CA1242394A - Controlled release device - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A controlled release device is provided herein. The device includes (i) a hydrogel, and incorporated therewith (ii), an active substance. At least part of at least one surface of the device comprises (iii) a layer which is impermeable to aqueous media. Such device is an improved so-called "zero order" release device in which the release is sustained over a prolonged period of time.

Description

This invention relates to` àontrolled release devices. More particularly, this invention relates to controlled release devices having enhanced duration and/or control of active substance release.
In British Patents Nos. 2,047,093 (NRDC) dated 21 March 1986 and 2,047,094~ (NRDC) dated 21 March 1986, controlled release compositions have been described which comprise an active substance and a polymeric carrier therefor comprising residues having a ratio of number average molecular weight of lO functionality greater than 1,000 which comprise polyethylene oxide and are cross-linked through urethane groups. In many therapeutic and propylactic medications it can be advantageous to provide a constant rate of delivery of the medication to the patient, so-called 2ero order release, sustained over a prolonged period o time. A number of active substances have been found to realise this aim when incorporated in controlled release compositions as aforesaid.
However, the release proile of an active sub3tance from an initially dry hydrogel depends, in a complex manner, on a number 20 of parameters including the physiochemical properties of the active substance; in particular, both its solubility characteristics and molecular size in the eluting medium; the geometry of the hydrogel; and the physiochemical properties of the hydrogel; in particular, both its rate of swelling and 7~ O
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- 2 a -equilibrium swelling of the device in the eluting medium at the temperature of diffusion. It has been found that the release profiles of activ0 substances with good solubility in the eluting medium, for example, an aqueous medium, from initially dry hydrogels, for example, hydrogels comprising polyethylene ' `' oxide, with an equilibrium swelling of 200 eph or more of a size suitable for administration are not constant; rather, the release rates are initially large and gradually fall during a less sustained period of time.
This invention is ox particular, but not exclusive, relevance of the tLeatment of the sexually transmitted disease caused by the virus Herpes Simplex II. it the present there is no effective therapy for this disease although the virus and/or its replication is known to be destroyed by addition of lithium salts. However, lithium salts are both very soluble and are also rapidly excreted from the body.
This invention seeks to provide an improved controlled release device of broad applicability to swellable hydrogels wherein a geeater degree of control over the release proile of an active substance thererom is obtained. This invention also seeks to provide effective lithium salt medication, especially in combating Herpes Simplex II virus.
ccordingly, therefore, by one broad aspect of this invention, a controlled release device is provided which com-prises: (i) a hydrogel; and incorporated therewith it anactive substance at least part of at least one surface of the device comprising (iii) a layer which is 0ffectively imper-meable to aqueous media.
The hydrogel (i) can comprise a natural or synthetic organic or inorganic material (for example. silica gel). It is preferred, by reason of the greater degree of control which can be achieved by tailoring the hydrogel structure, that the hydrogel ogel be of an organic material. It is also preferred,

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by reason of the gceatec reproducibility, that the hydrogel be a synthetic material.
Examples of natural organic materials include cross-linked bio-polymers; for example, crosslinked polysaccharides, e.g. starches, dextrans and celluloses crosslinked proteins or polypeptides e.g. collagen and gelatin.
Suitably the hydrogel comprises a synthetic hydro-philic homoor copolymer comprising residues derivable from at least one of the following monomer classes:
(a) (meth)acrylic acid, (meth)acrylamide, an unsub-stituted or hydroxy-substituted, propyl, ethyl, or other alkyl (meth)acrylate or a poly-(oxyethylene) (meth)acrylate:
(b) a substituted or unsubstituted cyclic mono or poly ethec having prom 3 to 6 ring atoms or cyclic imine having 3 ring atoms: or (c) a substituted or unsubstituted vinyl alcohol, aldehyde, ether, acetal, ketone, ester, anhydride or substituted or unsubstituted N or C vinyl heterocyclic compound.
my "(meth)acryl" we mean herein "methacryl" or "accyl"
or a copolymer comprising both.
Monomers in class (b) include epoxides e.g. ethylene oxide, propylene oxide, 1,2-epoxybutane, 2,3-epoxybutane glycidyl ethers, N-(epoxy substituted) heterocyclic compounds, e.g. ~-(2.3-epoxypcopyl) pyrrolidone; epihalohydrins, while not themselves cyclic ethers, do give homoand copolymers derivable therefrom: examples include epi~luorohydrin, epichlorohydrin , ,, I, 3~

