(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`12 May 2011 (12.05.2011) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2011/056240 A2
`
`
`International Patent Classification:
`A61K 9/16 (2006.01)
`
`International Application Number:
`PCT/US2010/00293 7
`
`(81)
`
`(51)
`
`(21)
`
`(22)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`International Filing Date:
`8 November 2010 (08.11.2010)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/259,567
`
`9 November 2009 (09.11.2009)
`
`US
`
`Applicant (for all designated States except US): XENO-
`PORT, INC. [US/US]; 3410 Central Expressway, Santa
`Clara, California 95051 (US).
`
`Inventors; and
`(for US only): MAO, Chen
`Inventors/Applicants
`[CN/US]; 205 Canoe Ct., Redwood City, California
`94065 (US). PARGAONKAR, Nikhil [IN/US]; 1181 W.
`Olive Ave., Sunnyvale, California 94086 (US). MAUR-
`ER, Laura E. [US/US]; 860 East Evelyn Avc., Sunny-
`vale, California 94086 (US). MA, Sarina Grace Harris
`[US/US]; 2181 RanchoMcCormick Blvd, Santa Clara,
`California 95050 (US).
`
`(74)
`
`Jean 3.; Finnegan, Henderson,
`Agent: FORDIS,
`Farabow, Garrett & Dunner LLP, 901 New York Avenue,
`
`N.W., Washington, District of Columbia 20001-4413
`(US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`Ao, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, Ls, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, Tz, UA, UG, us, UZ, VC, VN, ZA, ZM, zw.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to apply for and be granted
`apatent (Rule 4.17(ii))
`
`(54) Title: PHARMACEUTICAL COMPOSITIONS AND ORAL DOSAGE FORMS OF A LEVODOPA PRODRUG AND
`METHODS OF USE
`
`[Continued on nextpage]
`
`10000
`
`— C j Dryiéranuliesi15:%rwater
`— B - DryAGranulesig%—Water
`A — Levodopa—Prodrug (1)
`
`
`
`Intensity(counts)
`
`4000
`
`
`2000
`
`15
`
`20
`
`(57) Abstract: Pharmaceutical compositions and oral dosage forms of (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-di-
`hydroxyphenyl)propanoate mesylate and methods of treating diseases comprising orally administering such pharmaceutical com-
`positions and dosage forms are disclosed.
`
`2Theta (0)
`
`Figure 3
`
`1
`
`
`
`wo2011/056240A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`

`

`WO 2011/056240 A2 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`Published:
`
`— without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`

`

`WO 201 1/056240
`
`PCT/US2010/002937
`
`PHARMACEUTICAL CONIPOSITIONS AND ORAL DOSAGE FORMS OF A
`
`LEVODOPA PRODRUG AND METHODS OF USE
`
`[01]
`
`This application claims benefit of US. Provisional Application No.
`
`61/259,567, filed on November 9, 2009, which is incorporated by reference herein.
`
`[02]
`
`The disclosure relates to pharmaceutical compositions and oral dosage forms
`
`of a levodopa prodrug and to methods of treating a disease comprising orally administering
`
`such pharmaceutical compositions and dosage forms.
`
`[03]
`
`Parkinson’s disease is a disabling, progressive illness that affects one in 1,000
`
`people and generally occurs in people over the age of 50 years. Patients with Parkinson’s
`
`disease have a deficiency of the neurotransmitter dopamine in the brain as a result of
`
`nigrostriatal pathway disruption caused by degeneration of the substantia nigra. Levodopa
`
`(L—dopa or L—3,4-dihydroxyphenylalanine), an immediate precursor of dopamine, is the most
`
`commonly prescribed drug for treatment of this disease.
`
`[04]
`
`Following oral administration, levodopa is rapidly absorbed via an amino acid
`
`transporter present in the upper small intestine. Due to the narrow distribution of this
`
`transporter system, the window available for levodopa absorption is limited and the extent of
`
`absorption can depend on the rate at which the drug passes through the upper gastrointestinal
`tract.
