CA2184814A1 - Block and graft copolymers and methods relating thereto - Google Patents

Block and graft copolymers and methods relating thereto

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Publication number
CA2184814A1
CA2184814A1 CA002184814A CA2184814A CA2184814A1 CA 2184814 A1 CA2184814 A1 CA 2184814A1 CA 002184814 A CA002184814 A CA 002184814A CA 2184814 A CA2184814 A CA 2184814A CA 2184814 A1 CA2184814 A1 CA 2184814A1
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Prior art keywords
copolymer
graft
drug
block copolymer
sensitive
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CA002184814A
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French (fr)
Inventor
Allan S. Hoffman
Guohua Chen
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University of Washington
Alcon Vision LLC
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Individual
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C08F265/02Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of acids, salts or anhydrides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F13/15Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/45Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators characterised by the shape
    • A61F13/49Absorbent articles specially adapted to be worn around the waist, e.g. diapers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/90Block copolymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/91Graft copolymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52Amides or imides
    • C08F220/54Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/56Acrylamide; Methacrylamide
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C08F265/10Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of amides or imides
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F291/00Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02Polyalkylene oxides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54Polymers characterized by specific structures/properties
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Abstract

There is disclosed block and graft copolymers which, in one embodiment, contain both a temperature-sensitive polymer component and a pH-sensitive polymer component, and the use of such copolymers for topical drug delivery to a treatment area. The block and graft copolymers may be physically mixed with one or more drugs to form a copolymer-drug mixture. This mixture may be applied to the treatment as solid particles suspended in a pharmaceutically acceptable carrier, or as a liquid which gels upon contact with the treatment area. Upon contact with the treatment area, the pH-sensitive polymer component hydrates and swells, thereby causing release of the drug from the mixture. In addition, such hydration and swelling causes the pH-sensitive polymer component to adhere to the tissue of the treatment area, thus prolonging contact time. The temperature-sensitive polymer component resists hydration and swelling of the mixture, thereby imparting a sustained and controlled release of the drug to the treatment area. In another embodiment of this invention, bloc and graft copolymers, and hydrogels thereof, are disclosed having broad industrial applicability.

Description

~ wo95/24430 2 1 848 1 4 .~ Q
Descriytion BLOCK AND GRAFT COPOLY~RS
AND ~THODS REL~TING THERETO
.
T~hni~sl Field This invention relates generally to block and graft copolymers, and more specifically, to block and graft l,up~ which are effective in drug delivery, including copolymer-drug mixtures for the delivery and controlled release of a drug by topical 10 ~rplir~tinn Ro~ k~n~ln~l of th.~ InyPntinn The effective and efficient delivery ûf a therapeutic drug to a patient is a goal of plla.,..a~,cuLi,,.ll science. Targeted drug delivery, such as topical application of a 1~ therapeutic drug to a site of action, has many advantages over systemic drug delivery.
Typically, adverse side effects associated with systemic delivery may be greatly reduced when a therapeutic drug is delivered locally to the site of action by tûpical a~ LldLiu~. Therapeutic drugs which are systemically aJ,- i~,; ,L,dLcd are dispersed relatively non-selectively throughout the patient's body and ".. :,.I.ol;.. .~, thus reducing 20 their therapeutic elTel,~ with respect to dosage, as well as increasing the likelihood of adverse reaction. In contrast, an effective dosage of a topically aJ"u..;,L,~.LeJ therapeutic drug is often significantly less than that required through systemic aJ-"i, iaL, d~iOll. The diminution of dosage ~,ù-~ topical aJ.. i..;~L. dliOI~
reduces the possibility of adverse reaction to the drug. In addition, drug metabolism of 25 topically aJI~ ~.cl ed L;,~ . d,U.,U~ > is also minimized, thereby increasing their c~.,L; ~
While advantageous to systemic delivery, topical aJ.~ L~dL;~Il of a therapeutic drug is far from ideal. Perhaps the greatest single drawback to topical drug dJlllil~ ld~iOn is the actual delivery of the therapeutic drug to the tissue to be treatcd.
30 The absorption of the therapeutic drug by the tissue is often a slow process, and therefore requires a relatively long contact time between the tissue and the topical r."."~ ,, containing the therapeutic drug. For example, topical aJ,..;";,L,dLio" of solutions of therapeutic drugs can be rather problematic. The use of viscous solutions, gels, ointments, lotions, patches, and inserts containing therapeutic drugs is a routine 3~ altemative to the all, i";~L-dLion of L~ y~ in solution. These altemative rullllulcLiull~ serYe to enhance the contact time between the therapeutic drug and the tissue to be treated, thereby increasing the effectiveness of the topical treatment.

w0 9~4430 2 1 8 4 8 1 4 Ophthalmic drug delivery presents unique problems. Trdditionally, eyedrops are the preferred mode of topical delivery of therdpeutic drugs to the eye.
Indeed, solutions of therapeutic drugs are routinely dd~ f~ d by this technique.However, it is well I nown that a major loss of drugs a l.. i..~c.~ d to the eye is via the 5 lacrimal drdinage system. This drainage is so effective that only a small fraction of the therapeutic drug remains in contact with the eye for any extended period of time.
.q.,. 1ly, topical delivery of therapeutic drugs to the eye via an eyedrop solution is relatively ineffective and requires repetitive treatments. The usual alternatives to the ~IdllLuuaLlal;v~ of solutions, such as the use of ointments and lotions to prolong tissue 10 contact, are not pdlL;~.uLI.ly suitable for drug al..,i.,;.,~,dlion to the eye. Ointments and lotions are physically difficult to administer to the eye, and drug dosage is therefore difficult to control. The use of solid inserts has also been utilized to deliver therapeutic drugs to the eye. While this technique does assure a slow, effective release of the drug, patients often experience difficulty in placing and removing the insert into the cul-de-sac 15 ofthe eye.
An alternative approach to ophthalmic drug delivery is the use of therapeutic drug ru~ ul~ L;u~s which are liquids at roûm t..ll~J..dLul~ and which are rullll~l into gels upon warming through contact with tissue. These 1~
deliverable to the eye as liquid drops, may be readily dispensed and their dosage 20 controlled. More s;~;rl,~..Lly, once the liquid ~ ulGl;on is transformed into a gel on the surface of the eye, drainage of the therapeutic drug is retarded and its residence time on the eye is prolonged. The gelling of these formulations is dlll;bl~ lC to polymer .",~ which undergo solutiûn-to-gel transitions in respûnse to relatively small changes in environmental conditions (also called "triggers"), such as ~Clll~.,.dLUI~ or pH
25 Polymers which undergo sûlution-to-gel transition upon changes in ltilll,U~,.d~Ulc are often referred to as "thermally gelling polymers" or "I~ .dLu.~-sensitive polymers."
Similarly, poiymers which undergo solution-to-gel transition as a result of a change in pH are generally referred to dS "pH-sensitive polymers."
TemQerature-sensitive polymers which form gels upon warming undergo 30 a solution-to-gel trdnsition at their lower critical solution l~ ,.dLulc ("LCST"), also referred to as the "cloud point." The formation of the gel is believed to result from the gathering of portions of the lc-l~..d~ulc:-sensitive polymers into hydrophobic micro-domains which are maintained in aqueous solution by the hydrophilic portion of the polymer. Such lc...l.~,.d~u.c-sensitive polymers, although water soluble at low 35 I~ ,.d~UII:, generdlly possess some ll~ut~obic chardcter. The polymer's l.~Ilu~llo~
character is imparte~. by the monomer from which the polymer is derived. For eYample, poly(N-;~ uJld~,.ylamide) ("NIPAAm") is well known to change its structure in wO gs/24430 2 1 8 4 8 1 ~

response to ~ dlUI~: in aqueous solutions (see, e.g., Heskins et al., J. Macromol. Sci.
~hçm"~, 1441-45, 1968). At IClll~ d~U C: below the LCST of NIPAAm (i.e., 32C), polymer chains of NIPAA;n hydrate to fomm an expanded structure. while at l.dLUl~ above the LCST the chains fomm a compact structure which excludes 5 water. Thus, gel fommation is due to the association of the relatively llyJlùphub;~, isopropyl groups of the NlPAAm polyma.
Temperature-sensitive polymers have been employed as vehicles for ophthalmic drug delivery. For example, block cu~,oly....,.~ of ethylene oxide and propylene oxide have been disclosed in U.S. Patent No. 4,188,373 for this purpose.
10 However, in this system, the concentration of the polymer must be adjusted to provide the desired solution-to-gel transition Ltl-lU~.dLUlt:. The drawback to this system is that in order to acbieve a solution-to-gel tt~ . d~Ul t~ suitable for gelling at body.d~Ule the polymer must be present at a relatively low CI) I.C.l~ld~iull Thus, the ability to obtain a gel with the desired properties is limited by the desired physiologically 15 useful Le~ dlule range. The necessity for a low polymer concentration, in tum, limits the amount of drug that may be avllu~ Lel ~d by such a polymer system.
Polymers which are sensitive to changes in p~, such as polyacrylic acid ("polyAAc"), have also been utilized to fomm gels in ~hL including use as vehicles in ophthalmic c~ For example, U.S. Patent No. 4,888,168 discloses a 20 . ~ containing the hu.~ IJ rl -~ polyAAc, and gel fommation occurs upon thesubsequent addition of an acidic ~omr~n~nt Gel fommation results in this case by an increase in viscosity associated with the yl uLu~ ioll of the carboxylic acid groups at low pH. In water at neutral pH, the carboxy groups of polyAAc are ionized and the polymer is a liquid-in-water solution. Lowering the pH to 4.3-4.5 by the addition of an acid, 25 such as citric acid, results in gel fomlation by decreasing the ll.y~llul~hil;~ y and increasing the llydlu~Jllùbi~ y of the polymer. An ul.~ Iimitation of this system for use as an ophthalmic drug delivery vehicle is that gel formation requires sequential addition of two solutions (i.e., a first polyAAc solution and a second acid solution).
Due to the drawbacks of existing ~ Lul~-sensitive and pH-sensitive 3û polymers to provide suitable vehicles for topical drug delivery, researchers have studied random uu~,oly--.~ containing these ~ for use as a vehicle for topical drug delivery. Such random copolymers, however, have not proved suitable for physiological ~t In particular, random cupolyll~ of ~ . d~UI ~-sensitive and pH-sensitive monomers quickly lose their ~ .,d~ule sensitivity upon increasing the content or ratio 35 of the pH-sensitive monomers. Thus, by employing a ratio of the pH-sensitive component sufficient to impart pH sensitivity to the random copolymer, such a ratio destroys the ~ ,.dlul~ sensitivity sought by ill~ JUld~iOII of the ~ .,ld~ul~-sensitive _ . _ . . ..

w09sr24430 2 1 848 1 4 .~ 8 c, ~ In addition, cross-linking such random copolymers to form a hydrogel does not alleviate the problem. For example, cross-linked hydrogels of a random copolymer of acrylic acid ("AAc") and NIPAAm, when used as a vehicle for drug delivery, releases the drug at a more rapid rate as the AAc content of the random 5 copolymer is increased (Dong and Hoffman, J. Controlled ~ c~ 15:141-152, 1991).
Simila~ly, attempts have been made to employ aqueous solutions containing a mixture c\f Lt~ u. c-sensitive and pH-sensitive polymers for ophthalmic drug delivery. Such mixtures, however, have also been met with only limited success.
For example, U.S. Pa~ent No. 5,252,318 is directed to aqueous mixtures of Lt..lt~ ul c-10 sensitive and pH-sensitive reversibly gelling polymers. At physiological Lt~ ,,d~Ulc and rn buffered saline, such physical mixtures, when used for drug delivery, tend to separate as the tc--l~ u-c-sensitive polymer l~-C~ iL~-Lts and the pH-sensitive polymer dissolves. Thus, such polymer mixtures are largely ineffective due to loss of drug through drainage from the eye.
Despite the advantages associated with the use of gel-forming polymers as vehicles for topical ophthalmic drug delivery, limitations to their utility persist. As mentioned above, these rvll..uldLiol~ are delivered as solutions and are thus susceptible to drainage from the eye before gel formation can be effected. Accordingly, there is a need in the art for a simple, dosage reliable, topically dd...;l.;.~ ;..,. which20 provides for delivery of an ~ ly effective amount of a drug in a controlled release manner which does not suffer rapid drainage from the treatment area. In addition, there is a need in the art for methods relating to the use of such ~
for topical drug delivery. The present invention rulfills these needs, and provides further related advantages.
mm:l~y of the Invention In brief, ~ Y;Iu~ .,..tdlly-sensitive block and graft ~,ul~olyl~cl~ are disclosed. Such copolymers are particularly useful as vehicles for the controlled release of therapeutic drugs. In this t,...l,od;...~,..L, this invention is directed to graft copolymers 30 comprising a backbolle pH-sensitive polymer component with a pendant Lt-ll~ aLul~-sensitive polymer component grafted thereto, or a backbone tc...~ lu. ~:-sensitive polymer component with a pendant pH-sensitive polymer component grafted thereto. In either case, the graft copolymers have a lower solution critical ~tlll,u~,.a~ul~ ("LCST") ranging from 20C to 40C at pl.~,;olo~5i~1 pH.
In a related ~ ll.o,l;,.. ,l, there is disclosed block ~,u~olyll~ comprisinga pH-sensitive polymer component and a ~c.l.~,.dlu-~-sensitive polymer componentjoined thereto. As with the graft copolymers, the block ~O~JIYIII~ of this invention wo ss/24430 2 1 8 4 8 1 4 . ~l/L~, also have 8 LCST ranging from 20C to 40C at ~ D;o~ al pH.
The pH-sensitive polymer component of the block and graft ~ul~uly~ a preferably comprise a carboxylic acid-containing polymer component derived from ~ol~ ,l ,Ldl,L, carboxylic acids (such as acrylic acid and ...~,.1.4~ , acid), and S preferably are either IlUI~ ,Ia or cO~,olylll..a containing on~y a limited quantity of .:..,.,~.. .. The L~ ,.dLu.~;-sensitive polymer component has a LCST ranging from 20C to 40C at ~ D;olog;.,dl pH, and may be a ll~ opol,yll..,l or a random or block copolymer. The pH-sensitive or L~..,l~.,. dLu~ c-sensitive polymer ~ may also belightly cross-linked, resulting in cross-linked block and graft copolymer hydrogels.
In another ,~l.o.i;,., l, the present invention is directed to a physical mr~ture of a block or graft copolymer with a pllal llld~,~uL;~ally acceptable drug to form a copolymer-drug mixture For topical application to a treatment area, the copolymer-drug mixture is applied as a solid particle suspended in a ~llalllla~u~ ll.y acceptable carrier. Alternatively, the copolymer may be dissolved in a l)lla~ / acceptable 15 carrier in ~ with the ~lla~ a~ uL;~.dlly acceptable drug and applied as a liquid copolymer-drug mixture. Upon contact with the treatment area, the copolymer of the copolymer-drug mixture forms a gel Thus, this invention also discloses cnmrn~itin containing particles of the copolymer-drug mixture suspended in a ~ S~
acceptable carrier, as well as cnmrocitinn~ containing the copolymer and drug in20 c~....l. --- ;nl- with a pllal 'S' acceptable carrier. In yet a further embodiment.
there are disclosed methods for topically delivering a drug to a treatment area by aJ",i...aLt,;l,~ such a ~- -I,o~ thereto.
In yet a further ~;Il-buJ;l~ L, a block or graft copolymer may be lightly cross-linked to form a hydrogel. Suitable hydrogels comprise a backbone pH-sensitive 25 polymer component with a pendent tt,.,l,.,.dLu,~-sensitive component grafted thereto, or a backbone L~ ,.dLu~c-sensitive component with a pendent pH-sensitive component grafted thereto. In addition, block copolymer hydrogels are also disclosed comprising a pH-sensitive polymer component joined to a Lt~ ,.,.dLul~sensitive polymer ~nmrnn~nt Such hydrogels may contain one or more pl.all.la.ciuLi.,~ acceptable drugs in, for 30 example, a dissolved or dispersed form.
Still a further aspect of this invention involves block or graft l,u~Jol~ .., a (including hydrogels of the same) for general industrial use, including, for example, use as lubricants, I..~J;aLul;~,la, bulk-formers and/or absorbents. In this context of the present invention, the block and graft ~u~ul.yl~ la may used over a wide pH and 35 t~,..l~J.,.dLul~; range.
Other aspects of the present invention will become evident upon reference to the attached f gures and following detailed description.

