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(11) EP 1 913 001 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 489/08 (2006.01) A61K 31/485 (2006.01) 04.09.2013 Bulletin 2013/36 A61P 1/10 (2006.01) A61P 25/04 (2006.01)

(21) Application number: 06771163.0 (86) International application number: PCT/US2006/020233 (22) Date of filing: 25.05.2006 (87) International publication number: WO 2006/127899 (30.11.2006 Gazette 2006/48)

(54) (R)-N-METHYLNALTREXONE, PROCESSES FOR ITS SYNTHESIS AND ITS PHARMACEUTICAL USE (R)-METHYLNALTREXON, VERFAHREN ZUR HERSTELLUNG UND PHARMAZEUTISCHE VERWENDUNG (R)-METHYLNALTREXONE, PROCÉDÉ POUR LA FABRICATION ET UTILISATION PHARMACEUTIQUE

(84) Designated Contracting States: • IORIO, MARIA A. ET AL: " agonist/ AT BE BG CH CY CZ DE DK EE ES FI FR GB GR antagonist properties of quaternary HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI diastereoisomers derived from SK TR and " EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY , 19(4), 301-3 CODEN: (30) Priority: 25.05.2005 US 684616 P EJMCA5; ISSN: 0223-5234, 1984, XP009072981 • FUNKE, CAREL W. ET AL: "A proton and carbon- (43) Date of publication of application: 13 nuclear magnetic resonance study of three 23.04.2008 Bulletin 2008/17 quaternary salts of naloxone and oxymorphone" JOURNAL OF THE CHEMICAL SOCIETY, PERKIN (60) Divisional application: TRANSACTIONS 2: PHYSICAL ORGANIC 11180238.5 / 2 450 359 CHEMISTRY (1972-1999) , (5), 735-8 CODEN: JCPKBH; ISSN: 0300-9580, 1986, XP009072982 (73) Proprietor: PROGENICS PHARMACEUTICALS, • KOBYLECKI R J: "N-METHYLNALORPHINE: INC. DEFINITION OF N- ALLYL CONFORMATION FOR Tarrytown, NY 10591 (US) ANTAGONISM AT THE RECEPTOR" JOURNAL OF MEDICINAL CHEMISTRY, (72) Inventors: AMERICAN CHEMICAL SOCIETY. • DOSHAN, Harold, D. WASHINGTON, US, vol. 25, no. 11, 1982, pages Riverside, CT 06878 (US) 1278-1280, XP000978843 ISSN: 0022-2623 •PEREZ,Julio • BIANCHETTI A ET AL: "QUATERNARY Tarrytown, NY 01591 (US) DERIVATIVES OF NARCOTIC ANTAGONISTS : STEREOCHEMICAL REQUIREMENTS AT THE (74) Representative: Russell, Tim et al CHIRAL NITROGEN FOR IN VITRO AND VIVO Venner Shipley LLP ACTIVITY"LIFE SCIENCES, PERGAMON PRESS, 200 Aldersgate OXFORD, GB, vol. 33, no. SUPPL 1, 1983, pages London EC1A 4HD (GB) 415-418, XP000980615 ISSN: 0024-3205 cited in the application (56) References cited: • DE PONTI F: "METHYLNALTREXONE WO-A-2004/043964 US-A- 4 176 186 PROGENICS" CURRENT OPINION IN INVESTIGATIONAL DRUGS, PHARMAPRESS, US, vol. 3, no. 4, April 2002 (2002-04), pages 614-620, XP009066298 ISSN: 1472-4472

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 913 001 B1

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• YUAN CHUN-SU: "Clinical status of methylnaltrexone, a new agent to prevent and manage -induced side effects./TRIALS SO FAR SHOW THAT THIS PERIPHERAL ANTAGONIST CAN PREVENT OPIOID-INDUCED WITHOUT DIMINISHING PAIN PALLIATION" JOURNAL OF SUPPORTIVE ONCOLOGY, BIOLINK COMMUNICATIONS,, US, vol. 2, no. 2, March 2004 (2004-03), pages 111-117, XP002390438 ISSN: 1544-6794

2 1 EP 1 913 001 B1 2

Description and functional properties, although it is unpredictable whether this is the case in any particular circumstance. FIELD OF THE INVENTION is a cough suppressant, whereas its enantiomer, , is a potent narcotic. R,R- [0001] This invention relates to stereoselective synthe- 5 methylphenidate is a drug to treat attention deficit hyper- sis of (R)-N-methylnaltrexone (R-MNTX) and intermedi- activity disorder (ADHD), whereas its enantiomer, S,S- ates thereof, and the stereoselective synthesis of such methylphenidate is an antidepressant. S- fluoxetine is ac- intermediates. tive against migraine, whereas its enantiomer, R- fluoxe- tine is used to treat depression. The S enantiomer of BACKGROUND OF INVENTION 10 citalopram is therapeutically active isomer for treatment of depression. The R enantiomer is inactive. The S enan- [0002] Methylnaltrexone (MNTX) is a quaternary de- tiomer of omeprazole is more potent for the treatment of rivative of the pure , . It exists heartburn than the R enantiomer. as a salt. Names used for the bromide salt of MNTX in [0005] Bianchetti et al, 1983 Life Science 33 (Sup I): the literature include: Methylnaltrexone bromide;15 415-418 studied three pairs of diastereoisomers of qua- N-Methylnaltrexone bromide; Naltrexone methobro- ternary narcotic antagonist and their parent tertiary mide; Naltrexone methyl bromide; MRZ 2663BR. MNTX amines, , , and naloxone, to see was first reported in the mid-70s by Goldberg et al as how the configuration about the chiral nitrogen affected described in US Patent No. 4,176,186. It is believed that in vitro and in vivo activity. It was found that the activity addition of the methyl group to the ring nitrogen forms a 20 varied considerably depending on how the quaternary charged compound with greater polarity and less liposol- derivatives were prepared. In each series, only the dias- ubility than naltrexone. This feature of MNTX prevents it tereomer obtained by methylation of the N-allyl-substi- from crossing the blood-brain barrier in humans. As a tuted tertiary amine (referred to as "N-methyl diastere- consequence, MNTX exerts its effects in the periphery omer") was potent in displacing3H-naltrexone from rat rather than in the central nervous system with the advan- 25 brain membranes, and acting as a antagonist tage that it does not counteract the effects of in the guinea-pig ileum. Conversely, diastereoisomers on the central nervous system. obtained by reacting methyl- N- substituted tertiary [0003] MNTX is a chiral molecule and the quaternary amines with allyl halide (referred to as "N-allyl diastere- nitrogen can be in R or S configuration. (See FIG. 1.) It omers") did not displace 3H- naltrexone and had negligi- is unknown whether the different stereoisomers of MNTX 30 ble antagonist activity and slight agonist action in the exhibit different biological and chemical properties. All of guinea-pig ileum. In vivo findings were generally consist- the reported functions of MNTX described in the literature ent with those in vitro. Thus only the "N-methyl" but not indicate that MNTX is a peripheral opioid antagonist. the "N-allyl diastereomers" inhibited morphine-induced Some of these antagonist functions are described in U.S. constipation in rats and behaved as antagonists. The au- Patents 4,176,186, 4,719,215, 4,861,781, 5,102,887, 35 thor stated that the prepared materials appeared to be 5,972,954, 6,274,591, 6,559,158, and 6,608,075, and in pure by 1H and 13C nuclear magnetic resonance (NMR) U.S. Patent Application Serial Nos. 10/163,482analysis, but these methods are not accurate. The author (2003/0022909A1), 10/821,811 (20040266806),cites a literature reference for the assignment of the R 10/821,813 (20040259899) and 10/821,809configuration to the "N-methyl diastereomer" of nalor- (20050004155). These uses include reducing the side- 40 phine. No assignment is proposed for the levallorphan effects of opioids without reducing the analgesic effect and naloxone diastereomers. It would be adventurous to of opioids. Such side-effects include nausea, emesis, extrapolate the configuration to these diastereomers dysphoria, pruritus, urinary retention, bowel hypomotility, (R.J. Kobylecki et al, J. Med. Chem. 25, 1278-1280, constipation, gastric hypomotility, delayed gastric emp- 1982). tying and immune suppression. The art discloses that 45 [0006] Goldberg et al.’s US Patent No. 4,176,186, and MNTX not only reduces the side-effects stemming from more recently Cantrell et al.’s WO 2004/043964 A2 de- opioid analgesic treatment but also reduces the side- ef- scribe a protocol for the synthesis of MNTX. Both de- fects mediated by endogenous opioids alone or in con- scribe a synthesis of MNTX by quaternizing a tertiary N- junction with exogenous opioid treatment. Such side-ef- substituted morphinan alkaloid with a methylating agent. fects include inhibition of gastrointestinal motility, post- 50 Both Goldberg et al. and Cantrell et al. are silent as to operative gastrointestinal dysfunction, idiopathic consti- the stereoisomer(s) produced by the synthesis. The au- pation and other such conditions including, but not limited thors remained cautiously silent about the stereochem- to, those mentioned above. However, it is unclear from istry because the stereochemistry could not be deter- the art whether the MNTX used in these studies was a mined based on prior art. The cyclopropylmethyl side- mixture of R and S stereoisomers or a single stereoi-55 chain in naltrexone is different from the prior art side- somer. chains and may have affected the stereochemical out- [0004] The art suggests that isolated stereoisomers of come in the synthesis of MNTX, as may other reaction a compound sometimes may have contrasting physical parameters such as temperature and pressure. Based

3 3 EP 1 913 001 B1 4 on the method of synthesis described in each, it is un- MNTX is in R configuration with respect to nitrogen and known whether the MNTX so produced was R, S or a it contains HPLC detectable S- MNTX at a detection limit mixture of both. of 0.02% and a quantitation limit of 0.05%. [0007] Iorio Maria et al, European Journal of Medicinal [0016] According to one aspect of the invention the Chemistry,vol. 19, No.4, 1984,pages 301-303 describes 5 method provides MNTX, wherein at least 99.6%, 99.7%, narcotic agonist/antagonist properties of quaternary di- 99.8%, 99.85%, 99.9% , and even 99.95% of the MNTX astereoisomers derived from oxymorphone andis in the R configuration with respect to nitrogen, that can naloxone. be used in a composition further comprising and one or [0008] Funke Carel W et al, Journal of the Chemical more of a buffering agent, a chelating agent, a preserving Society, Perkin Transactions 2, 1986, pages 735-738 de- 10 agent, a cryoprotecting agent, a lubricating agent, a pre- scribesproton and 13Cnuclear resonance studies of qua- servative, an anti-oxidant, or a binding agent. ternary salts of naloxone and oxymorphone. [0017] R-MNTXis a salt. Thereforethere will be a coun- [0009] Kobylecki RJ, Journal of Medicinal Chemistry, terion, which for the present application, includes the American Chemical Society, vol. 25, No. 11, 1982, pages zwitterion. Typically, the counterion a halide, sulfate, 1278-1280 describes N- methylnalorphine and considers 15 phosphate, nitrate or an anionic-charged organic spe- the effect of equatorial and axial nitrogen substituents on cies. Halides include bromide, iodide, chloride, and flu- opioid antagonism. oride. In certain embodiments the halide is iodide and in [0010] Both Yuan Chun-Su, Journal of Supportive On- other important embodiments the halide is bromide. In cology, vol. 2, No. 2, March 2004 (2004-03), pages certain embodiments, the anionic-charged organic spe- 111-117 and De Ponti, Current Opinion in Investigational 20 cies is a sulfonate or a carboxylate. Examples of sul- Drugs, vol. 3, No. 4, April 2002, pages 614-620 describes fonates include mesylate, besylate, tosylate, and triflate. methylnaltrexone and its opioid antagonistic properties. Examples of carboxylates include formate, acetate, cit- [0011] S-MNTX in pure form, and a method of making rate, and fumarate. pure S-MNTX have not been described in the literature. [0018] The foregoing compositions that comprise Researchers would havebeen unableto definitively char- 25 MNTX in R configuration with respect to nitrogen in some acterize and distinguish the stereoisomer (s) obtained by important embodiments is a crystal, a solution, or a bro- the Goldberg et al. or Cantrell et al. synthesis in the ab- mide salt of MNTX. In other embodiments, the foregoing sence of pure S-MNTX as a standard. compositions are pharmaceutical preparations, prefera- bly in effective amounts and with a pharmaceutically ac- SUMMARY OF THE INVENTION 30 ceptable carrier. [0019] According to one aspect of the invention, the [0012] S-MNTX has now been produced in high purity method of the invention provides a crystal of MNTX that permitting the characterization of its relative retention is at least about 99.5%, or about 99.6% or about 99.7%, time in chromatography versus that of R- MNTX.The pure or is about 99.8%, or about 99.9%, or most preferably S-MNTX has been found to have activity different from 35 greater than 99.95% of MNTX in R configuration with the activity of MNTX reported in the literature. This high- respect to nitrogen. lights the need for methods of making and purifying R- [0020] According to one aspect of the invention, there MNTX to high purity. is provided a method for the stereoselective synthesis of [0013] The present invention provides R-MNTX inter- a compound of the formula: mediates, methods for making the semos, and novel40 methods for making substantially pure R-MNTX. [0014] The invention provides synthetic routes for ster- eoselective synthesis of R-MNTX, substantially pure R- MNTX, and crystals of substantially pure R-MNTX. [0015] The method of the invention provides MNTX in 45 Rconfiguration with respect to nitrogen presentat greater than 99.5%. In other embodiments the MNTX in R con- figuration with respect to nitrogen is present in greater than about 99.6 %, or about 99.7 %, or about 99.8 %, or about 99.9 %, or about 99.95 %, or even more preferably 50 greater than 99.95%. In one embodiment, there is no detectable S-MNTX using the chromatographic proce- dures described herein. Preferably, the method provides MNTX of the invention which is free of HPLC detectable S-MNTX. In one embodiment there is no HPLC detect- 55 wherein R is isobytyryl. able S-MNTX at a detection limit of 0.02% and a quanti- [0021] According to one aspect of the invention there tationlimit of0.05%. In yetanother embodiment the meth- is provided a compound of the formula: od of the invention provides MNTX where 99.85% of the

4 5 EP 1 913 001 B1 6

S-MNTX and R- MNTX as standards to determine relative retention/elution times. Relative retention times of R and S are described herein. [0025] Pure S-MNTX can be obtained according to the 5 following procedure: S- MNTX salt can be synthesized by combining iodomethylcyclopropane or another cyclopro- pylmethyl derivative with oxymorphone in a dipolar apro- tic solvent. The cyclopropylmethyl derivative contains a leaving group, preferably a halide, such as iodine or sul- 10 fonate. The dipolar aprotic solvent may be: N- methylpyr- rolidone (NMP), dimethyl formamide, methylphospho- wherein R is isobutyryl. The compound in one embodi- ramide, acetone, 1,4-dioxane, acetonitrile, or combina- ment is isolated. By isolated it is meant the compound is tions thereof. The synthesized S-MNTX can be purified at least 50% pure. The compound can be obtained at by chromatography, recrystallization, multiple recrystal- levels of even greater purity, such as 60%, 70%, 80%, 15 lizations, or a combination thereof. The reaction can be 90%, or even greater than 95% purity. In other embodi- carried out under atmospheric conditions across a wide ments the compound is in R configuration with respect temperature spectrum, for example, at 70 °C, or under a to nitrogen, the R form being present in greater than 50%, controlled reaction temperature between 65 °C to 75 °C. 60%, 70%, 80%, 90%, 95% , 99%, or even 99.5%% ver- Counterions may be substituted, optionally, for iodide by sus the S form. 20 transferring the S-MNTX iodo salt to a second solvent, [0022] According to another aspect of the invention, a such as isopropyl acetate or dioxane and exchanging method for stereoselective synthesis of R-MNTX is pro- iodide for a counterion other than iodide. Examples of vided. This method involves adding an isobutyryl group counterions are bromide, chloride, fluoride, nitrate, sul- to naltrexone to yield 3-O-protected-naltrexone; methyl- fonate, or carboxylate. The sulfonate can be mesylate, ating the 3-O-protected-naltrexone to yield 3-O-protect- 25 besylate, tosylate or triflate. The carboxylate can be for- ed-R-MNTX salt; and removing isobutyryl group to yield mate, acetate, citrate and fumarate. The reaction in the R-MNTX. In some embodiments of the invention the iso- second solvent can be conducted at room temperature. butyryl group can be added in the presence of each or [0026] The chromatography may be conducted using both: an organic solvent and/or a tertiary amine that is two solvents, solvent A and solvent B, wherein solvent not naltrexone, In some embodiments of the invention 30 A is an aqueous solvent and solvent B is a methanolic the naltrexone is methylated by reacting the 3- O-protect- solvent and wherein both A and B contain trifluoroacetic ed-naltrexone with methyl iodide to produce 3- O-protect- acid (TFA). Preferably, A is 0.1% aqueous TFA and B is ed-R-MNTX iodide salt. The 3- O-protected-naltrexone is 0.1% methanolic TFA. In important embodiments the col- protected that is by a hydroxyl protecting group isobutyr- umn comprises a bonded, end- cappedsilica. In important yl. In a preferred embodiment of the invention, the35 embodiments, the pore size of the column gel is 5 mi- 3-O-protected-R-MNTX iodide salt is treated with hydro- crons. In a most preferred embodiment, the column, flow bromic acid to remove the protecting group and produce rate and gradient program are as follows: R-MNTX bromide/ iodide salt, and the bromide/ iodide salt Column: Luna C18(2), 150 x 4.6 mm, 5 m is passed through an anion exchange resin column (bro- Flow Rate: 1 mL/min mide form) to yield R-MNTX bromide. In any of the fore- 40 Gradient Program: going aspects of the invention the tertiary amine that is not MNTX can be triethylamine. In any of the foregoing Time (min) %A %B aspects of the invention the organic solvent can be tet- 0:00 95 5 rahydrofuran. In the foregoing aspects of the invention the hydroxyl protecting group is isobutyryl. 45 8:00 65 35 [0023] The method of the invention may further com- 12:00 35 65 prise isolation and purification of R-MNTX, comprising passing the crude R-MNTX through a chromatography 15:00 0 100 column and collecting the R-MNTX which elutes at the 16:00 95 5 R-MNTX retention time. This process can be in addition 50 to the method described above, after the deprotecting 18:00 95 5 step and/or the anion exchange resin column step. [0024] R-MNTXof the inventionmay be usedin a meth- [0027] Detection can be carried out conveniently by od for analyzing R-MNTX in a mixture of R-MNTX and ultraviolet (UV) wavelength @ 230 nm. Quantitation Limit S-MNTX is provided. The method involves conducting 55 is the lowest amount of S- MNTX that can be consistently high performance liquid chromatography (HPLC) and ap- measured and reported, regardless of variations in lab- plying R-MNTX to the chromatography column as a oratories, analysts, instruments or reagent lots. Detec- standard. The method preferably involves applying both