`
`[05]
`
`Intestinal metabolism of levodopa is the major source of first pass loss of the
`
`drug. Approximately 35% of an administered dose of levodopa reaches the systemic
`
`circulation as intact levodopa after oral administration in patients (Sasahara, J. Pharm. Sci
`
`1990, 69, 261). Once absorbed, levodopa is rapidly metabolized to dopamine by L-aromatic
`
`amino acid decarboxylase (AADC) enzymes in the peripheral tissues (e.g., intestines and
`
`liver). For this reason, levodopa is normally co-administered with a decarboxylase enzyme
`
`inhibitor such as carbidopa or benserazide. When administered with carbidopa, the plasma
`
`concentration of intact levodopa increases and thus more levodopa becomes available to be
`
`transported into the central nervous system where it is converted to dopamine. Carbidopa
`
`and benserazide do not cross the blood-brain barrier to a significant extent and therefore do
`
`not inhibit the required conversion of levodopa to dopamine in the brain.
`
`[06]
`
`Levodopa prodrugs designed to be absorbed from both the small and large
`
`intestine have been described in US. Patent No. 7,323,585, US. Patent No. 7,342,131, US.
`
`Patent Application Publication No. 2008/0103200 (issued as US. Patent No. 7,671,089), US.
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`Patent No. 7,534,813, US. Patent Application Publication No. 2008/0171789 (issued as US.
`
`Patent No. 7,709,527), US. Patent Application Publication No. 2008/0214663, and US.
`
`Patent Application Publication No. 2009/0137834. These levodopa prodrugs can achieve an
`
`oral bioavailability of levodopa that is at least two times greater than the oral bioavailability
`
`of levodopa when orally administered on an equivalent molar basis. More specifically, US.
`
`Patent No. 7,342,131 and US. Patent No. 7,534,813 disclose the compound (2R)-2-
`
`phenylcarbonyloxypropyl (2S)—2-amino—3—(3,4—dihydroxyphenyl)propanoate hydrochloride in
`
`an amorphous or crystalline form. Crystalline (2R)-2-phenylcarbonyloxypropyl (25)-2-
`
`amino-3—(3,4—dihydroxyphenyl)propanoate mesylate 1:
`
`—S— O NH3+
`
`|O OOOO\/L
`
`HO
`
`OH
`
`(1)
`
`is described in US. Patent No. 7,563,821. These levodopa prodrugs can be incorporated into
`
`sustained release formulations to provide sustained systemic exposure to levodopa upon oral
`
`administration to a patient.
`
`[07]
`
`US. Application No. 12/581,810, filed on October 19, 2009 (US. Application
`
`Publication No. 2010/0099761), discloses crystalline hydrates of (2R)—2-
`
`phenylcarbonyloxypropyl (25)—2-amino-3-(3,4—dihydroxyphenyl)propanoate mesylate, and in
`
`particular (2R)—2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate, sesqui-hydrate. Hydrates of (2R)-2—
`
`phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate were
`
`found to be formed under certain conditions of environmental water content. Different
`
`crystalline forms and hydrates of a compound can have different solid state physical
`properties that can impact, for example, the processability of the compound, the rate of
`
`dissolution of the compound from a dosage form, and the stability of the compound. It is
`
`therefore desirable to control hydrate formation.
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`[08]
`
`Accordingly, pharmaceutical compositions and oral dosage forms are
`
`disclosed wherein hydrate formation of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-
`
`amino-3-(3,4-dihydroxyphenyl)propanoate mesylate is controlled.
`
`[09]
`
`In a first aspect, pharmaceutical compositions are provided comprising
`
`crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)—2—amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate and a €5.18 alkylsulfate or pharmaceutically acceptable
`
`salt thereof.
`
`[010]
`
`In a second aspect, oral tablet dosage forms are provided comprising
`
`crystalline (2R)-2—phenylcarbonyloxypropyl (2S)-2—amino—3—(3,4-
`
`dihydroxyphenyl)propanoate mesylate and a €6-13 alkylsulfate or pharmaceutically acceptable
`
`salt thereof.
`
`[011]
`
`In a third aspect, methods are provided for treating a disease in a patient such
`
`as Parkinson’s disease, schizophrenia, a cognitive impairment disorder, restless legs
`
`syndrome, a periodic limb movement disorder, tardive dyskinesia, Huntington’s disease,
`
`hypertension, and excessive daytime sleepiness comprising administering to a patient in need
`
`of such treatment a pharmaceutical composition comprising a therapeutically effective
`
`amount of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate, mesylate and a C643 alkylsulfate or pharmaceutically
`
`acceptable salt thereof.