woss/24430 2184814 r~l,.,. CIA.~

Brief Descri~tion of the Drawin~s Figure I illustrates the t~ Lu~ sensitive behavior of 0.2 wei~ht percent solutions of four block copolymers of pOly(N-iso~,.u~.rla..~lal....lc) and 5 polyacrylic acid ("~AAm-b-AAc"), with varying ratios ûf poly(N-;av~Jlu~,~la.,l~ll .fidc) ("NlPAAm") and polyacrylic acid ("AAc"), in aqueous phosphate buffered saline solution (pH 7.4).
Figure 2 illustrates the release of a drug (i.e., timolol) from NlPAAm-b-AAc copolymer-drug particles as compared to homopolyAAc-drug particles in 10 phosphate buffered saline (pH 7.4) at 34C.
Figure 3 illustrates the temperature-sensitive behavior of 0.2 weight percent solutiûns of four graft copolymers of NlPAAm-g-AAc with varying ratios of Nn'AArn/AAc in aqueous phosphate buffered saline solution (pH 7 4)~ as well as a50/50 physical mixture of the same.
Figure 4 illustrates the release of timolol from copolymer-drug particles of these graft copol~mers of NlPAAm-g-AAc as compared to random copolymers of N~AAm and AAc ir6 phosphate buffered saline (pH 7.4) at 34C.
Figure 5 illustrates the release of timolol from copolymer-drug particles of graft copolymers NIPAAm-g-AAc as compared to random ~,ulJoly~ ,.a of ~AAm 20 and AAc in phûsphate buffered saline (pH 7.4) at 37C.
Figure 6 illustrates the release of timolol from cast films of copolymer-drug mixtures of various graft copolymers of NlPAAm-g-AAc (oligomer molecular weight 2000 with 51 pendant ~ ' /bd~,6~bu.._, molecular weight 3300 with 31 pendant ~ Il...laflsa(,k~ull~, molecular weight 5800 with 18 graf~ ~,lla;llaA;a~,kLo,~e, polyAAc backbone molecular l~eight 250,000) in phosphate buffered saline (pH 7.4) at 34C.
Figure 7 illustrates the rate of both timolol release and graft copolymer-timolol mixture dissûlution from a cast film (oligomer molecular weight 3300 with 31 pendant ' ~/l,a L~ e, polyAAc backbone molecular weight 250,000) in phosphate buffered saline (pH 7.4) at 34C.
Figure 8 illustrates the release of timolol from cast films of polymer-drug mixtures: random copolymer with 30% NIPAAm; graft copolymer with 30% NlPAAm where NlPAArn has molecular weight of 3,300, a physical mixture of NlPAAm (molecular weight 3,300) and homopolyAAc (molecular weight 250,000) (30:70); andhomopolyAAc with molecular weight 250,000 in phosphate buffered saline (pH 7.4) at 35 34C.
Figure 9 illustrates the tt,..~,.,d~u,~-sensitive behavior of 0.2 weight percent solutions of cooligoNIPAAm-BMA and oligoNlPAAm in distilled water.
2 1 8 4 8 1 4 ~ ~ ;, ?~

Figure 10 illustrates the tt,n~,.,.dLulc-sensitive behavior of 0.2 weight pereent solutions of eooligoNIPAAm-BMA and oligoNIPMm in phosphate buffered saline (pH 7.4).
Figure 11 illustrates the ~c,.l~,.d~ulc-sensitive behavior of 0.2 weight 5 pereent solutions of graft eopolymer (NIP~Am-BMA)-g-Mc, eooligoNlPAAm-BMA
and homopolyAAe in phosphate buffered saline (pH 7.4).
Figure 12 illustrates the release of timolol from copolymer-drug partieles of graft eopolymer (NlPAAm-BM~)-g-Mc in phosphate buffered saline (pH 7.4) at 34C.
Figure 13 illustrates the release of timolol from cast f Ims of copolymer-drug mixtures for various graft copoly".~,~s of (NIPAAm-BMA)-g-Mc for various u~ c of NIPAA-BMA co-oligomer in phosphate buffered saline (pH 7 4) at 34C.
Figure 14 illustrates the synthesis of a It~l~aCll~dli~/e grafl copolymer hydrogel of this invention.
Figure 15 illustrates the degree of grafting for ~cylc~cllldLive graft copolymer hydrogels.
Figure 16 illustrates the swelling ratios for Ic~c~c-lld~ e graft copolymer hydrogels (open circle: 0.5 weight percent cross-linker, 58.97% grafting; filled square:
2.0 weight percent eros -linker, 48.41% grafting; open square: 2.0 weight percent cross-linker, 65.27% graRing).
Figure 17 illustrates the rate of release of timolol from cast films of copolymer-drug mixtures for several graft copolymer hydrogels of (NlPAAm-BMA)-g-AAc in phosphate buffered saline (pH 7.4) at 34C.
Figure 18 illustrates the l~ ,.dlu,c-sensitive behavior of 0.2 weight percent solution of a random copolymer of NIPAAm and AAc (89 mole % NIPAAm) at pH 4.0 and pH 7.4.
Figure 19 illustrates the ~t~ c.dlulc-sensitive behavior of a 0.5 weight percent solution of a commercially available block copolymer of ethylene oxide and propylene oxide ("EO/PO/EO").
Figure 20 illustrates the ~t l~ Lu~c-sensitive behavior of a 2.5 weight percent solution of a graft copolymer of the EO/PO/EO block copolymer of Figure 19 grafted to a hul~u~ulrl~l~,. backbone of AAc (i.e., EO/PO/EO-g-AAc) Figure 21 illustrates the drug release (timolol maleate) from graf cùp~ of EO/PO/EO-g-AAc at varying ratios of EO/PO/EP to AAc (i.e., 10:90, 20:80 and 30:70). For rr~mr~icAn purposes, drug release from a hulllu~oly~ ,l of AAc, woss/24430 2 1 8 4 8 1 4 ~ 8 and a physical mixture of the AAc l~u~ yOI~ and a EO/PO/EO block copolymer, are also illustrated.
Figure 22 illustrates drug release from graft ~,uyol~ of the EO/PO/EO block copolymer L-122 grafted to a l~ yOI~ backbone of AAc at 5 ratios of EO/PO/EO to AAc ranging from 10:90 to 50:50.
Figure 23 illustrates drug release from graft copol~,...,.~ of various EO/PO/EO block copolymers (i.e., L-61, L-92 and L-122) grafted to a l~ y backbone of AAc at a ratio of EO/PO/EO to AAc of 30:70.
10 Detailed nescription of the Invention The present invention is generally directed to environmentally-sensitive block and graft copolymers. Such ~,uyOlylll~ are particularly effective in therapeutic drug delivery and, even more specifically, in the sustained and controlled release of a therapeutic drug. In this ~.. ,I,o.l;,.. ,l the em/il~,.. ~".Lcll~-sensitive block and graf 15 copolymers of this invention may be physically mixed with one or more therapeutic drugs to form a copo~ymer-drug mixture. This mixture may then be administered as a solid particle (hereinafter re~erred to as a "copolymer-drug particle") to a treatment area by topical application. Alternatively, the em/ilun..l~l,L~.lly-sensitive block and graft may be ~ d in the form of a liquid which, upon contact with the treatment area, forms a gel. As used herein, the term "treatment area" means anysurface on or in an animal body suitable for topica~ application, including (but not limited to) the eye, an open wound or burn, and mucosal tissue (such as the respiratory and alimentary tracts and vagina), and which contains a sufficient waterrlon content to hydrate the particle or gel upon contact.
More specifically, the copolymer-drug mixtures of the present invention may be a.l.. . ~L~ d to the treatment area in a ~ o~;~;.,., wherein the copolymer-drug mixture is suspended as solid particles within a pl.~... "y acceptable carrier. The yLI. '~/ acc~ptable carriers of this invention must not cause significant dissolution of, or drug release from, the copolymer-drug particles suspended therein. In 30 one . ,I,o~ , the copolymer-drug particles may be suspended in a volatile carrier, such as a nuOI~ ull propellant. Upon contact with the treatment area, such as the eye, the volatile propellant evaporates, leaving the particles on the surface of the eye.
The particles then hydrate, swell and slowly release the drug from the copolymer-drug particle as it undergoes swelling and dissolution. In another ~IllI,od;ll~, the 35 copolymer-drug particles may be suspended in a non-volatile carrier, such as distilled or sterile water. As described above, upon contact with the treatment area, the particles hydrate, swell, and re~ease drug during particle swelling and dissolution. Alternatively, WO 95/24430 P~,llll...~
2184~14 the copolymer may be dissolved in a ~llal "y acceptable carrier in r~..,.l.' -l;.~.~
with the drug and ad~ Lclcd in the form of a liquid copolymer-drug mixture7 the copolymer component of which forms a gel upon contact with the treatment area. The physical changes which occur upon contact with the treatment area are discussed in 5 greater detail below.
As used in the context of this invention, the term "drug" includes the definition set forth in 21 C.F.R. 201~'g)(1), "Federal Food, Drug and Cosmetic Act Rcuu;lc~ relating to Drugs for Human and Animal Use" (hereby ;~lco.~u-Glcd by reference). Under this definition, a drug means (a) articles recognized in the official 10 United States Pllallllà~ ,;a, official TT-.",. ~ . Pl.~ of the United States,or official National Formulary, or any supplement thereof, and (b) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (c) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (d) articles intended for use as a component of 15 any articles specified in clause (a), (b) or (c) above; but does not include devices or their , parts or accessories. Water is specifically intended to be included in the definition of the term drug as used herein. The term "cosmetic ~ " includes ~OI~,l,f- l;""~ for skin care, hair care, care of nails, and toiletries, perfumes and fragrances. The term 'l~u~.,.ab:~u~ " means a hydrogel which, starting from a dry 20 material, will imbibe about 20 times its ovn weight of aqueous fluid (J. Gross, Absorbent Polymer Technology, L. Brannon-Peppas and R. Harland, ed., Elsevier, New York, New York, 1990, page 9)(;ll~ o~dlcd herein by reference) As mentioned above, in the practice of one embodiment of this invention, block and graft cupOIrl.l~ are used as a vehicle for the delivery of one or more drugs.
25 The graft and block .,~",ol~....,.~ accomplish controlled and sustained drug release from the copolymer-drug mixtures through the physical properties of the component parts of the copolymer. Specifically, the block and grafl CUIJIJI~ of the present invention are comprised oftwo polymer c~,...~,~".~,..i~. a Ic--~ lulc-sensitive polymer component and a pH-sensitive polymer .~ r Upon contact with the treatment area, the pH-30 sensitive polymer component of the graft and block ~,OI)Gl~ or hydrogels eitherhydrate and swell, or collapse, thereby causing release of the drug firom the copolymer-drug mixtures. Hydration and swelling of the pH-sensitive polymer component is due to the uptake of both water and ions from the treatment area. For example, when the pH-sensitive polymer component is a carboxylic acid-containing polymer (such as polyAAc), 35 the carboxylic acid groups ("COOH") are ionized by the uptake of cations (such as Na+
or K+) from the treatment area to yield neutralized carboxylic acid moieties (i.e., COO~
Na+). Ioniza;tion of the carboxylic acid groups is a ~ by the uptake of water WO 95/24430 2 1 8 4 8 1 4 F~ a.,~ 2638 which, in turn, results in the swelling and gelling of the copolymer-drug mixtures. In addition, such hydrr~tion and swelling causw the pH-sensitive poiymer component to adhere to the tissue of the treatment area (i.e., to become i~;v~ ). In contrast to the pH-sensitive polymer ~ r t, the L~ Lu-~sensitive polymer component 5 resists the hydration and sweiiing of the copolymer-drug mixture, thereby resulting in the sustained and controlled release of the drug from the copolymer-drug mixture.
As used herein, a "block copolymer" of the present invention has at least one L~ ,u~,.dLu-~-sensitive polymer component terminally linked to at least one pH-sensitive polymer component (i.e., an end-to-end link). Similarly, a "graft copolymer" of 10 the present invention has a pH-sensitive polymer component as a backbone polymer and at least one l.,.-l~ ul~-sensitive polymer component as a pendant polymer. or a temperature-sensitive polymer component as a backbone polymer and at least one pH-sensitive polymer component as a pendant polymer.
For purpose of clarity, a short review of polymer ~ ". ~ would be 15 helpful in Ull i~.~L~lll~i;ll~ this invention. In general, a polymer is a maulull~ul~uh~ (i.e., a molecular chain) derived from the polymerization of monomer units. The iinks of the molecular chain are the monomer units. For example, polyacrylic acid (polyAAc) is a polymer derived from the monomer acrylic acid (AAc). More specifically, polyAAc is a "llUlllU~Glylll~l~" a polymer consisting of a single repeating unit, namely, AAc. In 20 contrast, the polym~rs of the present invention are "copolymers." A copolymer is a polymer containing two (or more) different monomer units. A copolymer may generally be synthesized in several ways. For example, a copolymer may be prepared by the copGlylll~ iull of ~wo different monomers. Such a process yields a copolymer where the two different monomers, commoniy referred to as "u~ . a~ may be randomiy 25 distributed throughout the polymer chain. These uolJolylll~la are known as "random copolymers." Aitematively, copolymers may be prepared by the covalent coupling or joining of two hulllvpvlyll.~,.a. For example, the covalent coupling of one hulllu,~ulyll.~,.
to the terminus of a second, different hulllopolyll,~,, provides a "block copolymer". A
block copolymer containing l-U~IIU~UIYIII~I A and l~UIIIUIJOIYII~I B may be ' "y30 I~IJlca~ i by the following formula:
(A)x-L-(B)y where (A)x is a I~UIIIVI/UIYIII~I of x monomers of A, (B)y is a llulllvpvlylll~,l consisting of 35 y monomers of B, and L is a suitable covalent bond.
Depending upon the chemical nature of the llul~lu~vlylll~
an additional type of copolymer may also be prepared. For example, as mentioned wo 95/24430 ~ --Il .
above, polyAAc is a l~u~u~ of AAc moieties Cù~ u~ y, the polyAAc polymer chain is substituted with pendant carboxylic acid groups. The covalent coupling of a second, different IIU...J~ ,.II.,. to one or more of these pendant carboxylic acid groups provides a "graft copolymer." Essentially, the second polymer is graf~ed 5 onto the first. Thus, graft copolymers have a "backbone" polymer onto which one or more "pendant" polymers have been covalently attached. The nature of the graft copolymer may vary co~s;d~,~ly depending upon the degree of ~ of the pendant polymers onto the backbone polymer A graft copolymer having backbone hùl~u~ul~....,~ A onto which pendant hu~l~u~ûly~ B is attached may be s-'---- --'l~, 0 It~ li by the following formula:
. . . A A A A A

I

(B)y where " . AAAAA . " is a llo...u~,ùly".~,. of monûmer A, (B)y is a llul~u~oly~ ,. of y 15 monomers of B, and L is a suitable covalent bond The block and graft ~,upoly~ discussed above contain hu~"u~
A and B, which represent the lt...~,.,.dlu.~-sensitive polymer ~ and pH-sensitive polymer uu...l.o.~ of this invention In addition, the block and graft cù~.oly...~ of this invention may also be derived from polymers other than 20 llu~ ol~ . For example, rather than grafting pendant hu~opolyll~l B to backbone llu~opuly..l~,. A, copolymer CD may be grafted to llu~uuùlylll~.~ backbone A to yield a graft copolymer where the pendant polymer is itself a copolymer. In this case, hu~u,uulr~ A cu..~o.al~ to the pH-sensitive polymer component and copolymer CD is either a random copolymer or a block copolymer of, ~ C and D, and 25 COII.,..yul.li~ to the ~ellly~ lul~-sensitive copolymer rn~~p/-n~nt Alternatively, the backbone polymer may be the copolymer CD (which represents the t~,...,!.,.~u,~-sensitive polymer component), with the pendant polymer being the l~u~ulJulylll~. A
(which represents the pH-sensitive polymer component). The same is true for block colfulrl..-~--that is, copolymer CD (which represents the It~ u~-sensitive polymer 30 component) may be used in cu l,;,,,.ll., . with llo~ul~uly.~.,. A (which represents the pH-sensitive polymer component) While the pH-sensitive polymer component has generally been referred to as a hu~u~vl~ in the above discussion, the pH-sensitive wo95/24430 2 ~ 848 1 4 polymer component may itself be a copolymer subject to certain limitations which are discussed in greater detail below.
In the practice of this invention in the context of drug delivery, it is important that the graft and block CUIJO~ ,D undergo solution-to-gel phase transition S at a ~.I~ ,.d~UlC ranging from room ICIIIIJ~,.dlUIC to just above pll~ log;".ll t~ alulr~. The solution-to-gel or ~JlC.,;~ dl;Ull phase transition (referred to herein as the "lower critical solution t~ Ul C" or "LCST") may be detemlined by absorbanceD~ lUDl,UIJy by measuring the optical density of the block and graft copolymers in solution at a specifc wavelength (such as 500 nm) as a function of ~tlll~J.,ldLUlC (Chen et al.l Biom~teri?~ 625-36, 19~0). On wamling to its LCST1 the block and graft copolymers begin to a.ggregate, and the ~ldllD.l.;aD;ul, of light decreases. The cloud point of a copolymer solution is defined as the ~tlllLJ~ I dLUI e at which the solution has reached a certain value of its maximum opacity (such as 50%). (The d~Lc~ UI;UI~ of the LCST
of several le~ tdl;ve block and grûft copolymer solutions of the present invention are provided in Figul-e 1, Example IB, and in Figure 3, Example 2B, respectively.) Altematively, the phûse transition t~ .,.dlUIC may be detemlined by measuring the change in viscosity as a function of tclllSJ~.d~ule Upon wamming to the LCST, the viscosity of a block or graft copolymer solution ~;~,";r,~,~.,lly increases as it undergoes the liquid-to-gel phase transition. This phase transition may be deflned as the ~tlll~ Id~Ule at which the solution reaches a certain fraction of its maximum viscosity (such as 25%). Such viscosity Ill.,aDUI~ are preferred when the opacity of a copolymer solution does not Si~l,;r,.,~ ly change when reaching the liquid-to-gel phase transition ttlll~J~,.dlUlC. Other indicators of the phase transition include measuring the swell or collapse of the block or graft copolymer.
In one e~ll1,o~ ,.ll, the block and graft CU~OIYIII~D of the present invention have LCSTs (at a pH between 4.0 to 8.0) in the range from 20C to 40C, preferably in the range from 26C to 34C, and more preferably in the range from 28C
to 32C. Preferably, the block and graft copolymers have the above LCSTs at a pHwithin the range from 6.0 to 8.0, more preferably from 7.0 to 7.8, and most preferably at a ~llyD;ologk,dl pH of 7.4. In the context of this invention, the LCSTs of the block and graft copolymers are measured at an aqueous solution ~Ol~.lcllildl;Oll generally below 10% by weight. It should also be understood that ~rfr"";,lAl;"" ofthe LCST within the above pH range does not exclude use of the block and graft coyol~ at pll~;Olog;.,al conditions which may present higher or lower pHs. For example, ver,v low pHs (pH 1) 35 are cll"uuelcd in the stomach, and the block and graft cUI,~lr.,.~,.~ ofthis invention are suitable for oral ~ .J ~ thereto.