5 7 EP 1 913 001 B1 8 tion Limit is the lowest amount of S-MNTX in a sample packaged unit dosage is a solution. The pharmaceutical which can be detected but not necessarily quantitated composition in one embodiment is a solution. In another as an exact value. embodiment it is an enteric coated solid dosage form. In [0028] The foregoing HPLC also can be used to deter- still another embodiment it is a sustained release formu- mine the relative amount of S-MNTX and R-MNTX and 5 lation. R-MNTX prepared by a method of the invention the intermediates of the synthesis thereof by determining may be used in a pharmaceutical preparation containing the area under the respective R and S curves in the chro- R-MNTX in a lyophilized formulation is prepared by com- matogram produced. According to another aspect of the bining a cryoprotective agent, such as , with the invention a method for isolation and purification of R- R-MNTX formulation. The lyophilized preparation may MNTX and the 3- O-protected-R-MNTX salt intermediate 10 also contain any one of, any combination of, or all of a is provided, comprising recrystallizing the crude R- MNTX buffering agent, an antioxidant, an isotonicity agent and or intermediates thereof from a solvent or a mixture of an opioid. In some embodiment the aforementioned solvents. This process can be in addition to the method pharmaceutical composition can further comprise one described above, after the deprotection step and/or the pharmaceutical agent that is not an opioid antagonist. In anion exchange resin column step. 15 one embodiment of the invention the aforementioned [0029] According to another aspect of the invention, a pharmaceutical composition can comprise a pharmaceu- method is provided for stereoselective synthesis of tical agent that is an opioid. In yet another embodiment, 3-O-protected R-MNTX salt comprising methylating a 3- the pharmaceutical composition can further comprise at O-protected-naltrexone with a methylating agent to yield least one opioid, and at least one pharmaceutical agent 3-O-protected-R-MNTX salt. The hydroxyl protecting20 that is not an opioid or an opioid antagonist. In a preferred group of the 3-O-protected-naltrexone is isobutyryl. The embodiment the pharmaceutical agent that is not an opi- 3-O-protected R-MNTX is a salt with an anion that can oid or an opioid antagonist is an antiviral agent, an anti- be, for example, a halide, sulfate, phosphate, nitrate or infective agent, an anticancer agent, an antispasmodic an organic anionic-charged species. The halide is bro- agent, an anti-muscarinic agent, a steriodal or non-ste- mide, iodide, chloride, or fluoride. The organic anionic- 25 riodal anti-inflammatory agent, a pro-motility agent, a charged species can be, for example, a sulfonate or car- 5HT1 agonist, a 5HT3 antagonist, a 5HT4 antagonist, a boxylate. Exemplary sulfonates are mesylate, besylate, 5HT4 agonist, a bile salt sequestering agent, a bulk- form- tosylate, or triflate. Exemplary carboxylates are formate, ing agent, an alpha2-adrenergic agonist, a , acetate, citrate, or fumarate. The method can further in- an antidepressant, a herbal medicine, an anti-diarrheal volve exchanging the anion with a different anion. The 30 medication, a , a stool softener, a fiber or a he- methylating agent can be a methyl group susceptible to matopoietic stimulating agent. nucleophilic attack, and a leaving group. Exemplary [0031] The pharmaceutical compositions can be pro- methylating agents are selected from the group consist- vided in kits. The kits are a package containing a sealed ing of methyl halide, dimethyl sulfate, methyl nitrate and container comprising the pharmaceutical preparations of methyl sulfonate. Methyl halides are methyl iodide, me- 35 the present invention and instructions for use. The kits thyl bromide, methyl chloride and methyl fluoride. Methyl contain R-MNTX that is free of HPLC detectable S- sulfonates include methyl mesylate, methyl besylate, MNTX. The kit in one embodiment contains 40mg/mL R- methyl tosylate, and methyl triflate. In one embodiment, MNTX. The kit in another embodiment contains 30mg/mL the methylation is conducted at a temperature range from of R- MNTX. The kit can further include an opioid or opioid about >70°C to about 100°C, or from 80°C to about 90°C, 40 agonist, or it can include at least one pharmaceutical or preferably at about 88°C. The methylation reaction is agent that is not an opioid or an opioid antagonist. In one conducted for about 1 hour to 24 hours, or about 5 hour embodiment, the kit is a package containing a sealed to 16 hours and in one embodiment for about 10 hours. container comprising the pharmaceutical preparation The method can futher involve purification of the 3- O-pro- that is or the 3- O-protected-R-MNTX salt and instructions tected R-MNTX salt using at least one purification tech- 45 for use. The kit in one embodiment contains 40mg/mL nique, such as chromatography or recrystallization. The 3-O-protected-R-MNTX salt. The kit in another embodi- chromatography can be reverse-phase chromatography ment contains 30mg/mL of 3- O-pxotected-R-MNTX salt. or regular phase chromatography. In some embodi- The kit can further include an opioid or opioid agonist, or ments, the regular phase chromatography can use alu- it can include at least one pharmaceutical agent that is mina or silica gel. The 3-O-protected-naltrexone can be 50 not an opioid or an opioid antagonist. purified prior to methylation. [0032] R-MTX prepared by a method of the invention [0030] R-MNTX prepared by the method of invention may be used in, methods for ensuring the manufacture may be used in a pharmaceutical composition that com- of R-MNTX (which is an opioid antagonist) that is free of prises R-MNTX free of detectable S-MNTX by the chro- S-MNTX (which is an opioid agonist). The methods per- matography procedures described herein and a pharma- 55 mit for the first time the assurance that a pharmaceutical ceutically acceptable carrier. In one embodiment the preparation of R-MNTX which is intended for antagonist pharmaceutical composition is a packaged unit dosage activity is not contaminated with a compound that oppos- or a multi-unit dosage. In yet another embodiment the es the activity of R-MNTX. This is particularly desirable

6 9 EP 1 913 001 B1 10 when R- MNTX is administered to oppose the side effects may be used in a method of preparing a pharmaceutical of opioid therapy, as opioids appear to act synergistically product, by selecting a composition of R- MNTX because with S-MNTX to oppose the activity of R-MNTX. In this it contains S- MNTX at a level that is less than 0.4%, 0.3%, aspect of the invention, a method is provided for manu- 0.2%, 0.15%, 0.1%, 0.05% of , or is absent from the com- facturing R-MNTX. The method involves: 5 position, and formulating the composition into a unit or multi unit dosage for administration to a patient. R- MNTX (a) obtaining a first composition containing R- MNTX, prepared by a method of the invention may be used to (b) purifying the first composition by chromatogra- provide packaged product. phy, recrystallization or a combination thereof, (c) [0037] The package contains a composition compris- conducting HPLC on a sample of purified first com- 10 ing R-MNTX, wherein the composition is free of HPLC position using S-MNTX as a standard, and (d) de- detectable S-MNTX, and indicia on or contained within termining the presence or absence of S- MNTX in the the package indicating that the composition is free of de- sample. In an important embodiment, both R- MNTX tectable S-MNTX. The composition can take on a variety and S-MNTX are used as standards, to determine of forms, including, but not limited to, a standard for use for example relative retention time of R-MNTX and 15 in laboratory experiments, a standard for use in manu- S-MNTX. In one embodiment, the purifying is multi- facturing protocols, or a pharmaceutical composition. If ple recryallization steps or multiple chromatogr aphy the composition is a pharmaceutical composition, then steps. In another embodiment, the purifying is car- one important form of indicia is writing on a label or pack- ried out until S-MNTX is absent from the sample as age insert describing the characteristics of the pharma- determined by HPLC. It should be understood, how- 20 ceutical preparation. The indicia can indicate directly that ever, that the purified first composition in some as- the composition is free of S- MNTX, or it can indicate the pects of the invention is not necessarily free of de- same indirectly, by stating for example that the compo- tectable S-MNTX. The presence of such S-MNTX, sition is pure or 100% R-MNTX. The pharmaceutical for example, might indicate that further purification composition can be for treating any of the conditions de- steps should be conducted if purer R-MNTX is de- 25 scribed herein. The pharmaceutical composition can sired. The methods can further involve packaging contain an effective amount of the pure R- MNTX and can purified first composition that is free of HPLC detect- take any of the forms described below as if specifically able S-MNTX. The methods further can include pro- recited in this summary, including, but not limited to, so- viding indicia on or within the packaged, purified first lutions, solids, semi-solids, enteric coated materials and composition indicating that the packaged, purified 30 the like. first composition is free of HPLC detectable S- [0038] R-MNTX prepared by a method of the invention MNTX. The method further can involve packaging a may be used in a method for treating or preventing opioid- pharmaceutically effective amount for treating any- inducedside effects comprisingadministering to a patient one of the conditions described herein. The first com- the R-MNTX free of detectable S- MNTX by the chroma- position containing R- and S- MNTX can be obtained 35 tography procedures described herein or the 3-O-pro- by the methods described herein. tected-R-MNTX salt intermediate composition of any of the foregoing aspects of the invention in an amount ef- [0033] The purifying may be carried out until S-MNTX fective to treat the opioid- induced side effect. In one em- is less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05%, even bodiment of the invention the patient is chronically ad- is absent from the purified first composition as deter-40 ministered opioids. In another embodiment the patient is mined by HPLC with a detection limit of 0.02 and a quan- acutely administered opioids. The opioid-induced side itiation limit of 0.05%. effect is preferably selected from a group consisting of [0034] In one embodiment the method provides indicia constipation, immune suppression, inhibition of gastroin- on or with the packaged purified first composition indi- testinal motility, inhibition of gastric emptying, nausea, cating a level of S-MNTX in the packaged first purified 45 emesis, incomplete evacuation, bloating, abdominal dis- composition. tension, increased gastroesophageal reflux, hypoten- [0035] R-MNTX prepared by a method of the invention sion, bradycardia, gastrointestinal dysfunction, pruritus, may be used in a package that contains a composition dysphoria, and urinary retention. In one preferred em- comprising R-MNTX and indicia on or contained within bodiment the opioid-induced side effect is constipation. the package indicating a level of S-MNTX in the compo- 50 In another preferred embodiment the opioid- induced side sition. In one embodiment the level of S-MNTX is less effect is inhibition of gastrointestinal motility or inhibition than 0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05%, or is absent of gastric emptying. In yet another preferred embodiment from the sample. In yet another embodiment, the pack- the opioid-induced side effect is nausea or emesis. In yet age further contains, mixed together with the R-MNTX, another preferred embodiment the opioid-induced side one or more of a buffering agent, a chelating agent, a 55 effect is pruritus. In yet another preferred embodiment preserving agent, a cryoprotecting agent, a lubricating the opioid-induced side effect is dysphoria. In yet another agent, a preservative, an anti- oxidant, or a binding agent. preferred embodiment the opioid-induced side effect is [0036] R-MNTX prepared by a method of the invention urinary retention.

7 11 EP 1 913 001 B1 12

[0039] R-MNTX prepared by a method of the invention MNTX composition free of detectable S-MNTX by the may be used in a method for treating a patient receiving chromatography procedures described herein or the an opioid for pain resulting from surgery comprising ad- 3-0-protected-R-MNTX salt intermediate in an amount ministering to the patient an R-MNTX composition free effective to ameliorate at least one symptom of the irri- of detectable S-MNTX by the chromatography proce- 5 table bowel syndrome. In some embodiments of the in- dures described herein or the 3-O-protected-R-MNTX vention the R-MNTX composition or the 3-0-protected- salt intermediate in an amount effective to promote gas- R-MNTX salt composition further comprises at least one trointestinal motility, gastric emptying or relief of consti- irritable bowel syndrome therapeutic agent. The irritable pation. bowel syndrome therapeutic agent can be selected from [0040] R-MNTX prepared by a method of the invention 10 the groups consisting of antispasmodics, anti- muscarin- may be used in a method for inducing laxation in a patient ics, anti-inflammatory agents, pro-motility agents, 5HT1 in need of laxation, comprising administering to the pa- agonists, 5HT3 antagonists, 5HT 4 antagonists, 5HT 4 ag- tient an R- MNTX composition free of detectable S- MNTX onists, bile salt sequestering agents, forming bulk- by the chromatography procedures described herein or agents, alpha2-adrenergic agonists, mineral oils, antide- the 3-0-protected-R-MNTX salt intermediate in an effec- 15 pressants, herbal medicines, anti-diarrheal medication tive amount. and combinations thereof. [0041] R-MNTX prepared by a method of the invention [0046] R-MNTX prepared by method of the invention may be used in, a method for preventing and/or treating may be need in, methods for parenteral administration impaction in a patient in need of such prevention/treat- of R-MNTX including but not limited to intravenous, in- ment, comprising administering to the patient an R-20 tramuscular and subcutaneous administration. R- MNTX MNTX composition free of detectable S-MNTX by the may be in pharmaceutical preparations suitable for use chromatography procedures described herein or the in pre-filled syringes, pre-filled pen injectors, cartridges 3-0-protected-R-MNTX salt intermediate in an effective for use in pen injectors, reusable syringes or other med- amount. ical injectors, liquid dry injectors, needleless pen sys- [0042] R-MNTX prepared by a method of the invention 25 tems, syrettes, autoinjectors, or other patient-controlled may be used in, a method for preventing and/or treating injection devices. post-operative bowel dysfunction following surgery, in [0047] These and other aspects of the invention are particular abdominal surgery in a patient in need of such described in greater detail herein. prevention/treatment, comprising administering to the patient an R-MNTX composition free of detectable S- 30 BRIEF DESCRIPTION OF DRAWINGS MNTX by the chromatography procedures described herein or the 3- 0-protected-R-MNTX salt intermediate in [0048] an effective amount. [0043] R-MNTX prepared by a method of the invention FIG. 1 provides the chemical structure of bromide may be used in, a method for treating or preventing en- 35 salts of R-MNTX and S-MNTX. dogenous opioid-induced gastrointestinal dysfunction FIG. 2 is a chromatogram showing the separation of comprising administering to the patient an R- MNTX com- R and S forms of MNTX in a mixture of S- and R- position free of detectable S- MNTX by the chromatogra- MNTX. phy procedures described herein or the 3-0-protected- FIG. 3 is a chromatogram of R- MNTX with the addi- R-MNTX salt intermediate in an amount effective to treat 40 tion of approximately 0.1 % of the S-MNTX isomer. the endogenous opioid-induced gastrointestinal dys- FIG. 4 is a chromatogram of R- MNTX with the addi- function. The gastrointestinal dysfunction can be select- tion of approximately 1.0% of the S-MNTX isomer. ed from a group consisting of inhibition of gastrointestinal FIG. 5 is a chromatogram of R- MNTX with the addi- motility, constipation and ileus. In some embodiments of tion of approximately 3.0% of the S-MNTX isomer. the invention the ileus is selected from the group com- 45 FIG. 6 shows a reaction scheme for the synthesis of prising of: post-operative ileus, post-partum ileus, para- R-MNTX using a preferred hydroxyl protecting lytic ileus. group. [0044] R-MNTX prepared by a method of the invention FIG. 7 shows an alternative reaction scheme for the may be used in, a method for preventing or treating idi- synthesis of R- MNTX using a preferred hydroxyl pro- opathic constipation comprising administering to the pa- 50 tecting group. tient an R- MNTX composition free of detectable S- MNTX FIG. 8 shows a kit according to the invention. by the chromatography procedures described herein or the 3-0-protected-R-MNTX salt intermediate in an DETAILED DESCRIPTION amount effective to prevent or treat the idiopathic consti- pation. 55 [0049] The invention provides synthetic routes for ster- [0045] R-MNTX prepared by a method of the invention eoselective synthesis of R-MNTX, [morphinanium, 17R, may be used in, a method for treating irritable bowel syn- 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-17- drome comprising administering to the patient an R- methyl-6-oxo-,salt, (5α)-(9Cl)].

