~ ~4~4~8 This invention relates to devices which dispense active agents to a constant pH aqueous environment at a controlled, pre-determined rate over a prolonged period of time~
The use of poly(carboxylic acids) as enteric coatings has been reported by Lappas and McKeehan at 51 J. Pharm. Sci 808 (1962), at 54 J Pharm. Sci 176 (1965) and at 56 J. Pharm. Sci 1257 (1967). As is well known, enteric coatings are special coat-ings applied to ingestible tablets or capsules which prevent release and absorption of their contents until the tablets reach the intestines. In the highly acidic stomach (pH 2) poly (car-boxylic acids) are present completely as unioniæed hydrophobic species which are water insoluble and which prevent the release of any enclosed drug. As the poly(carboxylic acids) move on to the intestine, they are exposed to alkaline conditions (pH of up to 9) in which they ionize to soluble hydrophilic species and release the enclosed drug. Accordingly, the release is essentially a pH-dependent s~ep function. There is no release of drug in the acidic stomach; there is release of all the drug as the encapsulated drug enteTs the intestine and ~he pH of the environment changes to an alkal;ne value.
In Canadian, Patent Application Number 151,300, filed September 8, 1972 owned by applicant, ocular devices are disclosed which are formed of various materials that bioerode in the environ-ment of the eye concurrent with the delivery of drugs and which thus obviate the problems associated with the removal of ocular inserts from the eye.
The sustained release dispensing devices of this inven-tion are characterized as comprising an active agent dispersed through a hydrophobic poly(carboxylic acid) having one ionizable carboxylic hydrogen atom for each ~ to 22 carbon atoms, which body when placed in an aqueous envîronment having an essentially con-: . .. .: .. , .: , ' '. ' ~ -1~464~8 stant pH in the range of about 6 to about 9 erodes at a controlled rate over a prolonged period of time by a process of carboxylic hydrogen ionization, thereby releasing the dispersed active agentO
The methods of this invention are characterized by the step of introducing into an aqueous environment having an essentially constant pH in the range of about 6 to about 9 a body of a hydrophobic poly(carboxylic acid) having one ionizable carboxylic hydrogen atom for each 8 to 22 carbon atoms containing an active agent dispersed therethrough which body when in said environment erodes at a controlled rate over a prolonged period of time in response to the pH of the environment by a process of carboxylic hydrogen ionization, thereby dispensing the dispersed active agent to the environment.
Thus this invention seeks to provide a sustained release dispensing device for dispensing an active agent to an aqueous environment having an essentially constant pH, in the range of about 6 to 9 throughout the period of administration comprising an active agent dispersed through a body of a hydrophobic polytcarboxylic acid) of formula IR i2 ........ IR
C-OH -OH C-OH
Il 11 11 O O O
wherein the groups R represent organic radicals independently selected to provide an average of from 8 to 22 total carbon atoms for each ionizable 20~ carboxylic hydrogen atom, and n has a value providing an average molecular weight of from about 10,000 to about 800,000, which body when placed in said environment erodes at a controlled rate over a prolonged period of time in response to the essentially constant pH environment by a process of carboxylic hydrogen ionization, thereby releasing the dispersed active agent at a con-trolled rate over a prolonged period of time.
In the drawings:
Figure 1 is a cross sectional view of a device in accord with this invention for releasing active agent at a controlled rate over a pro-longed period of time.
- ~
.
1~)464~8 Figure 2 is a cross sectional view o~ a multi-layered device in accord ~Yith the invention which releases active agent at a varying rate.
Figures 3 - 7 inclusive are illustrative of the many embodiments the present invention may take Figure 3 is a perspective view of a disc-shaped tablet suitable for releasing drugs perorally or subcutaneously or for releasing other active agents to other constant pH environmentsO
-2a-''. ' , , .;
-- ~L046~
Figure 4 illustrates in perspective a device of this invention adapted to release a controlled amount of actîve agent into a liquid medium.
Figure 5 is a cross sectional view of a suppository embodying the present invention while Figures 6 and 7 are partially cut away elevational views of devices in accord with the present invention which are adapted to release a controlled amount of active agent into the uterus~
Figure 8 is a graph illustrating the linear release of active agent achieved with devices of this invention, Figure 9 is a cross sectional view of a layered ocular insert embodiment of the invention.
The terms "hydrophobic" and "hydrophobicity" broadly refer to the property of a substance to not absorb or not adsorb appreciable amounts of water. As used herein a hydrophobic mate-rial is defined as one which absorbs or adsorbs water in a maximum amount not exceeding 10% of its dry weight.
As used herein the term "prolonged period of time" shall have different meanings with respect to the various devices to which it is applied. Normally it will mean time periods of at least one hour. These periods may range up to 30 days or higher, even to a year or more.
The phrase "active agent" and the term "agents" as used herein means any compound, or mixture of compounds, composition of matter or mixture thereof which when dispersed produces a pre-determined beneficial and useful result. Such active agents are, for example, pesticides, germidices, biocides, algicides, rodenti-cides, fungicides, insecticides, . . - . ~ .
.
anti-oxiaan~s, plant growth promotors, plant growth inhibitors, preservating agen-ts,: surfactants, disin~ectants, sterilization agentsr catalysts, chemical reactants, fermentation agents, cosmetics, ~o~ds, nu~rients, food - supplements, dru~s, vitamins, sex sterilants, fertility inhibitors, fertility promotors, air purifiers and micro-organism att:enuators.
- "Drug" is used herein in its broadest.sense as :
~ncluding any composition or substance that will produce a pharmacological or biological response.. Suitable dru~s for use in therapy with the devices of the-invention include.
without limitation:
(1) Protein drugs such as insulin;
(2) Desensitizing ayents such as ragweed ana hay-~ever polle~ antigens, dust antige~ ana milk antigen;
- (3) ~accines such as. smatl pox, yellow fever., disiemper,.fowl pox, scarlet ~ever, diptheria.toxoid, .
