(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`10 March 2016 (10.03.2016)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2016/036308 A1
`
`(51)
`
`International Patent Classification:
`A61K 31/195 (2006.01)
`A61K 31/277 (2006.01)
`A61K 9/06 (2006.01)
`A61P 25/16 (2006.01)
`A61K 31/198 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/SE2015/050939
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`(74)
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`(81)
`
`Filing Language:
`
`Publication Language:
`
`4 September 2015 (04.09.2015)
`English
`
`English
`
`Priority Data:
`1451034-1
`1550344-4
`
`4 September 2014 (04.09.2014)
`24 March 2015 (24.03.2015)
`
`SE
`SE
`
`Applicant: LOBSOR PHARMACEUTICALS AK-
`TIEBOLAG [SE/SE]; KoloniV'agen 16, S-74144 Knivsta
`(SE).
`
`Inventor: BOLSOY, Roger; Kolonivagen 16, S-74144
`Knivsta (SE).
`
`Agent: BRANN AB; 12246, (Courier address, Fleming-
`gatan 7, 1 12 26 Stockholm), S-102 26 Stockholm (SE).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, RN, 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, G11, GM, GT,
`HN, HR, HU, ID, IL, IN, 1R, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, N1, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 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 of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, 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, KM, ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`of inventorship (Rule 4.1 7(iv))
`Published:
`
`with international search report (Art. 21(3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`(54) Title: PHARMACEUTICAL COMPOSITIONS COMPRISING LEVODOPA, A DOPAMINE DECARBOXYLASE INHIBIT-
`OR AND A COMT INHIBITOR AND METHOD OF ADMINISTRATION THEREOF
`
`(57) Abstract: A pharmaceutical gel composition for intra—intestinal administration comprises (i) a dopamine replacement agents,
`(ii) a dopamine decarboxylase inhibitor (DDI), and (iii) a COMT inhibitor.
`
`
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`WO 2016/036308
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`PCT/SE2015/050939
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`PHARMACEUTICAL COMPOSITIONS COMPRISING LEVODOPA, A DOPAMINE
`
`DECARBOXYLASE INHIBITOR AND A COMT INHIBITOR AND METHOD OF
`
`ADMINISTRATION THEREOF
`
`CROSS REFERENCE TO RELATED APPLICATIONS
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`[0001]
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`This application claims priority to and the benefit of, and incorporates herein by
`
`reference, each of Sweden Patent Application No. 1451034—1, filed September 4, 2014 and
`
`Sweden Patent Application No. 1550344-4, filed March 24, 2015.
`
`BACKGROUND
`
`[0002]
`
`Neurodegenerative disorders result when neurons normally do not reproduce or
`
`replace themselves, thus damaged neurons cannot be replaced. Progressive degeneration
`
`and/or death of neuronal cells often results in problems with movement (e.g., ataxias), or
`
`mental functioning (e.g., dementias). Many neurodegenerative disorders are currently
`
`considered to be incurable. Examples of neurodegenerative disorders include Parkinson’s
`
`disease (“PD”), Alzheimer’s disease (“AD”), and Huntington’s disease (“HD”).
`
`[0003]
`
`Parkinson’s disease is characterized by a progressive degeneration of the
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`dopaminergic pathway resulting in reduced concentration of the neurotransmitter dopamine in
`
`the brain which manifests itself as symptoms of slowness of movement (e. g.,bradykinesia),
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`rigidity, tremor and poor balance in the patient.
`
`[0004]
`
`Biochemically, dopamine (3,4—dihydroxyphenethylamine) is formed by
`
`metabolism of dopamine precursors. For example, dopamine is formed by decarboxylation of
`
`the precursor levodopa (L-dopa; L-3,4-dihydroxyphenylalanine) through the enzyme aromatic
`
`L-amino acid decarboxylase (also known as DOPA decarboxylase (DDC)), both in the brain
`
`and in the peripheral circulation. Levodopa is in turn produced from the amino acid L-
`
`tyrosine by the enzyme tyrosine hydroxylase (TH).
