(12) United States Patent (10) Patent No.: US 8,343,962 B2 Kisak Et Al

USOO83439.62B2

(12) United States Patent (10) Patent No.: US 8,343,962 B2 Kisak et al. (45) Date of Patent: *Jan. 1, 2013

(54) TOPICAL FORMULATION (58) Field of Classification Search ...... 514/226.5, 514/334, 420, 557, 567 (75) Inventors: Edward T. Kisak, San Diego, CA (US); See application file for complete search history. John M. Newsam, La Jolla, CA (US); Dominic King-Smith, San Diego, CA (56) References Cited (US); Pankaj Karande, Troy, NY (US); Samir Mitragotri, Goleta, CA (US) U.S. PATENT DOCUMENTS 5,602,183 A 2f1997 Martin et al. 5,648,380 A 7, 1997 Martin (73) Assignee: Nuvo Research Inc., Mississagua, 5,874.479 A 2, 1999 Martin Ontario (CA) 6,328,979 B1 12/2001 Yamashita et al. 7,001,592 B1 2/2006 Traynor et al. (*) Notice: Subject to any disclaimer, the term of this 7,795,309 B2 9/2010 Kisak et al. patent is extended or adjusted under 35 2002fOO64524 A1 5, 2002 Cevc U.S.C. 154(b) by 212 days. FOREIGN PATENT DOCUMENTS This patent is Subject to a terminal dis WO WO 2005/009 510 2, 2005 claimer. OTHER PUBLICATIONS International Search Report issued on Aug. 8, 2008 in application No. (21) Appl. No.: 12/848,792 PCT/IB2007/01983 (corresponding to US 7,795,309). Notice of Allowance issued on Apr. 29, 2010 by the Examiner in U.S. (22) Filed: Aug. 2, 2010 Appl. No. 12/281,561 (US 7,795,309). Office Action issued on Dec. 30, 2009 by the Examiner in U.S. Appl. (65) Prior Publication Data No. 12/281,561 (US 7,795,309). US 2011 FOO2846O A1 Feb. 3, 2011 Primary Examiner — Raymond Henley, III Related U.S. Application Data (74) Attorney, Agent, or Firm — Foley & Lardner LLP (63) Continuation-in-part of application No. 12/281,561, (57) ABSTRACT filed as application No. PCT/IB2007/001983 on Mar. It has been discovered that certain combinations compounds 6, 2007, now Pat. No. 7,795,309. are excellent penetration enhancers and, as such, can be incor porated in a topical formulation to facilitate administration of (60) Provisional application No. 60/778,847, filed on Mar. active agents. The increased penetration enhancement can 6, 2006. also lead to a reduction in the total concentration of skin irritants in the formulation. There is described herein a topical (51) Int. Cl. formulation comprising (i) at least one active agent; (ii) a first A6 IK3I/9 (2006.01) compound, and (iii) a second compound, wherein the first A 6LX3L/95 (2006.01) compound and second compound are different, and each is A6 IK3I/40 (2006.01) selected from the group consisting of N-lauroyl sarcosine, A6 IK3I/444 (2006.01) Sodium octyl sulfate, methyl laurate, isopropyl myristate, A6 IK3I/545 (2006.01) oleic acid, glyceryl oleate and sodium lauryl Sulfoacetate. (52) U.S. Cl...... 514/226.5: 514/334: 514/420; 514/557; 514/567 29 Claims, No Drawings US 8,343,962 B2 1. 2 TOPCAL FORMULATION the diffusion of molecules across the skin by, for example, disrupting the lipid bilayers of the stratum corneum. CROSS-REFERENCE TO RELATED Over 300 Substances have been identified as MPETMs but APPLICATIONS Surprisingly few have been Successfully developed into com mercial formulations. Many potent MPETMs are irritating to This application is a continuation in part of U.S. applica the cells of the epidermis which can limit both the choice and tion Ser. No. 12/281,561, filed on Jan. 12, 2009, now U.S. Pat. concentration of MPETMs suitable for topical formulations. No. 7,795,309, which is a national stage of PCT/IB2007/ Discovery of new MPETM's to increase skin permeability is 001983, filed on Mar. 6, 2007, which claims priority to U.S. highly desirable and has been an area of high activity over the Provisional Application No. 60/778,847, filed on Mar. 6, 10 last 30 years. However, the number of substances identified to 2006, the entire contents and disclosures of each of which are be penetration enhancers is still small relative to the more hereby incorporated by reference. than 25,000,000 substances identified in the CAS registry FIELD OF THE INVENTION (Chemical Abstracts Service, Columbus, Ohio, www.ca 15 S.orq). The present invention relates to a topical formulation of The number of candidate drugs suitable for topical and multiplexed molecular penetration enhancers. In a particu transdermal administration could be significantly increased larly preferred embodiment, the present invention relates to a with improved penetration enhancers. topical formulation of multiplexed molecular penetration One example of a commercialized formulation for use in enhancers for topical or transdermal administration of one or transdermal administration is described in U.S. Pat. No. more active ingredients such as a pharmaceutical agent. 4.575,515 Sandborn. Sandborn teaches a formulation that includes a medicine and dimethyl sulfoxide (DMSO), and DESCRIPTION OF THE PRIOR ART that purportedly allows for rapid and deep penetration of the medicine into the underlying tissue. Topical formulations for application to the skin can be 25 While the topical formulation taught by Sandborn repre useful in cosmetic applications, for treating conditions of the sents an advance in the art, there is room for improvement. upper skin layers and for transdermal administration of active For instance the formulation taught by Sandborn contains a agents to the local tissue underlying the skin or into the blood relatively high concentration of DMSO, which is known to for systemic distribution. Use of a topical formulation of for cause skin irritation. In particular there is a need for a topical instance, a pharmaceutical agent is advantageous in that it 30 formulation having improved flux of the active ingredient avoids firstpass metabolism, circumvents gastrointestinal through the skin as compared to the topical formulation (“GI) absorption, can allow delivery of an active ingredient taught by Sandborn. with a relatively short biological half-life and/or a narrow therapeutic window and facilitates uniform plasma dosing of SUMMARY OF THE INVENTION the active ingredient, and/or can improve user compliance. 35 In spite of the advantages, transdermal administration is It is an object of the present invention to provide a novel usually limited to about a dozen Small lipophilic drugs, avail topical formulation. able in transdermal patch format (including Scopolamine, It is another object of the present invention to provide a fentanyl, estradiol, nitroglycerine, nicotine and testosterone). novel topical formulation for topical or transdermal adminis Skin has evolved to impede the flux of exogenous mol 40 tration of an active agent. ecules So as to provide a strong barrier to molecular delivery, It is another object of the present invention to provide a particularly agents such as pharmaceutical agents. Transder topical formulation capable of providing improved fluxes of mal drug administration is difficult since skin is an excellent therapeutically active agents and other molecules through the diffusion barrier. skin as compared to the topical formulation taught by Sand Structurally, the skin consists of two principle parts: (i) a 45 born. relatively thin outermost layer (the epidermis), and (ii) a Accordingly, in one of its aspects, the present invention thicker inner region (the dermis). The outermost layer of the provides a topical formulation comprising: (i) at least one epidermis (the stratum corneum) consists of flattened dead active agent, (ii) a first compound, and (iii) a second com cells which are filled with keratin. The region between the pound, wherein the first compound and second compound are flattened dead cells of the stratum corneum is filled with lipids 50 different, and each is selected from the group of MPETMs which form lamellar phases. The highly impermeable nature consisting of N-lauroyl sarcosine, Sodium octyl sulfate, of skin is due primarily to the stratum corneum. The viable methyl laurate, isopropyl myristate, oleic acid, glyceryl ole epidermis underlying the stratum corneum is akin to other ate and sodium lauryl Sulfoacetate. living tissue. The dermis provides the skin's structural In another of its aspects, the present invention provides a strength as well as the nerve and vascular networks that Sup 55 topical formulation for use in topical or transdermal admin port the epidermis. istration of a Substance comprising: (i) at least one active Delivering an active agent into or through the skin in Suf agent, (ii) a first compound, (iii) a second compound, and (iv) ficient concentrations often requires some means for reducing a therapeutically acceptable carrier that is different from the the stratum corneum’s hindrance of penetration. A number of first compound and the second compound, wherein the first methods for lowering the stratum corneum’s barrier proper 60 compound and second compound are different, and each is ties have been developed, including electrically assisted tech selected from the group of MPETMs consisting of N-lauroyl niques such as iontophoresis or ultrasound, and bypassing the sarcosine, sodium octyl Sulfate, methyl laurate, isopropyl stratum corneum through microneedle arrays or ablation. myristate, oleic acid, glyceryl oleate and sodium lauryl Sul Molecular or chemical penetration enhancers provide an foacetate. effective and inexpensive means oftemporarily reducing skin 65 In yet another of its aspects, the present invention provides resistance to the passage of actives and other molecules. a topical formulation comprising a therapeutically active Molecular penetration enhancers or MPETM's can enhance agent, atherapeutically acceptable carrier and a skin penetra US 8,343,962 B2 3 4 tion enhancer, wherein the skin penetration enhancer consists pound are different, and each is selected from the group essentially of a mixture of N-lauroyl sarcosine and oleic acid. consisting essentially of N-lauroyl sarcosine, Sodium octyl Sulfate, methyl laurate, isopropyl myristate, oleic acid, glyc DETAILED DESCRIPTION OF THE PREFERRED eryl oleate and Sodium lauryl Sulfoacetate. EMBODIMENTS The preferred combinations of compounds that act as improved penetration enhancers include the following: The present invention provides a topical formulation that the first compound comprises N-lauroyl sarcosine and the may be used for the topical or transdermal administration of second compound comprises isopropyl myristate; at least one active agent. As used throughout this specifica the first compound comprises N-lauroyl sarcosine and the tion, the term transdermal” means in the broadest sense 10 second compound comprises oleic acid; through the skin. Further the terms transdermal and percu the first compound comprises sodium octyl sulfate and the taneous are used interchangeably throughout this specifica second compound comprises oleic acid; tion. the first compound comprises glyceryl oleate and the sec As used herein the term topical formulation refers to a ond compound comprises Sodium octyl sulfate; formulation that may be applied to skin or a mucosa. Topical 15 the first compound comprises glyceryl oleate and the sec formulations may, for example, be used to confer therapeutic ond compound comprises methyl laurate; benefit to a patient or cosmetic benefits to a consumer. Topical the first compound comprises sodium lauryl Sulfoacetate formulations can be used for both topical and transdermal and the second compound comprises methyl laurate; and administration of Substances. the first compound comprises sodium lauryl Sulfoacetate The term topical administration is used in its conven and the second compound comprises isopropyl tional sense to mean delivery of a Substance, such as a thera myristate. peutically active agent, to the skin or a localized region of the Preferably, the weight ratio of the first compound to the body. Topical administration of a drug may often be advan second compound is in the range of from about 1:9 to about tageously applied in, for example, the treatment of various 9:1. More preferably, the weight ratio of the first compound to skin disorders. 25 the second compound is in the range of from about 1:4 to The term transdermal administration is used to mean about 4:1. Even more preferably, the weight ratio of the first administration through the skin. Transdermal administration compound to the second compound is in the range of from is often applied where systemic delivery of an active is about 1:3 to about 3:1. Even more preferably, the weight ratio desired, although it may also be useful for delivering an active of the first compound to the second compound is in the range to tissues underlying the skin with minimal systemic absorp 30 of from about 1:2 to about 2:1. Most preferably, the weight tion. ratio of the first compound to the second compound is about The term penetration enhancer is used hereinto refer to an 1:1. agent that improves the transport of molecules such as an Preferably, the total concentration of the first compound active agent (e.g., a medicine) into or through the skin. Vari and the second compound is up to about 50 wt.% per unit ous conditions may occur at different sites in the body either 35 volume of the formulation. More preferably, the total concen in the skin or below creating a need to target delivery of tration of the first compound and the second compound is up compounds. For example, in products designed to produce to about 40 wt.% per unit volume of the formulation. Even artificial tans, delivery of dye substances into the stratum more preferably, the total concentration of the first compound corneum may be advantageous. A psoriasis treatment on the and the second compound is in the range of from about 1 to other hand may require delivery of therapeutic drug levels in 40 about to about 35 wt.% per unit volume of the formulation. deeper epidermal tissue. In a treatment for osteoarthritis, Even more preferably, the total concentration of the first delivery of the active agent into deeper underlying joint tissue compound and the second compound is in the range of from may be necessary to achieve therapeutic benefit. In yet other about 1 to about to about 30 wt.% per unit volume of the applications, for example in hormone replacement therapy, formulation. Even more preferably, the total concentration of delivery of drug to the systemic circulation may be an objec 45 the first compound and the second compound is in the range tive. Thus, a penetration enhancer may be used to assist in of from about 1 to about to about 25 wt.% per unit volume of the delivery of an active agent directly to the skin or under the formulation. Even more preferably, the total concentra lying tissue or indirectly to the site of the disease through tion of the first compound and the second compound is in the systemic distribution. A penetration enhancer may be a pure range of from about 1 to about to about 20 wt.% per unit Substance or may comprise a mixture of different chemical 50 volume of the formulation. Even more preferably, the total entities. In this specification the terms penetration enhancer. concentration of the first compound and the second com chemical penetration enhancer, molecular penetration pound is in the range of from about 1 to about to about 15 enhancer and MPETM are used interchangeably. wt.% per unit volume of the formulation. Even more prefer As used herein the term multiplexed molecular penetra ably, the total concentration of the first compound and the tion enhancers (“MMPETM) means a penetration enhancer 55 second compound is in the range of from about 1 to about to comprising two or more Substances wherein each of the two about 10 wt.% per unit volume of the formulation. Even more or more Substances is also penetration enhancer. preferably, the total concentration of the first compound and The present inventors have Surprisingly and unexpectedly the second compound is in the range of from about 1 to about discovered that certain combination of compounds are excel to about 7.5 wt.% per unit volume of the formulation. Even lent penetration enhancers and, as Such, can be incorporated 60 more preferably, the total concentration of the first compound in a topical formulation to facilitate administration of one or and the second compound is in the range of from about 1 to more active ingredients. The increased penetration enhance about to about 5 wt.% per unit volume of the formulation. ment can also lead to a reduction in the total concentration of Most preferably, the total concentration of the first com skin irritants in a formulation. pound and the second compound is in the range of from about The compounds acting as excellent penetration enhancers 65 2 to about to about 5 wt.% per unit volume of the formulation. are used in combination—i.e., two (or more) compounds are Within this most preferred embodiment, it can, in Some cases, selected from wherein the first compound and second com be preferable to have the total concentration of the first com US 8,343,962 B2 5 6 pound and the second compound in the range of from about 2 ceutically acceptable salts and Solvates thereof, and mixtures to about to about 4 wt.% per unit volume of the formulation. thereof. Preferably the phenethylamine is bupropion, or a In one aspect of the present invention, the at least one active pharmaceutically acceptable salt or Solvate thereof. Such as agent is an arylalkanoic acid, Such as an C-arylalkanoic acid. bupropion hydrochloride. The structure of bupropion, known As is known to a person skilled in the art, C-aryl alkanoic 5 to a person skilled in the art, is: acids are chemical compounds having the general structure of Formula I:

