(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`6 December 2007 (06.12.2007)
`
` (10) International Publication Number
`
`WO 2007/138086 A1
`
`(51) International Patent Classification:
`A61K 9/00 (2006.01)
`A61K 45/06 (2006.01)
`A61K 31/192 (2006.01)
`A 6IP 25/16 (2006.01)
`A61K 31/198 (2006.01)
`
`(21) International Application Number:
`PCT/EP2007/055275
`
`(22) International Filing Date:
`
`31 May 2007 (31.05.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`60/809,889
`
`English
`
`English
`
`31 May 2006 (31.05.2006)
`
`US
`
`(71) Applicant (for all designated States except US): SOLVAY
`PHARMACEUTICALS GMBH [DE/DE]; Hans—Béck—
`ler Allee 20, 30173 Hannover (DE).
`
`(71)
`(72)
`
`(72)
`(75)
`
`Applicant and
`Inventor: NYHOLM, Dag [SFJSE]; Hans—Bockler Allee
`20, do Solvay Pharmaceuticals GmbII, IPSI Department,
`30173 Hannover (DE).
`
`Inventors; and
`Inventors/Applicants (for US only): ASBERG, Stefan
`[SE/DE]; c/o Solvay Pharmaceuticals GmbH, IPSI De—
`partment, Hans—Béckler—Allee 20, 30173 Hannover (DE).
`BOLSOEY, Roger [SE/GD]; c/o Solvay Pharmaceuticals
`GmbH, IPSI Department, Hans—Biickler—Allee 20, 30173
`Hannover
`(DE). TUTSCHKE-SAETTLER, Mikael
`
`[SE/DE]; c/0 Solvay Pharmaceuticals GmbH, IPSI Depart—
`ment, Hans—Béckler—Allee 20, 30173 Hannover (DE).
`
`(74) Agents: GOSMANN, Martin et al.; c/o Solvay Pharma—
`ceuticals, IPSI Department, Hans B6ck1er Allee 20, 30173
`Hannover (DE).
`
`(81) Designated States (unless otherwise indicated, for ever
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`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, .IP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, MG, MK, MN, MW, MX,
`MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO,
`RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for ever
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report
`
`For tworletter codes and other abbreviations, refer to the ”Guide
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: LONG TERM 24 HOUR INTESTINAL ADMINISTRATION OF LEVODOPA/CARBIDOPA
`
`(57) Abstract: A method of treating Parkinson's Disease comprising intestinally administering to a patient in need thereof a phar—
`maceutically effective amount of a composition comprising levodopa and optionally carbidopa continuously over a period of greater
`than 16 hours.
`
`
`
`W02007/138086A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`LONG
`
`TERM
`
`24—HOUR
`
`INTESTINAL
`
`ADMINISTRATION
`
`OF
`
`LEVODOPA/CARBIDOPA
`
`RELATED CASES
`
`[0001]
`
`This application claims priority to U.S. Provisional Application Serial No.
`
`60/809,889 filed May 31, 2006, which is incorporated herein by reference in its entirety
`
`to the extent permitted by law.
`
`FIELD
`
`[0002]
`
`The present invention relates to the use of pharmaceutical compositions
`
`comprising levodopa and optionally carbidopa for the treatment of Parkinson’s Disease
`
`(“PD”).
`
`BACKGROUND
`
`[0003]
`
`Parkinson’s Disease is a progressive disorder; it continues to get worse. For
`
`example, as Parkinson’s becomes more advanced (“advanced PD”), facial movement,
`
`blinking and spontaneous smiling and expression all becomes more difficult, and
`
`people have increasing difficulty functioning independently.
`
`[0004]
`
`Intestinal, e.g., duodenal and/or jejunal administration (via external access
`
`point) of a pharmaceutical composition comprising levodopa/carbidopa, such as the
`
`composition sold outside the United States under the trade name Duodopa®, has
`
`evolved into a treatment alternative in patients with PD. Duodopa is recommended for
`
`daytime use only. One reason is that physicians fear the development of tolerance.