`
`[012]
`
`In a fourth aspect, methods are provided for treating a disease in a patient such
`
`as Parkinson’s disease, schizophrenia, a cognitive impairment disorder, restless legs
`
`syndrome, a periodic limb movement disorder, tardive dyskinesia, Huntington’s disease,
`
`hypertension, and excessive daytime sleepiness comprising administering to a patient in need
`
`of such treatment an oral dosage form comprising crystalline (2R)-2—
`
`phenylcarbonyloxypropyl (25)-2-amino-3-(3,4—dihydroxyphenyl)propanoate, mesylate and a
`
`C643 alkylsulfate or pharmaceutically acceptable salt thereof.
`
`[013]
`
`Those skilled in the art will understand that the drawings, described herein, are
`
`for illustration purposes only. The drawings are not intended to limit the scope of the present
`
`disclosure.
`
`.[014]
`
`Figure 1 shows dissolution profiles for SR4 and SR5 tablets prepared
`
`according to Example 5.
`
`[015]
`
`Figure 2 shows PXRD patterns for ground SR5 tablets prepared according to
`
`Example 5 following exposure to 40°C/75% relative humidity (RH) for up to 4 weeks.
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`[016]
`
`Figure 3 shows PXRD patterns for (2R)-2-phenylcarbonyloxypropyl (ZS)-2—
`
`amino-3—(3,4-dihydroxyphenyl)propanoate, mesylate and for granules comprising (2R)-2-
`
`phenylcarbonyloxypropyl (2S)—2-amino—3-(3,4—dihydroxyphenyl)propanoate, mesylate
`
`prepared using different amounts of water during high shear wet granulation.
`
`[017]
`
`Figure 4 shows the levodopa pharmacokinetic profile following oral
`
`administration of SR4 or SR5 tablets to fasted subjects.
`
`[018]
`
`Figure 5 shows the levodopa pharmacokinetic profile following oral
`
`administration of SR4 or SR5 tablets to fed subjects.
`
`[019]
`
`Figure 6 shows levodopa prodrug dissolution profiles for bilayer tablets
`
`prepared according to Example 9 and having the composition described in Table 5.
`
`[020]
`
`Figure 7 shows levodopa prodrug dissolution profiles for bilayer tablets
`
`prepared according to Example 9 and having the composition of formulations e, f, g, and h as
`
`described in Table 7.
`
`[021]
`
`Figure 8 shows levodopa prodrug dissolution profiles for bilayer tablets
`
`prepared according to Example 9 and having the compOsitions described in Tables 8-1 1.
`
`[022]
`
`Figure 9 shows carbidopa dissolution profiles for bilayer tablets prepared
`
`according to Example 9 and having the compositions described in Tables 8-11.
`
`[023]
`
`[024]
`
`“Patient” or “subject” includes mammals, such as for example, humans.
`
`“Pharmaceutically acceptable vehicle” refers to a pharmaceutically acceptable
`
`diluent, a pharmaceutically acceptable adj uvant, a pharmaceutically acceptable excipient, a
`
`pharrnaceutically acceptable carrier, or a combination of any of the foregoing with which a
`
`levodopa prodrug may be administered to a patient, which does not destroy the
`
`pharmacological activity thereof, and which is nontoxic when administered in doses
`
`sufficient to provide a therapeutically effective amount of levodopa.
`
`[025]
`
`“(2R)-2-Phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate (1)” has the following structure:
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`i?
`—fi—o‘ NH3+
`O
`‘
`
`o
`
`O\/L
`
`O
`
`O
`
`HO
`
`OH
`
`(1)
`
`[026]
`
`“Prodrug” refers to a derivative of an active compound (drug) that undergoes a
`
`transformation under the conditions of use, such as within the body, to release an active drug.
`
`Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into
`
`the active drug. Prodrugs can be obtained by bonding a promoiety (defined herein), typically
`
`via a functional group, to a drug. For example, (2R)-2-phenylcarbonyloxypropyl (ZS)-2—
`
`amino-3—(3,4-dihydroxyphenyl)propanoate, mesylate is metabolized within a patient’s body
`
`to form the parent drug levodopa.
`
`[027]
`
`“Promoiety” refers to a group bonded to a drug, typically to a functional group
`
`of the drug, via bond(s) that are cleavable under specified conditions of use. The bond(s)
`
`between the drug and promoiety may be cleaved by enzymatic or non—enzymatic means.