8 13 EP 1 913 001 B1 14

[0050] R-MNTX has the structure in the formula: from 1 to about 3 carbons. Exemplary alkyl groups in- clude methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. "Lower alkyl" refers to an alkyl group having 1 to 5 about 6 carbon atoms. Preferred alkyl groups include the lower alkyl groups of 1 to about 3 carbons. [0053] An "alkylating agent" is a compound that can be reacted with a starting material to bind, typically cov- alently, an alkyl group to the starting material. The alkylat- 10 ing agent typically includes a leaving group that is sep- arated from the alkyl group at the time of attachment to the starting material. Leaving groups may be, for exam- ple, halogens, halogenated sulfonates or halogenated wherein X- is a counterion. The counterion can be any acetates. An example of an alkylating agent is cyclopro- counter ion, including a zwitterion. Preferably the coun- 15 pylmethyl iodide. terion is pharmaceutically acceptable. Counterions in- [0054] "Methylating agent" means a reactive species, clude halides, sulfates, phosphates, nitrates, and anion- having electrophilic properties, that is capable of intro- ic-charged organic species. The halide can be iodide, ducing a "methyl group" at the nitrogen atom of naltrex- bromide, chloride, fluoride or a combination thereof. In one, so as to form a covalent bond therewith. Illustrative one embodiment the halide is iodide. In a preferred em- 20 methylating agents can be represented by the formula bodiment the halide is bromide. The anionic- charged or- CH3Z, wherein "Z" is a leaving group which, upon its de- ganic species may be a sulfonate or carboxylate. The parture, enables CH3 to form a covalent bond with the sulfonate may be mesylate, besylate, tosylate, or triflate. nitrogen atom of naltrexone, forming MNTX. Methylating The carboxylate may be formate, acetate, citrate, or fu- agents in general, and leaving groups in general, are well marate. 25 known to those of ordinary skill in the art and are de- [0051] The invention further provides an R-MNTX in- scribed extensively in both the patent literature and in termediate, isolated 3-0-protected-R-MNTX salt of the chemistry text books. Suitable Z groups include, but are formula : not limited to, fluoro, chloro, bromo, iodo, -OSO2CF3, CH3OSO2O-, 2CH3 -OSO,-OSO2C6H4-p-CH3, 30 -OSO2C6H4-p-Br. [0055] "Alkenyl", in general, refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms in the chain, and all combinations and subcombinations of ranges therein. 35 In certain preferred embodiments, the alkenyl group is a

C2 -C10 alkyl group, i.e., a branched or linear alkenyl group having from 2 to about 10 carbons. In other pre- ferred embodiments, the alkenyl group is a C 2 -C 6 alkenyl group, i.e., a branched or linear alkenyl group having 40 from 2 to about 6 carbons. In st ill other preferred embod-

iments, the alkenyl group is a C 3 -C10 alkenyl group, i.e., wherein R is isobutyryl, substantially pure 3- O-protected- a branched or linear alkenyl group having from about 3 R-MNTX salt, crystals of substantially pure 3-O-protect- to about 10 carbons. In yet other preferred embodiments, ed-R-MNTX salt, and methods for their use. The inven- the alkenyl group is a 2 C -C5 alkenyl group, i.e., a tion further provides synthetic routes for stereoselective 45 branched or linear alkenyl group having from 2 to about synthesis of the 3- O-protected-R-MNTX salt of the inven- 5 carbons. Exemplary alkenyl groups include, for exam- tion. ple, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, [0052] "Alkyl", in general, refers to an aliphatic hydro- octenyl, nonenyl and decenyl groups. carbon group which may be straight, branched or cyclic [0056] "Alkylene", in general, refers to a straight or having from 1 to about 10 carbon atoms in the chain, and 50 branched bivalent aliphatic hydrocarbon group having all combinations and subcombinations of ranges therein. from 1 to about 6 carbon atoms, and all combinations "Branched" refers to an alkyl group in which a lower alkyl and subcombinations of ranges therein. The alkylene group, such as methyl, ethyl or propyl, is attached to a group may be straight, branched or cyclic. Exemplary linear alkyl chain. In certain preferred embodiments, the alkylene groups include, for example, methylene (- CH2-), 55 alkyl group is a C1-C5 alkyl group, i.e., a branched or ethylene (-CH2-CH2-) and propylene (-(CH2)3-). There linear alkyl group having from 1 to about 5 carbons. In may be optionally inserted along the alkylene group one other preferred embodiments, the alkyl group is a C 1-C3 or more oxygen, sulfur or optionally substituted nitrogen alkyl group, i.e., a branched or linear alkyl group having atoms, wherein the nitrogen substituent is alkyl as de-

9 15 EP 1 913 001 B1 16 scribed previously. Preferred alkylene groups have from preferably an optionally substituted phenyl ring. Exem- about 1 to about 4 carbons. plary aryl-substituted alkyl groups include, for example, [0057] "Alkenylene", in general, refers to an alkylene phenylmethyl, phenylethyl and 3-(4-methylphenyl)pro- group containing at least one carbon--carbon double pyl. bond. Exemplary alkenylene groups include, for exam- 5 [0066] "Heterocyclic", in general, refers to a monocy- ple, ethenylene CH=CH-) (- and propenylene (- clicor multicylic ring systemradical containing fromabout

CH=CHCH2-). Preferred alkenylene groups have from 2 4 to about 10 members, and all combinations and sub- to about 4 carbons. combinations of ranges therein, wherein one or more of [0058] "Cycloalkyl", in general, refers to any stable the members is an element other than carbon, for exam- monocyclic or bicyclic ring having from about 3 to about 10 ple, nitrogen, oxygen or sulfur. The heterocyclic group 10 carbons, and all combinations and subcombinations may be aromatic or nonaromatic. Exemplary heterocyclic of ranges therein. In preferred embodiments, the cy- groups include, for example, isoxazole, pyrrole and pip- cloalkyl group is a C3 -C8 cycloalkyl group, i.e., a cy- eridine groups. cloalkyl group having from about 3 to about 8 carbons, [0067] "Organic solvent" has its common ordinary 15 with C3 -C6 cycloalkyl groups, i.e., cycloalkyl groups hav- meaning to those of skill in this art. Exemplary organic ing from about 3 to about 6 carbons being more preferred. solvents useful in the invention include, but are not limited The cycloalkyl group may be optionally substituted with to tetrahydrofuran, acetone, hexane, ether, chloroform, one or more cycloalkyl group substituents. Preferred cy- acetic acid, acetonitrile, chloroform, cyclohexane, meth- cloalkyl group substituents include alkyl, preferably C1 anol, and toluene. Anhydrous organic solvents are in- 20 -C3 alkyl, alkoxy, preferably C1 -C3 alkoxy, or halo. Ex- cluded. emplary cycloalkyl groups include, for example, cyclo- [0068] "Dipolar aprotic" solvents are protophilic sol- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl vents that cannot donate labile hydrogen atoms and that and cyclooctyl groups. exhibit a permanent dipole moment. Examples include [0059] "Cycloalkyl-substituted alkyl", in general, refers acetone, ethyl acetate, dimethyl sulfoxide (DMSO), to a linear alkyl group, preferably a lower alkyl group,25 dimethyl formamide (DMF) and N-methylpyrrolidone. substituted at a terminal carbon with a cycloalkyl group, [0069] "Dipolar protic" solvents are those that can do- preferably a C3 -C8 cycloalkyl group. Typical cycloalkyl- nate labile hydrogen atoms and that exhibit a permanent substituted alkyl groups include cyclohexylmethyl, cy- dipole moment. Examples include water, alcohols such clohexylethyl, cyclopentylethyl, cyclopentylpropyl, cyclo- as 2-propanol, ethanol, methanol, carboxylic acids such propylmethyl and the like. 30 as formic acid, acetic acid, and propionic acid. [0060] "Cycloalkenyl", in general, refers to an olefini- [0070] "Tertiary amines" has its common, ordinary cally unsaturated cycloalkyl group having from about 4 meaning. In general, the tertiary amines useful in the in- to about 10 carbons, and all combinations and subcom- vention have the general formula: binations of ranges therein. In preferred embodiments, 35 the cycloalkenyl group is a C5 -C8 cycloalkenyl group, i.e., a cycloalkenyl group having from about 5 to about 8 carbons. [0061] "Alkoxy", in general, refers to an alkyl- O- group where alkyl is as previously described. Exemplary alkoxy 40 groups include, for example, methoxy, ethoxy, propoxy, wherein R1, R2, and R3 are identical or a combination of butoxy and heptoxy. different straight or branched chain alkyl groups, alkenyl [0062] "Alkoxy-alkyl", in general, refers to an alkyl- groups, alkylene groups, alkenylene groups, cycloalkyl O-alkyl group where alkyl is as previously described. groups, cycloalkyl-substituted alkyl groups, cycloalkenyl [0063] "Acyl", in general, means an alkyl-CO- group groups, alkoxy groups, alkoxy- alkyl groups, acyl groups, wherein alkyl is as previously described. Preferred acyl 45 aryl groups, aryl-substituted alkyl groups, and heterocy- groups comprise lower alkyl groups, such as alkyl of clic groups. Exemplary tertiary amines useful according about 1 to about 3 carbons. Exemplary acyl groups in- to the invention are those where R 1-3 is an alkyl group of clude acetyl, propanoyl, 2-methylpropanoyl, and bu- the formula (C nH2n+1, n=1-4), or aralkyl group of the for- tanoyl. mula (C6H5(CH2)n- [n=1-2]. Exemplary tertiary amines [0064] "Aryl", in general, refers to an aromatic carbo- 50 useful according to the invention also are cycloalkyl ter- cyclic radical containing 6, 10 or 14 carbons. The phenyl tiary amines (e.g., N-methylmorpholine, N-methylpyrro- group may be optionally substituted with one or two or lidine, N-methylpiperidine), pyridine and Proton more substituents. Preferred aryl group substituents in- Sponge® (N,N,N’,N’-tetramethyl-1,8-naphthalene). clude alkyl groups, preferably C 1-C5 alkyl groups. Exem- [0071] As will be readily understood, functional groups plary aryl groups include phenyl and naphthyl. 55 present may contain protecting groups during the course [0065] "Aryl-substituted alkyl", in general, refers to an of synthesis. Protecting groups are known per se as linear alkyl group, preferably a lower alkyl group, substi- chemical functional groups that can be selectively ap- tuted at a carbon with an optionally substituted aryl group, pended to and removed from functionalities, such as hy-

10 17 EP 1 913 001 B1 18 droxyl groups and carboxyl groups. These groups are can be used to formulate pharmaceutical preparations. present in a chemical compound to render such function- The pharmaceutical preparations, when used alone or in ality inert to chemical reaction conditions to which the cocktails, are administered in therapeutically effective compound is exposed. amounts. A therapeutically effective amount will be de- [0072] Protecting groups can be selectively appended 5 termined by the parameters discussed below; but, in any to a functionality. These groups render such functionality event, is that amount which establishes a level of the inert to chemical reaction conditions to which the com- drug(s) effective for treating a subject, such as a human pound may be exposed. After the protecting group has subject, having one of the conditions described herein. served its purpose it can be selectively removed from the An effective amount means that amount alone or with functionality without altering the molecular structure. Pro- 10 multiple doses, necessary to delay the onset of, lessen tecting groups can be selectively appended to and re- the severity of, or inhibit completely, lessen the progres- moved from the functionality under mild conditions, in sion of, or halt altogether the onset or progression of the high yield. condition being treated or a symptom associated there- [0073] The Protecting group employed in the invention with. In the case of constipation, an effective amount, for is isobutyryl, due to its greater stability which results in 15 example, is that amount which relieves a symptom of higher yield and purity. Such a protecting group provides constipation, which induces a bowel movement, which yields of 3-O-protected-naltrexone of greater than 70, increases the frequency of bowel movements, or which preferably greater than 75%. In one embodiment, yield decreases oral-cecal transit time. The known and con- of 3-O-protected-naltrexone is about 80% or greater. ventional definition of constipation is (i) less than one [0074] The present invention provides a method for 20 bowel movement in the previous three days or (ii) less stereoselective synthesis of R-MNTX comprising; than three bowel movements in the previous week (See e.g., U.S. Patent 6,559,158). In other words, a patient is (a) methylating a 3-O-protected-naltrexone with a not constipated (i.e., has "regular bowel movements" as methylating agent to yield 3-O-protected-RMNTX used herein) if the patient has at least one bowel move- salt; and 25 ment every three days and at least three bowel move- (b) hydrolysis to remove the 3- hydroxyl protecting ments per week. Accordingly, at least one bowel move- group to yield R-MNTX, wherein the hydroxyl pro- ment every two days would be considered regular bowel tecting group of the 3-O-protected-R-MNTX salt in- movements. Likewise, at least one bowel movement per clude isobutyryl. day is a regular bowel movement. Effective amounts 30 therefore can be those amounts necessary to establish [0075] Unlike the method described by Goldberg et al or maintain regular bowel movements. which teaches room temperature for three weeks or 70°C [0079] In certain instances, the amount is sufficient to for seven days for the methylation reaction to produce induce a bowel movement within 12 hours of administra- N-MNTX, the stereoselective methylation conditions of tion of the R- MNTX, 10 hours, 8 hours, 6 hours, 4 hours, the present invention are conducted at a temperature 35 2 hours, 1 hour and even immediately upon administra- above 70°C, more preferably above 80°C. In one em- tion, depending upon the mode of administration. Intra- bodiment, thereaction is carriedout atabout 88°C, Based venous administration can produce an immediate effect on the standard principles of chemical reactions involving of laxation in chronic opioid users. Subcutaneous admin- stereoisomers, one would expect at higher temperatures istration can result in a bowel movement within 12 hours the reaction would proceed with kinetic control resulting 40 of administration, preferably within 4 hours of adminis- in a mixture of R-MNTX and S-MNTX with high percent- tration. When administered to a subject, effective ages of both stereoisomers. It was surprising that at el- amounts will depend, of course, on the particular condi- evated temperatures the method of the present invention tion being treated; the severity of the condition; individual provided predominantly the R-MNTX rather than a mix- patient parameters including age, physical condition, ture with a higher percentage of S-MNTX. 45 size and weight; concurrent treatment and, especially, [0076] The methylation reaction of the present inven- concurrent treatment with opioids where opioids are ad- tion is allowed to proceed from 1 hour to about 24 hours, ministered chronically; frequency of treatment; and the preferably about 5 hours to about 16 hours, more pref- mode of administration. These factors are well known to erably about 8 to 12 hours, most preferably about 10 those of ordinary skill in the art and can be addressed hours. This reaction time offers a major industrial scale 50 with no more than routine experimentation. advantage over the three weeks at room temperature or [0080] Patients amenable to such therapy include but seven days at 70°C taught by Goldberg et al. are not limited to terminally ill patients, patients with ad- [0077] In a preferred embodiment, the methylation re- vanced medical illness, cancer patients, AIDS patients, action is conducted at about 88° C for 10 hours. These post-operative patients, patients with chronic pain, pa- reaction parameters are highly desirable for the devel- 55 tients with neuropathies, patients with rheumatoid arthri- opment of a process amenable to scale-up in industrial tis, patients with , patients with chronic back scale. pain, patients with spinal cord injury, patients with chronic [0078] R-MNTX prepared by a method of the invention abdominal pain, patients with chronic pancreatic pain,