`
`[0005]
`
`Duodopa® (levodopa/carbidopa intestinal gel) may be useful
`
`for
`
`the
`
`treatment of advanced levodopa-responsive PD in which satisfactory control of severe,
`
`disabling motor fluctuations and hyper-/dyskinesia cannot be achieved with available
`
`combinations of Parkinson medicinal products. Duodopa® is delivered by direct
`
`administration (infusion) to the upper small intestine (duodenum or jejunum) by means
`
`of
`
`the portable, patient controlled CADD-Legacy Duodopa® pump, and requires
`
`insertion of a permanent access tube in the abdominal wall, by percutaneous
`
`endoscopic gastrostomy (PEG).
`
`Prior to insertion of the permanent PEG tube, a
`
`positive test of
`
`the clinical response to Duodopa® administered via a temporary
`
`nasoduodenal tube is recommended for all patients.
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`[0006]
`
`Currently,
`
`the dose Duodopa® may be administered in three individually
`
`adjusted doses: the morning bolus dose, the continuous maintenance dose, and extra
`
`bolus doses. The morning bolus dose is administered by the pump to rapidly achieve
`
`the therapeutic dose level (e.g., within 10-30 minutes). The total morning dose is
`
`usually about 5-10 mL, corresponding to about 100-200 mg levodopa. The total
`
`morning dose should not exceed about 15 mL (e.g., about 300 mg levodopa). The
`
`maintenance dose is adjustable in steps of about 2 mg/hour (0.1 mL/hour). The
`
`continuous maintenance dose should be kept within a range of about 1-10 mL/hour
`
`(e.g., about 20-200 mg levodopa/hour) and is usually about 2-6 mL/hour (e.g., about
`
`40-120 mg levodopa/hour). The extra dose should be adjusted individually, normally
`
`about 0.5-2.0 mL.
`
`[0007]
`
`The cassette containing Duodopa® should be attached to the portable pump
`
`and the system connected to the nasoduodenal
`
`tube or
`
`the transabdominal
`
`port/duodenal tube for administration just prior to use, according to the instructions
`
`provided in the pump instruction manual. The drug cassettes are for single use only
`
`and should not be used for longer than one day (up to 16 hours) even if some
`
`medicinal product remains. An opened cassette should not be re-used. By the end of
`
`the storage time (i.e., after 16 hours in use, or when approaching the expiration date)
`
`the gel might become slightly yellow. This does not influence the concentration of the
`
`drug or the treatment.
`
`[0008]
`
`However, because nighttime disability and sleep disturbance are common
`
`problems for patients with PD,
`
`in particular advanced PD,
`
`there is a need for a
`
`treatment method that can increase motor performance and improve sleep in patients
`
`with PD,
`
`in particular advanced PD, without developing clinically relevant tolerance or
`
`side effects.
`
`SUMMARY OF THE DISCLOSURE
`
`[0009]
`
`In one embodiment,
`
`the present disclosure provides pharmaceutical
`
`compositions
`
`in
`
`the form of
`
`intestinal gels comprising levodopa and optionally
`
`carbidopa for the treatment of PD which are administered continuously over a period of
`
`greater than 16 hours per day up to 24 hours per day.
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`[0010]
`
`In another embodiment, the present disclosure provides a method of treating
`
`PD comprising intestinally (9.9., in the duodenum or jejunum) administering to a patient
`
`in need thereof a pharmaceutically effective amount of a composition comprising
`
`Ievodopa and optionally carbidopa continuously over a period of 24 hours.
`
`[0011]
`
`In another embodiment, the present disclosure provides a method of treating
`
`PD comprising intestinally administering to a patient in need thereof a pharmaceutically
`
`effective amount of a composition comprising Ievodopa and optionally carbidopa
`
`continuously over a long term period of more than one day.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012]
`
`FIG.
`
`1
`
`is a line graph depicting five patients’ dose requirements of
`
`Ievodopa/carbidopa over time.
