CA2079676A1

CA2079676A1 - Polymeric drug delivery system

Info

Publication number: CA2079676A1
Application number: CA002079676A
Authority: CA
Inventors: Nienyuan J. Chang
Original assignee: Individual
Current assignee: Allergan Inc
Priority date: 1990-04-27
Filing date: 1991-04-19
Publication date: 1991-10-28
Also published as: US5474780A; EP0537165A4; EP0537165A1; EP0537165B1; DE69129696T2; ATE167800T1; WO1991016869A1; AU7796391A; IE911413A1; DE69129696D1; AU640232B2; JPH05507683A

Abstract

Erodible bioadhesive drug delivery vehicles for use in delivering pharmaceutical compounds to the eye and similar physiological environments are disclosed. The drug delivery vehicles are formed of a homopolymer or copolymer of maleic anhydride or lower alkyl maleic anhydride incorporating a pharmaceutical compound in either a monolithic matrix or encapsulated form. The bioadhesive erodible drug delivery vehicles are configured to be retained in the eye following administration while providing specific erosion profiles allowing convenient drug delivery schedules ranging from hourly to daily or weekly intervals.

Description

~9l/16869 PCT/US91/0~71~
-1- 2~7~
PO~Y~IC D~G D~IYE~Y 8Y8~EM

REFERENC~ ~0 E~RLIER ~PPLICATION
This application is a continuation-in-part of co-pending application Serial No. 07/516,110, filed April 27, 199 0 .

FI~hD OF ~ INVENTION
The present in~ention relates in general to an erodible, sustained release polymeric drug delivery vehicle. More particularly, the present invention is directed to drug delivery systems including a homopolymer ^r ~r7 ~ er o~ m-le~ -nhydr~de or ow r 31kyl ..alei~
anhydride intended for use in treating ocular conditions and in similar physiologic environments. The erodible polymer system simplifies the application and removal of the drug delivery system and ma~ be configured to provide specific erosion profiles allowing drug delivery administration to be scheduled at convenient daily or weekly time intervals.

. BACRGROUND OF T~E INVE~TION
A problem with the administration of many pharmaceutical medicaments and diagnostic compounds has been the need to retain sufficient quantities of these compounds in conta~t with the target tissues and systems for a sufficient period o~ .time to accomplish the therapeuti~ or diagnostic purpose. This problem is particularly ` acute in connection with compounds admini~tered to the eye. In the ocular environment, tear turnover and drainage through the lacrimal system quickly remove a major portion of any compound administered to the eye so that only a small fraction of the original dosage remains in the eye for an extended period of time. As a result, the repeated administration o~ relatively large dosages is required to compensata for this loss and to ensure that an effective concentration of the desired :, :
pharmaceutical :agent remains in contact with the eye.

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WO91~1~9 P~T/US91/02712~

2 ~J 7 ~ 2 Similar problems are also encountered in connection with the nasal mucosa, oral cavity and ~imilar physiologic environments.
An alternative approach to ophthalmic drug retention in the eye has been the use of viscous ointments and ge's designed to slow down the rapid loss of pharmaceutical compounds. These semi-solid drug containing compounds are applied directly to the conjunctiva of the eye and remain in the cul de sac until physically or mechanically removed.
Though reasonably effective at retaining adequat.e drug dosages in contact with the surface of the eye, a major disadvantage associated with ointments and gels is the difficulty -of delivering a controlled- dosage with such - --widely variable systems. To date, it has not been possible to deliver preformed gels from multiple dose containers in a ready and convenient fashion. Moreover, previously known drug containing ointments and gels may form barriers to sight as well as forming aesthetically unpleasant crusting along the edges of the eyelids. This and possible blockage o~ the lacrimal duct may lead to decreased patient acceptability and utilization of such systems.
Another approacb to the solution of these problems has been the utilization o~ drug containing ocular inserts.
Typically, thesa devices are formed of ~icroporous solid polymers incorporating a reservoir of the drug ar di~qnostic agent required. Shaped as a small disc r barrel or strip, these devices are inserted into the cul de sac o~
the eye where they xemain for periods of several days or weeks while the pharmaceutical compounds contained therein continuously dirfuse into the lacrimal ~luids. A
significant disadvantage associated with such solid insert devices is that many patients, especially the elderly, have a difficult time inserting or removing a solid object from the cul de ~ac of the eye. As a result, it is often 3S nec~6sary for medical personnel to positisn such devices as well as to r move them at the end of their useful lif2.
What is more, currently available ocular inserts often fall .
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: . ' ~ :,: - ::-'~'~91/16~69 PCT/US9ltO~712 3 ~ 7~ 3 ou~ o* position from the eye. ~dditionally, these devices may be uncomfortable when placed in the eye.
Another alternative approach to the solution of these problems has been the utilization of drug delivery compounds which are liquid at room temperature, but which form semi-solid compounds when warmed to body temperatures.
Similarly, compositions which trans~orm from liquids ~o semi-solids in response to changes in pH have also been proposed. Though e~fective at their intended purposes, such compounds may suf~er from ~any of the drawbacks associated with oin~ments and gels and still may require r~peated administration throughout the day.
- Alternatively, bioerodible microparticulate suspensions have also been utilized for the delivery of ophthalmic drugs. For example, United States Patent No.
~,001,388 discloses an orthoester homopolymer drug containing microparticulate suspended in a li~uid carrier such as physiological saline, silicone oil, mineral oil and the like. Similarly, United States Patent No. 4,865,846 disclo~es a drug delivery system formed o~ a liquid and ointment carrier containing an ophthalmic drug and a bio,erodible particula~e carrier incorporating additional drugs. ~he bioerodible feature is designed to prevent the buildup of particulate ma~erial in the eye, as well as to provide controlled drug release. 1~owever, in practice, significant loss through the lacrimal drainage system decrea es the effectiveness o~ such delivery systems.
Accordingly, it is a principal ob;ect of the present inv~ntion to provide a sustained release drug delivery vehicle for use in treating or diagnosing ophthalmic conditions as well as for use in physio~ogical environments similar to the ocular milieu.
It is an additional ob~ect of-the present invention to provids an erodible ocular drug delivery vehicle which can be installed in the cul de sac of the eye without need for profes ional medical assistance and which obviates the need .