~ w095/24430 2i84814 In the context of drug deliYery, block and graft copolymers with LCSTs outside of the 20C to 40C range are generally not suitable for use in the practice of this invention. Copolymers with LCSTs below 20C, in addition to being difficult to administer, are extremely resistant to dissolution and therefore are ineffective in drug 5 delivery. Copolymers with LCSTs above 40C will rapidly and completely dissolve at ~Plly ~;olo~;.,dl ~ dlule and pH, and therefore are ineffective in retarding drug delivery as a ,~.~",c~ of short residence period at the treatment area. (This aspect of the invention is discussed in greater detail below with regard to the ~ioa~l..,~h/c properties of the block and graft uo~,oly..,~ of this invention.) As mentioned above, the L~ "d~u~c-sensitive polymer component of the block and graft cùpùlylll~ of this invention may be derived from homopolymers or copolymers. In either case, the temperature-sensitive polymer component has a LCST
in the same range as that of the block and graft copolymers of this invention (i.e., for use as a drug delivery vehicle, in the range from 20C to 40C, preferably in the range from 15 26C to 34C, and more preferably from 28C to 32C within the above-identified pH
ranges). Thus, for drug delivery use, suitable ~ y~ldLul~-sensitive polymers of this invention have LCSTs ranging from 20C to 40C, and confer an LCST of the same range upon their respective block and graft copolymers. In the context of this invention, the LCSTs of the Lc,..~"dLu.~-sensitive polymers are measured at an aqueous solution 20 conc,,~..-dliu-- below 1% by weight, preferably from 0.01% to 0.5% by weight, and more preferably from û. 1% to 0.3% by weight.
Temperature-sensitive polymers of this invention may contain ester ether, amide, alcohol, and acid groups. These polymers may be ~yllLl~ .,d by the p~ d~io~l of vinyl monomers such as acrylamide or N-isu~,.u~,~la~ ld,l ide which25 provide polyacrylamide and poly(N-isol,.u~ y' ' ), .c~ , or esters of acrylic acid or Ill.,Lila.,lylic acid, for example, butyl acrylate or butyl Ill.,.ll~,lylaLe which provide poly(butyl acrylate) or poly(butyl l.~ yl~lc), . ~ ,L;~ . Similarly, pUlr~ .Liull of cyclic ether monomers such as ethylene oxide provide polyethers and p~ Li0l1 of vinyl acetate followed by hydroiysis provides pGI~' '--' Suitable 30 esters include esters of acrylic acid and its various derivatives such as Ill~,lla~,lyl;c acid.
Suitable ethers include ethylene oxide, propylene oxide, and vinyl methyl ether. Suitable alcohols include hydlw~ylJ~u~Jyl acrylate, and vinyl alcohol. Suitable amides include N-substituted a~,.yla.. id.,i., N ~ yl~/~.., ' ' ~, N ~i,.yl~ L~lllidc, N-vinyl ~". p~ , N ~ jlbuLyl '~, and ethyl oxazoline. Thus, block and graft 3~ copolymers of the present invention include Lclll~ dLule-sensitive polymer ~
containing polyesters, polyethers, poly~ l~,ol,ols, and polyamides. Preferably, the Lc~ ."dLu~c-sensitive polymer c....,l.o~ are selected from block copolymer of ....... .. . .. .. . .. . . . .. _ _ . ...... . _ _ _ .

W095~24430 21 848 1 4 r_~Uu ~

pG~ , oxide, pOlyylu~ c oxide, random Cù,uuly :~ of ethylene oxide and propylene oxide, polyvinyl methyl ether, pGl~ v~uAy~u,vyl acrylate, polyvinyl alcohol, poly(N-substituted)4~,.y' '', poly(N-v;..~.,u~.,vlidu..e), and polyethyl oxazoline.
Preferred t~ ,.dLu.e-sensitive polymers include poly(N-substituted d~,lyl4llud~,~) and 5 poly(N-substituted ' ~' ' ). These poly4.,.yld..ud~ may be derived from Gither ~nc~lhcfit~lfrr1 or mono- or di-N-substituted a.,,~l4..uJ.~.~ The N-~ of these a~.ly' '' may be alkyl, Cl-Clû; cycloalkyl, C3-C6; or alkoxyalkyl, C2-C10 The r~ l d.,. ~14..,iJ~,~ may be cy~,lu4llr;~ such as cyclopentyl and cyclohexylamide derivatives or lactams such as ~,4~,-ula~,~4---. In a preferred ~mhQriimr~nf, the 10 ~ti...L,~,.4Lu.c-sensitive polymer component is poly(N-alkyl substituted) acrylamide. (The synthesis and properties of a .cul~ d~ive ~c~ Lulc-sensitive llulllvpOlyll~ poly-N i~v~ylu,uylrl~,lylalll;dc (NIPA~m), is described in detail in Example IAI ) Altematively, the La l~ci4~ulc-sensitive polymers may be naturally occurring polymers fi.e, cellulose and its derivatives) which may be chemically modifed 15 to provide derivatives which possess the ~c~l,U.,.d~ult-sensitive behavior required for the practice ofthe presel~t invention Suitable naturally occurring polymers include cellulose and its derivatives such as methylcellulose, llyJ~u~.ylJluuyyl celluiose, and I'YJ~U~YI~uwl r.,~ ,liUlU:~G.
ln on~ c~ uJ;~ , the temperature-sensitive polymer component is a 20 I~U...UIJUIYII... made by the pvly~ 4L;ùn of one of tbe above monomers Aiternatively, the Lclll~ ul e-SenSitiVe polymer component is a random or block copolymer Suitable te...l,~,.4Lu-c-sensitive copolymers include (but are not limited to) copolymers derived from the poly,.-~ 41iun of hyJlu~y,ulu~u~l acrylate amd acrylamide or l~y~l~u~,~lyl acrylate; l~d~u~ lllyl acrylate and diacetone acrylamide or N-isopropyl 25 acrylamide; N-isoprol~yl acrylamide and I..~.ll.~..,lyla.. ide or ~ '4.,1yl4le; vinyl alcohol and vinyl acetate or vinyl butyrate; and vinyl acetate and vinyl ,uyllu~;dul~e For both hu~upol~ and copolymer tt...~.dlu,c-sensitive polymer c.,."~ their LCST
may be between 20C and 40C, and may confer an LCST to the resulting block and 8raft copolymers within the same range Cl'he synthesis of a Ic~ dLive tCl~ .
30 sensitive copolymer, poly(N-isu~,.u~'~ yl4...;dc) butyl~ ,.lldayl4~e (NlPAAm-BMA), is described in detail in Example 3AI ) In a preferred ~ ùJ;-~ , the ~cl~1~.,.4~ule-sensitive polymer component is a block copolymer of polyethylene oxide and poly,ulu~uyl~ae oxide. Such block copolymers are cù.. ~,., ' "y available from BASF-Wyandotte Corp (Wyandotte, Michigan) under the tradename Pluronics~, and have the 35 general formula HO(CH2CH2O)a(CH2CH(CH3)Oh(CH2CH2O)aH where b is at least 15 and (CH2CH2O)2a is varied from 20-90% by weight (The synthesis and properties of ~ey. ~On".t~live copolymers having various Pluronics~9 grafted to polyAAc are described in detail in Example 6).
As mentioned above, the pH-sensitive polymer component of the graft and block l~OpUly~ o of the present invention drives ~iccrlllltinn, as well as imparting 5 bioadhesive properties and, in some instances, drug binding ~ r~ to the block and graft copolymer. As used herein, the term "b;ud~h_i~;ve" refers to the ability of the copolymer-drug mixture to adhere to the tissue of the treatment area upon hydration and swelling of the mixture. For example, when the treatment area is the eye, adhesion between the copolymer-drug mixture and the surface of the eye is due to the attractive 10 interaction between chemical functional groups of the copolymer and eye's surface. The ionic nature of the pH-sensitive polymer component provides an adhesive interaction with the surface of the eye, thereby prolonging the residence time of the copolymer-drug mixture on the eye's surface.
In one embodiment, the pH-sensitive polymer component is a carboxylic 15 acid-containing polymer, and may be derived from pOly~ ablc carboxylic acids,including acrylic acid, ~ ,LI~ lyl;c~ acid, ethacrylic acid, ~ l.yl4~ 1;c acid, cis~-llyl~,lvlù~fi~, acid, trans- ..~ lwv~v~l;c acid, -buLyl~lu~un;~/ acid, -yli~,llyl~l~lyli~, acid, -b~yL~I,ly';~, acid, -cyclohexylacrylic acid, ~-pll~,llyla~lyl;~, acid, coumaric acid, and umbellic acid. Cd~bu~y~..,.llylcellulose may also be a suitable carboxylic acid-20 containing polymer. In a preferred rll.l.~.l;,....,l, the carboxylic acid-containing polymer is polyAhc.
In another ~;ll.bod;.l\~, the pH-sensitive polymer component is an amine-containing, a phosphate-containing, a sulfate-containing, or a sulfonate-containing polymer romrr~n~nt, or mixtures thereof. ln a preferred ~ ,J ,. .,l, the pH-sensitive 25 polymer component is an amine-containing or a phosphate-containing polymer c -r As described above, the pH-sensitive polymer component imparts 1,;,~= ll~ -; .., to the block and graft uo~uly...~.0 of the present invention. In the case of carboxylic acid-containing polymer r,v...yull~.lL0, on cQntact with a treatment area, such 30 as the eye or other mucosal tissue, the carboxylic acid moieties ionize and become bw~14LG salts, for example, sodium ~4lbuAyl4Lci or potassium ~ u~ e. The ~~ from carboxylic acid to carboxylate salt upon contact with the treatment areas results ir~ hydration of the copolymer-drug mixtures. The biOa(ll~O;ve properties of the mixtures are imparted upon hydration. Prior to hydration, the carboxylic acid 35 form may also be bio4dL,O;~. lonization to the ~,4l~u~.yl4~e salt causes the gel to swell and act "sticky", but it may lose its stickiness as it further hydrates. Similarly, the amine-, phosphate-, sulfate-, and sulfonate-containing polymer ~ u ~ are also capable of , . . . ... . ... .. _ .

wo95/24430 2 1 848 1 4 P~

ionizing upon contact ~vith the treatment area. Specifically, ions present in the treatment area are taken up by these pH-sensitive polymer ~u,. ~ to neutralize the ionizable moieties thereof lonization in tum is ~ c~ by water uptake, which causes the pII ~ ive polymer ct~mr~n~nt, and thus the copolymer-drug mixture, to swell and 5 become L iù~Jh~
In a preferred ~mhotiim~nt, the pH-sensitive polymer component is a hu".uyul~ (e.g., polyAAc). In a further ~..L ' t, the pH-sensitive polymer component may be a copolymer derived from the ~,u~,oly---.,. i dLiC~I~ of t~,vo pH-sensitive monomers (e.g., acryli.c acid and IlI . II Ir IyliU acid), or a pH-sensitive monomer and a lO non-pH-sensitive monomer. In either case, the content of the ...,".l ..., ...,.. (i.e., the non-pH-sensltive monomer or the different pH-sensitive monomer) must not be so great as to eliminate the bioadhesiveness of the pH-sensitive polymer comron.onf In otherwords, the pH-sensitive polymer component should consist essentially of a singlerepeating monomer unit, with other monomer units present to an extent which does not 15 si~l~ir~ ly diminish tlle bhJddl.~ c properties of the pH-sensitive polymer rr~mrl~n~nt Typically, a single pH-sensitive polymer component will comprise in excess of 90% of the same pH-sensitive monomer, preferably in excess of 95~O, and more preferably in excess of 99%.
In addition to imparting bioadhesiveness to the block and graft 20 copolymer, hydration of the pH-sensitive polymer component also causes the block and graft copolymer to swell, which leads to the ultimate dissolution of the copolymer-drug mixtures. Swelling and dissolution in tum lead to drug release. For the block and graf copolymers of the present invention, their rate of swelling and dissolution or erosion rate is controlled by t~Le lesistance of t~ .,.d~U~t:-sensitive polyrner component to the 25 swelling which is being driven by the ionization of the pH-sensitive polymer component.
The pH-sensitive polymer component of the block and graft copolymers of the present invention may also optionally bind the therapeutic drug via ionic.dC~iOns. For example, for therapeutic drugs which are cationic (i.e., positively charged), the anionic nature of the pH-sensitive polymer component (such as a 30 carboxylic acid-contaiLLing polymer component) may ionically bind a cationic drug.
(Such an interaction is described m Example I C for timolol-hydrogen maleate, a cationic therapeutic drug, and anionic polymer component, polyAAc, of block copolymer N~AAc-b-AAc.) The copolymer-dr Lg mixtures of this invention may be prepared by 35 illl Ul~JUld~iOI~ of the drug into the block or graft copolymer by physical entrapment, and/or by interaction ~vith the pH-sensitive polymer component of the block or graft copolymer. This may be ~ .u."~ d by dissolving the block or graft copolymer in a wo 95124430 2 1 8 4 8 1 4 1~ .
solution containing the drug, and then l!lC~ dL;llg the copolymer-drug solution into a non-solvent for the copolymer and drug, thus obtaining the copolymer-drug particles.
(For example, the fomnation of particles of the drug timolol-hydrogen maleate and the copolymer NlPAAm-b-AAc is described in Example IC.) Altematively, the block or 5 graft copolymer may be dissolved in a solution containing the drug, or dissolved in a solution to which the drug is then added, to yield a liquid copolymer-drug mixture.
Such a solution may be further .,ol~cl".L,dLed, or may be dried to yield, for example, a solid film. Suitable solutions include both aqueous and non-aqueous solvents. In one ,o~;.. ,1, the solution may contain at least 10% by weight of a non-aqueous solvent, 10 and in a further ~ ,I,o.~ ~ may contain at least 99C/o by weight of a non-aqueous solvent.
As for the synthesis of the block and graft copolymers, such polymers may generally be synthesized by covalent coupling of a suitably reactive Lc.l.~).,.dLulc-sensitive polymer component to a suitably reactive pH-sensitive polymer ~nmrnnPnt 15 The covalent link between the two polymer cu.ll~Jul.~.lL~ should be resistant to cleavage under conditions c~l~,uullLcled following topical a-llllill;~LldL;o,l. Accordingly, suitable covalent linkages include amide, ester, ether, thioester, thioether, urea, urethane and amine linkages. Such linkages result from the coupling of a suitably reactive dLule-sensitive polymer component with a rù".l.l.. "~,y pH-sensitive polymer 20 ~,u",~, For example, an amide linkage may be prepared either by coupling an amino-temlinated Lcll"J."dLule-SenSitiVe polymer component with a carboxylic acid-modified pH-sensitive polymer ~nmron~nf~ or by the coupling of an amino-terminated pH-sensitive polymer component with a carboxylic acid-temlinated t~ " dLul c-sensitive polymer rn~rnn~n~ Other linkages may be similarly prepared by standard25 techniques. For example"cl,.~ ,..LdLive syntheses of an amino-tem~inated pH-sensitive polymer (polyAAc) and a carboxylic acid-modified Le-ll~,~,.dLu,c-sensitive polymer (NlPAAm) are described in detail in Example IAI and IA~, respectively. The coupling of these species to provide an allu~ d block copolymer is described in Example IA3. A le~Jlc~c~lLdlive synthesis of an amino-terminated Itl~ ,.dLu~c-sensitive polymer 30 component and its covalent coupling to a carboxylic acid-modified pH-sensitive polymer component to yield an ' '~-I;.~e:i graft copolymer is described in Example 2A2.
Altematively, graft copolymers of the present invention may be synthesized by the ,upoly"l".i~alion of a suitable pH-sensitive monomer with a ~elll~,.dLule-sensitive Illa,lulllùl~ulll~,l. A ~c~ ,llLdLive synthesis of such a graft 35 copolymer is described in detail in Example 2AI.
In one clllbudilll~.lL, the copolymers of the present invention are block cu~Jul~ Block Cùln~ may be synthesized by the covalent coupling of the wo 95/24430 2 t 8 4 8 1 4 r~l~o . -~8 terminus of a pH-sensitive polymer component to the terminus of a lCI~ .,.dlUlC-sensitive polymer ~cmrnn-~nt The covalent linkage may be any one of the above-mentioned linkages, and in a preferred, l u l~ , the linkage is an amide linkage. The block copolymer may be prepared by the coupling of two hul~u~Jol~....,.~ (e.g., a pH-5 sensitive hull~u~!ul~ ,, and a Ic~ .,.41ulc-sensitive llùlllu~ol,yll~,.), a l~UIIIU~JOIYIII~ and a copolymer (e.g., a pH-sensitive l~u~u!~ul,1~11cl and a ~c~ ",alulc-sensitive copolymer or a pH-sensitive copolymer and a lcl.l~..d~u.c-sensitive llulllu~ol,~ ,.). or two copolymers (e.g., a p~-sensitive copolymer and a ~t...~,.,.d~U.c-sensitive copolymer). A
It~JlCaCll~dliVe example of a block copolymer derived from the coupling of two 10 hu~opcllylll~,.~ is described in Example 1.
In the contest of drug delivery, suitabie block copolymers of the present invention exhibit an LCST between 20C and 40C, and are derived from Ltl~ .d~U~C-sensitive polymer ~ having an LCST between 20C and 40C The block copolymers of the present invention preferably have an average molecular weight in the 15 range from 5,000 to 100,000 (and may go as high as 500,000), and the ~ClllLJ .d~UlC-sensitive polymer component preferably constitutes at least 10%-20C/o by weight of the block copolymer In another c...I,od;...c..~, the copolymers of the present invention are graft copolymers Graft ~u~ulylllclo are synthesized by the covalent coupling of a suitably 20 reactive polymer, either a pH-sensitive polymer component or a ~t~ ,d~u~c-SenSitiVe polymer cnmrnn~nt, to the pendant group of a backbone polymer, either a ~tlll~l~ .d~UlC-sensitive polymer component or a pH-sensitive polymer component. The covalent linkage may be any one of the above-mentioned linkages, and in a preferred Pmhû~iimP~t the linkage is an amide linkage. The graft copolymer may be prepared by the coupling 25 of two ho.llu~ul~.l..,,:, (e.g., a pH-sensitive l~UlllUI~CIr~ . and a ~t~ .,.dlu~c-sensitive homopolymer), a homopolymer and a copolymer (e.g., a pH-sensitive hul~ùpulylll~,. and a ~ ,d~u~c-sensitive copolymer or a pH-sensitive copolymer and a ~Clll~l..d~UlC-sensitive ho~l~u~c~ ), or two copolymers (e.g., a pH-sensitive copolymer and a .,.d~ulc-sensitive copo~ymer). As discussed above, the ~ "d~ulc-sensitive 30 polymer component o~the graft copolymers of the present invention may be a block or random copolymer, provided that, in the context of drug delivery, the copolymer has an appropriate LCST. Similarly, the pH-sensitive polymer component is preferably a IIOIIIU~JUI~ although block or random copolymers may be used to provide the b;Oauh~ oo of the pH-sensitive polymer-component is not s;~llil;~,allily diminished.
35 In a preferred ~ ,c~ ,l, the graft copolymer has a ~ vc I~UIIIUI~UI~
backbone with pendant It,...~,.,.d~u.c-sensitive polymer ~.c,.,.~ A It~lCo~ dl;Ve synthesis of a graft copolymer derived from the coupling of two hu~lu~Joiylll.,.O is w0 95/24430 2 1 8 4 8 1 4 . ~ .. 5.~ ?~