and epibromohydrin. Other cyclic mono- or poly- ethers include oxetane, tetrahydrofuran, dihydropyran, dioxolane and trioxane.
~omo- and copolymers derivable therefrom include partially Cl to C4 alkyl etherified celluloses and starches, homo- and co-poly(alkylene oxides), e.g. polyoxymethylene, polyethylene glycols and polypropylene glycols, and polyesters thereof with dicarboxylate acids, e.g. maleic acid, which may be cross-linked through reaction with isocyanate or unsaturated cyclic ethers groups.
Monomers in class (c) include methyl and ethyl vinyl ether, methyl vinyl ketone, methallyl alcohol, maleic anhydride, N~vinyl oxazole, N-vinyl methyloxa~olidone, vinyl formal, vinyl butyral, and vinyl methoxyacetal~ Homo- and copolymers derivable therefrom include polyvinyl acetate and polyvinyl alcohol.
The synthetic hydrophilic homo or copolymer may be chemiaally cross-linked to form the hydrogel. general process for accompolishing thls in a very satisfactory manner and resulting in a inely divided hydrogel is disclosed in British Patent No. 2,090,264 (NR~) dated 23 December 1981. Where the hydrophilic polymer comprises functional groups which comprise an active hydrogen atom (for example, hydroxyl, amino, mercapto, carboxylic or phosphoric acid, amide, thiolic or thionic analogues), chemical cross-lin~ing may be efected by reaction with a di- or poly-isocyanate, (e.g. bis-~4-isocyanatophenyl) methane), or a di- or polylinear or cyclic olefinically unsaturated ether, (e.g. acrolein tetramer); for example, as ~2~3~

disclosed in the above identified sritish Patents No. 2,047,093B, 2,047,094B and 2,108,517B tNRDC) dated 10 June 1982, from which it will be apparent that where a di-isocyanate or di-olefinically un~turated ether is used, a reactant comprising at least three active hydrogen atoms must also be present to ensure chemical cross-li~king.
Entanglement crosslinking may be utilized, especially where the hydrophilic polymer has a high molecular weight (for exam Mn greater than 20,000) by incorporating in the hydrophilic lO polymer and polymerisi~g monomers of functionally greater than two. Examples of such monomers include di- and poly-olefinicially unsaturated hydrocarbons, a.g. divinyl benzene or isoprene, and the diand poly-ole~inicially unsaturated esters or ethers, e.g. acrolein tetramer, triallyl cyanurate or glycol dimethacrylate.
Block eopolymer~ comprising both hydrophilie and hydrophobie domains (for example, ethylene oxide-higher alkyl~ne oxide, e.g.
propylene oxide, block eopolymers) art also very suitable.

Preferably, the hydrogel I) comprises a homo- or co-20 poly-~al~ylene oxide), preferably polyethylene oxide). It is also preferred that the polytalkylene oxide) is cross-linked through reaction with isocyanate or unsaturated cyclic ether groups. Very satisfactory examples of such hydrogels, and of their preparation, are disclosed in the aforementioned patents and patent application.
The present invention is of broad applicability in the formulation of active suhstances (ii), particularly, but not exclusively, biologically active substances releasable for a sustained period of time EYamples of olasses ox biologically ` , ~æ~23s~

active substances which may be incorporated in controlled release devices of the present invention include flavourings, pharmaceuticals, bacteriostats, viruscides, pesticides e.g.
insecticides, nematicides, molluscicides and lacvicides, herbi-cides, fungicides, algaecides, topical or dermatological agents, antifoulants for marine growth prevention, proteins, for example enzymes, peptides, microbiological and plant hydro-culture salts and nutrients and preservatives, veterinary trace metal formulations, and other growth eromoting factors used in animal husbandry: for example, anti-anaemia preparations and anabolic steroids. of particular interest is a device of an aspeet of the present invention eomprising, as biologieally aetive substanee, at least one pharmaeeutieal.
The devices of aspeets o this invention thus find wide application in medieal and surgieal, ineluding veterinary, eontext6 and in horticulture and agriculture as well as outside the6e areas.
Specific elas6e~ of drugs whieh may be utilised in a eontrolled release device of aspeets of the invention inelude abortifaeients e.g. prostaglandins, hypnoties, sedatives, tran-quilisers, anti-pyreties, anti-inflammatory agents, anti-hista-mines, anti-tussive6, anti-eonvulsants, musele relaxants, anti-tumour agents, for example those for the treatment of malignant neopla6ia, local anaesthetics, anti-Parkinson agents, topical or dermatological agents, diuretics, for example, those containing potassium, e.g. potassium iodide, pceparations for the treatment of mental illness, for example pceparations containing lithium for use in the treatment of manic depression :