`
`[0013]
`
`FIG. 2 is a bar graph depicting one patient’s PD sleep scale rating over time.
`
`DETAILED DESCRIPTION
`
`[0014] While the present invention is capable of being embodied in various forms,
`
`the description below of several embodiments is made with the understanding that the
`
`present disclosure is to be considered as an exemplification of the invention, and is not
`
`intended to limit the invention to the specific embodiments illustrated.
`
`[0015]
`
`The use of numerical values in
`
`the various
`
`ranges specified in
`
`this
`
`application, unless expressly indicated otherwise, are stated as approximations as
`
`though the minimum and maximum values within the stated ranges were both
`
`preceded by the word “about.” In this manner, slight variations above and below the
`
`stated ranges can be used to achieve substantially the same results as values within
`
`the ranges. As used herein, the terms “about” and “approximately” when referring to a
`
`numerical value shall have their plain and ordinary meanings to one skilled in the art of
`
`pharmaceutical sciences or the art relevant to the range or element at issue. The
`
`amount of broadening from the strict numerical boundary depends upon many factors.
`
`For example, some of the factors to be considered may include the criticality of the
`
`element and/or the effect a given amount of variation will have on the performance of
`
`the claimed subject matter, as well as other considerations known to those of skill
`
`in
`
`the art. Thus, as a general matter, “about” or “approximately” broaden the numerical
`
`value. For example,
`
`in some cases, “about” or “approximately” may mean i 5%, or
`
`3
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`:10%, or 120%, or 130% depending on the relevant technology. Also, the disclosure
`
`of ranges is
`
`intended as a continuous range including every value between the
`
`minimum and maximum values recited.
`
`[0016]
`
`It is to be understood that any ranges, ratios, and ranges of ratios that can
`
`be formed by any of
`
`the numbers or data present herein represent
`
`further
`
`embodiments of the present invention. This includes ranges that can be formed that do
`
`or do not include a finite upper and/or lower boundary. Accordingly, the skilled person
`
`will appreciate that such ratios, ranges, and values are unambiguously derivable from
`
`the data presented herein.
`
`[0017]
`
`As used herein, the term “improve” shall have its plain and ordinary meaning
`
`to one skilled in the art of pharmaceutical or medical sciences. Moreover, “improve”
`
`shall also mean to ameliorate the effects of PD, or to decrease or lessen a side effect
`
`of PD.
`
`[0018]
`
`As used herein,
`
`the term “reduce” or “reducing” shall have its plain and
`
`ordinary meaning to one skilled in the art of pharmaceutical or medical sciences.
`
`In
`
`addition, “reduce” shall mean to diminish or decrease the number of occurrences, the
`
`duration, or the intensity, of a PD side effect, such as dyskinesias or hallucinations.
`
`[0019]
`
`As used herein, the terms “treat” and “treating” shall have their plain and
`
`ordinary meaning to one skilled in the art of pharmaceutical or medical sciences.
`
`Further, “treat” and “treating” shall mean to improve the quality of life or reduce the
`
`symptoms of PD.
`
`[0020]
`
`As used herein, the terms “dose,” “dose unit,” and/or “dosage unit” refer to a
`
`portion of a pharmaceutical composition that contains an amount of a therapeutic agent
`
`suitable for a single administration to provide a therapeutic effect. Such dosage units
`
`may be administered continuously, one to a small plurality (e.g.,
`
`1
`
`to about 4) of times
`
`per day, or as many times as needed to elicit a therapeutic response. A particular
`
`dosage form can be selected to accommodate any desired frequency of administration
`
`to achieve a specified daily dose. Typically one continuous dose unit, one dosage unit,
`
`or a small plurality (e.g., up to about 4) of dose units, provides a sufficient amount of
`
`the active drug to result in the desired response or effect.
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`[0021]
`
`As
`
`used
`
`herein,
`
`the
`
`term “therapeutically
`
`effective
`
`amount”
`
`or
`
`“therapeutically and/or prophylactically effective amount” refers to an amount of
`
`compound or agent that is sufficient to elicit the required or desired therapeutic and/or
`
`prophylactic response, as the particular treatment context may require.