-tetanus, tox~id, who~ping couqh, influenzae, rabies, mumps, .. ~ ......... . . . . ........ .. . .
measle3, poliomy21itis ana ~ewca.stle disease;
~ 4) Anti-infectives, such as the antibiotics, penicillin, tetracycline, streptomycin, polymyxin, chloram~
phenicol,~and erythromycin; the sulfonamides, sulfacetamide, sulfamethizole, sulfadiazine,.and sulfisoxazole; anti-virals such as iaoxuridine; and other anti-infectives such as ni-tro--- furazone and soaium propionate;
(5~ Anti-allergenics such as antazoline, methapy- .
rilinej chlorpheniramine, pyrilamine and prophenpyrldamine;
i' - , ~04~4~
(~) Anti-inflammatories such as hydrocortisone;
cortisone, desamethasone, fluocinoline, triamcinolone, medrysone and.prednisolone;
(7) Decongestants.such as phenylephrine, - naphazoline., ana tetrahyarozol:ine;.
. ~8) Miotics and anticholinesterases such as pilo-carpine, eserine salicylate, carbachol, di-isopropyl fluoro- :~
- , phosphate, phospholine iodide, and demecarium bromide;
~ ` ~9? Mydriatics such às at~opine sul~ate, cyclopento- .
late, homatropine, scopolamine 3 tropicamide, eucatropine, and~hydroxy-amphetamine;
- (10) Sympathomimetics such as epinephrine, ., .
~ 11) Sedatives and hypnotics such as pentobarbital sodium, phenobarbital, secobarbital sodium and codeinei ~ 12). Psychic.energi~ers such as 3-t2-aminopropyl) indole acetate- and ~-(2-aminobutyl~ indole a~etate;
(13) Tranquili~ers such as reserpine,-chlorpromazine, and thiopropazate; ;
. (14). ~ndrogenic steroids such-as methyltestosterone . - , . . .
- and fluoxymesterone; - - .
- ............................... . . ~ ~: - . .. ;
. .~15) Estrogens such as estrone, 17-~-e~tradiol, - ~ ~ .
.
ethinyl estradiol, and diethyl stilbesterol;
- (16) Progestational agents such as proge3terone, `.
megestrol, melengestrol, chlormadinone, ethisterone~ nor-ethynodrel, l9-nor-progesterone, norethindrone and ~nedroxy-progesterone;
(17~ Humoral agents.such as the prostaglandins, for example, PGEl, PGE2, and PGF2;
_5_ - .
:` ', . ; ": ,.
' '' . : :
-'I 0464~8 ~ lB~ Antipyretics such as aspirinl sodium salicy-late, and salicylamide;
~ 19) Antispasmoaics such as atropine, methantheline, papaverine, and methscopolamine bromide; .
(20) Anti-malarials such as the 4-aminoquinolines, 8-aminoquinolines, chloroquine, and pyrimetham.ine; ~ :
(21) Antihistamines such as.diphenhydramine,. .
- . - ~ . . .
dimenhydrinate, tripelennamine, perphenazine,~and carphena- . ..
zine; and-~ 22~ Cardioactive agents such as hydrochlorothiazide, ~lumethiazide, chlorothiazide, and trolnitrate.
Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or nonirritating, - pharmacologically acceptable salts. For acidic drugs/ salts of metals., amines, or organic cations (e.g.,-quaternary ~.
. ammonium salts) can be employed. Furthermore,. simple derivatives.o~ the drugs such as ethers, esters and amidesr which have desirable characteristics, bu~ which are.easily -. :.
hydrolized ~y body p~ or enzymes may be employed.
In Figure 1 device 10 comprises.an active agent. . ..
21 dispersed throughout a body 22 of hydrophobic poly (carboxylic acid). When placed in an environment having a controlled and essentially constant p~, poly~carboxylic acid) body 22 bioerodes concomitantly releasing the active agent which is dispersed therethrough. These polyacids are characterized as being hydrophobic when unionized ana as having a specified proportion of carbo~ylic hydrogens - and are represen-~ed by th~ genera`.formula:
.
... . .. .
104~4~
p2 . . . ~
~--OH ~--OH ~--OH (I) wherein:
the Rls. are.organic radicals independently selected to.
provide, on average, from 8 to 22 total carbon atoms for each car~oxylic hydrogen-. ~ariations of this ratio within ;~~
- , . - . - . , this range can vary the erosion and active agent release - . rates o~. devices.prepared.Erom these polymeric aci.ds ~rganic radi.cals represented by ~1, R2, ~..Rn may be selected Erom hydrocarbon radicals and hetero-atom con- .
taining organic radicals. Suitable hetero atoms for - . .
employment in p~l, R2, Rn include oxygen, nitrogen, sulfur, and phosphorus as well as other hetero atoms so long as the required.hydrophobicity and carbon tO carboxy-.
lic hydrogen average ratio is maintained.. m e value oE n ana hence.the:average molecular.weight oE the polymer is not critical and may vary-over a wide range. Suitabl.e ~ .
molecular weights, for example, range rom about.lOrOD0 to . .
. abou~ ~00,000. Materials within this range erode to - `. -- . .
products which may be easily and innocuously passed ~ro~
- . .- .
l the environment o~ use. Preferred molecular weights are .-. . :.
! Erom about 15,000 to. about 500,~00. - ;
These polyacids may be made Erom monomers o~ at least two carbon atoms whic~ contain pol~merizable oleEinic carbon-carbon ~ouble bonds. At least a portion oE these monomers will have appended thereto one or more car~oxyl - radicals, or.suitable precursors thereoE and o~tionally also other hetero atom radicals. The polymer is Eormed .
.
~4640l3 by effecting addition of these monomers, one to another, across the polymerizable double bonds. This general method for forming polyacids is well known and does not comprise a part o the present invention~.-.
.. This preparative technique can be employea to pre-- .. ~
pare the poly(carbo~ylic acids) o~ General ~ormula I having hydrocarbon R's either by polymeri~ing suitable hydrocarbon substituted olefinically unsaturated acids such as substi-.. . .
tuted acrylic acids ana crotonic acids.or by copolymerizingolefinically unsaturatea acids, such as acrylic acid or hydrocarbon-substïtuted acrylic acids or the crotonic acid~
with unsaturated hydrocarbonsO The.unsatura-ted hydrocarbons which may be so copolymeri~ed with unsaturate* carboxylic acids include terminally olefinically unsaturated hydrocarbons.
and olefinically unsaturated hydrocarbons having-a conjugated carbon-carbon double bond such as ethylene-, prop~lene, butadiener isoprene, and styrene.
Poly(carboxylic acids) of General ~ormula I having ` . .