I 10 Air O

RI OH C 15 wherein Ar is an aryl group and R' is H or an alkyl group, wherein aryl includes aromatic and heteroaromatic groups In another aspect of the present invention, the at least one and alkyl includes acyclic and cyclic alkyl groups. The C-aryl active agent is a steroid, for example, Steroids that are hor alkanoic acid may be an anti-inflammatory drug Such as a mones, glucosteroids, androgens, adrenocortical steroids, non-steroidal anti-inflammatory drug (NSAID) or an analge anabolics, estrogens and/or progestin, specific examples of sic, specific examples of which are listed below. Preferably, which are listed below. As known to a person skilled in the art, the C-arylalkanoic acids is selected from the group consisting steroids are a class of compounds having as a core structure, of bromfenac, diclofenac, fenoprofen, flurbiprofen, ibupro 4 rings joined as shown in Formula III: fen, indomethacin, ketoprofen, ketorolac, naproxen, Sulindac and tolmetin, and pharmaceutically acceptable salts and Sol 25 vates thereofand mixtures thereof. Structures for these C-aryl III alkanoic acids, along with some common trade names, known to a person skilled in the art, are shown in Table 1. More preferably the C-arylalkanoic acid is selected from the group consisting of diclofenac, ibuprofen and ketoprofen, and phar 30 maceutically acceptable salts and Solvates thereof, and mix tures thereof. Other NSAIDs, that are not C-aryl alkanoic acids, as well as other compounds having antipyretic and analgesic actions are also included in the scope of the present wherein the carbon atoms are optionally substituted. Prefer invention. Examples of Such compounds include, acetami 35 ably the steroid is testosterone, or a pharmaceutically accept nophen (paracetamol), aspirin, celecoxib, diflunisal, etod able salt or solvate thereof. olac, etoricoxib, meclofenamic acid, mefenamic acid, Other suitable active agents include those in the class of meloxicam, nabumetone, Oxaprozin, piroxicam, Salsalate, COX-2 inhibitors such as celecoxib, rofecoxib, Valdecoxib, and rofecoxib. Structures for these compounds along with lumiracoxib, etoricoxib: Antifungals such as tolnaftate, Some common trade names, known to a person skilled in the 40 econazole, ciclopiroX; Antibiotics Such as clindamycin; Mus art, are shown in Table 2. culoskeletal agents such as dantrolene; Retinoids such as In another aspect of the present invention, the at least one isotretinoin; Antivirals such as acyclovir, Vasodilating agents active agent is a phenethylamine, for example, a phenethy Such as nitroglycerine, papaverine; Hormones and synthetic lamine that is an antidepressant, anti-anxiety agent, anticho Substitutes Such as androgens, estrogens, insulin; Opiate ago linergic agent, cholinergic, dopaminergic, stimulant, seroto 45 nist Such as fentanyl, oxycodone, hydromorphone; Local nin antiagonist, serotonin inhibitor, anti-emetic, Anaesthetics such as lidocaine, tocainide and mexiletine and antihistamine and/or antipsychotic, specific examples of butyl-para-aminobenzoate; Anti-inflammatories such as cor which are listed below. As is known to a person skilled in the ticosteroids; NMDA receptor antagonists such as ketamine, art, phenethylamines are chemical compounds having the dextromethorphan and amantadine. general core structure of Formula II: 50 Examples of other therapeutically active agents that may be used include the following: adrenergic agent, adrenocor tical steroid; adrenocortical Suppressant; aldosterone antago II nist; amino acid; anabolic; analeptic; analgesic; anesthetic; anorectic; anti-acne agent; anti-adrenergic; anti-allergic; 55 anti-amebic; anti-anemic; anti-anginal; anti-arthritic; anti asthmatic; anti-atherosclerotic; antibacterial; anticholin ergic; anticoagulant; anticonvulsant, antidepressant; antidia betic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; wherein the phenyl ring, ethylene chain and nitrogen can be antifibrinolytic; antifungal; antihemorrhagic; antihistamine; Substituted. The phenethylamine may be a psychoactive 60 antihyperlipidemia; antihypertensive; antihypotensive; anti agent that exerts its effect through a monoamine neurotrans infective; anti-inflammatory; antimicrobial; antimigraine; mitter system, for example dopamine, serotonin and/or nore antimitotic; antimycotic, antinauseant, antineoplastic, pinephrine receptors. Examples of phenethylamines, include, antineutropenic, antiparasitic; antiproliferative; antipsy for example, bupropion, amphetamine, hydroxyamphet chotic; antirheumatic; antiseborrheic; antisecretory; antis amine, dextroamphetamine, methamphetamine, ephedrine, 65 pasmodic; antithrombotic; antiulcerative; antiviral; appetite epinephrine, pseudoephedrine, dopamine, epinephrylborate, Suppressant; blood glucose regulator, bone resorption inhibi etafedrine, norepinephrine and oxidopamine, and pharma tor, bronchodilator; cardiovascular agent; cholinergic; US 8,343,962 B2 7 8 depressant; diagnostic aid; diuretic: dopaminergic agent; doxime; Anileridine: Anileridine Hydrochloride; Anilopam estrogen receptoragonist; fibrinolytic; fluorescentagent, free Hydrochloride; Anirolac, Antipyrine; Aspirin; Benoxapro oxygen radical Scavenger; gastric acid Suppressant, gas fen; Benzydamine Hydrochloride; Biciifadine Hydrochlo trointestinal motility effector, glucocorticoid; hair growth ride; Brifentanil Hydrochloride; Bromadoline Maleate; Bro stimulant; hemostatic; histamine H2 receptor antagonists; mfenac Sodium: Buprenorphine Hydrochloride; Butacetin: hormone; hypocholesterolemic; hypoglycemic, hypolipi Butixirate; Butorphanol; Butorphanol Tartrate; Carbam demic; hypotensive; imaging agent; immunizing agent; azepine; Carbaspirin Calcium; Carbiphene Hydrochloride: immunomodulator; immunoregulator; immunostimulant; Carfentanil Citrate: Ciprefadol Succinate; Ciramadol; Cira immunosuppressant, keratolytic; LHRHagonist; mood regu madol Hydrochloride; Clonixeril; Clonixin; Codeine; lator, mucolytic; mydriatic; nasal decongestant; neuromus 10 Codeine Phosphate: Codeine Sulfate; Conorphone Hydro cular blocking agent; neuroprotective; NMDA antagonist; chloride: Cyclazocine; Dexoxadrol Hydrochloride; Dex non-hormonal sterol derivative; plasminogenactivator, plate pemedolac; Dezocine; Diflunisal; Dihydrocodeine Bitartrate; let activating factorantagonist, platelet aggregation inhibitor, Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drin psychotropic; radioactive agent; scabicide; sclerosing agent; idene: Enadoline Hydrochloride: Epirizole; Ergotamine Tar sedative; sedative-hypnotic; selective adenosine Al antago 15 trate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; nist, serotonin antagonist; serotonin inhibitor, serotonin Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floc receptor antagonist; Steroid; thyroid hormone; thyroid inhibi tafenine: Flufenisal; Flunixin: Flumixin Meglumine: Flupir tor; thyromimetic, tranquilizer; amyotrophic lateral Sclerosis tine Maleate; FluproduaZone: Fluradoline Hydrochloride; agent; cerebral ischemia agent, Paget’s disease agent; Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: unstable angina agent; vasoconstrictor; vasodilator, wound Indoprofen; Ketazocine; Ketorfanol: Ketorolac healing agent; Xanthine oxidase inhibitor, and the like. Tromethamine: Letimide Hydrochloride; Levomethadyl Specific examples of pharmaceutical agents that may be Acetate; Levomethadyl Acetate Hydrochloride; Levonantra included within the present topical formulation, both alone or dol Hydrochloride; Levorphanol Tartrate; Lofemizole in combination, include but are not limited to: Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxi Adrenergic: Adrenalone; Amidephrine Mesylate; Apra 25 cam: Magnesium Salicylate; Mefenamic Acid; Menabitan clonidine Hydrochloride: Brimonidine Tartrate; Dapiprazole Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Deterenol Hydrochloride; Dipivefrin; Hydrochloride; Methadone Hydrochloride; Methadyl Dopamine Hydrochloride: Ephedrine Sulfate: Epinephrine; Acetate; Methopholine; Methotrimeprazine; Metkephamid Epinephrine Bitartrate: Epinephryl Borate; Esproduin Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphet 30 ride; MolinaZone: Morphine Sulfate; Moxazocine; Nabitan amine Hydrobromide: Levonordefrin; Mephentermine Sul Hydrochloride; Nalbuphine Hydrochloride; Nalmexone fate; Metaraminol Bitartrate; Metizoline Hydrochloride: Hydrochloride: Namoxyrate; Nantradol Hydrochloride: Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxi Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro dopamine: Oxymetazoline Hydrochloride; Phenylephrine chloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Phenylpropanolamine Hydrochloride; Phe 35 Hydrochloride; Ocfentanil Hydrochloride; Octazamide: nylpropanolamine Polistirex: Prenalterol Hydrochloride; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahy Hydrochloride: Oxycodone Terephthalate: Oxymorphone drozoline Hydrochloride; Tramazoline Hydrochloride; and Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; Xylometazoline Hydrochloride. Pentazocine Hydrochloride; Pentazocine Lactate; Adrenocortical steroid: Ciprocinonide; Desoxycorticos 40 Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo terone Acetate; Desoxycorticosterone Pivalate: Dexametha ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; sone Acetate: Fludrocortisone Acetate: Flumoxonide; Hydro Piroxicam Olamine; Pravadoline Maleate; Prodilidine cortisone Hemisuccinate; Methylprednisolone Hydrochloride; Profadol Hydrochloride; Propiram Fuma Hemisuccinate; Naflocort; Procinonide; Timobesone rate; Propoxyphene Hydrochloride; Propoxyphene Napsy Acetate; and Tipredane. 45 late: Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyr Adrenocortical Suppressant: Aminoglutethimide; and roliphene Hydrochloride; Remifentanil Hydrochloride; Trilostane. Salcolex: Salicylamide: Salicylate Meglumine; Salsalate: Alcohol deterrent: Disulfiram. Sodium Salicylate: Spiradoline Mesylate: Sufentanil; Sufen Aldosterone antagonist: Canrenoate Potassium, Can tanil Citrate; Talmetacin; Talniflumate; Talosalate; Tazad renone; Dicirenone; Mexrenoate Potassium; Prorenoate 50 olene Succinate; Tebufelone; Tetrydamine; Tifurac Sodium; Potassium; and Spironolactone. Tilidine Hydrochloride; Tiopinac; Tonazocine Mesylate: Tra Amino acid: Alanine; Arginine; Aspartic Acid; Carnitine; madol Hydrochloride; Trefentanil Hydrochloride; Trola Cysteine Hydrochloride: Cystine; Glycine: Histidine; Isoleu mine: Veradoline Hydrochloride: Verilopam Hydrochloride; cine; Leucine; Lysine; Lysine Acetate; Lysine Hydrochlo Volazocine: Xorphanol Mesylate; Xylazine Hydrochloride; ride; Methionine; Phenylalanine: Proline; Serine; Threonine: 55 Zomepirac Sodium; and Zucapsaicin. Tryptophan: Tyrosine; and Valine. Androgen: Fluoxymesterone; Mesterolone; Methyltest Ammonia detoxicant: Arginine Glutamate; and Arginine osterone; Nandrolone Decanoate; Nandrolone Phenpropi Hydrochloride. onate; Nisterime Acetate; Oxandrolone; Oxymetholone: Amyotrophic lateral Sclerosis agents: Riluzole Silandrone: Stanozolol; Testosterone; Testosterone Cypi Anabolic: Bolandiol Dipropionate; Bolasterone; Bold 60 onate; Testosterone Enanthate; Testosterone Ketolaurate; enone Undecylenate; Bolenol; Bolmantalate: Ethylestrenol; Testosterone Phenylacetate; Testosterone Propionate; Tres Methenolone Acetate; Methenolone Enanthate; Mibolerone; tolone Acetate. Nandrolone Cyclotate; Norbolethone; Pizotyline; Quin Anesthesia (adjunct to): Sodium Oxybate. bolone; Stenbolone Acetate; Tibolone; and Zeranol. Anesthetic: Aliflurane; Benoximate Hydrochloride; Ben Analeptic: Modafinil. 65 Zocaine; Biphenamine Hydrochloride; Bupivacaine Hydro Analgesic: Acetaminophen; Alfentanil Hydrochloride; chloride; Butamben; Butamben Picrate; Chloroprocaine Aminobenzoate Potassium; Aminobenzoate Sodium; Ani Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopro US 8,343,962 B2 10 pane; Desflurane; Dexivacaine; Diamocaine Cyclamate; Proroxan Hydrochloride; Solypertine Tartrate; Sotalol Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochlo Hydrochloride; Timolol; Timolol Maleate; Tiprenolol ride; Enflurane; Ether; Ethyl Chloride: Etidocaine; Etoxadrol Hydrochloride; Tolamolol; and Zolertine Hydrochloride. Hydrochloride; Euprocin Hydrochloride: Fluroxene; Hal Anti-allergic: Amlexanox; Astemizole, AZelastine Hydro othane; Isobutamben; Isoflurane; Ketamine Hydrochloride: chloride; EclaZolast; Minocromil Nedocromil Nedocromil Levoxadrol Hydrochloride; Lidocaine; Lidocaine Hydro Calcium; Nedocromil Sodium; Nivinedone Sodium; chloride; Mepivacaine Hydrochloride; Methohexital Pemirolast Potassium Pentigetide; Pirquinozol; Poisonoak Sodium; Methoxyflurane: Midazolam Hydrochloride: Mida Extract; Probicromil Calcium; Proxicromil: Repirinast: Tet Zolam Maleate; Minaxolone; Norflurane; Octodrine; Oxet razolast Meglumine; Thiazinamium Chloride; Tiacrilast; Tia hazaine; Phencyclidine Hydrochloride; Pramoxine Hydro 10 crilast Sodium; Tiprinast Meglumine; and TixanoX. chloride; Prilocaine Hydrochloride; Procaine Hydrochloride: Anti-amebic: Berythromycin; Bialamicol Hydrochloride; Propanidid; Proparacaine Hydrochloride; Propofol; Pro Chloroquine; Chloroquine Hydrochloride; Chloroquine poxycaine Hydrochloride; Pyrrocaine; Risocaine; Phosphate: Clamoxyquin Hydrochloride; Clioquinol; Emet Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane; Teflu ine Hydrochloride; Iodoquinol; Paromomycin Sulfate; Quin rane; Tetracaine; Tetracaine Hydrochloride; Thiamylal; Thia 15 famide: Symetine Hydrochloride; Teclozan; Tetracycline: mylal Sodium; Thiopental Sodium; Tiletamine Hydrochlo and Tetracycline Hydrochloride. ride; and Zolamine Hydrochloride. Anti-androgen: Benorterone; Cioteronel, Cyproterone Anorectic compound: Dexfenfluramine. Acetate; Delmadinone Acetate; Oxendolone; Topterone; and Anorexic agents: Aminorex: Amphecloral; Chlorphenter Zanoterone. mine Hydrochloride; Clominorex: Clortermine Hydrochlo Anti-anemic: Epoetin Alfa: Epoetin Beta; Ferrous Sulfate, ride; Diethylpropion Hydrochloride; Fenfluramine Hydro Dried; and Leucovorin Calcium. chloride; Fenisorex: Fludorex: Fluminorex; Levamfetamine Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; Succinate; Mazindol; Mefenorex Hydrochloride; Phemnetra Betaxolol Hydrochloride; Bevantolol Hydrochloride; Buto zine Hydrochloride; Phentermine; and Sibutramine Hydro prozine Hydrochloride; Carvedilol; Cinepazet Maleate; chloride. 