`
`[0022]
`
`It will be understood that a therapeutically and/or prophylactically effective
`
`amount of a drug for a patient is dependent inter alia on the body weight of the patient.
`
`A “patient” herein to which a therapeutic agent or composition thereof can be
`
`administered includes a human subject of either sex and of any age, and also includes
`
`any nonhuman animal, particularly a domestic or companion animal, illustratively a cat,
`
`dog, or a horse.
`
`[0023]
`
`Under
`
`the present
`
`invention, a gel containing levodopa and optional
`
`carbidopa is administered via intestinal administration. The gel can be administered (or
`
`“infused”) directly into the intestine, e.g., duodenum or the jejunum by a permanent
`
`tube via percutaneous endoscopic gastrostomy with an outer transabdominal tube and
`
`an inner intestinal
`
`tube.
`
`In another embodiment, gel can be administered via a
`
`radiological gastrojejunostomy. The gel can also be administered via a temporary
`
`nasoduodenal tube that is inserted into the patient initially to determine if the patient
`
`responds favorably to the treatment method of
`
`the present
`
`invention before the
`
`permanent tube is inserted.
`
`[0024]
`
`In one embodiment of the present invention, the gel is administered with a
`
`portable pump,
`
`such as the pump sold under
`
`the trade name, CADD-Legacy
`
`Duodopa® pump. Specifically, the gel is contained in a cassette, pouch, or vial that is
`
`attached to the pump to create the delivery system. The delivery system is then
`
`connected to the nasoduodenal tube, the transabdominal port, the duodenal tube, or
`
`the jejunum tube for intestinal administration.
`
`[0025]
`
`In another embodiment,
`
`there is disclosed a method of
`
`treating PD,
`
`comprising intestinally administering to a patient in need thereof a pharmaceutically
`
`effective amount of a composition comprising levodopa and, optionally, carbidopa
`
`continuously over a period of greater than 16 hours per day.
`
`[0026]
`
`Additionally, there is disclosed a method of reducing sleep disturbance in a
`
`patient with PD, comprising intestinally administering to a patient in need thereof a
`
`5
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`pharmaceutically effective amount of a composition comprising Ievodopa and,
`
`optionally, carbidopa continuously over a period of greater than 16 hours per day.
`
`[0027]
`
`In yet another embodiment, there is disclosed a method of improving motor
`
`performance in a patient with PD, comprising intestinally administering to a patient in
`
`need thereof a pharmaceutically effective amount of a composition comprising
`
`levodopa and, optionally, carbidopa continuously over a period of greater than 16 hours
`
`per day.
`
`[0028]
`
`In one embodiment, disclosed is a method of reducing nighttime disabilities
`
`in a patient with PD, comprising intestinally administering to a patient in need thereof a
`
`pharmaceutically effective amount of a composition comprising Ievodopa and,
`
`optionally, carbidopa continuously over a period of greater than 16 hours per day.
`
`[0029]
`
`Accordingly, all of
`
`the compositions of
`
`the present disclosure may be
`
`administered continuously over a period of about 17 hours, about 18 hours, about 19
`
`hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24
`
`hours. Further, the compositions may be administered continuously over a period of
`
`about 26 hours, about 28 hours, about 30 hours, about 32 hours, about 34 hours, about
`
`36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46
`
`hours, about 48 hours, or longer.
`
`[0030]
`
`In addition,
`
`the present disclosure relates to treating patients utilizing a
`
`composition comprising levodopa and, optionally, carbidopa in the form of particles
`
`suspended in an aqueous carrier, the particles having a maximum particle size not
`
`exceeding about 80 um and that said carrier has a viscosity of at least 300 mPas, at a
`
`moderate shear rate.
`
`In one embodiment, the particles are micronized. Micronization
`
`and particle size distribution analysis are performed by Micron Technologies UK. The
`
`particles may be characterized by a D90 value of about 20 um or less. Such particles
`
`may also be characterized by a D50 value of about 5 um or less.
