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(12) Patent Application Publication (10) Pub. No.: US 2004/0120895 A1 Dugger, III (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2004/0120895 A1 Dugger, III (43) Pub US 2004O120895A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0120895 A1 Dugger, III (43) Pub. Date: Jun. 24, 2004 (54) BUCCAL POLAR AND NON-POLAR SPRAY tion No. 09/537,118, filed on Mar. 29, 2000, which is OR CAPSULE CONTAINING DRUGS FOR a continuation-in-part of application No. PCT/US97/ TREATING DSORDERS OF THE CENTRAL 17899, filed on Oct. 1, 1997. NERVOUS SYSTEM Publication Classification (75) Inventor: Harry A. Dugger III, Flemington, NJ (US) (51) Int. Cl. ................................................... A61L 9/04 (52) U.S. Cl. ................................................................ 424/44 Correspondence Address: JONES DAY (57) ABSTRACT 51 Louisiana Aveue, N.W WASHINGTON, DC 20001-2113 (US) Buccal aeroSol Sprays or capsules using polar and non-polar solvent have now been developed which provide biologi (73) Assignee: Novadel Pharma, Inc., Flemington, NJ cally active compounds for rapid absorption through the oral (21) Appl. No.: 10/726,585 mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprise formulation I: acque (22) Filed: Dec. 4, 2003 ous polar Solvent, active compound, and optional flavoring agent; formulation II: acqueous polar Solvent, active com Related U.S. Application Data pound, optionally flavoring agent, and propellant; formula tion m: non-polar Solvent, active compound, and optional (60) Division of application No. 10/230,060, filed on Aug. flavoring agent; and formulation IV: non-polar Solvent, 29, 2002, which is a continuation-in-part of applica active compound, optional flavoring agent, and propellant. Patent Application Publication Jun. 24, 2004 US 2004/O120895 A1 TRANSMUCOSA FORMULATION ORAL FORMULATION STO MACH ORAL FORMULATION DISSOLUTION STOMACH SOLUTION OF DRUG FECES COLON PORTAL BLOOD ENEROHEPATC BILE RECIRCULATION BLE isis LIVER 1ST PASS ETABOTE ENEROHEPATIC COLON RECIRCULATION FECES SYSTEMIC CIRCULATION URINE RECEPTOR THERAPEUTIC EFFECT US 2004/O120895 A1 Jun. 24, 2004 BUCCAL POLAR AND NON-POLAR SPRAY OR 0005 The buccal polar aerosol spray compositions of the CAPSULE CONTAINING DRUGS FOR TREATING present invention, for transmucosal administration of a DSORDERS OF THE CENTRAL NERVOUS pharmacologically active compound Soluble in a pharmaco SYSTEM logically acceptable polar Solvent are also administrable in aeroSol form driven by a propellant. In this case, the com CROSS REFERENCE TO RELATED position comprises in weight % of total composition: aque APPLICATIONS ous polar solvent 10-97%, active compound 0.1-25%, Suit 0001. This application is a continuation-in-part of appli ably additionally comprising, by weight of total composition cation Ser. No. 09/537,118, filed Mar. 29, 2000 which is a a flavoring agent 0.05-10% and propellant: 2-10%. Prefer continuation-in-part of the U.S. national phase designation ably the composition comprises: polar solvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% and of PCT/US97/17899 filed Oct. 1, 1997, the disclosures of propellant 2–5%; most suitably polar solvent 25-97%, active which are incorporated by reference herein in their entirety. compound 0.2-25%, flavoring agent 0.1-2.5% and propel BACKGROUND OF THE INVENTION lant 2-4%. 0002. It is known that certain biologically active com 0006 The buccal pump spray composition of the present pounds are better absorbed through the oral mucosa than invention, i.e., the propellant free composition, for transmu through other routes of administration, Such as through the cosal administration of a pharmacologically active com stomach or intestine. However, formulations Suitable for pound wherein Said active compound is Soluble in a phar Such administration by these latter routes present their own macologically acceptable non-polar Solvent comprises in problems. For example, the biologically active compound weight % of total composition: non-polar Solvent must be compatible with the other components of the 30-99.69%, active compound 0.005-55%, and suitably addi composition Such as propellants, Solvents, etc. Many Such tionally, flavoring agent 0.1-10%. formulations have been proposed. For example, U.S. Pat. 0007. The buccal polar pump spray compositions of the No. 4,689,233, Dvorsky et al., describes a soft gelatin present invention, i.e., the propellant free composition, for capsule for the administration of the anti-coronary drug transmucosal administration of a pharmacologically active nifedipine dissolved in a mixture of polyether alcohols. U.S. compound Soluble in a pharmacologically acceptable polar Pat. No. 4,755,389, Jones et al., describes a hard gelatin Solvent comprises in weight% of total composition: aqueous chewable capsule containing nifedipine. A chewable gelatin polar solvent 30-99.69%, active compound 0.001-60%, Suit capsule containing a Solution or dispersion of a drug is ably additionally comprising, by weight of total composition described in U.