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Flumazenil N O—N US 20120295893A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2012/0295893 A1 Peled et al. (43) Pub. Date: Nov. 22, 2012 (54) COMPOSITIONS AND METHODS OF Related U.S. Application Data COUNTERACTING RESIDUAL SEDATIVE (60) Provisional application No. 61/286,033, filed on Dec. EFFECTS OF SLEEP/ HYPNOTIC DRUGS 14, 2009, provisional application No. 61/331,397, filed on May 5, 2010. (75) Inventors: Nir Peled, Hod Hasharon (IL); David Solomon, Zichron Yaakov Publication Classification (IL); Amir Toren, Zichron Yaakov (51) Int. Cl. (IL) A61R 31/5517 (2006.01) A6 IP II/00 (2006.01) A6IP 25/32 (2006.01) (73) Assignee: COERULEUS LTD., Katzrin (IL) A6IP 43/00 (2006.01) (21) Appl. No.: 13/515,747 (52) U.S. Cl. ........................................................ 514/220 (57) ABSTRACT (22) PCT Filed: Dec. 14, 2010 The present invention provides pharmaceutical compositions comprising a flumazenil, and methods of alleviating or coun (86) PCT No.: PCT/IL10/01062 teracting residual effects (e.g. drowsiness) associated with the administration of sleep/hypnotic drugs or alleviating effects § 371 (c)(1), of alcohol intoxication, using self administration modes of (2), (4) Date: Jun. 13, 2012 delivery. N O / Flumazenil N o—N N C15H1AFN303 F Cº. N O Patent Application Publication Nov. 22, 2012 Sheet 1 of 15 US 2012/0295893 A1 N O a / Flumazenil N o–N N Cash, FN303 F Cº. N O Figure 1 Figure 2 . 21 top closure 22 drug 23 Diffusion/active membrane 25 Removable 24 Adhesive sealing- tape layer Figure 3 Patent Application Publication Nov. 22, 2012 Sheet 2 of 15 US 2012/0295893 A1 SWITCH —ON SELECT SLEEP TIME AND PROGRAM P DELAY DO ACTIVATE WALWE 1 FOR RELEASE OF DRUG A FOR GENERATION OF PULSES ACCORDING TO PROGRAMMED TIME T1 |N PULSE MODE RELEASE RATE OF DRUG A BASED ON PROGRAM P SUPPLY OF CURRENT TO ELECTRODES ACCORDING DELAY DB TO RELEASE RATE A ACTIVATE WALWE 2 FOR GENERATION OF PULSES TIME T2 |N PULSE MODE ACCORDING TO PROGRAMMED BASED ON PROGRAM P RELEASE RATE OF DRUG B SUPPLY OF CURRENT TO ELECTRODES ACCORDING TO RELEASE RATE B ACTIVATE WALVE 5 FOR GENERATION OF PULSES TIME T3 |N PULSE MODE ACCORDING TO PROGRAMMED BASED ON PROGRAM P RELEASE RATE OF DRUG C AUTOMATIC TURN OFF SUPPLY OF CURRENT TO AFTER TIME T3, OR ELECTRODES ACCORDING MANUAL TURN OFF BY KEY TO RELEASE RATE B Figure 4 Patent Application Publication Nov. 22, 2012 Sheet 3 of 15 US 2012/0295893 A1 BLOOD & SLEEPING ORGAN TIME COLLECTION ! \ -D DIAZEPAM SEDATIVE REGAINING LOCOMOTOR |NJECTION HYPNOTIC t OF ACTIVITY EFFECTS RIGHTING DETERMINATION ARE FIRST TEST, REFERENCE REFLEX NOTED & CONTROL ITEMS ADMINISTRATION Figure 5 Patent Application Publication Nov. 22, 2012 Sheet 4 of 15 US 2012/0295893 A1 DSGOLO<!--NOCN– OCDC OC Ø Ø=Ø4s ÎNGOLO<!--NOCN– OCDC CDOC CO CD Patent Application Publication Nov. 22, 2012 Sheet 5 of 15 US 2012/0295893 A1 1200.0 1000.0 800.0 600.0 400.0 200.0 0.0 –200 Group No. Figure 7 2500.0 2100.0 - 1900.0 1700.0 1500.0 1300.0 1 100.0 900.0 700.0 500.0 j00.0 100.0 -100.0° 3F 4F 5F 6F Group No. Figure 8 Patent Application Publication Nov. 22, 2012 Sheet 6 of 15 US 2012/0295893 A1 92 U Q ‘s c 2. 3M 4M 5M 6M — 1 Group No. Figure 9A 92 CSp ‘s o 2 —1 Group No. Figure 9B Patent Application Publication Nov. 22, 2012 Sheet 7 of 15 US 2012/0295893 A1 2000.0 1500.0 - 1000,0– 500.0 - 0.0 - g I I "I IV Flum SL_22 SL_26 SL_Plac Treatment Figure 10A 1200.0 n= n=7 n= 800.0 - 400.0 0.0 - IV Flum SL_22 SL_26 SL Plac Treatment Figure 10B Patent Application Publication Nov. 22, 2012 Sheet 8 of 15 US 2012/0295893 A1 E 750 S. º ~5 .9 § 500 .5 Q) O 5 †. 250 O O I T . I —I IV Flum SL_22 SL_26 SL_Plac Treatment Figure 10C 600.0- . f Sº, ºr) 3 400.0 5 ?h .5 g 0.0 5 200. n=8 n=7 n=8 n= .0 O 0.0 IV Flum SL_22 SL_26 SL_Plac Treatment Figure 10D Patent Application Publication Nov. 22, 2012 Sheet 9 of 15 US 2012/0295893 A1 * 750 - O Sp.Q1) § 500 <! .E # H 250 0 + n=8 t-7 n=8 ||=8 IV Flum SL_22 SL_26 SL_Plac Treatment Figure 11A 750 Tº Glº J2. º 500 9 < .5 Q1) 250 E H. IV Flum SL 22 SL_26 SL_Plac Treatment Figure 11B Patent Application Publication Nov. 22, 2012 Sheet 10 of 15 US 2012/0295893 A1 7 – 6 Tº C? 9 5 E >O 4 - .Eº, 3 - g g 2 O 1 O = 20min 60min Time from spray administration Figure 12A 6 (?) (?) Q) ?º + CD Tº .5: (i) O) ?