(12) United States Patent
`Gurny et al.
`
`USOO64.4046OB1
`(10) Patent No.:
`US 6,440,460 B1
`(45) Date of Patent:
`Aug. 27, 2002
`
`(54) PHARMACEUTICAL COMPOSITIONS
`CONTAINING BUFFERED ORTHO ESTER
`POLYMERS
`
`(75) Inventors: Robert Gurny; Monia Zignani, both
`of Geneve; Cyrus Tabatabay, Bernex,
`all of (CH)
`(73) Assignee: Allergan Sales, Inc., Irvine, CA (US)
`* Y Not
`Subj
`y disclai
`h
`f thi
`Otice:
`ubject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.:
`09/117,359
`(22) PCT Filed:
`Feb. 26, 1997
`(86) PCT No.:
`PCT/EP97/00906
`S371 (c)(1),
`Jul. 27, 1998
`(2), (4) Date:
`(87) PCT Pub. No.: WO97/32606
`PCT Pub. Date: Sep. 12, 1997
`Foreign Application Priority Data
`(30)
`Mar. 5, 1996
`(EP) ............................................ 961O3391
`(51) Int. Cl." ................
`... A61K 9/10; A61K 47/34
`(52) U.S. Cl. ........................................ 424/486; 424/426
`(58) Field of Search ................................. 424/486, 426,
`424/428; 514/772.3
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1978 Choi et al.
`4,093,709 A
`2/1979 Choi et al.
`4,138,344 A *
`5/1981 Radici et al.
`4,268,643 A *
`4,346,709 A * 8/1982 Schmitt
`5,030,457. A
`7/1991 Ng et al.
`5,700,485 A * 12/1997 Berde et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`WO 91/03510
`WO 93/OO383
`
`3/1991
`1/1993
`
`* cited by examiner
`
`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 R1-COOH liberated from the decom
`position of the ortho ester polymer forms a buffer System in
`a physiologically acceptable pH range.
`
`8 Claims, 1 Drawing Sheet
`
`O
`
`2
`
`4.
`time days
`
`
`
`-O- POEO63 (Mw 6'800) + 1% 5-FU
`-- POE 063 (Mw 6'800) + 1% 5-FU+ 0.5% sodium acetate
`
`DiSSOtution of POE
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 1 of 10
`
`

`

`U.S. Patent
`
`Fig. 1
`
`Aug. 27, 2002
`
`US 6,440,460 B1
`
`O
`
`2
`
`4.
`time days
`
`6
`
`8
`
`-O-POEO63 (Mw 6'800) + 1% 5-FU
`-- POE 063 (Mw 6'800) + 1% 5-FU+ 0.5% sodium acetate
`
`Dissolution of POE
`
`Fig. 2
`
`f2O
`OO
`
`4.68 OOO
`
`2 O
`
`O
`
`
`
`2O
`time hours
`
`4O
`
`60
`
`-O-POE (Mw 6'800) + 5-FU 1%
`-o- POE (Mw 6'800) + 5-FU 1% + sodium acetate 0.5%
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 2 of 10
`
`

