(12) United States Patent
`Gurny et al.
`
`I lllll 1111111111111111 111111111111111 IIIII 111111111111111 1111111111 11111111
`
`US006440460B1
`US 6,440,460 Bl
`Aug. 27, 2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) PHARMACEUTICAL COMPOSITIONS
`CONTAINING BUFFERED ORfflO ESTER
`POLYMERS
`
`(75)
`
`Inventors: Robert Gnrny; Monia Zignani, both
`of Geneve; Cyrus Tabatabay, Bernex,
`all of (CH)
`
`(73) As.signee: Allergan Sales, Inc., Irvine, CA (US)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,093,709 A
`4,138,344 A
`4,268,643 A
`4,346,709 A
`5,030,457 A
`5,700,485 A
`
`•
`•
`•
`
`6/1978
`2/1979
`5/1981
`8/1982
`7/1991
`• 12/1997
`
`Choi et al.
`Choi et al.
`Radici el al.
`Sclunitt
`Ng et al.
`Berde el al.
`
`( *) Notice:
`
`(21) Appl. No.:
`
`(22) PCT Filed:
`
`S ubject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`09/117,359
`Feb. 26, 1997
`PCTJEP97 /00906
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`WO 91/03510
`WO 93/00383
`
`3/1991
`1/1993
`
`• cited by examiner
`
`(86) PCT No.:
`
`§ 371 (c)(l),
`Jul. 27, 1998
`(2), (4) Date:
`(87) PCT Pub. No.: WO97/32606
`
`PCT Pu b. Date: Sep. 12, 1997
`Foreign Ap1>llcatlon Priority Data
`
`(30)
`
`(EP) ............................................ 96103391
`
`Mar. 5, 1996
`(51) Int. Cl.7
`.......................... . A61K 9/ 10; A61K 47/34
`(52) U.S. CJ. ........................ ........ ...... .. 424/486; 424/426
`(58) Field of Search ......... , ....................... 424/486, 426,
`424/428; 514/772.3
`
`Primary Examiner-Edward J. Webman
`(74) Attorney, Agent, or Firm-Carlos A. Fisher; Martin A
`Voet; Robert J. Baran
`
`(57)
`
`ABSTRACT
`
`A pharmaceutical composition for the controlled release of
`therapeutic agents from carboxylic acid ortho ester polymers
`contains a pharmaceutically acceptable salt of an acid, which
`together with the acid Rl-COOH liberated from the decom(cid:173)
`position of the ortho ester polymer forms a buffer system in
`a physiologically acceptable pH range.
`
`8 Claims, 1 Drawing Sheet
`
`0
`
`2
`
`4
`
`6
`
`8
`
`time (days)
`
`-0- POE 063 (Mw 6'800) + 1 % 5-FU
`-+- POE 063 (Mw 6'800) + 1 % 5-FU+ 0.5% sodium acetate
`
`• Dissolution of POE
`
`FRESENIUS EXHIBIT 1065
`Page 1 of 10
`
`

`

`U.S. Patent
`
`Fig. 1
`
`Aug. 27, 2002
`
`US 6,440,460 Bl
`
`6
`
`2
`
`0
`
`2
`
`4
`
`6
`
`8
`
`time (days]
`
`-0- POE 063 (Mw 6'800) + 1% 5-FU
`
`__.,_ POE 063 (Mw 6'800) + 1 % 5-FU+ 0.5% sodium acetate
`
`• Dissolution of POE
`
`Fig. 2
`
`l
`
`(l)
`(/)
`«I
`Q)
`,_
`(l)
`=>
`4-
`lO
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`20
`time [hours]
`
`40
`
`60
`
`-0- POE (Mw 6'800} + 5-FU 1%
`....- POE (Mw 6'800) + 5-FU 1% + sodium acetate 0.5 %
`
`FRESENIUS EXHIBIT 1065
`Page 2 of 10
`
`

`

`US 6,440,460 Bl
`
`1
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING BUFFERED ORTHO ESTER
`POLYMERS
`
`The present invention relates to a pharmaceutical com(cid:173)
`position for the controlled release of therapeutic agents from
`carboxylic acid ortho ester polymers and to a process for the
`preparation of said pharmaceutical compositions.