described in Example 2, and a . c~ ..,4~ive synthesis of a graft copolymer derived from the coupling of a pendant t~ ,. dLul c-sensitive copolymer to a pH-sensitive r 15~ backbone is presented in Example 3. In a preferred cl.,boJ;....,..L, the graft copolymer has a pH-sensitive ho~u~Joly~.,. backbone of polyAAc with pendent 5 t~...l-.,.dlu-c-sensitive Pluronics~!D (i.e., block copol~ of ethylene oxide and propylene oxide) grafted thereto, as disclosed in Example 6.
The graft copolymers of the present invention have either a pH-sensitive polymer backbone with one or more pendant Ltllll.~,.dLu.c-sensitive polymer ', or a ~.,.--I.~,.dLu,~-sensitive polymer backbone with one or more pendant 10 pII-s~ ivc polymer CUl~llJUll~,~lL:~ The degree of ~ of the pendant polymer c~ o~ on the backbone polymer may be controlled by the chemical coupling reaction. For example, by adjusting the ratio of pendant groups to be reacted with the backbone polymer, the properties of the graft copolymer product may be controlled and optimized. Graft copolyl..~ with higher ratios of tt...~ dLu-c-sensitive polymer~')"'1'`~ ` .,1~ Will possess relatively slower dissolution rates. Accordingly, a balance in the pH-sensitive and Lt---~,.,.dlulc-sensitive polymer ~,ulll~ull.,.lL~ may provide an optimum copolymer which exhibits both preferred It --lu~.dLu~c-sensitive behavior with respect to dissolution and drug release, as well as preferred 1,;. IAI ~ 50 as to provide extended residence time upon ddllulli~LIdLiull.
The graft copolymers of the present invention preferably have average molecular weights in the range from lûû,ûûû to 6ûû,ûOû, and more preferably in the range from 250,000 to 500,00û In an alternative .,.llboJ;I~ L, the graf CU~JOIYIII~"~ of this invention may have average molecular weights in the range from 50,000 to l,ûOO,OOO. In addition, the L.,.l.l.~.dLu~c-sensitive polyrner component preferably constitutes at least 5%-l 0% by weight of the graft copolymer.
In a further ClllbOll;lll.,.~i of the present invention, the block and graft ~,upol~..l.,.~ may be lightly cross-linked. These block and graft ~.ul~ulJIll~.~ are referred to as "hydrogds." In one ~ ,I,o~ l, the backbone polymer component is a cross-bnked pH-sensitive polymer component with one or more pendant lc--~l~.,.dLu~c-sensitive polymer u.. l).~ In a preferred ,, I.o.l;,.. l the hydrogel is derived from a cross-linked pH-sensitive polymer backbone. Alternatively, the pH-sensitive polymer of a block copolymer may be lightly cross-linked. Suitable cross-linking agents are well known and include (but not limited to) relatively "short" cross-linkers, such as methylene-bis-acrylamide and ethylene glycol ' ' ~ LC (EGDMA), as well 35 as relative "long" cross-linkers, such as pol~ lt glycol ~ Le (PEGDMA).
The cross-linked hydrogels of the block and graft uuuGI~ effectively prevent rapid dissolution of the copolymer, while at the same time do not preclude Wo ss/24430 2 1 8 4 8 1 4 ~ 8 copolymer gelling. In some .. ,l,~.l:,.. l~, it may be preferred that the crosslink density is sufficiently light that the hydrogels are soluble or erodible. In other ~ Q~ . it may be preferred that the crosslink density is suffciently great that the gel is a permanent "chemical ~el" uith a permanent three .l~ polymeric network, which 5 maintains its structure and is not soluble or erodible. The level of wva~ g in a hydrogel is typically estimated by reporting the ratio of the molarity of crosslinker in solution to the molari~y of monomer. However, since an actual crosslink is only formed when the crosslinker molecule links to two different polymer chains, the number of actual crosslinks may be only a small fraction of the number of crosslinker monomers 10 present in the gel network.. The hydrogels of the present invention are lightly cross-linked, and contain preferably from 0.001%-10% by weight. The level of actual c.~ resulting from these crosslinker molecules is believed to be from 0.0001%
to 2% actual crosslin~s. Suitable cui~ccllLldLiull~ of cross-linker in the polymerization reaction range from 0.05%-1% by weight based on total cross-linking monomer with a 15 preferred range of 0.10%-0.50% by weight. The synthesis of a graft copolymer hydrogel is described in Example 4. As with the block and graft copolymers described above, the hydrogels of this invention are effective vehicles for the delivery of therapeutic drugs. H~drogel copolymer-drug mixtures may be prepared by swelling the hydrogel in a solution containing the drug. Hydrogels include gels where the solvent is 20 water, as well as gels where the solvent is s;~;";~ ,l,Lly non-aqueous. In one cllLul;ll..,..L, the solution may contain at least 10% by weight of a non-aqueous solvent, and in a further .. ,I oll" ..l may contain at least 99% by weight of a non-aqueous solvent. Hydrogels of this invention include any graft or block copolymers containing pH-sensitive and ~ .dLu~c-sensitive ~UIIIIJU~ ' ..1 of the LCST of the 25 resulting hydrogel. In one '.o.l~ of this invention, the hydrogels have an LCST
ranging from 20C to 40C at IJllyi>;Ologic~ll pH.
The copolymer-drug particles of the present invention may be formulated for topical il.l,. - -l".l,.~ll as ~ of solid particles in a ~ .cul;c~lly acceptable carrier, and one skilled in the art could readily prepare suitable rullllu6~;O
30 using known techniques and methods. Such îul,,.ul.lL;o.~ include, but are not limited to, solutions, creams and gels. The copolymer-drug particles may generally be present in these r~.,..,llAI,.~,.c in a range from 0.1% to 20% by weight ofthe total suspension, and preferably from 1% tc 10% by weight of the total suspension. In the practice of this invention the copolymer-drug particles have a particle size on average, less than about 35 50 ,um in diameter. and preferably less than about 30 um in diameter. Particles larger than 50 llm in diamete~ may be reduced to suitable particle size by mechanical milling or grinding.

wo 95/24430 2 1 8 4 8 1 4 . ~

As described above, the copolymer-drug partic~es may be ~uspended in a pl,~."~ acceptable carrier In one c...i~o i;~ L, the 1;'~
acceptable carrier may be a volatile carrier. Volatile carriers serve to transport the solid particles of the copolymer-drug particles to the treatment area and, upon contact with 5 the treatment area, rapidly evaporate, to effectively deposit the particles on the treatment area. Suitable volatile carriers include nuu~u~ b~l propellants (such as L~ ,.u~i;nuu., ' - and ~' ' ' u i;nuo., ' ) and such propellants may generally be present over a range from 5 to 20 times by weight the amount of copolymer-drug particles. The suspension of the copolymer-drug particles in the 10 volatiie carrier may be aJ..U~ Lt~ d to the treatment area by any device suitable for effective delivery of the suspension. Effective delivery of the suspension preferably includes accurate and ~L~udu~ dosing of the copolymer-drug particles, and include metered dose nebulizers and devices which deiiver the suspension as droplets (such as eye droppers).
In another .. ,i,oJ;.. ~"L, the copolymer-drug particles of the present invention may be a i...,. ~L~.~d as a suspension of particles in an aqueous carrier including distilled or sterile water. For ophthalmic a i..li-.;~.-aLiu.., the osmolality of these aqueous .r...~ .... are preferably adjusted to ~ ,;olog;"~,l osmolality for physical comfort. Such aqueous ~ulll~Jua;liolla may have an osmolality of from about 50 20 to about 400 mOsM, preferably from about 100 to 300 mOsM, and more preferablyabout 150 mOsl-q. A suitable osmolality may be achieved by addition of a pl-.1 Io" "y acceptable material such as a sugar or other nonionic compound.
In still a further ~ bùd;~ L, the copolymers of the present invention may be formulated for ~illlil~.,,LldLiù~ in liquid form by dissolving one or more of the 25 copolymers in a l~ y acceptable carrier. In one ~ bu i;~ L, the copolymer is present in these r,, ~ at a suftlciently high ,U~ LlaL;U~ such that the r.., .""~ will gel upon contact with the treatment area. Typically, suitable cc- of the copolymer in these ru...,ulGLiu..a range from 0.1% to 20% by weight of the ~ l;"", and preferably from 0.5% to 10% by weight of the 30 rr, ". ,~ In these ru~ Illuldiulla, the pi,~ uLi~àll~ acceptable drug may be present in a soluble or suspended form, or bound to a carrier. When the ru--,.ul~lLiun gels upon contact with the treatment area, at least a portion of the drug present within the r.."""1 ~ ;5 trappedwithinthegel.
In yet further ...,l,o,l: ,...l~, the copolymer-drug mixtures of this 35 invention may be formulated as a solution, cream, gel, ointment, tablet, capsule or auL".ûaiLuly. To this end, aul~uCl:~;Luly r~ ""l ~ may be particularly suited for rectal ad~lf~ aLlaLiull of the copolymer-drug mixtures, while tablet and capsule forms are WO 95/24430 2 1 8 4 8 1 4 F~,l/u..9! -~ ~

suitable for a i.. i. ia~dliu.l to the alimentary tract, including the stomach Solutions, creams, gels and ointments are, for example, preferred for topicai skin L. ," " The copolymer-drug mixtures may aiso be formulated for nasai or buccal ~ by known techniques. I;~.., .l -~ ;. . - for general systemic delivery are also within the scope 5 of thjs invention, and are readily prepared using known techniques.
Physicai mixtures of the block and graf~ ~,u~uly~ of this invention with one or more polymers, including hu~l~u~uly~ (such as a l~UIIIUIJOI~ I of AAc) and copolymers (such as ~andom or block cu~ulylll.,l~ of EO/PO/EO) are included within the scope of this invention.
As melltioned above, in the context of drug a i.. i.,i~ iu.. the block and graft copolymers of this invention preferably have LCSTs in the ran ,e from 20C to 40C. However, the graft and block copolymers (and hydrogels of the same) are not limited to oniy block and graf~ copolymers which satisfy this requirement. ror example, cosmetic ~ , wound dressings, iu..Lo~l.u~ ic devices, monitoring electrodes, 15 adhesives, suntan lotions, creams, foams, su,~ u~,;Lu.;~, tablets, and delivery gels may incorporate the block and graft copolymers of this invention having LCSTs well outside the above range. ru~Ll~ ult:, nasal, vaginal, oral ocular, rectal, dermal or otic delivery may simiiarly benefit by use thereof, as well as laxatives containing the same. With regard to vaginal delivery, the block or graf~ copolymer (or hydrogel) may be combined 20 with a spermicide, ovacide, ; ulu;,ll, antifungal, pl ( l~l inJ,~ , steriodal or null~lu;~ l fertility agent.
The block and graf~ copolymers (and hydrogels thereof) may also be used to control reactive cllemistry, separation of solution .. ~.. "l,.. ,l~. separation of ionic species or control of f ' ' ' ' work, as well as for controlling viscosity or flow.
25 Such coplymers (and hydrogels) may further be used to form a water or gas ;..,l... ,. Al.lf. barrier between a well casing and surrounding rock formation. In such industriai settings, the block and gMft ~,UIJOlylll~l~ (and hydrogels) of this invention may be used over a wide tClll~J~,lfllUlt; range (-20C to 250C). Similarly, in both industriai and drug-delivery .",~ ' , they may also be used over a wide pH range (pH 0 to 30 16).
The block and graf~ copolymers of this invention, particularly the hydrogels thereof, may also be used as an absorbent agent, and preferably as ~u~.,l~ulb~,llL agents, by exposing the hydrogel to a solvent or solution. Suitable solvents or solutions in this context include (but are not limited to) urine, feces, water, 35 blood, brine, and iOlliC water solutions. Thus, the hydrogels may be used as an absorbing component of a diaper, and preferably with a swelling ratio of not less tha-W095124430 2 1 8 4 8 ~ 4 r~l~u~