`

`US 6,440,460 B1
`
`1
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING BUFFERED ORTHO ESTER
`POLYMERS
`
`2
`This decreasing pH-level renderS pharmaceutical compo
`Sitions or administration Systems containing the above
`mentioned carboxylic acid ester ortho ester polymers leSS
`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. Toxicol. Sci. 19, 25–35 (1994),
`The addition of a base to achieve neutralization is deemed
`unsuitable, Since basic Substances produce a local pH level
`above 8 at the site of addition. This is not acceptable for
`implants and for various modes of administration, especially
`intravenous and intraocular administration.
`
`OBJECTS OF THE INVENTION
`Accordingly, the problem to which the present invention
`relates may be defined as 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 necessary to maintain the pH-level
`in a physiologically acceptable constant range between 5.0
`and 7.5.
`This problem has been Solved by adding a pharmaceuti
`cally acceptable Salt of an acid, which together with the acid
`being liberated from the decomposition of the carboxylic
`acid ortho ester polymer (I) forms a buffer System in a
`physiologically acceptable pH-range.
`
`GENERAL DESCRIPTION OF THE INVENTION
`The present invention, therefore, relates to a pharmaceu
`tical composition for the controlled release of therapeutic
`agents from a polymer 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
`
`R1
`
`O
`
`| X X /
`
`O
`
`O
`
`(I)
`
`The present invention relates to a pharmaceutical com
`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
`tially of monomer repeating units of the partial formula
`
`R1
`
`O
`
`| X X /
`
`O
`
`O
`
`(I)
`
`15
`
`wherein R represents hydrogen or C-alkyl and A repre
`Sents a hydrocarbon chain of the formula
`
`Rb
`
`Re
`
`Ra
`
`C-(CH) C-(CH2) ,
`
`(IA)
`
`25
`
`wherein R. R. und R independently of one another rep
`resent hydrogen or C-alkyl, and m and n independently of
`one another represent Zero or integers from one to three;
`methods for preparing Such ortho esters and their utility as
`carriers in So-called controlled release pharmaceutical com
`positions have been disclosed in Published International
`Patent Application (WO) 91/03510, International Publica
`tion Date: Aug. 23, 1990.
`The 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
`tional Publication Date: Jun. 18, 1992. Under physiologi
`cally acceptable conditions of pH 7.4, the hydrolysis of the
`ortho ester polymer (1) has been observed. This hydrolysis
`could formally be regarded as the reversal of the polymeri
`sation Step, whereupon a triol of the formula
`
`35
`
`40
`
`45
`
`OH
`
`OH-A-OH
`
`(II)
`
`50
`
`is generated and the acid R-COOH is being liberated.
`When an carboxylic acid ortho ester polymer consisting
`essentially of monomer repeating units of the partial formula
`
`55
`
`(I)
`
`CH,
`
`O >{ O
`
`(CH2)4
`
`is hydrolyzed, the acid CHCOOH is liberated. Upon pro
`gressive hydrolysis of the ortho ester polymers, an increas
`ing amount of carboxylic acids RCOOH is being liberated.
`This causes a decrease of the pH-level in-vitro from values
`of about 6.5 to 4.5 to even lower values in 1-5 days
`depending on the moleclur weight of the polymer.
`
`60
`
`65
`
`wherein R represents hydrogen or C-alkyl, and A
`represents a hydrocarbon chain of the formula
`
`Rb
`
`Re
`
`R -C-(CH2) -C-(CH2) ,
`
`(IA)
`
`wherein R, R, und R independently of one another
`represent hydrogen or C-alkyl, and m and n inde
`pendently of one another represent Zero or integers
`from one to three;
`c) a pharmaceutically acceptable Salt of an acid, which
`together with the acid R-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
`ponents:
`d) further pharmaceutically acceptable additives, and/or
`e) a pharmaceutically acceptable carrier liquid.
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 3 of 10
`
`