11 19 EP 1 913 001 B1 20 patients with pelvic/perineal pain, patients with fibromy- sufficient to induce laxation. This has particular applica- algia, patients with chronic fatigue syndrome, patients tion where the subject is a chronic opioid user. Chronic infected with HCV, patients with irritable bowel syn- opioid use as used herein includes daily opioid treatment drome, patients with migraine or tension headaches, pa- for a week or more or intermittent opioid use for at least tients with sickle cell anemia, patients on hemodialysis, 5 two weeks. It previously was determined that patients and the like. receiving opioids chronically become tolerant to opioids [0081] Patients amenable to such therapy also include and need increasing doses. Thus, a patient receiving oral but are not limited to patients suffering from dysfunctions doses of opioids chronically would be receiving typically caused by endogenous opioids, especially in post- oper- between 40 and 100 mg per day of a morphine- equivalent ative settings. In certain embodiments, the R-MNTX is 10 dose of opioid. It likewise was determined surprisingly present in an amount sufficient to accelerate discharge thatsuch subjects becomemore responsive tothe effects from hospital post-surgery, including abdominal surger- of MNTX and that surprisingly lower doses induced side ies such as rectal resection, colectomy, stomach, es- effects. Thus, to induce immediate laxation, it requires ophageal, duodenal, appendectomy, hysterectomy, or on the order of only about 0.15 mg/kg MNTX intravenous- non-abdominal surgeries such as orthopedic, trauma in- 15 ly. For oral administration, a sufficient dose is believed juries, thoracic or transplantation surgery. This treatment to be less than 3 mg/kg uncoated and even less when can be effective to shorten the length of the time in the the R-MNTX is enterically coated. hospital, or to shorten the time to a hospital discharge [0085] Patients using opioids chronically include late order written post-operatively by shortening the time to stage cancer patients, elderly patients with osteoarthritic bowel sounds after surgery, or first flatus, to first laxation 20 changes, maintenance patients, neuropathic or to solid diet intake following surgery. The R-MNTX pain and chronic back pain patients. Treatment of these may continue to be provided after the patient has ceased patients is important from a quality of life standpoint, as to receive opioid pain medications post-operatively. well as to reduce complications arising from chronic con- [0082] Certain patients particularly amenable to treat- stipation, such as hemorrhoids, appetite suppression, ment are patients having the symptoms of constipation 25 mucosal breakdown, sepsis, colon cancer risk, and my- and/or gastrointestinal immotility and who have failed to ocardial infarction. obtain relief or ceased to obtain relief or a consistent de- [0086] The opioid can be any pharmaceutically accept- gree of relief of their symptoms using a laxative or a stool able opioid. Common opioids are those selected from softener, either alone or in combination, or who are oth- the group consisting of , , asimado- erwise resistant to and/or stool softeners. Such 30 line, , burprenorphine, , co- patients are said to be refractory to the conventional lax- deine, , diacetylmorphine (), dihydroco- atives and/or stool softeners. The constipation and/or deine, , , , funaltrexam- gastrointestinal immotility may be induced or a conse- ine, , , levallorphan, lev- quence of one or more diverse conditions including, but omethadyl acetate, , , meperidine not limited to, a disease condition, a physical condition, 35 (), methadone, morphine, morphine-6-glucoro- a drug-induced condition, a physiological imbalance, nide, , nalorphine, , , oxy- stress, anxiety, and the like. The conditions inducing con- morphone, , , propoxyphene, stipation and/or gastrointestinal immotility may be acute remifentanyl, , , , and trama- conditions or chronic conditions. dol. The opioid also may be mixed together with the R- [0083] The subjects can be treated with a combination 40 MNTX and provided in any of the forms described above of R-MNTX, and a laxative and/or a stool softener (and in connection with R-MNTX. optionally, an opioid). In these circumstances the R- [0087] Generally, oral doses of R-MNTX will be from MNTX and the other therapeutic agent(s) are adminis- about 0.25 to about 19.0 mg/kg body weight per day. tered close enough in time such that the subject experi- Generally, parenteral administration, including intrave- ences the effects of the various agents as desired, which 45 nous and subcutaneous administration, will be from typically is at the same time. In some embodiments the about 0.01 to 1.0 mg/kg body weight depending on R-MNTX will be delivered first in time, in some embodi- whether administration is as a bolus or is spread out over ments second in time, and still in some embodiments at time such as with an I.V. drip. Generally, the I.V. dose the same time. As discussed in greater detail herein, the for post-operative bowel dysfunction (POBD) is invention contemplates pharmaceutical preparations50 0.3mg/kg. It is expected that doses ranging from 0.01 to where the R-MNTX is administered in a formulation in- 0.45 mg/kgbody weight will yield the desired results. Dos- cluding the R-MNTX and one or both of a laxative and a age may be adjusted appropriately to achieve desired stool softener (and, optionally, an opioid). These formu- drug levels, local or systemic, depending on the mode of lations may be parenteral or oral, such as the ones de- administration. For example, it is expected that the dos- scribed in U.S. Serial No. 10/821,809. Included are solid, 55 age for oral administration of the opioid antagonists in an semisolid, liquid,controlled release, lyophilizedand other enterically-coated formulation would be lower than in an such formulations. immediate release oral formulation. In the event that the [0084] The administered amount of R-MNTX may be response in a patient is insufficient at such doses, even

12 21 EP 1 913 001 B1 22 higher doses (or effectively higher dosage by a different, benzene sulfonic. more localized delivery route) may be employed to the [0091] It should be understood that when referring to extent that the patient tolerance permits. Multiple doses MNTX, R- and S-MNTX, and therapeutic agent(s), it is per day are contemplated to achieve appropriate sys- meant to encompass salts of the same. Such salts are temic levels of compounds. Appropriate systemic levels 5 of a variety well known to those or ordinary skill in the can be determined by, for example, measurement of the art. When used in pharmaceutical preparations, the salts patient’s peak orsustained plasma level of thedrug. Peak preferably are pharmaceutically- acceptablefor use in hu- plasma levels below 100 ng/ml are preferred in some mans. Bromide is an example of one such salt. instances. "Dose" and "dosage" are used interchangea- [0092] The pharmaceutical preparations may include bly herein. 10 or be diluted into a pharmaceutically-acceptable carrier. [0088] A variety of administration routes are available. The term "pharmaceutically-acceptable carrier" as used The particular mode selected will depend, of course, up- herein means one or more compatible solid or liquid fill- on the particular combination of drugs selected, the se- ers, diluents or encapsulating substances which are suit- verity of the condition being treated, or prevented, the able for administration to a human or other mammal such condition of the patient, and the dosage required for ther- 15 as non-human primate, a dog, cat, horse, cow, sheep, apeutic efficacy. The methods of therapy, generally pig, or goat. The term "carrier" denotes an organic or speaking, may be practiced using any mode of adminis- inorganic ingredient, natural or synthetic, with which the tration that is medically acceptable, meaning any mode active ingredient is combined to facilitate the application. that produces effective levels of the active compounds The carriers are capable of being commingled with the without causing clinically unacceptable adverse effects. 20 preparations of the present invention, and with each oth- Such modes of administration include oral, rectal, topical, er, in a manner such that there is no interaction which transdermal, sublingual, intravenous infusion, pulmo- would substantially impair the desired pharmaceutical ef- nary, intra-arterial, intra-adipose tissue, intra-lymphatic, ficacy or stability. Carrier formulations suitable for oral intramuscular, intracavity, aerosol, aural (e.g., via ear- administration, for suppositories, and for parenteral ad- drops), intranasal, inhalation, intra-articular, needleless 25 ministration, etc., can be found in Remington’s Pharma- injection, subcutaneous or intradermal (e.g., transder- ceutical Sciences, Mack Publishing Company, Easton, mal) delivery. For continuous infusion, a patient- control- Pa. led analgesia (PCA) device or an implantable drug de- [0093] Aqueous formulations may include a chelating livery device may be employed. Oral, rectal, or topical agent, a buffering agent, an anti- oxidant and, optionally, administration may be important for prophylactic or long- 30 an isotonicity agent, preferably pH adjusted to between term treatment. Preferred rectal modes of delivery in- 3.0 and 3.5. Examples of such formulations that are sta- clude administration as a suppository or wash. ble to autoclaving and long term storage are described [0089] The pharmaceutical preparations may conven- in co-pending U.S. Application Serial No. 10/821,811, iently be presented in unit dosage form and may be pre- entitled "Pharmaceutical Formulation." pared by any of the methods well known in the art of35 [0094] Chelating agents include, for example, ethylen- pharmacy. All methods include the step of bringing the ediaminetetraacetic acid (EDTA) and derivatives thereof, compounds of the invention into association with a carrier citric acid and derivatives thereof, niacinamide and de- which constitutes one or more accessory ingredients. In rivatives thereof, sodium desoxycholate and derivatives general, the compositions are prepared by uniformly and thereof, and L-glutamic acid, N, N-diacetic acid and de- intimately bringing the compounds of the invention into 40 rivatives thereof. association with a liquid carrier, a finely divided solid car- [0095] Buffering agents include those selected from rier, or both, and then, if necessary, shaping the product. the group consisting of citric acid, sodium citrate, sodium [0090] When administered, the pharmaceutical prep- acetate, acetic acid, sodium phosphate and phosphoric arations are applied in pharmaceutically acceptable com- acid, sodium ascorbate, tartaric acid, maleic acid, gly- positions. Such preparations may routinely contain salts, 45 cine, sodium lactate, lactic acid, ascorbic acid, imidazole, buffering agents, preservatives, compatible carriers, lu- sodium bicarbonate and carbonic acid, sodium succinate bricants, and optionally other therapeutic ingredients. and succinic acid, histidine, and sodium benzoate and When used in medicine the salts should be pharmaceu- benzoic acid, or combinations thereof. tically acceptable, but non-pharmaceutically acceptable [0096] Antioxidants include those selected from the salts may conveniently be used to prepare pharmaceu- 50 group consisting of an ascorbic acid derivative, butylated tically acceptable salts thereof and are not excluded from hydroxy anisole, butylated hydroxy toluene, alkyl gallate, the scope of the invention. Such pharmacologically and sodium meta-bisulfite, sodium bisulfite, sodium pharmaceutically acceptable salts include, but are not dithionite, sodium thioglycollate acid, sodium formalde- limited to, those prepared from the following acids: hy- hyde sulfoxylate, tocopheral and derivatives thereof, drochloric, hydrobromic, sulfuric, nitric, phosphoric,55 monothioglycerol, and sodium sulfite. The preferred anti- maleic, acetic, salicylic, p- toluenesulfonic, tartaric, citric, oxidant is monothioglycerol. methanesulfonic, formic, succinic, naphthalene-2-sul- [0097] Isotonicity agents include those selected from fonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and the group consisting of sodium chloride, mannitol, lac-

13 23 EP 1 913 001 B1 24 tose, dextrose, , and . ventional tablets with binders which dissolve in the stom- [0098] Preservatives that can be used with the com- ach. Coatings which dissolve at the pH of the stomach positions include benzyl alcohol, parabens, thimerosal, or which dissolve at elevated temperatures will achieve chlorobutanol and preferably benzalkonium chloride. the same purpose. Release only in the intestine is Typically, the preservative will be present in a composi- 5 achieved using conventional enteric coatings such as pH tion in a concentration of up to about 2% by weight. The sensitive coatings which dissolve in the pH environment exact concentration of the preservative, however, will of the intestine (but not the stomach) or coatings which vary depending upon the intended use and can be easily dissolve over time. Release throughout the gastrointes- ascertained by one skilled in the art. tinal tract is achieved by using sustained-release mate- [0099] R-MNTX can be prepared in lyophilized com- 10 rials and/or combinations of the immediate release sys- positions, preferably in the presence of a cryoprotecting tems and sustained and/or delayed intentional release agentsuch as mannitol, or lactose, sucrose, polyethylene systems (e.g., pellets which dissolve at different pHs). glycol, and polyvinyl pyrrolidines. Cryoprotecting agents [0103] In the event that it is desirable to release the which result in a reconstitution pH of 6.0 or less are pre- therapeutic agent(s) first, the therapeutic agent(s) could ferred. The composition can contain a cryoprotecting15 be coated on the surface of the controlled release formu- agent, such as mannitol or lactose, which is preferably lation in any pharmaceutically acceptable carrier suitable neutral or acidic in water. for such coatings and for permitting the release of the [0100] Oral, parenteral and suppository formulations therapeutic agent(s) , such as in a temperature sensitive of agents are well known and commercially available. pharmaceutically acceptable carrier used for controlled The therapeutic agent(s) can be added to such well20 release routinely. Other coatings which dissolve when known formulations. It can be mixed together in solution placed in the body are well known to those of ordinary or semi-solid solution in such formulations, can be pro- skill in the art. vided in a suspension within such formulations or could [0104] The therapeutic agent(s) also may be mixed be contained in particles within such formulations. throughout a controlled release formulation, whereby it [0101] A product containing therapeutic agent(s) and, 25 is released before, after or simultaneously with another optionally, one or more other active agents can be con- agent. The therapeutic agent (s) may be free, that is, sol- figured as an oral dosage. The oral dosage may be a ubilized within the material of the formulation. The ther- liquid, a semisolid or a solid. An opioid may optionally be apeutic agent(s) also may be in the form of vesicles, such included in the oral dosage. The oral dosage may be as wax coated micropellets dispersed throughout the ma- configured to release the therapeutic agent (s) before, af- 30 terial of the formulation. The coated pellets can be fash- ter or simultaneously with the other agent (and/or the ioned to immediately release the therapeutic agent(s) opioid). The oral dosage may be configured to have the based on temperature, pH or the like. The pellets also therapeutic agent(s) and the other agents release com- can be configured so as to delay the release of the ther- pletely in the stomach, release partially in the stomach apeutic agent(s), allowing the other agent a period of time and partially in the intestine, in the intestine, in the colon, 35 to act before the therapeutic agent(s) exerts its effects. partially in the stomach, or wholly in the colon. The oral The therapeutic agent(s) pellets also can be configured dosage also may be configured whereby the release of to release the therapeutic agent(s) in virtually any sus- the therapeutic agent(s) is confined to the stomach or tained release pattern, including patterns exhibiting first intestine while the release of the other active agent is not order release kinetics or sigmoidal order release kinetics so confined or is confined differently from the therapeutic 40 using materials of the prior art and well known to those agent(s). For example, the therapeutic agent(s) may be of ordinary skill in the art. an enterically coated core or pellets contained within a [0105] The therapeutic agent (s) also can be contained pill or capsule that releases the other agent first and re- within a core within the controlled release formulation. leases the therapeutic agent (s) only after the therapeutic The core may have any one or any combination of the agent(s) passes through the stomach and into the intes- 45 propertiesdescribed above in connectionwith the pellets. tine. The therapeutic agent (s) also can be in a sustained The therapeutic agent(s) may be, for example, in a core release material, whereby the therapeutic agent (s) is re- coated with a material, dispersed throughout a material, leased throughout the gastrointestinal tract and the other coated onto a material or adsorbed into or throughout a agent is released on the same or a different schedule. material. The same objective for therapeutic agent (s) release can 50 [0106] It should be understood that the pellets or core be achieved with immediate release of therapeutic agent may be of virtually any type. They may be drug coated (s) combined with enteric coated therapeutic agent (s). In with a release material, drug interspersed throughout ma- these instances, the other agent could be released im- terial, drug adsorbed into a material, and so on. The ma- mediately in the stomach, throughout the gastrointestinal terial may be erodible or nonerodible. tract or only in the intestine. 55 [0107] The therapeutic agent(s), may be provided in [0102] The materials useful for achieving these differ- particles. Particles as used herein means nano or micro- ent release profiles are well known to those of ordinary particles (or in some instances larger) which can consist skill in the art. Immediate release is obtainable by con- in whole or in part of the therapeutic agent (s) or the other