`
`BACKGROUND OF THE INVENTION
`Carboxylic acid ortho ester polymers consisting essen(cid:173)
`tially of monomer repeating unit5 of the partial formula
`
`5
`
`2
`This decreasing pH-level renders pharmaceutical cocnpo(cid:173)
`sitions or administration systems containing the above(cid:173)
`cnentioned carboxylic acid ester ortho ester polycners Jess
`feasible for various types of administration, especially
`intramuscular, subcutaneous and intraocular administration,
`since it has firmly been established that the injection of a
`formulation with an acidic pH could trigger inflammation,
`cf. Sekizawa et at., J. To:>.icol. Sci. 19, 25-35 (1994),
`The addition of a base to achieve neutralization i5 deemed
`10 unsuitable, since basic substances produce a local pH level
`above 8 at the site of addition. This is not acceptable for
`implant5 and for various modes of administration, especially
`intravenous and intraocular administration.
`
`(I)
`
`15
`
`OBJECTS OF THE INVENTION
`
`wherein R 1 represents hydrogen or C1-4-alkyl and A repre- 20
`senL5 a hydrocarbon chain of the formula
`
`R.-C-
`
`j•
`I
`
`(Gl,i)..---C-(CHi);;-,
`
`jc
`I
`
`(IA)
`
`Accordingly, the problem to which the present invention
`relates may be defined a5 follows: It is desirable to provide
`a pharmaceutical dosage form for the controlled release of
`active agents from carboxylic acid ortho ester polymers. To
`solve this problem, it is neces.5ary to maintain the pH-level
`in a physiologically acceptable constant range between 5.0
`and 7.5.
`This problem bas been solved by adding a pbarmaceuti-
`25 cally acceptable salt of an acid, which together with the acid
`being liberated frocn the decocnposition of the carboxylic
`acid ortho ester polymer (I) forms a buffer system in a
`physiologically acceptable pH-range.
`
`wherein Rm Rb und Re independently of one another rep(cid:173)
`resent hydrogen or Cu -alkyl, and m and n independently of 30
`one another represent zero or integers frocn one to three;
`cnethods for preparing such ortho esters and their utility as
`carriers in so-called controlled release pharmaceutical com(cid:173)
`positions have been disclosed in Published International
`Patent Application (WO) 91/03510, International Publica- 35
`lion Date: Aug. 23, 1990.
`Toe slow hydrolysis of these carboxylic acid ortho ester
`polymers and the controlled release of therapeutic agents
`from the polymer matrix has been disclosed in Published
`International Patent Application (WO) 93/00383, Interna- 40
`tional Publication Date: Jun. 18, 1992. Under physiologi(cid:173)
`cally acceptable conditions of pH 7.4, the hydrolysis of the
`ortho ester polymer (1) bas been observed. This hydrolysis
`could formally be regarded as the reversal of the polymeri(cid:173)
`sation step, whereupon a triol of the formula
`
`45
`
`OH
`I
`OH-A-OH
`
`(II)
`
`50
`
`is generated and the acid R1- COOH is being liberated.
`When an carboxylic acid ortho ester polymer consisting
`essentially of monomer repeating units of the partial formula
`
`(I') 55
`
`60
`
`is hydrolyzed, the acid CH3COOH is liberated. Upon pro(cid:173)
`gressive hydrolysis of the ortho ester polymers, an increas(cid:173)
`ing amount of carboxylic acids R1COOH is being liberated.
`This causes a decrease of the pH-level in.vitro from values 65
`of about 6.5 to 4.5 to even lower values in 1- 5 days
`depending on the moleclur weight of the polycner.
`
`GENERAL DESCRIPTION OF TIIE INVENTION
`
`The present invention, therefore, relates to a pharmaceu(cid:173)
`tical composition for the controlled release of therapeutic
`agents frocn a polymer comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic acid ortbo ester polymer
`consisting essentially of monomer repeating uniL5 of
`the partial formula
`
`(I)
`
`wherein R1 represenL5 hydrogen or C1_4-alkyl, and A
`represents a hydrocarbon chain of the formula
`
`R.-C-
`
`j·
`I
`
`(CH2)~C-(CH2)a,
`
`t
`I
`
`(IA)
`
`wherein R0 , Rb und Re independently of one another
`represent hydrogen or C 1_4 -alkyl, and m and n inde(cid:173)
`pendently of one another represent zero or integers
`frocn one to three;
`c) a pharmaceutically acceptable salt of an acid, which
`together with the acid R1-COOH being liberated from
`the decomposition of the carboxylic acid ortho ester
`polymer (I) forms a buffer system in a physiologically
`acceptable pH-range; and the following optional com(cid:173)
`ponents:
`d) further pharmaceutically acceptable additives; and/or
`e) a pharmaceutically acceptable carrier liquid.