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WO91/1~69 PCT/US91/0~712 -2 ~ 3 ~or subsequent removal of the vehicle by the patient or medical personnel.
It is a further object of the precent invention to provide an ophthalmic drug delivery vehicle which is self-5 lubricating for patient comfort, yet which exhibits muco-adhesive propsrties for retention on the conjunctival mucosa.
It is a further additional object of the present invention to provide an ophthalmic drug delivery vehicle : 10 that can be conveniently administered in co~trolled dosages at daily or weekly intervals, or more often if desired.

- 8~M~ARY OF T~B INVB~TION -~~
Generally stated, the present invention accomplishes 15 the above-described objectives by providing polymeric drug "
delivery vehicles which exhibit self-adhesive and bio-adhesive properties, yet which slowly erode in a controlled fashion to provide the sustained release of pharmaceutical or diagnostic compounds while eliminating the need for 20 medical assi~tance to install or remove the drug delivery system. What i~ more, the polymeric drug delivery vehicles of the present invention may be configur~d to comfortably remain in contact with t~e surface of a patient's eye for periods of hours, days, or even up to one week or more. :~
More particularly, the polymeric drug delivery vehicles of the present invention utilize an encapsulating membrane or supporting monolithic matrix formed of a homopolymer or copolymer of maleic anhydride or lower alkyl maleic anhydride which is designed to hydrolyze and erode in a controlled manner in order to slowly remove the drug delivery vehicle from the target site through the normal turnover of physiological fluids such as is encountered : with tear turnover and lacrimal dxainage in the eye. As those skilled in the art will appreciate, the erosion of the polymeric drug delivery vehicle also facilitates the release of encapsulated pharmaceutical agents or diagnostic compou~d~ which may be coated by the pol~mer or ' . ' - `' " `

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~1/16869 PCT/US91/0~712 2 ~ 7~ ~ 7 ~
homogeneously incorporated into the polymer matrix.
Moreover, polymer erosion also serves to coat the surface of the drug delivery vehicle with a self-lubricating layer of hydrolyzed polymer. Though it would normally be expected that such self-lubricating action would make placement of the drug delivery vehicle unstable, the unique polymeric drug delivery vehicle of the present invention exhibits mucoadhesive properties which facilitate its retention at the target site throughout the controlled erosion prooess.
In accordance with the teachings of the present invention, the polymeric drus delivery vehicles of the present invention--can be formed into a variety of three-dimensional structures and configuirations ranging from microparticulates to microcapsules to ocular inserts. In this manner, the available surface area and hence th~ rate o~ ~rosion can be controlled to produce drug delivery vehicles which will remain on site for speci~ic periods of time. Preferably, the microparticulate or microcapsule con~iguration will be sized to provide a 12 to 24 hour erosion pro~ile for convenient, once a day administration, though shorter profiles are also contemplated as being within the scope of the present inv~ntion. For longer treatment periods, the drug delivery vehicl~s of the present invention can be formed as macroscopic inserts which will remain in place for periods on the order of one week. ~iowever, in direct Gontrast to the prior art gels and insert devices which may reguire skilled medical personnel to remove the devices, the drug delivery vehicles of the pres~nt invention will slowly erode over the intend~d time period to the point where the drug delivery vehicle has been completely removed from the target site at the end of its anticipated useful life.
: It is contemplated as being within the scope of the present invention to suspend the microparticulate or microcapsu}e form o~ the polymeric drug delivery vehicles in an aqueous or non-aqueous solution for drop installation : , -- ~ , ~ : . : . . , - " , . :; ,, .

W091/16869 PCT/US91/0~712_ 2~7~7~

where desired. As those skilled in the art will appreciate, agueous suspensions w.ill require formulation immediately prior to administration whereas non-aqueous solutions can be formulated and stored over considerably longer periods of time prior to administration.
Additionally, it should also be noted that the adhesive . properties of the homopolymer or copolymer of maleic anhydride or lower alkyl maleic anhydride cause the microparticulate or microcapsule form~ of the drug delivery vehicles to self-adhere following hydrolyzation to form a unified agglomeration which remains in place ~ollowing administration.
~ As will be discussed in detail below,-a wide variety o~ therapeutic and diagnostic agents may be utilized with the poly~eric drug delivexy vehicle of the present inventionO These compounds can be incorporated into an homogeneous monolithic matrix to form microparticulates or macroscopic ocular inserts. Alternatively, the pharmaceutical agents can be encapsulated by a layer or membrane of the polymer as desired. Each configuration provides.alternative drug release and erosion profiles which can be modi~ied or ao~bined to produce optimal therapeutic bene~it.
. Further objects and advantages of the polymeric drug delivery ~ehicles of the present invention, as well as a better understanding thereof, will be afforded to those skilled in the art from a consideration of the following detailed explanation of preferred exemplary embodiments thereof. Reference will be made to the appended sheets of drawings which will now be first described briefly.

BRIBF DE8C~IPTION OF T~E DRAWINGS
FIG. l is a graphical i`llustration showing the release of various concentrations of dipivefrin (DPE) over ~ime from poly(me~hylvinylether/maleic anhydride) copolymers cont~ining different amounts of ~ree acid illuætrating the principles of the present invention;

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~'~9~1~69 P~T/US91/0~712 7 2 ~ 7 ~9 ~3 7 r~
FIG. 2 is a graphical illustration showing the : cumulative drug release and polymer erosion of a microparticulate drug delivery vehicle formed in accordance with the teachings of the prPsent invention;
FIG. 3 is a graphical illustration showing the concentration of rhodamine released from an ocular drug delivery vehicle produced in accordance with the teachings of the present invention:
FIG. 4 is a graphical illustration showing the concentration of sodium fluorescein released from a microparticulat~ drug dalivery vehicle formed in accordance with the teachings of the present invention; and - FIG. 5 is a graphical--illu~tration showing the change in intraocular pressure ~IOP) as a result o~ dipivefrin (DPE~ administration in accordance with the teachings o~
the present invention.