.
hydrocarbon Rls may also be prepared by other known techni~ues, such as for example by oxidizing terminal methyl groups~ on : suitable hydrocarbon polymers to carboxyl groups wi-~h alkaline ;:
permanganate or by carboxylating olefinically unsaturated .
hydrocarbon polymers by contacting them with carbon monoxide, water and optionally some hydrogen under conditions o~
elevated temperature and pressure in the presence oE strongly acidic catalysts, for example HF, BF3, an~ H2S04.
--'~
1~64Q~l Poly~car~oxylic acids) use~ul in the devices of the invention and illustrated.by General Formula I may suitably , incorporate oxyyen atoms in.their R's. Qxyhydrocarbon R's j incluae ester.group~ or ether-groups ~ Poly(carboxylic acids) I representea by Formula I incorporating ester ~roups r as ¦ R's, are especlally sultable in devices oE this inven~ion.
~ They may be readily prepare~ by co~olymerizin~ unsaturated -`
! carboxylic`acids with unsaturated car~oxylic acia ésters or ! . . ............ - . - -. ~ . .- . - ....................... .
.partially esterifying acid polymers.or copolymers, wh~ch -are themselves easily obtained. The latter o~er the aavantage of permitting simple varia.ion or the ra-tio o~ carbons to - ionizable carboxylic hydrogens by varyins the extent o~
partial esteri~i~ation or th~ esteriiyin~ alcohol employed.
As a.result, easy adjus-tment or erosion characteristics - o~ the poly(carboxylic acid) product and hence active agent release rate, is obtainea.
- As an example-o~ this easy controlt consider the .
case o~ polytacrylic acid~. Poly(acrylic-acid) is available commercially or may be easily prepared such as.by mixing , . 167 parts o~ 60% acrylic acid, 232 parts of water, 0-~50 i parts o~ potassium peroxydisul~ate and:0.2.5 parts o~
- . - -! potassium metabisul~ite and heating the mixture to 60C.
- Polytacrylic acid) per sej however, is not a. suitable - -poly(car~oxylic acia) for-use in devices of this invention as it is.su~stantially hydrophili.c and water soluble and does not have the carbon to ioni~able hydrogen ratio necessary to give suitable erosion and active agent release - - characteris~ics.
.
:~
2 _9_ 1 ', - ' . _ . .
- . . . ~ ,: ~ ` . -~046~8 When half thè carboxyl groups oE poly~acrylic acid) are esterified by reaction with a hexanol, the resulting partial ester is hydrophobic and has a carbon to ionizable hydrogen ratio within the range necessary for materials employed in the devices of this invention ti.e., 12:1), A similarly suitable material would result if 2~3 of the poly(acrylic.acid~ carboxyl groups were esterlfied with ethanol. . ~
. This partial esterification technique is of course not limited to treatment of acrylic acids. Any or~anlc lower poly(carboxylic acid) may.be partially esterified when necessary to achieve the required hydrophobici-ty and -carbon to acidic hydroger. ratio. Other polyacids which-often benefit from esterification include.homopolymers of unsaturated lower carboxylic acids such as the lower alkyl acrylic acids, for example methacrylic and ethacrylic acid; crotonic and propiolic acid; maleic acid and fumaric acid. Polymers of acid precursors such as poly~maleic ~ -anhydride) may by hydroly~ed and partially esterified as.
~well. Also suitable for esterification-are acids or pre-cursors copolymeri~ed with lower unsaturated hydrocarbons `
of from 2 to 8 carbons such as ethylene, propylene, butadiene and styrene or with lower unsaturated oxyhydrocarbons such as unsaturated ethers of from 3 to 8 carbon atoms~ Aicohols suitable for partially es-terifying the above-no~ea polyacids include the hydrocarbon alcohols, preferably the alkanols of from about one to about 16 carbon atoms; for example, methanol, ethanol r isopropanol, n-butanol, cyclohexanol r octanol, the decanols, and n-dodecanol. Combinations of alcohols may also be employed.
'. ' . , ' , ~_ '. . . ~ . ' . .
~C94~4~
Poly(carboxylic acids) of General Formula I incorpor-ating ether groups, as R's,may be made by copolymerizing an-unsaturated carboxylic acid with an unsaturated ether, for example, acrylic acid, maleic acid ana crotonic acid with vinyl ethers o~ ~rom about 3:to about 10 carbon atoms such as methyl - , . .
vinyl ether, ethyl vinyl ether, butyl vinyl ether and hexyl -v~nyl ether. Because ol the small number of carbon atoms . in many of these unsaturated ethers and acids it may be ` ~ .
- - .. .
desirable J to.achieve the required carbon/acidic hydrogen ratio, to terpolymerize these materials with a non-carboxylic : hydrogen-containing material, most suitably an unsaturated - terpolymerizable unsaturated hydroca~bon o~ from 2 to 8 carbon atoms such as ethylene, butadiene, or styrene.
. The R's o~ General.Formula I, as oxyhydrocarbons, .
may contain alcohol linkages~ The employment o~ alcohol linkage-containing oxyhydrocarbons as Rls can pose a prob-. . .
l~m, however,. as the alcohol linkages generally:decrease the.
hyarophobicity o~ the polya~id, o~ten to ~elow the extent of -~ . .
hydrophobicity required o~ polyacids for employment in this .
. . ...
- . invention. It is usually possible to incorporate up to.
- . -. s .
about 10%r basis total polymer, of-alcohol linkage-containing .
R r s in the polyacias.
- Nitrogen, sulfur and.phos~horus atoms may also be incorporated in R gxoups employed in the polymers repre-- sented by General Formula I. Nitrogen may be present as cyano groups, amide groups or imide groups. Amine groups are generally not suitable as they can result in internal salts being formed between the polymerized acid and amine groups -, -`~. 104641)~
Sulfur atoms may be present as mercaptan or disulEide linkage while phosphorus atoms may be present as phosphate linkages.
A preferred group o, poly~carboxylic acids) are ter-polymers of at least one ~, ~-unsaturated aliphatic acid of
3 to 8 carbon atoms and alkyl esters of such ~ unsaturated aliphatic acids in which said alkyl is of ~ to 8 car~on.atoms.
A particularly preferred.terpolymer comorises ~ to 75 mol%
butyl acrylate, 15 to 30 mol% methac:rylic acid and 5 to 15 mol%
- : .
acrylic acid.