15. The block and graft CO~CIlr , and hydrogels thereof, may also be used to providemoisture to, retain moisture at, or provide hydration to, the treatment area.
While the above disclosure is generally directed to block and graf~
copolymers comprising pH-sensitive and temperature-sensitive ~.. , ~1.. l~ it should be 5 recognized that polymer c.~.. ,l,.. ~ which are sensitive to other CllV;lUlUll.. L4i triggers may be employed. Thus, as used in the context of this invention, an ~..vi.~
sensitive polymer is a poiymer that reversibly undergoes a change from primarilyhydrophilic to primarily ~ ' ' in response to a change in an CllVilUlll~li4i condition, such as t~ ,.41ule, pH, solvent or solvent CU11 ~1~14~iull ions or ionic IU 1 UlI- C~ltl4~iUI~ light, or pressure. Materials and gels which exhibit these changes are known in the art. Tanaka, Phvsical Review Letters 40(12):82û-823, 1978; Tanaka et al., Phvsical Review Letters 38(14):771-774, 1978; Tanaka et al, Phvsical Review Letters 5 45:1636, 1980; Tlavsky, ~ ul~ol~ s 15:782, 1982; Hrouz et ai, Europ. Polvmer J .17:361, 1981; Ohmine et al, J. Chem Phvs. 8:6379, 1984; Tanaka et al, Science 218:462, 1982; Ilavsky et al, Polvmer Bull. 7:107, 1982; Geilrke, Res~onsive Gels:
Volume Transitions Il: ed K. Dusek Springer-Verlag, New York, pp. 81-114, 1993; Li et al, Ann. Rev. Mat. Sci. 22:243-277, 1992; Galaev et al, Enzvme Microb. Technol.
15:354 366, 1993 and Tayloret ai, J. Polymer Sci. 13:2551-2570, 1975 (all of which are ihl~,ul~Jul4~ed herein by reference). This change in hydrophilic to lly ilu~llulYIc character may be evidenced by a decrease in L1411~ ;o~ of light (cloud point), change in viscosity or swelling or collapse. As mentioned above, if an en-vilu,u,.~.lL~'!y sensitive polymer undergoes the change in response to a change in t~ ,d~UlC. it is a Ltlll~ 4lUI c-sensitive polymer, and if it undergoes the change in response to a change in pH, it is a pH-sensitive polymer.
Accordulgiy, in another ~,."l,o~i;",~,"L of this invention, block and grafr ~,ul~ul~ are disclosed which contain ~v;lu""~ 411y-sensitive polymer ~,o",l.u,~
which are responsive to different triggers. For example, block and graft culJol,ylll.,.a containing two different pH-sensitive polymer CUIII~UUII~ or two different lt~ ,,41ulc-sensitive polymer .-~ J"~ , may be used. Aiternatively, the block and graft ~,upc~ of this invention may contain, for example, a light-sensitive polymer component in ~ with either a tc~ ,.d~u~c-SenSitiVe or pH-sensitive polymer romronont or in ~u,~ with a different light-sensitive polymer, or in .-~
with a polymer component sensitive to other triggers The following examples are provided for purposes of iilustration, not 35 iimitation.

w095/24430 2 ~ 8481 4 r~ 7~Q

EXA~LES
Example I
El~vi~ S~n~itive Block Covolvmers Comprising Temperature Sensitive and vH-Sensitive llu~uyùlyll~ Components In this example, the synthesis and .,I,~ c.l.~,.,.d~u,=-sensitive behavior, and drug loading and release properties of block ~,uly~lyll..,.~ comprising a ~-sensitive polymer component and a pII s~ ;Livc polymer component is I O described.
A. Svnthesis ar~d CllAid~,~cli,~dliu~l of l~lock Copolv,-ners NlPAAm-b-AAc Block copolymers (NlPAAm-b-AAc) comprising a t~ .,ld~u~c-sensitive polymer component ,~'AAm) and a pH-sensitive polymer component (AAc) were 15 synthesized from oligomers of NlPAAm and AAc. The block ~,ulJol,~ were prepared by covalently coupling an amino-terminated AAc oligomer to the active ester carbonyl-terminated NIPAArn oligomer to yield an amide linked block copolymer (see 3. below). In the present method, an amino group was introduced into one end of the AAc oligomer (see 1. below) and an active ester group (an N-hydroxy ~ ,.,:.lc 20 group) was introduced into one end of the NIPAAm oligomer (see 2. below).
1. Svnthesis of Amino-Terminated OiigoAAc The .~mino-terminated oligoAAc was synthesized by radical pUI,yll..,liLd~;ùll of acrJlic acid (AAc) using A~ b~llylu~;Llile (AIBN) as an initiator 25 and 2-An~ i-u-,liu~;dc (AET-HCI) as a chain transfer reagent. The pUI~.l..,.;~d~;Ull was carried out at 60C using methanol as soivent. After p~ dL;ull. the polymer was collected by ,~IC~ iLd~;--,~ into diethyl ether, redissolving in ~ Ll~ylru~ i" a)M~) mixed with triethylamine to remove the salt,and IC,U~Cl..;~ d~ill,~ into diethyl ether. By changing the ratio of monomer to chain 30 transfer reagent, the amino-terminated oligoAAc could be obtained ~vith different molecular weights. The synthesis of the amino-terminated oiigomers of AAc is ICI.II J s~ y below.

~4~4 H H H H
`c=c' + ~H2CH2CH2SH AIBN ~ NH2CH2CH2S~--C~H
H ~=o HCI HCI H C=O
OH bH
The molecular weights of the oligomers were determined by end-group analysis as disclosed in Hazra et al., Analytical E~ioch~mistry 137: 437-43 (1984). In this method, 2~4~6-L-illiLlub~ rO"'~ acid (TNBS) was reacted with the amino end 10 group, and the absorbance of the product at 420 rlm was measured. A calibration curve was established using three different amines with different numbers of carbons as follows: H2N(CH2)2COOH, H2N(CH2)3COOH, and H2N(CH2)sCOOH Table I
~1111111 IA 1 l ~ ~ the synthetic conditions and results for the polylllc. ;~~ a of AAc~
TAh~ r~ly", j~AI;IIII DfAAG
AAc:AlBN:AET-HCI (mole) Polymn. Yield Time(h) (%wlw) Mwa 100:1:1 3.0 90 15200 100:1:2 3.5 73 6600 100:1:4 4 0 77 3500 100:1:6 4.0 55 2200 100:1:8 4.0 56 1500 100:1:10 4.0 42 1200 ~1'. ofnomerinme~hanol: 3.5molelL,p~ 60C;
aThe mo~ecular weight (MW) of the oligomer wæ detemuned by TNBS .
The molecular weight of the oligomers was controlled by changing the ratio of monomer to chain transfer re~gent, molecular weights ranging from 1200 to 15,200 were obtained. From the data in the table shown above, the chain transfercorstant for this system was calculated to be Cs = 0.62. These oligomers were used for the further synthesis of the block copolymer of NIPAAm-b-AAc.
AMENo~ S~E~

woss/24430 2 1 848 1 4 2. Svnth~sis of ~HS-Activated Oli~oNlPAAm The l~lHS-activated oligoN~AAm was prepared in t vo steps. First, the carboxy-terminated oGgoNlPAAm was prepared by radical pul~ aL;ul- using AIBN
as an irlitiator and 2-~ u~ ul~lu~J;vllG, acid as a chain transfer reagent. The 5 pol~...~,.i~iu.. was carried out at 6ûC using tert-butanol as solvent and the polymer was collected by ~ulc~ aLi..t~ into diethyl ether. Secondly, the carboxyl group at the end of oligoNIPAA:n. was actiYated by N-hydroxy ~ r (NHS) in the presence of an activating reagent, d;~ y~,lùllw~yG,~llJùd;;~ (DCC), in methylene chloride atûC-2ûC for 24 hours. A~er activation, the polymer was recovered by l!lcu;lJ;laL;~
10 into diethyl ether (see, Chen and Hof~`man, Bio.,ù,.;~ Chem. 4: 5û9-14, 1993). The synthesis of the NHiS-activated oligomers of NlPAAm is lcL,~ cd ~ y below.
H H
`H + HSCHlCHlCOoH ~
NH NH
CH ~H

o ~4N--OH O
O > ~ I CH~SCH2CHlC--O--NcH
~3C CH, wo 95/24430 1 ~ 1 / L ~.. b r ~8 3 . Synth~cic of Block Copolymer NIPAAm-b-AAc The block copolymer of N~AAm-b-AAc was synthesized by coupiing the amino-terminai group of the oligoAAc with the NHS-activated carboxyl group of the oligoNlPAAm by reaGtion in DMF at 60C overnight. The synthesis of the block Cuy~ of NlPAAm-b-AAc is ~CylC >c~l~ed ~ lly beiow.
H~C--C~SCH2CH2--C~ + ~
10 O_C H H ¢~Ho IH OH
CH

H H O H H
H~ I--C~SCH2CH2-C--NHCH2CHlS ~¢ ~ H
O=C H H =O
NH OH

The reaction mixture was poured into ethyl acetate to precipitate the 25 block copolymer product and unreacted oligoAAc. The unreacted oligoN~AAm is soluble and remained in solution. The precipitate containing the product block copolymer and umreacted oiigoAAc was then collected by filtration and dissolved in pH
7.4 phosphate buffer. The addition of saturated aqueous ammonium sulfate solution ylCC;y;l.Lt~,;i the block copolymer which was colleGted by filtration and washed with 30 diiute iI~dIU~ OI;G acid to remove residual ammonium sulfate. The block copolymer was dried in a vaGuum oven overnight. Table 2 presents the results of the block copolymer synthesis.

WO 95/24430 1 ~

Ts~hl~ 2 Cv~yl.~;l ;I ,. .~ of Block Co~olvmers NlPAAm-b-AAc Percent of NlPAAm 76% 58% 43% 24%
oligoNlPAAm MW 4800 4800 4800 4800 oligoAAc MW 1500 3500 6600 15200 Total MW 6300 8300 11400 20000 Block copolymers of NlPAAm-b-AAc with four different ~,u~ )Oa;~iulla 5 were synthesized. The L~ "dLu~sensitivity properties of these block copolymers are described below.
B. Temperature-Sensitive Behavior of Block Copolvmers of NlPAAm-b-A.Ac The pllase transition behavior of the block copolymer is a critical 10 property for topical drug delivery. To investigate the phase transition behavior of the copolymers, a a~ ,LIu~,O~ method was used to determine the light l.. ~.. ,.~ ," (or absorbance) of the copolymer solution at 500 nm as a function of time during a constant rate of t~ . ALu. c rise. Below the phase transition tt...~,, d~UI ~: (also known as LCST
or cloud point), lighc IIAII ~I\ is 100%. However, when the phase transition 15 ~e~ ,.d~ul~; is reached, the polymer begins to aggregate and light ~Idllaiaa;.,of the solution decreases, absorbance increases.
As illustrated in Figure 1, all of the block copolymers prepared as described above exhibit a cloud point (LCST) near 32C (2C below eye ~ J,.dLUI~) However, only the highest NlPAAm content block copolymer, 76% by weight, showed a relatively sharp phase transition. The common cloud point for the different block copolymers indicates ~:hat the ~ ,.41u~-sensitivity of the oligoNlPAAm componentchanges very little aRer being end-linked to other hydrophilic polymers.
C. Dru~ T nArli~ and ~ rl~ frr~m Block Copolvmers of NlPAAm-b-A~c 1 Dru~ L~Dading Generally, in this method, the block copolymer NIPAAm-b-AAc and the drug timolol-hydrogen maleate salt (timolol) were dissolved in a solvent (methanol) to yield a solution of the block copolymer and drug. The block copolymer-drug particle was recovered by p.e~ ,;Ldlio.. into a non-solvent (diethyl ether). For example, the 30 block copolymer with 20 wt% of N~PAAm and a total olecular weight of 19,000 2184~14 -(4,000 for oligoNIPAAm and 15,000 for oligoAAc) was used to prepare exemplary block copolymer-drug particles. A solution of 0.6 g Qf the copolymer and 6.0 mg of the drug in 8 mL of methanol was prepared. This solution was ,ult~ JiLdLt~ into 800 ml of ether. The ~ ;L~L~d block copolymer-drug particles were recovered by filtration,S washed three times with ether and dried under vacuum at room Lt-..~ Lu~e. The - recovery was 65% with a drug content of 1.1 wt%. In a control experiment, hUIIIU~ . (polyAAc)-drug particles were prepared in the same procedure as described above, except homopolyAAc having a molecular weight of 250,0ûO was used instead of the block copolymer NlPAAm-b-AAc. In this experiment, the percent recovery was 93% with a drug content of 1%. These materials were ground into small particles (ca. 20-40,u) for the drug release study described below.
2. Dru~ R,~
Solutions of 10 mg of the block copolymer with I . I wt% drug prepared as described above and polyAAc with 1% drug in 15 mL of PBS buffer (pH 7.4) wereprepared. The solutions were well-stirred during the drug release process. The amount of drug release from the polymers was determined by circulating the buffer to anabsorbance D~ ,LI~ trl where the absorbance of the drug solution at 294 nm was measured as a function of time. The drug release results are presented in Figure 2.
Despite the higher molecular weight of homopolyAAc (molecular weight 250,0ûO), the drug release from the block copolymer NlPAAm-b-AAc (molecular weight 19,000) was s;~ ~lLIy slower. Referring to Figure 2 above, 80% drug release from the block copolymer requires 12 minutes, while the same extent of drug release occurs in 5 minutes with homopolyAAc. For CUI~ ;V~ purposes, release data for graft copolymer NIPAAm-g-AAc and random copolymer NIPAAm-AAc is presented in Figure 5. Note that 8û% drug release is achieved in 8 minutes for the graft copolymer NlPAAm-g-AAc (20% by weight NIPAAm) and in 3 minutes for the random copolymer NlPAAm-AAc (30% by weight NIPAAm).
The slower release rate from the block copolymer may be attributed to its 3û t~ lu~sen5itive cnmrnn~nt~ N~?AAm. At 34C, the NIPAAm component aggregates and becomes ~J.I~u~l~ob;~" resulting in a kind of gelation of the block copolymer-drug mixture, leading to a retard2tion in both dissolution rate and drug release rate. In fact, it was found that the block copolymer was not quite soluble but only swollen in PBS buffer (pH 7.4) at 34C.
Figure 2 shows that a reduction in drug release rate is obtained compared to homopolyAAc by using the block copolyrner as a matrix, even for a block copolymer with a total molecular weight of only 19,000 and only 20 wt% of NIPAAm c~ r b~ n~o Sf~ -Wogsl24430 2 1 848 1 4 ~ 638 Exam~le 2 E ~1 Sensitive Graft Co~olYmers Com~ri~ Temperature-Sensitive ~n~l pH-Sensitive lIu,l,uy~ly~ ComFnn~nt~
In this example, the synthesis and .1,~ L~,.. y~,.aLul~:-sensitive behavior, and drug loading and drug release properties of graft cu~.oly,...,. ~ comprising a L-.---y~laLull:-sensitive llo,..u~,oly..._. component and a pH-sensitive homopolymer 10 component is described. Because of the nature of graft l,u~uly~ , two generalClllbOdllll.,ll~ are possible. The graft copolymer may possess a pH-sensitive polymer backbone with one or more pendant Lc..,~,.aLu.e-sensitive polymer ~,u---~,o.._.-l~.
Alternatively, the graft copûlymer may have a L~i."~,~,dlu,~-sensitive polymer backbone with one or more pendant pH-sensitive pûlymer ~ This example is directed 15 to a graft copolymer with a pH-sensitive l~u~u~ulyll.~. backbone with pendant Lc~y~ lu~ ~-sensitive llu~u~oly~ . culllyul~
A. SYnthesis and Cll~la~:l;LaL;ull sf~irafL Copolvmers NIPAAm-~-AAc Graft ~opolymers (~IPAAm-g-AAc) comprising a Lcllll~,.aLu~ci-sensitive 20 llul~lu~ lylll~,. component (NlPAAm) and a pH-sensitive homopolymer component(AAc) were synthesized by two methods. The gra~ copolymers were synthesized by l u~Jclyl~ iLaLiu~ of AAc with a l~ U~U~U~ ,. of NIPAAm and by the ~.,..j ,~,.I;n~ of oligomeric N~AAm to polyAAc.
1. M~ u~u~lolll~,. Cuyùlvlll.,.;~L;vll~Pth~
Copolymerization of acrylic acid and an appropriate IIIG~,IUIIIUIIUIII~I of NlPAAm results in the formation of a comb-like graft copolymer having a polyAAc backbone with pendant oligoN~AAm side chains. The Illa~,lulllul~Ol~.~,. of N~AAmappropriate for COpOly.ll~,liLaLiull ~vith acrylic acid is prepared from an amino-terminated 30 oligoNlPAAm as described below.

wo 95124430 2 1 8 4 ~ 1 4 ~ ~,~.s/ 8 a Synthesis of Amino-Terminated Oli,eoNIPAAm Rnd its Cu~ uu~lJi.l~ v~U...~,~
OligoNIPAAm was synthesized by free radical polyl...,.i~l lh,l. of NIPAAm in methanol solution (2.5 M NIPAAm) using AIBN and AET-HCI as initiator 5 and chain transfer reagent, ~.,~.,~,li~ly The poiymerization was carried out at 60C for 22 hours. The results for two l~l~CllldLiV~ syntheses are presented below in Table 3.
Table3: P~ ",~.;,d~;u..ûfNIPAAm NIPAAm:AIBN:AET-HCI Yield MWa 100:1:12 59 7 3300 100:1:8b 68.5 2200 10 aMolecularweight was estimated by ' h, titration with sodium h~droxide;
bpH of the monomer solution was adjusted to 1.0 pnor to pùl . ..1~,1 iLdliUII.
The III~I-,II.JIIIU.I~JIII.,. of NIPAAm may be prepared by reaction of an amino-terminated oligoNIPAAm with vinyl azlactone. In a ~ c~ d~iVe synthesis, a 15 solution of 5.0 g (2.27 mmol) amino-terminated oligoNIPAAm (MW 2200) and 0.94 g (6.79 m. mol) v;..~ in 120 mL ~c~ldllrdloruldll was stirred at 40C for 16 hours.
The reaction miAture was ~n~;,u;~d~cd into lOOOmL diethyl ether and the resulting precipitate was collected by filtration. The product was isolated in 82% yield. The synthesis of the IllA.,lU.~,..u.,..,. of NIPAAm is presented 5~h, m~fi~lly below.