25 Metoprolol Succinate; Molsidomine; Monatepil Maleate; Antagonist: Atipamezole; Atosiban; Bosentan, Cimeti Primidolol; Ranolazine Hydrochloride; Tosifen; and Vera dine: Cimetidine Hydrochloride; Clentiazem Maleate; pamil Hydrochloride. Detirelix Acetate; Devazepide; Donetidine: Etintidine Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Hydrochloride; Famotidine: Fenmetozole Hydrochloride: Binospirone Mesylate: Bretazenil; Glemanserin; Ipsapirone Flumazenil; Icatibant Acetate; Icotidine; Isradipine; Metia 30 Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron mide: Nadide; Nalmefene; Naloxone Hydrochloride; Naltr Hydrochloride; Panadiplon; Pancopride; Pazinaclone: exone; Nilvadipine; Oxilorphan: Oxmetidine Hydrochloride: Serazapine Hydrochloride; Tandospirone Citrate; and Oximetidine Mesylate; Quadazocine Mesylate; Ranitidine: Zalospirone Hydrochloride. Ranitidine Bismuth Citrate; Ranitidine Hydrochloride; Sufo Anti-arthritic: Lodelaben. tidine; Teludipine Hydrochloride; Tiapamil Hydrochloride; 35 Anti-asthmatic: Ablukast; Ablukast Sodium: Bunaprolast; Tiotidine: Vapiprost Hydrochloride; and Zaltidine Hydro Cinalukast; Cromitrile Sodium; Cromolyn Sodium; chloride. Enofelast; Isamoxole; Ketotifen Fumarate; Levcromakalim, Anterior pituitary activator: Epimestrol. Lodoxamide Ethyl; Lodoxamide Tromethamine; Mon Anterior pituitary Suppressant: Danazol. telukast Sodium; Ontazolast: Oxarbazole; Oxatomide; Pir Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; 40 iprost; Piriprost Potassium; Pirolate: Pobilukast Edamine: Bunamidine Hydrochloride: Butonate; Cambendazole; Car QuaZolast; Ritolukast; Sulukast; Tiaramide Hydrochloride: bantel Lauryl Sulfate; Clioxanide; Closantel: Cyclobenda Tibenelast Sodium; Tomelukast; Tranilast; Verlukast; and Zole; Dichlorvos; Diethylcarbamazine Citrate; Dribendazole; Verofylline Zarirlukast. Dymanthine Hydrochloride: Etibendazole: Fenbendazole; Anti-atherosclerotic: Mifobate; and Timefuronc. Furodazole: Hexylresorcinol; Mebendazole; Morantel Tar 45 Antibacterial: Acedapsone; Acetosulfone Sodium; Alame trate; Niclosamide: Nitramisole Hydrochloride; Nitrodan; cin; Alexidine: Amdinocillin; Amdinocillin Pivoxil; Amicy Oxantel Pamoate; Oxfendazole; Oxibendazole; Parbenda cline; Amifioxacin; Amifloxacin Mesylate; Amikacin; Ami Zole; Piperamide Maleate; Piperazine: Piperazine Citrate; kacin Sulfate; Aminosalicylate sodium; Aminosalicylic acid; Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate: Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilba 50 Apalcillin Sodium; Apramycin; Aspartocin, Astromicin Sul Zium Iodide; Tetramisole Hydrochloride; Thiabendazole; fate; A villamycin; A Voparcin, Azithromycin; AZlocillin; Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos: Azlocillin Sodium; Bacampicillin Hydrochloride: Bacitra and Zilantel. cin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Anti-acne: Adapalene; Erythromycin, Salnacedin, and Bambermycins; Benzoylpas Calcium: Betamicin Sulfate: Inocoterone Acetate. 55 Biapenem; Biniramycin; Bispyrithione Magsulfex; Butika Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride: cin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Car Atenolol; Bretylium Tosylate; Bunolol Hydrochloride; Car benicillin Disodium; Carbenicillin Indanyl Sodium; Carbe teolol Hydrochloride: Celiprolol Hydrochloride; Cetamolol nicillin Phenyl Sodium; Carbenicillin Potassium; Hydrochloride: Cicloprolol Hydrochloride; Dexpropranolol Carumonam Sodium; Cefaclor, Cefadroxil, Cefamandole; Hydrochloride; Diacetolol Hydrochloride; Dihydroergota 60 Cefamandole Nafate; Cefamandole Sodium; Cefaparole; mine Mesylate; Dilevalol Hydrochloride; Esmolol Hydro Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin chloride; Exaprolol Hydrochloride: Fenspiride Hydrochlo Sodium; Cefbuperazone; Cefdinir, Cefepime; Cefepime ride; Flestolol Sulfate; Labetalol Hydrochloride; Hydrochloride; Cefetecol; Cefixime; Cefnmenoxime Hydro Levobetaxolol Hydrochloride; Levobunolol Hydrochloride: chloride; Cefnetazole; Cefnmetazole Sodium; Cefonicid Metalol Hydrochloride; Metoprolol; Metoprolol Tartrate; 65 Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Nadolol; Pamatolol Sulfate; Penbutolol Sulfate; Phentola Ceforanide; Cefotaxime Sodium; Cefotetan: Cefotetan Diso mine Mesylate; Practolol; Propranolol Hydrochloride; dium; Cefotiam Hydrochloride: Cefoxitin: Cefoxitin US 8,343,962 B2 11 12 Sodium; Ce?pimizole; Ce?pimizole Sodium; Ce?piramide: Pyrazinamide: Pyrithione Zinc: Quindecamine Acetate; Ce?piramide Sodium; Ce?pirome Sulfate; Cefpodoxime Quinupristin: Racephenicol; Ramoplanin; Ranimycin; Relo Proxetil: Cefprozil; Cefroxadine; Cefsulodin Sodium; mycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rifa Ceftazidime; Ceftibuten; Ceftiroxime Pivoxetil: Ceftizoxime mide; Rifampin; Rifapentine; Rifaximin: Rolitetracycline; Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Axetil: Cefuroxime Sodium; Cephacetrile Sodium; Cephal Butyrate; Rosaramicin Propionate; Rosaramicin Sodium exin; Cephalexin Hydrochloride; Cephaloglycin; Cephalori Phosphate; Rosaramicin Stearate; Rosoxacin; Roxarsone; dine; Cephalothin Sodium; Cephapirin Sodium; Cephradine: Roxithromycin; Sancycline: Sanfetrinem Sodium; Sarmox Cetocycline Hydrochloride; Cetophenicol; Chlorampheni icillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sul col; Chloramphenicol Palmitate; Chloramphenicol Pantoth 10 fate; Sparfloxacin; Spectinomycin Hydrochloride; Spiramy enate Complex: Chloramphenicol Sodium Succinate; Chlo rhexidine Phosphanilate; Chloroxylenol; Chlortetracycline cin; Stallimycin Hydrochloride; Steffimycin; Streptomycin Bisulfate; Chlortetracycline Hydrochloride: Cinoxacin: Sulfate: Streptonicozid; Sulfabenz; Sulfabenzamide: Sulfac Ciprofloxacin: Ciprofloxacin Hydrochloride: Cirolemycin; etamide: Sulfacetamide Sodium; Sulfacytine; Sulfadiazine: Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; 15 Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamera Clindamycin Hydrochloride; Clindamycin Palmitate Hydro Zine; Sulfameter; Sulfamethazine; Sulfamethizole; Sul chloride; Clindamycin Phosphate; Clofazimine; Cloxacillin famethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfa Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate nilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole; Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Sodium; Cyclacillin: Cycloserine; Dalfopristin; Dapsone; Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem: Daptomycin; Demeclocycline; Demeclocycline Hydrochlo Sultamicillin; Suncillin Sodium; Talampicillin Hydrochlo ride; Demecycline; Denofungin: Diaveridine; Dicloxacillin; ride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipy Tetracycline Phosphate Complex; Tetroxoprim; Thiampheni rithione; Dirithromycin; Doxycycline; Doxycycline Cal col; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; cium; Doxycycline Fosfatex: Doxycycline Hyclate; Droxa 25 Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; cin Sodium: Enoxacin; Epicillin: Epitetracycline Tiodonium Chloride; Tobramycin; Tobramycin Sulfate: Hydrochloride; Erythromycin; Erythromycin Acistrate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisul Erythromycin Estolate; Erythromycin Ethylsuccinate; Eryth fapyrimidines; Troleandomycin; Trospectomycin Sulfate; romycin Gluceptate; Erythromycin Lactobionate; Erythro Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Vir mycin Propionate; Erythromycin Stearate; Ethambutol 30 giniamycin; and Zorbamycin. Hydrochloride; Ethionamide: Fleroxacin; Floxacillin: Flu Anti-cancer Supplementary potentiating agents: Amitryp dalanine: Flumequine; F osfomycin; F osfomycin tyline: Amoxapine: Amphotericin B; Antiarrhythmic drugs Tromethamine; Fumoxicillin; Furazolium Chloride; Furazo (e.g., Quinidine); Antihypertensive drugs (e.g., Reserpine); lium Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin Ca++ antagonists (e.g., Verapamil; Calmodulin inhibitors Sulfate: Gloximonam; Gramicidin; Haloprogin: Hetacillin; 35 (e.g., Prenylamine; Caroverine); Citalopram); Clomi Hetacillin Potassium: Hexedine: Ibafloxacin: Imipenem: pramine; Clomipramine); Desipramine; Doxepin; Mapro Isepamicin; Isoconazole; Isoniazid; Josamycin; Kanamycin tiline); Nifedipine; Nitrendipine: Non-tricyclic anti-depres Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin sant drugs (e.g., Sertraline; Nortriptyline: Protriptyline: Potassium; Lexithromycin; Lincomycin; Lincomycin Sulfoximine) and Multiple Drug Resistance reducing agents Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochlo 40 such as Cremaphor EL: Thiol depleters (e.g., Buthionine: ride; Lomefloxacin Mesylate: Loracarbef: Mafenide; Meclo Trazodone; Tricyclic anti-depressant drugs (e.g., Imi cycline; Meclocycline Sulfosalicylate; Megalomicin Potas pramine; Trifluoroperazine; Trimipramine; and Triparanol sium Phosphate; Mequidox: Meropenem; Methacycline: analogues (e.g., Tamoxifen). Methacycline Hydrochloride; Methenamine; Methenamine Anticholelithic: Monoctanoin. Hippurate; Methenamine Mandelate; Methicillin Sodium; 45 Anticholelithogenic: Chenodiol; Ursodiol. Metioprim; Metronidazole Hydrochloride; Metronidazole Anticholinergic: Alverinc Citrate; Anisotropine Methyl Phosphate: Mezlocillin: Mezlocillin Sodium; Minocycline: bromide: Atropine; Atropine Oxide Hydrochloride; Atropine Minocycline Hydrochloride; Mirincamycin Hydrochloride: Sulfate; Belladonna; Benapryzine Hydrochloride; Benzetim Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate ide Hydrochloride; Benzilonium Bromide: Biperiden; Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomy 50 Biperiden Hydrochloride; Biperiden Lactate; Clidinium Bro cin Palmitate; Neomycin Sulfate; Neomycin Undecylenate: mide: Cyclopentolate Hydrochloride; Dexetimide: Dicyclo Netilmicin Sulfate; Neutramycin; Nifarthiazole; Nifuradene: mine Hydrochloride; Dihexyverine Hydrochloride; Domazo Nifuraldezone; Nifuratel; Nifuratrone; Nifurdazil; Nifurim line Fumarate; Elantrine; Elucaine; Ethybenztropine; ide: Nifurpirinol; Nifurcquinazol; Nitrocycline; Nitrofuran Eucatropine Hydrochloride; Glycopyrrolate: Heteronium toin: Nitromide: Norfloxacin; Novobiocin Sodium; Ofloxa 55 Bromide: Homatropine Hydrobromide: Homatropine Meth cin: Onnetoprim; Oxacillin Sodium; Oximonam: Oximonam ylbromide: Hyoscyamine: Hyoscyamine Hydrobromide: Sodium; Oxolinic Acid: Oxytetracycline; Oxytetracycline Hyoscyamine Sulfate; Isopropamide Iodide; Mepenzolate Calcium: Oxytetracycline Hydrochloride; Paldimycin; Bromide: Methylatropine Nitrate; Metoquizine; Oxybutynin Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Chloride; Parapenzolate Bromide: Pentapiperium Methylsul Mesylate; Penamecillin: Penicillin G Benzathine; Penicillin 60 fate; Phencarbamide: Poldine Methylsulfate; Proglumide: G Potassium; Penicillin G Procaine; Penicillin G Sodium; Propantheline Bromide: Propenzolate Hydrochloride: Sco Penicillin V: Penicillin V Benzathine; Penicillin V Hydrab polamine Hydrobromide: Tematropium Methylsulfate; amine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Tiquinamide Hydrochloride; Tofenacin Hydrochloride: Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Toquizine; Triampyzine Sulfate; Trihexyphenidyl Hydro Piridicillin Sodium; Pirlimycin Hydrochloride: Pivampicillin 65 chloride; and Tropicamide. Hydrochloride: Pivampicillin Pamoate: Pivampicillin Anticoagulant: Ancrod; Ardeparin Sodium, Bivalirudin; Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin: Bromindione; Dalteparin Sodium Desirudin; Dicumarol; US 8,343,962 B2 13 14 Lyapolate Sodium; Nafamo.stat Mesylate; Phenprocoumon; Isophane; Insulin, Neutral; Linogliride; Linogliride Fuma Tinzaparin Sodium; and Warfarin Sodium. rate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium; Anticoccidal: Maduramicin. Pioglitazone Hydrochloride; Pirogliride Tartrate; Proinsulin Anticonvulsant: Albutoin: Ameltolide; Atolide; Buramate; Human; Seglitide Acetate; Tolazamide: Tolbutamide: Tolpyr Cinromide: Citenamide: Clonazepam; Cyheptamide; Dezi ramide; TroglitaZone; and Zopolrestat. namide: Dimethadione; Divalproex Sodium: Eterobarb: Antidiarrheal: Diphenoxylate Hydrochloride; Methyl Ethosuximide: Ethotoin: Flurazepam Hydrochloride: Fluzi prednisolone; Metronidazole; and Rolgamidine. namide; Fosphenytoin Sodium; Gabapentin; Ilepcimide; Antidiuretic: Argipressin Tannate; Desmopressin Acetate; Lamotrigine; Magnesium Sulfate; Mephenytoin: Mephobar and Lypressin. bital; Methetoin: Methsuximide: Milacemide Hydrochloride; 10 Antidote: Dimercaprol; Edrophonium Chloride; Fomepi Nabazenil; Nafimidone Hydrochloride; Nitrazepam; Phena Zole; Levoleucovorin Calcium; Methylene Blue; and Prota cemide; Phenobarbital; Phenobarbital Sodium; Phensuxim mine Sulfate. ide; Phenytoin: Phenytoin Sodium; Primidone; Progabide: Antidyskinetic: Selegiline Hydrochloride. Ralitoline: Remacemide Hydrochloride; Ropizine; Sabelu Anti-emetic: Alosetron Hydrochloride: Batanopride Zole: Stiripentol; Sulthiame: Topiramate; Trimethadione: 15 Hydrochloride: Bemesetron; Benzquinamide: Chlorprom Valproate Sodium; Valproic Acid; Vigabatrin: Zoniclezole azine; Chlorpromazine Hydrochloride; Clebopride: Cycliz Hydrochloride; and Zonisamide. ine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Antidepressant: Adinazolam, Adinazolam Mesylate; Ala Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate: proclate; Aletamine Hydrochloride; Amedalin Hydrochlo Domperidone; Dronabinol; Flumeridone; Galdansetron ride; Amitriptyline Hydrochloride: Aptazapine Maleate; Aza Hydrochloride; Granisetron; Granisetron Hydrochloride: loxan Fumarate; Azepindole: Azipramine Hydrochloride: Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopra Bipenamol Hydrochloride; Bupropion Hydrochloride: mide Hydrochloride; Metopimazine: Prochlorperazine; Butriptyline Hydrochloride; Caroxazone; Cartazolate: Prochlorperazine Edisylate: Prochlorperazine Maleate; Ciclazindol; Cidoxepin Hydrochloride: Cilobamine Mesy Promethazine Hydrochloride; Thiethylperazine. Thiethylp late; Clodazon Hydrochloride; Clomipramine Hydrochlo 25 erazine Malate: Thiethylperazine Maleate; Trimethobenza ride; Cotinine Fumarate; Cyclindole: Cypenamine Hydro mide Hydrochloride; and Zacopride Hydrochloride. chloride; Cyprolidol Hydrochloride; Cyproximide: Anti-epileptic: Felbamate; Iamotrigine; LorecleZole; and Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Tolgabide. Maleate; Dazepinil Hydrochloride: Desipramine Hydrochlo Anti-estrogen: Clometherone; Nafoxidine Hydrochloride; ride; Dexamisole; Deximafen; Dibenzepin Hydrochloride; 30 Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Dox Citrate; Toremifene Citrate; and Trioxifene Mesylate. epin Hydrochloride: Duloxetine Hydrochloride: Eclanamine Antifibrinolytic: Nafamostat Mesylate. Maleate; Encyprate; Etoperidone Hydrochloride; Fantridone Antifungal: Acrisorcin; Ambruticin; AZaconazole; AZaser Hydrochloride: Fenmetramide; Fezolamine Fumarate: Flu ine; Basifungin: Bifonazole; Butoconazole Nitrate; Calcium otracen Hydrochloride: Fluoxetine: Fluoxetine Hydrochlo 35 Undecylenate; Candicidin; Carbol-Fuchsin; Chlordantoin: ride; Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Ciclopirox: Ciclopirox Olamine: Cilofungin: Cisconazole; Sulfate: Imafen Hydrochloride: Imiloxan Hydrochloride: Clotrimazole; Cuprimyxin; Doconazole; Econazole; Econa Imipramine Hydrochloride; Indeloxazine Hydrochloride: Zole Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Intriptyline Hydrochloride; Iprindole: Isocarboxazid: Nitrate: Filipin: Fluconazole: Flucytosine; Fungimycin; Ketipramine Fumarate; Lofepramine Hydrochloride; Lorta 40 Griseofulvin; Hamycin, Itraconazole; Kalafungin; Keto lamine: Maprotiline: Maprotiline Hydrochloride; Melitracen conazole; Lomoftmgin; Lydimycin; Mepartricin; Micona Hydrochloride; Minaprine Hydrochloride; Mirtazapine; Zole; Miconazole Nitrate; Monensin; Monensin Sodium; Moclobemide: Modaline Sulfate; Napactadine Hydrochlo Naftifine Hydrochloride; Nifuratel Nifurmerone; ride; Napamezole Hydrochloride: Nefazodone Hydrochlo Nitralamine Hydrochloride; Nystatin; Octanoic Acid; ride; Nisoxetine; Nitrafudam Hydrochloride: Nomifensine 45 Orconazole Nitrate; Oxiconazole Nitrate; Oxifungin Hydro Maleate; Nortriptyline Hydrochloride; Octriptyline Phos chloride; Parconazole Hydrochloride; Partricin; Potassium phate; Opipramol Hydrochloride: Oxaprotiline Hydrochlo Iodide: Pyrrolnitrin; Rutamycin; Sanguinarium Chloride: ride; Oxypertine: Paroxetine; Phenelzine Sulfate; Piran Saperconazole; Selenium Sulfide: Sinefungin: Sulconazole damine Hydrochloride; Pride fine Hydrochloride; Prolintane Nitrate; Terbinafine; Terconazole; Thiram; Tioconazole; Tol Hydrochloride; Protriptyline Hydrochloride; Quipazine 50 ciclate: Tolindate; Tolnaftate; Triacetin; Triafungin: Unde Maleate; Rolicyprine; Seproxetine Hydrochloride; Sertraline cylenic Acid; Viridofulvin; Zinc Undecylenate; and Hydrochloride; Sulpiride; Suritozole; Tametraline Hydro Zinoconazole Hydrochloride. chloride; Tampramine Fumarate; Tandamine Hydrochloride: Antiglaucoma agent: AlprenoXime Hydrochloride; Col Thiazesim Hydrochloride; Thozalinone; Tomoxetine Hydro forsin; Dipivefrin Hydrochloride; Naboctate Hydrochloride: chloride; Trazodone Hydrochloride; Trebenzomine Hydro 55 Pilocarpine; and Pirnabine. chloride; Trimipramine Maleate; Venlafaxine Hydrochloride: Antihemorrhagic: Poliglusam. Viloxazine Hydrochloride; Zimeldine Hydrochloride; and Antihemorrheologic: Phentoxifylline. Zometapine. Antihistaminic: Acrivastine; Antazoline Phosphate; AZata Antidiabetic: Acetohexamide; Buformin; Butoxamine dine Maleate; Barmastine; Bromodiphenhydramine Hydro Hydrochloride; Camighbose; Chlorpropamide: Ciglitazone: 60 chloride; Brompheniramine Maleate; Carbinoxamine Male Englitazone Sodium: Etoformin Hydrochloride; Gliamilide; ate; Cetirizine Hydrochloride; Chlorpheniramine Maleate; Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide: Chlorpheniramine Polistirex: Cirmarizine; Clemastine: Glucagon; Glyburide; Glyhexamide: Glymidine Sodium; Clemastine Fumarate; Closiramine Aceturate; Cycliramine Glyoctamide; Glyparamide; Insulin; Insulin Human; Insulin Maleate; Cyclizine; Cyproheptadine Hydrochloride; Dex Human Zinc, Insulin Human Zinc, Extended; Insulin Human, 65 brompheniramine Maleate; Dexchlorpheniramine Maleate; Isophane; Insulin Lispro: Insulin Zinc, Insulin Zinc, Dimethindene Maleate; Diphenhydramine Citrate; Diphen Extended; Insulin Zinc, Prompt; Insulin, Dalanated; Insulin, hydramine Hydrochloride; Dorastine Hydrochloride; Doxy US 8,343,962 B2 15 16 lamine Succinate; Ebastine; Fexofenadine HCl, Levocabas Pentisomicin; Protease inhibitors of HIV and other retrovi tine Hydrochloride; Loratadine: Mianserin Hydrochloride; ruses; and Sarafloxacin Hydrochloride. Noberastine; Orphenadrine Citrate; Pyrabrom: Pyrilamine Anti-infective (topical): Alcohol; Aminacrine Hydrochlo Maleate: Pyroxamine Maleate; Rocastine Hydrochloride: ride; Benzethonium Chloride; Bithionolate Sodium; Bro Rotoxamine: Tazifylline Hydrochloride; Temelastine; Ter mchlorenone; Carbamide Peroxide; Cetalkonium Chloride; fenadine: Tripelennamine Citrate; Tripelennamine Hydro Cetylpyridinium Chloride; Chlorhexidine Hydrochloride: chloride; and Triprolidine Hydrochloride. Domiphen Bromide: Fenticlor: Fludazonium Chloride: Antihyperlipidemic: Cholestyramine Resin; Clofibrate; Fuchsin, Basic; Furazolidone; Gentian Violet; Halquinols: Colestipol Hydrochloride: Crilvastatin; Dalvastatin: Dex Hexachlorophene; Hydrogen Peroxide: Ichthammol: Imide trothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Lec 10 imibide; Lovastatin; Niacin; Pravastatin Sodium; Probucol; cyl Iodine: Iodine: Isopropyl Alcohol; Mafenide Acetate; Simvastatin; Tiqueside; and Xenbucin. Meralein Sodium; Mercufenol Chloride; Mercury, Ammoni Antihyperlipoproteinemic: Acifran; Beloxamide: Bezafi ated; Methylbenzethonium Chloride; Nitrofarazone: brate; Boxidine; Cetaben Sodium: Ciprofibrate; Gemcadiol; Nitromersol; Octenidine Hydrochloride: Oxychlorosene: Halofenate; Lifibrate; Meglutol; Nafenopin: Pimetine 15 Oxychlorosene Sodium; Parachlorophenol, Camphorated: Hydrochloride; Theofibrate; Tibric Acid; and Treloxinate. Potassium Permanganate; Povidone-Iodine; Sepazonium Antihypertensive: Alfuzosin Hydrochloride: Alipamide: Chloride; Silver Nitrate; Sulfadiazine, Silver: Symclosene: Althiazide; Amiquinsin Hydrochloride; Anaritide Acetate; Thimerfonate Sodium; Thimerosal; and Troclosene Potas Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol sium. Mesylate; Bendroflumethiazide; Benzthiazide: Bethanidine Anti-inflammatory: Alclofenac; Alclometasone Dipropi Sulfate; Biclodil Hydrochloride; Bisoprolol; Bisoprolol onate; Algestone Acetonide; Alpha Amylase; Amcinafal; Fumarate; Bucindolol Hydrochloride; Bupicomide: Buthiaz Amcinafide: Amfenac Sodium; Amiprilose Hydrochloride; ide: Candoxat rilat; Candoxatril; Captopril; Ceronapril; Anakinra, AnitraZafen; Apazone; Balsalazide Disodium; Chlorothiazide Sodium: Cicletanine: Cilazapril; Clonidine: Bendazac, Bromelains; Broperamole; Budesonide; Carpro Clonidine Hydrochloride; Clopamide: Cyclopenthiazide: 25 fen: Cicloprofen; Cintazone; Cliprofen; Clobetasol Propi Cyclothiazide: Darodipine; Debrisoquin Sulfate; Delapril onate; Clobetasone Butyrate; Clopirac; Cloticasone Propi Hydrochloride; Diapamide: Diazoxide; Diltiazem Hydro onate; Cormethasone Acetate; Cortodoxone; Deflazacort; chloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate: Desonide; DeSoximetasone; Dexamethasone Dipropionate; Ecadotril: Enalapril Maleate; Enalaprilat; Enalkiren: Diclofenac Potassium; Diclofenac Sodium; Diflorasone Endralazine Mesylate: Epithiazide: Eprosartan; Eprosartan 30 Diacetate; Diflumidone Sodium; Difluprednate; Diftalone: Mesylate: Fenoldopam Mesylate: Flavodilol Maleate; Flo Dimethyl Sulfoxide: Drocinonide; Endrysone; Enlimomab: rdipine: Flosequinan; Fosinopril Sodium; Fosinoprilat; Gua Enolicam Sodium; Etodolac; Felbinac; Fenamole: Fenbufen; nabenz: Guanabenz, Acetate; Guanacline Sulfate; Guanadrel Fenclofenac; Fenclorac: Fendosal: Fenpipalone: Fentiazac: Sulfate; Guancvdine; Guanethidine Monosulfate; Guanethi Flazalone; Fluazacort; Flufenamic Acid, Flumizole; dine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sul 35 Flunisolide Acetate: Fluocortin Butyl; Fluorometholone fate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guan Acetate; FluquaZone: Fluretofen; Fluticasone Propionate; oxabenz: Guanoxan Sulfate; GuanoXVfen Sulfate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propi Hydralazine Hydrochloride; Hydralazine Polistirex; Hydrof onate; Halopredone Acetate; Ibuprofen; Ibuprofen Alumi lumethiazide; Indacrinone Indapamide; Indolapril Hydro num; Ibuprofen Piconol; Ilonidap: Indomethacin Sodium; chloride; Indoramin; Indoramin Hydrochloride; Indorenate 40 Indomethacin; Indoprofen Indoxole: Intrazole; Isoflupredone Hydrochloride; Lacidipine; Leniquinsin; Lisinopril; Lofexi Acetate; Isoxepac: Isoxicam, Ketoprofen; Lomoxicam, dine Hydrochloride; Losartan Potassium; Losulazine Hydro Loteprednol Etabonate; Meclofenamate Sodium; Meclofe chloride; Mebutamate; Mecamylamine Hydrochloride: namic Acid; Meclorisonc Dibutyrate; Mesalamine; Mesecla Medroxalol; Medroxalol Hydrochloride; Methalthiazide Zone: Methylprednisolone Suleptanate; Morniflumate: Methyclothiazide Methyldopa; Methyldopate Hydrochlo 45 Nabumetone; Nimazone; Olsalazine Sodium; Orgotein; ride; Metipranolol; Metolazone Metoprolol Fumarate; Mety Orpanoxin: Oxaprozin: Oxyphenbutazone; Paranyline rosine; Minoxidil; Muzolimine; Nebivolol; Nifidipine; Ofor Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone nine: Pargyline Hydrochloride; Pazoxide: Pelanserin Sodium Glycerate; Piroxicam; Piroxicam Cinnamate; Pirpro Hydrochloride; Perindopril Erbumine; Phenoxybenzamine fen; Prednazate; Prednisolone Sodium Phosphate: Prifelone: Hydrochloride; Pinacidil: Pivopril; Polythiazide; Prazosin 50 Prodolic Acid; ProquaZone; Rimexolone; Romazarit; Sal Hydrochloride; Prizidilol Hydrochloride; Quinapril Hydro nacedin; SeclaZone; Sermetacin; Sudoxicam, Sulindac; chloride; Quinaprilat; Quinazosin Hydrochloride; Quinelo Suprofen; Talniflumate; Tenidap: Tenidap Sodium; Tenoxi rane Hydrochloride: Quinpirole Hydrochloride; Quinuclium cam; Tesicam, Tesimide; Tixocortol Pivalate; Tolimetin; Tol Bromide: Ramipril; Rauwolfia Serpentina; Reserpine; metin Sodium; Triclonide; Triflumidate; and Zidometacin. Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprus 55 Antikeratinizinq agent: Doretinel; Linarotene; and Pelre side; Sulfinalol Hydrochloride; Tasosartan; Temocapril tin. Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tia Antimalarial: Amodiaquine Hydrochloride; Amquinate; menidine; Tiamenidine Hydrochloride; Ticrynafen; Tinab Artefiene; Chloroquine; Chloroquine Hydrochloride; inol; TiodaZosin; Tipentosin Hydrochloride; Trichlormethi Cycloguanil Pamoate; Enpiroline Phosphate: Halofantrine azide; Trimazosin Hydrochloride; Trimethaphan Camsylate: 60 Hydrochloride; Hydroxychloroquine Sulfate; Mefloquine Trimoxamine Hydrochloride; Tripamide; Xipamide: Hydrochloride; Menoctone; Primaquine Phosphate: Zankiren Hydrochloride; and Zofenoprilat Arginine. Pyrimethamine; Quinine Sulfate; and Tebuduine. Antihypotensive: Ciclafrine Hydrochloride; and Mido Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imi drine Hydrochloride. durea; Lycetamine; Nibroxane: PiraZmonam Sodium; Propi Anti-infective: Acyclovir; Difloxacin Hydrochloride; Inte 65 onic Acid; Pyrithione Sodium; and Tigemonam Dicholine. grase Inhibitors of HIV and other retroviruses: Lauryl Iso Antimigraine: Naratriptan Hydrochloride: Sergolexole quinolinium Bromide; Moxalactam Disodium: Ornidazole; Maleate: Sumatriptan Succinate; and Zatosetron Maleate. US 8,343,962 B2 17 18 Antimitotic: Podofilox. Antagonist D: Antagonist G.; Antarelix; Antiandrogen, Pros Antimycotic: Amorolfine. tatic Carcinoma; Anti-Dorsalizing Morphogenetic Protein-I; Antinauseant: Buclizine Hydrochloride; and Cyclizine Antiestrogen; Antineoplaston; Antisense Oligonucleotides; Lactate. Aphidicolin Glycinate; Apoptosis Gene Modulators: Apop Antineoplastic: Acivicin; Aclarubicin; Acodazole Hydro tosis Regulators: Apurinic Acid; Ara-CDP-DL-PTBA: Argi chloride; Acronine; Adozelesin; Aldesleukin; Altretamine; nine Deaminase; ASulacrine; Atamestane; Atrimustine: Axi Ambomycin; Ametantrone Acetate; Amsacrine; AnastroZole; nastatin 1: Axinastatin 2: Axinastatin 3: AZasetron; AZatoxin; Anthramycin; Asparaginase; Asperlin; AZacitidine, AZetepa; AZatyrosine; Baccatin III Derivatives; Balanol; BCR/ABL AZotomycin; Batimastat; BenZOdepa; Bicalutamide; Bisant Antagonists; BenZochlorins; Benzoylstaurosporine; Beta rene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleo 10 Lactam Derivatives: Beta-Alethine; Betaclamycin B: Betu mycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; linic Acid; bFGF Inhibitor; Bisantrene; Bisaziridinylsper Cactinomycin; Calusterone; Caracemide: Carbetimer; Car mine; Bisnafide; Bistratene A, Breflate; Budotitane; Buthion boplatin: Carmustine; Carubicin Hydrochloride; Carzelesin; ine Sulfoximine; Calcipotriol: Calphostin C; Camptothecin Cedefingol; Chlorambucil; Cisplatin: Cladribine; Crisinatol Derivatives; Canarypox IL-2; Capecitabine; Carboxamide Mesylate: Cyclophosphamide: Cytarabine; Dacarbazine: 15 Amino-Triazole; Carboxyamidotriazole; CaRest MI; CARN Dactinomycin; Daunorubicin Hydrochloride; Decitabine; 700, Cartilage Derived Inhibitor; Casein Kinase Inhibitors Dexorinaplatin, DeZaguanine; DeZaguanine Mesylate; (1COS); Castanospermine; Cecropin B: Cetrorelix; Chlorins; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydro Chloroquinoxaline Sulfonamide: Cicaprost; Cis-Porphyrin; chloride; Droloxifene; Droloxifene Citrate; Dromostanolone Clomifene analogues; Collismycin A; Collismycin B: Com Propionate; Duazomycin; Edatrexate. Eflornithine Hydro bretastatin A4, Combretastatin Analogue; Conagenin: chloride; Elsamitrucin; Enloplatin: Enpromate: Epipropi Crambescidin 816: Crisinatol; Cryptophycin 8: Cryptophycin dine: Epirubicin Hydrochloride; Erbulozole; Esorubicin A Derivatives; Curacin A; Cyclopentanthraquinones; Cyclo Hydrochloride; Estramustine; Estramustine Phosphate platam; Cypemycin; Cytarabine Ocfosfate; Cytolytic Factor; Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto Cytostatin: Dacliximab: Dehydrodidenmin B: Dexifosfa poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz 25 mide: DexVerapamil: Didemnin B: Didox; Diethylnorspen arabine: Fenretinide; Floxuridine: Fludarabine Phosphate: nine; Dihydro AZacytidine; Dihydrotaxol. 