DET~I~3D lD1~8CR:S P3!ION OF PREFE~R~ED BNBODIM~N~8 In a broad aspect, the drug delivery vehicles o~ the present invention comprise a homopolymer or copolymer of maleic anhydride or lower alkyl maleic anhydride incorporating a therapeutic or diagnostic pharmaceutical compound. Because o~ the unique controlled hydrolysis and erosion properties exhibited by these compounds, the drug delivery vehicles formed in accordance with the teachings of the present invention are particularly well suited for use in oonnection with the diagnosis or treatment o~
injuries or diseases of the eye. However, tho~e skilled in the art will appr~ciate that the drug delivery vehicles of the present i~vention are also well suited ~or use in biological sy3tems axhibiting physiologic fluid turnover a~alogous to that of the lacrimal secretions common to the surface of the eye. Ac~ordingly, for purposes of explanation and without limiting the scope of the present invention, the following exemplary 2mbodiments will be discussed in the context o~ ocular drug delivery systems intended for use in delivering ophthal~ic compounds.

- . . . - .. , . . ... - . : .. , . .. -WO91/l~g PCT/VS91/0~71~-2 ~ 7 ~
However, these teachings are readily applicable to alternative physiologic systems.
More particularly, an exemplary ocular drug delivery vehicle produced in accordance with the teachings of the present invention can be formed from a homopolymer of maleic anhydride or lower alkyl maleic anhydride or a copolymer of maleic anhydride or l~wer al~yl maleic anhydrlde and another comonomer incorporating from approximately 1% by weight to 60~ by weight therapeutic or diagnostic pharmaceutical compound. The pharmaceutical compound of choice can be incorporated within the polymer to form a monvlithic matrix or, alternatively~ can be encapsulated-by--the pslymer to ~orm a microcapsule-.~ Each alternative configuration has its own attendant advantages and features.
For example, the monolithic matrix form of the copolymer drug delivery vehicle can be produced as a plurality of microparticulates preferably sized on the order of approximately 2 ~m to 200 ~m. This configuration providcs ~he highest degree of surface area and there~ore the associated factors o~ drug delivery rate and erosion rate ~re highest. Alternatively, the monolithic matrix drug delivery vehicle can be ~or~ed as an insert sized on the order of 500 ~m to 5,000 ~m. At this macroscopic size, the surfa~e area to volume ratio of the monolithic matrix is significa~tly reduced and, as a result, the drug release profile and erosion profile is also concomitantly reduced.
As an additional alternative, the drug delivery vehicle c~n be formulated in the microcapsule configuration wh~rein each microcapsule is preferably sized to be on the order of 2 ~m to 200 ~m. While the sur~ace area to volume ratio in this latter configuration is analogous to that produced with the microparticulate monolithic matrix form of the drug delivery vehicle, the drug loading can be considerably higher. Thus, it is contemplated as being within the scope of the present invention to form microparticulates and solid inserts from a monolithic .

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~91/16869 PCT/US91/027~2 matrix of a homopolymer of maleic anhydride or lower alkyl maleic anhydride or a copolymer of maleic anhydride or lower alkyl maleic anhydride and another comonomer incorporating from approximately 2% to 20% by weight pharmaceutical compound~ Alternatively, it is also contemplated as being within the scope of the present invention to produce microcapsules of such homopolymers or copolymers incorporating from approximately 5~ to 60% by weight phar~aceutical compound. Each of the foregoing alternative em~odiments of the drug delivery vehicle of the present invention exhibits a unique controlled hydrolysis and resultant co~trolled erosion profile that is - - particularly well suited to utilization --in -the ocular milieu and other analogous physioloqical systems.
Pra~erably, the comonomers and/or the lower alkyl maleic anhydride comprising the polymeric drug delivery systems of the present invention are selected to provide a polymer exhibiting a decreased hydrophilicity relative to maleic anhydride homopolymer. Thus, in accordance with the teachings of the present invention the drug delivery vehicle will pre~erably include a lower alkyl maleic anhydride or a comonomer suitable,for decreasing the hydrophilicity of the resulting polymer as compared to that of maleic anhydride homopolymer. More par~icularly, the mal~ic anhydride or the lower alkyl ~maleic anhydride containing homopoIymers and copolymers of the present invention ercde through hydrolysis to carboxylic radicals (~or example, car.boxylic acid and carboxylate radicals).
In maleic anhyAride homopolymer, the ratio of carbon atoms to carboxylic radicals is 2. Copolymerization of maleic anhydride with comonomers to increase the ratio of carbon atoms to carboxylic radicals from 2 to a preferable range of from about 3 to about 7 and, most preferably to about 3.5, functions to decrease the hydrophilicity of the copolymer and, as a result, retards the rate of hydrolysis and the associated rel~ase rate of the incorporated pharmaceutical compound. Similarly, replacing all or a . .
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2 ~ 7 ~ o portion of the maleic anhydride with a lower alkyl maleic anhydride will increase the ratio of carbon atoms to carboxylic radicals and thus retard the rate of hydrolysis.
As those skilled in the art will appreciate, to achieve the desired decrease in hydrophilicity the comonomer constituent should be substantially free of hydrophilic groups. Accordingly, hydrocarbon comonomers and hydrocarbon comonomers substituted with non-hydrophilic substituents are preferred. Exemplary non-hydrophilic substituents which ~ay be substituted on the comonomers of o o the present invention include: -X, -O-R, -O-C-R, -C-OR, wherein X is a-halogen radical (for example, a fluorine or-chlorine radical) and R is an alkyl radical, (~or example, a c1,2 ~nd preferably, a C~-a alkyl radi~al).
Thus, the following exemplary comonomers may be copolymerized with maleic anhydride to produce maleic anhydride copolymers within the scope and teachings of the present invention~ lower alkyl vinylethers including methylvinylether, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride, and C18 alkylesters o~ acrylic acid or methacrylic acid, including n-butylacrylate, 2-ethylhexylacrylate, methylmethacrylate, vinyl acetate, vinyl crotonate, vinylidene chloride, etc. Preferably, the como~omer will be a lower alkyl vinylether such as methylvinylether.
In accordance .with the teachings of the present invention the ratio of comonomer to maleic anhydride will vary from 0 to approximately 3 and preferabIy from about l to 2. Most preferably the comonomer to maleic anhydride or lower alkyl ~aleic anhydride ratio is about 1 and the copolymer is poly~methylvinylether/maleic anhydride), a hydrophobic polymer of the following general structure:

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~91/16869 PCT/U~91/02712 11 2 ~

Wherein R1 is OCH3 and R2 and R3 are each hydrogen.
Available from GAF under the trade name Gantrez AN~, poly~methylvinylether/maleic anhydride) can be purchased in . 10 a variety of number-averaged molecular weights reported as ranging from 20,000 to 100~000O As those skilled in the art will appreciat~, on a weight-averaged basis these same ~op~iym~xs ~r~ reported as havi~g molecular weights ran~ing from 250,000 to 1,100,000; The copolymer is relatively non-toxic tLD~o a 8 g/kg in white rats) and has a so~tening point near 225-C. ~pon con~ac~ with an aqueous medium, the anhydride ~un tionalities of the copolymer readily hydrolyze to form th~ frae acid. This initial hydrolysis ...
leads to the formation o~ a poly~eric soft hydrogel and, as hydrolysis proceeds, the copolyme~ becomes soluble in the surrounding aqueous ~edium. These propertdes are independen~ of molecular weight and thus any of the readily av~ilable molecular weight copoly~ers are suitable for practicing the present invention.
25It should be noted ~hat it is contemplated as being wi~hin~ the~scopé of the preæent invention t~ formulate : homopolymers cr copolymers of lower alkyl maleic anhydride derivéd fro~ a lower alkyl ~aleic anhydride monomer having the general structure:
' '30 q3 ~C--C ~ ---35 : ~ :~ 0~ 0 . :.
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WO91/168~9 P~T/VS91/02712---2 ~ 7 ~ 12 wherein R2 and R3 are selected from the group consisting of hydrogen and lower alkyl ranging from C~ 4. Preferably, either one of R2 or R3 is hydrogen and the other is lower alkyl. The utilization of these lowex alkyl maleic anhydride c~monomers alone, or the addition of these lower alkyl substituents to a maleic anhydride copolymer serves to ~urther decrease the hydrophilicity of the maleic anhydride comonomer and the associated erosion rate and drug release profile.
The maleic anhydride or lower alkyl maleic anhydride containing homopolymers or copolymers of the present invention discussed above may be synthesized at moderate -- temperatures and pressures-- in -the presence of a ~ree xadical initiator, or are available commercially. For example, synthesis may be accomplished at temperatures ranging from approximately 40C to approximately 80C at pressures ranging ~rom approximately 14 psi to approximately 50 psi in the presence of a free radical initiator such as a peroxide. Such homopolymers or copolymers may have a number-averaged molecular weight between lO,oO0 and 200,000, e.g. between about 50,000 and 100,000.
As will be appreciated by those skilled in the art, once placed in an aqueous environment such as the conjunctival ~c of the eye, the drug delivery vehicles of the pres~nt invention will rapidly form a soft, ~elf-lubricating gel which slowly dissolves in the tear film and safely erodes from the surface o~ the eye into the lacrimal drainage system. During this dissolution process, the incorporated drug is continuously released onto the surface o~ the eye for ef~ective treatment or diagnosis thereof.
Further contributing to the function of the drug delivery system, the bioadhesiveness of the homopolymers or copolymers of maleic anhydride or lower alkyl maleic anhydride of the present invention causes the microparticulates and/or microcapsules to gel together and to adhere to the conjunctlva mucin layer of the eye. This ' :: .. . - . : . . . . . : .

~r~ 9l/16869 PCT/US9l/0~712 13 2~7~
adhesive action ensure~i retention of the drug delivery system in a non-intrusive way in direct contrast to prior art microparticulates such as polystyrene latex beads (14 ~m to 50 ~m) which are retained for less than thirty minutes before being expelled from the eye. For example, the mucoadhesive force of poly(methylvinylether/maleic anhydride) is known to be similar to that o~ polyacrylates such as Carbopol 934~ and sodium alginate. This mucoadhesiveness also functions to secure ocular inserts as well.
As illustrated by the following non-limiting examples, the polymeric drug delivery vehicle of the present - - ~invention can be formulated utilizing a variety of-methods --currently known in the art. For example, a monolithic matrix of poly(methyl~inylether/maleic anhydride) copolymer incorporating a therapeutic or diagnostic pharmaceutical compound can be formulated by simply dissolving the copolymer and ~the pharmaceutical agent in a compatible solvent. Removing the solvent through rotary evaporation or vacuum evaporation will produce a ~ilm or particulate monolithic matrix loaded with the compound. Particulate siize can be adjusted utilizing grinding orl mil}ing techniques as known in the art. Alternati~ely, macroscopically sized monolithic matrix inserts can be cut ~rom the film so produced or ~ormed from the particulates through high pressure molding techni~ues.
Microencapsulation techni9ues are also known in the art.
For example, emulsions can be ~ormed by dissolving the copolymer in an appropriate solvent and adding the pharmaceutical agent of choice which is then coacervated to precipitate the copolymer and encapsulate the pharmaceutical compound therein. Examples of such ~ormation techniques are provided below.

35Example 1 ;
2.7 g o~ Gantrez AN-169 copolymer and 0.3 g of DPE-HCI
(dipi~alyl epinephrine hydrochloride~ were dissolved in lO0 ' .
.