- , The polytcarboxylic acias) employed in the devices of this invention a~e soluble in organic solvents. Accordingly, the devices may be conveniently formed by film castin~ techniques..
An organic solven~ed solu.tion of ,he polyacid, containin~ active agent, is prepared and cast or drawn to a.film. The solvent is then evaporate~ to yield a continuous film of the pol~acid. .
The devices may then be punched or cut from this.film. Alternativel~
the devices may be molded from such.a solution.. - .
It is often desirea to incorporate plasticizers in -~he poly~carbo~ylic acid) materials to improve or vary their phy~ical properties, such as to make them more flexible. Exemplary plas=
ticizers suitable or employment for the present purpose.are the pharmaceutically acceptable plasticizers conventionallv used,-such as acetyl tri-n-butyl citrate, epoxidized.soy bean oil, glycerol monoacetate, polyethylene glycol, propylene glycol dilaurate, decanol, dodecanol, 2-ethyl hexanol and 2, 2-butoxy-ethoxyethanol. The propor.tion of plasticizer used will vary within broad ~imits depending upon the characteristics o~ the poly ~carboxylic acid) involved. Tn 5eneral, from about. 0~01 parts to - about D.2 parts by weight of plasticizer for each part by weigh~
of the poly(carboxylic acid) can be used. When plas-ticizers are included in the poly(carboxylic acid) materials they are most suitably aaded prior to shaping the final forme~ structure, such as by dissolying or dispersing them in the solution from which the form is cast.
., . . ~ .
.. . . . . . . . .
1~6408 ' Active agent is released ~rom the delivery-devices of this inven-tion by erosion o:E the poly~carbo~ylic acid) body through which the agent is dispersed. ~s the body erodes, it releases the dispersed, entrapped ayent..- The poly(carboxylic acias) from which`'-~he bodies o~ the device.
of this invention are ~ormed are substantially imper~orate .~ ~
.. and impermeable to the passage of active agent by dif~usion. ''..' Hence, the rate of agent release is propartional to the.rate. -~o~ poly(carboxylic acid) erosion. When the rate of erosion ~'"'-''.'.~'' is constant the rate of release of agent-will also.be~con- -. ..r '` ' :~ '.`''' - stant, assuming that the dispersion o~ agent through.the ' -' body is uniform and that the area of the.device which is eroding remains constant.
---~
The a~orementioned poly(carboxylic acid) erodes at a controlled rate when placed in an environment having a.
, substantially constant pH. Environments in which the present .devices give very suitable controlled rates o~ erosion comp.rise - . .
aqueous environments having a p~ throughou-t~the.period o~ use ~' of the device selected in the range of ~rom about-6 to about 9. To give a smooth erosion and hence smooth release o~
- . ............ - - . ,.. .. ~
agent, the p~ shoul~ not vary by more than'about.~.S pH ~
units over ihe life of the device. Preferred environments '''`.~-vary by not more than about ~0.4 pX units and have a median pH in the range o~ from about 6.5 to about 8.5.. ~he more ' ...~.
alkaline the pH the more rapidly a given polycarboxylic acid.
erodes and releases entrapped agen-t. At pH's more acidic than about 6, the rate of erosion is too slow to be practical,:
while at pH's more basic than about 9, the rate is uncontrollably ~ast..
. ' ' ' ' -13_ . ~ . . .
.: ' . -: . . . . . - . . . ,. ~ . .. . : ...
109~64~15 Accordingly, the device of this invention may be used to administer drugs to those e~v.ironments within a mammalian patient which exhibit a constant p~1 in the range . .
of from about pH 6 to about p~ ~ throughou~ the period of use. .Unlike the gastrointestinal tract which presents a variably acidic. and basic pH environment, many areas of ~
mammalian bodies have essentially constant pX's which ~all -.
within the desired pH 6 - pH 9 range~ For exampler the ocular cavity has a-pX o~ about 7.4. Thé rectum has a .
,.
pH of about 7~5. The pH o~ the uterus or vagina is constan-t at about 7.3. The pH o~ blood is normally constant at about 7.2. .~ -In general the polyacids and their.erosion products are nonirritating to body tissuesO ~Iowever, in some in-stances it.may be desirable to coat devices of this invention which are used to administer drugs.to mammalian bodies with a non-interfering material such as a hydrophilic polymer, for examplè polyvinyl alcohol or gelatin, to increase the compati-bility o~ the device.to the body.
.
.
.- . .. .. . .. . . . . .
. .
~0~64C)~ -Without lntent to limit the scope o~ this invention by theoretical considerations, it is believed that the uni~orm and controllable rates of erosion observed with devices comprising hyarophobic polylcarboxylic acids~ having an avexage of 8 ta 22 carbons for each ionizable acidic-carbox~lic h drogen are the result.o~ equilibriums inherent in the erosion of these poly[carboxylic ac1ds~. ~ .. .
As shown in General Formu~a I, the poly(carboxylic :. .
. .
acids3 of this invention may be represented.as~
: . .
R
C~ OH ~ ON-The carboxyl groups are weak acids which, in their unioni~ed - ~orm,. are hydrophobic. ~hen placed in an aqueous fluid-a por- .. tion o~-~he carboxyl.groups ionize to yield hydrophilic - -,-~
~ O groups and hyaronium ions (~30 j As more o~. the : . .
O . - - ~ :'' ~ ' '' -' carboxyl groups in an initially hydrophobic polymer chain `.~
ionize, the chain assumes an increasingly hydrophilic charac- :
..
ter and eventually goes into solution in the fluid. This solubilization by ionization cccurs only on the outer sur~aces of th~ polycarboxylic acid ~odies. Even if minor.amounts of fluid do penetrate the surlace of the bodies insignificant ionization can occur there since the inner carboxyl groups, being surrounded by an essentially organic medium exhihit a ~ar higher p~a than do the carboxyl groups on the surface whi~h are in a more aqueous medium.
: -15-- -. - . -~
~Q~64~8 The erosion by surface ionization is a reversible reaction, the equilibrium of which is highly sensitive to pH, and thus, often self-limiting. As hydronium ions are generated, they tend to cluster about the polymer body from which they were generated, lower the pH in the area of the body, and prevent further so:Lubilization by ionization.
Some of the clustered hydronium ions gradual.Ly disperse or are consumed -by alkalinity of the fluid and are replenished via further ionization.