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or containing p~ostaglandins foL the treatment of schizophrenia, anti-spasmodics, anti-ulcer agents, preparations containing various substances for the treatment of infection by pathogens including anti-fungal agents, foe example metronidazole, anti-parasitic agents and other anti-microbials, anti-malarials, cardiovascular agents, preparations containing hormones, for example androgenic, estrogenic and proge6tational hoemones, notably steroids e.g. oestradiol, sympathomimetic agents, hypoglycaemic agents, contraceptives, nutritional agents, preparations containing enzyme of various types of activity, or example chymotrypsin, prepartions containing analgesics, for example acelylgalicylic acid, and agents with many othec types of action including nematocides and other agents ox vetecinary application. Mixtures of active substances may be incorporated into the controlled release device.
The controlled release devices o aspects of this invention may be used as a contraceptive device suitably con-taining, as active substance, at least one natural or synthetic steroid sex hormone for example an oestrogen or progestogen.
Suitably progestogens include the natural progesterone and its synthetic analogues, including ll-dehydroprogesterone, dela-lutin, 21-fluoro-17-acetoxy-6-c~-methylprogesterone, medroxy-progesterone acetate, megestrol acetate, chlormadinone acetate, ethisterone, dimethisterone, ~-norprogesterone, 19-norproge~-terone, 21-norproge~terone, normethandrone, norethynodrel, norethindrone and its acetate, DL and D-norgestrel, norgest-rienone, ethynodiol diacetate, lynstcenol, ethynylestradiol, retcogrogesterone, dydrogersterone, norvinodrel, ~uinges~ranol ..

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acetate, norethisterone and its acetate and oenanthate, anagesterone acetate, medrogestone, clamagestone, allyl estrenol and cingestol, preferably progesterone. Suitably, oestrogens include the natural b~-oestradiol and its synthetic analogues, principally ethinylo-estradiol or mestranol, preferably -oestradiol.
The controlled release devices of aspects of this invention are also useful in the treatment of diabetes and pernicious anaemia where, for example, the controlled release ïO Of insulin and cobalamin, respectively, may be utilised.
Moreover, the controlled release devices of aspects of this invention are particularly suited to treatment, both proehylactic and thereapeutic, of tropical diseases; for example malaria, leprosy, schistosomiasis and clonorchiasis.
Examples of deugs which can be used as biologically active substance in controlled relea6e devices of aspect6 of this invention for the treatment of these and other tropical diseases include quinine, 6ulphonamides, rifamycin, clof-azimine, thiambutasine, chlorphenyl derivatives, chlorguamide, cycloguanil, pyrimethamine sulphadiazine, trimethoprim, quino-line derivatives, e.g. pamaquine, chloroquine, pentaquine, primaquine and amodiquine, pararosaniline, sulphamethizole, quinacrine, dapsone, sodium sulphoxone, sulphetrone, sodium hydrocarpate and sodium chaulmoograte. Drugs of particular effectiveness are cycloquanil, pyrimethamine and sulphadiazine.
The controlled release devices of aspects of this invention are also very well suited to vetecinary applications.
Examples include preparations of antibiotics for general anti-:

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bacterial activity and also in the treatment of anaplasmosis incattle: preparations for the provision of a wide spectrum of activity against both ectoearasites, for example termites and endo~arasites including arthroeods, arrested larvae stages of nematodes, lungworms and geneeal strongyles: these may com-prise avermectins: preparaSions for provision of activity against tremotode, cestode and roundworm infections: these may comerise amoscanate and praziquantel: preparations for pro-vision of activity against theileria in cattle: these may comprise biologically active naphthoquinones e.g. menoctone:
ereParations foc provisions of activity against babesiosis in cattle, horses and dogs: these may comprise berenil, amidocarb and diampron; preearation for eroviison of activity against liver fluke in sheep and cattle and against Haemonchus seecies: these may comprise closantel.
In accocdance with a particulacly ereferred feature of this aseect of this invention, a controlled release device is erovided foc the teeatment of the ~lerees Simplex II virus whecein the active substance is a lithium compound, ~ceferably a lithium salt, especially a soluble lithium salt, e.g. a lithium halide, foc example, li.thium chloride.
In accordance with another ~refecred feature of this aspect of this invention, a controlled release device is erovided for the release of prostaglandins. Such controlled release devices can have a variety of effects on the body; for examele, they may be useful in the treatment of schizophrenia, particularly PGEl. They are, however, or particular interest in their action upon the female reproductive system of both ~L2~æ3~