`
`Under the conditions of use, for example following administration to a patient, the bond(s)
`
`between the drug and promoiety may be cleaved to release the parent drug. The cleavage of
`
`the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be
`
`catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a
`
`change of or exposure to a physical or environmental parameter, such as a change of
`
`temperature, pH, etc. The agent may be endogenous to the conditions of use, such as an '
`
`enzyme present in the systemic circulation of a patient to which the prodrug is administered
`
`or the acidic conditions of the stomach or the agent may be supplied exogenously. For
`
`example, for (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate, mesylate, the drug is levodopa and the promoiety has the
`
`structure:
`
`\/L O
`
`0
`
`*
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`[028]
`
`“Therapeutically effective amount” refers to the amount of a compound that,
`
`when administered to a subject for treating a disease or disorder, or at least one of the clinical
`
`symptoms of a disease or disorder, is sufficient to affect such treatment of the disease,
`
`disorder, or symptom; The therapeutically effective amount may vary depending, for
`
`example, on the compound, the disease, disorder, and/or symptoms of the disease, severity of
`
`the disease or disorder, and/or symptoms of the disease, the age, weight, and/or health of the
`
`patient to be treated, and the judgment of the prescribing physician. An appropriate amount
`
`may be ascertained by those skilled in the art or capable of determination by routine
`
`experimentation.
`
`[029]
`
`“Treating” or “treatment” of a disease refers to arresting or ameliorating a
`
`disease, disorder, or at least one of the clinical symptoms of a disease or disorder. In certain
`
`embodiments, “treating” or “treatment” refers to arresting or ameliorating at least one
`
`physical parameter of the disease or disorder, which may or may not be discernible by the
`
`patient. In certain embodiments, “treating” or “treatment” refers to inhibiting or controlling
`
`the disease or disorder, either physically (e.g., stabilization of a discernible symptom),
`
`physiologically (e.g., stabilization of a physical parameter), or both. In certain embodiments,
`
`“treating” or “treatment” refers to delaying, in some cases indefinitely, the onset of a disease
`
`or disorder.
`
`[030]
`
`Reference is now made in detail to certain embodiments of pharmaceutical
`
`compositions, dosage forms and methods. The disclosed embodiments are not intended to be
`
`limiting of the claims. To the contrary, the claims are intended to cover all alternatives,
`
`modifications, and equivalents.
`
`[031]
`
`Pharmaceutical compositions provided by the present disclosure comprise
`
`crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino—3-(3,4-
`
`dihydroxyphenyl)propanoate, mesylate and :1 C643 alkylsulfate or pharrnaceutically
`
`acceptable salt thereof.
`
`[032]
`
`Levodopa prodrugs are disclosed in US. Patent No. 7,323,585, US. Patent
`
`No. 7,342,131, US. Patent Application Publication No. 2008/0171789, and US. Patent
`
`Application Publication No. 2008/0214663 (issued as US. Patent No. 7,709,527). The
`
`levodopa prodrug, (2R)-2-phenylcarbonyloxypropyl (ZS)-2—amino-3-(3,4—
`
`dihydroxyphenyl)propanoate mesylate l:
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`l?
`_
`—fi—o NH3+ ML 0
`
`o
`
`\
`
`o
`
`.
`o
`
`HO
`
`OH
`
`0
`
`(1)
`
`and the crystalline form thereof, and methods of synthesis are disclosed in US. Patent No.
`
`7,563,821. Methods of synthesis are also disclosed in US. Application No. 12/581,808, filed
`
`on October 19, 2009 (US. Application Publication No. 2010/0099907). Hydrates of
`
`crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)-2—amino—3-(3,4-
`
`dihydroxyphenyl)propanoate, mesylate are disclosed in US. Application No. 12/581,810,
`
`filed on October 19, 2009 (US. Application Publication No. 2010/0099761).
`
`[033]
`
`One skilled in the art will appreciate that although crystalline (2R)-2-
`
`phenylcarbonyloxypropyl (25)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate is
`
`disclosed, a sample of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino—3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate can have various compositional and diastereomeric
`
`purities. In certain embodiments, crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-
`
`3-(3,4-dihydroxyphenyl)propanoate mesylate can exhibit a compositional purity of at least
`
`about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at
`
`least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about
`
`99%, and in certain embodiments, in excess of at least about 99%. In certain embodiments,
`
`crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate can exhibit a diastereomeric purity of at least about
`
`90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least
`
`about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%,
`
`and in certain embodiments, in excess of at least about 99%.