º tº; -- C) 20min 60min Time after spray administration Figure 12B Patent Application Publication Nov. 22, 2012 Sheet 11 of 15 US 2012/0295893 A1 | 20min 60min Time after spray administration Figure 12C 8 20min 60min Time after spray administration Figure 13 Patent Application Publication Nov. 22, 2012 Sheet 12 of 15 US 2012/0295893 A1 1.OE-HO 1 iceroof|-Mºw.OE + a MARKETED M TRANSDERMALfºr Pººl DRUGS SSES 1.0E–01 + | N FLUMAZENIL 1.OE–02 NOT FEASIBLE 1.OE–03 REGION # 1.OE–04 º 1.0E-05+ FEASIBLE 1.OE-06 REGION 1.OE–07 1.OE –08 O 100 200 300 400 500 600 700 Molecular Weight (g/mole) Figure 14A 1.OE+01 1.OE+00 –MAXIMUM LIMIT FOR PASSIVE TRANSDERMAL SYSTEMS .OE-H (2 MARKETED TRANSDERMAL DRUGS 1.OE–01 ZOLPLDEM 1.0E–02 NOT FEASIBLE # 1.OE–03 - º REGION 1.0E-05+ FEASIBLE 1.0F_06. REGION 1.OE-07 1.OE–08 O 1 OO 200 300 400 500 600 700 Molecular Weight (g/mole) Figure 14B Patent Application Publication Nov. 22, 2012 Sheet 13 of 15 US 2012/0295893 A1 i Minutes Figure 15 20000000 @ 15000000 5 <[ 10000000 5 D 5000000 O 0.0 0.5 1.0 1.5 Conch (ug/ml) Figure 16 Patent Application Publication Nov. 22, 2012 Sheet 14 of 15 US 2012/0295893 A1 0.60 0.50. 0.40 0.30 0.20 . O. 10 0.00 O 2 4. 6 8 10 12 Location (well) Figure 17A O.60 0.50 0.40 0.30 0.20 O. 10 0.00 –0.10 O 2 4 6 8 10 12 Location (well) Figure 17B Patent Application Publication Nov. 22, 2012 Sheet 15 of 15 US 2012/0295893 A1 0.60 0. 5 O 0. 4. O 0. 3 O 0. 2 O . 0.10 0.00 –0.10 O 2 4 6 8 10 12 Location (well) Figure 17C US 2012/0295893 A1 Nov. 22, 2012 [0021] According to yet another embodiment, the buffering general anesthesia in day procedures (like colonoscopy, agent is selected from the group consisting of citric buffer, endoscopy etc.) thereby allowing shorter post-sedation moni sodium chloride and combination thereof. toring, the method comprising administering to a subject in [0022] According to yet another embodiment, the surfac need thereof an effective amount of a flumazenil formulation tant is a cationic surfactant. According to yet another embodi according to the present invention. ment, the surfactant is benzalkonium chloride. [0033] The term ‘treating as used herein with respect to the [0023] According to yet another embodiment, the formula treatment of excessive sleepiness during waking hours in a tion comprises a plurality of agents selected from the group subject treated with a sleep drug using the formulation of the consisting of: a penetration enhancer, a preservative, a sur invention, refers to preventing the onset of or ameliorating, factant, a cyclodextrin, and a solubilizing agent. the excessive sleepiness during waking hours in a subject [0024] According to yet another embodiment, the flumaze treated with a sleep drug by the claimed formulation. nil formulation of the invention is provided in a form selected [0034] According to one embodiment, the flumazenil for from the group consisting of sublingual dosage form, trans mulation of the invention is administered by a route appro dermal dosage form, subdermal dosage form, aerosol form priate for self administration, such as: sublingual, subdermal, (for inhalation) and transmucosal dosage form. intranasal, by inhalation and transmucosal, though the afore [0025] According to yet another embodiment, the flumaze mentioned modes of administration may be used for admin nil formulation of the invention is provided in a form for istration to the patient by others (caretakers). According to yet transmucosal delivery to a mucosal surface of the oral cavity another embodiment, the flumazenil formulation of the or nasal cavity. According to yet another embodiment, the invention is administered repeatedly for as long as treatment mucosal surface is selected from the group consisting of the is required. In some embodiments, the formulation of the buccal mucosa, the sublingual mucosa, the gingival mucosa, invention is administered several times a day. In other the palatal mucosa, the labial mucosa, the sinusoidal mucosa, embodiments, the formulation of the invention is adminis the nasal mucosa, and a combination thereof. tered once a day, or once every other day, or a few times a [0026] According to yet another embodiment, the flumaze week, or once a week. nil formulation of the invention is suitable for chronic (re [0035] According to yet another embodiment, the flumaze peated) usage, such that it is administered a few times a day, nil formulation of the invention is a sublingual flumazenil daily, several times a week, weekly, and the like.
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