`
`In another
`
`embodiment, the maximum particle size does not exceed about 70 um, about 60 um,
`
`about 50 um, about 40 um, or about 30 um.
`
`In yet another embodiment, the carrier
`
`has a viscosity of about 350 mPas, about 400 mPas, about 450 mPas, about 500
`
`mPas, about 550 mPas, or about 600 mPas, at a moderate shear rate.
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`[0031]
`
`Such composition may be formulated such that the weight ratio of levodopa
`
`and carbidopa ranges from about 10:1 to about 1:1, or from about 5:1 to about 2:1, or
`
`from about 4.5:1 to about 3.5:1, or wherein the weight ratio is about 4:1.
`
`[0032]
`
`In another embodiment, the dose of the Ievodopa and/or carbidopa gel
`
`is
`
`adjusted to optimize the clinical
`
`response achieved by a patient, which means
`
`maximizing the functional ON-time during the day by minimizing the number and
`
`duration of OFF-time episodes (i.e., bradykinesia) and minimizing ON-time with
`
`disabling dyskinesia.
`
`[0033]
`
`In yet another embodiment, PD patients who are given levodopa and
`
`optionally carbidopa gel continuously over 24 hours experience an increase in sleep
`
`quality.
`
`[0034]
`
`Under one embodiment of the present invention, the levodopa and optionally
`
`carbidopa gel is given as a monotherapy.
`
`In another embodiment, the Ievodopa and/or
`
`carbidopa gel is given concurrently with other medicinal products used in the treatment
`
`of PD.
`
`[0035]
`
`In one embodiment, the dose of levodopa received by a patient according to
`
`methods of the present invention may be, for example, about 20 to about 5000 mg,
`
`about 20 mg to about 4000 mg, about 20 mg to about 3000 mg, about 20 mg to about
`
`2000 mg, or about 20 mg to about 1000 mg per day. For example, a patient according
`
`to methods of the present invention may receive about 20, 30, 40, 50, 60, 70, 80, 90,
`
`100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260,
`
`270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430,
`
`440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600,
`
`610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770,
`
`780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940,
`
`950, 960, 970, 980, 990, 1000, 1010, 1020, 1030,1040, 1050, 1060,1070, 1080,1090,
`
`1100, 1110,1120, 1130,1140,1150,1160, 1170,1180,1190,1200,1210, 1220,1230,
`
`1240, 1250,1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340,1350, 1360,1370,
`
`1380, 1390,1400, 1410,1420,1430,1440, 1450,1460,1470,1480,1490, 1500,1510,
`
`1520, 1530,1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620,1630, 1640,1650,
`
`1660, 1670,1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760,1770, 1780,1790,
`
`1800, 1810,1820, 1830,1840,1850,1860, 1870,1880,1890,1900,1910, 1920,1930,
`
`7
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`1940, 1950, 1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070,
`
`2080, 2090, 2100, 2110, 2120, 2130, 2140, 2150, 2160, 2170, 2180, 2190, 2200, 2210,
`
`2220, 2230, 2240, 2250, 2260, 2270, 2280, 2290, 2300, 2310, 2320, 2330, 2340, 2350,
`
`2360, 2370, 2380, 2390, 2400, 2410, 2420, 2430, 2440, 2450, 2460, 2470, 2480, 2490,
`
`2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800,
`
`3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 mg of
`
`levodopa per day.
`
`[0036]
`
`In another embodiment,
`
`the dose of carbidopa received by a patient
`
`according to methods of the present invention may be, for example, 0 to about 625 mg,
`
`0 mg to about 500 mg, 0 mg to about 375 mg, 0 mg to about 250 mg, or 0 mg to about
`
`125 mg per day. For example, a patient according to methods of the present invention
`
`may receive about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160,
`
`170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,
`
`340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500,
`
`510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670,
`
`680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840,
`
`850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010,
`
`1020, 1030,1040, 1050,1060,1070,1080, 1090,1100,1110,1120,1130, 1140,1150,
`
`1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, or 1250 mg of carbidopa per
`
`day.