`
`[034]
`
`Crystalline (2R)-2-phenylcarbonyloxypropyl (2S)—2—amino-3—(3,4-
`
`dihydroxyphenyl)propanoate mesylate may exist in several tautomeric forms. Accordingly,
`
`all possible tautomeric forms of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-
`
`(3,4-dihydroxyphenyl)propanoate mesylate are encompassed unless otherwise specified. All
`
`isotopically labeled forms of crystalline (2R)—2-phenylcarbonyloxypropyl (ZS)-2-amino-3-
`
`

`

`WO 2011/056240
`
`PCT/US2010/002937
`
`(3,4-dihydroxyphenyl)propanoate mesylate are also encompassed unless otherwise specified.
`
`Examples of isotopes that may be incorporated into crystalline (2R)-2-
`
`phenylcarbonyloxypropyl (2S)—2~amino—3—(3,4-dihydroxyphenyl)propanoate mesylate
`
`include, but are not limited to, 2H, 3H, “c, 13c, 14c, 15N, 18o, and 17o.
`
`[035]
`
`In certain embodiments, a powder X-ray diffraction (PXRD) pattern of
`
`anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amin0-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate exhibits characteristic diffraction peaks (°29) at 4.7° 1
`
`02°, 5.0° 4; 02°, 85° i 02°, 9.6° i 02°, 13.6° i 02°, 15.0° i 02°, l7.0° i 02°, 17.4° i
`
`02°, 17.7° i 02°, 19.1° i 02°, l9.5° i 02°, 20.0° i 02°, 20.4° i 02°, 21.1° i 02°, 223° i
`
`02°, 22.9° i 02°, 23.l° i 02°, 233° i 02°, 243° 1 02°, 25.0° i 02°, 253° i 02°, 25.7° i
`
`02°, 25.8° i 02°, 26.9° i 02°, 273° i 02°, 282° i 02°, 30.1° i 02°, 305° i 0.2, 32.0° i
`
`02°, 33.8° :t 0.2°, 343° i 02°, 37.6° :t 02°, and 384° i 0.2°. PXRD patterns of anhydrous
`
`crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate are shown in Figure 2 (patterns A-C) and Figure 3
`
`(pattern A).
`
`[036]
`
`One skilled in the art will recognize that slight variations in the observed
`
`°29 diffraction angles can be expected based on, for example, the specific diffractometer
`
`employed, the analyst, and the sample preparation technique. Greater variation can be
`
`expected for the relative peak intensities. Comparison of diffraction patterns can be based
`
`primarily on observed °29 diffraction angles with lesser importance attributed to relative peak
`
`intensities. For the powder X—ray diffraction patterns of anhydrous crystalline (2R)—2—
`
`phenylcarbonyloxypropyl (ZS)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate, the
`
`peaks that generally exhibit the most intensity are located at °26 diffraction angles of 50° i
`
`02°, 85° i 02°, 13.6° i- 0.2°, 15.0° i 02°, 17.0° i 02°, 17.7° i 02°, 20.4° i 02°, 21.1° i
`
`02°, 250° 1 02°, 25.8° i 02°, 282° i 0.2, 301° 1 02°, and 376° i 02°. A powder X-ray
`
`diffraction pattern that exhibits characteristic diffraction peaks (°29) at 50° i 02°, 85° 1-
`
`02°, 13.6° i 02°, 15.0° i 02°, 17.0° i 02°, 17.7° 1 02°, 20.4° i 02°, 21.1° i 02°, 25.0° i
`
`02°, 25.8° i 02°, 282° i 02°, 30.1 ° i 02", and 37.6° i 02° will be substantially the same
`
`as the X—ray powder diffraction pattern of anhydrous crystalline (2R)-2-
`phenylcarbonyloxypropyl (ZS)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate.
`
`-
`
`[037]
`
`In certain embodiments, anhydrous crystalline (2R)-2-
`
`phenylcarbonyloxypropyl (ZS)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate
`
`exhibits a melting point from about 157°C to about 162°C.
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`[038]
`
`In certain embodiments, anhydrous crystalline (2R)-2—
`
`phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate is
`
`characterized by a differential seaming calorimetry (DSC) thermogram having an
`
`endothermic peak at about 164.5°C, and in certain embodiments at about 164.5 J; 25°C.
