US009050293B2
(12) United States Patent (10) Patent No.: US 9,050,293 B2 Cohen et al. (45) Date of Patent: *Jun. 9, 2015
(54) SMALL MOLECULESOLUBLIZATION (56) References Cited SYSTEM U.S. PATENT DOCUMENTS (75) Inventors: David M. Cohen, Lauderdale By The 4,091,090 A 5/1978 Sipos Sea, FL (US); Eugene R. Cooper, 4,552,872 A 1 1/1985 Cooper et al. Berwyn, PA (US) 4,764,381 A 8, 1988 Bodor et al. 4.885,174 A 12/1989 Bodor et al. (73) Assignee: Juventio, LLC, Chatham, NJ (US) 4.954,487 A 9/1990 Cooper et al. 4,983,396 A 1/1991 Bodor et al. 5,073,372 A * 12/1991 Turner et al...... 424/401 (*) Notice: Subject to any disclaimer, the term of this 5,196.410 A 3, 1993 Francoeur et al. patent is extended or adjusted under 35 5,534,242 A 7/1996 Henry et al. U.S.C. 154(b) by 714 days. 5,534.246 A 7, 1996 Herb et al. 5,585,398 A 12, 1996 Ernst This patent is Subject to a terminal dis 5,853,732 A 12/1998 Munden claimer. (Continued) (21) Appl. No.: 12/503,929 FOREIGN PATENT DOCUMENTS
(22) Filed: Jul. 16, 2009 CA 2446.060 A1 11 2002 EP 95813 A2 12/1983 (65) Prior Publication Data (Continued) US 2010/0016442 A1 Jan. 21, 2010 OTHER PUBLICATIONS Related U.S. Application Data United States District Court Southern District of Florida, Case No. (60) Provisional application No. 61/135,103, filed on Jul. 09-cv-60284-GRAHAM/TORRES, Complaint dated Feb. 20, 2009. 16, 2008. (Continued) (51) Int. C. Primary Examiner — Paul Zarek A6 IK3I/64 (2006.01) (74) Attorney, Agent, or Firm — Hoffmann & Baron, LLP A6 IK9/00 (2006.01) A61 K 47/10 (2006.01) (57) ABSTRACT A61 K 47/24 (2006.01) The invention provides a drug delivery system for the topical A61 K 47/38 (2006.01) administration of therapeutic agents, including therapeutic (52) U.S. C. agent in an amount between 0.001 and 20% by weight, pro CPC ...... A6 IK3I/I64 (2013.01); A61 K9/0014 pylene glycol in an amount between 2 and 6% by weight, (2013.01); A61 K47/10 (2013.01); A61 K47/24 oleyl alcohol in an amount between 2 and 6% by weight, and (2013.01); A61 K47/38 (2013.01) a volatile component in an amount between 60 and 95% by (58) Field of Classification Search weight. CPC ...... A61 K31 (164 See application file for complete search history. 15 Claims, 1 Drawing Sheet
US 9,050,293 B2 Page 2
(56) References Cited tiffs Complaint with Affirmative Defenses and Counterclaim dated Mar. 23, 2009. U.S. PATENT DOCUMENTS International Search Report for PCT/US2009/004173 dated Jun. 26, 2008. 5,891.462 A 4/1999 Carrara et al. United States District Court Southern District of Florida, Case No 6,295,469 B1 9, 2001 Linkwitz et al. 09-cv-60284-GRAHAM/TORRES, Condensed Transcript of Confi 6,319,913 B1 1 1/2001 Mak et al. dential Deposition dated Mar. 11, 2009. 6,528,086 B2 3/2003 Zhang United States District Court Southern District of Florida, Case No. 6,579,865 B2 6, 2003 Mak et al. 09-cv-6084-GRAHAM/TORRES, Settlement Agreement and 6,635,674 B1 10/2003 Kaneko et al. Release dated Sep. 11, 2009. 6,894,078 B2 5, 2005 Castillo Galinsky et al., “Basic Pharmacokinetics and Pharmacodynamics.” 7,157,097 B2 1/2007 Mak et al. 7,273,887 B1 9/2007 Wepfer Remington: The Science and Practice of Pharmacy, (2006) p. 1171. 7,335,379 B2 2/2008 Carrara et al. Lippincott Williams & Wilkins, Baltimore. 7,504,114 B1 3/2009 Kurita et al. Rodu et al., "Clinical and chemical properties of a novel mucosal 2003/0O27833 A1 2/2003 Cleary et al. bioadhesive agent.” J Oral Pathol. (1988) 17:9-10. 2003/OO54017 A1 3/2003 Castillo Cooper, E., “Vehicle Effects on Skin Penetration.” Percutaneous 2004/O131665 A1 7/2004 Wepfer Absorption, (1985) pp. 525-529, R L. Bronaugh and H. I. 2004O162989 A1 8, 2004 Kirovski Maibach, Eds., Marcel Dekker, Inc. New York. 2004/0175416 A1 9, 2004 Taravella et al. Cooper, E. R. “Increased Skin Permeability for Lipophilic Mol 2004/0208.914 A1* 10, 2004 Richlin et al...... 424/448 ecules,” J. Pharm. Sci. (1984) pp. 1153-1156 73:8. 2005, OO 14823 A1 1/2005 Soderlund et al. Cooper, E. R. et al., “Effect of Fatty Acids and Alcohols on the 2005/0276842 Al 12/2005 Zhang et al. 2005/0281750 A1 12, 2005 Willcox et al. Penetration of Acyclovir Across Human Skin in Vitro. J. Pharm. 2006, O155922 A1 7/2006 Gorobets et al. Sci., (1985) pp. 688-689, 74:6. 2006/0280783 Al 12/2006 Dipietro et al. Cooper, E. R. et al., "Skin Permeability.” Methods in Skin Research, 2007, OO15590 A1 1/2007 Jackson et al. (1985) pp. 407-432, D. Skerrow and C.J. Skerrow, Eds. John Wiley 2007/O189978 A1 8/2007 Zhang et al. and Sons, Chichester. 2007/0269393 A1 1 1/2007 Wepfer Material Safety Data Sheet Cyclohexylmethanol, 99%. Fisher Sci 2008. O176948 A1 7/2008 Cohen et al. entific online). Mar. 7, 2006 retrieved on Apr. 20, 2008 Retrieved 2009 OO48347 A1 2/2009 Cohen et al. from the Internet USR:
US 9,050,293 B2 1. 2 SMALL MOLECULESOLUBLIZATION therapeutic agent, an alkane diol, a Cs-C fatty acid or cor SYSTEM responding alcohol or ester having a melting point below 40° C., and a volatile component. In certain embodiments, the RELATED APPLICATIONS therapeutic agent is present in an amount Such that upon topical application to a Surface, evaporation of the Volatile This application claims the benefit of priority to U.S. Pro component occurs such that the remaining Solution is near visional Patent Application No. 61/135,103, filed Jul. 16, saturation, at Saturation, or above Saturation with the thera 2008, which application is hereby incorporated by reference peutic agent at the temperature of the Surface. in its entirety. For example, the present invention provides a drug delivery BACKGROUND 10 system for topical administration of a therapeutic agent com prisingi) a first component which is a therapeutic agent, Such The medical community is continually engaged in efforts as any one of the therapeutic agents listed below, ii) a second to enhance the effective delivery of drugs across the skin. component selected from propylene glycol or a butane diol Many of the concerns associated with oral administration can with adjacent hydroxyl groups (e.g., butane-1,2-diol or often be avoided by topically administering an active agent to 15 butane-2,3-diol), iii) a third component selected from oleyl a subject in need thereof. For example, reliable delivery of a alcohol, oleic acid, ester derivatives of oleic acid such as the pharmaceutically active agent to organs or tissues in need methyl ester, any Co to Ca Saturated alcohol or correspond thereof via oral administration is often difficult due to vari ing acid which is a liquid at room temperature, or any C2 to able rates of absorption and metabolism associated with oral C mono- or poly-unsaturated or branched chain alcohol or delivery. In contrast, topical administration of a pharmaceu corresponding acid which is a liquid at room temperature, and tically active agent can provide high doses of the active agent iv) a fourth component which is a volatile component, such as directly to the desired area, often minimizing side effects. One Such way of delivering drugs across the skin Surface is one or more short-chain alcohols, Volatile silicones, or com by way of a non-occlusive transdermal and/or topical dosage binations thereof. form. Some non-limiting examples of non-occlusive trans In certain embodiments, the drug delivery system of the dermal and topical semi-solid dosage forms include creams, 25 present invention may further comprise a thickener, Such as ointments, gels, foams, sprays, Solutions, and lotions (i.e., any suitable thickener that is soluble in the total solvent emulsions, or Suspensions). However, the inefficiencies of system. drug permeation across the skin are well known. In fact, the The present invention also provides a method for adminis permeation of a drug in a non-occlusive transdermal dosage tering the drug delivery system of the present invention to an form can be as little as 1% and usually is no more than 15%. 30 animal in need of Such treatment comprising applying an Thus, a vast majority of the active drug remains unabsorbed effective amount of the drug delivery system according to the on the skin. Because the vast majority of the drug does not present invention. penetrate the skin surface, the bioavailability of the particular The present invention further provides a method for the drug is not optimal, and a high risk of contamination of other treatment or prophylaxis of a disease or condition in an ani individuals in close proximity to the user is presented by the 35 mal which comprises administering to a dermal Surface of an unwanted transfer of the pharmaceutical formulation in the animal in need of such treatment a therapeutically effective non-occlusive dosage form. Various methods have been tried amount of a drug delivery system according to the present to improve the percutaneous absorption of pharmacologically invention. active substances. For example, pharmacologically active Substances were modified to form prodrugs and complexes. 40 DETAILED DESCRIPTION OF THE DRAWINGS However, administration of these agents requires detailed studies on the individual pharmacologically active Substance, resulting in large monetary and time investments. FIG. 1 shows the six Zones of the lateral periocular regions Occlusive dosage forms present some advantages over for administration of dermatological injections. non-occlusive dosage forms, such as assisting the rate of 45 DETAILED DESCRIPTION OF THE INVENTION penetration of drugs across the skin. However, occlusive dos age forms also exhibit several major drawbacks. For example, occlusive dosage forms present a high potential of local irri The present invention provides a drug delivery system for tation caused by the prolonged contact of the drug, Volatiles, topical administration of a therapeutic agent comprising a vehicle excipients, and the adhesive used to attach the occlu therapeutic agent, an alkane diol, a C-C fatty acid or cor sive device, e.g., the patch, to the skin. In addition, the occlu 50 responding alcohol or ester having a melting point below 40° sive nature of certain dosage forms, such as the patch device, C., and a volatile component. In certain embodiments, the also restrict the natural ability of the skinto “breathe, thereby therapeutic agent is present in an amount Such that upon increasing the risk of irritation. In addition to the aforemen topical application to a Surface, evaporation of the Volatile tioned drawbacks of occlusive dosage forms, significant seri component occurs such that the remaining Solution is near ous hazards have been documented regarding the high drug 55 saturation, at Saturation, or above Saturation with the thera loading that is specific to patches. peutic agent at the temperature of the Surface. Although attempts have been made to overcome draw In certain embodiments, the drug delivery system com backs associated with both occlusive and non-occlusive topi prises between 0.001 and 20 percent by weight of the thera cal drug forms, such attempts have been unsuccessful. peutic agent (e.g., any one of the therapeutic agents listed Accordingly, there remains a need to provide a pharmaceuti 60 below), such as between 0.01 and 20 percent, or 0.1 and 20 cally acceptable topical pharmaceutical formulation system percent by weight of the therapeutic agent. In certain embodi that overcomes the disadvantages of these systems. ments, the drug delivery system comprises between four and eight percent by weight of the therapeutic agent (e.g., any one SUMMARY OF INVENTION of the therapeutic agents listed below). 