`
`[0005]
`
`Dopamine is metabolized to homovanillic acid (HVA) mainly through two
`
`metabolic pathways, namely (i) via 3,4-dihydroxyphenylacetic acid (DOPAC) by the enzymes
`
`monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), and (ii) via 3-
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`methoxytyramine by the enzymes catechol-O-methyltransferase (COMT) and monoamino
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`oxidase (MAO).
`
`[0006]
`
`The most common treatment of PD aims at restoring the dopamine concentration
`
`in the brain. Administration of dopamine is ineffective because it does not cross the blood-
`
`brain barrier. However, since the precursor levodopa does cross the blood-brain barrier, and
`
`is converted to dopamine in the brain, administration of levodopa has for a long time been,
`
`and still is, the drug of first choice for PD treatment.
`
`SUMMARY
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`[0007]
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`The present invention provides particular compositions and strategies for treating
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`certain dopamine-related diseases, disorders and conditions, including certain
`
`neurodegenerative disorders (e.g., Parkinson’s Disease (PD)) and/or for administering agents
`
`useful in such treatment. Among other things, the present invention encompasses
`
`identification of the source of a problem with certain known compositions and/or strategies
`
`for treating such diseases, disorders or conditions and/or for administering relevant agents.
`
`[0008]
`
`In some embodiments, the present disclosure encompasses the insight that
`
`administering a combination of agents that includes each of (i) a dopamine replacement
`
`agents, (ii) a dopamine decarboxylase inhibitor (DDI), and (iii) a COMT inhibitor to a subject,
`
`particularly when one or more of the agents is delivered by intra-intestinal administration of a
`
`pharmaceutical gel, provides certain unexpected advantages and/or solves one or more
`
`problems associated with prior strategies for treating neurodegenerative disorders (e.g., PD).
`
`[0009]
`
`In some embodiments, the present disclosure provides methods in which a COMT
`
`inhibitor is administered in combination with therapy that involves administering a dopamine
`
`replacement agents and/or a DDI by intra-intestinal administration of a pharmaceutical gel.
`
`[0010]
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`In some embodiments, the present invention encompasses the insight that in
`
`various contexts may be useful to deliver a COMT inhibitor by intra-intestinal administration
`
`of a pharmaceutical gel, and provides particular methods and reagents relating thereto.
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`[0011]
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`Among other things, the present invention encompasses identification of the
`
`source of a problem with certain known compositions and/or strategies for administering a
`
`dopamine replacement agent (e. g., levodopa). For example, the present disclosure
`
`encompasses the recognition of a need for treatment strategies that minimize a subj ect’s
`
`intake of and/or exposure to the metabolic precursor, while maintaining therapeutic benefit of
`
`such intake or exposure. The present disclosure provides such treatment strategies (e. g.,
`
`compositions and/or methods that achieve reduced patient exposure, while maintaining
`
`therapeutic benefit, as compared with a relevant reference strategy (e. g., a currently accepted
`
`standard therapy).
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`[0012]
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`In some embodiments, the present disclosure encompasses the recognition of a
`
`need for improved pharmaceutical compositions for intra-intestinal administration ofa
`
`dopamine replacement agent, and particularly of levodopa. The present disclosure provides
`
`such compositions.
`
`[0013]
`
`In some embodiments, the present disclosure identifies the source of a problem
`
`with storage characteristics (e. g., stability to long term storage and/or storage under particular
`
`conditions) of certain compositions comprising a dopamine replacement agent, and
`
`particularly of compositions comprising levodopa. Among other things, the present
`
`disclosure encompasses the recognition of a need for pharmaceutical compositions
`
`comprising dopamine replacement agents, and particularly of compositions comprising
`
`levodopa, which have particular storage stability characteristics. The present disclosure
`
`provides such compositions.
`
`[0014]
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`In many embodiments, intra-intestinal administration typically is duodenal and/or
`
`jej unal administration via an external access point.
`
`[0015]
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`In some embodiments, a pharmaceutical gel composition for intra-intestinal
`
`administration comprises a dopamine replacement agent, a dopamine decarboxylase inhibitor
`
`(DDI), and a catechol—O—methyltransferase (COMT) inhibitor.