human and non-human animals. By that action, the controlled release compositions of aspects ox this invention have found use as abortifacients in the induction of labouc; in a con-traceptive role and in the tceatment of cervical incompetence, particularly in administcation prioc to artificial insemination in non-human animals. Both naturally-occuring and synthetic analogues of prostaglandins are of interest.
The natural erostaglandins of importance in re-production are those of the E and P groups (for example PGEl, PGFl , PGE2, PGF2~' PGE3 and 3~)' PGI2 (prostacyclin) the compounds PGE2 and PGF2 , specific de-~ivative of clinical promise being 15-methyl-PFG2, P~F2 , 16,16-dimethyl-PGE2, and also 16,16-dimethyl-PGE2 para-benzaldehyde semicarbazone ester, 16-phenoxy-17,lB,l9, 20-tetranor-PGE2 and especially 16,16-dimethyl trans -PGEl which may vecy suitably be ormulated according to aspects of the present invention, for example in the form of an ester, e.g. the methyl ester. Particular prostaglandins may of course be of especial interest for particular applications so that PGE2, for example, is of more interest in the induction of labour whilst 16,16-dimethyl trans ~2-PG~l is of more interest in inducing abortion. It will be appreciated that the invention will be applicable to subsequently prepared novel peostaglandin derivatives having similar but modified pLoperties, f or example greater potency, prolonged action, greater specificity, to those at present known and used as abortifacients. ThU6, for example, there is considerable interest in "luteolytic~ pro6taglandins, e.g. 16-(13-tri~luoro-/~ - 11 ,.

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methylphenoxy)-17,18,19,20-tetranor-PGF2 and their use in a contraceptive role. It will be appreciated that, if desired, the eolymeric carrier may incoreorate two or moce prostag-landins.
By "incorpocated therewith is meant herein that the active sub6tance (ii) may be homogeneously or inhomogeneou61y dispersed throughout the hydrogel (i) or may be contained in a reservoic within the hydrogel or, indeed, both.
The Gontrolled release devices of aspects of the in-vention may be formed in a variety of configurations; forexample, one which is as a rod, slab, film, hemisphere or is of a hollow or periodic, for example sinusoidal, profile.
The impermeable layer (iii) is preferably hydrophobic;
it is preferably also impermeable to the active substance (ii). Suitably, the impermeable layer (iii) covers all of at least one surface, preferably a curved surface, of the device thereby defining at least one orifice thereon through which the hydrogel (i) is contactable by aqueous media. Whece the device is formed as a rod, slab or film, the impermeable layer may cover sub6tantially all of the surfaces except one oc both end ecofiles (that is the surfaces usually, but not necessarily, substantially planar and of smallest area) the or each of which end profiles defines an orifice. Such a device, especially one comprising only one orifice, has a much longer half-life of release than like devices without the impermeable layer. Where the device is formed with a single or bis-sinusoidal profile along its length (the first sinusoidal profile may be reflected or out of phase with the second) the impecmeable layec may , .
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covec substantially all ox the surfaces except one or both end profiles. Such a device, especially one comprising only one orifice, exhibits a pulsatile release rate. Where the device is formed as a hemisphere, the impeemeable layer can cover substantially all of the surfaces except a polar orifice in which case the device will erovide a very prolonged release, the rate of which will either increase or remain constant with time. Where the entire curved surface oî such a device is covered by the impermeable layer with the equatorial surface uncovered as the oeifice the rate of release decreases with time.
The device may also be formed as a ring of hydrogel with the impermeable layer covering all the surfaees exceet the internal, typically cylindrical, surface which acts as the orifice. Sueh a deviee can provide a longer half-life of re-lease and exhibit a rate of release which is constant or in-ereases with time.
Furthermore, a multielieity of orifices, for example, in a layer which substantially eompletely covecs the device whieh may be formed as a rod enables a very precise regualtion of half-life of release.
All of the aforementioned exemplary devices may be produced by simple technology. Thus, hydrogel for the eylindrieal and slab devices may be moulded or continuously produced by reactive extrusion. The hydrogel may then be dip coated (a plurality of coats may be provided) in an organic solution of a thermoplastic elastomer or sleeved with a pre-focmed silicone, natural or synthetic polydinenes or butyl - 12a -:~ it ~23~
elastomers and then sliced to the desired dimensions. the slicing exposing one or two orifices. The sleeving may be facilitated by incorporating a swelling agent in the sleeve or, in a preferred embodiment especially in relation to rods or slabs,deformlng the hydrogel in accordance with our pending British application GB2161819A(NRDC) dated 12 July 1985.The hydrogel for the hemispherical and sinusoidal devices may be moulded, coated (preferably by dip coating) and cut in an essentially similar mannar. The hemispheres may be moulded in tandem via a s2rue which, after coating, is cut to expose a polar orifice in each hemisphere. The orifice may also be formed by lasing the fully coated device. The hydrogel for the ring device may be initially formed as a rod, which is then sliced, coated and, thereafter has an axial hole punched therethrough.
Spray and powder coating technology may also be utilised to form the impermeable coatings which apart from the aforementioned, may comprise drying oils, alkyds, urethanes, acrylics and epoxides. In situ curing may be used, enhanced by thermal, W or electron beam irradiation in known manner.
The devices of aspects of this invention exhibit a much longer half-life of release than like devices without the impermeable layer. This valuable attribute may be used as such or may be utilised to reduce the size of the dosage prom, or indeed both. It will be seen, therefore, that the devices are particularly suited to formulating oral dosage forms.