The overall erosion rate which results with the poly(carboxylic acids) of this invention is surprisingly slow, perfectly suited for employment in erodible devices such as device 10 designed to release agents over prolonged periods such as periods of from about 1-2 hours to about 60 days. To operate effectively, there must be some removal of hydronium ions, such as the addition of fresh 1uid or of base or by means of a buffer.
The self-limiting pH control inherent with these certain poly-(carboxylic acids) offers the further advantage of preventing the pH
of the fluid of use from dropping, by reason of excess hydronium ion release, to a level which would be irritating or corrosive.
The exact rate of erosion is in part dependent upon the chemical nature of the poly(carboxylic acid). The more hydrophobic the polyacid is, the greater the number of ionized carboxyl groups necessary to solubiLize it and the slower its erosion rate. Thus, by changing the hydrophobicity of the certain poly(acids), as may be done by varying their ratio of total carbons to ionizable hydrogens within the range in accord with this invention, the rate of erosion may be ~464~8 controlled.
Further description of the delivery devices of this invention can be provided by reference to the drawings.
Figure 1, as already noted, illustrates generically the delivery device (device 10) of this invention. Device 10 comprises drug 21 dispersed through polyacid body or matrix 22. Drug 21 may assume a variety of configurations in device lO. It may be in the form of liquid or solid particles, droplets, a colloid, a molecular solution or other form which is dispersed through body 22. Device 10 is shown sectioned. This is to indicate that device 10 is substantially longer than it is thick. A preferred pattern of erosion and release results when the thickness of the deuice is smaller than either of its other dimensions, preferably the thickness is less than 10% of the length or width. With such a configurationJ an essentially constant surface area is presented throughout the period of erosion. Since erosion rate and hence agent release rate are proportional to surface area, a constant, -or zero order, rate of release results. Exemplary shapes of such "zero order release devices" would be an 9 mm disc and a 6 mm by 12 mm -ellipsoid, each punched out of 0.4 mm thick drug-containing poly(car-boxylic acid) sheet. ;
Figure 2 illustrates, by reference numeral 20, an embodiment of this invention with which a variable rate of agent release may be achieved. Device 20 is comprised of a series of three concentric layers.
The outer layer comprises a matrix 22 of ionizable hydrophobic poly(car- ~ -' ~' ""
. : .
-17- ~
' , .
iO~640~
boxylic acid) of this invention that can release agent 21 at a controlled rate over a prolonged period, in the same manner that the matrix in device 10 released agent. When the outer layer comprising matrix 22 and agent 21 has eroded away, middle layer 31 is exposed, and begins to erode.
Layer 31 is formed from a bioerodible material, very suitably either the same or different hydrophobic poly~carboxylic acid) employed in matrix 22.
Layer 31, as illustrated contains no agentl cmd thus during the erosion provides a period where no drug would be released. When layer 31 has been eroded the innermost layer is exposed comprising ionizable hydrophobic poly~carboxylic acid) matrix 22a that has particles of agent 21a dispersed therethrough. As matrix 22a erodes, agent 21a is released at a controlled rate for a prolonged period of time. Many variations of device 20 will be apparent. For example, a greater number of layers may be employed, a variety of agents or concentrations may be employed in the several layers, or polyacids having different erosion rates may be used in different layers.
Figure 3 illustrates in cut-away perspective view, by reference numeral 30 a disc-shaped device in accord with this invention. Device 30 comprises particles of agent 21, dispersed throughout body 22 of poly~car-boxylic acid). As body 22 erodes, agent 21 is released. A device of such shape could find application as an agricultural additive for slowly re-leasing a variety of active agents such as biocides, fertili7ers and the like to constant pH irrigation fluids. A device of such shape might also .
, : ''. ' ~ :: - ' 104~
find application as a depot for drugs. For example, it could be placed in the sac of the eye, ther~ to release ocular drugs at a controlled rate for a prolonged period of time. Ocular devices of this invention may be used to deliver drugs which are substantially insoluble in water as well as those which are essentially water-soluble. It is preferred, however, that the drugs employed in the ocular devices of this invention not be highly water soluble. Best results are obtained when the drugs are in a form which is not soluble in tear fluids to an extent greater than about 20,000 ppm by weight.
Figure 4 illustrates in cut-away perspective view by reference numeral 40 an embodiment of this invention suitable for releasing an active agent to an aqueous environment of constant pH. Device 40 comprises active agent 21 dispersed through body 22 of poly(carboxylic acid). Said material is enclosed within net container 32 having ring 33 on its top surface and leads 34 attached to ring 33. Device 40 could be placed, for :
example, in a water closet and there attached by means of leads, where it would release detergent, disinfectant or the like to the water contained therein. Device 40 might also be affixed in a dishwasher or clothes washer where it would meter, as active agent, wash aides, water softeners, ;
spot preventors, or fabric softeners to the wash water. Similarly, device 40 containing as active agent corrosion inhibitors or lubricants might be placed in an automobile cooling system where it would dispense such agents over a prolonged period of time.
.. : , . . . . ..
~0~ 8 Figures 5, 6 and 7 relate to embodiments o~ this invention adapted for delivering drugs to a mammalian patient. Figure 5 illustrates as 50 a suppository suitable for rectal or vaginal use.
Suppository 50 is rounded at its top end to permit simple, non-painful insertion. Suppository 50 comprises drug 21 dispersed through~oly(carboxylic`acid) ~od~ 22.
~hen pIaced in the constant pH vagina or rectum, device 50 erodes and releases drug at a controlled rate over a prolonged period of time.
In Figure 6 there is depicted an intrauterine drug delivery device 60 embodying the invention. Drug delivery device 60 comprises a body of poly~carboxvlic acid) 22 having particles of drug 21 dispersed therethrough. Device 60 consiets of two continuous loops each having a cross-sectional diameter of about 1.5 to 2.~ cm. ~he larger of the two loops is adapted to be located within the uterine cavity 36 where it contacts the sides 37 as well as the ~undus uteri 38 of the uterus. The smaller loop is positioned in the neck of the uterus to assist in maintaining device 60 within uterine cavity 36. Device 6~ slowly erodes in the uterus releasing drug 21 over a prolonged period o~ time.