`
`[0016]
`
`In some particular embodiments, the present invention provides a pharmaceutical
`
`gel composition for intra—intestinal administration, comprising at least about 10 mg/ml of
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`levodopa and at least about 2.5 mg/ml of a dopamine decarboxylase inhibitor, wherein the gel
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`composition further comprises at least about 10 mg/ml ofa COMT inhibitor.
`
`[0017]
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`In certain provided gel compositions and/or methods, one or more active
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`compounds (e.g., levodopa and/or one or more DDIs [e.g., carbidopa] and/or one or more
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`COMT inhibitors [e.g., entacapone]) may be provided and/or utilized in the form of a
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`pharmaceutically acceptable salt thereof, and/or in a hydrate or solvate form thereof.
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`In some
`
`particular embodiments, certain compositions and/or methods may utilize one or more active
`
`compounds may be provided and/or utilized in a solid form; in some such embodiments, the
`
`solid form may be or comprise a crystalline form; in some such embodiments, the solid form
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`may be or comprise an amorphous form. In some embodiments, a solid form comprises or
`
`consists of an amorphous form, or a single particular crystalline form.
`
`[0018]
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`In some embodiments, a pharmaceutical gel composition comprises at most 200
`
`mg/ml of levodopa, at most 50 mg/ml of a dopamine decarboxylase inhibitor, and at most 200
`
`mg/ml of a COMT inhibitor.
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`[0019]
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`Exemplary dopamine decarboxylase inhibitors include carbidopa, benzerazide, 0L-
`
`difluoromethyldopa [(ZS)-2-amino-2-[3,4-dihydroxyphenyl)-methyl]-3,3-difluoropropanoic
`
`acid] and d—methyldopa [(S)—2—amino—3—[3,4—dihydroxyphenyl)—2—methyl—propanoic acid].
`
`[0020]
`
`In some embodiments, a dopamine decarboxylase inhibitor is carbidopa,
`
`benserazide, or any combination thereof.
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`[0021]
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`In some embodiments, a dopamine decarboxylase inhibitor is carbidopa.
`
`[0022]
`
`In some embodiments, a COMT inhibitor is selected from the group consisting of
`
`entacapone, tolcapone, opicapone and any combination thereof.
`
`[0023]
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`In some embodiments, a COMT inhibitor is entacapone.
`
`[0024]
`
`In some embodiments, a pharmaceutical gel composition comprises a DDI such as
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`carbidopa, and further comprises a substance capable of inhibiting degradation of carbidopa to
`
`hydrazine.
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`[0025]
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`In some embodiments, a substance capable of inhibiting degradation of carbidopa
`
`to hydrazine comprises entacapone.
`
`[0026]
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`In some embodiments, a pharmaceutical gel composition comprises about 20
`
`mg/ml oflevodopa, 5 mg/ml ofcarbidopa, and 20 mg/ml of entacapone.
`
`[0027]
`
`In some embodiments, a pharmaceutical gel composition as described herein that
`
`comprises one or more COMT inhibitors and at least one additional active compound is
`
`characterized by increased stability (e.g., reduced degradation) of the at least one additional
`
`active compound, for example relative to that observed for an otherwise comparable
`
`composition lacking (or, in some embodiments, containing a different absolute or relative
`
`amount of) the COMT inhibitor. In some such embodiments, stability is assessed over time
`
`(e.g., after a particular period of time has elapsed) and/or under particular storage conditions.
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`For example, in some embodiments, such increased stability is observed over a period of time
`
`that extends for at least 1 week, 2 weeks, 5 weeks, 7 weeks, 10 weeks, 15 weeks, 20 weeks or
`
`more, for example under refrigerated conditions (e. g., conditions under which the
`
`composition(s) is/are maintained at a temperature below about 15 oC and, preferably, within a
`
`range of about 0 CC to about 15°C, about 0 °C to about 12 °C, about 0 °C to about 10 °C,
`
`about 0 °C to about 8 °C, or about 2 °C to about 8 °C).
`
`[0028]
`
`In some embodiments, a provided intra—intestinal gel composition comprises
`
`and/or is prepared from a gel characterized by a pH not higher than about 5.7 and/or is
`
`maintained at a pH not higher than about 5.7. In some embodiments, such provided
`
`compositions that include one or more active agents (e.g., levodopa, a DDI, a COMT
`
`inhibitor, etc.) are characterized by improved stability of one or more such active agents as
`
`compared with a relevant reference composition that differs, for example, in value of pH.