`
`FRESENIUS EXHIBIT 1065
`Page 3 of 10
`
`

`

`US 6,440,460 Bl
`
`10
`
`4
`hydrochloride, mesylate, acetate, succinate, lactate, tartrate,
`i'umarate, sulfate or maleate salt.
`Preferred therapeutic agents are immunosuppressants,
`such as cyclosporin, cytostatics, such as edatrexate (10-
`E DAM), doxorubicin, cytarabine, trifosamide,
`cyclophosphamide, ftuorouracil or methotrexate and zinc
`phthalocyanine as well as water-soluble sulfa derivatives of
`phthalocyanine, for example tetrasulfophthalocyanine,
`which can be used in photo-dynamic chemotherapy.
`The therapeutic agents mentioned above are present in the
`pharmaceutical composition either as individual agents or in
`fixed combinations with other therapeutic agents. The dose
`administered is the close prescribed for each agent, the mode
`of administration intended and the disease and condition
`indicated for therapy.
`In preferred embodiments of the invention, therapeutic
`agents are administered by subconjunctival and intraocular
`injection, such as 5-fluorouracil (5-FU) and mitomycin, after
`glaucoma filtering surgery; 5-FU or dexamethasone for the
`treatment of proliferative vitroretinopatby; by subcutaneous
`20 and intramuscular injection, such a.s naltrexone as narcotic
`antagonisms; insulin for treatment of diabetes mellitus,
`norethisterone and levonorgestrel as contraceptive agents;
`demineralized bone matrix and bone graft agents for bone
`formation; 5-FU and naltrexone for the treatment of tumors,
`pyrimethamine or halofantrine for prophylaxis of malaria,
`homosulphanilamid for the treatment of burned skin, or
`tetracycline for periodontal injection.
`Component b)
`A suitable bioerodible carboxylic acid ortho ester polymer
`present in the pharmaceutical composition consists essen(cid:173)
`tially of monomer repeating units of the partial formula
`
`(I)
`
`wherein R1 represents hydrogen or C1_4 -alkyl and A repre(cid:173)
`sents a hydrocarbon chain of tbe formula
`
`40
`
`3
`The pharmaceutical composition is suitable for implants
`and also for various types of administration, especially
`parenteral administration by injection, e.g. intramuscular,
`subcutaneous, subconjunctival, intraocular or periodental
`administration. The controlled release of the active agent 5
`administered follows an approximate "zero order" pattern
`( constant amounts of active agent are released within
`defined time periods). The decomposition products of the
`polyortho esters defined above are physiologically accept(cid:173)
`able and no removal of undesirable decomposition products
`from the site of administration is deemed necessary.
`The general terms used throughout the specification of
`this invention are preferably defined as follows:
`The term pharmaceutical composition defines a mixture
`containing the therapeutic agent or combination of thera(cid:173)
`peutic agents to be administered in the selected dosage form 15
`to a host in a therapeutic method of treating the di5ea.5e or
`condition indicated. Intramuscular and intraocular adminis(cid:173)
`tration of the pharmaceutical composition are particularly
`preferred.