65 In certain embodiments, the alkane diol comprises a C3 or The present invention provides a drug delivery system for C4 alkane diol. In certain such embodiments, the alkane diol topical administration of a therapeutic agent comprising a is selected from propylene glycol or a butane diol with adja US 9,050,293 B2 3 4 cent hydroxyl groups, such as butane-1,2-diol or butane-2,3- bon atoms); palmitoleyl alcohol (cis-9-hexadecan-1-ol; 16 diol. In certain embodiments, the drug delivery system com carbonatoms, unsaturated, CH (CH) CH=CH(CH)OH): prises between two and 35 percent by weight of the alkane isostearyl alcohol (16-methylheptadecan-1-ol; 18 carbon diol, such as between two and 30 percent by weight of the atoms, branched, (CH)2CH-(CH2)5OH); elaidyl alcohol alkane diol. In certain embodiments, the drug delivery system 5 (9E-octadecen-1-ol; 18 carbon atoms, unsaturated, CH comprises between two and eight percent by weight of the (CH),CH=CH(CH2)5OH); oleyl alcohol (cis-9-octadecen alkane diol. In certain Such embodiments, the drug delivery 1-ol; 18 carbon atoms, unsaturated); linoleyl alcohol (9Z, system comprises between two and six percent by weight of 12Z-octadecadien-1-ol; 18 carbon atoms, polyunsaturated); the alkane diol, such as between three and five percent by elaidolinoleyl alcohol (9E,12E-octadecadien-1-ol; 18 carbon weight of the alkane diol. Such as four percent by weight of 10 atoms, polyunsaturated); linolenyl alcohol (9Z,12Z, 15Z-oc the alkane diol. In certain embodiments, the alkane diol com tadecatrien-1-ol; 18 carbon atoms, polyunsaturated); elaid prises propylene glycol, an organic compound known also by olinolenyl alcohol (9E,12E, 15-E-octadecatrien-1-ol; 18 car the systematic name propane-1,2-diol. bonatoms, polyunsaturated); ricinoleyl alcohol (12-hydroxy In certain embodiments, the Cs-C fatty acid or corre 9-octadecen-1-ol; 18 carbon atoms, unsaturated, diol, CH sponding alcohol orester having a melting point below 40°C. 15 (CH)-CH(OH)CH-CH=CH(CH)OH); arachidyl alcohol comprises a C-C fatty acid or corresponding alcohol or (1-eicosanol; 20 carbon atoms); behenyl alcohol ester having a melting point below 40°C. In certain embodi (1-docosanol; 22 carbon atoms); erucyl alcohol (cis-13 ments, the Cs-C fatty acid or corresponding alcohol orester docosen-1-ol; 22 carbon atoms, unsaturated, CH (CH), is liquid at room temperature (e.g., is liquid at 21-24°C.). In CH=CH(CH2)2OH); lignoceryl alcohol (1-tetracosanol; 24 certain embodiments, the ester is a methyl ester. In certain carbon atoms); ceryl alcohol (1-hexacosanol; 26 carbon embodiments the Cs-C fatty acid or corresponding alcohol atoms); montanyl alcohol (1-octacosanol; 28 carbon atoms); or ester having a melting point below 40°C. is selected from myricyl alcohol (1-triacontanol; 30 carbon atoms); and ged oleyl alcohol, oleic acid, ester derivatives of oleic acid such as dyl alcohol (1-tetratriacontanol: 34 carbon atoms). the methyl ester, any Co to Ca Saturated alcohol or corre In certain embodiments, the Volatile component comprises sponding acid or ester which is a liquid at room temperature 25 one or more short-chain alcohols, Volatile silicones, or com (e.g., is liquid at 21-24°C.), or any C to C mono- or binations thereof. In certain embodiments, the volatile com poly-unsaturated or branched chain alcohol or corresponding ponent comprises a non-aqueous volatile solvent. In certain acid or ester which is a liquid at room temperature (e.g., is embodiments, the short-chain alcohol is selected from the liquid at 21-24°C.). In certain embodiments, the Cs-C fatty isomers ofbutanol, isomers of propanol, ethanol, and metha acid or corresponding alcohol or ester having a melting point 30 nol. Alternatively, any other short-chain alcohol safe for topi below 40°C. is selected from a Co to Ca saturated alcohol, cal administration would be appropriate. In certain embodi C mono- or polyunsaturated alcohol or branched-chain ments, the volatile component comprises a short-chain alcohol that is a liquid-at-room-temperature (e.g., is liquid at alcohol other than methanol. In certain such embodiments, 21-24°C.), a Co to Ca Saturated acid, and a C mono- or the Volatile component comprises ethanol, propanol, isopro polyunsaturated acid or branched-chain acid that is a liquid 35 panol, butanol, or butan-2-ol. In certain embodiments, the at-room-temperature (e.g., is liquid at 21-24°C.). In certain Volatile component comprises ethanol or isopropanol. In cer embodiments, the drug delivery system comprises between tain embodiments, the Volatile component comprises a com two and 30 percent by weight of the Cs-C fatty acid or bination of one or more Volatile solvents, such as a combina corresponding alcohol or ester having a melting point below tion of one or more short-chain alcohols. In certain Such 40° C. In certain embodiments, the drug delivery system 40 embodiments, the Volatile component comprises a combina comprises between two and seven percent by weight of the tion of one or more volatile solvents selected from ethanol, Cs-C fatty acid or corresponding alcohol or ester having a propanol, isopropanol, butanol, and butan-2-ol. In certain melting point below 40°C. In certain such embodiments, the embodiments, the Volatile component comprises one or more drug delivery system comprises between between two and six volatile silicones. In certain embodiments, the volatile sili percent by weight of the Cs-C fatty acid or corresponding 45 cone is odorless and/or has a low heat of evaporation So it does alcohol or ester having a melting point below 40° C. Such as not create a cold sensation when evaporating after being between three and five percent by weight of the C-C fatty deposited on the skin. In certain embodiments, the volatile acid or corresponding alcohol or ester having a melting point silicone comprises a volatile polydimethylsiloxane. Exem below 40°C., such as four percent by weight of the C-C, plary volatile silicone compounds include, but are not limited fatty acid or corresponding alcohol or ester having a melting 50 to, Volatile, low molecular weight polydimethylsiloxane point below 40°C. In certain embodiments, the Cs-C fatty compounds. Such compounds can be either a linear or a cyclic acid or corresponding alcohol or ester having a melting point polydimethylsiloxane compound having a viscosity from below 40° C. comprises oleic acid or oleyl alcohol. about 0.5 to about 10 cst (centistokes). In certain embodi Generally, the fatty alcohol can be a Co to Ca Saturated ments, the Volatile silicone comprises the cyclic, Volatile, low alcohol, a C to C mono- or polyunsaturated alcohol or 55 molecular weight polydimethylsiloxanes designated as branched-chain alcohol that is a liquid at room temperature, cyclomethicones. Suitable cyclomethicones are available or those same compounds in acid form. Fatty alcohols are commercially under the trade names DOW CORNING 244 aliphatic alcohols derived from natural fats and oils. They are Fluid, DOW CORNING 245 Fluid, DOW CORNING 344 the counterparts of fatty acids. They usually (but not always) Fluid and DOW CORNING 345 Fluid from DOW CORN have an even number of carbon atoms. They find use in the 60 ING Corporation, Midland, Mich., and SILICONE SF-1173 cosmetics and food industry. Fatty alcohols are a common and SILICONE SF-1202 from General Electric, Waterford, component of waxes, mostly as esters with fatty acids but also N.Y. In certain embodiments, the volatile silicone comprises as alcohols themselves. Those with common names include a linear, low molecular weight, Volatile polydimethylsiloxane capryl alcohol (1-octanol; 8 carbon atoms); pelargonic alco compound designated as hexamethyldisiloxane, decameth hol (1-nonanol; 9 carbon atoms); capric alcohol (1-decanol, 65 yltetrasiloxane, octamethyltrisiloxane, or decamethylpenta decylalcohol; 10 carbonatoms); lauryl alcohol (1-dodecanol: siloxane. In certain embodiments, the Volatile silicone com 12 carbon atoms); myristyl alcohol (1-tetradecanol; 14 car prises hexamethyldisiloxane having a viscosity of 0.65 cST. US 9,050,293 B2 5 6 In certain embodiments, the Volatile component comprises a effective amount of the drug delivery system according to the combination of a Volatile silicone and one or more short-chain present invention, e.g., to the skin of the animal. alcohol. In certain embodiments, the drug delivery system The present invention further provides a method for the comprises between 60 and 90 percent by weight of the vola treatment or prophylaxis of a disease or condition in an ani tile component, such as between 60 and 85 percent by weight mal which comprises administering to a dermal Surface of an of the volatile component. animal in need of such treatment a therapeutically effective For example, the present invention provides a drug delivery amount of a drug delivery system according to the present system for topical administration of a therapeutic agent com invention. prisingi) a first component which is a therapeutic agent, Such In certain embodiments, the animal is a human. as any one of the therapeutic agents listed below, ii) a second 10 Specific non-limiting examples of therapeutic agents that component selected from propylene glycol or a butane diol can be used in the pharmaceutical compositions of the present with adjacent hydroxyl groups (e.g., butane-1,2-diol or invention include analgesics and anti-inflammatory agents, butane-2,3-diol), iii) a third component selected from oleyl anti-helminthics, anti-anginal