USOO6969.508B2 (12) United States Patent (10) Patent No.: US 6,969,508 B2 Dugger, III (45) Date of Patent: Nov. 29, 2005 (54) BUCCAL POLAR AND NON-POLAR SPRAY 6,071,539 A 6/2000 Robinson et al. ........... 424/466 OR CAPSULE CONTAINING DRUGS FOR 6,110,486 A 8/2000 Dugger, III ................. 424/435 TREATING PAIN 6,299,900 B1 10/2001 Reed et al. 6,458.842 B1 10/2002 Dickinson et al. (75) Inventor: Hy A. Dugger, III, Flemington, NJ 6,706.2556,676.931 B2 3/20041/2004 Dugger,Dickinson III. et al. ( ) 2003/0077227 A1 4/2003 Dugger 2003/0082107 A1 5/2003 Dugger (73) Assignee: NovalDel Pharma, Inc., Flemington, NJ 2003/0211047 A1 * 11/2003 Dugger, III .................. 424/45 (US) 2004/0120895 A1 * 6/2004 Dugger, III .................. 424/44 2004/0141923 A1 7/2004 Mohammed (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. DE 3.338978 5/1984 DE 3246081 6/1984 (21) Appl. No.: 10/726,625 DE 4OOO7705 9/1991 DE 40382O3 6/1992 (22) Filed: Dec. 4, 2003 DE 41.12303 10/1992 (65) Prior PublicationO O Data EPDE O1404344132176 5/19854/1993 US 2004/0120896 A1 Jun. 24, 2004 EP O213 108 3/1987 EP O315960 5/1989 Related U.S. Application Data EP O3867OO 3/1990 EP 0471161. 2/1992 (60) Division- - - of application No. 10/230,059, filed on Aug. 29, EP O656206 A1 * 6/1992 2002, which is a continuation-in-part of application No. EP 0504112 9/1992 09/537,118, filed on Mar. 29, 2000, which is a continuation- EP O605483 4/1993 in-part of application No. PCT/US97/17899, filed on Oct. 1, EP O55.7129 8/1993 1997. EP O6562O6 6/1995 (51) Int. Cl." ............................. A61K9/12; A61K 9/08 (Continued) (52) U.S. Cl. .......................... 424/45; 424/434; 424/435 (58) Field of Search .......................... 424/45, 435, 434, OTHER PUBLICATIONS 424/46, 43,52; 514/772.6, 781, 782; 128/200.14 - 0 Rote Liste 1995 "Arzneimitteluerzeichnis des BPI and (56) References Cited UFA. Flemington Pharmaceutical Corporation webpage, www. U.S. PATENT DOCUMENTS flemington-pharma.com. 3,155,574 11/1964 Silson et al. .................. 167/54 Goodman and Gilman's The Pharmacological Basis of 3,304.230 2/1967 Abramson et al. ... 167/82 Therapeutics, 9" ed., pp. 490. 3,784,.684 1/1974 Bossert et al. ..... ... 424/37 Goodman and Gilman's The Pharmacological Basis of 4,232,002 11/1980 Nogrady ............ ... 424/25 4,689.233 8/1987 Dvorsky et al. ... ... 424/455 Therapeutics, 9" ed., pp. 496. 4.755,389 7/1988 Jones et al. ........ ... 424/456 Goodman and Gilman's The Pharmacological Basis of 4,857,312 8/1989 Hegasy et al. .. ... 424/80 Therapeutics, 9" ed., pp. 497. 4.919,919 4/1990 Aouda et al. ...... ... 424/45 4,935,243 6/1990 Borkan et al. ..... ... 424/441 Primary Examiner-Gary Kunz 5,011,678 4/1991 Wang et al. .... ... 424/45 Assistant Examiner Mina Haghighatian 5,047,230 9/1991 Nagy et al. ..... ... 424/45 5,128,132 7/1992 Parnell ........... 424/195.1 (74) Attorney, Agent, or Firm-Dickstein Shapiro Morin & 5,135,753 8/1992 Baker et al. ................ 424/435 Oshinsky LLP 5,186,925 2/1993 Cholcha ......... ... 424/43 (57) ABSTRACT 5,364,616 * 11/1994 Singer et al. ................. 451/52 5,370,862 12/1994 Klokkers-Bethke et al. .. 424/47 Buccal aeroSol Sprays or capsules using polar and non-polar 5,428,006 6/1995 Bechgaard ................... 424/45 solvent have now been developed which provide biologi 5,456.677 10/1995 Spector ...................... 604/290 5,457,100 10/1995 Daniel ............... ... 514/220 cally active compounds for rapid absorption through the oral 5,474,759 12/1995 Fassberg et al. .............. 424/45 mucosa, resulting in fast onset of effect. The buccal polar 5,502.076 3/1996 Dixit et al. compositions of the invention comprise formulation I: acque 5,519,059 5/1996 Sawaya ...................... 514/599 ous polar Solvent, active compound, and optional flavoring 5,593,684 1/1997 Baker et al. .... ... 208/252 agent; formulation II: aqueous polar Solvent, active 5,605,674 * 2/1997 Purewal et al. ............... 424/45 compound, optionally flavoring agent, and propellant; for 5,635,161 6/1997 Adjei et al. mulation III: non-polar Solvent, active compound, and 5,719, 197 2/1998 Kanios et al. ........... 514/772.6 optional flavoring agent, and formulation IV: non-polar 5,766,573 6/1998 Purewal et al. ... 424/45 Solvent, active compound, optional flavoring agent, and 5,869,082 2/1999 Dugger, III ................. 424/435 propellant. 5,908,611 6/1999 Gottlieb et al. 5,955,098 9/1999 Dugger, III ................. 424/435 5,981,591 11/1999 Deihl ......................... 