14 25 EP 1 913 001 B1 26 agents as described herein. The particles may contain a delayed release system designed to release a drug in the therapeutic agent(s) in a core surrounded by a coat- response to, for example, a change in pH; the second is ing, including, but not limited to, an enteric coating. The a timed-release system designed to release a drug after therapeutic agent(s) also may be dispersed throughout a predetermined time; and the third is a microflora en- the particles. The therapeutic agent(s) also may be ad- 5 zyme system making use of the abundant enterobacteria sorbed into the particles. The particles may be of any in the lower part of the gastrointestinal tract (e.g., in a order release kinetics, including zero order release, first colonic site-directed release formulation). order release, second order release, delayed release, [0111] An example of a delayed release system is one sustained release, immediate release, and any combi- that uses, for example, an acrylic or cellulosic coating nation thereof, etc. The particle may include, in addition 10 material and dissolves on pH change. Because of ease to the therapeutic agent(s), any of those materials rou- of preparation, many reports on such "enteric coatings" tinely used in the art of pharmacy and medicine, includ- have been made. In general, an enteric coating is one ing, but not limited to, erodible, nonerodible, biodegrad- which passesthrough thestomach without releasing sub- able, or nonbiodegradable material or combinations stantial amounts of drug in the stomach (i.e., less than thereof. The particles may be microcapsules which con- 15 10% release, 5% release and even 1% release in the tain the antagonist in a solution or in a semi-solid state. stomach) and sufficiently disintegrating in the intestinal The particles may be of virtually any shape. tract (by contact with approximately neutral or alkaline [0108] Both non-biodegradable and biodegradable intestine juices) to allow the transport (active or passive) polymeric materials can be used in the manufacture of of the active agent through the walls of the intestinal tract. particles for delivering the therapeutic agent (s). Such pol- 20 [0112] Various in vitro tests for determining whether or ymers may be natural or synthetic polymers. The polymer not a coating is classified as an enteric coating have been is selected based on the period of time over which release published in the pharmacopoeia of various countries. A is desired. Bioadhesive polymers of particular interest coating which remains intact for at least 2 hours, in con- include bioerodible hydrogels described by H.S. Sawh- tact with artificial gastric juices such as HCl of pH 1 at 36 ney, C.P. Pathak and J.A. Hubell in Macromolecules, 25 to 38 °C and thereafter disintegrates within 30 minutes (1993) 26:581-587. These include polyhyaluronic acids, in artificial intestinal juices such as a KH2PO4 buffered casein, gelatin, glutin, polyanhydrides, polyacrylic acid, solution of pH 6.8 is one example. One such well known alginate, chitosan, poly(methyl methacrylates), poly system is EUDRAGIT material, commercially available (ethyl methacrylates), poly(butylmethacrylate), poly(iso- and reported on by Behringer, Manchester University, butyl methacrylate), poly(hexylmethacrylate), poly(iso- 30 Saale Co., and the like. Enteric coatings are discussed decyl methacrylate), poly (lauryl methacrylate), poly (phe- further, below. nyl methacrylate), poly(methyl acrylate), poly(isopropyl [0113] A timed release system is represented by Time acrylate), poly(isobutyl acrylate), and poly (octadecyl acr- Erosion System (TES) by Fujisawa Pharmaceutical Co., ylate). Ltd. and Pulsincap by R. P. Scherer. According to these [0109] The therapeutic agent(s) may be contained in 35 systems, the site of drug release is decided by the time controlled release systems. The term "controlled release" of transit of a preparation in the gastrointestinal tract. is intended to refer to any drug- containing formulation in Since the transit of a preparation in the gastrointestinal which the manner and profile of drug release from the tract is largely influenced by the gastric emptying time, formulation are controlled. This refers to immediate as some time release systems are also enterically coated. well as nonimmediate release formulations, with nonim- 40 [0114] Systems making use of the enterobacteria can mediate release formulations including but not limited to be classified into those utilizing degradation of azoaro- sustained release and delayed release formulations. The matic polymers by an azo reductase produced from en- term "sustained release" (also referred to as "extended terobacteria as reported by the group of Ohio University release") is used in its conventional sense to refer to a (M. Saffran, et al., Science, Vol. 233: 1081 (1986)) and drug formulation that provides for gradual release of a 45 the group of Utah University (J. Kopecek, et al., Pharma- drug over an extended period of time, and that preferably, ceutical Research, 9(12), 1540-1545 (1992)); and those although not necessarily, results in substantially constant utilizing degradation of polysaccharides by beta-galac- blood levels of a drug over an extended time period. The tosidase of enterobacteria as reported by the group of term "delayed release" is used in its conventional sense Hebrew University (unexamined published Japanese to refer to a drug formulation in which there is a time delay 50 patent application No. 5-50863 based on a PCT applica- between administration of the formulation and the re- tion) and the group of Freiberg University (K. H. Bauer lease of the drug therefrom. "Delayed release" may or et al., Pharmaceutical Research, 10(10), S218 (1993)). may not involve gradual release of drug over an extended In addition, the system using chitosan degradable by chi- period of time, and thus may or may not be "sustained tosanase by Teikoku Seiyaku K. K. (unexamined pub- release." These formulations may be for any mode of 55 lished Japanese patent application No. 4-217924 and administration. unexamined published Japanese patent application No. [0110] Delivery systems specific for the gastrointesti- 4-225922) is also included. nal tract are roughly divided into three types: the first is [0115] The enteric coating is typically, although not

15 27 EP 1 913 001 B1 28 necessarily, a polymeric material. Preferred enteric coat- L-30D in that the ratio of free carboxyl groups to ester ing materials comprise bioerodible, gradually hydrolyza- groups is approximately 1:2. EUDRAGIT S is insoluble ble and/or gradually water-soluble polymers. The "coat- at pH below 5.5, but unlike EUDRAGIT L-30D, is poorly ing weight," or relative amount of coating material per soluble in gastrointestinal fluids having a pH in the range capsule, generally dictates the time interval between in- 5 of5.5 to 7.0, suchas inthe small intestine. This copolymer gestion and drug release. Any coating should be applied is soluble at pH 7.0 and above, i.e., the pH generally to a sufficient thickness such that the entire coating does found in the colon. EUDRAGIT S can be used alone as not dissolve in the gastrointestinal fluids at pH below a coating to provide drug delivery in the large intestine. about 5, but does dissolve at pH about 5 and above. It Alternatively, EUDRAGIT S, being poorly soluble in in- is expected that any anionic polymer exhibiting a pH- 10 testinal fluids below pH 7, can be used in combination dependent solubility profile can be used as an enteric with EUDRAGIT L- 30D, soluble in intestinal fluids above coating in the practice of the present invention. The se- pH 5.5, in order to provide a delayed release composition lection of the specific enteric coating material will depend which can be formulated to deliver the active agent to on the following properties: resistance to dissolution and various segments of the intestinal tract. The more disintegration in the stomach; impermeability to gastric 15 EUDRAGIT L-30D used, the more proximal release and fluids and drug/ carrier/enzyme while in the stomach; abil- delivery begins, and the more EUDRAGIT S used, the ity to dissolve or disintegrate rapidly at the target intestine more distal release and delivery begins. It will be appre- site; physical and chemical stability during storage; non- ciated by those skilled in the art that both EUDRAGIT L- toxicity; ease of application as a coating (substrate friend- 30D and EUDRAGIT S can be replaced with other phar- ly); and economical practicality. 20 maceutically acceptable polymers having similar pH sol- [0116] Suitable enteric coating materials include, but ubility characteristics. In certain embodiments, the pre- are not limited to: cellulosic polymers such as cellulose ferred enteric coating is ACRYL- EZE™ (methacrylic acid acetate phthalate, cellulose acetate trimellitate, hydrox- co-polymer type C; Colorcon, West Point, PA). ypropylmethyl cellulose phthalate, hydroxypropyhmethyl [0118] The enteric coating provides for controlled re- cellulose succinate and carboxymethylcellulose sodium; 25 lease of the active agent, such that drug release can be acrylic acid polymers and copolymers, preferably formed accomplished at some generally predictable location. from acrylic acid, methacrylic acid, methyl acrylate, am- The enteric coating also prevents exposure of the ther- monium methylacrylate, ethyl acrylate, methyl methacr- apeutic agent and carrier to the epithelial and mucosal ylate and/or ethyl methacrylate (e.g., those copolymers tissue of the buccal cavity, pharynx, esophagus, and sold under the trade name EUDRAGIT); vinyl polymers 30 stomach, and to the enzymes associated with these tis- and copolymers such as polyvinyl acetate, polyvinylac- sues. The enteric coating therefore helps to protect the etate phthalate, vinylacetate crotonic acid copolymer, active agent, carrier and a patient’s internal tissue from and ethylene-vinyl acetate copolymers; and shellac (pu- any adverse event prior to drug release at the desired rified lac). Combinations of different coating materials site of delivery. Furthermore, the coated material allows may also be used. Well known enteric coating material 35 optimization of drug absorption, active agent protection, for use herein are those acrylic acid polymers and copol- and safety. Multiple enteric coatings targeted to release ymers available under the trade name EUDRAGIT from the active agent at various regions in the gastrointestinal Rohm Pharma (Germany). The EUDRAGIT series E, L, tract would enable even more effective and sustained S, RL, RS and NE copolymers are available as solubilized improved delivery throughout the gastrointestinal tract. in organic solvent, as an aqueous dispersion, or as a dry 40 [0119] The coating can, and usually does, contain a powder. The EUDRAGIT series RL, NE, and RS copol- plasticizer to prevent the formation of pores and cracks ymers are insoluble in the gastrointestinal tract but are that would permit the penetration of the gastric fluids. permeable and are used primarily for extended release. Suitable plasticizers include, but are not limited to, triethyl The EUDRAGIT series E copolymers dissolve in the citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl stomach. The EUDRAGIT series L, L-30D and S copol- 45 triethyl citrate (Citroflec A2), Carbowax 400 (polyethyl- ymers are insoluble in stomach and dissolve in the intes- ene glycol 400), diethyl phthalate, tributyl citrate, tine, and are thus most preferred herein. acetylated monoglycerides, glycerol, fatty acid esters, [0117] A particular methacrylic copolymer propylene is glycol, and dibutyl phthalate. In particular, a EUDRAGIT L, particularly L-30D and EUDRAGIT L coating comprised of an anionic carboxylic acrylic poly- 100-55. In EUDRAGIT L-30D, the ratio of free carboxyl 50 mer will usually contain approximately 10% to 25% by groups to ester groups is approximately 1: 1. Further, the weight of a plasticizer, particularly dibutyl phthalate, pol- copolymer is known to be insoluble in gastrointestinal yethylene glycol, triethyl citrate and triacetin. The coating fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH can also contain other coating excipients such as detack- generally present in the fluid of the upper gastrointestinal ifiers, antifoaming agents, lubricants (e.g., magnesium tract, but readily soluble or partially soluble at pH above 55 stearate), and stabilizers (e.g., hydroxypropylcellulose, 5.5, i.e., the pH generally present in the fluid of lower acids and bases) to solubilize or disperse the coating gastrointestinal tract. Another particular methacrylic acid material, and to improve coating performance and the polymer is EUDRAGIT S, which differs from EUDRAGIT coated product.

16 29 EP 1 913 001 B1 30

[0120] The coating can be applied to particles of the lease membrane or film. The membrane may be semi- therapeutic agent(s), tablets of the therapeutic agent(s), permeable, as described above. A semipermeable mem- capsules containing the therapeutic agent (s) and the like, brane allows for the passage of water inside the coated using conventional coating methods and equipment. For device to dissolve the drug. The dissolved drug solution example, an enteric coating can be applied to a capsule 5 diffuses out through the semipermeable membrane. The using a coating pan, an airless spray technique, fluidized rate of drug release depends upon the thickness of the bed coating equipment, or the like. Detailed information coated film and the release of drug can begin in any part concerning materials, equipment and processes for pre- of the GI tract. Suitable membrane materials for such a paring coated dosage forms may be found in Pharma- membrane include ethylcellulose. ceutical Dosage Forms: Tablets, eds. Lieberman et al. 10 [0123] In another embodiment, drug dosage forms are (New York: Marcel Dekker, Inc., 1989), and in Ansel et provided that comprise a sustained release device hous- al., Pharmaceutical Dosage Forms and Drug Delivery ing a formulation. In this embodiment, the drug- contain- Systems, 6th Ed. (Media, PA: Williams & Wilkins, 1995). ing formulation is uniformly mixed with a sustained re- The coating thickness, as noted above, must be sufficient lease polymer. These sustained release polymers are to ensure that the oral dosage form remains intact until 15 high molecular weight water-soluble polymers, which the desired site of topical delivery in the lower intestinal when in contact with water, swell and create channels tract is reached. for water to diffuse inside and dissolve the drug. As the [0121] In another embodiment, drug dosage forms are polymers swell and dissolve in water, more of drug is provided that comprise an enterically coated, osmotically exposed to water for dissolution. Such a system is gen- activated device housing a formulation. In this embodi- 20 erally referred to as sustained release matrix. Suitable ment, the drug- containing formulation is encapsulated in materials for such a device include hydropropyl methyl- a semipermeable membrane or barrier containing a small cellulose, hydroxypropyl cellulose, hydroxyethyl cellu- orifice. As known in the art with respect to so- called "os- lose and . motic pump" drug delivery devices, the semipermeable [0124] In another embodiment, drug dosage forms are membrane allows passage of water in either direction, 25 provided that comprise an enteric coated device housing but not drug. Therefore, when the device is exposed to a sustained release formulation .In this embodiment, the aqueous fluids, water will flow into the device due to the drug containing product described above is coated with osmotic pressure differential between the interior and ex- an enteric polymer. Such a device would not release any terior of the device. As water flows into the device, the drug in the stomach and when the device reaches the drug-containing formulation in the interior will 30 beintestine, the enteric polymer is first dissolved and only "pumped" out through the orifice. The rate of drug release then would the drug release begin. The drug release will be equivalent to the inflow rate of water times the would take place in a sustained release fashion. drug concentration. The rate of water influx and drug ef- [0125] Enterically coated, osmotically activated devic- flux can be controlled by the composition and size of the es can be manufactured using conventional materials, orifice of the device. Suitable materials for the semiper- 35 methods and equipment. For example, osmotically acti- meable membrane include, but are not limited to, poly- vated devices may be made by first encapsulating, in a vinyl alcohol, polyvinyl chloride, semipermeable polyeth- pharmaceutically acceptable soft capsule, a liquid or ylene glycols, semipermeable polyurethanes, semiper- semi-solid formulation of the compounds as described meable polyamides, semipermeable sulfonated polysty- previously. This interior capsule is then coated with a renes and polystyrene derivatives; semipermeable poly 40 semipermeable membrane composition (comprising, for (sodium styrenesulfonate), semipermeable poly(vinyl- example, cellulose acetate and 4000 benzyltrimethylammonium chloride), and cellulosic pol- in a suitable solvent such as a methylene chloride- meth- ymers such as cellulose acetate, cellulose diacetate, cel- anol admixture), for example using an air suspension ma- lulose triacetate, cellulose propionate, cellulose acetate chine, until a sufficiently thick laminate is formed, e.g., propionate, cellulose acetate butyrate, cellulose trivaler- 45 around 0.05 mm. The semipermeable laminated capsule ate, cellulose trilmate, cellulose tripalmitate, cellulose tri- is then dried using conventional techniques. Then, an octanoate, cellulose tripropionate, cellulose disuccinate, orifice having a desired diameter (e.g., about 0.99 mm) cellulosedipalmitate, cellulose dicylate, cellulose acetate is provided through the semipermeable laminated cap- succinate, cellulose propionate succinate, cellulose ac- sule wall, using, for example, mechanical drilling, laser etate octanoate, cellulose valerate palmitate, cellulose 50 drilling, mechanical rupturing, or erosion of an erodible acetate heptanate, cellulose acetaldehyde dimethyl element such as a gelatin plug. The osmotically activated acetal, cellulose acetate ethylcarbamate, cellulose ace- device may then be enterically coated as previously de- tate methylcarbamate, cellulose dimethylaminoacetate scribed, For osmotically activated devices containing a and ethylcellulose. solid carrier rather than a liquid or semi- solid carrier, the [0122] In another embodiment, drug dosage forms are 55 interior capsule is optional; that is, the semipermeable provided that comprise a sustained release coated de- membrane may be formed directly around the carrier- vice housing a formulation. In this embodiment, the drug- drug composition. However, preferred carriers for use in containing formulation is encapsulated in a sustained re- the drug-containing formulation of the osmotically acti-