agents (e.g., nitrates), anti-ar alcohol, oleic acid, ester derivatives of oleic acid Such as the rhythmic agents, anti-arthritics, anti-asthma agents, anti-bac methyl ester, any Co to Ca Saturated alcohol or correspond 15 terial agents, anti-viral agents, anti-coagulants, anti-depres ing acid which is a liquid at room temperature (e.g., is liquid sants, anti-diabetics, anti-emetics, anti-epileptics, anti-fungal at 21-24°C.), or any C2 to C mono- or poly-unsaturated or agents, anti-gout agents, anti-hypertensive agents, anti-ma branched chain alcohol or corresponding acid which is a larials, anti-migraine agents, anti-muscarinic agents, anti liquid at room temperature (e.g., is liquid at 21-24°C.), and neoplastic agents and immunosuppressants, anti-parkinso iv) a fourth component which is a volatile component, such as nian agents, anti-psychotics, anti-protozoal agents, anti one or more short-chain alcohols, Volatile silicones, or com spasmodics, anti-thrombotic agents, anti-thyroid agents, anti binations thereof. tussives, anxiolytic, sedatives, hypnotics and neuroleptics, In certain embodiments, the drug delivery system of the beta-blockers, cardiovascular drugs, cardiac inotropic agents, present invention may further comprise a thickener, such as cerebral vasodilators, chemotherapeutic agents, cholinergic any suitable thickener that is soluble in the total solvent 25 antagonists, contraceptives, coronary vasodilators, corticos system. In certain embodiments, the thickener is soluble in teroids, diuretics, anti-parkinsonian agents, gastro-intestinal the Volatile component of the drug delivery system. Examples agents, histamine (e.g., H and H-) receptor antagonists, of thickeners that may be used in the drug delivery system of immunosuppressive agents, keratolytics, lipid regulating the present invention include cellulose derivatives, such as agents, muscle relaxants, narcotic antagonists, opioids, polymers comprising carboxymethyl-, hydroxyethyl-, 30 peripheral vasodilators, anti-anginal agents, nutritional hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; agents, analgesics, sex hormones, stimulants, vitamins and synthetic polymers, such as those comprising polyacrylates, anesthetics. polymethacrylates, poly(hydroxyethyl)-, poly(hydroxypro Examples of Such therapeutic agents include without limi pyl)-, poly(hydroxypropylmethyl)methacrylate, polyacry tation: 3-ketodesogestrel, 4-dihydrotestosterone, abecarnil. lonitrile, methallyl-Sulphonate, polyethylenes, polyoxyethyl 35 acamprostate, acavir, acebutolol, aceclofenac, acemetacin, enes, polyethylene glycols, polyethylene glycol-lactide, acetaminophen, acetaminosalol, acetanilide, acetohexamide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, poly acetophenazine maleate, acetophenazine, acetoxolone, vinyl alcohols, poly(propylmethacrylamide), poly(propylene acetoxypregnenolone, acetretin, acrisorcin, acrivastine, acy fumarate-co-ethylene glycol), poloxamers, polyaspartamide, clovir, adinazolam, adiphenine hydrochloride, adrafinil, hyaluronic acid (e.g., hydrazine cross-linked hyaluronic 40 adrenolone, agatroban, ahnitrine, akatinol, alatrofloxacin, acid), and silicone; natural gums, such as those comprising albendazole, albuterol, aldioxa, alendronate, alfentanil, ali alginates, carrageenan, guar-gum, gelatine, tragacanth, (ami bendol, alitretinoin, allopurinol, allylamines, allylestrenol, dated) pectin, Xanthan, chitosan collagen, agarose; mixtures alminoprofen, almotriptan, alosetron, aloXiprin, alprazolam, and further derivatives or co-polymers thereof and/or other alprenolol, amantadine, ambucetamide, amidephrine, amidi pharmaceutically acceptable polymers. In certain embodi 45 nomycin, amiloride, aminoarylcarboxylic acid derivatives, ments, the drug delivery system of the present invention fur aminoglutethimide, aminoglycosides, aminopentamide, ami ther comprises hydroxypropylcellulose. Pharmaceutical nopromazine, aminorex, amiodarone, amiphenazole, ami grade hydroxypropylcellulose is commercially available in a prilose, amisulpride, amitriptyline, amlexanoX, amlodipine, variety of molecular weights, any of which would be suitable amodiaquine, amoSulalol, amotriphene, amoxapine, amox in the formulation of the current invention. In certain embodi 50 icillin, amphecloral, amphetamine, amphomycin, amplicillin, ments of the present invention wherein the drug delivery ampiroXicam, amprenavir, amrinone, amsacrine, amyl system further comprises a thickener, the drug delivery sys nitrate, amylobarbitone, anagestone acetate, anastrozole, tem comprises between 0.1 and 3.5 percent by weight of the andinocillin, androstenediol, androstenediol-17-acetate, thickener. In certain Such embodiments, the drug delivery androstenediol-17-benzoate, androstenediol-3-acetate, system comprises between 2.5 and 3.5 percent by weight of 55 androstenediol-3-acetate-17-benzoate, androstenedione, the thickener. androsterone acetate, androsterone benzoate, androsterone In certain embodiments, the drug delivery system of the propionate, androsterone, angiotensin, anidulafungin, anirac present invention comprises a thickener and a volatile sili etam, apaZone, apicycline, apoatropine, apomorphine, apra cone. In certain embodiments, the drug delivery system of the clonidine, aprepitant, aprotinin, arbaprostil, ardeparin, arip present invention comprises a thickener and a volatile sili 60 iprazole, arnikacin, arotinolol, arstiinol, arylacetic acid cone, wherein the thickener is hydroxypropylcellulose derivatives, arylalkylamines, arylbutyric acid derivatives, (HPC). In certain such embodiments, the drug delivery sys arylcarboxylic acids, arylpiperazines, arylpropionic acid tem comprises between about 2.5 and about 3.5 percent by derivatives, aspirin, astemizole, atenolol, atomoxetine, ator weight of hydroxypropylcellulose (HPC). vastatin, atovaquone, atropine, auranofin, azapropaZone, aza The present invention also provides a method for adminis 65 thioprine, azelastine, azetazolamide, azithromycin, baclofen, tering the drug delivery system of the present invention to an bambuterol, bamethan, barbitone, barnidipine, basalazide, animal in need of Such treatment comprising applying an beclamide, beclobrate, beclomethasone, befimolol, beme US 9,050,293 B2 7 8 gride, benazepril, bencyclane, bendazac, bendazol, bendrof dihydromorphine, dihydropyridine derivatives, dihydrostrep lumethiazide, benethamine penicillin, benexate hydrochlo tomycin, dihydrotachysterol, dihydroxyaluminum acetylsali ride, benfurodil hemisuccinate, benidipine, benorylate, cylate, diiodohydroxyquinoline, diisopromine, dilaZep, dil bentazepam, benzhexol, benziodarone, benznidazole, ben evalol, dilitaZem, diloxanide furoate, diloxanide, diltiazem, Zoctamine, benzodiazepine derivatives, benzodiazepine, ben 5 dimefline, dimenhydrinate, dimethisterone, dimetofrine, Zonatate, benzphetamine, benzylmorphine, beperiden, dimorpholamine, dinitolmide, dioxaphetyl butyrate, diox bephenium hydroxynaphthoate, bepridil, bepridil, betahis ethedrine, dipheniethoxidine, diphenhydramine, diphenoxy tine, betamethasone, betaxolol, bevantolol, bevonium methyl late, diphetarSone, diplivefrin, diponium bromide, dipy Sulfate, bexarotene, beZafibrate, bialamicol, biapenem, ridamole, dirithromycin, disopyramide, divalproex sodium, bicalutamide, bietamiverine, binedaline, binifibrate, birico 10 dofetilide, domperidone, doneZepil, dopexamine, dopradil, dar, bisacodyl, bisantrene, bisoprolol, bitolterol, bopindolol, doSmalfate, doxapram, doxazosin, doxefazepam, doxepin, boswellic acid, bradykinin, bretylium, bromazepam, bro doxycycline, drofenine, dromostanolone propionate, dromo mocriptine, bromperidol, brotizolam, brovincamine, buci stanolone, dronabinol, droperidol, droprenilamine, d-threo clate, bucloxic acid, bucumolol, budesonide, budralazine, methylphenidate, dulloxetine, dutasteride, ebrotidine, eburna bufeniode, bufetolol, buflomedil, bufuralol, bumetanide, 15 monine, ecabet, ecenofloxacin, edavarone, edoxudine, bunitrolol, bupranolol, buprenorphine, buproprion, bus efavirenz, effivarenZ, efloxate, eledoisin, eletriptan, elgo pirone, buSulfan, butalamine, butarphenol, butaverine, butid dipine, ellipticine, emepronium bromide, emetine, enalapril, rine hydrochloride, butobarbitone, butoconazole, butofilol. enanthate, encainide, enlopitat, enoXimone, enprostil, enta butorphenol, butropium bromide, cabergoline, calcifediol. capone, epanolol, ephedrine, epinastine, epinephrine, epiru calcipotriene, calcitriol, caldiribine, cambendazole, camiox bicin, epleronone, eposartan, ergocalciferol, ergoloid mesy irole, camo.stat, camptothecin, candesartan, candoxatril, lates, ergotamine, ertapenum, erythromycin, erytlirityl capecitabine, caprate, capsaicin, captopril, carazolol, carba tetranitrate, esaprazole, escitalopram, esmolol, esomepra cephems, carbamates, carbameZepine, carbapenems, carbar Zole, esonarimod, estaZolam, estradiol benzoate, estradiol. Sone, carbatrol, carbenoXolone, carbimazole, carbromal, car estramustine, estriol Succinate, estriol, estrone acetate, buterol, carisoprodol, carotenes, caroverine, carteolol. 