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

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