17 31 EP 1 913 001 B1 32 vated device are solutions, suspensions, liquids, immis- itories are compounded so as to melt, soften, or dissolve cible liquids, emulsions, sols, colloids, and oils. Particu- in the body cavity (around 98.6 °F) thereby releasing the larly preferred carriers include, but are not limited to, medication contained therein. Suppository bases should those used for enterically coated capsules containing liq- be stable, nonirritating, chemically inert, and physiolog- uid or semisolid drug formulations. 5 ically inert. Many commercially available suppositories [0126] Cellulosecoatings include those ofcellulose ac- contain oily or fatty base materials, such as cocoa butter, etate phthalate and trimellitate; methacrylic acid copoly- coconut oil, palm kernel oil, and palm oil, which often melt mers, e.g. copolymers derived from methylacrylic acid or deform at room temperature necessitating cool stor- and esters thereof, containing at least 40% methylacrylic age or other storage limitations. U.S. Patent No. acid; and especially hydroxypropyl methylcellulose10 4,837,214 to Tanaka et al. describes a suppository base phthalate. Methylacrylates include those of molecular comprised of 80 to 99 percent by weight of a lauric- type weight above 100,000 daltons based on, e.g. methylacr- fat havinga hydroxyl value of 20 orsmaller and containing ylate and methyl or ethyl methylacrylate in a ratio of about glycerides of fatty acids having 8 to 18 carbon atoms 1:1. Typical products include Endragit L, e.g. L 100-55, combined with 1 to 20 percent by weight diglycerides of marketed by Rohm GmbH, Darmstadt, Germany. Typical 15 fatty acids (which erucic acid is an example of). The shelf cellulose acetate phthalates have an acetyl content of life of these type of suppositories is limited due to deg- 17-26% and a phthalate content of from 30-40% with a radation. Other suppository bases contain alcohols, sur- viscosity of ca. 45-90 cP. Typical cellulose acetate trim- factants, and the like which raise the melting temperature ellitates have an acetyl content of 17-26%, a trimellityl but also can lead to poor absorption of the medicine and content from 25-35% with a viscosity of ca. 15-20 cS. An 20 side effects due to irritation of the local mucous mem- example of a cellulose acetate trimellitate is the marketed branes (see for example, U.S. Patent No. 6,099,853 to product CAT (Eastman Kodak Company, USA). Hydrox- Hartelendy et al., U.S. Patent No. 4,999,342 to Ahmad ypropyl methylcellulose phthalates typically have a mo- et al., and U.S. Patent No. 4,765,978 to Abidi et al. ). lecular weight of from 20,000 to 130,000 daltons, a hy- [0130] The base used in the pharmaceutical supposi- droxypropyl content of from 5 to 10%, a methoxy content 25 tory composition includes, in general, oils and fats com- of from 18 to 24% and a phthalyl content from 21 to 35%. prising triglycerides as main components such as cacao An example of a cellulose acetate phthalate is the mar- butter, palm fat, palm kernel oil, coconut oil, fractionated keted product CAP (Eastman Kodak, Rochester N.Y., coconut oil, lard and WITEPSOL®, waxes such as lanolin USA). Examples of hydroxypropyl methylcellulose andreduced lanolin; hydrocarbons such as VASELINE®, phthalates are the marketed products having a hydrox- 30 squalene, squalane and ; long to medium ypropyl content of from 6-10%, a methoxy content of from chain fatty acids such as caprylic acid, lauric acid, stearic 20-24%, a phthalyl content of from 21-27%, a molecular acid and oleic acid; higher alcohols such as lauryl alcohol, weight of about 84,000 daltons, sold under the trademark cetanol and stearyl alcohol; fatty acid esters such as butyl HP50 and available from Shin-Etsu Chemical Co. Ltd., stearate and dilauryl malonate; medium to long chain car- Tokyo, Japan, and having a hydroxypropyl content, a 35 boxylic acid esters of glycerin such as triolein and tris- methoxyl content, and a phthalyl content of 5-9%, tearin; glycerin-substituted carboxylic acid esters such 18-22% and 27-35%, respectively, and a molecular as glycerin acetoacetate; and polyethylene glycols and weight of 78,000 daltons, known under the trademark its derivatives such as and cetomacrogol. HP55 and available from the same supplier. They may be used either singly or in combination of two [0127] The therapeutic agents may be provided in cap- 40 or more. If desired, the composition may further include sules, coated or not. The capsule material may be either a surface-active agent, a coloring agent, etc., which are hard or soft, and as will be appreciated by those skilled ordinarily used in suppositories. in the art, typically comprises a tasteless, easily admin- [0131] The pharmaceutical composition may be pre- istered and water soluble compound such as gelatin, pared by uniformly mixing predetermined amounts of the starch or a cellulosic material. The capsules are prefer- 45 active ingredient, the absorption aid and optionally the ably sealed, such as with gelatin bands or the like. See, base, etc. in a stirrer or a grinding mill, if required at an for example, Remington: The Science and Practice of elevated temperature. The resulting composition, may Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Pub- be formed into a suppository in unit dosage form by, for lishing Co., 1995), which describes materials and meth- example, casting the mixture in a mold, or by forming it ods for preparing encapsulated pharmaceuticals. 50 into a gelatin capsule using a capsule filling machine. [0128] A product containing therapeutic agent(s)can [0132] The compositions also can be administered as be configured as a suppository. The therapeutic agent a nasal spray, nasal drop, suspension, gel, ointment, (s) can be placed anywhere within or on the suppository cream or powder. The administration of a composition to favorably affect the relative release of the therapeutic can also include using a nasal tampon or a nasal sponge agent(s). The nature of the release can be zero order, 55 containing a composition. first order, or sigmoidal, as desired. [0133] The nasal delivery systems can take various [0129] Suppositories are solid dosage forms of medi- forms including aqueous preparations, non-aqueous cine intended for administration via the rectum. Suppos- preparations and combinations thereof. Aqueous prep-

18 33 EP 1 913 001 B1 34 arations include, for example, aqueous gels, aqueous of an accessible body surface, such as, for example, the suspensions, aqueous liposomal dispersions, aqueous skin (the outer integument or covering) and the mucosa emulsions, aqueous microemulsions and combinations (the mucous-producing, secreting and/or containing sur- thereof. Non-aqueous preparations include, for example, face). Exemplary mucosal surfaces include the mucosal non-aqueous gels, non-aqueous suspensions, non- 5 surfaces of the eyes, mouth (such as the lips, tongue, aqueous liposomal dispersions, non-aqueous emul- gums, cheeks, sublingual and roof of the mouth), larynx, sions, non-aqueous microemulsions and combinations esophagus, bronchial, nasal passages, vagina and rec- thereof. The various forms of the nasal delivery systems tum/anus; in some embodiments, preferably the mouth, can include a buffer to maintain pH, a pharmaceutically larynx, esophagus, vagina and rectum/ anus; in other em- acceptable thickening agent and a humectant. The pH 10 bodiments,preferably the eyes, larynx,esophagus, bron- of the buffer can be selected to optimize the absorption chial, nasal passages,and vagina and rectum/anus. As of the therapeutic agent(s) across the nasal mucosa. noted above, local application herein refers to application [0134] With respect to the non-aqueous nasal formu- to a discrete internal area of the body, such as, for ex- lations,suitable forms ofbuffering agents can be selected ample, a joint, soft tissue area (such as muscle, tendon, such that when the formulation is delivered into the nasal 15 ligaments, intraocular or other fleshy internal areas), or cavity of a mammal, selected pH ranges are achieved other internal area of the body. Thus, as used herein, therein upon contact with, e.g., a nasal mucosa. The pH local application refers to applications to discrete areas of the compositions should be maintained from about 2.0 of the body. to about 6.0. It is desirable that the pH of the compositions [0140] With respect to topical and/or local administra- is one which does not cause significant irritation to the 20 tion of the compositions, desirable efficacy may involve, nasal mucosa of a recipient upon administration. for example, penetration of therapeutic agent(s) into the [0135] The viscosity of the compositions can be main- skin and/or tissue to substantially reach a hyperalgesic tained at a desired level using a pharmaceutically ac- site to provide desirable anti- hyperalgesic pain relief. The ceptable thickening agent. Thickening agents that can efficacy of the compositions may be about the same as be used include methyl cellulose, xanthan gum, car-25 that achieved, for example, with central opiate analge- boxymethyl cellulose, hydroxypropyl cellulose, car- sics. But, as discussed in detail herein, the efficacy bomer, polyvinyl alcohol, alginates, acacia, chitosans achieved with therapeutic agent (s) is preferably obtained and combinations thereof. The concentration of the thick- without the undesirable effects that are typically associ- ening agent will depend upon the agent selected and the ated with central including, for example, respira- viscosity desired. Such agents can also be used in a pow- 30 tory depression, sedation, and addiction, as it is believed der formulation discussed above. that therapeutic agent(s) does not cross the blood brain [0136] The compositions can also include a humectant barrier. to reduce or prevent drying of the mucus membrane and [0141] Also in certain preferred embodiments, includ- to prevent irritation thereof. Suitable humectants that can ing embodimentsthat involveaqueous vehicles, the com- be used include sorbitol, mineral oil, vegetable oil and 35 positions may also contain a glycol, that is, a compound glycerol; soothing agents; membrane conditioners; containing two or more hydroxy groups. A glycol which sweeteners; and combinations thereof. The concentra- is particularly preferred for use in the compositions is tion of the humectant in the present compositions will propylene glycol. In these preferred embodiments, the vary depending upon the agent selected. glycol is preferably included in the compositions in a con- [0137] One or more therapeutic agents may be incor- 40 centration of from greater than 0 to about 5 wt. %, based porated into the nasal delivery system or any other de- on the total weight of the composition. More preferably, livery system described herein. the compositions contain from about 0.1 to less than [0138] A composition formulated for topical adminis- about 5 wt. % of a glycol, with from about 0.5 to about 2 tration may be liquid or semisolid (including, for example, wt. % being even more preferred. Still more preferably, a gel, lotion, emulsion, cream, ointment, spray or aerosol) 45 the compositions contain about 1 wt. % of a glycol. or may be provided in combination with a "finite" carrier, [0142] For local internal administration, such as intra- for example, a non-spreading material that retains its articular administration, the compositions are preferably form, including, for example, a patch, bioadhesive, dress- formulated as a solution or a suspension in an aqueous- ing or bandage. It may be aqueous or non-aqueous; it based medium, such as isotonically buffered saline or may be formulated as a solution, emulsion, dispersion, 50 are combined with a biocompatible support or bioadhe- a suspension or any other mixture. sive intended for internal administration. [0139] Important modes of administration include top- [0143] Lotions, which, for example, may be in the form ical application to the skin, eyes or mucosa. Thus, typical of a suspension, dispersion or emulsion, contain an ef- vehicles are those suitable for pharmaceutical or cos- fective concentration of one or more of the compounds. metic application to body surfaces. The compositions 55 The effective concentration is preferably to deliver an ef- provided herein may be applied topically or locally to var- fective amount, typically at a concentration of between iousareas in the bodyof a patient. As noted above,topical about 0.1-50% [by weight] or more of one or more of the application is intended to refer to application to the tissue compounds provided herein. The lotions also contain [by

19 35 EP 1 913 001 B1 36 weight] from 1% to 50% of an emollient and the balance ylene glycols, glycerol, ethoxylated glycerol, propoxylat- water, a suitable buffer, and other agents as described ed glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl above. Any emollients known to those of skill in the art sorbitol, polyethylene glycol [M.W. 200-6000], methoxy as suitable for application to human skin may be used. polyethyleneglycols 350, 550,750, 2000, 5000,poly (eth- These include, but are not limited to, the following: (a) 5 ylene oxide) homopolymers [M.W. 100,000-5,000,000], Hydrocarbon oils and waxes, including mineral oil, pet- polyalkylene glycols and derivatives, hexylene glycol (2- rolatum, paraffin, ceresin, ozokerite, microcrystalline methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6,-hex- wax, polyethylene, and perhydrosqualene. b) Silicone anetriol, ethohexadiol USP ethyl- (2- 1,3-hexanediol), oils, including dimethylpolysiloxanes, methylphenyl- C.sub.15 -C.sub.18 vicinal glycol and polyoxypropylene polysiloxanes, water-soluble and alcohol-soluble sili- 10 derivatives of trimethylolpropane. (n) polyhydric alcohol cone-glycol copolymers. (c) Triglyceride fats and oils, in- esters, including, but not limited to, ethylene glycol mono- cluding those derived from vegetable, animal and marine and di-fatty acid esters, diethylene glycol mono-and di- sources. Examples include, but are not limited to, castor fatty acid esters, polyethylene glycol [M.W. 200-6000], oil, safflower oil, cotton seed oil, corn oil, olive oil, cod mono- and di-fatty esters, propylene glycol mono- and liver oil, almond oil, avocado oil, palm oil, sesame oil, and 15 di-fatty acid esters, polypropylene glycol 2000 mo- soybean oil. (d) Acetoglyceride esters, such as acetylat- nooleate, polypropylene glycol 2000 monostearate, ed monoglycerides. (e) Ethoxylated glycerides, such as ethoxylated propylene glycol monostearate, glyceryl mo- ethoxylated glyceryl monstearate. (f) Alkyl esters of fatty no- and di-fatty acid esters, polyglycerol poly-fatty acid acids having 10 to 20 carbon atoms. Methyl, isopropyl esters, ethoxylated glyceryl monostearate, 1,3-butylene andbutyl estersof fattyacids are usefulherein. Examples 20 glycol monostearate, 1,3-butylene glycol distearate, include, but are not limited to, hexyl laurate, isohexyl lau- polyoxyethylene polyol fatty acid ester, sorbitan fatty acid rate, isohexyl palmitate, isopropyl palmitate, isopropyl esters, and polyoxyethylene sorbitan fatty acid esters. myristate, decyl oleate, isodecyl oleate, hexadecyl stea- (o) Wax esters, including, but not limited to, beeswax, rate, decyl stearate, isopropyl.isostearate, diisopropyl spermaceti, myristyl myristate, and stearyl stearate and adipate, diisohexyl adipate, dihexyldecyl adipate, diiso- 25 beeswax derivatives, including, but not limited to, poly- propyl sebacate, lauryl lactate, myristyl lactate, and cetyl oxyethylene sorbitol beeswax, which are reaction prod- lactate. (g) Alkenyl esters of fatty acids having 10 to 20 ucts of beeswax with ethoxylated sorbitol of varying eth- carbon atoms. Examples thereof include, but are not lim- ylene oxide content that form a mixture of ether-esters. ited to, oleyl myristate, oleyl stearate, and oleyl oleate. (p) Vegetable waxes, including, but not limited to, car- (h) Fatty acids having 9 to 22 carbon atoms. Suitable30 nauba and candelilla waxes. (q) phospholipids, such as examples include, but are not limited to, pelargonic, lau- lecithin and derivatives. (r) Sterols, including, but not lim- ric, myristic, palmitic, stearic, isostearic, hydroxystearic, ited to, cholesterol and cholesterol fatty acid esters. (s) oleic, linoleic, ricinoleic, arachidonic, behenic, and erucic Amides, such as fatty acid amides, ethoxylated fatty acid acids. (i) Fatty alcohols having 10 to 22 carbon atoms, amides, and solid fatty acid alkanolamides. such as, but not limited to, lauryl, myristyl, cetyl, hexa- 35 [0144] The lotions further preferably contain [by decyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, weight] from 1% to 10%, more preferably from 2% to 5%, behenyl, erucyl, and 2-octyl dodecyl alcohols. (j) Fatty of an emulsifier. The emulsifiers can be nonionic, anionic alcohol ethers, including, but not limited to ethoxylated or cationic. Examples of satisfactory nonionic emulsifiers fatty alcohols of 10 to 20 carbon atoms, such as, but are include, but are not limited to, fatty alcohols having 10 to not limited to, the lauryl, cetyl, stearyl, isostearyl, oleyl, 40 20 carbon atoms, fatty alcohols having 10 to 20 carbon and cholesterol alcohols having attached thereto from 1 atoms condensed with 2 to 20 moles of ethylene oxide to 50 ethylene oxide groups or 1 to 50 propylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon groups or mixtures thereof. (k) Ether- esters, such as fatty atoms in the alkyl chain condensed with 2 to 20 moles acid esters of ethoxylated fatty alcohols. (1) Lanolin and of ethylene oxide, mono- and di-fatty acid esters of eth- derivatives, including, but not limited to, lanolin, lanolin 45 ylene oxide, mono- and di-fatty acid esters of ethylene oil, lanolin wax, lanolin alcohols, lanolin fatty acids, iso- glycol where the fatty acid moiety contains from 10 to 20 propyl lanolate, ethoxylated lanolin, ethoxylated lanolin carbon atoms, diethylene glycol, polyethylene glycols of alcohols, ethoxylated cholesterol, propoxylated lanolin molecular weight 200 to 6000, propylene glycols of mo- alcohols, acetylated lanolin, acetylated lanolin alcohols, lecular weight 200 to 3000, glycerol, sorbitol, sorbitan, lanolin alcohols linoleate, lanolin alcohols ricinoleate, ac- 50 polyoxyethylene sorbitol, polyoxyethylene sorbitan and etate of lanolin alcohols ricinoleate, acetate of ethoxylat- hydrophilic wax esters. Suitable anionic emulsifiers in- ed alcohols-esters, hydrogenolysis of lanolin, ethoxylat- clude, but are not limited to, the fatty acid soaps, e.g., ed hydrogenated lanolin, ethoxylated sorbitol lanolin, and sodium, potassium and triethanolamine soaps, where liquid and semisolid lanolin absorption bases. (m) poly- the fatty acid moiety contains from 10 to 20 carbon atoms. hydric alcohols and polyether derivatives, including, but 55 Other suitable anionic emulsifiers include, but are not not limited to, propylene glycol, dipropylene glycol, poly- limited to, the alkali metal, ammonium or substituted am- propylene glycol [M.W. 2000-4000], polyoxyethylene monium alkyl sulfates, alkyl arylsulfonates, and alkyl polyoxypropylene glycols,polyoxypropylene polyoxyeth- ethoxy ether sulfonates having 10 to 30 carbon atoms in