25 estrone sulfate, etafedrine, etafenone, ethacrynic acid, carvedilol, cefaclor, cefazolin, cefbuperaZone, cefepime, ethamivan, ethinamate, ethinylestradiol 3-acetate, ethi cefoselis, ceftibuten, celcoxib, celecoxib, celiprolol, cephae nylestradiol 3-benzoate, ethinylestradiol, ethionamide, ethis line, cephalosporin C, cephalosporins, cephamycins, cerivas terone (17O-ethinyltestosterone), ethopropazine, ethotoin, tatin, certoparin, cetamolol, cetiedil, cetirizine, cetraxate, ethoxyphenamine, ethylestrenol, ethylmorphine, ethylnore chloracizine, chlorambucil, chlorbetamide, chlordantoin, 30 pinephrine, ethynodiol diacetate, etodolac, etofibrate, etopo chlordiazepoxide, chlormadinone acetate, chlormethiazole, side, etoricoxib, etretinate, everolimus, exalamide, exames chloroquine, chlorothiazide, chlorpheniramine, chlorphe tane, examorelin, eZemitibe, falecalcitriol, famciclovir, noxamide, chlorphentermine, chlorproguanil, chlorprom famotidine, fantofarone, farapenum, fargilitazar, fasudil, fel azine, chlorpropamide, chlorprothixene, chlortetracycline, bamate, felodipine, femalamide, fenbufen, fenbutrazate, chlorthalidone, cholecalciferol, chromonar, ciclesonide, 35 fendiline, fenfluramine, fenofibrate, fenofibric acid, ciclonicate, cidofivir, ciglitaZone, cilansetron, cilostaZol. fenoldopam, fenoprofen, fenoterol, fenoverine, fenoxazo cimetidine, cimetropium bromide, cinepazet maleate, cin line, fenoxedil, fenpiprane, femproporex, fenspiride, fentanyl. namedrine, cinnarizine, cinolazepam, cinoxacin, ciprofi fexofenadine, flavoxate, flecainide, flopropione, floredil, brate, ciprofloxacin, cisapride, cisplatin, citalopram, citi floxuridine, fludarabine, fludiazepam, fludrocortisone, flufe coline, clarithromycin, clebopride, clemastine, clenbuterol, 40 namic acid, flunanisone, flunarizine, flunisolide, fluni clidanac, clinofibrate, clobazam, clobenfurol, clobenzorex, trazepam, fluocortolone, fluoxetine, flupenthixol decanoate, clofazimine, clofibrate, clofibric acid, cloforex, clomi fluphenazine decanoate, fluiphenazine enanthate, fluphena pramine, clonazepam, clonidine, clonitrate, clopidogrel, clo Zine, fluproduaZone, flurazepam, flurbiprofen, flurogestone pirac indomethacin, cloranolol, cloricromen, clorprenaline, acetate, fluticasone propionate, fluvastatin, fluvoxamine, clortermine, clotiazepam, cloxacillin, clozapine, cinepazide, 45 fominoben, formoterol, foScarnet, fosinopril, fosphenyloin, codeine methyl bromide, codeine phosphate, codeine Sulfate, frovatirptan, fudosteine, fumagillin, furazolidone, furazoli codeine, colloidal bismuth Subcitrate, cortisone, cromafiban, done, furfurylmethyl amphetamine, furosemide, gabapentin, cromolyn, cropropamide, crotethamide, curcumin, cyclande gabexate, gaboXadol, galanthamine, gallopamil, gamma late, cyclarbamate, cyclazocine, cyclexedrine, cyclizine, parin, ganciclovir, ganglefene, gefarnate, gemcitabine, gem cyclobenzaprine, cyclodrine, cyclonium iodide, cyclopen 50 fibrozil, gepirone, gestadene, ghrelin, glatiramer, glaucaru tamine, cyclosporine, cypionate, cyproheptadine, cyproter bin, glibenclamide, gliclazide, glimepiride, glipizide, one acetate, cyproterone, cytarabine, dacarbazine, dalfopris gluconic acid, glutamicacid, glyburide, glyceryl trinitrate, tine, dantrolene Sodium, dapiprazole, darodipine, decanoate, glymepiride, granisetron, grepafloxacin, guaiaZulene, guana decitabine, decoquinate, dehydroemetine, dehydroepi benz, guanfacine, halofantrine, haloperidol decanoate, halo androsterone, delavirdine, delaviridine, demeclocycline, 55 peridol, haloxazolam, hepronicate, heptanoate, hexobendine, denopamine, deramciclone, descitalopram, desipramine, hexoprenaline, hydramitrazine, hydrazides, hydrochlorothi desloratadine, desogestrel, desomorphine, desoxymetha azide, hydrocodone, hydrocortisone, hydromorphone, Sone, detomidine, dexamethasone, dexamphetamine, dex hydroxyamphetamine, hydroxymethylprogesterone acetate, anabinol, dexchlorpheniramine, dexfenfluramine, dexmeth hydroxymethylprogesterone, hydroxyprogesterone acetate, ylphenidate, dexraZOxane, dextroamphetamine Sulfate, 60 hydroxyprogesterone caproate, hydroxyprogesterone, hyme dextroamphetamine, dextropropoxyphene, DHEA, diacetate, cromone, hyoscyamine, ibopamine, ibudilast, ibufenac, ibu diamorphine, diazemine, diazepam, diaZOxide, dibromopro profen, ibutilide, idebenone, idoxuridine, ifenprodil, pamidine, dichlorophen, diclofenac, dicoumarol, didanosine, igmesine, iloprost, imatinib, imidapril, imidazoles, imi dideoxyadenosine, diethylpropion, difemerine, difenami penem, imipramine, imolamine, incadronic acid pergolide, Zole, diflunisal, digitoxin, digoxin, dihydroergotamine, dihy 65 indanazoline, indenolol, indinavir, indomethacin, indoramin, drocodeine, dihydrocodeinone enol acetate, dihydroergota inosinepranobex, inositol niacinate, iodoquinol, ipidracine, mine mesylate, dihydroergotamine, dihydrogesterone, iproniazid, irbesartan, irinotecan, irsogladine, isobutyrate, US 9,050,293 B2 10 isocaprate esters, isoetharine, isometheptene, isoproterenol, mivir, oxaliplatin, oxamniquine, Oxandrolone, oxantel isosorbide dinitrate, isosorbide mononitrate, isosorbide dini embonate, oxaprozin, oxatomide, pemirolast, oxazepam, trate, isoXSuprine, isradipine, itasetron, itramintosylate, iver oXcarbazepine, Oxfendazole, oxiconazole, oxiracetam, OXo mectin, kallidin, kallikrein, kanamycin, ketamine, ketopro linic acid, oXprenolol, oxycodone, oxyfedrine, oxymetazo fen, ketorolac, ketotifen, labetalol, lafutidine, lamifiban, line, oxymorphone, oxyphenbutaZone, oxyphencyclimine, lamivudine, lamotrigine, lanatoside c. lanSoprazole, lasofox oxyprenolol, oZagrel, paclitaxel, palonosetron, pantoprazole, ifene, leflunomide, leminoprazole, lercanadipine, lesopitron, papaverine, paracalcitol, paramethadione, parecoxib, letrozole, leucovorin, levalbuterol, levallorphan, levetirac pariprazole, paromomycin, paroxetine, parsalmide, paZina etam, levobunolol, levodopa, levofloxacin, levonorgestrel, clone, pemoline, penbutolol, penciclovir, penicillin G benza levophacetoperane, levorphanol, lidoflazine, lifibrol, 10 thine, penicillin G procaine, penicillin V, penicillins, pen limaprost, lineZolid, lintitript, liranaftate, lisinopril, lisuride, taerythritol tetranitrate, pentapiperide, pentazocine, lobeline, lobucavir, lodoxamide, lomefloxacin, lomerizine, pentifylline, pentigetide, pentobarbitone, pentorex, pentoxi lomustine, loperamide, lopinavir, loprazolam, loracarbef, fylline, pentrinitrol, perenzepine, pergolide, perhexiline, per loratadine, lorazepam, lorefloxacin, lormetazepam, losartan, indopril erbumine, perospirone, perphenazine, pimozide, lovastatin, loxapine Succinate, loxapine, 1-threo-meth 15 perphenazine, phanquinone, phenacemide, phenacetin, ylphenidate, lumiracoxib, lynestrenol, lysine acetylsalicy phenaZopyridine, phencarbamide, phendimetrazine, late, lysozyme, lysuride, mabuterol, mafenide, magnesium phenelZine, phenindione, phenmetrazine, phenobarbitone, acetylsalicylate, malgramostin, mannitol hexanitrate, mapro phenoperidine, phenothiazines, phenoxybenzamine, phen tiline, mazindol, mebendazole, meclizine, meclofenamic Suximide, phentermine, phentolamine, phenyl salicylate, acid, mecloxaminepentapiperide, medazepam, medibazine, phenylacetate, phenylbutaZone, phenylephrine hydrochlo medigoxin, medrogestone, medroxyprogesterone acetate, ride, phenylpropanolamine hydrochloride, phenylpropanola mefenamic acid, mefenorex, mefloquine, megestrol acetate, mine hydrochloride, phenylpropyl-methylamine, phenytoin, megestrol, melengestrol acetate, melphalan, mematine, phloroglucinol, pholedrine, physostigmine salicylate, phys mepenZolate bromide, meperidine, mephenoxalone, ostigmine, phytonadiol, piapenum, picilorex, piclamilast, mephentermine, mepindolol, mepixanox, meprobamate, 25 picrotoxin, picumast, pifamine, pilsicainide, pimagedine, meptazinol, mercaptopurine, merropenum, mesalamine, pimeclone, pimecrolimus, pimethylline, pimozide, pinav mesalazine, mesoridazine, besylate, mesoridazine, mestra erium bromide, pindolol, pioglitaZone, piperacillin, pipera nol, metaclazepam, metamfepramone, metampicillin, metap Zine estrone Sulfate, piperazine derivatives, piperilate, pirac roterenol, metaraminol, methacycline, methadone hydro etam, pirbuterol, pirenzepine, piribedil, pirifibrate, chloride, methadone, methamphetamine, methaqualone, 30 piroXicam, pitavastatin, pizotyline, plaunotol, polaprezinc, methoin, methotrexate, methoxamine, methSuximide, meth polybenzarsol, polyestrol phosphate, practolol, pralnacasan, ylhexaneamine, methylphenidate, d-threo-methylphenidate, pramipexole, pranlukast, prasterone, pravastatin, prazepam, methylphenobarbitone, methylprednisolone, methysergide, praziquantel, praZosin, prednisolone, prednisone, pregabalin, metiazinic acid, metizoline, metoclopramide, metolaZone, prenalterol, prenylamine, pridinol, pri?inium bromide, primi metoprolol, metoxalone, metripranolol, metronidazole, 35 done, primipramine, probenecid, probucol, procainamide, mexiletine, mexilitene, mianserin, mibefradil, midazolam, procarbazine, procaterol, prochlorperazine, progesterone, midodrine, miglitol, milnacipran, milrinone, minoxidil, mir proguanil, pronethalol, propafenone, propamidine, propatyl tazapine, misoprostol, mitomycin, mitotane, mitoxantrone, nitrate, propentofyline, propiram, propoxyphene, propra mizolastine, modafinil, mofebutaZone, mofetil, molindone nolol, propylhexedrine, propylthiouracil, protokylol, protrip hydrochloride, molindone, molsidomine, monatepil, mon 40 tyline, proxazole, pseudoephedrine, purines, pyrantel telukast, monteplase, moprolol, moricizine, morphine hydro embonate, pyrazoles, pyrazolones, pyridofylline, chloride, morphine Sulfate, morphine, morpholine salicylate, pyrimethamine, pyrimidines, pyrrolidones, quazepam, que mosapramine, moxifloxacin, moxisylyte, moxonidine, tiapine, quetuapine, quinagolide, quinapril, quinestrol, quin mycophenolate, nabumetone, nadolol, nadoxolol, nadro famide, quinidine, quinine Sulfate, quinolones, quinupritin, parin, nafamo.stat, nafronyl, naftopidil, nalbuphine, nalidixic 45 rabalzotan, rabeprazole Sodium, rabeprazole, racefimine, acid, nalmefene, nalorphine, naloxone, naltrexone, nan ramatroban, ramipril, ranitidine, ranolazine, ranSoprazole, drolone benzoate, nandrolone cyclohexanecarboxylate, nan rasagiline, rebamipide, refludan, repaglinide, repinotan, repi drolone cyclohexane-propionate, nandrolone decanoate, rinast, reproterol, reserpine, retinoids, ribavirin, rifabutine, nandrolone furylpropionate, nandrolone phenpropionate, rifampicin, rifapentine, rillmenidine, riluzole, rimantadine, naphazoline, naproxen, naratriptan, natamycin, nateglinide, 50 rimiterol, rioprostil, risperidone, ritanovir, ritapentine, riti nebivalol, nedocromil, nefazodone, nefopam, nelfinavir, penem, ritodrine, ritonavir, rivastigmine, rizatriptan, rociver nemonapride, neomycin undecylenate, neomycin, neotrofin, ine, rofecoxib, rohypnol, rolipram, romoxipride, ronifibrate, nesiritide, n-ethylamphetamine, nevibulol, nevirapine, nexo ropinirole, ropivacaine, rosaprostol, rosiglitaZone, rosuvasta pamil, nicametate, nicardipine, nicergoline, nicofibrate, nico tin, rotinolol, rotraxate, roXatidine acetate, roXindole, rubite furanose, nicomorphine, nicorandil, nicotinyl alcohol, nicou 55 can, Salacetamide, Salicin, salicylamide, Salicylic acid deriva malone, nifedipine, nifenalol, nikethamide, nilutamide, tives, Salmeterol, saquinavir, Scopolamine, secnidazole, nilvadipine, nimodipine, nimorazole, nipradillol, nisoldipine, Selegiline, semotiadil, seratrodast, sertindole, Sertraline, nitisinone, nitrazepam, nitrofurantoin, nitrofuraZone, nitro Sibutramine, sildenafil. Simfibrate, simvastatin, siramesine, glycerin, nizatidine, norastemizole, norepinephrine, nore Sirolimus, sitaxsentan, Sofalcone, Somotiadil, Sorivudine, thindrone acetate, norethindrone, norethisterone acetate, 60 