`
`[0029]
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`In some embodiments, an intra-intestinal gel composition is deoxygenized (e. g.,
`
`via nitrogen purging). In some embodiments, such provided compositions that include one or
`
`more active agents are characterized by improved stability of one or more such active agents
`
`as compared with a relevant reference composition that differs, for example, in presence
`
`and/or duration of such deoxygenization.
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`[0030]
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`In some embodiments, a pharmaceutical gel composition includes antioxidants
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`(e.g., ascorbic acid or citric acid). In some embodiments, such provided compositions that
`
`include one or more active agents are characterized by improved stability of one or more such
`
`active agents as compared with a relevant reference composition that differs, for example, in
`
`presence and/or amount (e. g., absolute or relative values) of such antioxidants.
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`[0031]
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`In some embodiments, deoxygenation is combined with lowered pH or
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`antioxidant.
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`[0032]
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`In some embodiments, a provided gel composition is substantially free of (e.g.,
`
`lacks detectable and/or material levels of) a metal chelating agent, such as EDTA, in some
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`embodiments, a provided gel composition is substantially free of any metal chelating agent.
`
`[0033]
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`In some embodiments, a pharmaceutical gel composition is provided in a light-
`
`protected container.
`
`[0034]
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`In some embodiments, one or more active substances, (e.g., levodopa, dopamine
`
`carboxylase inhibitor (e. g., carbidopa) and COMT inhibitor (e. g., entacapone) are in the form
`
`of particles, for example having a maximum particle size not exceeding about 80 um, which
`
`particles may, in some embodiments, be suspended in a carrier (e. g., in an aqueous carrier), in
`
`some such embodiments, the carrier has a viscosity of at least 300 mPas, measured at a
`
`moderate shear rate.
`
`[0035]
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`In some embodiments, viscosity of an intra—intestinal gel composition is at least
`
`1800 mPas. In another embodiment, the viscosity is in the range of 2200 to 4500 mPas.
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`[0036]
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`While a carrier typically may be of polysaccharide type, and, for example, be
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`selected from cellulose, methyl cellulose (MC), ethyl cellulose, carboxymethyl cellulose
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`(CMC) and salts thereof, xanthan gum, carrageenan, and combinations thereof the carrier may
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`also be a synthetic polymer, such as polyvinylpyrrolidone (PVP, Povidon) or polyacrylic acid
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`(PAA, Carbomer). An exemplary carrier is the sodium salt of carboxymethyl cellulose
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`(NaCMC).
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`[0037]
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`In some embodiments, a pharmaceutical gel composition comprises about 2 %
`
`(w/w) micronized levodopa, about 0.5 % (w/w) micronized carbidopa, 2 about % (w/w)
`
`micronized entacapone, and 2.92 about % (w/w) sodium carboxymethyl cellulose.
`
`[0038]
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`In some embodiments, a pH value of a pharmaceutical gel composition is selected
`
`to be the lowest pH value equal to or greater than about 5.0 to about 5.5 where viscosity of an
`
`aqueous carrier after 12 days at 25 0C is at least 300 mPas at a moderate shear rate.
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`[0039]
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`In some embodiments, a carrier of a pharmaceutical gel composition is NaCMC,
`
`and the pH value is 5.5 :: 0.2.
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`[0040]
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`In some aspects of the present invention provides a pharmaceutical gel
`
`composition for a treatment of neurodegenerative disorders (e. g., Parkinson’s Disease).
`
`[0041]
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`In some aspects of the present invention, there is provided a method of treating
`
`Parkinson’s Disease, which comprises intra-intestinally administering a pharmaceutical gel
`
`composition according to certain aspects of the present invention as described above.
`
`[0042]
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`In some embodiments, a pharmaceutical gel composition is administered
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`continuously over a period less than about 16 hours per day.
`
`[0043]
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`In some embodiments, a pharmaceutical gel composition is administered
`
`continuously over a period greater than about 16 hours per day.
`
`[0044]
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`In some embodiments, a pharmaceutical gel composition is administered
`
`continuously as a long—term treatment for more than 1 day.