20 37 EP 1 913 001 B1 38 the alkyl moiety. The alkyl ethoxy ether sulfonates con- ical compositions of ophthalmic irrigation solutions and tain from 1 to 50 ethylene oxide units. Among satisfactory solutions for topical application]. Such solutions, which cationic emulsifiers are quaternary ammonium, morpho- have a pH adjusted to about 7.4, contain, for example, linium and pyridinium compounds. Certain of the emol- 90-100 mM sodium chloride, 4-6 mM dibasic potassium lients described in preceding paragraphs also have emul- 5 phosphate, 4-6 mM dibasic sodium phosphate, 8-12 mM sifying properties. When a lotion is formulated containing sodium citrate, 0.5-1.5 mM magnesium chloride, 1.5-2.5 such an emollient, an additional emulsifier is not needed, mM calcium chloride, 15-25 mM sodium acetate, 10-20 though it can be included in the composition. mM D.L.-sodium, .β.-hydroxybutyrate and 5-5.5 mM glu- [0145] The balance of the lotion is water or a C 2 or C3 cose. alcohol, or a mixture of water and the alcohol. The lotions 10 [0150] Gel compositions can be formulated by simply are formulated by simply admixing all of the components admixing a suitable thickening agent to the previously together. Preferably the compound, such as loperamide, described solution or suspension compositions. Exam- is dissolved, suspended or otherwise uniformly dis- ples of suitable thickening agents have been previously persed in the mixture. described with respect to the lotions. [0146] Other conventional components of such lotions 15 [0151] The gelled compositions contain an effective may be included. One such additive is a thickening agent amount of therapeutic agent(s), typically at a concentra- at a level from 1% to 10% by weight of the composition. tion of between about 0.1-50% by weight or more of one Examples of suitable thickening agents include, but are or more of the compounds provided herein.; from 5% to not limited to: cross-linked carboxypolymethylene poly- 75%, preferably from 10% to 50%, of an organic solvent mers, ethyl cellulose, polyethylene glycols, gum traga- 20 as previously described; from 0.5% to 20%, preferably canth, gum kharaya, xanthan gums and bentonite, hy- from 1% to 10% of the thickening agent; the balance be- droxyethyl cellulose, and hydroxypropyl cellulose. ing wateror other aqueous or non- aqueous carriers, such [0147] Creams can be formulated to contain a concen- as, for example, an organic liquid, or a mixture of carriers. tration effective to deliver an effective amount of thera- [0152] The formulations can be constructed and ar- peutic agent(s) to the treated tissue, typically at between 25 ranged to create steady state plasma levels. Steady state about 0.1%, preferably at greater than 1% up to and plasma concentrations can be measured using HPLC greater than 50%, preferably between about 3% and techniques, as are known to those of skill in the art. 50%, more preferably between about 5% and 15% ther- Steady state is achieved when the rate of drug availability apeutic agent(s). The creams also contain from 5% to is equal to the rate of drug elimination from the circulation. 50%, preferably from 10% to 25%, of an emollient and 30 In typical therapeutic settings, the therapeutic agent(s) the remainder is water or other suitable non- toxic carrier, willbe administeredto patients either on a periodic dosing such as an isotonic buffer. The emollients, as described regimen or with a constant infusion regimen. The con- above for the lotions, can also be used in the cream com- centration of drug in the plasma will tend to rise immedi- positions. The cream may also contain a suitable emul- ately after the onset of administration and will tend to fall sifier, as described above. The emulsifier is included in 35 over time as the drug is eliminated from the circulation the composition at a level from 3% to 50%, preferably by means of distribution into cells and tissues, by metab- from 5% to 20%. olism, or by excretion. Steady state will be obtained when [0148] These compositions that are formulated as so- the mean drug concentration remains constant over time. lutions or suspensions may be applied to the skin, or, In the case of intermittent dosing, the pattern of the drug may be formulated as an aerosol or foam and applied to 40 concentration cycle is repeated identically in each inter- the skin as a spray-on. The aerosol compositions typi- val between doses with the mean concentration remain- cally contain [by weight] from 25% to 80%, preferably ing constant. In the case of constant infusion, the mean from 30% to 50%, of a suitable propellant. Examples of drug concentration will remain constant with very little such propellants are the chlorinated, fluorinated and oscillation. The achievement of steady state is deter- chlorofluorinated lower molecular weight hydrocarbons. 45 mined by means of measuring the concentration of drug Nitrous oxide, carbon dioxide, butane, and propane are in plasma over at least one cycle of dosing such that one also used as propellant gases. These propellants are can verify that the cycle is being repeated identically from used as understood in the art in a quantity and under a dose to dose. Typically, in an intermittent dosing regimen, pressure suitable to expel the contents of the container. maintenance of steady state can be verified by determin- [0149] Suitably prepared solutions and suspensions 50 ing drug concentrations at the consecutive troughs of a may also be topically applied to the eyes and mucosa. cycle, just prior to administration of another dose. In a Solutions, particularly those intended for ophthalmic use, constant infusion regimen where oscillation in the con- may be formulated as 0.01%- 10% isotonic solutions, pH centration is low, steady state can be verified by any two about 5-7, with appropriate salts, and preferably contain- consecutive measurements of drug concentration. ing one or more of the compounds herein at a concen- 55 [0153] FIG. 8 shows a kit. The kit 10 includes a vial 12 tration of about 0.1%, preferably greater than 1%, up to containing an opioid tablet. The kit 10 also includes a vial 50% or more. Suitable ophthalmic solutions are known 14 containing R-MNTX tablets which contain pellets, [see, e.g., U.S. Pat. No. 5,116,868, which describes typ- some of which are enterically coated with pH sensitive

21 39 EP 1 913 001 B1 40 material and some of which are constructed and ar- ranged to release the R- MNTX immediately in the stom- Time (min) %A %B ach. The kit also includes instructions 20 for administer- ing the tablets to a subject who is constipated or who has 0:00 95 5 symptoms of constipation or gastrointestinal immotility. 5 8:00 65 35 The instructions include indicia, for example writing, in- 12:00 35 65 dicating that the R-MNTX is pure R-MNTX free of S- MNTX. 15:00 0 100 [0154] The kit 10 can include optimally or alternatively 16:00 95 5 a pharmaceutical preparation vial 16, and a pharmaceu- 10 tical preparation diluents vial 18. The vial containing the 18:00 95 5 diluents for the pharmaceutical preparation is optional. The diluents vial contains diluents such as physiological Mobile phase A =0.1% Aqueous TFA saline for diluting what could be a concentrated solution Mobile phase B = 0.1% Methanolic TFA or lyophilized powder of R-MNTX. The instructions can 15 TFA = trifluoroacetic acid include instructions for mixing a particular amount of the diluents with a particular amount of the concentrated HPLC Method II: pharmaceutical preparation, whereby a final formulation for injection or infusion is prepared. The instructions 20 [0158] Chromatographic Conditions and Parameters: can include instructions for treating a patient with an ef- 20 Analytical Column Description: Phenomenex Inertsil fective amount of R- MNTX. It also will be understood that ODS-3 150 x 4.6 mm, 5 mm; Column Temperature: 50.0 the containers containing the preparations, whether the °C; Flow Rate: 1.5 mL/min; Injection Volume: 20 mL; De- container is a bottle, a vial with a septum, an ampoule tection Wavelength: with a septum, an infusion bag, and the like, can contain additional indicia such as conventional markings which 25 280 nm Mobile Phase: change color when the preparation has been autoclaved A = Water : MeOH : TFA (95:5:0.1%; v/v/v) B = or otherwise sterilized. Water : MeOH : TFA (35:65:0.1%; v/v/v) Analysis [0155] This invention is not limited in its application to Time: 50 min the details of construction and the arrangement of com- Quantitation limit: 0.05% ponents set forth in the following description or illustrated 30 Detection limit: 0.02% in the drawings. The invention is capable of other em- bodiments and of being practiced or of being carried out Gradient Profile: in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should [0159] not be regarded as limiting. The use of "including," "com- 35 prising," or "having," "containing", "involving", and varia- Time (min) %A %B Curve tions thereof herein, is meant to encompass the items listed thereafter as well as additional items. 0:00 100 0 Initial 45 50 50 Linear EXAMPLES 40 48 100 0 Linear Example 1 55 100 0 Hold

HPLC Analysis of R- and S-MNTX 45 Mobile Phase A (Water : MeOH : TFA :: 95 : 5 : [0156] HPLC analysis was performed on a Varian 0.1%, v/v/v) ProStar HPLC controlled by Varian Star software using Mobile Phase B (Water : MeOH : TFA :: 35 : 65 : the following method: 0.1%, v/v/v) MeOH = Methanol TFA = trifluoroacetic acid HPLC Method I: 50 [0160] The synthesis and purification of R- MNTX were [0157] monitored using the above HPLC protocol. S-MNTX is Column: Luna C18(2), 150 x 4.6 mm, 5 m distinguished from R-MNTX using the HPLC conditions Flow Rate: 1 mL/min described. Authentic S-MNTX for use as a standard may Detection: UV @ 230 nm 55 be made using the protocol as described herein. In a Gradient Program: typical HPLC run, S- MNTX elutes about 0.5 minutes be- fore R-MNTX elutes. The retention time of S-MNTX is approximately 9.3 minutes; the retention time of R- MNTX

22 41 EP 1 913 001 B1 42 is about 9.8 minutes. 33.8, 31.2, 30.7, 22.9, 19.0, 18.9, 9.4, 4.0, 3.8. MS [0161] As illustrated in FIG. 2, the S and R forms of [M+H]+ : 412. MNTX can be distinguished clearly on an HPLC chroma- [0166] 3-O-Isobutyryl-N-Methylnaltrexone Iodide togram. FIG. 3 is an HPLC chromatogram of a mixture salt (3). Compound (2) (689 mg, 1.67 mmol) was trans- of 0.1% by weight of authentic S form added to 99.5% 5 ferred by spatula into a glass pressure vessel. The vessel by weight of authentic R form; FIG. 4 is a chromatogram was purged gently with nitrogen on the manifold for 5 of 1.0% by weight of authentic S form added to 99.0% minutes and was then evacuated under high vacuum. by weight of authentic R form. FIG. 5 is a chromatogram When the vacuum was constant, the lower part of the of 3.0% by weight of authentic S form added to 98.0% vessel was immersed in liquid nitrogen. Methyl iodide by weight of authentic R form. This has permitted appli- 10 (973 mg, 6.85 mmol) was dispensed into a separate flask cants to devise and test for the first time stereoselective on the manifold into a nitrogen atmosphere and frozen protocols for synthesis and purification that yield highly in liquid nitrogen. The frozen methyl iodide vessel was pure R-MNTX from 3-O-protected-naltrexone. evacuated under high vacuum. The main manifold cham- ber was isolated from the high vacuum pump. The methyl Example 2 15 iodide was allowed to warm to ambient temperature and sublime via the main chamber onto the liquid nitrogen Stereoselective Synthesis of R-MNTX cooled 3-O-Isobutyryl-Naltrexone. When sublimation was complete, nitrogen was slowly allowed to leach into [0162] The synthetic scheme for Example 2 is shown the glass pressure vessel. The vessel was then sealed in FIG. 6. 20 tight, removed from the manifold and heated in an oil [0163] General. All anhydrous reactions were carried bath at 88-90°C for 17 hrs. The vessel was allowed to out in oven-dried (130 °C) glassware under an atmos- cool to ambient temperature before allowing nitrogen to phere of dry nitrogen (N2). All commercial reagents and flow into the vessel. The vessel was then evacuated un- solvents were used without any additional purification. der high vacuum to remove residues of unreacted methyl Nuclear magnetic resonance (NMR) spectra were ob- 25 iodide giving a white solid. A sample of the solid was tained using either a Varian Gemini or Varian Mercury removed for 1H NMR analysis. This showed good con- 300 MHz spectrometer. Mass spectra were determined version to product. Thin layer chromatography (TLC) of on a Finnigan LCQ. HPLC purity was determined using theproduct [dichloromethane /methanol 9: 1(v/v), normal a Waters 717 Autosampler and Waters 996 Photodiode phase silica, UV detection] showed a trace of starting 30 Array Detector. material (2) (Rƒ= 0.8) and a diffuse region (Rƒ= 0-0.4). [0164] 3-O-Isobutyryl-Naltrexone (2). To a solution The solid was dissolved in dichloromethane / methanol of compound (1) (1.62 g, 4.75 mmol) in anhydrous tet- (4:1, minimum volume) and applied to a silica gel column rahydrofuran (THF) (120 mL) at 0 °C was added triethyl- (ultrapure silica gel, 22 g in dichloromethane, bed dimen- amine (NEt3) (1.4 mL, 10 mmol). After the reaction was sions: stirred for 15 min. at 0 °C, isobutyryl chloride (1.05 mL, 35 10 mmol) was added dropwise. Reaction mixture was 200mm x 20mm id). The column was eluted as fol- stirred at 0 °C for 1 hr, then at room temperature for 18 lows: hr before being quenched with saturated sodium bicar- Dichloromethane / methanol 98:2 (300 ml) bonate (NaHCO3) (aq) (70 mL) and 30 ml of H2O. The Dichloromethane / methanol 97:3 (300 ml) 40 reaction was extracted with methylene chloride (CH 2Cl2) Dichloromethane / methanol 94:6 (200 ml) (2 x 200 mL). The extracts were combined, washed with Dichloromethane / methanol 92:8 (400 ml) brine (130 ml), dried over (Na 2SO4) (50g), Fractions were analyzed by TLC [dichloromethane filtered and concentrated in vacuo. The crude material / methanol 9:1 (v/v), normal phase silica, UV detec- was purified by flash chromatography on silica gel (col- tion]. Fractions containing exclusively the principal 45 umn size 40X450 mm, silica gel was loaded 40X190mm) component (Rƒ= 0.4) were combined rinsing togeth- (9.8:0.2 → 9.6:0.4 → 9.4:0.6 CH2C12/MeOH) to give er with methanol, and concentrated to yield 867 mg compound (2) (1.5 g 76.8%) as a white solid. of white solid. This represents a 91% yield based on 1 1 [0165] H NMR (300M Hz, CDCl 3) δ 6.82 (d, J=8.0 Hz, 3-O-Isobutyryl-Naltrexone. H NMR is consistent. 1H), 6.67 (d, J=8.0 Hz, 1H), 4.69 (s, 1H), 3.21 (d, J=6.0 Hz, 1H), 3.12-2.96 (m, 2H), 2.93-2.82 (m, 1H), 2.71 (dd, 50 [0167] N-Methylnaltrexone Bromide/Iodide salt (4). J=4.5 Hz, 1H), 2.62 (dd, J=6.2 Hz, 1H), 2.48-2.28 (m, Compound (3) (862 mg, 1.56 mmol) was dissolved in 4H), 2.19-2.10 (m, 1H), 1.93-1.86 (m, 1H), 1.68-1.59 (m, methanol (13 ml). To this mixture was added sterile water

2H),1.34 (d, J=0.8 Hz, 3H, CH 3-isobutyryl), 1.31 (d, J=0.8 (11.5 ml) followed by 48% aqueous hydrobromic acid Hz, 3H, CH 3-isobutyryl), 0.90-0.83 (m, 1H, CH- cyclopro- (1.5 ml). The resultant mixture was stirred under nitrogen 55 pyl), 0.60-0.54 (m, 2H, CH2-cyclopropyl), 0.18-0.13 (m, and heated in an oil bath at 64-65°C for 6.5 hr. TLC anal- 2H, CH2-cyclopropyl). 13C NMR (75.5 MHz, CDCl3) δ ysis of a sample (dispersed in methanol) of the reaction 207.6 (CO), 174.7 (COO/Pr)147.8, 132.8, 130.1, 130.0, mixture showed no starting material (3) remaining (Rƒ= 122.8, 119.2, 90.5, 70.0, 61.9, 59.2, 50.6, 43.4, 36.1, 0.4) and conversion to material at Rƒ= 0-0.15. The mix-