`
`[0037]
`
`In another embodiment, the present invention comprises a pharmaceutical
`
`composition that is a gel comprising levodopa and carbidopa in a ratio of 4 to 1.
`
`In one
`
`embodiment, the formulation (Duodopa®) comprises the following ingredients (w/w):
`
`Levodopa 2.0%
`
`Carbidopa monohydrate 0.5%
`
`Carmellose sodium 2.92%
`
`qs to 100% with purified water
`
`[0038]
`
`In
`
`another
`
`embodiment,
`
`continuous
`
`intestinal
`
`administration
`
`of
`
`a
`
`pharmaceutical composition comprising levodopa and optionally carbidopa reduces the
`
`motor fluctuations and increases the “on”-time for patients with advanced PD who have
`
`previously received tablet treatment with levodopa/decarboxylase inhibitor. The motor
`
`fluctuations and hyper-/dyskinesias are reduced by the present invention due to the
`
`fact that the plasma concentrations of levodopa are kept at a steady level within the
`
`8
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`WO 2007/138086
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`PCT/EP2007/055275
`
`individual
`
`therapeutic window.
`
`In yet another embodiment,
`
`therapeutic effects on
`
`motor fluctuations and hyper-/dyskinesias are achieved during the first treatment day.
`
`[0039]
`
`Applicant has unexpectedly found that low tolerance or low tachyphylaxis
`
`results from continuous intestinal administration of the Ievodopa/carbidopa composition
`
`described herein. Moreover, in one embodiment, the dose of the continuous intestinal
`
`administration of the Ievodopa/carbidopa was increased over a period of one year, yet
`
`no increase in side-effects such as dyskinesias or hallucinations was observed.
`
`In yet
`
`another embodiment,
`
`the dose of
`
`the continuous intestinal administration of
`
`the
`
`Ievodopa/carbidopa was increased over a period of two years, yet no increase in side-
`
`effects
`
`such as dyskinesias or hallucinations was observed.
`
`In
`
`still another
`
`embodiment,
`
`the
`
`dose
`
`of
`
`the
`
`continuous
`
`intestinal
`
`administration
`
`of
`
`the
`
`Ievodopa/carbidopa was increased over a period of three years, yet no increase in
`
`side-effects such as dyskinesias or hallucinations was observed.
`
`[0040]
`
`In
`
`addition,
`
`the
`
`half-life of
`
`levodopa is
`
`lengthened with continuous
`
`administration.
`
`[0041]
`
`Accordingly,
`
`the present compositions can be continuously administered
`
`intestinally without the need to orally administer Ievodopa/carbidopa during the night to
`
`aid sleep. As shown in the example below, sleep is improved and other disabilities
`
`associated with PD are reduced when the composition is administered continuously.
`
`In
`
`one embodiment, patients experienced improved sleep quality with the intestinal
`
`administration of levodopa and carbidopa.
`
`In yet another embodiment, patients who
`
`were examined with PDSS reported an increase in total score by 130% (from 53 to
`
`122) from one night to another, when around-the-clock administration was initiated.
`
`In
`
`still another embodiment, patients who were examined with PDSS reported an increase
`
`in total score by about 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%,
`
`190%, or 200% from one night to another, when around-the-clock administration was
`
`initiated.
`
`In yet another embodiment, the improvement in PDSS score was shown to
`
`be persistent at a follow-up two years later.
`
`[0042]
`
`In one embodiment,
`
`the present
`
`invention encompasses the use of a
`
`composition comprising 20 mg/mL of levodopa, 5mg/mL of carbidopa, a thickening
`
`agent (e.g., cellulose), and water.
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`[0043]
`
`Compositions of the invention optionally comprise one or more additional
`
`pharmaceutically acceptable excipients.
`
`The term “excipient” herein means any
`
`substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a
`
`therapeutic agent to a subject or added to a pharmaceutical composition to improve its
`
`handling or storage properties or to permit or facilitate formation of a unit dose of the
`
`composition.