Sotalol, Soterenol, sparfloxacin, spasmolytol, spectinomycin, norethisterone, norethynodrel, norfenefrine, norfloxacin, spiramycin, spironolactone, Spizofurone, stanozolol, stavu norgestimate, norgestrel, norgestrienone, normethadone, dine, Streptomycin, Succinylsulfathiazole, Sucralfate, Sufen normethisterone, normorphine, norpseudoephedrine, tanil, Sulconazole nitrate, Sulfacetamide, Sulfadiazine, Sulfa nortriptyline, novantrone, nylidrin, octamylamine, octodrine, loxic acid, Sulfarside, Sulfinalol, Sulindac, Suloctidil, octopamine, ofloxacin, olanzapine, olapatadine, olmesartan, 65 Sulphabenzamide, Sulphacetamide, Sulphadiazine, Sulpha olopatidine, olsalazine, omapatrilat, omeprazole, ondasetron, doxine, Sulphafurazole, Sulphamerazine, Sulphamethox opium, oprevelkin, orlistat, ornidazole, ornoprostil, oselta azole, Sulphapyridine, SulphaSalazine, Sulphinpyrazone, US 9,050,293 B2 11 12 Sulpiride, Sulthiame, Sultopride, Sultroponium, Sumanirole, nolol, atenolol, bupranolol, carteolol, labetalol, metoprolol. Sumatriptan, Sunepitron, Superoxide dismutase, Suplatast, nadolol, nadoxolol, Oxprenolol, pindolol, propranolol. Suramin Sodium, synephrine, tacrine, tacrolimus, tadalafil. Sotalol, timolol and timolol maleate, cardiotonic glycosides talinolol, talipexole, tamoxifen, tamsulosin, targretin, tazano Such as digoxin and other cardiac glycosides and theophylline last, tazarotene, taZobactum, tecastimezole, teclozan, tedis derivatives, adrenergic stimulants such as adrenaline, ephe amil, tegaserod, telenzepine, telmisartan, temazepam, tenipo drine, fenoterol, isoprenaline, orciprenaline, rimeterol, Salb side, teprenone, teraZosin, terbutaline Sulfate, terbutaline, utamol, salmeterol, terbutaline, dobutamine, phenylephrine, terfenadine, terodiline, terofenamate, tertatolol, testolactone, phenylpropanolamine, pseudoephedrine and dopamine, testosterone, tetracyclics, tetracycline, tetrahydrocannabinol, vasodilators such as cyclandelate, isoxSuprine, papaverine, tetrahydrozoline, thalidomide, theofibrate, thiabendazole, 10 dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl thiazinecarboxamides, thiocarbamates, thiocarbamizine, alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, thiocarbarSone, thioridazine, thiothixene, tiagabine, tiameni pentaerythritol tetranitrate and Xanthinol, and antimigraine dine, tianeptine, tiaprofenic acid, tiaramide, ticlopidine, tig preparations such as ergotamine, dihydroergotamine, methy loidine, tilisolol, timolol, tinidazole, tinofedrine, tinzaparin, Sergide, pizotifen and Sumatriptan; tipranavir, tirapazamine, tirofiban, tiropramide, titanicene, 15 drugs affecting blood and haemopoietic tissues including tizanidine, tocainide, tolaZamide, tolaZoline, tolbutamide, anticoagulants and thrombolytic agents such as warfarin, tolcapone, tolciclate, tolfenamic acid, toliprolol, tolterodine, dicoumarol, low molecular weight heparins such as enox tonaberstat, topiramate, topotecan, torasemide, toremifene aparin, Streptokinase and its active derivatives, and haemo citrate, toremifene, toSufloxacin, tramadol, tramaZoline, tran static agents such as aprotinin, tranexamic acid and prota dollapril, tranilast, tranylcypromine, trapidil, traXanox, traZ mine; odone, tretoquinol, triamcinolonc, triamterine, triazolam, an agent for central nervous system including analgesics, triazoles, tricromyl, tricyclics, trifluoperazine hydrochloride, antipyretics including the opiod analgesics such as buprenor trifluoperazine, triflupromazine, trifluridine, trihexyphenidyl phine, dextromoramide, dextropropoxyphene, fentanyl. hydrochloride, trihexyphenidyl, trimazosin, trimebutine, tri alfentanil, Sufentanil, hydromorphone, methadone, mor metazidine, trimethoprim, trimgestone, trimipramine, trimo 25 phine, oxycodone, papaveretum, pentazocine, pethidine, prostil, trithiozine, troglitaZone, trolnitrate phosphate, phenoperidine, codeine and dihydrocodeine, and others tromethamine, tropicamide, trovafloxacin, troXipide, tuami include acetylsalicylic acid (aspirin), paracetamol, and noheptane, tulobuterol, tymazoline, tyramine, undecanoate, phenaZone, hypnotics and sedatives such as the barbiturates, undecanoic acid, urinastatin, urSodeoxycholic acid, Valacy amylobarbitone, butobarbitone and pentobarbitone and other clovir, Valdecoxib, Valerate, Valganciclovir, Valproic acid, 30 hypnotics and sedatives such as choral hydrate, chlormethia Valsartan, Vancomycin, Vardenafil. Venlafaxine, Vinorelbine, Zole, hydroxy Zine and meprobamate, antianxiety agents such Verapamil, vidarabine, vigabatrin, Vincamine, vinpocetine, as the benzodiazepines, alprazolam, bromazepam, chlordiaz Viomycin, Vicquidil, Visnadine, Vitamin a derivatives, Vitamin epoxide, clobazam, chloraZepate, diazepam, flunitrazepam, a, vitamin b2, Vitamin d, Vitamin e, Vitamin k, Voglibose, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam Voriconazole, Xaliproden, Xamoterol, Xanthinol niacinate, 35 and triazolam, neuroleptic and antipsychotic drugs such as Xeny tropium bromide, Xibenolol, Ximelagatran, Xylometazo the phenothiazines, chlorpromazine, fluphenazine, peri line, yohimbine, Zacopride, Zalirlukast, Zafirlukat, Zalcitab cyazine, perphenazine, promazine, thiopropazate, thior ine, Zaleplon, Zanamivir, Zatebradine, Ziconotide, Zidovudine, idazine and trifluoperazine and the butyrophenones, droperi Zileuton, Zimeldine, Zinc propionate, Ziprasidone, Zolimidine, dol and haloperidol and the other antipsychotic drugs such as Zolmitriptan, Zolpidem, Zonisamide, Zopiclone, lidocaine, 40 pimozide, thiothixene and lithium, antidepressants such as articaine, bupivacaine, chloroprocaine, etidocaine, levobupi the tricyclic antidepressants amitryptyline, clomipramine, vacaine, oxyprocaine, mepivacaine, piperocaine, prilocaine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, tetracaine, procaine, dibucaine, benzocaine, dyclaine, amo opipramol, protriptyline and trimipramine and the tetracyclic rolfine, isoconazole, clotrimazole, econazole, econazole antidepressants such as mianserin and the monoamine oxi nitrate, miconazole, nystatin, terbinafine, bifonazole, ampho 45 dase inhibitors such as isocarboxazid, phenelizine, tranyl tericin, griseofulvin, ketoconazole, fluconazole and flucy cypromine and moclobemide and selective serotonin re-up tosine, Salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, take inhibitors such as fluoxetine, paroxetine, citalopram, pyrithione, Zinc pyrithione, Sodium pyrithione, butenafine, fluvoxamine and sertraline, CNS stimulants such as caffeine, butoconazole, butoconazole nitrate, clioquinol, itraconazole, anti-alzheimer's agents such as tacrine, antiparkinson agents lanoconazole, neticonazole, tioconazole, terconazole, ciclo 50 Such as amantadine, benserazide, carbidopa, levodopa, ben piroX olamine, octanoic acid, Sorbic acid, hexanoic acid, tri Ztropine, biperiden, benzhexol, procyclidine and dopamine-2 closan, or benzoic acid. agonists such as S(-)-2-(N-propyl-N-2-thienylethylamino)- For example, the therapeutic compound may be selected 5-hydroxytetralin (N-0923), anticonvulsants such as pheny from one or more of the following: toin, valproic acid, primidone, phenobarbitone, methylphe an agent for the alimentary system including antidiarrhoe 55 nobarbitone and carbamazepine, ethoSuximide, als such as diphenoxylate, loperamide and hyoscyamine; methSuximide, phensuximide, Sulthiame and clonazepam, an agent for the cardiovascular system including antihy antiemetics, antinauseants such as the phenothiazines, pertensives Such as hydralazine, minoxidil, captopril, enala prochloperazine, thiethylperazine and 5HT3 receptor pril, clonidine, praZosin, debrisoquine, diaZoxide, guanethi antagonists Such as ondansetron and granisetron and others dine, methyldopa, reserpine, and trimetaphan, calcium 60 Such as dimenhydrinate, diphenhydramine, metoclopramide, channel blockers such as diltiazem, felodopine, amlodipine, domperidone, hyoscine, hyoscine hydrobromide, hyoscine nitrendipine, nifedipine and Verapamil, antiarrhyrthmics Such hydrochloride, clebopride and brompride; as amiodarone, flecainide, disopyramide, procainamide, an agent for musculoskeletal system including non-steroi mexiletene and quinidine, antiangina agents such as glyceryl dal anti-inflammatory agents including their racemic mix trinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, 65 tures or individual enantiomers where applicable, such as mannitol hexanitrate, perhexilene, isosorbide dinitrate and ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac, nicorandil, beta-adrenergic blocking agents such as alpre aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, US 9,050,293 B2 13 14 indomethacin, mefenamic acid, naproxen, phenylbutaZone, derivatives or analogs such as corticotrophin, thyrotropin, piroXicam, Salicylamide, Salicylic acid, Sulindac, desox follicle stimulating hormone (FSH), luteinising hormone ySulindac, tenoxicam, tramadol and ketoralac, and additional (LH) and gonadotrophin releasing hormone (GnRH), non-steroidal antiinflammatory agents which can be formu hypoglycaemic agents such as insulin, chlorpropamide, glib lated in combination with the dermal penetration enhancers enclamide, gliclazide, glipizide, tolaZamide, tolbutamide and include Salicylamide, Salicylic acid, flufenisal, Salsalate, tri metformin, thyroid hormones Such as calcitonin, thyroxine ethanolamine salicylate, aminopyrine, antipyrine, oxyphen and liothyronine and antithyroid agents such as carbimazole butaZone, apaZone, cintaZone, flufenamic acid, clonixeril, and propylthiouracil, and other miscellaneous hormone clonixin, meclofenamic acid, flunixin, colchicine, demecol agents such as octreotide, pituitary inhibitors such as bro cine, allopurinol, oxypurinol, benzydamine hydrochloride, 10 mocriptine, and ovulation inducers such as clomiphene; dimefadane, indoxole, intrazole, mimbane hydrochloride, an agent for the genitourinary system including diuretics paranylene hydrochloride, tetrydamine, benzindopyrine Such as the thiazides, related diuretics and loop diuretics, hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cin bendrofluazide, chlorothiazide, chlorthalidone, dopamine, chophen, diflumidone sodium, fenamole, flutiazin, metaza cyclopenthiazide, hydrochlorothiazide, indapamide, mefru mide, letimide hydrochloride, nexeridine hydrochloride, 15 side, methychlothiazide, metolaZone, quinethaZone, bumet octaZamide, molinazole, neocinchophen, nimazole, proX anide, ethacrynic acid and frusemide and potassium-sparing