23 43 EP 1 913 001 B1 44 ture was concentrated on the rotary evaporator with the of methanol (1 ml) was added to triturate the solid. The bath at 22-25°C until approximately 1 ml of oily liquid supernatant liquors were decanted as before and the res- remained. Acetonitrile (10 ml) was added and the mixture idue was triturated further with methanol (2 ml). The su- was reconcentrated. This was repeated a further three pernatant liquors were decanted and the residue was times, using 10 ml of acetonitrile, to give a ginger colored 5 dried to give a white solid, batch B (266.0 mg). HPLC crisp foam (590 mg, 86% crude yield). analysis of batch B showed 97.39% of R-MNTX, and [0168] Preparation of Anion Exchange Resin Col- 2.61% of S-MNTX. Batches A and B together represent umn. 30 g of AG 1- X8 resin was packed into an medium a total yield of 436.8 mg (64%).1H NMR is consistent. pressure liquid chromatography (MPLC) column (20 mm MS [M+H]+: 356. id) using 100 ml water to create a resin slurry. The resin 10 [0172] As demonstrated in batches A and B, recrystal- bed was washed with 1.0N aqueous hydrobromic acid lization from methanol yields product with high percent- (200 ml) and then sterile water until the pH of the aqueous age of R- MNTX. In a reaction carried out under the same 14 eluate was pH 6-7. Approximately 1.5 L of water was conditions with CH3-labelled material, it was found that required. the composition of the crude reaction mixture before re- [0169] N-Methylnaltrexone Bromide (5). The foam 15 crystallization from methanol was 94.4% R-MNTX* and (4) (597 mg) was dispersed in water (6 ml) / methanol (2 4.7% S-MNTX*. Recrystallization from methanol yielded ml). Some dark oil remained undissolved. The clear su- product containing 98.0% R- MNTX* and 1.5% S- MNTX*. pernatant liquid was decanted and applied to the pre- A second recrystallization from methanol yielded 98.3% pared anion exchange resin column. The residue was R-MNTX* and 1.2% S-MNTX*. washed twice with methanol (0.2 ml) / water (3 ml). The 20 [0173] It should be understood that it is believed that supernatant liquors were applied to the column. The col- the synthetic protocol results in greater than 94% R form umn was eluted with 4.2 L of sterile water and fractions with only a small percentage of the S form. Using syn- of ∼ 20 ml were collected. The presence of N-Methylnal- thesis Scheme 1, the substantially pure material, could trexone salt was detected by liquid chromatography/ be processed further on a chromatography column, pre- mass spectometry (LC/MS). The majority of N-Methyln- 25 parative HPLC or recrystallization. In one recrystalliza- altrexone was located in the initial 1.5 L of eluate of which tion following ion exchange, the purity of the R form was the first 600 ml contained the most pure material by TLC greater than 98%. A second recrystalization yielded (4:1 dichloromethane / methanol, normal phase silica). 98.3% R-MNTX. It is understood that further recrystalli- Thefirst 600 ml of eluate was combinedand concentrated zations and/or chromatography, anywhere between one on the rotary evaporator to give a whitish glass. The water 30 and four, (or even six or as many as ten) times ensures bath was maintained at ∼35°C. Care was needed to con- greater than 99.95% R form and eliminates traces of the trol foaming of the eluate while evaporating. S form, if present. [0170] Purification of N-Methylnaltrexone Bromide (5). Recrystallization from methanol. The residue was Example 3 warmed in methanol (60 ml) under nitrogen to just below 35 reflux and then filtered through a glass sinter to remove Stereoselective Synthesis of R-MNTX a small amount of insoluble material. This filtrate was then blown down in a stream of nitrogen to approximately [0174] The synthetic scheme for Example 3 is shown 10 ml and then cooled under nitrogen in ice / water. Some in FIG. 7. In Example 3, the method taught by Goldberg white precipitate was formed but clearly much solid re- 40 et al for protecting groups was followed. Acetyl, Goldberg mained in solution. The mixture was then concentrated et al’s preferred protecting group, instead of isobutyryl by evaporation to give a slightly colored gum. This was was used as the protecting group. The reactions were triturated with methanol (3 ml x 2). Methanol was cau- carried out as described in Example 2. It was surprisingly tiously decanted by pipette between triturations. The found using the scheme shown in FIG. 7 that the acetyl white residue was dissolved in methanol (60 ml) and fil- 45 protecting group tended to fall off during purification of tered througha glass sinter. The filtratewas concentrated intermediate 2 (O-acetyl-naltrexone). This made it diffi- to approximately 1 ml and a further portion of methanol cult to obtain pure intermediate 2. The yield of interme- (1 ml) was added to triturate the solid. The supernatant diate 2 with the acetyl group was only 36.3% rendering liquors were decanted as before. The solid was dried to the scheme shown in FIG. 7 unsuitable for commercial give a white solid, batch A (178.0 mg). HPLC analysis 50 scale-up. In contrast using the synthetic scheme with iso- showed 97.31% of R-MNTX, and 2.69% of S-MNTX. butyryl as the protecting group (FIG. 6), intermediate 2 [0171] All filtrates / supernatant liquors in methanol (3-0-isobutyryl-naltrexone) was quite stable during puri- were combined and concentrated to give a white glass. fication resulting in a yield of 76.8%. This residue was triturated with methanol (3 ml x 2) and the supernatant liquors were removed carefully as be- 55 fore. The residue was dissolved in methanol (50 ml) and filtered through a glass sinter. The filtrate was concen- trated to approximately 1 ml solution and a further portion

24 45 EP 1 913 001 B1 46

Example 4 3. Add 19.9 mg of sodium citrate and 35 mg of citric acid (as buffering agents) to the tank and stir till dis- Manufacturing Process for a Pharmaceutical Formu- solved. lation of R-MNTX 4. Add 2000 mg of R-MNTX to the tank and stir till 5 dissolved. [0175] A manufacturing process can be outlined as fol- 5. Add 850 mg of sodium chloride, an isotonicity lows: agent, to the tank and stir till dissolved. 6. Adjust the pH of the solution if necessary. 1. Add required amount of water for injection ( ∼80% 7. Add water for injection to increase the volume to or final volume) to a stainless steel tank. 10 100 ml. 2. Add chelating agent to the tank and stir till dis- 8. Transfer the material to supply pressure vessel. solved. 9. Sterile filter using a 0.22 micron filter into a sterile 3. Add buffering agent to the tank and stir till dis- stainless steel pressure vessel. solved. 10. Fill, purge with nitrogen and then stopper the 4. Add R-MNTX to the tank and stir till dissolved. 15 bottles/vials. 5. Add isotonicity agent to the tank and stir illt dis- 11. Sterilize the filled vials by autoclaving. solved. 6. Adjust the pH of the solution to pH 3.25. Example 6 7. Add water for injection to increase the volume to the required amount. 20 Preparation of a Subcutaneous Formulation of R- 8. Transfer material to supply pressure vessel. MNTX 9. Sterile filter into a sterile stainless steel pressure vessel. [0181] A formula for a low citrate/EDTA formulation is 10. Fill into bottles/ vials, purgewith nitrogen and then listed below: stopper the bottles/vials. 25 11. Sterilize the filled vials by autoclaving. Ingredient mg/mL R-MNTX 30 mg Exact amount of excipients to be used: Sodium chloride 4 mg Citric acid 0.0875 mg [0176] 30 Trisodium citrate 0.0496 mg Disodium edetate = 0.75 mg/ml Added in step 2 Disodium edetate 0.75 mg Sodium citrate = 0.199 mg/ml Added in step 3 Water for injection q.s. to 1 g Citric acid = 0.35 mg/ml Added in step 3 Sodium chloride = 8.5 mg/ml Added in step 5 35 [0182] The pH of this solution is 3.5 and can withstand an autoclaving process. [0177] The order of addition of excipients is described above. Steps 2 to 5 can take place in any order. Example 7 [0178] When all excipients and drug have been added, step 6, pH of the solution is adjusted by addition of acid. 40 Manufacturing Process for a Lyophilized Pharma- If a buffering agent is used in the solution, pH adjustment ceutical Formulation of R-MNTX may not be required. [0179] There are no specifics on the temperature or [0183] The lyophilization cycle is used for the prepa- the stirring speed during the formulation. The tempera- ration of lyophilized preparation of R-MNTX. Forty milli- ture during formulation can be as high as 80 °C. 45 grams of R-MNTX is mixed with 32 mg of the cryopro- tecting agent, mannitol and q.s. to 1mL using water for Example 5 injection.

Preferred Manufacturing Process for a Pharmaceu- 1. Load chamber at room temperature (20-25°C) tical Formulation of R-MNTX 50 2. Lower shelf temp to -45 degrees C at 1.0 degrees C/min [0180] A preferred manufacturing process for 100 ml 3. Hold shelf temp at -45 for 120 minutes of 20 mg/ml solution of R-MNTX solution is as follows: 4. When condenser is below -50 degrees C, evacu- ate the chamber to 100-125 mt. 1. Add 80 ml of water for injection∼ 80%( or final 55 5. Ramp shelf to -20 degrees C at 0.5 degrees C/min. volume) to a stainless steel tank. 6. Hold at -20 degrees C for 16 hours 2. Add 75 mg of disodium edetate, a chelating agent, 7. Ramp shelf to +27 degrees C at 0.10 degrees to the tank and stir till dissolved.

25 47 EP 1 913 001 B1 48

C/min. 8. Hold for a minimum of 8 hours. Maintain chamber pressure at 100-125mt for the entire cycle. 9. Restore chamber to 11.0 PSIA + or- 1.0 with sterile filtered Nitrogen and then seat the closures (2" Hg), 5

then bleed to atmospheric pressure with N2 to un- load. The pH of the solution after lyophilization and reconstitution is 5.0.

[0184] Having thus described several aspects of at 10 least one embodiment of this invention, it is to be appre- ciated various alterations, modifications, and improve- ments will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intend- wherein R is isobutyryl and X- is a counterion, ed to be part of this disclosure, and are intended to be 15 wherein the compound is in the (R) configuration within the scope of the invention. Accordingly, the fore- with respect to the nitrogen; and, going description and drawings are by way of example (b) removal of R to yield (R)- N-methylnaltrexone only. salt.

20 3. The method of claim 2, wherein the methylating Claims agent comprises a methyl group susceptible to nu- cleophilic attack, and a leaving group, preferably the 1. A compound of the formula: methylating agent is selected from the group con- sisting of methyl halide, dimethyl sulfate, methyl ni- 25 trate and methyl sulfonate.

4. The method of claim 2, wherein X - is a halide.

5. The method of claim 2, wherein step (b) comprises 30 hydrolysis with hydrobromic acid to remove the R group to yield R-MNTX bromide/iodide salt, and the method further comprises passing the R- MNTX bro- mide/iodide salt through an anion exchange (bro- mide form) to yield R-MNTX bromide salt. 35 6. A method for stereoselective synthesis of a com- wherein R is isobutyryl and X - is a counterion, where- pound of formula: in the compound is in the (R) configuration with re- spect to the nitrogen. 40 2. A method for stereoselective synthesis of an (R)-N-methylnaltrexone salt comprising:

(a) methylating a compound of formula: 45

50 wherein R is isobutyryl and X - is a counterion, where- in the compound is in the (R) configuration with re- spect to the nitrogen, comprising methylating a compound of formula: 55

wherein R is isobutyryl with a methylating agent to yield a compound of formula:

26 49 EP 1 913 001 B1 50

5

10

wherein R is isobutyryl.

zu ergeben, wobei R Isobutyryl ist und -X ein Patentansprüche 15 Gegenion ist, wobei die Verbindung in Bezug auf den Stickstoff in der (R)-Konfiguration ist; 1. Verbindung der Formel: und (b) Entfernen von R, um ein R-(N)-Methylnalt- rexon-Salz zu ergeben. 20 3. Verfahren nach Anspruch 2, wobei das Methylie- rungsmittel eine Methylgruppe, die für einen nukleo- philen Angriff anfällig ist, und eine Abgangsgruppe umfasst, wobei vorzugsweise das Methylierungsmit- 25 tel aus der Gruppe bestehend aus Methylhalogenid, Dimethylsulfat, Methylnitrat und Methylsulfonat aus- gewählt ist.

4. Verfahren nach Anspruch 2, wobei X - ein Halogenid 30 ist.

5. Verfahren nach Anspruch 2, wobei Schritt (b) eine wobei R Isobutyryl ist und X - ein Gegenion ist, wobei Hydrolyse mit Bromwasserstoffsäure umfasst, um die Verbindung in Bezug auf den Stickstoff in der die R-Gruppe zu entfernen, um ein R-MNTX-Bro- (R)-Konfiguration ist. 35 mid-/Iodidsalz zu ergeben, und das Verfahren wei- terhin das Leiten des R-MNTX-Bromid-/Iodidsalzes 2. Verfahren zur stereoselektiven Synthese eines durch einen Anionenaustausch (Bromidform) um- (R)-N-Methylnaltrexon-Salzes, wobei das Verfahren fasst, um ein R-MNTX-Bromidsalz zu ergeben. Folgendes umfasst: 40 6. Verfahren zur stereoselektiven Synthese einer Ver- (a) Methylieren einer Verbindung der Formel: bindung der Formel:

45

50

55 wobei R Isobutyryl ist, mit einem Methylierungs- mittel, um eine Verbindung der Formel: wobei R Isobutyryl ist und X - ein Gegenion ist, wobei die Verbindung in Bezug auf den Stickstoff in der

27 51 EP 1 913 001 B1 52

(R)-Konfiguration ist, wobei das Verfahren das Methylieren einer Verbin- dung der Formel:

5

10

dans laquelle R est le groupe isobutyryle et X- est un contre- ion, le composé étant dans la con- figuration (R) en ce qui concerne l’atome 15 d’azote ; et (b) l’élimination de R pour produire le sel de (R)-N-méthylnaltrexone. umfasst, wobei R Isobutyryl ist. 3. Procédé selon la revendication 2, dans lequel l’agent 20 de méthylation comprend un groupe méthyle sus- Revendications ceptible de subir une attaque nucléophile et un grou- pe partant, de préférence l’agent de méthylation est 1. Composé représenté par la formule : choisi parmi un halogénure de méthyle, le sulfate de diméthyle, le nitrate de méthyle et le sulfonate de 25 méthyle.

4. Procédé selon la revendication 2, dans lequel X - est un halogénure.

30 5. Procédé selon la revendication 2, dans lequel l’étape (b) comprend une hydrolyse avec de l’acide bromhy- drique pour enlever le groupe R pour produire le sel bromure/iodure de R-MNTX et le procédé compre- nant en outre le passage du sel bromure/iodure de 35 R-MNTXdans un échange d’anions (forme bromure) dans laquelle R est le groupe isobutyryle et X- est pour produire le sel bromure de R-MNTX. uncontre- ion,le composé étantdans laconfiguration (R) en ce qui concerne l’atome d’azote. 6. Procédé pour la synthèse stéréosélective d’un com- posé de formule : 2. Procédé pour la synthèse stéréosélective d’un sel 40 de (R)-N-méthylnaltrexone comprenant :

(a) la méthylation d’un composé de formule :

45

50

dans laquelle R est le groupe isobutyryle et X- est un contre-ion, dans lequel le composé est dans la configuration (R) en ce qui concerne l’atome d’azote, 55 comprenant la méthylation d’un composé de dans laquelle R est le groupe isobutyryle avec formule : un agent de méthylation pour produire un com- posé de formule :

28 53 EP 1 913 001 B1 54

5

10 dans laquelle R est le groupe isobutyryle.

15

20

25

30

35

40

45

50

55

29 EP 1 913 001 B1

30 EP 1 913 001 B1

31 EP 1 913 001 B1

32 EP 1 913 001 B1

33 EP 1 913 001 B1

34 EP 1 913 001 B1

35 EP 1 913 001 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

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Non-patent literature cited in the description

• BIANCHETTI et al. Life Science, 1983, vol. 33 (I), • Remington’s Pharmaceutical Sciences. Mack Pub- 415-418 [0005] lishing Company [0092] • R.J. KOBYLECKI et al. J. Med. Chem., 1982, vol. • H.S. SAWHNEY ; C.P. PATHAK ; J.A. HUBELL. 25, 1278-1280 [0005] Macromolecules, 1993, vol. 26, 581-587 [0108] • IORIO MARIA et al. European Journal of Medicinal • M. SAFFRAN et al. Science, 1986, vol. 233, 1081 Chemistry, 1984, vol. 19 (4), 301-303 [0007] [0114] • FUNKE CAREL W et al. Journal of the Chemical So- • J. KOPECEK et al. Pharmaceutical Research, 1992, ciety, Perkin Transactions, 1986, vol. 2, 735-738 vol. 9 (12), 1540-1545 [0114] [0008] • K. H. BAUER et al. Pharmaceutical Research, 1993, • KOBYLECKI RJ. Journal of Medicinal Chemistry. vol. 10 (10), S218 [0114] American Chemical Society, 1982, vol. • 25, Pharmaceutical Dosage Forms: Tablets. Marcel 1278-1280 [0009] Dekker, Inc, 1989 [0120] • BOTH YUAN CHUN-SU. Journal of Supportive On- • ANSEL et al. Pharmaceutical Dosage Forms and cology, March 2004, vol. 2 (2), 111-117 [0010] Drug Delivery Systems. Williams & Wilkins, 1995 • DE PONTI. Current Opinion in Investigational Drugs, [0120] April 2002, vol. 3 (4), 614-620 [0010] • Remington: The Science and Practice of Pharmacy. Mack Publishing Co, 1995 [0127]

36