`
`[0044]
`
`Illustrative excipients include antioxidants, agents to adjust
`
`the pH and
`
`osmolarity, preservatives, thickening agents, colorants, buffering agents, bacteriostats,
`
`and stabilizers. Generally speaking, a given excipient, if present, will be present in an
`
`amount of about 0.001% to about 95%, about 0.01% to about 80%, about 0.02% to
`
`about 25%, or about 0.3% to about 10%, by weight.
`
`[0045]
`
`Illustrative antioxidants for use in the present invention include, but are not
`
`limited to, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite,
`
`and the like.
`
`[0046]
`
`Illustrative agents that increase viscosity (e.g.,
`
`thickening agents) include,
`
`but are not
`
`limited to, cellulose, methylcellulose, carboxymethylcellulose sodium,
`
`ethylcellulose, carrageenan, carbopol, and/or combinations thereof.
`
`[0047]
`
`In one embodiment, compositions of the invention optionally comprise a
`
`buffering agent. Buffering agents include agents that reduce pH changes.
`
`Illustrative
`
`classes of buffering agents for use in various embodiments of the present invention
`
`comprise a salt of a Group IA metal
`
`including, for example, a bicarbonate salt of a
`
`Group IA metal, a carbonate salt of a Group IA metal, an alkaline or alkali earth metal
`
`buffering agent, an aluminum buffering agent, a calcium buffering agent, a sodium
`
`buffering agent, or a magnesium buffering agent. Suitable buffering agents include
`
`carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates,
`
`succinates of any of the foregoing,
`
`for example sodium or potassium phosphate,
`
`citrate, borate, acetate, bicarbonate and carbonate.
`
`[0048]
`
`Non-limiting examples of
`
`suitable buffering agents include aluminum,
`
`magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate,
`
`calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium
`
`glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium
`
`10
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`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium
`
`hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium
`
`succinate, dry aluminum hydroxide gel, magnesium acetate, magnesium aluminate,
`
`magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium
`
`citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium
`
`metasilicate
`
`aluminate, magnesium oxide, magnesium phthalate, magnesium
`
`phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium
`
`acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium
`
`citrate, potassium metaphosphate, potassium phthalate, potassium phosphate,
`
`potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium
`
`tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate,
`
`sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide,
`
`sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium
`
`pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium
`
`tripolyphosphate, synthetic hydrotalcite,
`
`tetrapotassium pyrophosphate,
`
`tetrasodium
`
`pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometarnol. (Based
`
`in part upon the list provided in The Merck Index, Merck & Co. Rahway, NJ. (2001)).
`
`Furthermore, combinations or mixtures of any two or more of the above mentioned
`
`buffering agents can be used in the pharmaceutical compositions described herein.
`
`[0049]
`
`The foregoing excipients can have multiple roles as is known in the art.
`
`Therefore, classification of excipients above is not to be construed as limiting in any
`manner.
`
`[0050]
`
`These and many other aspects of the invention will be fully apparent to one
`
`of ordinary skill in the art in view of the example set forth below. The example provided
`
`herein is illustrative and is not to be construed as limiting the invention in any manner.
`
`EXAMPLE 1
`
`[0051]
`
`Most patients with PD suffer from sleep disturbance.
`
`In advanced PD,
`
`dopaminergic medication is sometimes frequently used during nighttime to improve
`
`sleep. Continuous 24-hour administration of levodopa has only been investigated in a
`
`very small number of patients and during short periods of time because of the fear of
`
`tolerance development and psychiatric side-effects. Five cases of 24-hour duodenal
`
`administration of levodopa/carbidopa (Duodopa®) for up to 37 months were studied.
`
`11
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`WO 2007/138086
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`
`[0052] Method
`
`[0053]
`
`The hospital charts were reviewed retrospectively in five PD patients who
`
`were given continuous 24-hour duodenal administration of levodopa/carbidopa in a 4:1
`
`ratio by weight in a gel via intestinal administration (Duodopa®). The formulation is
`
`described in US. Patent No. 5,635,213, which is incorporated herein by reference.