`

`US 6,440,460 B1
`
`4
`hydrochloride, meSylate, acetate, Succinate, lactate, tartrate,
`fumarate, Sulfate or maleate Salt.
`Preferred therapeutic agents are immunosuppreSSants,
`Such as cycloSporin, cytostatics, Such as ediatrexate (10
`EDAM), doxorubicin, cytarabine, trifosamide,
`cyclophosphamide, fluorouracil or methotrexate and Zinc
`phthalocyanine as well as water-soluble sulfo 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 dose 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 vitroretinopathy; by Subcutaneous
`and intramuscular injection, Such as 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
`tially of monomer repeating units of the partial formula
`
`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
`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
`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
`peutic agents to be administered in the Selected dosage form
`to a host in a therapeutic method of treating the disease or
`condition indicated. Intramuscular and intraocular adminis
`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
`peutic or prophylactic agents in all major therapeutic? pro
`phylactic areas of medicine. Suitable therapeutic agents
`include the following pharmaceutical agents: antiinflamma
`tory agents, for example dexamethasone, Sodium dexam
`ethasone Sulfate, hydrocortisone or prednisolone, coronary
`dilators, for example nifedipine, isosorbitol dinitrate,
`nitroglycerine, diltiazem, trapidil, dipyridamole or dilazep,
`prostaglandins, for example prostaglandin E, E, or FA,
`peripheral vasodilators, for example ifenprodil, cinepaZet
`maleate, cyclandelate, cinnarizine or pentoxyphylline,
`antibiotics, for example amplicillin, amoxycillin, cephalexin,
`cephradine, cefroXadin, cefaclor, erythromycin,
`bacamplicillin, minocycline or chloramphenicol,
`antispasmodics, for example propantheline, atropine or
`Scopolamine, antituSSives and antiasthmatics, for example
`theophylline, aminophylline, methylephedrine, procatechol,
`trimethoduinol, codeine, clo?edanolol or dextromethorphan,
`diuretics, for example furoSemide or acetazolamide, muscle
`relaxants, for example chlorphenesin carbamate, tolperison,
`eperison or baclofen, mild tranquilisers, for example
`Oxazolam, diazepam, clotiazepam, medazepam, temazepam
`or fluidiazepam, potent tranquilisers, for example Sulpiride,
`clocapramine or Zotepin, beta-blockers, for example
`pindolol, propranolol, carteolol, Oxprenolol, metoprolol or
`labetalol, antiarrhythmics, for example procainamide,
`disopyramide, ajimalin or quinidine, antigout agents, Such as
`allopurinol, anticoagulants, Such as ticlopidine,
`antiepileptics, for example phenytoin or valproat,
`antihistamines, for example chlorpheniramine, clemastine,
`meguitazine, alimemazine, cyproheptadine, agents for treat
`ing nausea and dizziness, for example diphenidol,
`methochlopromide, domperidone or be tahistine,
`antihypertensives, for example reserpine, rescinnamine,
`methyldopa, praZoSin, clonidine or budrala Zin,
`Sympathomimetics, for example dihydroergotamine, isopro
`terenol or etillefrin, expectorants, for example bromheXine,
`carbocisteine, L-ethylcysteine or L-methylcysteine, oral
`antidiabetics, for example glibenclamide or tolbutamide,
`cardiovascular agents, for example ubidecarenon or adenos
`ine.
`Therapeutic agents can be converted into pharmaceuti
`cally acceptable Salts, for example into a hydrobromide,
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`R1
`
`O
`
`| X X /
`
`O
`
`O
`
`(I)
`
`wherein R represents hydrogen or C-alkyl and A repre
`Sents a hydrocarbon chain of the formula
`
`Rb
`
`Re
`
`R -C-(CH2) -C-(CH2) ,
`
`(IA)
`
`wherein R, R, und R independently of one another rep
`resent hydrogen or C-alkyl, and m and n independently of
`one another represent Zero or integers from one to three;
`A particularly preferred carboxylic acid ortho ester poly
`mer present in the pharmaceutical composition consists
`essentially of monomer repeating units of the partial formula
`
`(I)
`
`CH,
`
`9 X O
`
`(CH2)4
`
`The term bioerodible as used herein to describe the proper
`ties of the defined ortho ester polymerS is synonymous with
`the term biodegradable. These terms denote the property of
`a body of Solid or Semisolid polymers to undergo
`degradation, erosion and Solubilization as a result of
`hydrolysis of labile linkages at the physiological conditions
`of use.
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 4 of 10
`
`

`

`S
`Monomer repeating units of the partial formula I are
`Structurally recurring units or monomer units of the car
`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
`tical compositions containing copolymers and homopoly
`merS. Homopolymers are particularly preferred.
`In the monomer repeating units of the partial formula (I)
`R represents hydrogen or C-alkyl, e.g. methyl, ethyl, n
`or isopropyl or n-butyl. Methyl is particularly preferred. In
`15
`ortho ester polymers wherein R represents methyl, acetic
`acid is liberated upon hydrolysis of the polymer. in a
`hydrocarbon chain of the formula
`
`Rb
`
`Re
`
`Ra
`
`C-(CH) C-(CH2) ,
`
`(IA)
`
`R., R., and R. preferably represent hydrogen. One or two of
`R., R., and R may represent hydrogen and the other(s)
`C-alkyl, particularly methyl. In the alternative, R., R., and
`R may all represent identical or different C-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
`merS is known and comprises the following Steps: A triol of
`the formula
`
`25
`
`35
`
`OH
`
`OH-A-OH,
`
`(II)
`
`40
`wherein A represents the alkylene chain of the formula IA
`defined above, is reacted under the conditions of a conden
`sation reaction with a carboxylic acid ortho ester of the
`formula
`
`45
`
`R1
`
`Oalk
`
`Oalk,
`Oalk
`
`(III)
`
`wherein Oalk represents the C-alkoxy group and R is as
`defined above, to give an ortho ester polymer consisting
`essentially of monomer repeating units of the partial formula
`
`R1
`
`O
`
`| X X /
`
`O
`
`O
`
`(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
`col dimethyl ether (glyme) or the like. Typical concentra
`tions of the reactants may range from essentially 100%
`
`50
`
`55
`
`60
`
`65
`
`US 6,440,460 B1
`
`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
`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 1% molar (based on the amount
`of triol present).
`A preferred Synthesis compriseS reacting under the con
`ditions of a condensation reaction mentioned above the trial
`of the formula
`
`CH-CH-(CH2)-CH,
`
`OH, OH
`
`OH
`
`with the acetic acid ester of the formula
`
`CH
`
`Oak
`
`Oalk,
`Oak
`
`(II)
`
`(III)
`
`wherein Oalk represents the C-alkoxy group, to give an
`acetic acid ortho ester polymer consisting essentially of
`monomer repeating units of the partial formula
`
`(I)
`
`CH,
`
`° X O
`
`(CH2)4-.
`
`Component c)
`A pharmaceutically acceptable Salt of an acid, which
`together with the acid R-COOH being liberated from the
`decomposition of the ortho ester polymer (I) forms a buffer
`System in a physiologically acceptable pH-range, is defined
`by the definition of R in the ortho ester polymer (I). 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 R is hydrogen, formic acid will be liberated upon
`hydrolysis of the ortho ester polymer (I). A suitable phar
`maceutically acceptable Salt of formic acid is, e.g. Sodium or
`potassium formiate. When R is methyl, acetic acid will be
`liberated upon hydrolysis. A pharmaceutically acceptable
`Salt of acetic acid is, e.g. Sodium or potassium acetate.
`When R is ethyl, n-propyl or n-butyl, the corresponding
`C-, C-, or Cs-carboxylic acids will be liberated upon
`hydrolysis. Preferred pharmaceutically acceptable acids of
`these acids are the Sodium Salts. The addition of pharma
`ceutically acceptable Salts of other acids is also possible.
`Their structure is unrelated with the group R in the ortho
`ester polymer (I), but these salts also form together with the
`acid R-COOH being liberated from the decomposition of
`the ortho ester polymer (I) a buffer system in the physi
`ologically acceptable pH-range defined above. Such Salts
`are, for example, Sodium citrate, Salts from amino acids,
`Sodium ascorbate, glycolate, lactate, tartrate, maleate,
`fumarate, maleinate, Succinate, benzoate and others.
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 5 of 10
`
`