`
`[0045]
`
`In some aspects, the present invention provides use of entacapone in a
`
`pharmaceutical gel composition comprising levodopa and carbidopa for inhibiting
`
`degradation of carbidopa to hydrazine.
`
`[0046]
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`In some embodiments, a pharmaceutical gel composition comprises a
`
`pharmaceutically active agent and formulated for intra-intestinal delivery, wherein the
`
`pharmaceutically active agent is or comprises entacapone.
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`[0047]
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`In some embodiments, a pharmaceutical gel composition for intra-intestinal
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`administration comprises levodopa, a dopamine decarboxylase inhibitor and a COMT
`
`inhibitor, wherein the weight ratio of the COMT inhibitor to the dopamine decarboxylase
`
`inhibitor is about 10:1 to about 2: 1, or about 5:1 to about 3:1.
`
`[0048]
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`In some embodiments, a pharmaceutical gel composition for intra-intestinal
`
`administration comprises levodopa, a dopamine decarboxylase inhibitor, and a COMT
`
`inhibitor, wherein the weight ratio of the dopamine decarboxylase inhibitor to levodopa is at
`
`least about 1:10.
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`[0049]
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`In some embodiments, a pharmaceutical gel composition for intra—intestinal
`
`administration comprises levodopa, a dopamine decarboxylase inhibitor, and a COMT
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`inhibitor, wherein the levodopa, the dopamine decarboxylase inhibitor and the COMT
`
`inhibitor are in the form of particles, and the particles are suspended in an aqueous carrier,
`
`and have the particle size of no greater than about 80 pm.
`
`[0050]
`
`In some embodiments, a method of prolonging shelf life of a pharmaceutical gel
`
`comprises providing a first gel comprising levodopa and a dopamine decarboxylase inhibitor
`
`and including a COMT inhibitor in the first gel.
`
`[0051]
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`In some embodiments, a method for reducing hydrazine production and/or
`
`accumulation in a pharmaceutical composition comprising levodopa and carbidopa and/or
`
`upon its administration comprises a step of including a COMT inhibitor in the pharmaceutical
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`compositions.
`
`[0052]
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`Some embodiments are set forth in the dependent claims.
`
`[0053]
`
`A more complete understanding of the invention, as well as further features and
`
`advantages thereof, will be obtained by reference to the following detailed description read in
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`conjunction with the accompanying drawings.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`[0054]
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`Figure 1 is a graph showing an exemplary level of carbidopa degradation product
`
`DHPA versus pH at the end of a 10 days stability test at 25 °C on a
`
`levodopa/carbidopa/entacapone gel formulation.
`
`[0055]
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`Figure 2 is a graph showing an exemplary level of carbidopa degradation product
`
`DHPPA versus pH at the end of a 10 days stability test at 25 0C on a
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`levodopa/carbidopa/entacapone gel formulation.
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`[0056]
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`Figure 3 is a graph showing an exemplary level of entacapone degradation product
`
`RRT 11.8 versus pH at the end of a 10 days stability test on a levodopa/carbidopa/entacapone
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`10
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`gel formulation.
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`[0057]
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`Figure 4 is a graph showing an exemplary level of reduced Viscosity versus pH at
`
`the end of a 12 days stability test on a levodopa/carbidopa/entacapone gel formulation.
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`[0058]
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`Figure 5 is a graph showing exemplary levels of carbidopa degradation product
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`hydrazine during a 20 weeks storage stability test in refrigerated condition (2—8 0C) on a
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`lcvodopa/carbidopa gcl formulation (upper curve) and a lcvodopa/carbidopa/cntacaponc gcl
`
`formulation (lower curve).
`
`[0059]
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`Figure 6 is a graph showing exemplary levels of carbidopa degradation product
`
`hydrazine during a 20 weeks storage stability test in refrigerated condition (2-8 0C) on two
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`levodopa/carbidopa/entacapone gel formulations of different pH; upper curve pH 5.5 and
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`lower curve pH 5.0.