`Component a)
`The term therapeutic agent as used herein is intended to
`define a compound or composition of matter which, when
`administered to a human being or an animal, induces a
`desired pharmacological and/or physiological effect by local
`and/or systemic action. In general, this term includes thera- 25
`peutic or prophylactic agents in all major therapeutic/ pro(cid:173)
`phylactic areas of medicine. Suitable therapeutic agents
`include the following pharmaceutical agents: antiinflamma(cid:173)
`tory agents, for example dexamethasone, sodium dexam(cid:173)
`etha.sone sulfate, hydrocortisone or prednisolone, coronary 30
`dilators, for example nifedipine, isosorbitol dinitrate,
`nitroglycerine, diltiazem, trapidil, dipyridamole or dilazep,
`prostaglandins, for example prostaglandin E1 , E2 or F2A,
`peripheral vasodilators, for example ifenprodil, cinepazet
`maleate, cyclandelate, cinnarizine or pentoxyphylline, 35
`antibiotics, for example ampicillin, amoxycillin, cephalexin,
`cephradine, cefroxadin , cefaclor, ery thromycin,
`bacampicillin, minocycline or chloramphenicol,
`antispasmodics, for example propantheline, atropine or
`scopolamine, antitussives and antiasthmatics, for example
`theophylline, aminophylline, methylephedrine, procatechol,
`trimethoquinol, codeine, clofedanolol or dextromethorphan,
`diuretics, for example furosernide or acetazolamide, muscle
`relaxants, for example chlorphenesin carbamate, tolperison,
`eperison or baclofen, mild tranquilisers, for example 45
`oxazolam, diazepam, clotiazepam, medazepam, temazepam
`or ftudiazepam, potent tranquilisers, for example sulpiride,
`clocapramine or zotepin, beta-blockers, for example
`pindolol, propranolol, carteolol, oxprenolol, metoprolol or
`labetalol, antiarrhythmics, for example procainamide, 50
`disopyramide, ajimalin or quinidine, anti gout agents, such as
`allopurinol, anticoagulants, such as ticlopidine,
`antiepileptics, for example phenytoin or valproat,
`antihistamines, for example chlorpheniramine, clemastine,
`mequitazine, alimemazine, cyproheptadine, agents for treat- 55
`ing nausea and dizziness, for example diphenidol,
`me thochlopromide, domperidone or betahistine,
`antihypertensives, for example reserpine, rescinnamine,
`methyldopa, prazosin, clonidine or budralazin,
`sympathomimetics, for example dihydroergotamine, isopro- 60
`terenol or etilefrin, expectorants, for example bromhexine,
`carbocisteine, L-ethylcysteine or L-methylcysteine, oral
`antidiabetics, for example glibenclamide or tolbutarnide,
`cardiovascular agents, for example ubidecarenon or adenos(cid:173)
`ine.
`Therapeutic agents can be converted into pharmaceuti(cid:173)
`cally acceptable sails, for example into a hydrobrornide,
`
`ib
`• I
`
`t
`""' I
`
`R -C-(CH.' -C-(CH-' -
`
`,.,. ,
`
`(IA)
`
`wherein R,,, Rb und Re independently of one another rep(cid:173)
`resent hydrogen or C1-4-alkyl, and m and n independenlly of
`one another represent zero or integers from one to three;
`A particularly preferred carboxylic acid ortho ester poly(cid:173)
`mer present in the pharmaceutical composition consists
`essentially of monomer repeating units of the partial formula
`
`([')
`
`The term bioerodible as used herein to describe the proper(cid:173)
`ties of the defined ortho ester polymers is synonymous ,,vith
`the term biodegradable. l bese terms denote the property of
`a body of solid or semisolid polymers to undergo
`65 degradation, erosion and solubilization as a result of
`hydrolysis of labile linkages at the physiological conditions
`of use.
`
`FRESENIUS EXHIBIT 1065
`Page 4 of 10
`
`

`

`US 6,440,460 Bl
`
`5
`Monomer repeating units of the partial formula I are
`structurally recurring units or monomer units of the car(cid:173)
`boxylic acid ortho ester polymers provided by the present
`invention. The monomer repeating units may be the same or
`different; when different, they may be arranged in block
`sequential order or random fashion. When all monomer
`repeating units are the same or identical, the polymer is
`called a homopolymer. When there are 2 or more different
`monomer repeating units in a polymer, the polymer is called
`a copolymer. The present invention comprises pharmaceu(cid:173)
`tical compositions containing copolymers and homopoly(cid:173)
`mers. Homopolymers are particularly preferred.
`In the monomer repeating units of the partial formula (I)
`R1 represents hydrogen or C1 •4 -alJ...')'1, e.g. methyl, ethyl, n(cid:173)
`or isopropyl or n-butyl. Methyl is particularly preferred. In
`ortho ester polymers wherein R1 represents methyl, acetic
`acid is liberated upon hydrolysis of the polymer. in a
`hydrocarbon chain of the formula
`
`6
`(neat) down through about 10% by weight or lower, when
`solvent is used. The presence of anhydrous conditions is
`maintained. The reaction can be carried out under reflux
`conditions and thus, depending upon the solvent, at tem-
`5 peratures in the range of 50-150° C., preferably 50- 90° C.
`The approximate molar ratio of the reactants is about 1:1. It
`is typically preferred to carry out the reaction in the presence
`of an acid catalyst. Examples of suitable acid catalysts
`include p-toluenesulfonic acid and methanesulfonic acid.
