use, a corro~ion inhibiting ~gent or an antiseptic material.

Claims (11)

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

1. A coherent composite structure releasably incorporating an active material therein, said composite structure comprising a polymeric matrix material and a particulate glass composition dis-persed in said matrix material, said polymeric matrix material being essentially insoluble in aqueous medium and said particulate glass composition being soluble at a controlled dissolution rate in said aqueous medium whereby said composite structure shields said active material from release until contacted by said aqueous medium and when said composite structure is contacted by said aqueous medium, said particulate glass composition dissolves at a controlled rate thereby increasing the aqueous permeability of said composite struc-ture to release said active material incorporated therein at a con-trolled rate.

2. A structure as claimed in claim 1 and in the form of a monolithic block woven or single fibres, a sheet, a film or granules.

3. A structure as claimed in claim 1, wherein the active material is selected from the group consisting of fertilisers, sel-ective or non-selective herbicides, insecticides, pheromones, mol-luscides, larvicides, nematocides, fungicides, algicides, slimicides, rodenticides, and mixtures thereof.

4. A structure as claimed in claim 1, wherein the active material is selected from the group consisting of nutrients, prophyl-actic agents, therapeutic agents, antibiotics, antiseptic agents, parasiticides, hormones, and contraceptives.

5. A structure as claimed in claim 1, wherein the particulate glass material comprises 50-90% by volume of the composite material.

6. A therapeutic device being an implant or percutaneous device, a bolus or other device capable of oral, rectal or surgical administration formed from a structure as claimed in claim 1.

7. A device as claimed in claim 6, wherein the composite is in the form of a film or sheet comprising a surface coating on a solid body.

8. A device as claimed in claim 6, wherein the structure is in the form of a body containing one or more cavities each containing active material.

9. A device as claimed in claim 8, wherein the active material is a drug or medicament.

10. The composite structure of claim 1, wherein said particu-late glass composition consists essentially of from 50-75 mole per-cent of phosphorus pentoxide as a glass forming oxide; from 1-20 mole percent of an alkali metal oxide as the principal glass modi-fier, the remainder including from 1-25 mole percent of an oxide selected from the group consisting of an alkaline earth metal oxide, an oxide of a metal of Group III A of the Periodic Table, a transis-tion metal oxide and combinations of the foregoing.

11. The composite structure of claim 10, wherein a portion, not exceeding 10 mole percent of the phosphorus pentoxide in said particulate glass composition is replaced by another glass-forming oxide selected from the group consisting of SiO3, B2O3, GeO2, As2O3, Sb2O3 and an oxide containing the group SO4.