azole citrate, tesicam, tesimide, tolmetin, and triflumidate, diuretics, spironolactone, amiloride and triamterene, antidi antirheumatoid agents such as penicillamine, aurothioglu uretics such as desmopressin, lypressin and vasopressin cose, Sodium aurothiomalate, methotrexate and auranofin, including their active derivatives or analogs, obstetric drugs muscle relaxants such as baclofen, diazepam, cyclobenza including agents acting on the uterus Such as ergometrine, prine hydrochloride, dantrolene, methocarbamol, oxytocin and gemeprost, and prostaglandins such as alpros orphenadrine and quinine, agents used in gout and hyperuri tadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin caemia Such as allopurinol, colchicine, probenecid and Sul F2-alpha) and misoprostol; phinpyrazone; antimicrobials such as antimicrobials including the cepha hormones and steroids including oestrogens such as oestra 25 losporins such as cephalexin, cefoxytin and cephalothin, diol, oestriol, oestrone, ethinyloestradiol, mestranol, stil penicillins such as amoxycillin, amoxycillin with clavulanic boestrol, dienoestrol, epioestriol, estropipate and Zeranol, acid, amplicillin, bacampicillin, benzathine penicillin, ben progesterone and other progestagens Such as allyloestrenol, Zylpenicillin, carbenicillin, cloxacillin, methicillin, phenethi dydrgesterone, lynoestrenol, norgestrel, norethyndrel, nore cillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, thisterone, norethisterone acetate, gestodene, levonorgestrel, 30 piperacillin, ticarcillin and azlocillin, tetracyclines such as medroxyprogesterone and megestrol, antiandrogens such as minocycline, chlortetracycline, tetracycline, demeclocycline, cyproterone acetate and danazol, antioestrogens such as doxycycline, methacycline and oxytetracycline and other tet tamoxifen and epitioStanol and the aromatase inhibitors, racycline-type antibiotics, aminoglycosides such as amika exemestane and 4-hydroxy-androstenedione and its deriva cin, gentamicin, kanamycin, neomycin, netilmicin and tobra tives, androgens and anabolic agents such as testosterone, 35 mycin, antifungals such as amorolfine, isoconazole, methyltestosterone, clostebol acetate, drostanolone, clotrimazole, econazole, miconazole, nystatin, terbinafine, furazabol, nandrolone oxandrolone, Stanozolol, trenbolone bifonazole, amphotericin, griseofulvin, ketoconazole, flu acetate, dihydro-testosterone, 17-alpha.-methyl-19-nortest conazole and flucytosine, Salicylic acid, fezatione, ticlatone, osterone and fluoxymesterone, 5-alpha reductase inhibitors tolnaftate, triacetin, Zinc pyrithione and sodium pyrithione, such as finasteride, turosteride, LY-191704 and MK-306, cor 40 triclosan, quinolones such as nalidixic acid, cinoxacin, cipro ticosteroids Such as betamethasone, betamethasone Valerate, floxacin, enoxacin and norfloxacin, Sulphonamides Such as cortisone, dexamethasone, dexamethasone 21-phosphate, phthalylsulphthiazole, Sulfadoxine, Sulphadiazine, Sulpha fludrocortisone, flumethasone, fluocinonide, fluocinonide methizole and Sulphamethoxazole, Sulphones such as dap desonide, fluocinolone, fluocinolone acetonide, fluocor Sone, other miscellaneous antibiotics such as chlorampheni tolone, halcinonide, halopredone, hydrocortisone, hydrocor 45 col, clindamycin, erythromycin, erythromycin ethyl tisone 17-valerate, hydrocortisone 17-butyrate, hydrocorti carbonate, erythromycin estolate, erythromycin glucepate, Sone 21-acetate methylprednisolone, prednisolone, erythromycin ethylsuccinate, erythromycin lactobionate, prednisolone 21-phosphate, prednisone, triamcinolone, tri roXithromycin, lincomycin, natamycin, nitrofurantoin, spec amcinolone acetonide, and further examples of steroidal anti tinomycin, Vancomycin, aztreonam, colistin IV, metronida inflammatory agents including cortodoxone, fluoracetonide, 50 Zole, tinidazole, fusidic acid and trimethoprim; 2-thiopyri fludrocortisone, difluorsone diacetate, flurandrenolone dine N-oxide; halogen compounds, particularly iodine and acetonide, medrysone, amcinafel, amcinafide, betametha iodine compounds such as iodine-PVP complex and Sone and its other esters, chloroprednisone, clorcortelone, diiodohydroxyquin; hexachlorophene; chlorhexidine, chlo descinolone, desonide, dichlorisone, difluprednate, illuclo roamine compounds; benzoyl peroxide, antituberculosis ronide, flumethasone, flunisolide, flucortolone, fluorometha 55 drugs such as ethambutol, isoniazid, pyrazinamide, rifampi lone, fluperolone, fluprednisolone, meprednisone, meth cin and clofazimine, antimalarials such as primaquine, ylmeprednisolone, paramethasone, cortisone acetate, pyrimethamine, chloroquine, hydroxychloroquine, quinine, hydrocortisone cyclopentylpropionate, cortodoxone, fluc mefloquine and halofantrine, antiviral agents such as acyclo etonide, fludrocortisone acetate, flurandrenolone acetonide, Vir and acyclovir prodrugs, famciclovir, Zidovudine, medrysone, amcinafal, amcinafide, betamethasone, 60 didanosine, stavudine, lamivudine, Zalcitabine, saquinavir, betamethasone benzoate, chloroprednisone acetate, clocor indinavir, ritonavir, n-docosanol, tromantadine and idoxuri tolone acetate, descinolone acetonide, desoximetaSone, dine, anthelmintics such as mebendazole, thiabendazole, dichlorisone acetate, difluprednate, flucloronide, flumetha niclosamide, praziquantel, pyrantel embonate and diethylcar Sone pivalate, flunisolide acetate, fluperolone acetate, flu bamazine, and cytotoxic agents such as plicamycin, cyclo prednisolone Valerate, paramethasone acetate, prednisola 65 phosphamide, dacarbazine, fluorouracil and its prodrugs, mate, prednival, triamcinolone hexacetonide, cortivaZol. methotrexate, procarbazine, 6-mercaptopurine and formocortal and nivaZol, pituitary hormones and their active mucophenolic acid; US 9,050,293 B2 15 16 an agent for metabolism including anorectic and weight amorolfine, isoconazole, clotrimazole, econazole, econazole reducing agents such as dexfenfluramine, fenfluramine, nitrate, miconazole, nystatin, terbinafine, bifonazole, ampho diethylpropion, mazindol and phentermine, agents used in tericin, griseofulvin, ketoconazole, fluconazole and flucy hypercalcaemia Such as calcitriol, dihydrotachysterol and tosine, Salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, their active derivatives or analogs; pyrithione, Zinc pyrithione, Sodium pyrithione, butenafine, an agent for the respiratory system such as antitussives butoconazole, butoconazole nitrate, clioquinol, itraconazole, Such as ethylmorphine, dextromethorphan and pholcodine, lanoconazole, neticonazole, tioconazole, terconazole, ciclo expectorants such as acetylcysteine, bromhexine, emetine, piroX olamine, octanoic acid, Sorbic acid, hexanoic acid, tri guaiphenesin, ipecacuanha and Saponins, decongestants such closan, or benzoic acid. as phenylephrine, phenylpropanolamine ans pseudoephe 10 In certain embodiments wherein a specific therapeutic drine, bronchospasm relaxants such as ephedrine, fenoterol, agent is duplicated in the exemplary listings above, no pref orciprenaline, rimiterol, Salbutamol, Sodium cromoglycate, erential indication is intended. Rather, certain agents above cromoglycic acid and its prodrugs, terbutaline, ipratropium are repeated for the purpose of providing clarity as to the bromide, salmeterol and theophylline and theophylline classes of agents suitable for the topical formulation system derivatives; 15 of the present invention as well as the individual agents Suit an agent for allergy and the immune system such as anti able for the topical formulation system of the present inven histamines such as meclozine, cyclizine, chlorcyclizine, tion. hydroxy Zine, brompheniramine, chlorpheniramine, clemas The term “volatile component as used herein refers to a tine, cyproheptadine, dexchlorpheniramine, diphenhy component (e.g., a solvent or combination of solvents) that dramine, diphenylamine, doxylamine, mebhydrolin, phe changes readily from Solid or liquid to a vapor, e.g., that niramine, tripolidine, azatadine, diphenylpyraline, evaporates readily at some temperature at or below body methdilazine, terfenadine, astemizole, loratidine and cetiriz temperature and less readily at room temperature. Such as a ine; component that evaporates rapidly between 21 and 37°C. at local anaesthetics Such as bupivacaine, amethocaine, atmospheric pressure. lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine 25 The term “healthcare providers' refers to individuals or and etidocaine; organizations that provide healthcare services to a person, stratum corneum lipids, such as ceramides, cholesterol and community, etc. Examples of “healthcare providers' include free fatty acids, for improved skin barrier repair; doctors, hospitals, continuing care retirement communities, neuromuscular blocking agents such as Suxamethonium, skilled nursing facilities, Subacute care facilities, clinics, mul alcuronium, pancuronium, atracurium, gallamine, tub 30 tispecialty clinics, freestanding ambulatory centers, home ocurarine and vecuronium; health agencies, and HMOs. Smoking cessation agents such as nicotine, bupropion and The term “treating refers to: preventing a disease, disorder ibogaine; or condition from occurring in a cell, a tissue, a system, insecticides and other pesticides which are suitable for animal or human which may be predisposed to the disease, local or systemic application; and 35 disorder and/or condition but has not yet been diagnosed as dermatological agents, such as vitamins A and E. Vitamin E having it; stabilizing a disease, disorder or condition, i.e., acetate and vitamin E Sorbate, allergens for desensitisation arresting its development; and relieving one or more symp Such as house dust mite allergen, nutritional agents, such as toms of the disease, disorder or condition, i.e., causing regres Vitamins, essential amino acids and essential fats, keratolytics sion of the disease, disorder and/or condition. Such as the alpha-hydroxy acids, glycollic acid and salicylic 40 As used herein, a therapeutic that “prevents” a disorder or acid, psychic energisers, such as 3-(2-aminopropyl)indole, condition refers to a compound that, in a statistical sample, 3-(2-aminobutyl)indole, and the like, anti-acneagents such as reduces the occurrence of the disorder or condition in the containing isotretinoin, tretinoin and benzoyl peroxide, anti treated sample relative to an untreated control sample, or psoriasis agents such as containing etiretinate, cyclosporin delays the onset or reduces the severity of one or more symp and calcipotriol, anti-itch agents such as capsaicin and its 45 toms of the disorder or condition relative to the untreated derivatives such as nonivamide, and anticholinergic agents control sample. which are effective for the inhibition of axillary sweating and As used herein, the term “saturation” refers to the point at for the control of prickly heat, such as the antiperspirant which a solution of a Substance (e.g., a therapeutic agent) can activity of agents such as methatropine nitrate, propantheline dissolve no more of that Substance and additional amounts of bromide, Scopolamine, methScopolamine bromide, and the 50 it will appear as a precipitate. The phrase “near Saturation” new class of soft antiperspirants, quaternary acyloxymethyl refers to a solution which is at least 90% saturated, such as ammonium salts. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% In certain embodiments of the present invention, more than saturated. The phrase “above saturation” refers to a solution one therapeutic agent (e.g., more than one of the therapeutic which has a higher concentration of Substance (e.g., a thera agents listed above) may be present in the drug delivery 55 peutic agent) than the concentration at which the Solution is system according to the present invention. In certain embodi saturated (e.g., it is greater than 100% Saturated). ments of the drug delivery system of the present invention, the The drug delivery system and methods of the present therapeutic agent may be a combination of more than one invention may be utilized to treat an individual in need therapeutic agent listed above. thereof. In certain embodiments, the individual is a mammal In certain embodiments, the therapeutic compound is not 60 Such as a human, or a non-human mammal ananesthetic agent, such as a local anesthetic agent. In certain The phrase “pharmaceutically acceptable' is employed embodiments, the therapeutic compound is not an antifungal herein to refer to those compounds, materials, compositions, agent. In certain embodiments, the therapeutic compound is and/or dosage forms which are, within the scope of Sound not lidocaine, articaine, bupivacaine, chloroprocaine, eti medical judgment, Suitable for use in contact with the tissues docaine, levobupivacaine, oxyprocaine, mepivacaine, piper 65 of human beings and animals without excessive toxicity, irri ocaine, prilocaine, tetracaine, procaine, dibucaine, ben tation, allergic response, or other problem or complication, Zocaine, dyclaine, amethocaine, lignocaine, cinchocaine, commensurate with a reasonable benefit/risk ratio. US 9,050,293 B2 17 18 The drug delivery system of the present invention can be drug delivery system ortherapeutic agent at levels lower than administered to a Subject topically, for example, as a gel. that required in order to achieve the desired therapeutic effect foam, Solution, lotion, cream, ointment or spray applied to the and gradually increase the dosage until the desired effect is skin. Details of appropriate routes of administration and com achieved. By “therapeutically effective amount” is meant the positions suitable for same can be found in, for example, U.S. concentration of a therapeutic agent that is sufficient to elicit Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427, the desired therapeutic effect. It is generally understood that 798, 5.358,970 and 4,172,896, as well as in patents cited the effective amount of the therapeutic agent will vary accord therein. ing to the weight, sex, age, and medical history of the Subject. The drug delivery system may conveniently be presented in Other factors which influence the effective amount may unit dosage form and may be prepared by any methods well 10 include, but are not limited to, the severity of the patients known in the art of pharmacy. The amount of active ingredient condition, the disorder being treated, the stability of the thera which can be combined with a carrier material to produce a peutic agent, and, if desired, another type of therapeutic agent single dosage form will vary depending upon the host being being administered with the therapeutic agent of the inven treated, the particular mode of administration. The amount of tion. A larger total dose can be delivered by multiple admin active ingredient that can be combined with a carrier material 15 istrations of the agent. Methods to determine efficacy and to produce a single dosage form will generally be that amount dosage are known to those skilled in the art (Isselbacher et al. of the therapeutic agent which produces a therapeutic effect. (1996) Harrison's Principles of Internal Medicine 13 ed., Besides the components outlined above, the drug delivery 1814-1882, herein incorporated by reference). system of the present invention can also include adjuvants In general, a suitable daily dose of an active therapeutic Such as Wetting agents, emulsifying and Suspending agents, agent used in the drug delivery systems and methods of the Sweetening, flavoring, coloring, perfuming and preservative invention will be that amount of the therapeutic agent that is agents. the lowest dose effective to produce atherapeutic effect. Such Drug delivery systems of the present invention for topical an effective dose will generally depend upon the factors or transdermal administration include powders, sprays, oint described above. ments, pastes, creams, lotions, gels, Solutions, patches and 25 If desired, the effective daily dose of the active therapeutic inhalants. The therapeutic agent may be mixed under sterile agent may be administered as one, two, three, four, five, six or conditions with the other components of the drug delivery more sub-doses administered separately at appropriate inter system, and with any preservatives, buffers, or propellants vals throughout the day, optionally, in unit dosage forms. In that may be required. certain embodiments of the present invention, the active The ointments, pastes, creams and gels may contain, in 30 therapeutic agent may be administered two or three times addition to the therapeutic agent, excipients, such as animal daily. In further embodiments, the active therapeutic agent and vegetable fats, oils, waxes, paraffins, starch, tragacanth, will be administered once daily. cellulose derivatives, polyethylene glycols, silicones, bento The patient receiving this treatment is any animal in need, nites, silicic acid, talc and Zinc oxide, or mixtures thereof. including primates, in particular humans, and other mammals Sprays can contain, in addition to a therapeutic agent, 35 Such as equines, cattle, Swine and sheep; and poultry and pets excipients such as lactose, talc, silicic acid, aluminum in general. hydroxide, calcium silicates and polyamide powder, or mix In certain embodiments, the drug delivery system of the tures of these substances. Sprays can additionally contain present invention may optionally be administered conjointly customary propellants. Such as chlorofluorohydrocarbons with another therapeutic agent. As used herein, the phrase and Volatile unsubstituted hydrocarbons, such as butane and 40 “conjoint administration” refers to any form of administra propane. tion of two or more different therapeutic compounds such that The drug delivery systems of the present invention may the second compound is administered while the previously also contain adjuvants such as preservatives, wetting agents, administered therapeutic compound is still effective in the emulsifying agents and dispersing agents. Prevention of the body (e.g., the two compounds are simultaneously effective action of microorganisms may be ensured by the inclusion of 45 in the patient, which may include synergistic effects of the various antibacterial and antifungal agents, for example, two compounds). For example, the different therapeutic com paraben, chlorobutanol, phenol Sorbic acid, and the like. pounds can be administered either in the same drug delivery Actual dosage levels of the active ingredients in the drug system or in a separate formulation, either concomitantly or delivery system may be varied so as to obtainan amount of the sequentially. Thus, an individual who receives Such treatment active ingredient that is effective to achieve the desired thera 50 can benefit from a combined effect of different therapeutic peutic response for a particular patient, composition, and compounds. mode of administration, without being toxic to the patient. This invention includes the use of pharmaceutically The selected dosage level will depend upon a variety of acceptable salts of the therapeutic compounds listed above. In factors including the activity of the particular therapeutic certain embodiments, contemplated salts of the invention agent or combination of therapeutic agents employed, or the 55 include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. ester, salt or amide thereof, the route of administration, the In certain embodiments, contemplated salts of the invention time of administration, the rate of excretion of the particular include Na, Ca, K, Mg., Zn or other metal salts. compound(s) being employed, the duration of the treatment, Wetting agents, emulsifiers and lubricants, such as Sodium other drugs, compounds and/or materials used in combina lauryl Sulfate, as well as coloring agents, release agents, and tion with the particular compound(s) employed, the age, sex, 60 perfuming agents, preservatives and antioxidants can also be weight, condition, general health and prior medical history of present in the drug delivery systems. the patient being treated, and like factors well known in the Examples of pharmaceutically acceptable antioxidants medical arts. include: (1) water soluble antioxidants, such as ascorbic acid, A physician or veterinarian having ordinary skill in the art cysteine hydrochloride, Sodium bisulfate, sodium met can readily determine and prescribe the therapeutically effec 65 abisulfite, sodium sulfite and the like; (2) oil-soluble antioxi tive amount of the drug delivery system required. For dants, such as ascorbyl palmitate, butylated hydroxyanisole example, the physician or veterinarian could start doses of the (BHA), butylated hydroxytoluene (BHT), lecithin, propyl US 9,050,293 B2 19 20 gallate, alpha-tocopherol, and the like; and (3) metal chelat 4% lidocaine ing agents, such as citric acid, ethylenediamine tetraacetic 4% propylene glycol acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the 