`The amount of acid catalyst can range from 0% (based on its
`optional presence) to about I% molar (based on the amount
`of trio! pre.sent).
`A preferred synthesis comprises reacting under the con(cid:173)
`ditions of a condensation reaction mentioned above the trial
`of the formula
`
`10
`
`15
`
`R.-
`
`j•
`I
`
`C-
`
`(Gl,i)..---C-(CHi);;-,
`
`jc
`I
`
`(IA) 20
`
`IH2-,H-
`
`(CH2)J-f1·l2,
`
`OH OH
`
`OH
`
`with the acetic acid ester of the formula
`
`(111
`
`(III')
`
`R0 , Rb and Re preferably represent hydrogen. One or two of
`R., Rb and R., may represent hydrogen and the other(s)
`C1-4-alkyl, particularly methyl. In the alternative, R0 , Rb and
`Re may all represent identical or different C1_4-alkyl groups.
`The parameters m and n independently of one another
`represent zero or integers from one to three; m preferably is
`zero and n preferably is three.
`The preparation of the carboxylic acid ortho ester poly(cid:173)
`mers is known and comprises the following steps: A trio[ of
`the formula
`
`OH
`I
`OH-A-OH,
`
`(II)
`
`wherein A represents the alkylene chain of the formula IA
`defined above, is reacted under the conditions of a conden(cid:173)
`sation reaction with a carboxylic acid ortho ester of the
`formula
`
`Oalk
`
`R1~0alk,
`
`Oalk
`
`(Ill)
`
`wherein Oalk represents the C1•4 -alkoxy group and R 1 is as
`defined above, to give an ortho ester polymer consisting
`essentially of monomer repeating units of the partial formula
`
`(I)
`
`wherein A represents the alkylene chain of the formula IA
`The synthesis reaction of the ortho ester monomer (III)
`and the triol (II) is carried out neat or in an aprotic solvent
`such as tetrahydrofuran (THF), cyclohexane, ethylene gly(cid:173)
`col dimethyl ether (glyme) or the like. Typical concentra(cid:173)
`tions of the reactants may range from essentially 100%
`
`25
`
`Oalk
`
`CH3~ 0 a l k,
`
`Oalk
`
`wherein Oalk represents the C 1_4-alkoxy group, to give an
`30 acetic acid ortho ester polymer consisting essentially of
`monomer repeating units of the partial formula
`
`([')
`
`35
`
`40 Component c)
`A pharmaceutically acceptable salt of an acid, which
`together with the acid R1-COOH being liberated from the
`decomposition of the ortho ester polymer (I) forms a buffer
`system in a physiologically acceptable pH-range, is defined
`45 by the definition of R1 in the ortho ester polymer ([). The
`pH-level in a physiologically acceptable range is between
`6.5 and 7.5. The pH of 7.5 must not be exceeded when
`intraocular or intramuscular administration is intended.
`When R1 is hydrogen, formic acid will be liberated upon
`50 hydrolysis of the ortho ester polymer (I). A suitable phar(cid:173)
`maceutically acceptable salt of formic acid is, e.g. sodium or
`potassium formiate . When R1 is methyl, acetic acid will be
`liberated upon hydrolysis. A pharmaceutically acceptable
`salt of acetic acid is, e.g. sodium or potassium acetate.
`When R1 is ethyl, n-propyl or n-butyl, the corresponding
`C3- , C4 - , or C5-carboxylic acids will be liberated upon
`hydrolysis. Preferred pharmaceutically acceptable acids of
`these acids are the sodium salts. The addition of pharma(cid:173)
`ceutically acceptable salts of other acids is also possible.
`60 Their strncture is unrelated with the group R1 in the ortho
`ester polymer (I), but these salts also form together with the
`acid R 1- COOH being liberated from the decomposition of
`the ortho ester polymer (I) a buffer system in the physi(cid:173)
`ologically acceptable pH-range defined above. Such salts
`65 are, for example, sodium citrate, salts from amino acids,
`sodium ascorbate, glycolate, lactate, tartrate, maleate,
`i'umarate, maleinate, succinate, benzoate and others.