9-; Dioxamycin; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Diphenyl Spiromustine; Docosanol; Dolasetron; Doxifluri Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198: dine; Duocarmycin SA: Ebselen; Ecomustine; Edelfosine: Hydroxyurea; Idarubicin, Hydrochloride; Ifosfamide: Ilmo Edrecolomab: Eflomithine; Elemene; Emitefur; Epirubicin; fosine; Interferon Alfa-2a: Interferon Alfa-2b: Interferon 30 Estramustine Analogue; Estrogen Agonists; Estrogen Alfan3; Interferon Alfa-nI; Interferon Beta-I a; Interferon Antagonists; Exemestane; Fadrozole; Fiezelastine, Fla Gamma-Ib: Iproplatin: Irinotecan Hydrochloride: Isotretin vopiridol; Fluasterone: Fludarabine: Fluorodaunorunicin oin; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Hydrochloride; Forfenimex: Formestane; Fostriecin; Fote Liarozole Hydrochloride; Lometrexol Sodium; Lomustine: mustine; Gadolinium Texaphyrin; Gallium Nitrate; Galocit Losoxantrone Hydrochloride: Masoprocol; Maytansine: 35 abine; Ganirelix; Gelatinase Inhibitors; Glutathione Inhibi Mechlorethamine Hydrochloride; Megestrol Acetate; tors; Hepsulfam; Heregulin; Hexamethylene Bisacetamide: Melengestrol Acetate; Melphalan: Menogaril; Mercaptopu Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idraman rine; Methotrexate; Methotrexate Sodium; Metoprine; tone; Ilomastat. Imidazoacridones; Immunostimulant Pep Meturedepa; Mitindomide: Mitocarcin; Mitocromin: tides; Insulin-Like Growth Factor-I Receptor Inhibitor; Inter Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane: 40 feron Agonists; Interferons; Interleukins; Iobenguane; Mitoxantrone Hydrochloride: Mycophenolic Acid; Nocoda Iododoxorubicin; Ipomeanol, 4-, Irinotecan; Iroplact; Zole; Nogalamvcin; Ormaplatin: Oxisuran: Paclitaxel; Pegas IrSogladine; IsobengaZole; Isohomohalicondrin B; Itasetron; pargase; Peliomycin; Pentamustine: Peplomycin Sulfate; Jasplakinolide; Kahalalide F: Lamellarin-N Triacetate; Lan Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydro reotide; Leinamycin; Lentinan Sulfate; Leptolstatin: Leuke chloride; Plicamycin; Plomestane: Porfimer Sodium; Predni 45 mia Inhibiting Factor; Leukocyte Alpha Interferon; Leupro mustine: Procarbazine Hydrochloride; Puromycin; Puromy lide--Estrogen-Progesterone; Leuprorelin; Levamisole; cin Hydrochloride: Pyrazofurin; Riboprine; Rogletimide: Liarozole; Linear Polyamine Analogue; Lipophilic Disac Safingol Safingol Hydrochloride: Semustine; SimtraZene: charide Peptide: Lipophilic Platinum Compounds; Lissocli Sparfosate Sodium; Sparsomycin; Spiro germanium Hydro namide 7: Lobaplatin: Lombricine; Lometrexol; chloride; Spiromustine; Spiroplatin: Streptonigrin: Strepto 50 Lonidamine; Losoxantrone; Lurtotecan; Lutetium Texaphy Zocin; Strontium Chloride Sr 89: Sulofenur; Talisomycin; rin; Lysofylline; Lytic Peptides; Maitansine: Mannostatin A; Taxane: Taxoid; Tecogalan Sodium; Tegafur, Teloxantrone Marimastat; Maspin; Matrilysin Inhibitors; Matrix Metallo Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testo proteinase Inhibitors; Merbarone; Meterelin; Methioninase; lactone; Thiamiprine; Thioguanine: Thiotepa; TiaZofarin; Metoclopramide: MIF Inhibitor; Mifepristone; Miltefosine: Tirapazamine; Topotecan Hydrochloride; Triciribine Phos 55 Mirimostim; Mismatched Double Stranded RNA; Mitogua phate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Zone; Mitolactol; Mitomycin analogues; Mitonafide; Mito Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vap toxin Fibroblast Growth Factor-Saporin; Mitoxantrone: reotide: Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Mofarotene; Monoclonal Antibody, Human Chorionic Gona Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglyci dotrophin; Monophosphoryl Lipid A+Myobacterium Cell nate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vin 60 Wall Sk; Mopidamol; Multiple Drug Resistance Gene Inhibi rosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin: tor; Multiple Tumor Suppressor I-Based Therapy: Mustard Zinostatin; and Zorubicin Hydrochloride. Anticancer Agent; Mycaperoxide B: Mycobacterial Cell Wall Anti-neoplastic compounds (additional): 20-epi-1.25 Extract; Myriaporone; N-Acetyldinaline; Nafarelin; Dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Acyl Nagrestip; Naloxone--Pentazocine; Napavin; Naphterpin; fulvene; Adecypenol; ALL-TK Antagonists; Ambamustine; 65 Nartograstim; Nedaplatin: Nemorubicin; Neridronic Acid; Amidox: Amifostine; Aminolevulinic Acid, Amrubicin; Neutral Endopeptidase; Nilutamide: Nisamycin; Nitric Anagrelide; Andrographolide; Angiogenesis Inhibitors; Oxide Modulators; Nitroxide Antioxidant; Nitrullyn; N-Sub US 8,343,962 B2 19 20 stituted Benzamides; 06-Benzylguanine; Okicenone; Oligo Antiprotozoal: Amodiaquine; AZanidazole; Banmidazole; nucleotides; Onapristone; Ondansetron: Oracin; Oral Cytok Camidazole; Chlortetracycline Bisulfate Chlortetracycline ine Inducer, Osaterone; Oxaliplatin: Oxaunomycin; Hydrochloride: Flubendazole: Flunidazole; Halofuginone Paclitaxel Analogues: Paclitaxel Derivatives; Palauamine: Hydrobromide: Imidocarb Hydrochloride; Ipronidazole; Palmitoylrhizoxin; Pamidronic Acid; Panaxytriol: Misonidazole; Moxinidazole; Nitarsone; Ronidazole; Panomifene; Parabactin; Pazelliptine: Peldesine; Pentostatin: Sulnidazole; and Tinidazole. Pentrozole; Perflubron; Perillyl Alcohol; Phenazinomycin; Antipruritic: Methdilazine; Methdilazine Hydrochloride; Phenylacetate; Phosphatase Inhibitors; Picibanil; Pilocarpine and Trimeprazine Tartrate. Hydrochloride; Pirarubicin; Piritrexim; Placetin A: Placetin Antipsoriatic: Acitretin: Anthralin; Azaribine; Calcipot B: Plasminogen Activator Inhibitor; Platinum Complex: 10 riene; Cycloheximide: Enazadrem Phosphate; Etretinate; Platinum Compounds; Platinum-Triamine Complex: Propyl LiaroZole Fumarate; Lonapalene; and Tepoxalin. Bis-Acridone: Prostaglandin J2: Proteasome Inhibitors; Pro Antipsychotic: Acetophenazine Maleate; Alentemol tein A-Based Immune Modulator; Protein Kinase CInhibitor; Hydrobromide: Alpertine; Azaperone: Batelapine Maleate; Protein Kinase C Inhibitors, Microalgal; Protein Tyrosine 15 Benperidol; BenZindopyrine Hydrochloride; Brofoxine; Bro Phosphatase Inhibitors; Purine Nucleoside Phosphorylase mperidol; Bromperidol Decanoate: Butaclamol Hydrochlo Inhibitors; Purpurins; Pyrazoloacridine: Pyridoxylated ride; Butaperazine; Butaperazine Maleate; Carphenazine Hemoglobin Polyoxyethylene Conjugate; Raf Antagonists; Maleate; Carvotroline Hydrochloride; Chlorprothixene; Cin Raltitrexed; Ramosetron; Ras Famesyl Protein Transferase perene; Cintriamide: Clomacran Phosphate: Clopenthixol; Inhibitors; Ras Inhibitors; Ras-GAP Inhibitor; Retelliptine Clopimozide; Clopipazan Mesylate: Cloroperone Hydro Demethylated; Rhenium, Re 186 Etidronate; Rhizoxin; chloride; Clothiapine; Clothixamide Maleate; Clozapine; Ribozymes: RII Retinamide; Rohitukine; Romurtide; Roqui Cyclophenazine Hydrochloride; Droperidol; Etazolate nimex: Rubiginone B 1: Ruboxyl; Safingol: Saintopin: Hydrochloride: Fenimide: Flucindole: Flumezapine; SarCNU; Sarcophytol A; Sdi 1 Mimetics; Senescence Fluphenazine Decanoate: Fluphenazine Enanthate: Derived Inhibitor 1: Sense Oligonucleotides; Signal Trans 25 Fluphenazine Hydrochloride: Fluspiperone: Fluspirilene: duction Inhibitors: Signal Transduction Modulators; Single Flutroline; Gevotroline Hydrochloride; Halopemide: Halo Chain Antigen Binding Protein; Sizofiran; Sobuzoxane: peridol; Haloperidol Decanoate; Iloperidone: Imidoline Sodium Borocaptate; Sodium Phenylacetate; Solverol; Hydrochloride; Lenperone; Mazapertine Succinate: Somatomedin Binding Protein; Sonermin; Sparfosic Acid; Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper Spicamycin D: Splenopentin; Spongistatin 1; Squalamine; 30 one: Milipertine; Molindone Hydrochloride; Naranol Hydro Stem Cell Inhibitor; Stem-Cell Division Inhibitors; Stipi chloride: Neflumozide Hydrochloride; Ocaperidone; Olanza amide: Stromelysin Inhibitors: Sulfinosine: Superactive pine; Oxiperomide: Penfluridol; Pentiapine Maleate: Vasoactive Intestinal Peptide Antagonist; Suradista; Perphenazine: Pimozide; Pinoxepin Hydrochloride; Pipam Suramin; Swainsonine; Synthetic Glycosaminoglycans; Tal perone; Piperacetazine; Pipotiazine Palmitate; Piquindone limustine; Tamoxifen Methiodide; Tauromustine; Tellurapy 35 Hydrochloride; Promazine Hydrochloride: Remoxipride: rylium; Telomerase Inhibitors: Temozolomide; Tetrachloro Remoxipride Hydrochloride; Rimcazole Hydrochloride: decaoxide; Tetrazomine; Thaliblastine; Thalidomide: Seperidol Hydrochloride: Sertindole: Setoperone; Spiper Thiocoraline: Thrombopoietin: Thrombopoietin Mimetic: one: Thioridazine: Thioridazine Hydrochloride; Thiothixene; Thymalfasin; Thymopoietin Receptor Agonist; Thymotri Thiothixene Hydrochloride; Tioperidone Hydrochloride: nan; Thyroid Stimulating Hormone; Tin Ethyl Etiopurpurin; 40 Tiospirone Hydrochloride; Trifluoperazine Hydrochloride: Titanocene Dichloride; Topotecan; Topsentin; Toremifene: Trifluperidol; Triflupromazine; Triflupromazine Hydrochlo Totipotent StemCell Factor; Translation Inhibitors; Triacety ride; and Ziprasidone Hydrochloride. luridine; Triciribine; Tropisetron; Turosteride; Tyrosine Antirheumatic: Auranofin, Aurothioglucose: Bindarit; Kinase Inhibitors; Tyrphostins; UBC Inhibitors: Ubenimex: Lobenzarit Sodium; Phenylbutazone; Pirazolac: Prinomide Urogenital Sinus-Derived Growth Inhibitory Factor: Uroki 45 Tromethamine; and Seprilose. nase Receptor Antagonists; Variolin B; Vector system, Eryth Antischistosomal: Becanthone Hydrochloride; Hycan rocyte Gene Therapy; Velaresol; Veramine: Verdins; Vinorel thone; Lucanthone Hydrochloride; Niridazole: Oxam bine; Vinxaltine; Vitaxin, Zilascorb; and Zinostatin niquine; Pararosaniline Pamoate; and Teroxalene Hydrochlo Stimalamer. ride. Antineutropenic: Filgrastim; Lenograstim; Molgra 50 Antiseborrheic: Chloroxime; Piroctone; Piroctone Ola mostim; Regramostim; and SargramoStim. mine; and Resorcinol Monoacetate. Antiobsessional agent: Fluvoxamine Maleate. Antisecretory: Arbaprostil; Deprostil: Fenoctimine Sul Antiparasitic: Abamectin; ClorSulon; and Ivermectin. fate; Octreotide; Octreotide Acetate; Omeprazole Sodium; Antiparkinsonian: Benztropine Mesylate; Biperiden; Rioprostil; Trimoprostil. Biperiden Hydrochloride; Biperiden Lactate; Carbidopa 55 Antispasmodic: Stilonium Iodide; Tizanidine Hydrochlo Levodopa; Carmantadine: Ciladopa Hydrochloride; Dopam ride. antine; Ethopropazine Hydrochloride; Lazabemide: Antithrombotic: Anagrelide Hydrochloride; Dalteparin Levodopa; Lometraline Hydrochloride; Mofegiline Hydro Sodium; Danaparoid Sodium; Dazoxiben Hydrochloride: chloride: Naxagolide Hydrochloride; Pareptide Sulfate; Pro Efegatran Sulfate; Enoxaparin Sodium: Ifetroban; Ifetroban cyclidine Hydrochloride; Ropinirole Hydrochloride; and Tol 60 Sodium; and Trifenagrel. capOne. Antitussive: Benzonatate; Butamirate Citrate; Chlophedi Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; anol Hydrochloride: Codeine Polistirex: Codoxime; Dex Fluperamide; Lidamidine Hydrochloride; Loperamide tromethorphan: Dextromethorphan Hydrobromide: Dex Hydrochloride; Malethamer; Nufenoxole; Paregoric. tromethorphan Polistirex: Ethyl Dibunate; Guaiapate: Antipneumocystic: Atovaquone. 65 Hydrocodone Bitartrate; Hydrocodone Polistirex; Levopro Antiproliferative agent: Piritrexim Isethionate. poxyphene Napsylate: Noscapine; Pemerid Nitrate; Antiprostatic hypertrophy: Sitogluside. Pipazethate; and Suxemerid Sulfate. US 8,343,962 B2 21 22 Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Oxiramide: Pirmenol Hydrochloride: Pirolazamide; Prano Iodine; Cetraxate Hydrochloride; Enisoprost: Isotiquimide: lium Chloride: Procainamide Hydrochloride; Propafenone Lansoprazole; Lavoltidine Succinate; Misoprostol; Nizati Hydrochloride: Pyrinoline; Quindonium Bromide: Quinidine dine; Nolinium Bromide; Pantoprazole; Pifarnine: Piren Gluconate; Quinidine Sulfate; Recainam Hydrochloride: Zepine Hydrochloride; Rabeprazole Sodium; Remiprostol; Recainam Tosylate: Risotilide Hydrochloride; Ropitoin Roxatidine Acetate Hydrochloride; Sucralfate. Sucrosofate Hydrochloride: Sematilide Hydrochloride: Suricainide Potassium; and Tolimidone. Maleate: Tocainide; Tocainide Hydrochloride; and Tran Anti-urolithic: Cysteamine: Cysteamine Hydrochloride: Scainide. and Tricitrates. Cardioprotectant: Dexrazoxane; and Draflazine. Antiviral: Acemannan; AcVclovir, Acyclovir Sodium; 10 Cardiotonic agent: Actodigin; Amrinone; Bemoradan; Adefovir; Alovudine; Alvircept Sudotox: Amantadine Butopamine; Carbazeran; Carsatirin Succinate; Deslanoside; Hydrochloride; Aranotin: Arildone: Atevirdine Mesylate: Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Avridine; Cidofovir, Cipamfylline; Cytarabine Hydrochlo Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar ride; Delavirdine Mesylate; Desciclovir; Didanosine; Disox trate; Enoximone: Imazodan Hydrochloride; Indolidan; Iso aril: Edoxudine; Enviradene; Enviroxime; Famciclovir, 15 mazole Hydrochloride; Levdobutamine Lactobionate; Lix Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari azinone Sulfate; Medorinone; Millrinone; Pelrinone late; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Gan Hydrochloride: Pimobendan; Piroximone: Prinoxodan; ciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobu Proscillaridin; Quazinone; Tazolol Hydrochloride; and cavir; Memotine Hydrochloride; Methisazone; Nevirapine; Vesnarinone. Penciclovir, Pirodavir, Ribavirin; Rimantadine Hydrochlo Cardiovascular agent: Dopexamine; and Dopexamine ride; Saquinavir Mesylate: Somantadine Hydrochloride; Hydrochloride. Sorivudine: Statolon; Stavudine; Tilorone Hydrochloride: Cerebral ischemia agent: Dextrorphan Hydrochloride. Trifluridine; Valacyclovir Hydrochloride: Vidarabine; Choleretic: Dehydrocholic Acid: Fencibutirol; Hymec Vidarabine Phosphate; Vidarabine Sodium Phosphate: romone; Piprozolin; Sincalide; Tocamphyl. Viroxime; Zalcitabine; Zidovudine; and Zinviroxime. 25 Cholinergic: Aceclidine. Bethanechol Chloride; Carba Appetite suppressant: Dexfenfluramine Hydrochloride: chol; Demecarium Bromide; Dexpanthenol; Echothiophate Phendimetrazine Tartrate; and Phentermine Hydrochloride. Iodide: Isoflurophate; Methacholine Chloride; Neostiamine Benign prostatic hyperplasia therapy agent: Tamsulosin Methylsulfate; Neostigmine Bromide; Physostigmine; Phys Hydrochloride. ostigmine Salicylate; Physostigmine Sulfate; Pilocarpine Blood glucose regulators: Acetohexamide and Glipizide; 30 Nitrate; and Pyridostigmine Bromide. Chloropropamide; and Human insulin. Cholinergic agonist. Xanomeline; and Xanomeline Tar Bone resorption inhibitor: Alendronate Sodium: Etidr trate. onate Disodium; and Pamidronate Disodium. Cholinesterase Deactivator: Obidoxime Chloride; Prali Bronchodilator: Albuterol; Albuterol Sulfate; AZanator doxime Chloride; Pralidoxime Iodide; and Pralidoxime Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate: 35 Mesylate. Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydro Coccidiostat: Arprinocid; Narasin; Semduramicin; and chloride; Colterol Mesylate; Doxaprost; Doxofylline: Semduramicin Sodium. Dyphylline; Enprofylline; Ephedrine; Ephedrine Hydrochlo Cognition adjuvant: Ergoloid Mesylates; Piracetam; ride; Fenoterol: Fenprinast Hydrochloride; Guaithylline; Pramiracetam Hydrochloride; Pramiracetam Sulfate; and Hexoprenaline Sulfate; Hoquizil Hydrochloride; Ipratropium 40 Tacrine Hydrochloride. Bromide: Isoetharine: Isoetharine Hydrochloride: Isoet Cognition enhancer: Besipirdine Hydrochloride; Linopir harine Mesylate: Isoproterenol Hydrochloride: Isoproterenol dine; and Sibopirdine. Sulfate; Metaproterenol Polistirex: Metaproterenol Sulfate; Contrast Media: Barium Sulfate; Diatrizoate Sodium; Nisbuterol Mesylate: Oxtriphylline: Picumeterol Fumarate; Erythrosine Sodium; Iopanoic Acid; Ipodate Calcium; Piquizil Hydrochloride: Pirbuterol Acetate; Pirbuterol 45 Metyrapone; and Tyropanoate Sodium. Hydrochloride; Procaterol Hydrochloride; Pseudoephedrine Diagnostic aid: Aminohippurate Sodium; Anazolene Sulfate; QuaZodine; Quinterenol Sulfate; Racepinephrine; Sodium; Arclofenin; Bentiromide; Benzylpenicilloyl Polyl Racepinephrine Hydrochloride; Reproterol Hydrochloride: ysine; Butedronate Tetrasodium: Butilfenin; Coccidioidin; Rimiterol Hydrobromide: Salmeterol: Salmeterol Xinafoate: Corticorelin Ovine Triflutate; Corticotropin Zinc Hydroxide: Soterenol Hydrochloride; Sulfonterol Hydrochloride: Sulox 50 Corticotropin, Repository; Diatrizoate Meglumine; Diatri ifen Oxalate; Terbutaline Sulfate; Theophylline: Xanoxate Zoic Acid; Diphtheria Toxin for Schick Test: Disofenin: Sodium; Zindotrine; and Zinterol Hydrochloride. Ethiodized Oil: Etifenin; Exametazime; Ferristenc; Feru Carbonic anhydrase inhibitor: Acetazolamide: Acetazola moxides; Ferumoxsil; Fluorescein; Fluorescein Sodium; mide Sodium; Dichlorophenamide: Dorzolamide Hydro Gadobenate Dimeglumine; Gadodiamide; Gadopentetate chloride; Methazolamide; and Sezolamide Hydrochloride. 