In the accompanying drawings:

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~2~23~314 - 12 c -Figure 1 shows two graphs, the upper one s-howing total release, in per cent, as ordinate and time, in minutes, as abscissa, and the lower one showing rate of release in per cent/minute as ordinate and time, in minutes, as abscissa, of lithium ions released from a thin disc cut from a cylinder made with a hydrogel of the prior art;
Figure 2 shows two graphs, the upper one showing total release, in per cent, as ordinate and time, in minutes, as abscissa, and the lower one showing rate of release in per cent/minute as ordinate and time, in minutes, as abscissa t of lithium ions released from thick pieces cut from a cylinder made with a hydrogel of the prior art;
Figure 3 shows two graphs t the upper one showing total release, in per cent, as ordinate and time, in minutes, as abscissa, and the lower one showing rate of release in per cent/minute as ordinate and time, in minutes, as abscissa, of lithium ions released from a cylinder made with a hydrogel of the prior art;
Figure ll shows two graphs, the upper one showing total release, in per cent, as ordinate and time, in hours, as abscissa, and the lower one showing rate, in mg/h, as ordinate, and time, in hours, as abscissa, of lithium ions released from an embodiment of a controlled release reservoir cylinder of this invention made from a hydrogel of the prior art;
Figure 5 shows two graphs, the upper one showing total release, in per cent, as ordinate and time, in hours, as I, , .

~Z~3~4 - 12 cl _ abscissa and the lower one showing rate, in mg/h, as ordinate and as time, in hours, as abscissa, of lithium ions released from a second embodiment of a controlled release reservoir cylinder of this invention made from a hydrogel of the prior art;
Figure 6 shows two graphs, the upper one showing total release, in per cent, as ordinate and time, in hours, as abscissa. and the lower one showing rate, in mg/h, as ordinate and time, in hours, as abscissa, of lithium ions released from a third embodiment of a controlled release reservoir cylinder of this invention made from a hydrogel of the prior art; and Figure 7 shows two graphs, the upper one showing total release, in per cent, as ordinate, and time, in days, as abscissa, and the lower one showing rate, in mg/h, as ordinate, and time, in days, as absclssa, of lithium ions released from a fourth embodiment of a controlled release reservoir cylinder of this invention made from a hydrogel of the prior art.
COMPARATIVE EXAMPLES
polyethylene oxide hydrogel was prepared essentially as described in Example l of G~,2047093A by reacting 1 mole of polyethylene oxide (Mn~300) with 0.75 mole of 1,2,6-he~anetriol and 2.12~ moles of is-(4-isocyanatocyclohexyl)methane. The hydrogel was found to have an equilibrium swelling in water, at 20~C., of 400 pph, based on the initial dry weight of hydrogel.

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- 12 c2 -Three cylinders of the hydrogel, 6 mm in diameter and 15 mm in length, were cast. The first was sliced into 20 discs each approximately 0.75 mm thick; the second was cut into six pieces each approximately 2.5 mm thick; and the third was kept intact.
The 20 discs, 6 pieces and intact cylinder were next swollen in a

4 mg ml~l LICl solution and dried. Three size 0 hard gelatin capsules were respectively packed with the 20 discs, 6 pieces and intact cylinder; and capped.
To simulate oral dosing, the loaded capsules were separately immersed in 0.01 N hydrochloric acid at 37C. and shaken at 200 vibrations per minute in a Grant Shaking Thermostat Bath at 37C.
A fourth gelatin capsule comprising a small amount of methyl violet was also immersed in the hydrochloric acid to ascertain the time to disintegration of the capsule (which was found to be 10 minutes). Aliquots of the hydrochloric acid were removed periodically and their lithium , ~2g~3~

context was detecmined by atomic absorption spectroscopy (Perkin Elmee 360 atomic absocption spectrophotometer). The hydrochloric acid removed was initially replenished by fcesh 0.01 N hydrochloric acid at 37C and, after the first hour, by distilled water at 37C.
The results are shown in Figures 1 to 3 of the accom-panying drawings.
The following examples illustate various aspects and embodiments of the invention.
Examples 1 to 3, inclusive, illustrate the ereParation of controlled release cesecvoic devices of aseects of the invention in an attempt, successfully realised in Example 3, to secuce release of approximately 1 g of lithium chloride at a substantially constant rate over a one week period. In all case6 where plugs were not retained by means other than fciction, the high osmotic pressure expelled them, vitiating the expeeiments (not exemplified).