WO9l/~6~69 PCT/US91/0~71~-2~
ml of acetonitrile to form a solution at room temperature in a round bottom flask. Acetonitrile was subsequently removed by evaporation using a rotor-evaporator operated at 40C to leave behind a homogeneous, dry monolithic matrix of DPE~HCl and the copolymer. The solid mixture was then ground into microparticles using a Tekmar mill. The resulting microparticles were dried in a vacuum oven for 24 hours to remove any solvent residue. The average particle size of the microparticles was 65 micron. The drug (DPEHCl) loading in the microparticles was 9.82~ w/w as determined by XPLCo - Example-2 ~
1.9 g of Gantrez AN-169 copolymer and 0.1 g of levo-bunolol hydrochloride were dissolved in 50 ml of dimethylformamide to form a solution at room temperature in a round bottom flask. Dimethyl formamide was subsequently removed by evaporation using a rotor-evaporator opera~ed at 70~C
and under high vacuum to leave behind a homogeneous, dry monolithic matrix of levo-bunolol hydrochloride and the copolymer. The solid mixture was ground into micropaxticles using a Tekmar mill. The resulting microparticles were dried in a vacuum oven for 24 hours to rmove any solvent residue. The average particle size of the microparticles was 46 micron. The drug (levo-bunolol hydrochloride) loading in the microparticles was 5.1~ w/w as deter~ined by HPLC.

E~a~
9.8 g of Gantrez AN-169 copolymer and 0.2 g of 5-bromo-6-~imidazolin-2-ylamino)-quinoxaline were dissolved in 200 ml of acetonè to form a solution at room temperature. A Brinkmann spray dryer was employed to produce small particles from the solution. The particles collected frem the spray dryer were agglomerates which were ground to microparticles usLng a Tekmar mill. The :

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~091/l~K9 PCT/US91/Ot712 15 2$7~7~
resulting microparticles were dried in a vacuum oven for 24 hours to remove any solvent residue. The average particle size of the microparticles was 41 micron. The drug loading in the microparticles was 2.0% w/w as determined by HPLC.
Example 4 1.9 g of Gantrez AN-169 copolymer and 0.1 g of pilocarpine were dissolved in 50 ml of acetonitrile to form a solution at room temperature. The solution was slowly dropped at 50 microliter drop size into mineral oil with stirring. The temperature of the mineral oil was controlled at 50C. Acetonitrile was evaporated in two hours. The microparticles formed in the mineral oil were spherical in shape with an average size of 50 ~m. The-~
micropar~icles were washed by decantation with petroleum ether to give a free-flowing powder, and were dried in a vacuum ovPn.

Example 5 0.005 g of microparticles prepared from the Gantrez AN-169 copolymer containing 5% w/w dipivalyl epinephrine hydrochloride were compression molded into a disk using a Carver laboratory press at room temperature. The disk wa~
0.5 cm in diameter and 0.03 cm thick.

Example 6 0.02 g of microparticles prepared from the Gantrez AN-1~9 copolymer containing 2% w/w sodium fluorescein were compression molded into a disk using a Carver laboratory , press at room temperature. The disk was 0.5 cm in diameter and 0~11 cm thick.

As those skilled in the art will appreciate, the size of the drug delivery vehicl~ produced in accordance with the teachings of the present invention is partially determinative of the erosion rate and the release rate of the pharmaceutical compound contained therein~ Smaller partioles will hydrolyze and erode at a more rapid pace . .

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WO91/1fi869 PCT/US91/~712.~ .
2~ 16 than larger p~rticles due to their relatively higher surface area. Microparticulates and microcapsules sized from approximately 5 ~m to 50 ~m are preferred for drug delivery intervals lasting up to approximately 24 hours.
Microparticulates and microcapsules are most readily administered to the target site by suspending the drug delivery vehicles in a liquid carrier such as an agueous or non-aqueous solution. Those skilled in the art will appreciate that the particle concentration as well as the drug loading can be varied as needed to produce the desired delivery dosage. Exemplary non-aquéous solutions are perfluorhydr~carbons as they elimi~ate the need to prepare - the suspension im~ediately priox to delivery. -However, it is also contemplated as being wi~hin the scope of the present invention to utilize aqueous suspensions which are formulated in individual dosages prior to administration.
Convers~ly, drug delîvery inserts may be formed from the monolithic matrix drug delivery vehicle of the present in~ention for delivery periods of 24 hours or more. Such inserts can be formed through compression molding or cutting from the monolithic matrix films produced in the ~or2going examples. Preferably, the,inserts will be formed as disks, drums or strips which can be readily inserted into the cul de ~ac of the eye and comfortably retained in place for period~ up to one week or ~ore.
It is also contemplated as being within the scope of the present invention to prepare drug delivery vehicles co~prising a mixture o~ particle sizes or mixture~ of microparticles and ~icrocapsules. Such combinations can be designed to provide specific drug release profiles including high initial concentrations or zero order deliveries.
Any pharmaceutical compound which is suitable for therapeutic or diagnostic purposes and is reasonably compatible with homopolymers or copolymers of maleic anhydride or lower alkyl maleic anhydride may be incorporated into the drug delivery vehicle of the present ' . ' , `" ' " - ~' ' ' ;" ~ ~ ' ' '. ' " ' ." ' ` '' " " ' ' ' ~'~91/16869 PCT/US91/0~712 17 2~7~
invention. Exemplary pharmaceutical compounds include antibacterials, antihistaminics, anti-inflammatories, miotics and anticoloneurgics, mydriatics, antiglaucoma compounds, antiparisit~c compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, peptides, proteins, diagnostic agents and immunosuppressive agents. Preferred pharmaceutical compounds for use in ocular situations include dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5-bromo-6-(imidazolin-2 ylamino)-quinoxaline, pilocarpine, dipivefrin, sodium fluorescein, timolol, betaxolol, ofloxocin, and ibuprofen.
These- compounds can be incorporated into the drug - delivery vehicle of the present invention in ranges from approximately 2% by weight to approximately 60% by weight.
Those skilled in the art will appreciate that the upper level concen~ration is determined by the form of the ocular drug delivery vehicle as well as the desired delivery period. For example, a monolithic matrix drug delivery vehicle produced in accordance with the teachings of the present invention will contain from approximately 1% by weight to approximately 10~ by weight of the pharmaceutical compound. Alternatively, microcapsules may contain from approximately 2% by weight to approximately 60% by weight, with approximately 10% by weight being pre~erred.
As will be appreciated by those skilled in the art, the polymeric drug delivery v~hicles of the present invention may be utilized to deliver pharmaceutical compounds to the eye or other similar physiological systems. This me~hod for delivering pharmaceutical compounds comprises the steps of preparing a monolithic matrix or microcapsule suspension and introducing the drug delivery vehicle suspension into the conjunctival sac of the eye. Similarly, it is also contemplated as being within the scope o~ the present invention to form an ocular insert from the monolithic matrix and introducing the insert into the conjunctival sac of the eye.