55 Dimegiumine; Gadoteridol: Gadoversetamide: Histoplas Cardiac depressant: Acecainide Hydrochloride: Acetyl min: Impromidine Hydrochloride; Indigotindisulfonate choline Chloride; Actisomide; Adenosine; Amiodarone; Sodium; Indocyanine Green: Iobenguane Sulfate I 123; Aprindine: Aprindine Hydrochloride; Artilide Fumarate; Iobenzamic Acid, Iocarmate Meglumine; Iocarmic Acid, Ioc Azimilide Dihydrochloride; Bidisomide; Bucainide Maleate; etamic Acid, Iodamide: Iodamide Megilumine; Iodipamide Bucromarone; Capobenate Sodium; Capobenic Acid; Cifen 60 Meglumine; Iodixanol; Iodoxamate Meglumine: Iodoxamic line; Cifenline Succinate; Clofilium Phosphate: Disobuta Acid, Ioglicic Acid, Ioglucol, Ioglucomide: Ioglycamic Acid; mide: Disopyramide; Disopyramide Phosphate; Dofetilide; Iogulamide: Iohexol; Iomeprol; Iopamidol; Iopentol; Drobuline; Edifolone Acetate; Emilium Tosylate; Encainide Iophendylate; Ioprocemic Acid, Iopronic Acid, Iopydol; Hydrochloride; Flecainide Acetate; Ibutilide Fumarate; Iopy done; Iosefamic Acid, Ioseric Acid, IoSulamide Meglu Indecainide Hydrochloride: Ipazilide Fumarate; Lorajmine 65 mine; IoSumetic Acid; Iotasul; Iotetric Acid; Iothalamate Hydrochloride; Lorcainide Hydrochloride; Meobentine Sul Meglumine; Iothalamate Sodium; Iothalamic Acid; Iotrolan; fate; Mexiletine Hydrochloride: Modecainide; Moricizine: IotroXic Acid, Ioversol, Ioxagiate Sodium; Ioxaglate Meglu US 8,343,962 B2 23 24 mine; Ioxaglic Acid, Ioxilan, Ioxotrizoic Acid, Ipodate Gonad-stimulating principle: Buserelin Acetate; Clomi Sodium; Iprofenin; Isosulfan Blue; Leukocyte Typing Serum; phene Citrate; Ganirelix Acetate; Gonadorelin Acetate; Lidofenin; Mebrofenin; Meglumine; Metrizamide: Metri Gonadorelin Hydrochloride; Gonadotropin, Chorionic; and Zoate Sodium; Metyrapone Tartrate; Mumps Skin Test Anti Menotropins. gen; Pentetic Acid; Propyliodone; Quinaldine Blue: Schick Hormone: 17 Alpha Dihydroequilenin; 17 Alpha Dihy Test Control; Sermorelin Acetate; Sodium Iodide I 123; droequilin; 17 Alpha Estradiol; 17 Beta Estradiol; 17 Sprodiamide: Stannous Pyrophosphate: Stannous Sulfur Col Hydroxy Progesterone; Androstenedione; Clomiphene: loid; Succimer; Teriparatide Acetate; Tetrofosmin; Tolbuta Cosyntropin: Dehydroepiandrosterone; Dihydroestosterone: mide Sodium; Tuberculin; and Xylose. Equilenin; Ethyndiol; Follicle Regulatory Protein; Follicle Diuretic: Ambuphylline; Ambuside; Amiloride Hydro 10 Stimulating Hormone; Folliculostatin: Gonadoctrinins: chloride; Azolimine; AZosemide; Brocrinat: Bumetanide; Gonadorelin; Gonadotropins; Han Memopausal Gonadotro Chlorothiazide; Chlorthalidone; Clazolimine; Clorexolone; pins; Human Chorionic Gonadotropin; Insulin Growth Fac Ethacrynate Sodium: Ethacrynic Acid; Etozolin; Fen tor; Leuprolide; Levonorgestrel; Luteinizing hormone; quizone; Furosemide: Hydrochlorothiazide: Isosorbide: 15 Luteinizing Hormone Releasing Hormone and Analogs; Mannitol Mefruside; Ozolinone: Piretanide; Spiroxasone: Medroxyprogesterone; Megestrol; Metogest; Norethindrone: Torsemide; Triamterene; Triflocin, and Urea. Norethynodrel; Norgestrel; Oocyte Maturation Inhibitor; Dopaminergic agent: Ibopamine. Oxytocin; Pituitary, Posterior; Progesterone: Relaxin; Serac Ectoparasiticide: Nifluridide; Permethrin. tide Acetate. Somalapor, Somatrem: Somatropin; Some Emetic: Apomorphine Hydrochloride. nopor: Somidobove; Tamoxifen; Urofollitropin; and Vaso Enzyme inhibitor: 30 Polignate Sodium; Acetohydrox pressin. amic Acid. Alrestatin Sodium; Aprotinin; Benazepril Hydro Hypocholesterolemic: Lifibrol. chloride; Benazeprilat; Benurestat; Bromocriptine; Bro Hypoglycemic: DarglitaZone Sodium; and Glimepiride. mocriptine Mesylate: Cilastatin Sodium; Flurofamide: Hypolipidemic: AzalanstatDihydrochloride; Colestolone: Lergotrile; Lergotrile Mesylate; Levcycloserine; Libenza 25 Surfomer; and Xenalipin. pril; Pentopril; Pepstatin: Perindopril; Sodium Amylosulfate; Hypotensive: Viprostol. Sorbinil; Spirapril Hydrochloride; Spiraprilat; Taleranol: Immunizing agent: Antirabies Serum; Antivenin; Antive Teprotide; Tolfamide; and Zofenopril Calcium. nin (Crotalidae) Polyvalent; BCG Vaccine. Botulism Anti Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbestrol; toxin; Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Diethylstilbestrol Diphosphate; Equilin; Estradiol; Estradiol 30 Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Cypionate; Estradiol Enanthate; Estradiol Undecylate; Estra Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine diol Valerate; EstraZinol Hydrobromide; Estriol; Estrofurate; Live: Meningococcal Polysaccharide Vaccine Group A; Men Estrogens, Conjugated; Estrogens, Esterified; Estrone; ingococcal Polysaccharide Vaccine Group C; Mumps Virus Estropipate; Ethinyl Estradiol: Fenestrel; Mestranol: 35 Vaccine Live: Pertussis Immune Globulin; Pertussis Vaccine; Nylestriol; and Quinestrol. Pertussis Vaccine Adsorbed; Plague Vaccine; Poliovirus Vac Fibrinolytic: Anistreplase; Bisobrin Lactate; and Brino cine Inactivated; Poliovirus Vaccine Live Oral; Rabies lase. Immune Globulin; Rabies Vaccine; Rho(D) Immune Globu Free oxygen radical scavenger: Pegorgotein. lin; Rubella Virus Vaccine Live: Smallpox Vaccine; Tetanus Gastric Acid Suppressant: Lansoprazole, Pantoprazole and 40 Antitoxin; Tetanus Immune Globulin; Tetanus Toxoid: Teta Omeprazole. nus Toxoid Adsorbed; Typhoid Vaccine; Vaccinia Immune Gastrointestinal Motility agents: Cisapride. Globulin; VaricellaZoster Immune Globulin; and Yellow Glucocorticoid: Amcinonide; Beclomethasone Dipropi Fever vaccine. onate; Betamethasone; Betamethasone Acetate. Betametha Immunomodulator: Dimepranol Acedoben; Imiquimod; sone Benzoate: Betamethasone Dipropionate; Betametha 45 Interferon Beta-Ib: Lisofylline: Mycophenolate Mofetil; and sone Sodium Phosphate: Betamethasone Valerate; Prezatide Copper Acetate. Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Immunoredulator: Azarole; Fanetizole Mesylate; Frenti Pivalate; Cloprednol; Corticotropin; Cortisone Acetate; Cor Zole: Oxamisole Hydrochloride: Ristianol Phosphate; Thy tivaZol; Descinolone Acetonide; Dexamethasone; Dexam mopentin; and Tilomisole. ethasone Sodium Phosphate; Diflucortolone; Diflucortolone 50 Immunostimulant: Loxoribine; and Teceleukin. Pivalate: Flucloronide; Flumethasone: Flumethasone Piv Immunosuppressant: Azathioprine; Azathioprine Sodium; alate: Flunisolide; Fluocinolone Acetonide; Fluocinonide; Cyclosporine; Daltroban: Gusperimus Trihydrochloride: Fluocortolone: Fluocortolone Caproate: Fluorometholone: Sirolimus; Tacrolimus. Fluperolone Acetate: Fluprednisolone: Fluprednisolone Val Impotence therapy adjunct: Delequamine Hydrochloride. erate: Flurandrenolide; Formocortal: Hydrocortisone: 55 Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Hydrocortisone Acetate; Hydrocortisone Buteprate; Hydro Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel; cortisone Butyrate; Hydrocortisone Sodium Phosphate: Docebenone: Epoprostenol; Epoprostenol Sodium; Epris Hydrocortisone Sodium Succinate; Hydrocortisone Valerate; teride; Finasteride: Flurbiprofen Sodium; Furegrelate Medrysone; Methylprednisolone Acetate; Methylpredniso Sodium; Lufironil; Miglitol; Orlistat; Pimagedine Hydro lone Sodium Phosphate; Methylprednisolone Sodium Succi 60 chloride; Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Ben nate; Nivazol; Paramethasone Acetate; Prednicarbate; Pred Zathine; Sulbactam Pivoxil; Sulbactam Sodium; Suronacrine nisolone; Prednisolone Acetate; Prednisolone Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine Hemisuccinate; Prednisolone Sodium Succinate; Predniso Hydrochloride; Tirilazad Mesylate: Tolrestat; Velnacrine lone Tebutate; Prednisone; Prednival; Ticabesone Propi Maleate; Zifrosilone; and Zileuton. onate; Tralonide; Triamcinolone; Triamcinolone Acetonide; 65 Keratolytic: Alcloxa; Aldioxa; Dibenzothiophene; Etaro Triamcinolone Acetonide Sodium; Triamcinolone Diacetate; tene: Motretinide-I Picotrin Diolamine; Salicylic Acid; and Triamcinolone Hexacetonide. Sumarotene; Tazarotene; Tetroquinone; and Tretinoin. US 8,343,962 B2 25 26 LHRH agonist: Deslorelin; Goserelin; Histrelin; Lutrelin Thyroxine I 125; Thyroxine 1131; Tolpovidone 1131; Tri Acetate; and Nafarelin Acetate. olein 1125; and Triolein 1131. Liver disorder treatment: Malotilate. Regulator: Calcifediol; Calcitonin; Calcitriol: Clodronic Luteolysin: Fenprostalene. Acid; Dihydrotachysterol: Etidronic Acid: Oxidronic Acid; Memory adjuvant: Dimoxamine Hydrochloride; and Rib Piridironate Sodium; Risedronate Sodium; and Secalciferol. aminol. Relaxant: Adiphenine Hydrochloride; Alcuronium Chlo Mental performance enhancer: Aniracetam. ride; Aminophylline: Azumolene Sodium; Baclofen; Ben Mood regulator: Fengabine. Zoctamine Hydrochloride; Carisoprodol; Chlorphenesin Car Mucolytic: Acetylcysteine; Carbocysteine; and Domiodol. bamate; ChlorZoxazone; Cinflumide: Cinnamedrine; Mucosal Protective agents: Misoprostol (Cytotec). 10 Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene: Mydriatic: Berefrine. Dantrolene Sodium; Fenalamide: Fenyripol Hydrochloride: Nasal decongestant: Nemazoline Hydrochloride; Pseu Fetoxylate Hydrochloride: Flavoxate Hydrochloride; Fle doephedrine Polistirex. tazepam; Flumetramide: Hexafluorenium Bromide: Isomy Neuroleptic: Duoperone Fumarate; and Risperidone. lamine Hydrochloride; Lorbamate; Mebeverine Hydrochlo Neuromuscular blocking agent: Atracurium Besylate; 15 ride; Mesuprine Hydrochloride; Metaxalone; Methixene Cisatracurium Besylate; Doxacurium Chloride; Gallamine Hydrochloride; Methocarbamol; Nafomine Malate: Nelleza Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pan prine Maleate; Papaverine Hydrochloride; Pipoxolan Hydro curonium Bromide; Pipecuronium Bromide: Rocuronium chloride; Quinctolate; Ritodrine; Ritodrine Hydrochloride: Bromide: Succinylcholine Chloride; Tubocurarine Chloride: Rolodine: Theophylline Sodium Glycinate: Thiphenamil and Vecuronium Bromide. Hydrochloride; and Xilobam. Neuroprotective: Dizocilpine Maleate. Repartitionind agent: Cimaterol. NMDA antagonist: Selfotel. Scabicide: Amitraz: Crotamiton. Non-hormonal sterol derivative: Pregnenolone Succinate. Sclerosing agent: Ethanolamine Oleate; Morrhuate Oxytocic: Carboprost; Carboprost Methyl: Carboprost Sodium; Tribenoside. Tromethamine; Dinoprost; Dinoprost Tromethamine; Dino 25 Sedative: Propiomazine. prostone; Ergonovine Maleate; Meteneprost; Methylergono Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam: vine Maleate; and Sparteine Sulfate. Amobarbital Sodium; Bentazepam; Brotizolam: Butabar Paget’s disease agents: Tiluldronate Disodium. bital; Butabarbital Sodium: Butalbital; Capuride; Carboclo Progestin: Algestone Acetophenide; Amadinone Acetate; ral; Chloral Betaine; Chloral Hydrate; Chlordiazepoxide Anagestone Acetate; Chlormadinone Acetate; Cingestol; 30 Hydrochloride; Cloperidone Hydrochloride; Clorethate: Clogestone Acetate; Clomegestone Acetate; Desogestrel; Cyprazepam; Dexclamol Hydrochloride; Diazepam; Dichlo Dimethisterone; Dydrogesterone: Ethynerone; Ethynodiol ralphenazone; Estazolam Ethchlorvynol; Etomidate: Diacetate; Etonogestrel; Flurogestone Acetate; Gestaclone; Fenobam; Flunitrazepam; Fosazepam; Glutethimide: Gestodene; Gestonorone Caproate: Gestrinone; Haloproges Halazepam, Lon-netazepam, Mecloqualone; Meprobamate; terone; Hydroxyprogesterone Caproate; Lynestrenol; 35 Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pento Medrogestone; Medroxyprogesterone Acetate; Methynodiol barbital Sodium; Perlapine; Prazepam; Quazepam; Diacetate; Norethindrone Acetate; Norgestimate; Norg Reclazepam; Roletamide: Secobarbital; Secobarbital estomet, Oxogestone Phenpropionate; Quingestanol Acetate; Sodium; Suproclone: Tracazolate: Trepipam Maleate; Triaz Quingestrone; and Tigestol. olam; Tricetamide; Triclofos Sodium; Trimetozine; Prostaglandin: Cloprostenol Sodium; Fluprostenol 40 Uldazepam; Zaleplon; Zolazepam Hydrochloride; and Zolpi Sodium; Gemeprost; Prostalene; and Sulprostone. dem Tartrate. Prostate growth inhibitor: Pentomone. Selective adenosine A1 antagonist: Apaxifylline. Prothyrotropin: Protirelin. Serotonin antagonist: Altanserin Tartrate; Amesergide; Psychotropic: Minaprine. Ketanserin; and Ritanserin. Radioactive agent: Fibrinogen I 125: Fludeoxyglucose F 45 Serotonin inhibitor: Cinanserin Hydrochloride: Fenclo 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane nine; Fonazine Mesylate; and Xylamidine Tosylate. I 123: Iodipamide Sodium I 131; Iodoantipyrine I 131; Iodo Serotonin receptor antagonist: Tropanserin Hydrochlo cholesterol I 131; Iodohippurate Sodium I 123: Iodohippurate ride. Sodium I 125; Iodohippurate Sodium I 131; Iodopyracet I Steroid: Dexamethasone Acefurate; and Mometasone 125; Iodopyracet I 131; Iofetamine Hydrochloride I 123; 50 Furoate. Iomethin I 125; Iomethin I 131; Iothalamate Sodium I 125; Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampy Iothalamate Sodium I 131; Iotyrosine I 131; Liothyronine I zine Sulfate; Arbutamine Hydrochloride; Azabon; Caffeine: 125; Liothyronine I 131: Merisoprol Acetate Hg 197; Mer Ceruletide; Ceruletide Diethylamine; Dazopride Fumarate; isoprol Acetate Hg203; Merisoprol Hg 197; Selenomethion Dextroamphetamine; Dextroamphetamine Sulfate; Diflua ine Se75; Technetium Tc 99m Antimony Trisulfide Colloid; 55 nine Hydrochloride; Dimefline Hydrochloride; Doxapram Technetium Tc 99m Bicisate; Technetium Tc 99m Disofenin; Hydrochloride; Ethamivan; Etryptamine Acetate: Fenethyl Technetium Tc 99m Etidronate; Technetium Tc 99m Exam line Hydrochloride: Flubanilate Hydrochloride: Flurothyl: etazime; Technetium Tc 99m Furifosmin; Technetium Tc Histamine Phosphate: Indriline Hydrochloride; Mefexamide: 99m Gluceptate; Technetium Tc 99m Lidofenin; Technetium Methamphetamine Hydrochloride; Methylphenidate Hydro Tc 99m Mebrofenin; Technetium Tc 99m Medronate; Tech 60 chloride; Pemoline: Pyrovalerone Hydrochloride: Xamot netium Tc 99m Medronate Disodium; Technetium Tc 99m erol; and Xamoterol Fumarate. Mertiatide; Technetium Tc 99m Oxidronate; Technetium Tc Suppressant: Amflutizole; Colchicine; Tazofelone. 99m Pentetate; Technetium Tc 99m Pentetate Calcium Triso Symptomatic multiple Sclerosis: Fampridine. dium; Technetium Tc 99m Sestamibi; Technetium Tc 99m Synergist Proadifen Hydrochloride. Siboroxime; Technetium Tc 99m Succimer; Technetium Tc 65 Thyroid hormone: Levothyroxine Sodium; Liothyronine 99m Sulfur Colloid; Technetium Tc 99m Teboroxime; Tech Sodium; and Liotrix. netium Tc 99m Tetrofosmin, Technetium Tc 99m Tiatide; Thyroid inhibitor: Methimazole; and Propylthiouracil. US 8,343,962 B2 27 28 Thyromimetic: Thyromedan Hydrochloride. Aspalatone; Asperfuran; Aspoxicillin; Atazanavir Sulfate; Tranquilizer: Bromazepam; Buspirone Hydrochloride; Atenolol, S ; Atevirdine; Atomoxetine Hydrochloride; Chlordiazepoxide; Clazolam; Clobazam; Clorazepate Dipo Atpenin B; Atrinositol; Aureobasidin A; AVobenzone; Aza tassium; CloraZepate Monopotassium; DemoXepam, dirachtine; AZelaic Acid, AZelastine; AZelnidipine; Azimil Dexmedetomidine: Enciprazine Hydrochloride; Gepirone ide: Azithromycin Dihydrate; Aztreonwn; Baccatin III: Baco Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro side A: Bacoside B: Bactobolamine; Balazipone: chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, Balhimycin; Balofloxacin; Balsalazide; Bambuterol; Bao LorZafone; Loxapine; Loxapine Succinate; Medazepam huoside 1: Barnidipine; Batebulast; Beauvericin; Becapler Hydrochloride; Nabilone; Nisobamate: Oxazepam; Pent min; Becliconazole; Beclomethasone Dipropionate Monohy abamate; Pirenperone; Ripazepam, Rolipram; Sulazepam, 10 drate; Befloxatone; Bellenamine; Benflumetol; Benidipine; Taciamine Hydrochloride; Temazepam; Triflubazam; Bentoquatam; Benzisoxazole; Benzoidazoxan; Benzoyl Per Tybamate; and Valnoctamide. oxide; BenZphetamine Hydrochloride; Benzquinamide Unstable angina agents: Tirofiban Hydrochloride. Hydrochloride; Benztropine; Benzyl Benzoate; Benzyl Peni Uricosuric: BenZbromarone; Irtemazole; Probenecid; cilloyl-Polylysine: Bepridil; Beractant; Beraprost; Ber Sulfinpyrazone. 