`
`[039]
`
`In certain embodiments, anhydrous crystalline (2R)-2-
`
`phenylcarbonyloxypropyl (2S)—2—amino—3—(3,4-dihydroxyphenyl)propanoate mesylate is
`
`stable, e. g., does not absorb moisture and/or convert to another isomorphic form under typical
`
`pharmaceutical processing and/or storage conditions.
`
`[040]
`
`The physical properties and characteristics of crystalline (2R)-2—
`
`phenylcarbonyloxypropyl (2S)-2—amino—3—(3,4—dihydroxyphenyl)propanoate mesylate
`
`prepared by methods disclosed in US. Patent No. 7,563,821 are consistent with that of a
`
`single isomorph. The environmental stability of the single isomorphic form of crystalline
`
`(2R)-2—phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate
`
`recommends its use in pharmaceutical compositions.
`
`[041]
`
`Under certain conditions of water activity as disclosed in US. Application No.
`
`12/581,810, filed on October 19, 2009 (US. Application Publication No. 2010/0099761),
`
`anhydrous crystalline (2R)—2-phenylcarbonyloxypropyl (2S)—2—amino—3-(3,4—
`
`dihydroxyphenyl)propanoate, mesylate will convert to a crystalline hydrate.
`
`[042]
`
`In certain embodiments, crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-
`
`' amino-3-(3,4-dihydroxyphenyl)propanoate mesylate, hydrate is characterized by a powder X-
`
`ray powder diffraction pattern having characteristic scattering angles measured using Cu-Ka
`
`radiation (°26) at least at 60° 2: 0.2°, 91° 1 0.2°, 9.6° i 0.2°, 12.0° : 0.2°, l3.8° i 0.2°, 14.6°
`
`t 0.2°, 15.1° 1' 0.2°, 15.6° i 0.2°, 16.1° i 0.2°, 16.6° : 0.2°, 17.6° i 0.2°, 185° i 0.2°, and
`
`192° : 0.2°. In certain embodiments, crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)—2-
`
`amino~3-(3,4-dihydroxyphenyl)propanoate mesylate, hydrate is characterized by a powder X—
`
`ray diffraction pattern having characteristic scattering angles measured using Cu—Ka radiation
`
`(°29) at least at 60° i 0.2°, 91° 1 0.2°, 9.6° i 0.2°, 12.0° 4.- 0.2°, 138° 1 0.2°, 14.6° i 0.2°,
`
`15.1° i 0.2°, 15.6° i 0.2°, 16.1° : 0.2°, 166° 1- 0.2°, 17.6° i 0.2°, 18.5° : 0.2°, 19.2° i 0.2°,
`
`20.8° i 0.2°, 21.9° i 0.2°, 228° i 0.2°, 23.4° i 0.2°, 23.7° 1 0.2°, 23.9° i 0.2°, and 265° i
`
`0.2°. In certain embodiments, crystalline (2R)~2—phenylcarbonyloxypropyl (23)—2—amino—3—
`
`(3,4—dihydroxyphenyl)propanoate mesylate, hydrate is characterized by a powder X—ray
`
`diffraction pattern having characteristic scattering angles measured using Cu-Ka radiation
`
`(°26) at least at 6.0° :t 0.2°, 9.l° : 0.2°, 9.6° i 0.2°, 1 12° 1 0.2°, 12.0° : 0.2°, 12.8° : 0.2°,
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`13.8° i O.2°, 143° :1: O.2°, 14.6° 1- 02°, 15.l° t O.2°, 15.6° i O.2°, l6.1° i O.2°, 16.6° i O.2°,
`
`l7.6° : 0.2°, 185° 1 O.2°, 18.7° 1 02°, 19.20 : O.2°, 205° 1 O.2°, 208° 1 O.2°, 21 .1° i O.2°,
`
`21.9° i O.2°, 22.8° i O.2°, 23.4° i O.2°, 23.7° i O.2°, 23.9° i O.2°, 24.7° : O.2°, 265° x O.2°,
`
`282° 1- 02°, 28.3° i O.2°, and 295° 1 02°. PXRD patterns of crystalline (2R)—2-
`
`phenylcarbonyloxypropyl (25)-2-amino-3—(3,4-dihydroxyphenyl)propanoate mesylate,
`
`hydrate are shown in Figure 3 (pattern C). The crystalline hydrate may be formed during
`
`processing such as during high shear wet granulation or during exposure to certain
`
`temperature and humidity conditions.