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WO91/168~9 PCT/US91/02712 -.

2~ The following examples are illustrative of the erosion and drug release profiles of exemplary drug delivery vehicles produced in accordance with the teachings of the present invention. All of the following examples were conducted utilizing Gantrez AN-169~ reportedly having a number-average~ molecular weight of 67,000.
Microparticulates ranging in size from lO to lO0 ~m were prepared using a solvent ~vaporation method in which from 2% to 5% by weight of the pharmaceutical compound of choice were dissolved with the polymer in- acetonitrile. The solvent was subsequently evaporated to leave behind a homogeneous dry film of drug/polymer matrix which was -- - mechanically ground to the desired particle~~size. -The results from a variety of in vitro and in ~ivo experiments and acute toxicity tests are summarized as follows:

Example 7 In v~ro: The di~solution experiment was performed using standard USP methodology with a Hanson dissolution apparatus operated at 37-C and 50 rpm. The dissolution medium was buf~ered at pH 7.4 with 0.05 M of RH2PO4, and s.ink conditions were ensured. The cumulative,drug release and the extent of polymer erosion were monitored by ass~ying the amounts of free drug and ~ree copolymer acid in the aqueous medium using HPLC/ W .
As shown in FIG. l, the release profile of dipive~rin .
(DPE) ~rom the monolithic matrix particles was not much affected when the loading was increased ~rom 2~ to 5%. The release characteri tics ` are sensitive ~o the pH of the di~solution medium, however. Accordingly, an organic acid can be incorporated into the matrix to regulate the local pH within the microparticles to slow down the polymer erosion and the drug release rates when the dissolution medium is maintained at pH 7.4, as under physiological conditions. Additionally, as shown in FIG. ~, the polymer erosion rate, and hence the drug release rate, can be ~urthcr controlled by varying th- amount of ~ree acid . ;- ~. - . . . . . , :, ., : - . .
:: . . :. . .

-~'~91/1~9 PCT/US91tO~71~
19 2~7~
contained in the polymer. Reducing the free acid content decreases the drug release rate.
It was also noted that the microparticles tended to agglomerate together t~ form a translucent gel, which swelled as water penetrated during operation. Thus, the matrix underwent bulk erosion and the drug release rate accelerated ~fter the initial induction period as shown in FIG. 2.

lOExample 8 In ~ivo: The release of drug from the Gantrez monolithic matrix in rabbits' eyes was studied by assaying ---- the drug concentration -in-the tear -film over time. To increase the detection limit, either rhodamine 6G or sodium fluorescein was incorporated in the matrix instead of a drug. A six~hour experiment shows that rhodamine 6G was released slowly initially and began to increase after four hours while sodium fluorescein (which is extremely hydrophilic) was released primarily in the first hour as shown in FIGS. 3 and 4, respectively.
The hydrophobicity of the dye apparently played a significant role. The in vitro release periods of the above two matrices are four hours (rhodamine) and 0.25 hour (fluorescein), respectively. This demonstrates that the drug release rate is far slower in vivo than in vitro.
~ore particularly, depending upon the animal pecies utilized, the dr~g release rate in vivo is slower by a factor of 2-5 than the corresponding drug release xate in vitro. Accordingly, a 24-hour drug release period in vivo 3 0 i8 readily achievable by the present invention.

Exa~le 9 A retention study of the Gantrez monolithic matrix particles was also conducted in rabbits for six hours. It waæ found that the microparticles are well retained in the conjunctival sac even a~ter six hours, regardless of the dose volume (20-50 ~1) and the particle concentration in ' : .
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WO91~16B69 PCT/US91/0~71~_~
r~ 20 the suspension (10-20%). The microparticles swell in the rabbit eye and appeared to stick to the conjunctival sac and to themselves. This is in striking contrast to the polystyrene latex beads (14 and 50 ~m), which were retained for less than 30 minutes before being expelled from the corner of the eye.

Example l0 A pharmacological study was conducted to determine whether the drug delivery system would actually increase the duration of action of a drug preparation. A suspension of microparticulate drug delivery vehicles prepared in ---accoxdance with the teachings of the present invention~
containing 2~ by weight dipivefrin was introduced into the eye of each of three owl monkeys. Net amount of drug administered into each eye was 5 ~g and the dose volume was lO ~l. A control group was dosed with a 0.05~ dipivefrin aqueous solution. Intraocular pressure (IOP) measurements .
were taken each hour at zero through six hours while the subjects were restrained.
As shown in FIG. 5, the IOP lowering effect of the microparticulate suspenslon extended for a longer duration than did that of the aqueous solution.

~xample ll A probe acute toxicity test was conducted for one day on the Gantrez monolithic ~atrix microparticles loaded with 5~ sodium fluorescein. Suspension concentrations of 2.5%
and 10% were studied. Both samples were found to be only slightly discom~orting ~o the eye, non-irritating to the conjunctiva, and not toxic or cytotoxic to the cornea.
.
~ ydrolysis rate experiments of alternative molecular weight copolymers were conducted to determine the common 3S ~unctional performance characteristics of several copolymexs within the scope of the present invention as ~ollow~

' - ' , "~91/16869 - PCT/US91~02712 21 2i~
Examle 12 0.05 g o~ Gantrez ANll9 powder, mw 20,000, (number-averaged as reported by GAF) was dispersed in 103 ml of water, which was controlled at pH 9.5 by titration of 0.lM
NaOH using a Radlometer autotitrator at room temperature.
The particle size o~ the copolymer was 23 ~m as determined by laser light scattering. Complete hydrolysis of the ~Nll9 copolymer was observed after 10 hours. Similar experiments showed that the complete hydrolysis of AN139 (~w ~1,000), AN169 (mw 67,000), and AN179 (mw 80,000) took 6.5 hours, 12 hours, and 9.5 hours, respectively.
~ .
Similarly, microspheres and microparticules were for~ed from alt~rnativ~ oopolymers within the scope of the 15 present invention as illustrated in the following non- -limiting examples.