W095~24430 2 1 8 4 8 ~ 4 ~ u~ ~

H H ~ ~I~ H
`f~C' I N-oligoN~AAm T ~ C~
O ~ NH
~C C/'CH3 c=o NH

~ H2 H--~--H
1~ H--1--C--N--(~

Ma...,...v.~u...~. of l~'lPAAm b. Cu~)vly The graft copolymer N~PAAm-g-AAc was prepared by l,u~vly~ .. i~L;v~l of AAc with the ~ ., .u...o..v...~. of NIPAAm prepared a3 described above. In a It~ Ld~;V~ pUIyl~ dl;ull, the monomer Cul~ .lLIaL;ull was 12% ~ lL/vululll~:i inmethanol with AIBN as initiator. The pvl~ ,;Ldl;vll was carried out at 60C for 15 hours. The copolymer product was collected by l)lt~ d~;UII into methyl ethyl ketone, 30 and was further puri~ied by Iqllo~ ;Ld~iul~ into ~ldll1dlvruldll. The results for two ~y~ ali~ ~ynth~ re; ~se4ted bdow in Table 4 - F ~ l / L ~J5/r~ X
WO 95/24430 2 ~ ~ 4 ~ ~ ~

Table 4: CU~IGIV~ ;OI1 of AAc and h~ ul~ul~ r ~PAAm Feed Copoly~mer WA A r/wNTpA Am Yield W A ArlW~pA Am MA A rlM~TpA Am The synthesis of the gra~ copolyrner NlPAAm-g-AAc by the S ~UPU~ ;UII method is l=~lcacll~=d a. 11~ ;. A11Y below.
H H H H
10 H~ c,H H`C C'H AIBN > r C C ~ r C--bH ~ 60 C

~0 ~0 NH ~
CH2 ~H2 H2 ~ H2 2û H--~--H H--~--H
H--L 11 ~ H--C--C--~--~
L~ I `CH L~ H `CH3 25 M;~IU~O~ o~N~AAm poly ~NIPAAm-g-A.~c) WO 95/24430 2 1 ~1 4 8 1 4 . ~ ~

2. CoqJuFation Method The graft copolymer of N~PAAm-g-AAc was synthesized by reaction of the amino group of the amino-terminated oligoNIPAAm with the carboxyl groups on the polyAAc backbone. In a lc~ d~ive reaction, amide bond formation was 5 achieved by treatmet~t of polyAAc (MW 250,000) and amino-terminated oligoNIPAAm ~hT 3300) with d;~,lol~w~yll,~i " ' in methanol at room Lc...~!.,.dlulc for 24 hours. The product graft copolymer was isolated by IJICI,;~ d~;UII into methyl ethyl ketone, and further purified by lc~,lc.,;~ dLiu,. into Le~l ' ydlUI'Uldll. The results of the are prescnted below in Table 5.
Table 5: Conju ation of NIPAAm to PolvAAc NIPAAm in Feed NIPAAm in Copolymera mole% wt% Yield mole% wt%
0.5 20 83 0 5 19 0.7 25 78 0.7 24 0.9 30 93 0.9 29 2.1 50 91 2.0 49 a~'nTArn~i~inn of NrrAAm was determined by bacA- titration of the polyAAc component.
The synthesis of the graft copolymer NIPAAm-g-AAc by the nnnjll~:ltil-n method is represented ~ below.
H HNHl H H H H
~C--C~ .,. CH2 DCC ~ {~-C C~C--C 1 20H C= CH2 Mcthanol ~ ~ O H C--bH ~ ~ NH bH
H--~--H CH
H--1--C_~T_C~ CH2 ~ H CH3 H--~--H
H~ --N--C' H
N-oligo~lPA.~m Pol~ (~AAm-g-AAc) w095/24430 21 ~4~ ~ 4 r~ Q

B. Temverature-Sensitive ~PI~vjor ofthe Gr~ Co~olYmers The thermal-sensitiYity of the graft "opfJly~ prepared by ~.U~ ;.. and f.~ ;.l exhibit similar ~ y~,~aLul~ sensitivity. The graft CU,UfJI,~ prepared by direct ru~ l;.. " with 20% to 50% NIPAAm (l .. ~l.,-lr S phase separation between 30C and 35C and are most à~ u~Jl as vehicles for drug delivery. The Lt~ ,.d~u~c-sensitive behaYior of the graft ~.uy~lJ~ NIPAAm-g-AAc is presented in Figure 3. The graft copolymer cu.,,l,,,~:l;...,~ begin to phase separate around 32C and their response to ~tllllJ..d~Ult: is rather broad due to the in'duence of the backbone COO~a+ moieties.
C. Dru~ Loading and 1~ PIP~P frf\m the Gr~ CopolYmers 1. Dru,e Loadin~
Graft copolymer drug loading was performed as described generally in Example IC1. Solution of 0.5 g ofthe graft copolymer and 5.0 mg oftimolol maleate in 15 8 ml methanol was IJlti.;l);LdLtli into 8ûû mL of diethyl ether. White, sphere-like particles of the graft copolymer with an average 2-3 mm diameter were obtained. The percent recovery was 92% with I wt% of drug loaded The material was ground into ca.
20-40,u particles for the drug release experiment.
2û 2. DruF ~PIP~P
A suspension of 4û mg graft copolymer NlPAAm-g-AAc/timolol mixture in 40 mL of PBS buffer was prepared. As described above in Example IC2, the amount of drug released from the complex was determined as a function of time by d~ ,. Illillillg the absorbance of the solution. The results of the drug release at 34C and 37C are presented in Figures 4 and 5" ~ .,ly .
As shown in Figure 4, drug release from graft ~.u~f l~ is slower than from particles of random CU~.JI~III.,I~ with similar ~...,..l.f.~.l;" ~ at 34C. Increasing the ~tlll~)..d~UI~: ofthe release medium to 37C (Figure 5) slows down the release rate from the graft CUI uly..~ but not the release rate from the random copolymers. The results 30 indicate that the increased IIY~1IUPIIO~ ;LY of the graft chains contributes to the slower release of drug.
Alternatively, copolymer dissolution and drug release may be determined ' 'y by casting the copolymer-drug mixture on a glass disc. In this method, a copolymer-dru~ mixture is cast onto a glass disc forming a film. The coated glass disc is 35 then suspended in an d~J~J.u~JIicL~ medium such as phosphate buffered saline, pH ~.4, or distilled water. The , .dLul~ of the drug released into the medium may also be controlled to investigate ~tl-l~).,-aLult: effects on dissolution and drug release. The WO 95/24430 2 1 8 4 8 1 4 ~ ~

method facilitates the d~ f~ . of drug relwsed by ~ of the absorbance of the medium o~er tirne as described above, and ' l~, permits the d ~ ,.. of th~ amount of copolymer-drug mixture dissolved by measuring the weight of the film wst onto the hanging glass disc.
The results for drug relwse and dissolution for graft copolymer-timolol mixtures determined by the film cast on glass disc method are presented in Figures 6 and 7. hgure 6 illustrates the effect on drug release of MW of oligoNlPAAm used in the graft copolymers prepared as described above. Figure '7 illustrates the difference in the rates of release and dissolution for a graft copolymer NIPAAm-g-AAc (30% weight NIPAAm).
Figure 8 compares the effect of polymer structure on the rate of relwse of timolol from various polymer-drug cast films The rate of relwse of timolol from homopolyAAc (mo~ecular weight 250,000) is compared to different polymer-drug mrxtures wch containing 30 weight percent NIPAAm (i.e.. random copolymer, graft 15 copolymer, and a physical mixture of homopolyNIPAAm and homopolyAAc). The results rl..~ ,ar that release from the random copolymer is essentially completewithin about 5 mimltes while release from the graft copolymer is the most prolonged, nearly complete release taking about 20 minutes Drug release from the physical mixture of llu.~ul,olyNIAPPa and homopolyAAc was comparable to the rate of release 20 from homopolyAAc, indicating that the physical mixture of temperature-sensitive and pH-sensitive llulllv~ul~ iS no more effective than the use of the pH-sensitive l~o~u~ul~ . alone and si~,l.;r.~",."ly less effective that the uullca~Jù~ld;ll~ graft copolymer.
Exam~le 3 EIIYilU~ 'f ~ Sensitive Graft Cûpûlvmers Cûmprisin~ Temperature-Sensitive Copolvmer and pH-S~n~i~ive Hu~llu~ul~ " Components In this example, the synthesis and ~,ll.L.~ ~r~ "" . dLu-c-sensitive behavior, and drug loading and drug release properties of graft copolymers comprising a Lc~ u-~sensitive copolymer component and a pH-sensitive l~o---u~ul,~,--~,.
component is descri~ed. Two general ~lllbO.l;l~ a are possible. The graft copolymer may possess a pH-sensitive polymer backbone with one or more pendant ttl~-~.J.,.~lulc-sensitive polymer ~....1.l .... l~ Alternatively, the graft copolymer may have a35 It~ u~t:-sensitive polymer backbone with one or more pendant pH-sensitive polymer UUIII~J ' This example is directed to a graft copolymer with a pH-sensitive ho.l,u~.vlr.,l~,. backbone with pendant L~ ,."dLu~t;-sensitive copolymer ~u"~

wo 95i24430 2 1 8 4 ~ 1 4 ~ 1 v~v 7~Q

A. Svllthpcic and CL~ ;u~l of Grafi Cs~olvmers ND~AAm-BMA-~-AAc Graft ,u~ (N~AAm-BMA-g-AAc) comprising a Ltllly~,.d~le-sensitive copoiymer component (NlPAAm-BMA) and a pII ~ ;Live l~u~ vpol~..l., 5 component (AAc) were synthesized from oligomers of NIPAAm-BMA and AAc. The graft cu~ were synthesized by covalently coupling an amino-terminated NlPAAm-BMA oligomer (see 1. below) to one or more carboxyl groups on the polyAAc backbone (see 3. below).
Iû 1. Synthesis of Amino-Terminated Co-oligo(NIPAAm-BMA) Cop~ dLiu" of NlPAAm with a more ily ilu~ JiJi~, monomer produces a copolymer with a lower LCST (cloud point) than the l~UIIIU
polyN~AAm. A co-oligomer with a lower LCST was synthesized by c~vpOl,yll~ dlivllof N~AAm with a more hydrophobic l ~ Lyl~ lld~lylate (BMA) in the 15 presence of chain transfer reagent, 2 : "~. :l,- .. :l.i,-l hydrochioride (AET-HCI) to obtain an amino-terminated co-oligomer NIPAAm-BMA. The co-oligomer was then grafted onto polyAAc.
In a l~,ult~;llLdlive synthesis, 3 mole% of BMA and 97 mole% of N~PAAm were charged with the molar ratio of monomer to initiator (AIBN) to chain2û transfer reagent (AET-HCI) of lûû:l:S, 40mL of DMF was used as solvent and the pOl~ dL;ull was performed at 6ûC for I hour. The co-oligomer thus formed was recovered by ~ dL;ll,~; into ether. The yield was 45/O and the number average molecular weight of the co-oligomer deterrnined by vapor pressure osmometry (VPO) was 3100. The BMA composition in the co-oligomer was determined to be 4 mole% by25 IH-NMR. The synthesis of co-oligomer NlPAAm-BMA is l~ ed 5~.1....IAI;~ . ~!y below.

wos~/24430 2 1 848 1 4 ~ 8 `C C' + C=CI . + HCI H2NCH2CH2SH
bCH2CH2CH2CH3 NH
CH

A~3N
IN DMF
i KOH

H2NCHlCH2S~C C~ I C J H
NH bCH2CH2CH2CH3 H3C' CH3 2. D~L~ liv~ of LCST ofthe Co-olivomerNlpAAm-BMA
The LCST of the co-oligomer was ~ ,LI ~ .y measured at 500 nm using a 0.2% polymer solution in either pure water or PBS buffer, pH 7.4, as described above in Example IB. The results are presented in Figures 9 and 10"t~ ,.,Li~
Referring to Figures 9 ~nd 10, the co-oligomer shows a phase transition in pure water at 30C, ca. 4C lower than the oligoNIPAAm, and yet retains the same sharp response. In PBS buffer, the co-oligomer shows an even lower phase transition at 24C, ca. 5C lower than oligoNlPAAm. The lower phase transition for the co-oligomer in PBS as compared to water is believed to be due to a salt effect. Theintroduction of B~ , . units into the oligoNlPAAm provides a co-oligomer N~AAm-BMA with a lower LCST (cloud point) than oligoNlPAAm. The 4C-5C
dlfference in the LCST of the co-oligomer NIPAAm-BMA compared oligomer NlPAAm provides for increased versatility in the ~ .,.C~ ;-sensitive polymer component of the graft copolymer of the present invention.

-w095/24430 2 1 84 8 1 4 P ~ 638 3. Svnthesis of Graft Coyolymer of Co-oli~to N~AAm-BMA-~-AAc The graft copolymer of co-oligo[ND'AAm-BMA]-g-AAc was synthesized by reaction of the amino group of the amino-terminated co-oligomer 5 N~AAm-BMA with the carboAyl group(s) on the polyAAc backbone. Amide bond formation was achieved in the presence of dicyclul..,Ayl~,a.bou~ e (DCC) at roomILII.~J~"aLUI~; for 24 hours. The weight ratio of polyAAc to co-oligomer used for the reaction was 1, i.e., 50/50 (wt/wt) varied from 50l50 to 95/5 (wt/wt). The graftcopolymer was recovered in 75%-90% yield by ~,lc.,;LJ;Ld~iu,l into L~:~l.dlydlulù
10 (1~), Table 6~ CovslYmer Synthesis Results Co-sligomer in Co-oligomerin ~.u~uly.ll.,.a Sample No. feed in wt% Yield wt%
9 1 45.5 220 80 19.0 330 77 28.0 410 74 8.9 5 5 82 4.5 aC . of co-oligomer in the graf copol~mer ~vaS detemlined by back titration of the 15 polyAAc component.
The synthesis of graft copolymers (NlPAAm-BMA)-g-AAc is t:,~llL~I ~.1.. ~1;. ,1~ below.