`
`[043]
`
`It has been determined that adding a small amount of an alkylsulfate or
`
`pharmaceutically acceptable salt thereof to a pharmaceutical composition can control or
`
`prevent the conversion of anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (25)-2-
`
`amino—3—(3,4—dihydroxyphenyl)propanoate, mesylate to the hydrated form. Accordingly,
`
`pharmaceutical compositions and oral dosage forms provided by the present disclosure
`
`comprise, in addition to crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4—
`
`dihydroxyphenyl)propanoate, mesylate, a C643 alkylsulfate or pharmaceutically acceptable
`
`salt thereof. In certain embodiments, a C543 alkylsulfate or pharmaceutically acceptable salt
`
`thereof is a €3-15 alkylsulfate or pharmaceutically acceptable salt thereof, and in certain
`
`embodiments a C1044 alkylsulfate or pharmaceutically acceptable salt thereof. In certain
`
`embodiments, the €6-18 alkylsulfate or pharmaceutically acceptable salt thereof is a salt of
`
`lauryl sulfate (C12 alkylsulfate), and in certain embodiments, is sodium lauryl sulfate. In
`
`certain embodiments, the amount of a C643 alkylsulfate or pharmaceutically acceptable salt
`
`thereof in a pharmaceutical composition is greater than about 0.5 wt-%, where wt-% is based
`
`on the total dry weight of the composition. In certain embodiments, the amount of €5.13
`
`alkylsulfate or pharmaceutically acceptable salt thereof in a pharmaceutical composition or
`
`oral dosage form can range from about 0.5 wt-% to about 2.0 wt-%, from about 0.5 wt-% to
`
`about 1.5 wt-%, and in certain embodiments is about 0.6 wt-% to about 0.9 wt-%. The
`
`amount of €6-13 alkylsulfate or pharmaceutically acceptable salt thereof is sufficient to control
`
`or prevent conversion of anhydrous crystalline (2R)-2—phenylcarbonyloxypropyl (25)—2-
`
`amino—3—(3,4—dihydroxyphenyl)propanoate, mesylate to a hydrated form.
`
`[044]
`
`In certain embodiments, the pharmaceutical compositions and oral dosage
`
`forms provided by the present disclosure may further comprise one or more pharmaceutically
`
`acceptable excipients.
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`[045]
`
`In certain embodiments, the pharmaceutical composition comprises about 50
`
`wt-% to about 90 wt-% crystalline (2R)-2-phenylcarbonyloxypropyl (25)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate mesylate; about 0.5 wt-% to about 2.0 wt-% €5.13 alkylsulfate
`
`or pharmaceutically acceptable salt thereof; about 6 wt-% to about 20 wt—%
`
`hydroxypropylmethylcellulose; and about 0.5 wt-% to about 2.0 wt—% magnesium stearate;
`
`wherein wt—% is based on the total dry weight of the composition. In certain embodiments,
`
`the pharmaceutical composition comprises about 80 wt-% to about 90 wt-% crystalline (2R)-
`
`2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate;
`
`about 0.5 wt—% to about 1.0 wt—% €5-13 alkylsulfate or pharmaceutically acceptable salt
`
`thereof; about 6 wt-% to about 10 wt-% hydroxypropylmethylcellulose; and about 0.5 wt-%
`
`to about 2.0 wt—% magnesium stearate; wherein wt—% is based on the total dry weight of the
`
`composition.
`
`[046]
`
`As disclosed in US. Application No. 12/581 ,810, filed on October 19, 2009
`
`(US. Application Publication No. 2010/0099761) and in Example 3 herein, high shear wet
`
`granulation processing of anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)—2-
`
`amino—3-(3,4-dihydroxyphenyl)propanoate, mesylate results in conversion to crystalline (2R)-
`
`2—phenylcarbonyloxypropyl (2S)-2—amino-3-(3,4-dihydroxyphenyl)propanoate, mesylate,
`
`hydrate. As demonstrated in Example 6, the addition of a small amount of sodium lauryl
`
`sulfate to the high shear wet granulation formulation controls or prevents conversion of
`anhydrous crystalline (2R)-2—phenylcarbonyloxypropyl (25)—2—amino-3—(3,4-
`
`dihydroxyphenyl)propanoate, mesylate to the hydrated form. The use of anionic surfactants
`
`to control solid-state phase transformations in general (Davey et al., J Am Chem Soc 1997,
`
`119, 1767-1772; and Ataab et al., Adv Mater 1990, 2(1), 40-43) and during high shear wet
`
`granulation (Airaksinen et al., AAPS PharmSciTech 2005, 6(2), E311-E322; and Wikstrom et
`
`al., Pharmaceutical Research 2008, 25(4), 923-935) is known in the art.