Example_13 2.0 g of Gantrez ANll9 and 0.05 g of dipivefrin hydrochloride were dissolved in 25 ml o~ aceton~ to form a solution at room temperature. An oil phase containing 0.3 g o~ soybean lecithin and l50ml of light/heavy mineral oil ~50/50) was separately prepared. ~he acetone solution was slowly dropped into the oil phase with stirring. The temperature of the oil phase was maintained at 257C, and the aceton~ was evaporat~d overnight. The resulting micro6pheres in the oil phase were washed with petroleum ether and were dried. The average size of the microspheres was 43 ~m. ~.
Example 14 O.1 g of acid orange dye and 4.9 g of AN179 were dissolved in 200 ml of dimethyl ~ormamide to form a solution at room temperature in a round bottom flask.
Dimethyl for~amide was subsequently removed by rotor-evaporation at 80~C under high vacuum. The resulting solid film was~ground into microparticles with a Tekmar mill and - . . : ' . .: -~ .

- ~ , . , .:
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WO91/~6869 PCT/US91/0~71 7 ~ 22 dry ice. The average particle size was 20 ~m. The dye loading in the matrix was 2.01~ w/w as determined by a W
spectrophotometer.

Hydrolysis rate experiments of exemplary alternative copolymers were conducted as follows.

Example 15 `~
O.05 g of poly(ethylene/maleic anhydride) powder (Polysciences) was added into 80 mL of water, and the polymer immediatel.y agglomerated to form a clear gel. ~he pH of the aqueous system was controlled at 9.5 by titration of 0.1M- NaOH using a Radiometer- autoitrator at room temperature. Complete hydrolysis of the copolymer was observed after 45 minute~. The gel totally disappeared and the aqueous solution was clear at the end of the hydrolysis experiment.

Æx,a,mple 16 0~05 g of poly(butadiene/maléic anhydride~ copolymer was added into 80 mL of water from an acetone solution. A
yellow opaque gel ~ormed instantly in the water. The sample was then subjec~ed to the routine pH-stat hydrolysis experiment at pH 9.5 as described in the previous examp}e.
The ~opolymer was slow to hydrolyze. About 50% of the poly(butadiene/malei anhydride) copolymer was hydro}yzed a~ter 24 hours, and complate hydrolysis of the copolymer took 3 days.

Having thus described prefer~ed exemplary embodiments of the present invention, it shou}A be noted by those skilled in the art that the disclosures herein are exemplary only and that alternatives, adaptations and modifications may be made within the scope o~ the present ' ''' invention. Thus, by way of example and not limitation, it is contemplated~ that alternative forms of the polymer delivery vehicle may be utilized. Such forms may include , .
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91/l~K9 PCT/US91/02712 layered inserts with graded concentrations o~
pharmaceutical compound to produce alternative drug delivery profiles. Additionally, the Gantrez AN-169 copolymer may be substituted by the following copolymers~
and hompolymers (The ratio of monomers is given in parts per hundred):
75 maleic anhydride/25 methylvinylether 25 maleic anhydride/75 methylvinylether 50 maleic anhydride/50 propylvinylether 50 maleiG anhydride/50 n-butylacrylate 50 maleic anhydride/50 vinylacetate 50 maleic anhydride/50 ethylene ~ ~~ ~ -~ 50 ~aleic anhydride/50 styrene -- -- -50 maleic anhydride/25 vinylchloride/25 2-ethylhexylacrylate 50 maleic anhydride/50 methylmaleic anhydride 50 maleic anhydride/50 vinylidene chloride lO0 butyl~aleic anhydride Accordingly, the present invention is not limited to the ~peciflo e~bodimc~ts i~lustrat-d heroin.

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Claims

I CLAIM:

1. An erodible, self-lubricating, bio-adhesive drug delivery vehicle comprising:
poly(methylvinylether/maleic anhydride) copolymer;and from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incnrporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

2. The drug delivery vehicle of claim l wherein said pharmaceutical compound is incorporated within said polymer to form a monolithic matrix.

3. The drug delivery vehicle of claim 2 wherein said monolithic matrix is formed as a plurality of microparticulates, said microparticulates being sized on the order of approximately 2 µm to 200 µm.

4. The drug delivery vehicle of claim 2 wherein said monolithic matrix is formed as an insert sized on the order of approximately 500 µm to 5000 µm.

5. The drug delivery vehicle of claim 3 wherein said microparticulates are suspended in a liquid carrier.

6. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is encapsulated by said copolymer to form a plurality of microcapsules.

7. The drug delivery vehicle of claim 6 wherein each of said microcapsules is sized on the order of approximately 2 µm to 200 µm.

8. The drug delivery vehicle of claim 6 wherein said microcapsules are suspended in a liquid carrier.

9. The drug delivery vehicle of claim l wherein said pharmaceutical compound is selected from the group consisting of antibacterials, antihistaminics, anti-inflammatories, miotics, anticoloneurgics, mydriatics, antiglaucoma compounds, antiparisitic compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, peptides, proteins, diagnostic agents or immunosuppressive agents.

10. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, pilocarpine, dipivefrin, sodium fluorescein, timolol, betaxolol,.
ofloxacin, or ibuprofen.

11. The drug delivery vehicle of claim 2 wherein said pharmaceutical compound is present at a concentration of approximately 1% to 20% by weight.

12. The drug delivery vehicle of claim 6 wherein said pharmaceutical compound is present at a concentration of approximately 2% to 60% by weight.