woss/24430 21~4814 -- ~

~C C~ + HzNCH2CH2S~C C~C C~H
H C=O H l=o H (!:=0 bH NH bCH2CH2CH2CH3 CH

DCC
rn Medlanol H :H H H
15 H C--~H C=O
OH NH

,~
H--f H O
H--C--C ' CH3 L , NH--CH
E `CH
H--I ;'--H
H--C--C~

H

B. Te~r~pPraturc-s~nci~iye Behavjor of the Graft Copolymers The phase transition behavior of the graft copoiymer NlPAAm-Bi~A-g-AAc was determined as described above in Example lB. The phase transition data for 35 the graft copolymer (NlPAAm-BMA)-g-AAc, the co-oligomer NIPAAm-BMA, and homopolyAAc are pre3ented in Figure ] 1. Referring to Figure 11, the graft copolymer wo ss/24430 2 1 8 4 ~ 1 4 starts its phase transition in PBS at 28C and at 34C the phase transition is almost complete. The L~ IdU~Cd phase transition i , dLUl~; for the above-described graft copolymer is s;~ r~ ly lowered by the ;~lUdU~;UII of IIJdlUIJIIUIJ;I~
units (BMA) into the oligoNlPAAm. At eye lCIIl~,.dLUIC (34C), the graft co-oligomer S chain becomes sufficiently llydlupl~ol)i~, to s;~;ll;rl~,~lllLly reduce the drug release rate.
C. Drug Lûading and ~PI~CP from Ciraft Copolvmers 1. Dru~ Loading Graft copolymer drug loading was performed as described generally in 10 Example ICI . A solution of 0.5 g of the graft copolymer and 5.0 mg of timolol-maleate in 8 ml methanol was ~.c~ d~ed into 800 mL of diethyl ether. White, sphere-like particles of the graft copolymer with an average 2-3 mm diameter were obtained. The percent recovery was 92% with I wt% of drug loaded. The material was ground intoca. 10-2011 particles for the drug release experiment.
2. Dru~ Release A suspension of 40 mg graft copolymer (NlPAAm-BMA)-g-AAc/drug mixture in 40 mL of PBS buffer was prepared. As described above in Example IC2, the amount of drug released from the mixture was determined as a function of time by2û d t,...,;";"p the absorbance of the solution. The results of the drug release are presented in Figure 12. For comparison, the drug release data for graft copolymer NIPAAm-g-AAc and random copolymer NIPAAm-AAC is presented in Figure 5.
Referring to Figures 5 and 12, complete release of the drug from graft copolymer poly([NlPAAm-BMA]-g-AAc) requires 80 to 90 minutes, while complete 25 release from the graft ~,u~Jolylll~,.a which have pure oligoNlPAAm as the graft component requires only about 20 minutes. The conclusion is that a more l~,yd~u~ ul;~, grafted oligomer provides for slower release rates. By increasing the l~,ydlu~llul/;~ y of the graft copolymer, the drug release rate is reduced s;~ ;L~ ly compared to polyAAc.
Graft cùpOlyl~ a with less than 20% by weight co-oligomer are erodible and show a 30 reduced rate of drug release. Graft copolymers with greater than 20% by weight co-oligomer also a;glliL~ ly reduce the drug release rate, but these uop~ly..,.,.~ are not erodible.
The drug release from copolymer-drug mixture films cast on glass disc is presented in Figure 13. Figure 13 compares the rates of release of timolol from cast 35 filrns of drug complexes of graft copolymers [NlPAAm-BMA]-g-AAc of varying cooligomer NIPAAm-BMA content with homopoly AAc. The data presented compares drug release into phosphate buffered saline (pH 7.4) at 34C for copolymers derived w0 95/24430 2 1~3 4 814 r~l~u. -~8 from homopolyAAc with molecular weight 250,000 and ~,ùol;~;u~ ,. NlPAAm-BMA
with molecular weight 3,100. The homopolyAAc reference had a molecular weight of250,ûO0.
The i~ uJu~,Liul~ of h~Jlu~l.o~ic component units, BMA, into oligo 5 N~AAm lowers the thermally-induced phase transition Lt...l,~.dLu.~:. As shown in Figure 13, at physiol~gic t~,~lly~.~dLul~: and pH, the cooligomer chain, N~AAm-BMA, imparts ~J~u!~h~b;~;Ly tû the graft copolymer sufficient to a;~fiGLallLly reduce the rate of drug rdease compared to homopolyAAc. However, the graft cu~,uly.~ a containing 20% or more cooligomer NIPAAm-BMA are too llydlu~llob;~, and therefore not 10 erodible under the above conditions of drug release. The graft copolymers containing less than Z0% cooligomer N~AAm-BMA (i.e., 5% and 10% cooligomer) do erode and provide drug release over a prolonged period compared to homopolyAAc. Moreover, these grafted copolymers with lower content of pendant ~tlll~ laLul~:-sensitive polymer maintain bioadhesive properties sufilcient to render these graft copolymer 15 effective not only with respect to drug release, but also in relation to prolonged residence time in the treatment area. Accordingly, graft copolymers [NlPAAm-B~IA]-g-AAc with cooligomer NIPAAm-BMA content between 5% and 20% are suitable for sustained release drug delivery and graft copolymers with coologimer content between 10% and 15% are preferred.

Example 4 EllVil~ Y-SensitiveHvdrg~els Comprisinv Temperature Sensitive and pH-Sensitive Homopolvmer Components In this example, the synthesis and .,II~.ld.,L~ dLion, swelling, and drug loading and release properties of lightly cross-linked graft copolymers comprising a carboxylic acid-cûntaining polymer backbone and with pendant Lel"~,~ldLu- ::-sensitive polymer ,,~ The cross-linked carboxylic acid-containing polymer was 30 prepared followed by grafting of the It...~,l dLul ~:-sensitive polymer.
A. Svnthesis ~n~i ClldlC~LeliL~LiOI~ of Cross-linked Hydro~el NIPAAm-~-AAc A series of hydrogels was prepared from AAc monomer solutions (40 weight % of AAc monomer) with a fixed amount of initiator, ammonium persulfate, and 35 various amounts of cross-linker, ethylene glycol d;~ .L~ ylate (EGDMA), in distilled water. The ~,u,,~,~,..L-~Liu,~ of EGDMA was varied from 0.3%, 0.5%, 1.0%, to 2.0% by weight based on total AAc monomer. In a l.,~Jlta~ dLi~e synthesis, the solution was -woss/24430 21 8~1 4 P(,~ 8 degassed wjth nitrogen and injected into the 1.5 mm space between two giass plates.
PUI.~ d~iU~I waS continued for 17 hours at 6ûC. The resulting hydrogel sheet was washed by suspending the sheet in an ethanol bath for 48 hours. Disc-shaped hydrogels were obtained by cutting the gel sheet with a cork borer (15 mm diameter), followed by 5 drying for 48 hûurs in air and for 24 hours under vacuum.
To graft the ~ .,.d~Ul ~-sensitive polymer component to the pH-sensitive cross-linked hydrogel, the dried gels prepared as described above, were swoilen in methanol solutions containing varying amounts of amino-terminated N~AAm, molecular weight 3,300 g/mol (solution cor.~ dLiu-~s from 0.65 g/L to 10 32.89 glL). The swelling was carried out at room temperature for 48 hours. The uptake of amino-terminated NiPAAm by the gels was calculated from the equilibrium swollen volume of the gel. The hydrogel absorbed amino-terminated NlPAAm was then grafted (covalently coupled) to the polyAAc backbone by immersion of the hydrogel into a methanol solution containing a three-fold excess (relative to the amino-terminated 15 NIPAAm) of coupling agent, dicyclohexylcarbodiimide (DCC). The coupling was carried out for 48 hours at room temperature. The resulting grafted hydro~el waswashed with methanol and dried for 48 hours in air and for 24 hours under vacuum.
The synthesis ofthe graft copolymer hydrogels is ~ c~ d s..l .,.-li. "), in Figure 14.
The degree of grafting was determined by comparing the dry weight of the pure 20 polyAAc hydrogel with the product grafted hydrogel. The degree of grafting is ~p~cllLt;d graphically in Figure IS.
Generally, the percent grafting increased linearly with coll~illLldliull of amino-terminated NIPAAm in solution with the initial reaction rate of the grafting being higher as the density of the cross-linking was decreased. A plateau of grafting level was 25 reached for all samples.
B. Swrlli~p of the Gr~P~1 EiYdroFels To determine the swelling ellGI d~,L~ of the grafted hydrogels prepared as described above, gratted hydrogel discs were incubated in O.OS M phosphate 30 buffer solution containing 0.15 M sodium chloride at pH 7.4 at 34C. A Lab-Line water shaker-bath was used for L~ .dlul~ control. In a ~ .,l.idlb~e ~ ;."" a solution of the grafted hydrogel was shaken at 150 rpm and the swelling weights of the hydrogels measured by weighing the sample at various times. The weights were measured afte~ removing the gel from the buffer, and blotting adhered water with3s weighing paper. The swelling ratios were determined as the swollen weightldried weight (WtlWo) and are presented in Figure 16.

W095/24430 2l 84814 r_"O.., ~A7~

At high cross-link density, the greater the amount of grafted Nll?AAm to the polyAAc, the slower the initial swelling rate. The slower rate is probably due to the increased l~yd~ imparted to the graft hydrogel by the NIPAAm pendant chains.
At low cross-link density, the uptake rates are more rapid, and the effect of grafting on 5 these rates was less important.
C. DruF Loadin~ and Release from Grafted Hydrogels 1. Dru~ l ~r~i~
Timolol hydrogen maleate was loaded into the graft copolymer hydrogel 10 by swelling the hydrogel in the drug-methanol solution at room L~ Lult: for 24 hours. The drug-loaded hydrogels were dried for 24 hours in air and for 24 hours under vacuum. The drug loading was deterrnined to be 2% by weight of the dried copolymer hydrogel.
2. Drl~g Release Gra~ copolymer hydrogel drug release was determined as generally described in Example IC2. The initial drug release rates are dependent upon the graft level and the length of the graft chains. The higher the graft level and/or the shorter the length of the graft chains, the slower the drug releases from the hydrogel. The release of 20 drug from the graft copolymer hydrogel is presented in Figure 17. As shown in Figure 17, the greater degree of grafting or the lower the molecular weight of the pendant oligoN~AAm, the slower the rate of drug release from the hydrogel.
l~ample 5 Random CopolYmers Derived From COUOIVIII~.;~L;I)I~ of NlPAAm and AAc For purposes of COl,lua,iau" to the en-vi~l "y-sensitive block and graft copolymers of the present invention, this example describes the synthesis,30 ~ t~ Lulc:-sensitive behavior, and drug loading and release properties of random copolymers derived from the ~olylll~,l;~Liui~ of N-;~ù,u~ul~L~ u~e (N~AAm) and acrylic acid (AAc).

W095/24430 ~18~814 r~ #
4~i A. Synthesis and Clla~ 1;ul~ of Random CopolYmers of NlPAAm and AAc Random UUIJV',~ were synthesized by COPOIY~ ;LI L;V~ of N-;~u~..u~.~' y' '- and acrylic acid by standard radical PC~ ;U~ procedures.
Various random copolymers were prepared by varying the mole percent of NlPAAm 5 monomer in the p~ly....,.iL. Lioll reaction. The synthesis of the random copolymer is .t!,.u.~.a~,J, ~ below.
0 C ~n MeOH H C=O H C=O
OH NH bH I`,-H
CH C
H3C CH3 H C' `HCH
20 The synthetic results and the ~ a~ul~-sensitive behavior of the ransom cu~ulrlll~ is ~.. . --., d in Table 7.

WO 95/24430 2 1 8 4 8 1 4 r T~hl.~ 7. Svnthesis and T~mr~r:~t~re-Sensitive Provertil~c of ~andom Coyolvmers tN~PA~m (inPolym. FN~PA.9ma LCST
monomer) Time ConversioD (in copolymers) Mwb (C) mol%(h) ~wto/o) wt% mol% (x 10'5) pH~ o pH7.4 10020.0 76.3 100 100 - 30.7 32.6 92 2 355,0 93 89 - 32.2 64.1 85 1.345.0 88 82 - 34.6 >95 72 4.041.0 79 71 2.01 38.1 ~95 49 3.035.7 67 56 2.01 61.0 >95 30 3.026.7 57 46 2.01 ~95 >95 10 4.018.3 46 35 1.75 >95 >95 76.041.1 38 28 1.75 >95 >95 36.559.5 33 24 1.70 ~95 >95 ~ Monomer; INIPAAm + AAcl = 8.0fi (~ ,.,.. of iniOator [AiBNI =
0.02% (w/v); solvent. methdnol; ~1) temperature, 60 oc;
a The composition of NlPAAm in copolyrners was determined by ' titration vith o. l N NaOH. wilich detects Lhe caro.~yl group LTom AAc monomer unit;
b Tile molecuiar weight of the copoiymers was determineo by GPC using ~1) ~ ' asstandard, water as an eluent S B Temperature-~ncitive Behavior of ~n~r~m Cspolvmers The ~ ,.d~ul~-sensitive behavior of the random Col)u~ ,lv prepared as described above was investigated as generally described in Example IB. The LCSTs for the random copolymers are VUIILII~ d in Table 7 and the lell~ d~ul~-sensitive behavior for a random copolymer comprising 89 mole percent NIPAAm is illustrated in 10 Figure 18 The resul~s show that random copolymers of N~PAAm and AAc with molepercents of AAc grevter than about 10% do not undergo thermal phase separations at ;olo~ l pH (pH 7.4) or iJI~JvulOgi~ CIIIIJ~,.dLUI~ (34C) As illustrated in hgure 18, the random copolymer does undergo a sharp phase transition at 31C at pH
4 0 and at 64C at pH 7.4.
Rando~n copolymers as described above are ineffective in the practice of the present invention because the mole percent of AAc present in the random copolymer to achieve the requisite ttlllp~,.dLul~-sensitivity reduces the l,ioddll~ ,,,v of the copolymer below that effective for sustained drug release. rulLh~,.lllul~, for those i-andom copoly.mers uhich do undergo phase transitions, either the ~ellli,~,.dlul~ required 20 for the phase transition or the pH is well outside physiological conditions wo 95/24430 2 1 8 4 8 1 4 C. Dru~e Loading and Release from Random Covolymers 1. Dru~ L~ ~ ' Generally, random copolymer-drug complexes were prepared as 5 described in Example lCI.
The random copolymer-drug particles were prepared by dissolving 0.5 g of polymer and 5 mg of timolol (feed ratio is I wt%) in 10 mL of methanol and then IJIC~ J;L~ into 500 mi.. of diethyl ether. The precipitate was then dried under vacuum overnight. The drug content in the particles were determined by dissolving the particles 10 to for~n a solution, and ~ ,a~ J;"dlly measuring the absorbance of the drug in the solution at 294 nm. The results of drug loading for the random copolymer prepared as described above and the graft copolymers prepared as described in Example 3 are presented in Table 8 Table 8.
Comi~arison of Random and Gr~ Copoivmer Dru Loadin~
Polymer: Random copolymer Graft copolymer wt% NIPAAm in copolymer 26 32 39 20 30 50 Polymer added (g) 0.5 0.5 0.5 0.5 0.5 0.5 Drug added (mg) 5.0 5.0 5.0 5.0 5.0 5.0 Poiymer recovery (% wlw) 94 94 94 74 90 90 Drugloaded(mglgPolymer) 9.4 9.2 9.1 9.9 10.0 10.8 2. Dru~ C~
20 Generally, the IlI~lal~CIII~ of drug released from the random copolymer-drug particles was determined as described in Example IC2. The drug release results for the various random culJolylll~,.a are compared to graft co~olyll..,.a of similar ~ o~ -, at 34C and 37C in Figures 4 and 5, respectively. The results show that drug release from the random copolymers at 34C is about twice as fast as release 25 from the graft c~Olyll..,~a. For the random copolymers, the drug is completely released within 10 minutes. The results at 37C are qualitatively similar to those at 34C, aithough complete release of drug takes about 24 minutes.

wo 95/_4430 2 1 8 4 8 1 4 , ~ I, ~ ~ 7A t8 Example 6 E.l.;.~ "~ SensitiveGrai'tCopolymersComprising Temperature-Sensitive Copolymer and pH-Sensitive IIc"~.uj~u~ Cnmr/mf~ntc In ti~iis example, the synthesis and ~ r~ ,.dLu~sensitiVe behavior, and drug loading and drug release properties of graft i,ùjJGIy~ comprising t.,",j~d~lil~sensitive copolymer and pH-sensitive l~u~i~uj~uiylll~ are described. Specific~ily, the t~,...j,.,.dLu~t:-sensitive copolymer component is a block 10 copolymer of ethylene oxide and propylene oxide ("EO/POIEO"), and the pII S~ ;
llu~ujJulyll~ component is a l~u~uj~uly~ ,, of acrylic acid (AAc). The AAc llulllùj~ulyll.~,, was utilized as the backbone of the grafi copolymer.
A. Synthesis and Cl,il,d~ GLiu.. of Graft Copolymers of EO/PO/EO-g-AAc 1. Synthesis of Amino-Terminal Block Copolymer of EO/PO/EO
Block copolymers of EO/PO/EO are ~,ull~ u;dlly available as surfactants from BASF-Wyandotte Corp. (Wyandotte, Michigan) and sold under the tradename Pluronic.~ Such block copolymers of EO/PO/EO have the following general structure:
Cl H3 H~ [CH2CH20]a--[CH CHO]b [CH2CH20]a-H
where the ratio of a:b:a varies as illustrated in the following Table 9:
Table 9 Block Copolymers of EO/PO/EO
Pluronic~lg EO/PO/EORatio TotalM.W. (avg.) L-61 4130/4 2.000 L-81 713817 2,750 L-122 13/69/13 5,000 The LCST of PluronicaD L-12~ was evaluated by measuring absorbance as a function of ItllllJ~dLui~e Spccifically, a 0.5% by weight solution of L-122 (PBS
buffer, pH 7.4) was prepared, and iight absorbance (at 500 nm) was measured at Lc~ .dLu~ ranging from 15C to 30C. The LCST ofthe L-122 solution was found 35 to be 26C, and the results ofthis experiment are presented in Figure 19.

wo9s/7,4430 21 8481 4 r ~ 7~#

The above block copc,l~ of EOIPOIEO were then derivatized to yield a reactive amino-terminal by a two step reaction First, 20g of L-122 (4 mmole) was reacted with 1.0g (5 mmole) of 4-nitrophenyl cLluluru.~ ., in methyl chloride in the presence of ~ ,lhJ' at room le.l~_.4lulc for 4 hours to yield a 1 upl~_..yl 5 formated-derivatized ;lllclll~2d;~lld. This illlcllll di. ie was recovered by extraction using petrolium ether for three times, resulting in 14 g of product with a yield of 72% by weight. In the second step, 10 g (2 mmole) of the ...~ Le was reacted with 0.36 g (6 mmole) ûf t' ~ , in methylene chloride at room lelll~J_.dlule overnight.
The amino-terminated L-122 derivative was recovered by extraction with petrolium10 ether for three times, dialysis against distilled water using a membrane with MW cut-off of 3500 for three days, and evaporated of water to obtain the product (8.8 g, yield of 88% by weight). r, ~ ~ of the amino-terminated derivative was determined by titration as 0.91 i: 0.1.
The other block ~,UIJUIY~ of EO/PO/EO were similarly derivatized to 15 yield a reactive amino-terminal by the reaction scheme illustrated below.