514/568 13 Claims, 1 Drawing Sheet US 6,969,508 B2 Page 2 FOREIGN PATENT DOCUMENTS WO WO 99/16417 1/1997 WO WO 97/38662 10/1997 EP O719549 7/1996 WO WO 97/38663 10/1997 EP 1029536 8/2000 WO WO 97/38687 10/1997 FR 26 33933 1/1990 WO WO 98/29097 12/1997 GB 2O82457 3/1982 WO WO OO/27359 11/1999 WO WO 90/O1046 2/1990 WO WOOO/62757 10/2000 WO WO93/04671 3/1993 WO WO 01/66089 9/2001 WO WO 941328O 6/1994 WO WO O2/O94232 11/2002 WO WO94/13280 6/1994 WO WO95/24893 9/1995 * cited by examiner U.S. Patent Nov. 29, 2005 US 6,969,508 B2 TRANSMUCOSAL FORMULATON ORAL FORMULATION STOMACH ORA FORMULATION DISSOLUTION STOMACH SOLUTION OF DRUG PORTAL BLOOD ENTEROHEPATC BLE RECIRCULATION Blf - 1S PASS 1ST PASS METABOLITES ENTEROHEPATIC RECIRCU AION Ko FECES SYSTEMIC CIRCULATION URINE RECEPOR THERAPEUTIC EFFECT US 6,969,508 B2 1 2 BUCCAL POLAR AND NON-POLAR SPRAY logically acceptable polar Solvent are also administrable in OR CAPSULE CONTAINING DRUGS FOR aeroSol form driven by a propellant. In this case, the com TREATING PAN position comprises in weight % of total composition: aque ous polar solvent 10-97%, active compound 0.1-25%, Suit CROSS REFERENCE TO RELATED ably additionally comprising, by weight of total composition APPLICATIONS a flavoring agent 0.05-10% and propellant: 2-10%. Prefer ably the composition comprises: polar solvent 20-97%, This application is a divisional of U.S. application Ser. active compound 0.1-15%, flavoring agent 0.1-5% and No. 10/230,059, filed Aug. 29, 2002, which is a propellant 2–5%; most suitably polar solvent 25-97%, continuation-in-part of application Ser. No. 09/537,118, filed active compound 0.2-25%, flavoring agent 0.1-2.5% and Mar. 29, 2000 which is a continuation-in-part of the U.S. propellant 2-4%. national phase designation of PCT/US97/17899 filed Oct. 1, The buccal pump Spray composition of the present 1997, the disclosures of which are incorporated by reference invention, i.e., the propellant free composition, for transmu herein in their entirety. cosal administration of a pharmacologically active com BACKGROUND OF THE INVENTION 15 pound wherein Said active compound is Soluble in a phar macologically acceptable non-polar Solvent comprises in It is known that certain biologically active compounds are weight % of total composition: non-polar Solvent better absorbed through the oral mucosa than through other 30-99.69%, active compound 0.005–55%, and suitably routes of administration, Such as through the Stomach or additionally, flavoring agent 0.1-10%. intestine. However, formulations Suitable for Such adminis The buccal polar pump Spray compositions of the present tration by these latter routes present their own problems. For invention, i.e., the propellant free composition, for transmu example, the biologically active compound must be com cosal administration of a pharmacologically active com patible with the other components of the composition Such pound Soluble in a pharmacologically acceptable polar Sol as propellants, Solvents, etc. Many Such formulations have vent comprises in weight % of total composition: aqueous been proposed. For example, U.S. Pat. No. 4,689,233, 25 polar solvent 30–99.69%, active compound 0.001-60%, Dvorsky et al., describes a Soft gelatin capsule for the Suitably additionally comprising, by weight of total compo administration of the anti-coronary drug nifedipine dis sition a flavoring agent 0.1-10%. Preferably the composition solved in a mixture of polyether alcohols. U.S. Pat. No. comprises: polar solvent 37-98.58%, active compound 4,755,389, Jones et al., describes a hard gelatin chewable 0.005–55%, flavoring agent 0.5-8%; most suitably polar capsule containing nifedipine. A chewable gelatin capsule solvent 60.9–97.06%, active compound 0.01–40%, flavor containing a Solution or dispersion of a drug is described in ing agent 0.75-7.5%. U.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919, The Soft bite gelatin capsules of the present invention for 919, Aouda et al, and U.S. Pat. No. 5,370,862, Klokkers transmucosal administration of a pharmacologically active Bethke, describe a nitroglycerin Spray for administration to compound, at least partially Soluble in a pharmacologically the oral mucosa comprising nitroglycerin, ethanol, and other 35 acceptable non-polar Solvent, having charged thereto a fill components. An orally administered pump Spray is composition comprise in weight % of total composition: described by Cholcha in U.S. Pat. No. 5,186,925. Aerosol non-polar solvent 4-99.99%, emulsifier 0-20%, active com compositions containing a hydrocarbon propellant and a pound 0.01-80%, provided that said fill composition con drug for administration to a mucosal Surface are described in tains less than 10% of water, suitably additionally U.K.