`
`55
`
`FRESENIUS EXHIBIT 1065
`Page 5 of 10
`
`

`

`US 6,440,460 Bl
`
`5
`
`8
`muscular administration is intended, oily carrier liquids,
`such as propylene glycol, polyethylene glycol, sesame oil or
`olive oil, but also lecithin, may be added. Carrier liquids are
`particularly preferred when intramuscular, or intraocuJar
`administration is intended. The carrier liquid ethanol, if
`desired, is added in the degree of purity (96%) prescribed for
`injection formulations in accordance with the regulations of
`national pharmacopoeias, such as The U.S. Pharmacopoeia
`(USP) or Deul5cbes Arzneibucb (DAB). The proportion of
`ethanol can vary within wide limits from approximately 1 %
`to approximately 50%, preferably from approximately 1 % to
`approximately 10%. The carrier liquid water bas the degree
`of purity prescribed for intravenous administration and is
`germ- and pyrogen-free in accordance with the regulations
`15 of the national pharmacopoeias.
`
`7
`Pharmaceutically acceptable salts of the acids defined
`above have the particular advantage of buffering the phar(cid:173)
`maceutical composition on acceptable pH-levels. In the
`beginning and in all subsequent stages of the hydrolytic
`decomposition of the ortho ester polymer (I) biocompatibil-
`ity is maintained. Initial raises of the pH-level when decom(cid:173)
`position begins, to basic pH-levels and subsequent lowering
`to acidic pH-levels is avoided.
`The amount of the salt added is determined by the amount
`of the ortho ester polymer present in the pharmaceutical 10
`composition. The addition of molar equivalent amounts of
`salt i5 preferred. For each molar amount of acid liberated, the
`addition of a molar amount of the above-defined salt is
`suggested. The salt may aL5() be added in less than equivalent
`and excess amounl5, e.g. up to 2 molar equivalenl5.
`Component d)
`Suitable pharmaceutically acceptable additives are deter(cid:173)
`mined by the dosage form for the intended mode of
`administration, e.g. parenteral administration. A preferred
`mode of administration i5 especially intramuscular and 20
`subcutaneous, but also topical, e.g. ocular.
`Additives for topical formulations are listed in standard
`textbooks, e.g. Remington's Pharmaceutical Sciences or
`Hagers Ha.ndbuch der Pharmazeutischen Praxis. Topical
`formulations are in particular creams, ointments, gels, pastes 25
`or topically administered aerosols and also suspensions of
`nanoparticles or ophthalmic compositions. Suitable addi(cid:173)
`tives for topical and especially ophthalmic compositions are
`in particular inert carriers, solubilizers, tonicity-increasing
`agenl5, buffer substances, preservatives, thickeners, and 30
`other adjuncts. Such additives are e.g. vegetable oil, mineral
`oil containing hydroxyethyl cellulose, ethyl oleate, car(cid:173)
`boxymethyl cellulose, polyvinylpyrrolidone, and other non(cid:173)
`toxic water-soluble polymers intended for ophthalmic use,
`e.g . cellulose ethers such as methyl cellulose, alkali metal 35
`salts of carboxymethyl cellulose or hydroxymethyl,
`hydroxyethyl, or hydroxypropyl cellulose, acrylates or
`methacrylates such as sall5 of polyacrylic acid or ethyl
`acrylate, polyacrylamides, natural products such as gelatin,
`alginates, pectins, tragacanth, karaya gum, xanthan gum, 40
`carrageenan, agar or acacia, starch derivatives such as starch
`acetate and hydroxypropyl starch, and also other synthetic
`additives such as polyvinyl alcohol, polyvinylpyrrolidone,
`polyvinyl methyl ether, polyethylene oxide, preferably
`crosslinked polyacrylic acid, such as neutral Carbopol® or 45
`mixtures of these polymers.
`Tonicity-enhancing agents are, for example, ionic
`compounds, such as alkali metal or alkaline earth metal
`halides, e.g. CaC12 , KBr, KCl, LiCl, Nal, NaBr, or NaCl, or
`boric acid. Non-ionic tonicity-enhancing agents are, for 50
`example, urea, glycerol, sorbitol , mannitol, propylene
`glycol, or dextrose. Sufficient tonicit y-enhancing agent is
`added that the ophthalmic composition has an osmolality in
`a preferred range of about 50 to 400 mOsmol.