`
`[047]
`
`Oral dosage forms provided by the present disclosure comprise crystalline
`
`(2R)-2-phenylcarbonyloxypropyl (28)—2—amino-3-(3,4—dihydroxyphenyl)propanoate,
`
`mesylate, and a €6-13 alkylsulfate or pharmaceutically acceptable salt thereof. In certain
`
`embodiments, dosage forms may be capsules or tablets. In certain embodiments, an oral
`
`dosage form comprises granules, wherein the granules comprise crystalline (2R)—2-
`
`phenylcarbonyloxypropyl (ZS)-2—amino-3-(3,4-dihydroxyphenyl)propanoate mesylate; and a
`
`C643 alkylsulfate or pharmaceutically acceptable salt thereof. In certain embodiments of oral
`
`dosage forms and granules, a €6.13 alkylsulfate or pharmaceutically acceptable salt thereof is
`
`a €3-16 alkylsulfate or pharmaceutically acceptable salt thereof, and in certain embodiments a
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`C1014 alkylsulfate or pharmaceutically acceptable salt thereof. In certain embodiments, the
`
`€6-18 alkylsulfate or pharmaceutically acceptable salt thereof is a salt of lauryl sulfate (C12
`
`alkylsulfate), and in certain embodiments, is sodium lauryl sulfate. In certain embodiments,
`
`the granules comprise about 90 wt-% to about 99 wt-% crystalline (2R)-2-
`
`phenylcarbonyloxypropyl (2S)—2-amino—3—(3,4—dihydroxyphenyl)propanoate mesylate; and
`
`about 0.5 wt-% to about 2 wt-% €6-13 alkylsulfate or pharmaceutically acceptable salt thereof;
`
`wherein wt-% is based on the total dry weight of the granules. In certain embodiments,
`
`granules comprise about 90 wt—% to about 99 wt—% crystalline (2R)-2—
`
`phenylcarbonyloxypropyl (ZS)-2-amino—3-(3,4—dihydroxyphenyl)propanoate mesylate; and
`
`about 0.5 wt-% to about 1 wt-% sodium lauryl sulfate; wherein wt—% is based on the total dry
`
`weight of the granules.
`
`[048]
`
`Granules comprising crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)-2-
`
`amino-3-(3,4-dihydroxyphenyl)propanoate, mesylate, and a C643 alkylsulfate or
`
`pharmaceutically acceptable salt thereof can be prepared using high shear wet granulation.
`
`To prepare granules crystalline (2R)-2-phenylcarbonyloxypropyl (ZS)-2-amino-3-(3,4-
`
`dihydroxyphenyl)propanoate, mesylate, and a €5-13 alkylsulfate or pharmaceutically
`
`acceptable salt thereof are combined with water. In certain embodiments, the amount of
`
`water added during high shear wet granulation is about 6 wt-% to about 10 wt-%, in certain
`
`embodiments, about 7 wt-% to about 10 wt-%, and in certain embodiments, about 7 wt-% to
`
`about 9 wt-%, where wt—% is based on the total weight of the water and dry materials added
`
`during high shear wet granulation.
`
`[049]
`
`Dosage forms comprising granules may comprise a suspension in which
`
`granules comprising crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-
`dihydroxyphenyl)propanoate mesylate are dispersed in a pharmaceutically acceptable solvent
`
`formulation. Solvent formulations may include water, ethanol, flavorings, colorings, or
`
`combinations of any of the foregoing. Liquid oral dosage forms can include aqueous and
`
`non-aqueous solutions, emulsions, suspensions, and solutions and/or suspensions
`
`reconstituted from non-effervescent granules, containing suitable solvents, emulsifying
`
`agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents,
`
`preservatives, and combinations of any of the foregoing. The solvent