HO--[CH2CH2O]a--[CH2CHO]b--[CH2CH2O]a-H
1l ~N2 HO--[CH2CH20]a--[CH2CHO]b--[CH2CH20]--C--O--~NO2 HO--[CH2CH2O]a [CH2CHO]b--[cH2cH2o]a--C--NHCH2CH2NH2 2. Synthesis of Ciraft Copolymers of EO/POlEO-g-AAc Graft cu~,ul~l.. ,.~ of EO/PO/EO-g-AAc were prepared by coupling the reactive amino-terminals of the derivatized block CUIJO~ of EO/PO/EO onto the IIGIIIUIJOI~ -. backbone of AAc. Specifically, reaction between the amino group of the amino-terminated EO/PO/EO derivative and a carboxyl group of AAc, in the presence of di~"lol.~,~l .,all,c ' '- ~CC), resulted in amide bond formation. The reaction W0 95/24430 2 1 8 4 8 1 4 ~ 8 was carried out in m~thanoi (100 rnL) at room l~ u.c for 24 hours, with a mole ratio of the block copolyrner of EO/PO/EO to DCC of 2:1. Synthesis of the graf~
copolymers of EO/PO/EO-g-AAc is Iclulc:.clllt~ y below:
--[CH2~H]~CH2~-- ~ NH2 DCC . --[CH2CI H]--[CH2CI H]--OH H H2 ~lH OH
¢H2 r o L ~La r~
r CH2 I CHz CH3--CH ~La ~Lb I CH2 1 l~H2 ~b L~a r~

L$1a H
The resulting graft copolymers were recovered from the reaction solution by IJIt~ dLiVII into T~IF or diethylether. CL, ~i~ I r~ 11 of the graft copolyrners was performed using GPC with Waters 500A, 103~ and 10~ UlLI~Lylcll~fi~ columns, DMF
10 as mobile phase, at 40C and an elution rate of 0.7 mL/min.
Graft copolymers were prepared at varying ratios of fv ~l,v - l~, and using various block copolyrners of EO/PO/EO as identified in Table 10.
Table 10 Gra~t Copolyn~.ers of Block EO/PO/EO and PolyAAc Pluronic~ Pluronic~/PolyAAc Yield (%) L-61 10/90(wt%) 79 L-61 20/80(wt%) 55 L-61 30/70(wt%) 86 L-92 30/70(wt%) 94 L-122 10/90(wt%) 80 L-122 20/80(wt%) 80 L-122 30/70(wt%) 68 L-122 40/60(wt%) 78 L-122 50/50(wt%) 65 B. Temperature-Sensitive Behavior of Graft Copolymers of EO/PO/EO-g-AAcThe graft copolymers of EO/PO/EO of this example form a translucent gel at a~ U~l~ldt~,ly 32C. Accordingly, rather than using an absorbance IlI~,a~Ultlll~
for LCST, the solution-to-gel phase transition t~,l.l,U.,.d~U~C was determined by 10 measuring viscosity as a function of temperature by the following procedure.
A 5rintill~tinn vail containing a stir bar was weighed, and 2.8 g of an aqueous solution containing 0.76% NaCI and 1.25% NaOH was added thereto. NeAt, 0.125 g of the L-122-30/70(wt%) graft copolymer was added. followed by 1.2 g of a 0.76% NaCI solution. The L-122-30/70(wt%) graft copolymer was dissolved by stirring the solution in an ice bath for about 2 hours, and then by keeping the ,. ;.,~ ;nll vial in the l.,r~i~,.,.d~O. overnight. A sufficient amount of 1 N NaOH was added to the solution to yield a pH of 7.2. To this was added 0.05 g of 8.5% NaCI, and sufficient water was added to bring the solution to 5.0 g. The resulting solution contained 2.5% by weight of the L-122-30/70(wt%) graft copolymer, and had a pH of 7.2.
The viscosity of the solution was then measured at various ~tlll~J~,.dLUlt~
ranging from 25C to 40C using a Brookfield DV III RV viscometer fitted with a CP-52 spindle. The ltlll~J.,ldLUlC was controlled by circulating water from a constant LtllllJ~,.d~ulc water bath through the jacket of the viscometer cup. About 0.6 mi of the solution was placed in the viscometer cup. The viscosity IlI~,a:~ul-,lll~,llL:~ were carried out at 0.1 rpm (shear rate 0.2/second) for 3 minutes at a fiAed ~tlll~,.dlUlt;. The viscosity vaiue at the end of 3 minutes was recorded, and the results of these IllCd:iUltlll~ i are presented in Figure 20. As determined by this technique~ the LCST of the L-122-30/70(wt%) graft copolymer was found to be 32C at 25% of maxAimum viscosity.
C. Drug Loading and Release from Graft Copolymers of EO/PO/EO-g-AAc Drug loading and release from the copolymer-drug mrAture was determined by casting a film of a copolymer-drug mixture (containing 5% by weight timolol maleate) on a glass disk as disciosed in Example IC2. In these CA~I.~I;III~.II~:>, the thicicness of the films was ca. 150 ~L, the diameter was ca. 0. 54-0.5 8 mm, and the weight of each film was ca. 5 mg. The coated glass discs were suspended in PBS buffer (pH
7.4) at 34C, and the amount of drug release was measured as a function of time. The results ofthis experiment are presented in Figures 21, 22 and 23.

w095/24430 2 1 ~ 4 8 1 4 Specifically, Figure 21 iliustrates drug release from graft ~v"vly~ of EO/PO~EO-g-AAc ~t varying ratios of EO/PO/EO to AAc (i.e., 70% AAc grafted with 30% L-61, 80% AAc grafted with 20% L-61, and 90% AAc grafted with 10% L-61).
For ~ puri~oses, drug release firom a homopolymer of Mc (i.e., 100% AAc), 5 as weli as a physicai rnixture of 80% hv...v~,vl~l....,. Mc and 20% L-61, are also presented in Figure 21. In this example, graft copolymers of EO/PO/EO and AAc showed '~ y retarded drug release profiles compared to the AAc hv,..vpvl~......
aione or the physical mixture of the same with L-61. Moreover, complete drug release was delayed to over I hour when the content of L~6 I was 20% (or higher) compared to 10 AAc.
Figure 22 illustrates drug release firom graft copolymers utilizing L-122 as the block copolyrler of EO/PO/EO. In this experiment, graft copolymers of L- 122-g-AAc at ratios varying from 90% AAc/10% L-122 to 50% AAc/50% L-122 were employed. With 30% (or more) L-122 grafted to AAc, complete drug release time was 15 more than 4 hours.
Lastly7 Figure 23 illustrates the drug release properties associated with the use of different bloc'x copolymers of EO/PO/EO - that is, L-61, L-92 and L-122.
Graft copolymers or70% AAc and 30% L-61, L-92 or L-122 were tested. The block copolymer L-122, when grafted to the AAc backbone, resulted in a prolonged drug time 20 of over four hours. In addition, a physical mixture of a temperature-sensitive polymer (such as the Pluronic~9 L-122) with a copolymer-drug mixture of this invention may, in certain instances, prDlong drug release therefrom, and is within the scope of the present invention.
From the foregoing, it will be appreciated that, although specific - I u~ of this invention have been described herein for the purposes of iliustration, various ",..,l;ll. ~ may be made without departing from the spirit and scope ofthe invention. Accordingly, the invention is not limited except by the appended claims

Claims

Claims 1. A graft copolymer that is not cross-linked, comprising a backbone pH-sensitive polymer component with a pendant temperature-sensitive copolymer component grafted thereto, wherein the graft copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 6.0 to 8Ø
2. A graft copolymer that is not cross-linked, comprising a backbone temperature sensitive polymer component with a pendant pH-sensitive polymer component grafted thereto, wherein the graft copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 6.0 to 8Ø
3. A block copolymer that is not cross-linked, comprising a pH-sensitive polymer component and a temperature-sensitive polymer component joined thereto, wherein the block copolymer has a lower critical solution temperature ranging from 20°C to 40°C
measured at a pH between 6.0 to 8Ø
4. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the lower critical solution temperature is determined at a pH between 7.0 to 7.8.
5. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the lower critical solution temperature ranges from 26°C to 34°C.
6. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the lower critical solution temperature ranges from 28°C to 32°C.
7. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the pH-sensitive polymer component comprises a carboxylic acid-containing polymer.

8. The graft or block copolymer of claim 7 wherein the carboxylic acid-containing polymer is derived from polymerizable carboxylic acids selected from the group consisting of acrylic acid, methacrylic acid, ethacrylic acid, .beta.-methylacrylic acid, cis-.alpha.-methylacrylic acid, trans-.alpha.-methylcrotonic acid, .alpha.-butylcrotonic acid, .alpha.-phenylacrylic acid, .alpha.-benzylacrylic acid, .alpha.-cyclohexylacrylic acid, .beta.-phenylacrylic acid, coumaric acid and umbellic acid.
9. The graft or block copolymer of claim 7 wherein the carboxylic acid-containing polymer is carboxymethylcellulose.
10. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the pH-sensitive polymer component consists essentially of a homopolymer.
11. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the pH-sensitive polymer component is a homopolymer.
12. The graft or block copolymer of claim 11 wherein the homopolymer is polyacrylic acid.
13. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the pH-sensitive polymer component is a random or block copolymer.
14. The graft or block copolymer of any one of claims 2 or 3 wherein the temperature-sensitive polymer component is a homopolymer.
15. The graft or block copolymer of claim 14 wherein the homopolymer is poly(N -isopropylacrylamide).
16. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the temperature-sensitive polymer component is a random or block copolymer.

17. The graft or block copolymer of claim 16 wherein the temperature-sensitive polymer component is a random copolymer of N-isopropylacrylamide and butylmethacrylate.
18. The graft or block copolymer of claim 16 wherein the temperature-sensitive polymer component is a block copolymer of ethylene oxide and propylene oxide.
19. The graft or block copolymer of any one of claims 1, 2 or 3 wherein the pH-sensitive polymer component is a homopolymer and the temperature-sensitive polymer component is a random or block copolymer.
22. A graft copolymer-drug mixture comprising a drug and a graft copolymer, wherein the graft copolymer is not cross-linked and comprises a backbone pH-sensitive polymer component with a pendant temperature-sensitive copolymer component grafted thereto, and wherein the graft copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 4.0 to 8Ø
23. A graft copolymer-drug mixture comprising a drug and a graft copolymer, wherein the graft copolymer is not cross-linked and comprises a backbone temperature-sensitive polymer component with a pendant pH-sensitive polymer component grafted thereto, and wherein the graft copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 4.0 to 8Ø
24. A block copolymer-drug mixture comprising a drug and a block copolymer, wherein the block copolymer is not cross-linked and comprises a pH-sensitive polymer component and a temperature-sensitive polymer component joined thereto, and wherein the block copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 4.0 to 8Ø

25. The copolymer-drug mixture of any one of claims 22, 23 or 24 wherein the copolymer has a lower critical solution temperature ranging from 20°C to 40°C measured at a pH between 6.0 and 8Ø
26. The copolymer-drug mixture of any one of claims 22, 23 or 24 wherein the mixture is in the form of a solid particle.
27. The copolymer-drug mixture of claim 26 wherein the solid particle is suspended in a pharmaceutically acceptable carrier.
28. The copolymer-drug mixture of any one of claims 22, 23 or 24 wherein the mixture is formulated as a liquid, gel or ointment.
29. The copolymer-drug mixture of claim 28 wherein the mixture is formulated as a liquid which gels upon administration to a treatment area 30. A method for administering a drug to a treatment area, comprising applying to the treatment area a copolymer-drug mixture of any one of claims 22, 23 or 24.
31. The method of claim 30 wherein the copolymer-drug mixture is applied in the form of a solid particle.
32. The method of claim 31 wherein the solid particle is applied as a suspension within a pharmaceutically acceptable carrier.
33. The method of claim 30 wherein the mixture is applied as a liquid, gel or ointment.
34. The method of claim 30 wherein the mixture is applied as a liquid which gels upon administration to the treatment area.

35. A covalently cross-linked graft copolymer hydrogel comprising a first backbone environmentally-sensitive polymer component with a second pendant environmentally-sensitive polymer component grafted thereto, wherein the first and second polymer components are each responsive to a different trigger, and wherein the backbone polymer is not the reaction product of a polyalkyleneoxide.
36. A covalently cross-linked block copolymer hydrogel comprising a first environmentally-sensitive polymer component and a second environmentally-sensitive polymer component joined thereto, wherein the first and second polymer components are each responsive to a different trigger.
37. The hydrogel of any one of claims 35 or 36 comprising at least one polymer component responsive to a thermal trigger and at least one polymer component responsive to a pH trigger.
38. The hydrogel of any one of claims 35 or 36 comprising at least two polymer component responsive to thermal triggers and with different transition temperatures.
39. The hydrogel of any one of claims 35 or 36 comprising at least two polymer components responsive to pH triggers with different pH transition ranges.
40. The copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36 further comprising a solvent.
41. The copolymer or hydrogel of claim 40 wherein the solvent comprises at least 10% by weight a non-aqueous liquid.

42. The copolymer or hydrogel of claim 40 wherein the solvent comprises at least 99% by weight a non-aqueous liquid.
43. A method of absorbing a solvent or solution, comprising exposing the hydrogel of any one of claims 35 or 36 to the solvent or solution and allowing the hydrogel to swell.
44. The method of claim 43 wherein the solvent or solution comprises a material selected from the group consisting of urine, feces, water, blood, brine and an ionic water solution.
45. The method of claim 43 wherein the swelling ratio of the hydrogel is not less than 15.
46. A diaper where a superabsorbant component comprises the hydrogel of any one of claims 35 or 36.
47. A copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24. 35 or 36 wherein the graft or block copolymer or hydrogel provides moisture to a treatment area 48. A copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36 wherein the graft or block copolymer or hydrogel retains moisture at a treatment area.
49. A copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36 wherein the graft or block copolymer or hydrogel provides hydration to a treatment area.
50 A graft or block copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36 wherein at least one of the polymer components comprises a bioadhesive.

51. A cosmetic composition, a wound dressing, a pharmaceutical composition comprising a drug, an iontophoretic device, a monitoring electrode, an adhesive, a cream, a foam, a suppository, a tablet, a delivery gel, a device for nasal, vaginal, oral, ocular, rectal, dermal or otic delivery, or a laxative, comprising a graft or block copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36.
52. A device for vaginal delivery of a drug according to claim 51 wherein the drug is selected from a spermicide, ovacide, antimicrobial, antifungal, prostaglandin, and steroidal or nonsteroidal fertility agent.
53. A device for drug delivery according to claim 51 wherein the drug is contained in a medicinally inert matrix in the form of a three-dimensional structure having at least one surface portion.
54. The device of claim 53 wherein the three-dimensional structure is capsular in form and has a largest dimension of about 1 nanometer to about 5000 microns.
55. A system for control of reactive chemistry, separation of solution components, separation of ionic species, or control of chemomechanical work, comprising a graft or block copolymer or hydrogel of any one of claims 1, 2, 3, 22, 23, 24, 35 or 36.
56. A system for control of viscosity or flow comprising a hydrogel of any one of claims 35 or 36.
57. A graft or block copolymer or hydrogel of any one of claims 17 2, 3, 22, 23, 24, 35 or 36 mixed with a polymer selected from a homopolymer, a random copolymer, a block copolymer and a graft copolymer.
58. The graft or block copolymer or hydrogel of claim 57 wherein the polymer is a homopolymer of acrylic acid.

59. The graft or block copolymer or hydrogel of claim 57 wherein the polymer is a block copolymer of ethylene oxide and propylene oxide.
60. A pharmaceutical formulation for administering a drug to a treatment area, comprising the copolymer-drug mixture of any one of claims 22, 23 or 24, wherein the formulation is in the form of a liquid which gels upon administration to the treatment area.
CA002184814A 1994-03-04 1995-03-03 Block and graft copolymers and methods relating thereto Abandoned CA2184814A1 (en)

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US6486213B1 (en) 2002-11-26
DE69523044D1 (en) 2001-11-08
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DE69523044T2 (en) 2002-06-20
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EP0748342A1 (en) 1996-12-18
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