`Examples of preservatives are quaternary ammonium 55
`salts such as cetrimide, benzalkonium chloride, alkylmer(cid:173)
`cury salts of tb iosalicylic acid such as thiomersal, pbenylm(cid:173)
`ercury nitrate, acetate, or borate, parabens such as meth(cid:173)
`ylparaben or propylparaben, alcohol, e.g . cblorobutanol,
`benzyl alcohol, or pbenylethanol, guanidine deriva tives, e.g. 60
`cblorhexidine, or polybexametbylenebiguanide, or sorbic
`acid. If desired, the amount of preservative which is neces(cid:173)
`sary to ensure sterility is added to the ophthalmic compo-
`sition.
`Component e)
`A suitable pharmaceutically acceptable carrier liquid is
`defined by the intended mode of administration. If intra-
`
`PREFERRED EMBODIMENTS OF THE
`INVENTION
`The present invention particularly relates to a pharma(cid:173)
`ceutical composition comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic acid ortho ester polymer
`consisting essentially of monomer repeating units of
`the partial formula
`
`([')
`
`c) a pharmaceutically acceptable salt of an acid, which
`together with the acid CH3COOH being liberated from
`the decomposition of the ortbo ester polymer (I') forms
`a buffer system in a physiologically acceptable
`pH-range; and, optionally,
`d) further pharmaceutically acceptable additives.
`An especially preferred embodiment of the invention
`relates to a pharmaceutical composition comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic ortbo ester polymer consisting
`e.ssenti ally of monomer repeating units of the partial
`formula (I');
`c) the alkali metal salt X+CH3Coo-, which together with
`the acid CH3COOH being liberated from the decom(cid:173)
`position of the ortho ester polymer (I') forms a buffer
`system in the physiologically acceptable pH-range of
`5.5- 7.5; and, optionally,
`d) further pharmaceutically acceptable additives.
`A highly preferred embodiment of the invention relates to
`a pharmaceutical composition comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a non-rigid, bioerodible ortho ester polymer consisting
`essentially of monomer repeating units of the partial
`formula (I');
`c) the sodium salt Na+CH3COo-, which together with the
`acid CH3COOH being liberated from the decomposi(cid:173)
`tion of the ortbo ester polymer (I'), forms a buffer
`system;
`d) further pharmaceutically acceptable additives suitable
`for intraocular administration.
`
`65
`
`FRESENIUS EXHIBIT 1065
`Page 6 of 10
`
`

`

`9
`The present invention also relates to a process for the
`preparation of the above-mentioned pharmaceutical compo(cid:173)
`sition which process comprises preparing a non-rigid, bio(cid:173)
`erodible ortho ester polymer consisting essentially of mono(cid:173)
`mer repeating units of the partial formula (I) mentioned
`above; and adding and mixing, in any order of the subse(cid:173)
`quent process steps, component a), the therapeutic agent or
`a combination of therapeutic agents to be administered;
`component c), a pharmaceutically acceptable salt of an acid,
`which together with the acid R1--COOH being liberated
`from the decomposition of the ortho ester polymer (I), forms
`a buffer system in a physiologically acceptable pH-range;
`and, optionally, component d), further pharmaceutically
`acceptable additives; and/or component e ), a pharmaceuti(cid:173)
`cally acceptable carrier liquid.
`Mixing can be effected by vigorous shaking when using 15
`a dispersing machine, for example a Vortex mixer, or using
`dispersing machines produced by IKA(Staufen, Germany),
`a static mixer and conventional stirring machines having a
`propeller or paddle blade or tLSing a magnetic stirrer or phase
`mixer. In order to obtain an especially homogeneous 20
`mixture, stirring is carried out at high speed. Approximately
`from 0.1 to 50% by weight of the constituents (without the
`water component), based on the total weight of the mixture,
`preferably approxinlately from 2 to 20% by weight, can be
`dispersed in the carrier liquid.
`The following Example illustrates the invention:
`
`10
`
`25
`
`EXAMPLE 1
`a) Synthesis of The Ortho Ester Polymer
`34.68 g (300 mMol) of trimethyl ortho acetate (99%(cid:173)
`Aldricb Chemie, Steinbeim Germany) are mixed under 30
`anhydrous conditions with 40.25 g (300 mMol) of 1,2,6-
`hexanetriol (98%--Aldrich). The mixture is introduced into
`a round bottom flask, placed on a magnetic stirrer with 400
`ml of cyclohexane added. The reaction is catalyzed by the
`addition of 25 mg p-TSA: p-toluenesulfonic acid (Fluka). 35
`The reaction flask is equipped with a distillation column and
`heated to 120° C. under argon atmosphere and vigorous
`stirring. In a first step, the reaction by-product methanol is
`removed at 54° C. during the first 4 h of the distillation. In
`a second step, the temperature at the column bead climbs 40
`above 54° C. The distillation flow is decreased and the
`solution is heated for an additional 6 h until the boiling point
`of 81 ° C. is reached. The solution then is cooled to room
`temperature, and 10 drops of trietbylamine (Fluka) are added
`to neutralize the acid catalyst. Excess solvent is pured off 45
`and the polymer is dried overnight under vacuum at 40° C.