`
`Dosage, efficacy, sleep pattern, and side-effects were recorded.
`
`[0054]
`
`The patients were treated with this regime for their well-being. Thus, no
`
`prospective study protocols were used. PD Sleep Scale (“PDSS”) was used in one
`
`case to assess the impact of the administration on sleep.
`
`[0055]
`
`Demographic and clinical data are shown below in Table One. All patients
`
`had “on-off” fluctuations on individually optimized combinations of conventional drugs
`
`and all experienced nocturnal akinesia. Duodenal
`
`levodopa administration,
`
`initially
`
`daytime only,
`
`led to a marked reduction of motor fluctuations and dyskinesias in all
`
`patients. On 24-hour administration all patients were initially given lower administration
`
`rates at night, but three eventually needed the optimal dose around-the-clock. Daily
`
`mean dosage at latest follow-up was 3,015 mg levodopa (range 2,002 mg to 4,320
`
`mg).
`
`[0056]
`
`Table One: Patient Demographics Dosage & Outcome
`
` Case No. 1 2 3 4 5 Mean
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sex
`
`Age
`
`at
`
`onset
`
`of
`
`PD
`
`Symptoms (Years)
`
`Age
`
`at
`
`initiation
`
`of oral
`
`levodopa therapy (years)
`
`Age at initiation of 24-hour
`
`administration
`
`therapy
`
`M
`
`35
`
`36
`
`M
`
`37
`
`M
`
`35
`
`M
`
`43
`
`40
`
`38
`
`44
`
`M
`
`47
`
`52
`
`64
`
`39
`
`42
`
`55
`
`en, ro, to
`
`(years)
`
`Medication
`
`prior
`
`to
`
`ap-inf
`
`administration, concomitant
`
`br, en,
`
`br, en,
`
`ap-inf
`
`am,
`
`ap-inf
`
`(16),
`
`ap-
`
`to levodopa/ decarboxylase
`
`se
`
`ro
`
`(24)
`
`(16), en, ro
`
`inj, br, ca,
`
`inhibitor
`
`

`

`WO 2007/138086
`
`PCT/EP2007/055275
`
`Table One: Patient Demographics Dosage & Outcome
`
`Duration
`
`of
`
`24-hour
`
`administration (months)
`
`Daily
`
`levodopa dose
`
`at
`
`latest follow-up (mg)
`
`Change
`
`in
`
`daytime
`
`administration
`
`rate
`
`during
`
`24-hour
`
`administration from initiation
`
`20
`
`29
`
`37
`
`16
`
`13
`
`23
`
`2002
`
`2544
`
`4320
`
`3408
`
`2800
`
`3015
`
`14
`
`up to latest follow-up (%)
`
`
`Motor performance at latest
`
`follow—up
`
`Stable
`
`Stable
`
`Stable
`
`_
`Fluctuatlng
`
`Stable
`
`PD = Parkinson’s Disease; br = bromocriptine; en = entacapone; se: selegiline;
`
`ro
`
`ropinirole;
`
`ap-inf = apomorphine administration (16-hour or 24-hour); am
`
`amantadine; ap-inj =
`
`apomorphine
`
`ca = cabergoline; to = tolcapone
`
`injection;
`
`[0057]
`
`Case 1 was initially treated with daytime administration for 2.5 years. On 24-
`
`hour administration, sleep was markedly improved and the patient was able to sleep for
`
`6 hours, which he had not been able to do for many years. Self-scoring on the PDSS
`
`increased from 53 to 122 the morning after his first night on continuous administration.
`
`At latest follow-up, both motor function and sleep were good.
`
`[0058]
`
`Case 2 had earlier experienced side effects including hallucinations on
`
`dopamine agonists. After
`
`1 year of daytime administration, continuous 24-hour
`
`administration substantially improved both motor function and sleep at nig