13. A dropable or injectable self-lubricating, self-adhesive, bio-adhesive, erodible drug delivery vehicle comprising:
a microparticulate suspension of a monolithic matrix of poly(methylvinylether/maleic anhydride) copolymer and an effective amount of a therapeutic or diagnostic pharmaceutical compound, each of said microparticulates being sized on the order of approximately 2 um to 200 um, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

14. The drug delivery vehicle of claim 13 wherein said pharmaceutical compound i5 selected from the group consisting of antibacterials, antihistaminics, anti-inflammatories, miotics, anticoloneurgics, mydriatics, antiglaucoma compounds, antiparisitic compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, peptides, proteins, diagnostic agents or immunosuppressive agents.

15. The drug delivery vehicle of claim 13 wherein said pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5 bromo-6-(imidazolin-2 ylamino)-quinoxaline, pilocarpine, dipivefrin, sodium fluorescein, timolol, betaxolol, ofloxacin, or ibuprofen.

16. An erodible, self-lubricating, self-adhesive, bio-adhesive drug delivery vehicle comprising an insert formed of a monolithic matrix of poly(methylvinylether/maleic anhydride) copolymer and an effective amount of a therapeutic or diagnostic pharmaceutical compound, said insert being sized on the order of approximately 500 um to 5000 um, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

17. The drug delivery vehicle of claim 16 wherein said pharmaceutical compound is seleated from the group consisting of antibacterials, antihistaminics, anti-inflammatories, miotics, anticoloneurgics, mydriatics, antiglaucoma compounds, antiparisitic compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, peptides, proteins, diagnostic agents or immunosuppressive agents.

18. The drug delivery vehicle of claim 16 wherein said pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, pilocarpine, dipivefrin, sodium fluorescein, timolol, betaxolol, ofloxacin, or ibuprofen.

19. A dropable or injectable self-lubricating, self-adhesive, bio-adhesive, erodible drug delivery vehicle comprising a plurality of microcapsules, each of said microcapsules formed of approximately 5% to 60% by weight therapeutic or diagnostic pharmaceutical compound encapsulated by poly(methylvinylether/maleic anhydride) copolymer, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

20. The drug delivery vehicle of claim 19 wherein said pharmaceutical compound is selected from the group consisting of antibacterials, antihistaminics, anti-inflammatories, miotics, anticoloneurgics, mydriatics, antiglaucoma compounds, antiparisitic compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, peptides, proteins, diagnostic agents or immunosuppressive agents.

21. The drug delivery vehicle of claim 19 wherein said pharmaceutical compound is selected from a group consisting of dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, pilocarpine, dipivefrin, sodium fluorescein, timolol, betaxolol, ofloxacin, or ibuprofen.

22. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:
preparing an erodible, self-lubricating, self-adhesive, bio-adhesive monolithic matrix of poly(methylvinylether/maleic anhydride) copolymer and an effective concentration of at least one pharmaceutical compound: and introducing said monolithic matrix into the conjunctival sac of the eye, wherein said copolymer erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

23. The method of claim 22 further comprising the additional step of:
forming a microparticulate suspension of said monolithic matrix prior to introducing said matrix into said conjunctival sac.

24. The method of claim 22 further comprising the additional step of:
forming an ocular insert from said monolithic matrix, prior to introducing said monolithic matrix into said conjunctival sac, said ocular insert being sized on the order of approximately 500 µm to 5000 µm.

25. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:
preparing a dropable or injectable suspension of self-lubricating, erodible, self-adhesive, bio-adhesive microcapsules, each of said microcapsules being formed of from approximately 2% to 60% by weight of said pharmaceutical compound encapsulated in poly(methylvinylether/maleic anhydride) copolymer; and introducing said suspension into the conjunctival sac of the eye, wherein said microcapsules erode by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

26. An erodible, self-lubricating, bio-adhesive drug delivery vehicle comprising:
a lower alkyl maleic anhydride or maleic anhydride copolymer of the formula wherein R1 is C1-4 alkyl, alkylether, alkylester, or halogen;
R2 and R3 are each selected from the group consisting hydrogen, C1-4; and from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incorporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals ranging from about 3 to 7.

27. An erodible, self-lubricating, bio-adhesive drug delivery vehicle comprising:
a maleic anhydride or a lower alkyl maleic anhydride homopolymer or copolymer; and from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incorporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals ranging from 2 to 7.

28. The vehicle of claim 27 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

29. The vehicle of claim 27 comprising a maleic anhydride copolymer.

30. The vehicle of claim 28 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of X, -O-R, and wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

31. The vehicle of claim 30 wherein said comonomer is selected from the goup consisting of C1 to C4 lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters of acrylic acid or methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.

32. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:
preparing an erodible, self lubricating, self-adhesive, bio-adhesive monolithic matrix of a maleic anhydride or a lower alkyl maleic anhydride homopolyer or copolymer and an effective concentration of at least one pharmaceutical compound; and introducing said monolithic matrix into the conjunctival sac of the eye, wherein said matrix erodes by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals from 2 to 7.

33. The vehicle of claim 32 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

34. The vehicle of claim 32 comprising a maleic anhydride copolymer.

35. The vehicle of claim 33 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of -X, -O-R, and wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

36. The vehicle of claim 35 wherein said comonomer is selected from the consisting of C1 to C4 lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters of acrylic acid or methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.

37. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:
preparing a dropable or injectable suspension of self-lubricating, erodible, self-adhesive, bio-adhesive microcapsules, each of said microcapsules being formed of from approximately 2% to 60% by weight of said pharmaceutical compound encapsulated in a maleic anhydride or a lower alkyl maleic anhydride homopolymer or copolymer and introducing said suspension into the conjunctival sac of the eye, wherein said microcapsules erode by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals from 2 to 7.

38. The vehicle of claim 37 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

39. The vehicle of claim 37 comprising a maleic anhydride copolymer.

40. The vehicle of claim 38 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of -X, -O-R, and wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

41. The vehicle of claim 40 wherein said comonomer is selected from the goup consisting of C1 to C4 lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters of acrylic acid or methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.