`

`US 6,440,460 B1
`
`7
`Pharmaceutically acceptable Salts of the acids defined
`above have the particular advantage of buffering the phar
`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
`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
`composition. The addition of molar equivalent amounts of
`Salt is preferred. For each molar amount of acid liberated, the
`addition of a molar amount of the above-defined salt is
`Suggested. The Salt may also be added in less than equivalent
`and exceSS amounts, e.g. up to 2 molar equivalents.
`Component d)
`Suitable pharmaceutically acceptable additives are deter
`mined by the dosage form for the intended mode of
`administration, e.g. parenteral administration. A preferred
`mode of administration is especially intramuscular and
`Subcutaneous, but also topical, e.g. ocular.
`Additives for topical formulations are listed in Standard
`textbooks, e.g. Remington's Pharmaceutical Sciences or
`Hagers Handbuch der Pharmazeutischen Praxis. Topical
`formulations are in particular creams, ointments, gels, pastes
`or topically administered aerosols and also Suspensions of
`nanoparticles or ophthalmic compositions. Suitable addi
`tives for topical and especially ophthalmic compositions are
`in particular inert carriers, Solubilizers, tonicity-increasing
`agents, buffer Substances, preservatives, thickeners, and
`other adjuncts. Such additives are e.g. Vegetable oil, mineral
`oil containing hydroxyethyl cellulose, ethyl oleate, car
`boxymethyl cellulose, polyvinylpyrrolidone, and other non
`toxic water-Soluble polymers intended for ophthalmic use,
`e.g. cellulose etherS Such as methyl cellulose, alkali metal
`salts of carboxymethyl cellulose or hydroxymethyl,
`hydroxyethyl, or hydroxypropyl cellulose, acrylates or
`methacrylates Such as Salts of polyacrylic acid or ethyl
`acrylate, polyacrylamides, natural products Such as gelatin,
`alginates, pectins, tragacanth, karaya gum, Xanthan gum,
`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 Carbopolf) or
`mixtures of these polymers.
`Tonicity-enhancing agents are, for example, ionic
`compounds, Such as alkali metal or alkaline earth metal
`halides, e.g. CaCl, KBr, KCl, LiCl, Nal, NaBr, or NaCl, or
`boric acid. Non-ionic tonicity-enhancing agents are, for
`example, urea, glycerol, Sorbitol , mannitol, propylene
`glycol, or dextrose. Sufficient tonicity-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
`Salts. Such as cetrimide, benzalkonium chloride, alkylmer
`cury Salts of thiosalicylic acid Such as thiomersal, phenylm
`ercury nitrate, acetate, or borate, parabens Such as meth
`ylparaben or propylparaben, alcohol, e.g. chlorobutanol,
`benzyl alcohol, or phenylethanol, guanidine derivatives, e.g.
`chlorhexidine, or polyhexamethylenebiguanide, or Sorbic
`acid. If desired, the amount of preservative which is neces
`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
`
`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 intraocular
`5 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 Deutsches Arzneibuch (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 has the degree
`of purity prescribed for intravenous administration and is
`germ- and pyrogen-free in accordance with the regulations
`of the national pharmacopoeias.
`
`15
`
`PREFERRED EMBODIMENTS OF THE
`INVENTION
`The present invention particularly relates to a pharma
`' 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
`
`25
`
`(I)
`
`CH,
`
`° X O
`
`(CH.)
`
`:
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`c) a pharmaceutically acceptable Salt of an acid, which
`together with the acid CHCOOH 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.
`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 ortho ester polymer consisting
`essentially of monomer repeating units of the partial
`formula (I);
`c) the alkali metal salt X"CHCOO, which together with
`the acid CHCOOH being liberated from the decom
`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"CHCOO, which together with the
`acid CHCOOH being liberated from the decomposi
`tion of the ortho ester polymer (I), forms a buffer
`System;
`d) further pharmaceutically acceptable additives Suitable
`for intraocular administration.
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 6 of 10
`
`

