Note: Descriptions are shown in the official language in which they were submitted.
-- 2
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
,~,.
` '`!~
: ` '
~g~
- 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
'
`'
394
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,
3 --
I,
I I.
.` .
:
:~L2~3~
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
-- 4 --
,
,, I,
3~
-- 5
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~
-- 6 --
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
:
~l2~a ~3~1~
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
..
- 8 -
3~
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-
:
g
'I'''
I,
, . .
~L2a~2~
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
-- 10 --
~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
,.
~2~23~
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
- 12 -
, .
It
~6.
'
~2423~
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:
- 12b -
. . .
~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.
`''
,
~Ik2~ 3gl~
- 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).
EXAMPLE 1
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.
FXAMPLE 2
A size O hard gelatin capsule was packed with lithium
chloride crystals; capped: and suspended axially and centrally
- 12e -
. I,
. .
~23~
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.
EXAMPLE 3
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.
- 12f -
3L2~2~39~
- 13 -
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.
EXAMPLE 4
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.
EXAMPLE 5
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.
- 14 -
I' .
1~239~
-- 15 --
a) o o a O
o
,
U
Us
a h
P O O
tO
o
g
on f
d
e ,~
d U
U
o ,a d ¦
U
By AL
o
O Us o o o o o o
,o ,1 f o o o o o o
So
e ,~
o o
O _I .C Us Us
MY
I!
,~
.
.
~æ3~
- 16 -
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.
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
145 45 7 7
231 76 10 17
312 88 10 27
6 94 9 36
5 3 97 8 ~4
6 1 98 8 52
7 0 98 8 60
EXAMPLE 7
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.
. .
~2~23~
O
o
o
, oo
3 o us
,,
o
~~ o ,~
h l 1 Us us
i o a)
00 Us
o 3 d
o
O
,,
O O cr us
Q~ a
t.
;~
IY ED
o
Jo
a
f o Jo o f us
z3~
EXAMPLE 8
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.
~Z4~39~L
, g
'~U I; r en
o
I,
O it f r
~0
~0 'I
it
O
o 3 X :)
.,
~d~
O
~:1
.~
C
l V~ o
td a O I
F~
Jo ye
O o
,~ 3
. o
O us l Us Ln I
,~ _ _
o
'
En
.
.
,~ ;
: : '
3~
- 20 -
EXAMPLE 9
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.
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
9 61 2 15
6 7 68 3.5 18.5
7 6 74 2.5 21
79 3 24
. .
,.. , ., ............ :
,
.
:
~ILZ~2~
21 -
EXAMPLE 10
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
1 75 11 18 28 26 47
2 96 20 35 55 48 76
3 - 28 53 70 65 90
4 - 36 72 81 76 97
- 42 81 87 83
6 - 47 86 91 ~7
7 - 52 90 94 91
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.
EXAMPLE 11
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.
I' :
,
23~
- 22 -
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.
:
I.
I:
.
,: ,:
-- 23 --
Ed
? r o
e
a
a
I_
P. i O It O
O ., O
o 3
e
w a
O O Cal ED _l Ox Ox
O _ O 0
O
O D
Ed 0 O
O Q) O O `D
l Ul
Ul
if h
Ed 5 C I 00 0 3
D O . 1~u~ I O oo us
e 8 ye
Ed
o I `' o
:~ Ed (I `D O do
~3 o us Jo f
oD o 0
Us