Two polyethylene oxide hydrogels were prepared essent-ially as described in Example 1 of GB.2047093B by reacting, in a first case, 1 mole of polyethylene oxide (Mn=3,207) with 1 mole of 1,2,~-hexanetriol and 2.5 mole of bis-(4-isocyanato-- cyclohexyl) methane: and, in a second case, 1 mole of the same polyethylene oxide with 2 moles of 1,2,6-hexanetriol and moles of bis-(4-isocyanatocyclohexyl)methane.
A blank hollow cylinder of the second hydro~el, 12 mm in extecnal diameter, 6 mm in internal diameter, 3 mm in basal thickness and 30 mm in length, was cast. An internal annular -I - 12d -:

groove was then machined from the cylinder near its mouth and its cavity was packed with 1 g of lithium chloride cyrstals.
The first hydrogel was next cast as a plug mating with the annular groove and which, due to its higher swelling, woul become tighter on swelling. The eesulting cylindrical ceservoir was then sheathed with tight-fitting silicone rubber tubing (known by the Trade Mark of SILESCOL translucent silicon rubbec tubing ex ~sco (Rubber) Ltd.) which had a bore o 8 mm and a wall thickness of l.6 mm. The tubing was first softened by swelling in diethyl ether for 5 minutes thereupon it was readily possible to insert the hydrogel cylinder into the swollen tube. Thereafter, the diethyl ether was expelled by rapid evaporation in a laminar flow cabinet and then in vacuo.
The silicone rubber was B mm longer than the cylinder to keep the curved wall of the cylinder covered during swelling; it alto contained lfi small t2.0 mm in diameter) holes linearly eunched thecein and evenly spaced apart.
The eonteolled celea~e ceseevoir device 60 formed was immersed in distilled watec of 37C in a thermostated shaking bath at the same tempecature in order to avoid a build-up of a static layer of lithium chloride around the device. Aliquots of the water were removed periodically and their lithium con-text was determined by atomic absorption spectroscopy.
The results are shown in Figure 4 ox the accompanying drawings.

A size O hard gelatin capsule was packed with lithium chloride crystals; capped: and suspended axially and centrally - 12e -. I, . .

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by a nylon thread in a polyethylene vial, 12 mm in internal diametec and 55 mm in length. which acted as a mould. An amount of the second reactant mixture mentioned in Example 1 was then cast into the mould aLound the capsule. The cylinder tl2 mm x 50 mm) was removed from the mould by making radially-opposed, axial cut6 in the vial and stripping the vial there-from; and next sheathed with tight-fitting silicone rubber tubing as described in Example 1, except that it contained only 8 small holes.

The contLolled release reservoir device so formed was then tes~,ed as described in Example 1 and the results were shown in Figure 5 of the accompanying drawings.

Two size O hard gelatin capsules were packed with a total of 1 g lithium chloride ccystals capped; and inserted into a blank, hollow cylinder of the second hydrogel as des-cribed in Example 1. A separately cast plug of the first hydrogel in Example 1 was inserted in the cylinder and retained by a steel pin.

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radially driven through both cylinder and plug. The cylinder was then sheathed with tight-fitting silicone rubber tubing as described in Example 2.
- The controlled release reservoir device so formed was thPn 05 tested as described in Example 1 and the results were shown in Figure 6 of the accompanying drawings.
Example 4 illustrates the preparation of a controlled release reservoir device comprising a hydrogel of a lower equilibrium swelling in water than is the case in Example 1 to 3 and wherefrom plugs are found not be expelled on swelling.

A polyethylene oxide hydrogel was prepared essentially as described in Example 1 by reacting 1 mole of polyethylene oxide (Mn=3,330) with 4 moles of 1,2,6-hexanetriol and 7 moles of bis-(4-isocyanatocyclohexyl)methane. The hydrogel was cast to form ablank, hollow cylinder 12 mm in external diameter, 6 mm in internal diameter, 4 mm in basal thickness and 50 mm in length.
The cylindrlcal cavity was then packed with 1 g lithium chloride crystals and a plug of the same hydrogel 6 mtn in diameter and 6 mm in length was tightly inserted. The resulting cylindrical reservoir was then sheAthed as in Example 2.
The controlled release reservoir device 50 formed was immersed in distilled water at 37C in a Grant Shaking Thermostat Bath.
The release medium was removed daily (being replaced by distilled water at 37) for determination of its lithium content by atomic absorption spectroscopy.
The results are shown in Figure 7 of the accompanying drawings.
It will be seen that lithium first appeared in the release medium on day 3; thereafter a uniform release rate is established in day 4 which persists into day 9 by which time 70% of the total lithium chloride had been released.