15 lafenone; Bertosamil: Besipirdine: Beta-Carotene; Betaine, Vasoconstrictor: Angiotensin Amide; Fely pressin; Methy Anhydrous: Betamipron: Betaxolol; Betazole Hydrochlo sergide; and Methysergide Maleate. ride; Bevantolol; Bexarotene; Bifemelane; Bimakalim, Vasodilator: Alprostadil; AZaclorzine Hydrochloride: Bimatoprost; Bimithil; Binospirone: Biotin; Bioxalomycin Bamethan Sulfate; Bepridil Hydrochloride; Buterizine: Alpha2: Biriperone; Bisaramil: Bisaziridinylspermine; Bis Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Benzimidazole A; Bis-Benzimidazole B: Bismuth Subsalicy Dipyridamole; Droprenilamine; Erythrity1 Tetranitrate; Fello late; Bistramide D: Bistramide K; Boldine: Bopindolol; Bort dipine: Flunarizine Hydrochloride; Fostedil: Hexobendine: eZomib; Brefeldin; Brimonidine; Brinzolamide; Bromfenac: Inositol Niacinate; Iproxamine Hydrochloride: Isosorbide Bucindolol; Budipine: Bunazosin; Butenafine; Butenafine Dinitrate; Isosorbide Mononitrate; IsoxSuprine Hydrochlo Hydrochloride; Butixocort Propionate; Cabergoline; Caf ride; Lidoflazine; Mefenidil; Mefenidil Fumarate; Mibefradil 25 feine Citrate; Calanolide A: Calcitonin Human; Calcitonin, Dihydrochloride; Mioflazine Hydrochloride: Mixidine: Salmon; Calcium, Calcium Acetate; Calcium Gluceptate; Nafronyl Oxalate; Nicardipine Hydrochloride; Nicergoline; Calcium Metrizoate; Califactant; Camonagrel, Candesartan; Nicorandil; Nicotinyl Alcohol; Nimodipine; Nisoldipine; Candesartan Cilexetil, CandoXatrilat, Capromab, Capsaicin; Oxfenicine; Oxprenolol Hydrochloride; Pentaerythritol Tet Carbarnazepine; Carbazomycin C; Carbetocin; Carbidopa/ ranitrate; Pentoxifylline: Pentrinitrol; Perhexiline Maleate; 30 Levodopa; Carbovir; Carboxymethylated Beta-I.3-Glucan: Pindolol; Pirsidomine: Prenylamine: Propatyl Nitrate; Suloc Carperitide; Carteolol; Carumonam; Carvotroline; Caspo tidil; Terodiline Hydrochloride: Tipropidil Hydrochloride: fungin Acetate; Cebaracetam; CefadroxillCefadroxil Hemi Tolazoline Hydrochloride; and Xanthinol Niacinate. hydrate; Cefcapene Pivoxil; Cefdaloxime Pentexil Tosilate: Wound healing agent: ErSofermin. Cefditoren Pivoxil; Cefepime Hydrochloride (Arginine For Xanthine oxidase inhibitor: Allopurinol; and Oxypurinol. 35 mulation); Cefetamet; Cefetamet Pivoxil; Cefffietazole; Cef Other active agents include: 16-Alpha Fluoroestradiol; luprenam; Cefninox; Cefodizime; Cefoselis; Cefotiam: 16Alpha-Gitoxin; 16-Eplestriol; 17 Alpha Estradiol; 17Beta Cefotiam Hexetil: CefoZopran; Ce?pirome; Cefsulodin; Estradiol; IAlpha-Hydroxyvitamin D2: 1-Decpyrrolidinone; Ceftazidime (Arginine Formulation); Ceftazidime Sodium; 1-Dodecpyrrolidinone; 22-Oxacalcitriol: 2CVV; 2'-Nor Cefiteram; Ceftibuten Dihydrate; Ceftriaxone; Celastrol; cGMP; 3-Isobutyl GABA: 6-FUDCA: 7-Methoxytacrine: 40 Celecoxib; Celikalim; Celiprolol: Cellulose Sodium Phos Abacavir Sulfate; Abanoquil; Abecarnil; Acadesine; Acamp phate; Cepacidine A; Cericlamine; Cerivastatin: Cerivastatin rosate; Acebutolol Hydrochloride; Aceclofenac; Acetome Sodium; Certoparin Sodium; Cetiedil; Cetirizine; Cetyl pregenol; Acetrizoate Sodium, Acetylcysteine, N-Acetyl Alcohol; Cevimeline Hydrochloride; Chlormerodrin, digitoxin: Acetyl-L-carnitine; Acetylmethadol; Acipimox; Hg-197; Chlormezanone; Chloroorienticin A; Chloroorienti Acitemate; Aclatonium; Aconiazide, Acrivastinet, Adafenox 45 cin B: Cholecalciferol: Cholestyramine; Choriogonadotropin ate; Adatanserin; Adefovir Dipivoxil; Adelmidrol; Ademe Alfa: Chromic Phosphate, P-32; Chymopapain; Chymot tionine; Adiposin; Adrafinil; Alacepril; Aladapcin; Alaptide; rypsin; Cibenzoline: Ciclesonide: Cicloprolol; Cilansetron; Alatrofloxacin Mesylate; Albolabrin; Albumin Chromated Cilnidipine: Cilobradine: Cilostazol; Cimetropiurn Bromide: Cr-51 Serum; Albumin Human; Albumin Iodinated I-125 Cinitapride; Cinolazepam: Ciprostene: Cisapride Monohy Serum; Albumin Iodinated 1-131 Serum; Aldecalmycin; 50 drate; Cisatracurium, Besilate: Cistinexine: Citalopram; Cit Alendronic Acid, Alentemol; Alfacalcidol; Alfuzosin; allopram Hydrobromide: Citicoline; Citreamicin Alpha; Alglucerase; Alinastine; Alitretinoin, Alkavervir, Allopu Clausenamide; Clidinium Bromide; Clinafloxacin; Clom rinol Sodium; Almotriptan Malate; Alosetron: Alpha ethiazole; Clopidogrel; Clopidogrel Bisulfate; Cobalt Chlo Idosone: Alpha-Tocopherol; Alpha-Tocopherol Acetate; ride, Co-57; Cobalt Chloride, Co-60; Colesevelam Hydro Alseroxylon; Altromycin B; Amantadine-HCl, Ambenonium 55 chloride; Colestimide: Colfosceril Palmitate; Complestatin: Chloride; Amelometasone; Amezinium Metilsulfate; Amfeb Contignasterol; Contortrostatin: CorticotropinZinc Hydrox utamone; Amifloxacin; Aminolevulinic Acid Hydrochloride; ide: Cosalane; Costatolide; Cotinine; Cournermycin AI; Aminosalicylic Acid Resin Complex: Amiodarone Hydro Cryptenamine Acetates; Cryptenamine Tannates: Cucumari chloride; Amisulpride; Amlodipine; Ammonium Lactate; osid; Curdlan Sulfate; Curiosin; Cyanocobalamin; Cyanoco Amphetamine Adipate; Amphetamine Aspartate; Amphet 60 balamin, Co-57: Cyanocobalamin, Co-58: Cyanocobalamin, amine Resin Complex: AmpiroXicam, Amprenavir, Amylin; Co-60; Cyclazosin: Cyclic HPMPC: Cyclobenzaprine: Amythiamicin; Ananain; Anaritide; Anileridine Phosphate: Cyclobut A: Cyclobut G: Cyclocapron; Cyclosin: Cyclothia Anisindione; Anordrin; Apadoline: Apafant; Apraclonidine; lidine; Cyclothiazomycin; Cycrimine Hydrochloride; Cypro Aprepitant; Aprosulate Sodium; Aprotinin Bovine; Apti terone: Cysteamine Bitartrate; Cytochalasin B; Dactimicin; ganel; Aranidipine; Arbekacin; Arbidol; Arbutamine: Arecat 65 Daidzein; Daidzin; Danaparoid; Daphnodorin A; Dapipra annin B1; Argatroban; Aripiprazol; Aripiprazole; Arotinolol; Zole; Dapitant; Darifenacin: Darlucin A; Darsidomine: Articaine Hydrochloride: Ascorbic Acid; Asimadoline; Daunorubicin Citrate; DdUTP, Decamethonium Bromide: US 8,343,962 B2 29 30 Deferiprone; Deferoxamine Mesylate: Dehydrodidemnin B; Acetate; Hyaluronidase; Hydrocortamate Hydrochloride; Delapril; Delequarnine; Delfaprazine; Delmopinol; Del Hydrocortisone Cypionate; Hydrocortisone Probutate; phinidin; Deoxypyridinoline; Deprodone; Depsidomycin Hydro quinone; Hydroxocobalamin; Hydroxypropyl Cellu deramciclane; Dermatan Sulfate; Deserpidine; Desirudin; lose; Hydroxy stilbamidine Isethionate; Ibandronate Sodium; Desloratadine; Desmopressin: Desoxoamiodarone; DeSox Ibogaine; Ibudilast; Ibuprofen Potassium: Icodextrin; Illi yribonuclease: Detajrniurn Bitartrate; Dexketoprofen; Dex maquinone; Iloprost, Imatinib Mesylate: Imidapril; Imidaze loxiglumide; Dexmethylphenidate Hydrochloride; Dexra nil. Imiglucerase: Imipramine Pamoate; Inamrinone Lactate; Zoxane Hydrochloride; Dexsotalol: Dextrin 2-Sulphate: Indapamide: Indinavir, Indinavir Sulfate; Indium In-III Dextroamphetamine Adipate; Dextroamphetamine Resin Oxyquinoline; Indium In-III Pentetate Disodium; Indium In Complex; Dextroamphetamine Saccharate; Dextrose; 10 III Pentetreotide Kit; Indometacin; Indometacin Farnesil; Diclofenac Digolil; Dicranin; Dienogest; Diethylhomospen Indomethacin Sodium; Inocoterone; Inogatran; Inolimomab; nine; Diethylnorspermine; Difenoxin Hydrochloride; Dihy Insulin Aspart; Insulin Aspart Protamine; Insulin Glargine; drexidine; Diltiazeim; Dimethyl Prostaglandin Al; Dimeth Insulin Lispro Protamine; Interferon Alfa: Interferon Alfa ylhomospermine; Dimiracetarn; Dimyristoyl Lecithin; NI; Interferon Beta; Interferon Beta-Ial; Interferon Gamma-I Diphemanil Methylsulfate; Diphencyprone; Diphenylpyra 15 A: Interferon Gamma-I B; Interferon Omega; Interferon, line Hydrochloride; Diprafenone; Dipropylnorspermine: Consensus; Interleukin-3; Interleukin-1, Interleukin-I Beta; Discodermolide; Divalproex: Docarparnine; Docosanol, 1-: Interleukin-10; Interleukin-II; Interleukin-12; Interleukin Dolasetron Mesylate Monohydrate; Domitroban; Donepezil 15: Interleukin-2: Interleukin-4; Interleukin-5; Interleukin-7: Hydrochloride; Dorzolamide; Dosmalfate; Dotarizine; Dox Interleukin-8; Interleukin I Alpha; Intrinsic Factor; Inulin; azosin; Doxercalciferol: Draculin; Drosperidone; Dro Invert Sugar, Iobenguane Sulfate I 131; Iobitridol; Iodamide spirenone; Drotaverine Acephyllinate; Droxicam; Dutast Meglumine: Iodipamide Sodium; Iodoamiloride: Iodohippu eride; Ebiratide: Ebrotidine; Ecabapide; Ecabet; Ecdisteron; rate Sodium, 1-123: Iodohippurate Sodium, 1-131; Iofe Echicetin; Echistatin; Ecteinascidin 722; Ecteinascidin 729; tamine Hydrochloride 1-123: Iofratol; Iopromide: Iopyrol: Ecteinascidin 743; Edaravone; Edetate Calcium Disodium; Iorneprol; Iothalamate Sodium, 1-125; Iotriside; Ioxaglate Edetate Disodium; Edobacomab; Edrecolornab; Efavirenz; 25 Sodium; Ipazilide; Ipenoxazone; Ipidacrine; Ipomeanol. 4; Efegatran; Efonidipine; Egualen; Elcatonin; Eletriptan; Elet Ipriflavone; Ipsapirone; Irbesartan; Irloxacin; Iron Dextran; riptan Hydrobromide; Elgodipine; Eliprodil; Eltenac: Iron Sucrose; Irternazole; Isalsteine; Isbogrel, Iseparnicin; Emakalim; Emedastine; Emedastine Difumarate; Emiglitate; Isofloxythepin; Isopropyl Unoprostone; Itameline; Itopride; Emoctakin; Emtricitabine; Enalapril: Enazadrem; Enfu Ketoprofen, R-; Ketoprofen, S ; Ketorolac, Lactitol; Lac Virtide; EnglitaZone; Entacapone; Enterostatin: Eplerenone; 30 tivicin, Lactulose; Laennec; Lafutidine; Lanoconazole; Lan Epoxymexrenone; Eptastigmine: Eptifibatide; Erdosteine: perisone; Larnifiban; Larnotrigine; Latanoprost; Lateritin; Ergocalciferol: Ersentilide: Ertapenem Sodium: Erythritol: Laurocaprarn: Leflunomide: Lemefloxacin: Leminoprazole; Escitalopram Oxalate; Esomeprazole Magnesium: Esta Lenercept; Lepirudin; Leptin; Lercanidipine; Lerisetron; Zolam: Estradiol Acetate; Esuprone; Etanterol: Ethacizin; Lernildipine; Lesopitron: LetraZuril; Leucomyzin; Leval Ethchlorvynol; Ethinamate; Ethinylestradiol: EthoXZola 35 buterol Hydrochloride; Levallorphan Tartrate; Levamisole mide: Etidocaine Hydrochloride: Etizolam: Etrabamine; Hydrochloride; Levetiracetam; Levobetaxolol; Levobunolol; Eveminomicin; Examorelin; Ezetimibe; Faerieftmgin; Levobupivacaine; Levobupivacaine Hydrochloride; Levo Fantofarone; Famciclovir; Faropenem; Fasidotril; Fasudil; cabastine; Levocarnitine; Levodropropizine; Levofloxacin; Fedotozine; Felbarnate; Fenofibrate: Fenoldopam; Fen Levopropoxyphene Napsylate, Anhydrous; Levormelox spiride; Fentanyl: Fenticonazole; Fepradinol; Ferpifosate 40 ifene; Levornoprolol; Levosimendan; LevoSulpiride; Lin Sodium; Ferristene; Ferrixan; Ferrous Citrate, Fe-59; Fex dane; Linezolid; Linotroban; Linsidormine; Lintitript; Linto ofenadine Hydrochloride; Fibrinogen, 1-125; Fibrinolysin; pride; Lipase, Lirexapride; Lithium Carbonate; Lithium Flecainide; Flerobuterol; Flesinoxan; Flezelastine; Flobufen; Citrate; Lodoxamide; Lomerizine; Lonazolac, Lopinavir, Flomoxef Florfenicol; Florifenine; Flornastat; Flosatidil; Lorglumide: Losartan; Losigamone; Loteprednol; Loviride; Fludeoxyglucose, F-18; Flumecinol; Flunarizine: Fluocal 45 Loxapine Hydrochloride; LpdR; Lubeluzole; Lutetium: Luz citriol; Fluoxetine, R—: Fluoxetine, S ; Fluparoxan: Flu indole; Lydicamycin; Lysostaphin, Magainin 2 Arnide; Mag pirtine: Flurbiprofen Axetil: Flurithromycin; Flutamide: nesium Acetate; Magnesium Acetate Tetrahydrate; Mag Flutrimazole; Fluvastatin: Fluvoxamine; Folic Acid; Fol nolol; Malathion; Mallotochromene; Mallotojaponin; litropin Alfa: Follitropin Alfa/Beta; Fomivirsen Sodium; Mangafodipir; Mangafodipir Trisodium; Manidipine: Mani Fondaparinux Sodium; Forasartan; Formoterol; Formoterol 50 wamycin A; Mannitol; Manurnycin E: Manurnycin F: Mapi Fumarate; Formoterol, R.R. Fosinopril; Fosphenytoin: Fro nastine; Martek 8708; Martek 92211; Massetolide; Meglu Vatriptan Succinate; Fulvestrant; Furosernide; Gadobenic mine Metrizoate; Meloxicam; Melphalan Hydrochloride; Acid; Gadobutrol: Gadodiamide-EOB-DTPA; Gadopen Menadiol Sodium Diphosphate; Menadione; Meprednisone: tetate Dimeglumine; Gadoteric Acid, Galantamine; Galan Mequinol; Mersalyl Sodium; Mesna; Metformin Hydrochlo tamine Hydrobromide; Galdansetron; Gallopamil: Gamo 55 ride; Methantheline Bromide; Metharbital; Methoxamine lenic Acid; Gatifloxacin; Gefitinib; Gemifloxacin Mesylate: Hydrochloride; Methoxatone; Methoxsalen; Methscopola Gemtuzumab OZogamicin; Gepirone; Girisopam; Glaspi mine Bromide; Methyclothiazide; Methyldopa; Methylhista mod: Glatiramer Acetate; Glaucocalyxin A; Glucagon mine, R-alpha; Methylinosine Monophosphate; Methylpred Hydrochloride: Glucagon Hydrochloride Recombinant: Glu nisolone Aceponate; Methyprylon; Metiparinide; cagon Recombinant, Gluconolactone; Glutapyrone; Glu 60 Metipranolol Hydrochloride; Metolazone: Metoprolol tathione Disulfide; Glycopine; Glycopril; Goserelin Acetate; Fumarate; Metoprolol, S ; Metoprotol Tartrate; Metri Grepafloxacin; Grepafloxacin Hydrochloride; Guaifenesin: fonate; Metrizoate Magnesium; Metrizoic Acid; Mezlocillin Guanidine Hydrochloride; Halichondrin B; Halofantrine; Sodium Monohydrate; Michellarnine B: Microcolin A; Halomon; Haloperidol Lactate; Halopredone; Hatomarubi Midodrine; Miglustat; Milacernide; Milarneline; Mildronate: gin C. Hatornambigin D; Hatornamicin; Hatornarubigin A; 65 Milnacipran; Milrinone Lactate; Miokarnycin; Mipragoside: Hatornarubigin B; Heparin Calcium; Heparin Sodium; Hexo Mirfentanil; MivaZerol; Mixanpril; Mizolastine; Mizoribine; cyclium Methylsulfate; Hexylcaine Hydrochloride; Histrelin Moexipril; Moexipril Hydrochloride; Mofezolac: Mometa US 8,343,962 B2 31 32 sone; Mometasone Furoate Monohydrate; Monobenzone: sidase; Safflower Oil: Safironil; Salbutamol, R—; Salnace Montirelin; Moracizine; Moricizine Hydrochloride: din, R-; Samarium Sm 153 Lexidronam Pentasodium; San Mosapramine; Mosapride: Motilide; Moxifloxacin Hydro fetrinem; Saprisartan; Sapropterin; Saquinavir, Sarcophytol chloride; Moxiraprine; Moxonidine; Mupirocin; Mupirocin A Sargramostim; Sarneridine, Sarnpatrilat, Sarpogrelate; Calcium; Mycophenolate Mofetil Hydrochloride; Nadifloxa 5 Saruplase; Saterinone; Satigrel; Satumomab Pendetide; Sco cin; Nadroparin Calcium; Nafadotride; Nafamostat; Naftopi polamine; Secretin: Selenomethionine, Se-75; Sematilide; dil; Naglivan; Nalmefene Hydrochloride; Naltrexone Hydro Sermorelin; Sermotiadil; Sertaconazole; Sertraline; Sertra chloride; Napadisilate; Napsagatran; Naratriptan; line-HCl; Setiptiline: Sevelamer Hydrochloride: Sevirurnab: Nasaruplase; Nateglinide; Nateplasel; Nelfinavir Mesylate: Sezolamide: Sildenafil Citrate; Silipide: Silteplase; Silver Nesiritide; Niacinamide; Nicotine; Nicotine Polacrilex; 10 Sulfadiazine; Simendan; Simethicone; Simethicone-Cellu Niperotidine; Niravoline; Nisin; Nitazoxanide; Nitecapone: lose: Sinitrodil; Sinnabidol; Silpatrigine; Sirnvastatin: Nitisinone; Nitrendipine, S ; Nitrofurantoin Monohydrate; Somatomedin C; Somatropin Recombinant; Sorbitol; Sor Nitrofurantoin Sodium; Nitrofurantoin, Macrocrystalline; natomedin B: Somatrem: Somatropin; Sotalol; Staurospo Nitrofurazone: Nitroglycerin: Nonoxynol-9; Norel rine; Stepronin; Stobadine: Strontium Chloride, Sr-89: Suc gestromin; Octyl Methoxycinnamate; Olmesartan Medox 15 cibun; Sulfanilamide: Sulfaphenazole; Sulfapyridine: omil; Olopatadine; Olopatadine Hydrochloride; Olprinone; Sulfoxamine; Sulfoxone Sodium; Sulfur, Sultamicillin; Sul Olsalazine; Omeprazole Magnesium, Ondansetron, R-; topride: Sumatriptan; Sutilains; Symakalim; Talbutal; Tan Oral Hypoglyceremics; Orphenadrine Hydrochloride; Osel doSpirone; Tannic Acid; Tapgen; Taprostene; Tartaric Acid; tamivir Phosphate: Otenzepad: Oxamisole: Oxaprozin Potas Tazanolast; Tegaserod Maleate; Telenzepine; Telmesteine: sium, Oxcarbazepine; Oxiconazole; Oxiracetam; Oxodipine; Telmisartan; Temocapril; Tenofovir Disoproxil Fumarate; Oxybenzone; Oxybutynin: Oxyphencyclimine Hydrochlo Tenosal; Tepirindole; Terazosin; Terbinafine Hydrochloride: ride; Oxyphenonium Bromide: OZagrel; Palauarnine: Pali Terflavoxate; Terguride; Terlipressin; Terodiline; Tertatolol; navir; Palonosetron