`
`[0060]
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`Figure 7 is a graph showing exemplary pharmacokinetic studies of LECIGONTM
`
`vs DUODOPA®. Y—axis depicts LECIGONTM’s Area Under Curve (AUC) increase per dose
`
`of levodopa compared to DUODOPA® (i.e., bioavailability increase). X—axis depicts
`
`levodopa dose of LECIGONTM.
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`DEFWITIONS
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`RECTIFIED SHEET (Rule 91)
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`[0061]
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`As used herein, the term “activating agent” refers to an agent whose presence or
`
`level correlates with elevated level or activity ofa target, as compared with that observed
`
`absent the agent (or with the agent at a different level). In some embodiments, an activating
`
`agent is one whose presence or level correlates with a target level or activity that is
`
`comparable to or greater than a particular reference level or activity (e. g., that observed under
`
`appropriate reference conditions, such as presence of a known activating agent, e.g., a positive
`
`control).
`
`[0062]
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`As used herein, the term “administration” refers to the administration of a
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`composition to a subject or system. Administration to an animal subject (e. g., to a human)
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`may be by any appropriate route. For example, in some embodiments, administration may be
`
`bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial,
`
`intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal,
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`intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral,
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`rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation),
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`transdermal, vaginal and vitreal. In some embodiments, administration may involve
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`intermittent dosing. In some embodiments, administration may involve continuous dosing
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`(e.g., perfusion) for at least a selected period of time. As is known in the art, antibody therapy
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`is commonly administered parenterally (e.g., by intravenous or subcutaneous injection).
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`[0063]
`
`As used herein, the term “approximately” or “about,” as applied to one or more
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`values of interest, refers to a value that is similar to a stated reference value. In certain
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`embodiments, the term “approximately” or “about” refers to a range of values that fall within
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`25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%,
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`4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference
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`value unless otherwise stated or otherwise evident from the context (except where such
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`number would exceed 100% of a possible value).
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`[0064]
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`Two events or entities are “associated” with one another, as that term is used
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`herein, if the presence, level and/or form of one is correlated with that of the other. For
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`example, a particular entity (e.g., polypeptide, genetic signature, metabolite, etc.) is
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`considered to be associated with a particular disease, disorder, or condition, if its presence,
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`level and/or form correlates with incidence of and/or susceptibility to the disease, disorder, or
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`condition (e. g., across a relevant population). In some embodiments, two or more entities are
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`physically “associated” with one another if they interact, directly or indirectly, so that they are
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`and/or remain in physical proximity with one another.
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`In some embodiments, two or more
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`entities that are physically associated with one another are covalently linked to one another, in
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`some embodiments, two or more entities that are physically associated with one another are
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`not covalently linked to one another but are non-covalently associated, for example by means
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`of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and
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`combinations thereof.
`
`[0065]
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`As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or
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`vehicle with which a composition is administered. In some exemplary embodiments, carriers
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`can include sterile liquids, such as, for example, water and oils, including oils of petroleum,
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`animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral
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`oil, sesame oil and the like.
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`In some embodiments, carriers are or include one or more solid
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`components.
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`[0066]
`
`As used herein, the term “combination therapy” refers to those situations in which
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`a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more
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`therapeutic agents). In some embodiments, two or more agents or may be administered
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`simultaneously; in some embodiments, such agents may be administered sequentially; in
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`some embodiments, such agents are administered in overlapping dosing regimens.
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`[0067]
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`A "composition" or a "pharmaceutical composition" according to this invention
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`refers to the combination of two or more agents as described herein for co-administration or
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`administration as part of the same regimen. It is not required in all embodiments that the
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`combination of agents result in physical admixture, that is, administration as separate co-
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`agents each of the components of the composition is possible, however many patients or
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`practitioners in the field may find it advantageous to prepare a composition that is an
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`admixture of two or more of the ingredients in a pharmaceutically acceptable carrier, diluent,
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`or excipient, making it possible to administer the component ingredients of the combination at
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`the same time.