A polyethylene oxide hydrogel was prepared essentially as described in Example 1 by reacting 1 mole of polyethylene oxide ~Mn=8,400? with 0.75 mole of 1,2,6-hexanetriol and 2.125 moles of ~a:4;~:3~

bist4-iso~yanatocyclohexyl)methane. The hydrogel was wound to have an equilibcium swelling (weight gain) in water, at 37C, of 292 pph.
The hyd~ogel was cast to form a mass 10 mm x 30 mm x 40 mm which was then cut ino slabs each 10 mm x 30 mm x 1.35 mm which we.e next trimmed to provide slabs each 10 mm x 22 mm x 1.35 mm and whose profiles had rounded ends. The slabs wece swollen in a 0.1 M p-aminobenzoic acid aqueous solution con-taining 0.1 M ammonia at 37C. after equilibeium was attained the swollen slabs were dcied at room temperature under vacuum to constant weight. 10~ w/v solution of a the~mo-elastic cubber (known by the Trade Mark of CARIFLEX TR-llol ex Shell Chemicals) was next preeared in chlorofoem. The dried slabs were dip coated in thi6 solution; dried in air at room tempecatuce; and the erocess was eepeated as cequired until a tough, watee-impermeable coating had accceted. The coated slabs were then cut to 20 mm lerlgths removing the semi-circular coated ends and leaving both ends of 10 mm breadth and 1.35 thickness uncoated to form a controlled release device.
Typically each such device weighed about 300 mg and contained about 12.0 mg of P-aminobenzoic acid.
The controlled celease device so formed was immersed in 1000 ml of a simulated intestinal fluid (6.~ g KH2PO4, 38 ml 1 M NaOH pee litce, adjusted to pH 7.5) in metal baskets which wece eotated at 100 cpm. The release of ~-aminobenzoic acid was deteemined by measueing the increase in the ultca-violet absocption at 264 mm at houely intervals.
The results are shown in Table 1.

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EXAMPL_ 6 Hydrogel slabs prepared essentially as described ln Example 5 were swollen in a 0.~% w/v solution of benzocaine in chloroform and dried a room temperature under vacuum to constant wright.
05 The dried slabs were then dip coated as described in Example 5.
Typically, each such controlled release device contained about 9.0 mg of benzocaine.
Release and determination procedure was essentially as described in Example 5; the results are shown in Table 2.

Release of benzocaine from .
coated hydrogel devices of slab geometry a Uncoated control b 3 Coats _ Time % Release Cumulative % Release Cumulative (Hour) per hour Release (%~ per hour Relea

5 3 97 8 ~4

6 1 98 8 52

7 0 98 8 60 In this Example the variation of release with the length of controlled release devices essentially as described in Example 5 is described. Elydrogels slabs prepared, swollen and dried essen-tially as described in Example 5 were then given three dip coatings and cut to lengths to 6 mm, 10 mm or 20 mm. Typically, such a controlled release device 20 mm in length contained about 140 mg of p-aminobenzoic acid.
Release and determination procedure was essentially as described in Example 6; the results are shown in Table 3.

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A polyethylene oxide hydrogel was prepared essentially as described in Example 1 by reacting 1 mole of polyethylene oxide (M z7,000) with 2 moles of 1,2,6-hexanetriol and 4 moles of 05 bis-(4-isocyanatocyclohexyl) methane. The llydrogel was found to have an equilibrium swelling (weight gain) in water, at 37Ct of 215 pph. The hydrogel was cast to form a cylinder 500 mm in length and 6 mm in diameter. The cylinder was then swollen and dried essentially as described in Example 5, and cut into 10 mm lengths. Some of these lengths remained, as controls, uncoated;
some were given four dip coatings as described in Example 5 with one or both flat ends of the coating cut away; some were sheathed with silicone rubber tubing as descrbed in Example 1 but cut to the length of the device and free from punched holes.
Release and determination procedure were essentially as described in Example 5; the results are shown in Table 4.

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A polyethylene oxide hydrogel was prepared essentially as described in Example 1 by reacting 1 mole of polyethylene oxide - (Mn=7,000) with 2 moles of 1,2,6 hexanetriol and 4 moles of bis-05 (4-isocyanato-cyclohexyl)methane. The hydrogel was cast to form a cylindrical mass 12 mm in diameter from which a number of discs 5 mm in height were cut. The discs were then swollen in a 0.1 M p-amino-benzoic acid aqueous solution containing 0.1 M ammonia at 37 CO
After equilibrium was attained (194% weight gain) the swollen slabs were dried at room temperature under vacuum to constant weight.
A cylindrical hole 3.2 mm in diameter was next punched axially through the centre of each disc to produce an annular mass into the central channel of which a well-fitting steel rod was introduced.
The annular masses were then each dip coated five times in a solution as described in Example 5. The steel rod was carefully removed leaving an annular controlled release device coated on the entire external surface but with an uncoated central channel 3.2 mm in diameter therethrough.
Release and determination procedures were essentially as described in Example 5; result as shown in Table 5.