Figure 7 depicts another intrauterine drug delivery device 70 in accord with the invention. This device is in a l'Tl' configuration, having a lateral member 41 attached to a depending vertical member 39 and is adapted to be located within a uterine cavity 36, wherein it optionally contacts sides 37 as well as fundus uteri 38. Device 70 is pre~erably -2~--1~)464~1~
designed with rounded, non-traumatising ends and a lead 42 attached to the trailing end of member 39, distal ~rom the lead or inserting end of the device, for manually re-moving device 70 ~rom uterus 3~. ~ead can ~e any suitable material, ~or example, nylon surgical thread having a thickness o~ about 0.0~2 inches, and the like.
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Device 70 is fa~ricated with a center core 42 not containing drug, and an outer layer 22 of poly(carboxylis ': , " '". - :' -.
acid) having particles of drug dispersed therethrough. The - . . . .
thickness o~ layer 22 is small compared to the area o~ device' 70. Thus, the area o~ erosion does not change substàntially auring ~he period o~ exosion and the rate o~ erosion remains essentially constant. '' Figure 9 illustrates, ~y reerence~numeral 80, an ocular insert embodying this invention which demonstrates how -several variables may be manipulated to control the rate and perioa o drug release. Ocular insert 8D comprises 6 layers,, identi~ied as layers A-F. Layers A-E inclusive each comprise a matrix 22 o~ hydrophobic poly~car~oxylic acid) in accord with the present invention having dispersed therethrough particles o~ druy 21. Layer F comprises a slowly eroding,poly~carhoxy~
lic acid~ which contains no drug. The rate o~ erosion o layer F lS slow enough such that it will not be eroded auay until a~ter the top 5 layers have disappeared. Thus the erosion shall proceed sequentially, with layer A eroding ~irst r layer -B erod}ng second and so ~orth.
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The amount of agent employed in devices in accord with this invention may vary over a wide range, depending upon the type of agent and the delivery rate desired and the size and type of device in which the agent is employed. The amount may vary from the minimum effective single delivery of the agent employed to a maximum amount of agent limited by the size and/or erosion characteristics of the devices. In general, agent is usually present in an amount equivalent to up to about 90% of the weight of the poly~carboxylic acid).
The rate of erosion and agent release of materials employed in the invention can be determined experimentally in vitro by testing them under simula~ed environmental conditions. For example, the rate of erosion of a device in a moving aqueous stream can be determined by placing a device in such a stream and repeatedly weighing it to determine its weight loss. Similarly, the rate of erosion of a material in tear fluidsJ
as would occur with an ocular drug delivery device, may be measured by placing a small weighed sample of the material in a 0.026 M HC03 solution of pH about 7.4 ~simulated tear fluids) at body temperature ~37C), agitating for a timed interval, and periodically measuring the amount of material eroded into the solution. To accurately predict in vivo results, it is necessary to multiply the in vitro rates by an experimentally deter-mined constant which takes into account differences in stirring rate and fluid volumes between the living body and the in vitro test apparatus. This constant may be derived by .
~o~ 8 fi~t placing a plurality of ~mall weighed sa~ples of material in a plurality of eyes and sequentially, over a period of time, removing and weighing the samples. The rate thus determined, divided by the rate o~ erosion observed in vitro with the same material equals the necessary constant.
For a more complete understanding of the nature o~
this invention, reference should be made to the following examples which are given merely as further illustrations of ~ -th~ invention, and are not to be construed in a limiting sense. ~ -All parts are given by weight, unless stated to the contrary. ;
A device suitable for releasing drug to the essentially constant pH environment of the eye employing a hydrophobic poly(carboxylic acid) having on an average from 8 to 22 total carbon atoms for each ionizable acidic carboxylic hydrogen and containing hydrocortisone is prepared in the ollowing manner:
A. Preparation of poly(carboX~lic acid~. 12.6 Grams (0.10 equivalents) of ethylene-maleic anhydride copolymer -(Monsanto EMA*, Grade 31) is stirred with 50 ml (0.4 moles) of n-hexyl alcohol at 120 - 125 C. for 7 hours. The solution is cooled to room temperature and methylene chloride is gradually added to the cloud point. Then more methylene chloride is added to precipitate the product (total vol. 3Q). The precipitate is thoroughly leached with the methylene chloride. The solvent is decanted and ' ;,'': ""' ' ' ' *Trade Mark ~ ', .
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1(~4~8 the product dissolved in 75 ml warm acetone. Methylene chloride is added to the cloud point. Then,more methylene chloride is added to pre-cipitate the product (total vol. 2~-). The precipitate is then thoroughly leached with the methylene chloride. The solvent is decanted and the pro- , , duct dissolved in 75 ml acetone. The solution is transferred to a poly-propylene container and solvent is removed under vacuum at 50C to yield the polymer product. The infrared spectrum of the polymer shows broad bands at 1680 and 1780 cm 1 indicative of ester carboxyl. Titration with base shows that the hexyl half ester-of maleic acid has been formed, and thus the ratio of total carbons to ionizable hydrogens on average is 12:1.
A sample of the polymer is tested for hydrophobicity by measuring its water absorption and is found to pick up only 6% by weight of water.
B. Preparation of hydrocortisone-containing ocular insert.
1.8 Grams of the half ester polymer of part A is dissolved in 5 ml of acetone, with stirring at 25C. 0.2 Grams of micronized hydrocortisone ~ ' are dispersed in the solution with stirring. The resulting viscous dis-persion is drawn on a polyethylene film to a wet thickness of about 0.75 mm. The cast plate is allowed to dry thoroughly to yield a 0.3 mm thick dry film. The resulting film is removed from the polyethylene film by stripping, and is punchcut into desired shapes and sizes. A 6 mm diameter circular disc weighs 7 mg and contains 0.7 mg of hydrocortisone.
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C. Testing of inserts. A series of 0.3 mm thick ocular inserts ~ -prepared in part B are each placed in 60 ml portions of simulated tear fluids ~water containing 0.1 moles of K2HP04 per liter and having a substan-tially constant pH of 7.4) and agitated at 37C for 40 minutes. Sequential-ly the ocular inserts are retrieved, dried and weighed. The samples of simulated tear fluids are analyzed by ultraviolet absorption at 248 milli-microns wave length for hydrocortisone content. The results of these tests indicate that the inserts erode in this solution of simulated tear fluids in 40 minutes at a uniform rate and that the drug release parallels the erosion. The erosion rate in vitro could be decreased almost two ordersof magnitude by decreasing the buffer concentration and the rate of stirring.