4% oleyl alcohol like. 2 or 3% hydroxypropylcellulose The present invention provides a kit comprising: a) a drug delivery system for topical administration of a 68 or 69% isopropyl alcohol (IPA) therapeutic agent comprising 17% hexamethyldisiloxane. i) a first component which is a therapeutic agent, Such as Formulation #1 contained 3% hydroxypropylcellulose any one of the therapeutic agents listed above, ii) a (e.g., KLUCELTM (hydroxypropylcellulose)) and 68% iso second component selected from propylene glycolor propyl alcohol. Formulation #2 contained 2% hydroxypropy a butane diol with adjacent hydroxyl groups (e.g., 10 lcellulose (e.g., KLUCELTM (hydroxypropylcellulose)) and butane-1,2-diol or butane-2,3-diol), iii) a third com 69% isopropyl alcohol. Both formulations were clear to trans ponent selected from oleyl alcohol, oleic acid, ester lucent liquids. Formulation #1 was slightly thicker than For derivatives of oleic acid Such as the methyl ester, any mulation #2 but both were sufficiently viscous so as not to Co to Ca Saturated alcohol or corresponding acid drip when applied. Product was placed around the area of the which is a liquid at room temperature, or any C to 15 C mono- or poly-unsaturated or branched chain lips with a cotton swab and then rubbed into the area. alcohol or corresponding acid which is a liquid at Patient #1—Formulation #1—experienced numbness almost room temperature, and iv) a fourth component which immediately and was able to be injected after 15 minutes is a volatile component, such as one or more short exposure. No pain due to the needle Stick was noted. chain alcohols, Volatile silicones, or combinations Patient #2—Formulation #2—experienced numbness almost thereof, and immediately and was able to be injected after 15 minutes b) instructions for the administration of the drug delivery exposure. Patient indicated that the pain at injection was system to an individual in need thereof. similar to previous procedures that utilized lidocaine/ In certain embodiments, the kit further comprises instruc prilocaine cream sold under the brand name EMLA. How tions for the administration of the drug delivery system con 25 jointly with another therapeutic agent. In certain embodi ever, previous procedures allowed the EMLA to remain on ments, the kit further comprises a second pharmaceutical the skin for over 60 minutes prior to injection. formulation, including but not limited to a drug delivery Patient #3—Formulation #1—two applications 15 minutes system according to the present invention comprising a sec apart were made. Patient experienced pain on injections simi ond therapeutic agent. lar to previous injections. Again, previous procedures utilized In certain embodiments, the invention relates to a method 30 EMLA with greater than 60 minutes exposure. for conducting a pharmaceutical business, by manufacturing Patient #4—Formulations #1 and #2 Products were applied a drug delivery system of the present invention, or a kit as to the left and right side of the site to evaluate the products described herein, and marketing to healthcare providers the side-by-side. Formulation #1 was judged superior by the benefits of using the drug delivery system or kit for the treat patient; numbness was experienced more quickly. Injections ment of an individual in need thereof. 35 were made 15 to 20 minutes after application. In certain embodiments, the invention relates to a method Two additional patients were evaluated. Samples were for conducting a pharmaceutical business, by providing a applied as per Patient #4 above. In both cases, Formulation #1 distribution network for selling a drug delivery system of the was judged Superior. In addition, one patient that required present invention, or kit as described herein, and providing removal of a growth was treated with Formulation #1 and, instruction material to patients or physicians for using the 40 after 15 minutes, had no pain at the site of biopsy. drug delivery system or kit for the treatment of an individual in need thereof. Example 2 In certain embodiments, the invention comprises a method for conducting a pharmaceutical business, by determining an The application of a drug delivery system according to the appropriate drug delivery system of the present invention comprising an appropriate dosage of a therapeutic agent for 45 present invention was tested prior to the injection of 4 units of the treatment of an individual in need thereof, conducting Botox(R) (onabotulinumtoxin.A) to the crow's feet wrinkles. therapeutic profiling of identified drug delivery systems for A topical anesthetic comprising 4% lidocaine, 4% propy efficacy and toxicity in animals, and providing a distribution lene glycol, 4% oleyl alcohol, 1.75% hydroxypropylcellu network for selling an identified drug delivery system as lose, 69.25% isopropyl alcohol (IPA), and 17% hexamethyl having an acceptable therapeutic profile. In certain embodi 50 disiloxane was prepared for use in the following ments, the method further includes providing a sales group dermatological procedures. for marketing the drug delivery system to healthcare provid Twelve subjects received a total of six Botox R (onabotu CS. linumtoxin.A) injections at four units each in six separate In certain embodiments, the invention relates to a method Zones demarcated in the lateral periocular regions bilaterally. for conducting a pharmaceutical business by determining an 55 The six Zones are depicted in FIG. 1. The administration of appropriate drug delivery system of the present invention the injections to the specific Zones was randomized among the comprising an appropriate dosage of a therapeutic agent for subjects. The first injection was administered at time 0 min the treatment of an individual in need thereof, and licensing, utes in the absence of the topical anesthetic solution. Follow to a third party, the rights for further development and sale of ing the initial injection, the topical anesthetic Solution the formulation. 60 described above was applied to the remaining 5 Zones. Injec tions were then given at 5 minutes, 15 minutes, 25 minutes, 35 EXEMPLIFICATION minutes, and 45 minutes following application of the anes thetic Solution. Immediately following each injection, Example 1 patients were asked to rank their perceived pain on the visual 65 analog scale (VAS) from 1-10. Patients were instructed that 1 Two formulations were evaluated comprising the follow indicates “no pain'. 5 indicates “moderate pain', and 10 ing components: indicates “worst pain'. A ranking of 3 is generally believed to US 9,050,293 B2 21 22 indicate minimal pain, and a ranking of two or less is gener 3. The drug delivery system of claim 2, wherein the drug ally believed to indicate almost no perceived pain. delivery system comprises between 0.1 and 3.5 percent by The average pain perceived on the VAS at times 0 minutes, weight of the thickener. 5 minutes, 15 minutes, 25 minutes, 35 minutes, and 45 min 4. The drug delivery system of claim 2 or 3, wherein the utes was 5.2+2.4, 5.8+2.7, 5.0+2.6, 3.11.8, 1.9-1.7, and 5 thickener comprises hydroxypropylcellulose. 2.7-2.2, respectively. The data shows a slight increase in 5. A method for administering the drug delivery system of perceived pain from time 0 minutes to time 5 minutes with the claim 1 to an animal in need of Such treatment, comprising least amount of pain experienced at time 35 minutes. applying an effective amount of the drug delivery system. Three subjects experienced mild burning and irritation to 6. A method for the treatment or prophylaxis of a disease or the skin as well as slight irritation of the eyes following 10 application of the topical anesthetic solution to the lateral condition in an animal comprising administering to a dermal periocular regstions. However, no redness or irritation was Surface of an animal in need of Such treatment a therapeuti observed. cally effective amount of a drug delivery system according to Incorporation by Reference claim 1. All publications and patents mentioned herein are hereby 15 7. The method of claim 5 or 6, wherein the animal is a incorporated by reference in their entirety as if each indi human. vidual publication or patent was specifically and individually 8. The drug delivery system of claim 1, wherein the pro indicated to be incorporated by reference. In case of conflict, pylene glycol and oleyl alcohol are present in a ratio of 1:1. the present application, including any definitions herein, will 9. The drug delivery system of claim 1, wherein the volatile control. component comprising a volatile polydimethylsiloxane is a linear or cyclic polydimethylsiloxane compound having a EQUIVALENTS viscosity from about 0.5 to about 10 cst. 10. The drug delivery system of claim 9, wherein the linear While specific embodiments of the subject invention have polydimethylsiloxane is selected from the group consisting of been discussed, the above specification is illustrative and not 25 hexamethyldisiloxane, decamethyltetrasiloxane, octameth restrictive. Many variations of the invention will become yltrisiloxane, decamethylpentasiloxane and combinations apparent to those skilled in the art upon review of this speci thereof. fication and the claims below. The full scope of the invention 11. The drug delivery system of claim 10, wherein the should be determined by reference to the claims, along with linear polydimethylsiloxane is hexamethyldisiloxane. their full scope of equivalents, and the specification, along 30 with Such variations. 12. The drug delivery system of claim 11, wherein the The invention claimed is: hexamethyldisiloxane has a viscosity of 0.65 cST. 1. A drug delivery system for topical administration of a 13. The drug delivery system of claim 9, wherein the cyclic therapeutic agent comprising the therapeutic agent lidocaine polydimethylsiloxane compound is a cyclomethicone. present in an amount of 4% by weight, propylene glycol in an 35 14. The drug delivery system of claim 1, wherein the vola amount between 2 and 6% by weight, oleyl alcohol in an tile component further comprises one or more short-chain amount between 2 and 6% by weight, and a volatile compo alcohols. nent comprising a volatile polydimethylsiloxane in an 15. The drug delivery system of claim 1, wherein the vola amount between 60 and 90% by weight. tile component is present in an amount of between 60 and 85 2. The drug delivery system of claim 1, further comprising percent by weight. a thickener.