Release of p-aminobenzoic acid Erom externally coated devices of annular geometry ox 1 b Coated devices Time% Release Cumulative % Release Cumulative (hour)per hour release (%) per hour release (%) 1 17 17 3.5 3.5 2 14 31 3 6~5 3 11 42 3 9.5 4 10 52 3.5 13 6 7 68 3.5 18.5 7 6 74 2.5 21 . .

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The preparation, release and determination procedures of Example 5 were followed except that the slabs were swollen in a 2% w/v aqueous solution of caffeine at 37C the results are shown 05 in Table 6.
Table _ Release of caffeine from coated -hydrogel devices of slab geometry Cumulative release (%) a Uncoated control b 3 Coats c 2 Coats Time (hour) 20 mm 10 mm 5 mml 8 mm 4 mm 6 - 47 86 91 ~7 Length of dried controlled release device.
This Example shows clearly the effect of the mechanical properties of the layer; thus, the more coats the more does the layer restrict the swelling of the hydrogel and items reduced the release of active substance.

A polyethylene oxide hydrogel was prepared essentially as described in Example 1 by reacting 1 mole of polyethylene oxide (MD=4,360) with 1 mole of 1,2,6-hexanetriol and 2.5 moles of bis-(4-isocyanatocyclohexyl)methane. The hydrogel was cast to form a cylindrical mass 6 mm in diamter from which cylindrical masses 5 mm or 10 mm in height were cut. The cylinders were then swollen in a 2% w/v aqueous solution of sodium p-aminobenzoate at 37C. After equilibrium was attained (191% weight gain) the swollen cylinders were dried at room temperature under vacuum to constant weight.

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Each such cylinder was next dip coated five times to produce a cylindrical controlled release device coated on its curved surface but with uncoated ends.
Release of the p-aminobenzoate was followed continuously by 05 UV spectrometry. The results are shown in Table 7.

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Claims (19)

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

1. A controlled release device which comprises:
(i) a hydrogel; and incorporated therewith (ii) an active substance;
at least part of at least one surface of said device comprising:
(iii) a layer which is impermeable to aqueous media.

2. A controlled release device according to claim 1 wherein said hydrogel (i) comprises a hydrophilic homo- or copolymer comprising residues derivable from at least one of the following monomer classes:
(a) (meth)acrylic acid, (meth)acrylamide, an unsubstituted or hydroxy-substituted alkyl (meth)acrylate, or a poly(oxyethylene) (meth)-acrylate; or (b) a substituted or unsubstituted cyclic mono- or poly ether having from 3 to 6 ring atoms, or a cyclic imine having 3 ring atoms; or (c) a substituted or unsubstituted vinyl alcohol, aldehyde, ether, acetal, ketone, ester, anhydride or substituted or unsubstituted N - or C - vinyl heterocyclic compound.

3. A controlled release device according to claim 1 wherein said hydrogel (i) comprises a mono- or copoly(alkylene oxide).

4. A controlled release device according to claim 3 wherein said hydrogel (i) comprises a poly(ethylene oxide).

5. A controlled release device according to claim 3 wherein said poly(alkylene oxide) is cross-linked through reaction with isocyanate or unsaturated cyclic ether groups.

6. A controlled release device according to claim 1 wherein said active substance (ii) comprises a lithium salt.

7. A controlled release device according to claim 1 wherein said active substance (ii) comprises a prostaglandin.

8. A controlled release device according to claim 1 wherein said active substance (ii) is homogeneously or inhomogeneously dispersed throughout the hydrogel (i).

9. A controlled release device according to claim 1 wherein said active substance (ii) is contained in a reservoir within said hydrogel (i).

10. A controlled release device according to claim 1 which is formed as a rod, slab, or film hemisphere and is of hollow or sinusoidal profile.

11. A controlled release device according to claim 1 which is of hollow or sinusoidal profile.

12. A controlled release device according to claim 1 wherein said impermeable layer (iii) is hydrophobic.

13. A controlled release device according to claim 1 wherein said impermeable layer (iii) is also impermeable to said active substance (ii).

14. A controlled release device according to claim 1 wherein said impermeable layer (iii) covers all of at least one surface of said device, thereby defining at least one orifice thereon through which the hydrogel (i) is contactable by aqueous media.

15. A controlled release device according to claim 1 which comprises a rod, slab or film of hydrogel (i), wherein said impermeable layer (iii) covers all of the surfaces except one or both end profiles.

16. A controlled release device according to claim 1 wherein said rod or slab of hydrogel (i), is formed with a single or bis-sinusoidal profile along its length.

17. A controlled release device according to claim 1 which comprises a hemisphere of hydrogel (i). wherein said impermeable layer (iii) covers all of the surfaces except a polar orifice.

18. A controlled release device according to claim 1 which comprises a ring of hydrogel (i), wherein said impermeable layer (iii? covers all of the external surfaces.

19. A controlled release device according to claim 1 which comprises a plurality of orifices.