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`[0068]
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`As used herein, the term “comparable” refers to two or more agents, entities,
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`situations, sets of conditions, etc., that may not be identical to one another but that are
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`sufficiently similar to permit comparison there between so that conclusions may reasonably
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`be drawn based on differences or similarities observed. In some embodiments, comparable
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`sets of conditions, circumstances, individuals, or populations are characterized by a plurality
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`of substantially identical features and one or a small number of varied features. Those of
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`ordinary skill in the art will understand, in context, what degree of identity is required in any
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`given circumstance for two or more such agents, entities, situations, sets of conditions, etc to
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`be considered comparable. For example, those of ordinary skill in the art will appreciate that
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`sets of circumstances, individuals, or populations are comparable to one another when
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`characterized by a sufficient number and type of substantially identical features to warrant a
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`reasonable conclusion that differences in results obtained or phenomena ob served under or
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`with different sets of circumstances, individuals, or populations are caused by or indicative of
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`the variation in those features that are varied.
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`[0069]
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`The term ”dopamine replacement agent”, as used herein, refers to an agent whose
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`administration to a human, correlates with increased dopamine levels in the brain as compared
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`with those observed absent such administration.
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`In some embodiments, a dopamine
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`replacement agent is characterized by an ability to cross the blood-brain barrier. In some
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`embodiments, a dopamine replacement agent is selected from the group consisting of
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`metabolic precursors of dopamine (e.g.,
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`levodopa, melevodopa, etilevodopa etc and
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`combinations thereof), dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline,
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`dihydroergocristine mesylate, pergolide, piribedil pramipexole, ropinirole, rotigotine , etc and
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`combinations thereof), agents that block dopamine degradation (e.g., MAO-B inhibitors such
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`as selegiline, rasagiline, etc. and combinations thereof) and/or agents (e. g., budipine) that
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`otherwise stimulate dopamine production. Various commercial formulations and preparations
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`of such agents are known in the art, including certain oral (e. g, capsule or tablet), transdermal
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`(e.g., patch), parenteral (e. g, subcutaneous, intravenous, intrathecal, etc., particularly for
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`infusion), and/or other (e.g., gel, and particularly intra—intestinal gel) formulations.
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`[0070]
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`As used herein, the term “dosage form” refers to a physically discrete unit of an
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`active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Each unit
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`contains a predetermined quantity of active agent. In some embodiments, such quantity is a
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`unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance
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`with a dosing regimen that has been determined to correlate with a desired or beneficial
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`outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
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`Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition
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`or agent administered to a particular subject is determined by one or more attending
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`physicians and may involve administration of multiple dosage forms.
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`[0071]
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`As used herein, the term “dosing regimen” refers to a set of unit doses (typically
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`more than one) that are administered individually to a subject, typically separated by periods
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`of time. In some embodiments, a given therapeutic agent has a recommended dosing
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`regimen, which may involve one or more doses. In some embodiments, a dosing regimen
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`comprises a plurality of doses each of which are separated from one another by a time period
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`of the same length; in some embodiments, a dosing regimen comprises a plurality of doses
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`and at least two different time periods separating individual doses. In some embodiments, all
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`doses within a dosing regimen are of the same unit dose amount. In some embodiments,
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`different doses within a dosing regimen are of different amounts. In some embodiments, a
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`dosing regimen comprises a first dose in a first dose amount, followed by one or more
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`additional doses in a second dose amount different from the first dose amount. In some
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`embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one
`
`or more additional doses in a second dose amount same as the first dose amount In some
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`embodiments, a dosing regimen is correlated with a desired or beneficial outcome when
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`administered across a relevant population (i.e., is a therapeutic dosing regimen).
`
`[0072]
`
`As used herein, the term “excipient” refers to a non-therapeutic agent that may be
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`included in a pharmaceutical composition, for example to provide or contribute to a desired
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`consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example,
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`starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate,
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`glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,
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`water, ethanol and the like.
`
`[0073]
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`As used herein, the term “gel” refers to a viscoelastic material whose rheological
`
`properties distinguish it from, for example, a solution, a solid, etc.
`
`In some embodiments, a
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`material or composition is considered to be a gel if its storage modulus (G') is larger than its
`
`modulus (G”). In some embodiments, a composition is considered to be a gel if there are
`
`chemical or physical cross—linked networks in solution, for example as distinguished from
`
`entangled molecules in viscous solution. In some embodiments, a gel composition may be or
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`comprise particles of a first material suspended or otherwise distributed within a matrix. In
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`some e