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda et al, and U.S. Pat. No. 5,370,862, a flavoring agent 0.1-10%. Preferably the composition com Klokkers-Bethke, describe a nitroglycerin Spray for admin prises: polar solvent 37-98.58%, active compound 0.005-55 istration to the oral mucosa comprising nitroglycerin, etha %, flavoring agent 0.5-8%; most suitably polar solvent nol, and other components. An orally administered pump 60.9-97.06%, active compound 0.01-40%, flavoring agent spray is described by Cholcha in U.S. Pat. No. 5,186,925. O.75-7.5%. AeroSol compositions containing a hydrocarbon propellant 0008. The soft bite gelatin capsules of the present inven and a drug for administration to a mucosal Surface are tion for transmucosal administration of a pharmacologically described in U.K. 2,082,457, Su, U.S. Pat. No. 3,155,574, active compound, at least partially Soluble in a pharmaco Silson et al., U.S. Pat. No. 5,011,678, Wang et al., and by logically acceptable non-polar Solvent, having charged Parnell in U.S. Pat. No. 5,128,132. It should be noted that thereto a fill composition comprise in weight % of total these references discuss bioavailability of solutions by inha composition: non-polar solvent 4-99.99%, emulsifier 0-20 lation rather than through the membranes to which they are %, active compound 0.01-80%, provided that said fill com administered. position contains less than 10% of water, Suitably addition ally comprising, by weight of the composition: flavoring SUMMARY OF THE INVENTION agent 0.01-10%. Preferably, the soft bite gelatin capsule 0003) A buccal aerosol spray or soft bite gelatin capsule comprises: non-polar solvent 21.5-99.975%, emulsifier using a polar or non-polar Solvent has now been developed 0-15%, active compound 0.025-70%, flavoring agent 1-8%; which provides biologically active compounds for rapid most suitably: nonpolar solvent 28.5-97.9%, emulsifier absorption through the oral mucosa, resulting in fast onset of 0-10%, active compound 0.1-65.0%, flavoring agent 2-6%. effect. 0009. The soft bite polar gelatin capsules of the present 0004. The buccal aerosol spray compositions of the invention for transmucosal administration of a pharmaco present invention, for transmucosal administration of a logically active compound, at least partially Soluble in a pharmacologically active compound Soluble in a pharmaco pharmacologically acceptable polar Solvent, having charged logically acceptable non-polar Solvent comprise in weight% thereto a composition comprising in weight % of total of total composition: pharmaceutically acceptable propellant composition: polar solvent 25-99.89%, emulsifier 0-20%, 5-80%, nonpolar solvent 19-85%, active compound 0.05 active compound 0.01-65%, provided that said composition 50%, suitably additionally comprising, by weight of total contains less than 10% of water, suitably additionally com composition a flavoring agent 0.01-10%. Preferably the prising, by weight of the composition: flavoring agent composition comprises: propellant 10-70%, non-polar Sol 01-10%. Preferably, the soft bite gelatin capsule comprises: vent 25-89.9%, active compound 0.01-40%, flavoring agent polar solvent 37-99.95%, emulsifier 0-15%, active com 1-8%; most suitably propellant 20-70%, non-polar solvent pound 0.025-55%, flavoring agent 1-8%; most suitably: 25-74.75%, active compound 0.25-35%, flavoring agent polar solvent 44-96.925%, emulsifier 0-10%, active com 2-7.5%. pound 0.075-50%, flavoring agent 2-6%. US 2004/O120895 A1 Jun. 24, 2004 0010. It is an object of the invention to coat the mucosal 0019 Soft gelatin capsules are well known in the art. See, membranes either with extremely fine droplets of Spray for example, U.S. Pat. No. 4,935,243, Borkan et al., for its containing the active compounds or a Solution or paste teaching of Such capsules. The capsules of the present thereof from bite capsules. invention are intended to be bitten into to release the low Viscosity Solution or paste therein, which will then coat the 0011. It is also an object of the invention to administer to buccal mucosa with the active compounds. Typical capsules, the oral mucosa of a mammalian in need of Same, preferably which are Swallowed whole or bitten and then Swallowed, man, by Spray or bite capsule, a predetermined amount of a deliver the active compounds to the Stomach, which results biologically active compound by this method or from a Soft in Significant lag time before maximum blood levels can be gelatin capsule. achieved or Subject the compound to a large first pass effect. 0012. A further object is a sealed aerosol spray container Because of the enhanced absorption of the compounds containing a composition of the non polar or polar aeroSol through the oral mucosa and no chance of a first pass effect, Spray formulation, and a metered valve Suitable for releasing use of the bite capsules of the invention will eliminate much from Said container a predetermined amount of Said com of the lag time, resulting in hastened onset of biological position.
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