The most reproducible results are obtained at the buffer concentration and rapid stirring rate employed. Figure 8 illustrates by a graph, drug re-lease rates observed when several series of these inserts are tested in vitro.
A series of these ocular inserts are placed in rabbits' eyes, where they exhibit a similarly uniform but slower rate of erosion and drug release to that observed in the simulated ~in vitro) experiments. About 175+ hours are required for complete erosion. The factor In vitro~ equals 0.01. -~
During the in vivo tests, the rabbits are carefully watched for evidence of ocular irritation. In accordance with the Draize method of measuring ocular irritation, the following conditions are watched for:
hyperemia, edema and necrosis of the lids; hyperemia, tearing, chemosis, and necrosis of the conjunctiva; exudate from the conjunctiva; follical :10464~
hypertrophy; and damage to the cornea or iris. Over the period of testing these ocular inserts, at worst mild irritation is noted.
-The ocular insert preparation of Example l, parts A and B~ is repeated 5 times with one variation. The molar excess of n-hexanol employed in Example 1 is replaced with a similar amount of other alkanols as follows:
Example Alkanol .
2 n-butanol 3 n-pentanol
4 n-heptanol n-octanol 6 n-dodecanol The ratio of total carbon atoms to ionizable carboxylic hydrogens in each of the resulting half esters is as follows:
~atio Carbons:
Example lonizable Hydrogens . . .
3 ll Water absorption tests show the products to be increasingly hydrophobic, with the product of Example 2 giving the greatest water pickup with the product of Example 6 giving the smallest water pickup.
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Erosion tests under the simulated conditions of Part C of Example 1 are carried out. Constant erosion rates and release rates are noted for each of the materials. The results of these tests, as well as the in vivo results which would be predicted using the factor derived in Part C of Example 1 are as follows: ~
Time to Time to -Completely Erode In Completely Erode Exa~ple Vitro, Min. In Vivo, Hrs.
2 lO 10-15 4 50 ClO
A. Preparation of ~olymer. A mixture of five grams of poly~vinyl methyl ether-maleic anhydride) 1:1 molar ratio copolymer (GAF Corp., Gantrez AN 169*) and 30 ml of n-pentyl alcohol is stirred at 120C for 16 hours to yield a viscous product. This product is poured into 500 ml of 2% Na2CO
solution. The resulting solution is extracted twice with 400 ml volumes of hexane and acidified to pH 1-2 with HCl. The precipitated polymer is collect-ed, washed with slightly acidulated water and dried. The product is found to be the n-pentyl half ester of maleic acid. The product is hydrophobic, exhibiting an equilibrium water pickup of 9~ by weight. It has an average 12 carbon atoms for each ionizable carboxylic hydrogen.
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B. Preparation of drug delivery-material. A five gram portion of ~he half ester product of part A is dissolved in 10 grams of acetone with stirring. Micronized progesterone (0.5 grams) is added to the syrupy ethanol solution of ester. The progesterone does not dissolve in the ester solution but forms a uniform suspension. The suspension is cast to a wet thickness of 1.0 mm on silicone release paper. The film is dried in moist air at 25C for 72 hours and stripped from the release paper as a cloudy film having a final dry thickness of 0.3 mm. Although the film is somewhat brittle, it is easily punch-cut into a variety of shapes suitable for inser-tion in the uterus.
C. Testing of material. A 20 mm by 5 mm strip of this film (30 mg) is attached to a Lippes loop intrauterine device and inserted into the uterus of an adult human female. The drug delivery material erodes over a period of 30 days releasing about 100 mg of progesterone per day.
A. Preparation of n-butyl acrylate-methacrylate acid copolymer.
A solution of 288 ml (0.2 mole) of n-butyl acrylate, 85.1 ml (1.0 mole) of methacrylate acid, 0.10 g of benzoyl peroxide, and 1000 ml of ethanol is stirred under nitrogen at 50-53C for 27 hours. The product is isolated by precipitation into petroleum ether and triturated with ethyl ether.
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~04~408 B. Preparation'of' ins'erts. In a stirred flask, polymex product of part ~ 20% of dodecyl benzene sulfonate surfactant, 10% of benzalkonium chloride disinfectant and 2% of water-soluble green dye. The mixture if cast into 10 gram pellets. When one of these pellets is placed in ~ ' the water closet of a standard toilet it releases dye, disinfectant and surfactant to the constant pH water in the water closet over a prolonged period of time, in a manner characterized by being a continuous and prolonged release.
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A Preparation of-inserts. ~ series of ocular inserts are prepared using poly(carboxylic acids) similar ,, , to that employed in Example 7. The poly acids employed are the commercially available half esters of poly (vinyl methyl ether-maleic acid) marketed by GAF Corporation as , Gantrez* ES-225 (the ethyl half ester), Gantrez* ES-335 I
(the isopropyl half ester) and Gantrez* ES-425 (the n-butyl half ester).
Ocular inserts are produced using these polymers 20 and as drug. Hydrocortisone, pilocarpine hydrochloride and `
chloroamphenicol by the following method: a five gram portion of the polymer is dissolved in lQ grams of acetone with , stirring. Drug (0.5 grams) is added to the syrupy acetone solution of polymer. The resulting mixture is drawn to a wet thickness of lQ. mm on silicone release paper. The film is dried in moist air at 25 C. for 72 hours and stripped ,-from the release paper as a cloudy film having a final dry *Trade Mark ~3~ '':' ~ . .,:
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1~46~08 thickness of 0.3 mm. Inserts are punch cut from the film. Hydrocortisone yields suspensions in the polymers while chloroamphenicol and pilocarpine dissolve in the polymer at this drug loading ~10%). The poly~carboxylic acid) drug ocular insert combinations produced in these Examples were as follows:
Poly(carboxylic Drug and amount, Drug thickness Example acid) %, Basis Polymer of insert, microns _ _ 9 ethyl ester hydrocortisone 300 10%
isopropyl ester hydrocortisone 300 10%
11 butyl ester hydrocortisone 300 10%
12 butyl ester hydrocortisone 300
5%
13 butyl ester pilocarpine 300 hydrochloride 10%
14 butyl ester chloroamphenicol 300 10%
B. Testing of in_erts. The inserts of Part A are tested for bioerosion and drug release rate by the simulated ocular environment method of Example 1. Smooth rates of erosion and constant, essentially zero order rates of drug release are noted with the inserts of Examples 9-14 inclusive.