`

`9
`The present invention also relates to a proceSS for the
`preparation of the above-mentioned pharmaceutical compo
`Sition which process comprises preparing a non-rigid, bio
`erodible ortho ester polymer consisting essentially of mono
`mer repeating units of the partial formula (I) mentioned
`above, and adding and mixing, in any order of the Subse
`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 R-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
`cally acceptable carrier liquid.
`Mixing can be effected by Vigorous Shaking when using
`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 using a magnetic Stirrer or phase
`mixer. In order to obtain an especially homogeneous
`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 approximately from 2 to 20% by weight, can be
`dispersed in the carrier liquid.
`The following Example illustrates the invention:
`EXAMPLE 1.
`a) Synthesis of The Ortho Ester Polymer
`34.68 g (300 mMol) of trimethyl ortho acetate (99%–
`Aldrich Chemie, Steinheim Germany) are mixed under
`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).
`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 head climbs
`above 54 C. The distillation flow is decreased and the
`solution is heated for an additional 6 huntil the boiling point
`of 81 C. is reached. The solution then is cooled to room
`temperature, and 10 drops of triethylamine (Fluka) are added
`to neutralize the acid catalyst. ExceSS Solvent is pured off
`and the polymer is dried overnight under vacuum at 40 C.
`The polymer is then purified by dissolution in 100 ml of
`tetrahydrofurane (THF) and and precipitation in 500 ml
`anhydrous methanol containing 10 drops of triethylamine.
`After Separating off the Solvent, the polymer is dried under
`high vacuum for 48 h. An 0.2u 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 after 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 Ortho
`ester polymer. This mixture is Suitable as implant or for
`intraocular administration.
`c) pH Determination
`The pH was measured during hydrolysis of the ortho ester
`polymer in order to assess 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
`
`10
`(Haling, Aigle, Switzerland) at 37° C. under light shaking
`(100 U/min). The pH measurements were taken every days
`during the first week and then every week until degradation
`was complete, with a pH-meter Mettler DL25 (N
`anikon-Uster, Switzerland) and a combined pH-glass micro
`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.
`What is claimed is:
`1. A pharmaceutical composition for the controlled
`release of therapeutic agents from a polymer matrix com
`prising:
`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:
`
`-14N4.
`
`(I)
`
`wherein R1 represents hydrogen or C1-4-alkyl and A
`represents a hydrocarbon chain of the formula
`
`Rb
`
`Re
`
`R -C-(CH) C-(CH2) ,
`
`(IA)
`
`wherein Ra, Rb, and Rc independently represent hydro
`gen or C1-4-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 R1-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
`
`US 6,440,460 B1
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1065, p. 7 of 10
`
`

`

`US 6,440,460 B1
`
`(I)
`
`11
`
`CH,
`
`° X O
`
`(CH2)4-.
`
`12
`
`R1
`
`O |X) /
`
`O
`
`O
`
`(I)
`
`c) a pharmaceutically acceptable Salt of an acid, which
`together with the acid CHCOOH 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.
`3. A pharmaceutical composition according to claim 2
`comprising:
`a) the therapeutic agent or a combination of therapeutic
`agents to be administered;
`b) a bioerodible carboxylic ortho ester polymer consisting
`essentially of monomer repeating units of the partial
`formula (I);
`c) the alkali metal salt X"CHCOO, which together with
`the acid CHCOOH being liberated from the decom
`position of the ortho ester polymer (I) forms a