`The polymer is then purified by dissolution in 100 ml of
`tetra hydrofurane (THF) and and precipitation in 500 ml
`anhydrous methanol containing 10 drops of triethylamine.
`After separating off the solvent, the polymer is dried under 50
`high vacuum for 48 h. An 0.2,u air filter is added during the
`solvent evaporation in order to avoid air contamination
`when the vacuum is broken. No bacterial growth has been
`observed aft.er 48 h of incubation of test samples at 37° C.
`b) Preparation of the Drug Loaded Polymer
`A 5-fluorouracil (5-FU) loaded polymer is prepared by
`mixing under laminar flow 25 mg of gamma-sterilized (2.0
`Mrad) 5-FU and 12.5 mg of sodium acetate and dispersing
`the mixture with 2.5 g of aseptically prepared poly ortbo
`ester polymer. This mixture is suitable as implant or for 60
`intraocular administration.
`c) pH Determination
`The pH was measured during hydrolysis of the ortho ester
`polymer in order to asses.s the decrease of pH induced by the
`release of acetic acid.
`1 g (w/w) ortho ester polymer (POE) and 10 ml 0.9%
`sodium chloride solution were placed in an incubator
`
`65
`
`55
`
`US 6,440,460 Bl
`
`10
`(Haling, Aigle, Switzerland) at 37° C. under light shaking
`(100 U/min). The pH measurements were taken every days
`during the firs t week and then every we-ek until degradation
`was complete, with a pH-meter Mettler DL25 (N
`5 anikon-Uster, Switzerland) and a combined pH-glass micro(cid:173)
`electrode.
`Some results are shown in the accompanying drawing in
`which
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph showing pH profiles of the POE
`containing 5-FU, with or without addition of sodium acetate,
`and
`FIG. 2 is a graph showing 5-FU release profiles with and
`without addition of acetate.
`As shown in FIG. 1 stabilization of the pH level between
`5 and 6 is observed upon addition of sodium acetate.
`Without addition of acetate the pH level falls below 4 after
`one week. and thereafter further to 2.5.
`
`FIG. 2 shows that the release of 5-FU is only slightly
`affected by the adjunction of 0.5% sodium acetate.
`W hat is claimed is:
`1. A pharmaceutical composition for the controlled
`release of therapeutic agents from a polymer matrix com(cid:173)
`prising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic acid ortbo ester polymer
`consisting essentially of monomer repeating unit5 of
`the partial formula:
`
`(I)
`
`wherein Rl represents hydrogen or Cl-4-alkyl and A
`represents a hydroca rbon chain of the formula
`
`ib
`• I
`
`t
`m I
`
`R -C-(CHi)-C-(CH,' -
`Zl•
`
`(IA}
`
`'
`
`wherein Ra, Rb, and Re independently represent hydro(cid:173)
`gen or Cl-4-alkyl, and m and n independently
`represent zero or integers from one to three;
`c) a pharmaceutically acceptable salt of an acid, which
`together with the acid Rl -COOH being liberated from
`the decomposition of the ortho ester polymer (I) forms
`a buffer system in a physiologically acceptable pH
`range; and the following optional components;
`d) further pharmaceutically acceptable additives; and or
`e) a pharmaceutically acceptable carrier liquid .
`2. A pharmaceutical composition according to claim 1
`comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic acid ortho ester polymer
`consisting essentially of monomer repeating units of
`the partial formula
`
`FRESENIUS EXHIBIT 1065
`Page 7 of 10
`
`

`

`US 6,440,460 Bl
`
`11
`
`12
`
`(I')
`
`(1)
`
`c) a pharmaceutically acceptable salt of an acid, which
`together with the acid CH3 COOH being liberated from
`the decomposition of the ortho ester polymer (I') forms
`a buffer system in a physiologically acceptable
`pH-range; and, optionally,
`d) further pharmaceutically acceptable additives.