The results of the tests of inserts of Examples 9-14 are as follows:
In vitro Time to complete erosion rate, erosion in the eye, Example microns~minute hours ~0~641~19 It should be noted that the rates of erosion of the inserts of Examples 9, 10 and 11 decrease as the hydrophobicity of the polymer in-creases. Also by comparing the erosion rate of the insert of Example 11 with that of the insert of Example 12, it is seen that rate of erosion is independent of drug loading. The rate of release of highly water-soluble pilocarpine hydrochloride is substantially the same with the insert of Example 13 as are the rates of release of less soluble drugs from the inserts of Examples 11 and 14. During the in vivo test of the material of Example 9, some edema is noted as a result of the amount of the acidity generated by the rapid ionization of the polymer. No serious ocular damage is noted, however.
A. Preparation of half esters of N-vinyl pyrrolidone-maleic anhydride copolymers. A mixture of 11.6 g ~0.118 mole) of maleic anhydride ~Aldrich Chemical Co.), 12.7 ml ~0.121 mole) of N-vinyl pyrrolidone (Aldrich Chemical CO~)J 0.12 g azodiisobutyronitrile and 140 ml benzene is stirred under dry nitrogen at 60C for 42 hours. The mixture is cooled to room -temperature and the product 17.3 g (71%) collected by filtration and characterized as follows: mp 260-270 C: ~ KBr max 1680, 1780, 1850 cm soluble H20, DMF; insoluble CH30H, acetone.
The n-hexyl and n-decyl half esters of the poly N-vinyl pyrroli-done-maleic anhydride copolymer are prepared according to the procedure for the preparation of the n-pentyl half ester of (methyl vinyl ether-maleic ~ -anhydride) copolymer given in Part A of Example 7. Both materials are hydrophobic.
B. Production of inserts. Hydrocortisone ~10%, basis polymer) is added to the polymer and the mixture formed into a viscous solution in acetone. This solution is cast into a l-.O mm thick film which is dried, recovered and punch-cut into shapes suitable for ocular inserts.
C. Testing. The inserts of Part B are tested in the slmulated ocular environment described in Example 1. The n-hexyl half ester insert bioerodes and releases drug at a constant rate over a 20-minute period. The , : . , .
l~4~4n~
n-decyl ester isert bioerodes in about 20+ hours.
EXAMPLE l?
A. Preparation of n-butyl'acryIate-acrylic acid copolymer. A
solution of 14.4 ml (0.10 mole) of n-butyl ac:rylate, 6.85 ml (0.10 mole) of acrylic acidl 0.10 g benzoyl peroxide, and 50 ml ethanol is stirred under nitrogen at 48 to 52C for 40 hours. The product is isolated by precipita-tion into petroleum ether.
B. Insert production. In acetone, polymer product of part A
and 10~ of hydrocortisone are blended. The mixture is cast and formed into in-serts in accord with the procedures of Example 1, part B. The final inserts are 0.3 mm thick.
C. Testing of inserts. The inserts of part B are tested in the simulated ocular environment test of Example 1, and found to give a uniform rate of erosion and drug release, eroding over a period of 15 minutes.
A. Preparation of polymer. Gne hundred grams of benzene, 10.4 grams of styrene and 10.0 grams of maleic anhydride are stirred in the presence of 0.1 grams of bis-azodiisobutyronitrile at 70 overnight. The mixture is cooled and the product is separated by filtration and washed.
Characterization and analysis shows that it is the 1:1 mole ratio copolymer of s~yrene and maleic anhydride. Ten grams of this polymer is refluxed in ethanol for 10 hours to yield a viscous product. Analysis shows the product to be the ethyl half ester of styrene-maleic acid copolymer, a product which is hydrophobic and has an average of 14 carbon atoms for each ionizable acidic carboxylic hydrogen.
B. Preparation of ocular inserts. Ten per cent by weight hydro-cortisone ocular inserts are prepared by the casting method of Examples 9-14.
Acetone is used as solvent for the casting solution. The finished inserts are 0.5 mm thick.
C.''Testing'of inserts. The inserts of part B are tested by the method of Example 1, part C and found to give a linear erosion and drug release.
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,, . , , ' :, .: :' . ""' ' : ': . :,: ' .. . :, ~04~4~8 EXAMPLE`l9 A. Preparation of n-butyl acryIate-acrylic acid-methacrylic acid terpolymer. A solution of 207.1 g ~1.617 mole of n-butyl acrylate, 21.46 g -(0.301 mole) acrylic acid, 41.31 g ~0.480 mol~e) methacrylic acid, 1.30 g benzoyl peroxide and 650 ml of ethanol is stirred under nitrogen at 50-53C
for 65 hours. The product is isolated by precipitation into 12 1 of hexane and purified by repeated dissolution in approximately 600 ml acetone and precipitation into hexane.
B. Preparation of ocular inserts. Ten per cent by weight hydro-cortisone ocular inserts are prepared by the casting method of Examples 9-14.
Ethanol is used as solvent for the casting solution. The finished inserts are 0.5 mm thick.
C. Testing of inserts. The inserts of part B are tested by the method of Example 1, part C and found to give a linear erosion and hydro-cortisone release.
A. Preparation of n-pentyl acrylate-n-hexyl methacrylate-acrylic acid terpolymer. A solution of 116.59 g (0.82 mole) of n-pentyl acrylate, 85.12 g (0.50 mole) n-hexyl methacrylate, 77.82 g ~1.08 mole) acrylic acid, ~
1.30 g benzoyl peroxide and 650 ml of ethanol is stirred under nitrogen at '!'' ~ ' 50-53 C for 65 hours. The product is isolated by precipitation into 12 1 of hexane and purified by repeated dissolution in approximately 600 ml acetone and precipitation into hexane.
B. Preparation of ocular inserts. Ten per cent by weight hydro- ;
cortisone ocular inserts are prepared by the casting method of Examples 9~14.
Ethanol is used as solvent for the casting solution. The finished inserts are 0.5 mm thick.
C. Testing of inserts. The inserts of part B are tested by the method of Example 1, part C and found to give a linear erosion and hydro-cortisone release.
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