Hydrochloride; Pamaparin Sodium; Pan Testosterone Buciclate: Thallous Chloride, TI-201; Thia amesine; Pancrelipase; Panipenem; Panipenum; Pannorin; mine; Thiamine Hydrochloride; Thiofedrine; Thiomarinol: Panornifene; Pantethine; Pantoprazole Sodium; Pantothenic 25 Thioperamide: Thiosemicarbazone; Thonzonium Bromide: Acid; Paramethadione; Paricalcitol; Parnaqueside; Par Thyroglobulin; Thyrotropin; Thyrotropin Alfa; Tiagabine; nicogrel; Paroxetine Hydrochloride; Paroxetine Mesylate: Tiagabine Hydrochloride; Tianeptine; Tiapafant; Ticlopi Parthenolide; PaZufloxacin; Pegademase Bovine; Pegviso dine: Tienoxolol; Tilisolol; Tilnoprofen Arbamel: Tiludronic mant; Pemirolast; Pemirolast Potassium; Penciclovir Acid; Tiopronin; Tiotropium Bromide; Tirandalydigin; Tir Sodium; Penicillamine; Pentafuside; Pentagastrin; Pentami 30 ilazad; Tirofiban; Tiropramide; Tocopherol Acetate; Toltero dine; Pentamidine Isethionate; Pentetate Calcium Trisodium dine Tartrate; Torasemide; Trafennin; Trandolapril; Tranyl Yb-169; Pentigetide; Pentolinium Tartrate; Pentosan: Per cypromine Sulfate; Travoprost; Traxanox; Trazodone-HCl; flexane: Perfluoropolymethylisopropyl Ether; Perflutren: Treprostinil Sodium; Tretinoin Tocoferil; Triarntevene: Tri Pergolide; Pergolide Mesylate: Perindoprilat; Pernedolac: caprilin; Trichohyalin; Trichosanthin, Alpha; Triclosan; Perospirone; Phenaridine; Phenindione; Pheniramine Male 35 Tridihexethyl Chloride; Trientine; Trientine Hydrochloride: ate; Phenmetrazine Hydrochloride; Phenotoxifvline: Triflavin; Trimegestone; Trimethoprim Hydrochloride; Tri Phenserine; Phensuccinal; Phentermine Resin Complex: oxsalen; Triptorelin Pamoate: Trolamine Polypeptide Oleate Phentolamine Mesilate; Phenylalanyl Ketoconazole; Phe Condensate; Trombodipine; Trometarnol; Tromethamine: nylephrine Bitartrate; Phenytoin Sodium, Extended; Pheny Tropine Ester; Trospectomycin; Trovafloxacin; Trovafloxa toin Sodium, Prompt; Phosphoric Acid; Phytonadione: 40 cin Mesylate; Trovirdine; Tucaresol; Tulobuterol; Tylogenin: Picenadol; Picroliv; Picumeterol; Pidotimod: Pilsicainide; Tyloxapol: Undecoylium Chloride; Undecoylium Chloride Pimagedine: Pimecrolimus; Pimilprost; Pinocebrin; Pioglita Iodine Complex: Unoprostone Isopropyl; Urapidil; Urea, Zone: Piperonyl Butoxide: Pirlindole: Pirmenol; Pirodornast; C-13; Urea, C-14; Uridine Triphosphate; Valaciclovir; Valde Polyestradiol Phosphate: Polyethylene Glycol 3350; Polytet coxib; Valganciclovir Hydrochloride; Valproate Magnesium; rafluoroethylene; Poractant Alfa: Potassium Chloride; Prami 45 Valproate Semisodium; Valrubicin; Valsartan: Vamicamide: pexole Dihydrochloride; Praziquantel; Prazosin; Prilocaine; Vanadeine; Vaninolol; Vasopressin Tannate; Venlafaxine; Procaine Merethoxyline: Proguanil Hydrochloride: Verapamil, (S); Veratrum Viride: Veroxan: Vexibinol; Vinbur Propagermanium; Propentofylline: Propiolactone: Propiom nine Citrate; Vinburnine Resinate; Vinconate; Vinpocetine; azine Hydrochloride: Propionylcamitine, L-; Propiram; Vinpocetine Citrate; Vintoperol; Viomycin Sulfate; Vitamin Propiram-- Paracetarnol; Propiverine; Prostratin: Protegrin: 50 A; VitaminA Palmitate; Vitamin E: Vitamin K; Voriconazole; Protein Hydrolysate; Protokylol Hydrochloride; Protosu Voxergolide; Warfarin Potassium; Xemilofiban: Ximopro floxacin; Prulifloxacin; Pyrethrins; Pyridoxine: Pyridoxine fen, Yangarnbin, Zabicipril; Zacopride; Zacopride, R-; Hydrochloride; Quazeparn; Quetiapine; Quetiapine Fuma Zafirlukast; Zalospirone; Zaltoprofen, Zanamivir; Zanar rate; Quiflapon; Quinagolide; Quinapril; QuinethaZone; Qui nivir; Zankiren, Zatebradine; Zatosetron; Zenarestat; nidine Polygalacturonate; Raloxifene: Ramatroban; Ranelic 55 Zinostatin Stimalarner; Ziprasidone; Ziprasidone Mesylate: Acid; Ranolazine; Rapacuronium Bromide; Recainarn; Zoledronic Acid; Zolmitriptan; Zolpidern; Zopiclone; Zopi Regavirumab, Repaglinide; Rescinnamine; Resinferatoxin; clone, S ; Zopolrestat; and Zotepine. Reticulon; Reviparin Sodium; Revizinone; Riboflavin; Ribo Still other examples of therapeutically active agents are flavin Phosphate Sodium; Ricasetron; Rilopirox; Rimanta listed in 2000 MedAdNews 19:56-60 and The Physicians dine; Rimexolone; Rimoprogin; Riodipine; Ripisartan; 60 Desk Reference, 53rd. Edition, pages 792-796, Medical Eco Risedronic Acid; Rispenzepine; Ritipenem Acoxil; Ritipen nomics Company (1999). ern; Ritonavir; Rivastigmine Tartrate; Rizatriptan Benzoate: The topical formulations of the present invention may Rnibefradil; Rnivacurium Chloride; Rofecoxib; Rokitamy include one or more skin care actives. "Skin care actives' cin; Ropinirole; Ropivacaine; Ropivacaine Hydrochloride means all compounds or Substances now known or later dem Monohydrate; Roquinirnex; Rose Bengal Sodium, 1131; 65 onstrated to provide benefit when applied to skin and all Rosiglitazone Maleate; Roxatidine; Roxindole; Rubidium compounds now claimed or in the future claimed to provide Chloride Rb-82; Rufloxacin: Rupatidine. Ruzadolane; Sacro benefit when applied to skin. Skin care actives may provide US 8,343,962 B2 33 34 benefits, or claimed benefits, in areas Such as one or more of suitable NSAIDs that may be used in the present topical wrinkle removal or wrinkle reduction, firming of skin, exfo formulation are described above. For example the formula liation of skin, skin lightening, treatment of dandruff, treat tion described above may includediclofenac, and particularly ment of acne, skin conditioning, development of tans and diclofenac sodium, as the at least one active agent. artificial tans, improvement of skin moisture content, The topical formulation described above may also include improvement of skin barrier properties, control of Sweat, propylene glycol. The propylene glycol may be present in the anti-aging, reduction or avoidance of irritation and reduction formulation between about 1% to about 25% w/w. Addition or avoidance of inflammation. Examples of skin care actives ally the topical formulation may also include ethanol and/or include molecules such as peptides, proteins, oligonucle polyethylene glycol 300. The ethanol may be present in the otides, fullerenes as well as small molecules. Skin care 10 formulation between about 1% to about 25% w/w. The poly actives may be protease and/or enzyme inhibitors, anti-coen ethylene glycol 300 may be present in the range of between Zymes, chelating agents, antibodies, antimicrobials, humec about 1% to about 80% w/w. In addition the topical formula tants, vitamins, skin protectants, antioxidants and/or skin tion may include at least one moisturizer/humectant. Soothing agents, plant extracts and the like. Examples of skin The present invention provides an improved topical formu care actives include but are not limited to vitamin C, vitamin 15 lation for preferably facilitating topical or transdermal E (alpha tocopherol), retinoids, Soy derivatives (e.g. isofla administration of at least one therapeutically active agent. Vones), green tea polyphenols, alpha hydroxy acids (e.g. gly This enhanced effect is discussed further below and illus colic and lactic acids), betahydroxy acids (e.g. salicylic acid), trated in preferred embodiments of the invention described in polyhydroxy acids, alpha lipoic acid, hemp oil (glycerides), the Examples. In another preferred embodiment the topical niacinamide, dimethylamino ethanol, coenzyme Q10, kine formulation of the present invention provides a means for tin (plant growth hormone), dimethyl sulfone and botulinum targeting atherapeutically active agent to local tissue either in toxin. Other examples of skin care actives may be found in the skin or the underlying tissue. This latterpreferred embodi The Perricone Prescription by Nicholas Perricone, Harper ment may be particularly beneficially applied for treatment of Collins Publishers Inc., New York, 2002. conditions such as osteoarthritis and dermatological condi The topical formulations described herein may also 25 tions. The topical formulations may be applied either occlu include one or more cosmetically orpharmaceutically accept sively or nonocclusively to the skin. In another preferred able carriers/excipients. Suitable carriers/excipients that may embodiment of the invention, in applications where the objec be used in the topical formulations discussed herein are tive is transdermal administration of a therapeutically active known in the art and include, but are not limited to, solubi agent to the systemic circulation, the topical formulation is lizers such as C. to Cs straight and branched chain alcohols, 30 applied to the skin under occlusion in a transdermal patch. diols and triols, moisturizers and humectants such as glycer The present topical formulation may be applied to the skin ine, amino acids and amino acid derivatives, polyaminoacids by any means known in the art including, but not limited to, by and derivatives, pyrrolidone carboxylic acids and their salts an aerosol, spray, pump-pack, brush, Swab, or other applica and derivatives, Surfactants such as Sodium laureth Sulfate, tor. Preferably, the applicator provides either a fixed or vari Sorbitan monolaurate, emulsifiers such as cetyl alcohol, 35 able metered dose application Such as a metered dose aerosol, Stearyl alcohol, thickeners such as methyl cellulose, ethyl a stored-energy metered dose pump or a manual metered dose cellulose, hydroxymethylcellulose, hydroxypropylcellulose, pump. Preferably the drug delivery system is applied to the polyvinylpyrrolidone, polyvinyl alcohol and acrylic poly skin of the human or animal covering a delivery Surface area mers. Other examples of suitable excipients, such as binders between about 10 and 800 cm, more preferably between and fillers are listed in Remington's Pharmaceutical Sci 40 about 10 and 400 cm, and most preferably about 10 and 200 ences, 18th Edition, Ed. Alfonso Gennaro, Mack Publishing cm. The application is most preferably performed by means Co. Easton, Pa., 1995 and Handbook of Pharmaceutical of a topical metered dose spray combined with an actuator Excipients, 3rd Edition, Ed. Arthur H. Kibbe, American Phar nozzle shroud which together accurately control the amount maceutical Association, Washington, D.C. 2000. and/or uniformity of the dose applied. One function of the The topical formulations of the present invention may also 45 shroud is to keep the nozzle at a pre-determined height above, beformulated to include other chemical penetration enhanc and perpendicular to, the skin to which the drug delivery ers which have significant ability to enhance transport of system is being applied. This function may also be achieved actives. Such substances may have the character of Surfac by means of a spacer-bar or the like. Another function of the tants, a Zone-like compounds, solvents, alcohols, fatty acids, shroud is to enclose the area above the skin in order to prevent fatty esters, aliphatic thiols and the like. Examples of chemi 50 or limit bounce-back and/or loss of the drug delivery system cal penetration enhancers are reported in the paper of Santus to the surrounding environment. Preferably the area of appli et al. (Santus, C. G. and Baker, R. W., Transdermal enhancer cation defined by the shroud is substantially circular in shape. patent literature. Journal of Controlled Release 1993.25:1- The drug delivery system may be a unit volume dispenser 20.) with or without a roll-on or other type of applicator. It may The topical formulation of the present invention may be 55 also be necessary to apply a number of dosages on untreated formulated by those skilled in the art as liquids, Solutions, skin to obtain the desired result. emulsions, creams, lotions, Suspensions, triturates, gels, jel Embodiments of the invention will be described with ref lies, foams, pastes, ointments, shampoos, adhesives and the erence to the following Examples which are provided for like. illustrative purposes only and should not be used to limit the The penetration enhancing effect may be measured using 60 Scope of or construe the invention. techniques known in the art. An example of one measurement method is described in the Examples below. EXAMPLES Preferably, the topical formulation includes at least one active agent such as a therapeutically effective agent or a skin Materials and Methods for Examples 1-7 care active. Examples of Suitable active agents are described 65 A number of formulations (described in Examples 1-7 above. Preferably, the at least one active agent comprises a below) containing diclofenac sodium (a non-steroidal anti non-steroidal antiinflammatory drug (NSAID). Examples of inflammatory drug or NSAID) were tested for permeation US 8,343,962 B2 35 36 through porcine skin using the Franz diffusion cells as gen Example 1 erally described in Franz T J. Percutaneous absorption. On the relevance of in vitro data. J. Invest Dermatol 1975; In this Example, N-lauroyl sarcosine (NLS) and isopropyl myristate (IM) were added to the base formulation. The 64:190-195. details of each formulation and the results of the Franz diffu More specifically, Franz cells with a 5 ml receptor well sion cell experiments are set out in Table 3. Volume were used in conjunction with full-thickness porcine With reference to Table 3, it can be seen that Formulation 2 skin harvested at Perry Scientific (San Diego, Calif.). The (containing a mixture of NLS and IM each at a concentration porcine skin was shaved free of hair, washed with water and 2.5% wt/vol.) was more effective at enhancing diclofenac subcutaneous fat was removed. The donor well had an area of sodium flux rates through the skin when compared to either of ~0.5 cm.Receptor wells were filled with isotonic phosphate 10 Formulation 3 (containing 5% wt./vol NLS and no IM) or buffered saline (PBS) doped with 0.01% sodium azide. The Formulation 4 (containing 5% wt.?vol IM and no NLS). flanges of the Franz cell were coated with vacuum grease to Further and Surprisingly, Formulation 1 (containing a mix ensure a complete seal and were clamped together with uni ture of NLS and IM each at a concentration of 1.5% wt./vol) was approximately seven times more effective at enhancing form pressure using a pinch clamp (SS #18 VWR 80073 15 350). the flux rate of the diclofenac sodium when compared to After the Franz cells were assembled, the porcine skin was Formulation 2. allowed to pre-hydrate for 45 minutes with isotonic PBS. Example 2 Isotonic PBS was then removed and 200 ml of the formula tion was applied to the donor well. Receptor wells of the In this Example, N-lauroyl sarcosine (NLS) and oleic acid Franz cells were maintained at 37° C. (temperature on the (OA) were added to the base formulation. The details of each surface of the skin is -30°C.) in a stirring block with con formulation and the results of the Franz diffusion cell experi tinual agitation via a stir bar. ments are set out in Table 4. The flux rates were calculated by assuming a radius of 0.4 With reference to Table 4, it can be seen that Formulation 5 cm in the donor well (i.e., an area of 0.503 cm). The HPLC 25 (containing a mixture of NLS and OA each at a concentration calibration curve for diclofenac was determined to have a 1.5% wt/vol.) was more effective at enhancing diclofenac slope of 115.6 AUC/(ug diclofenac/ml). sodium flux rate through the skin when compared to either of Samples were drawn from the receptor wells at t=24 hours Formulation 6 (containing 5% wt.?vol NLS and no OA) or and t=46 hours for all formulations. Franz diffusion cell mea Formulation 7 (containing 5% wt.?vol OA and no NLS). It is notable that the flux rate of the NSAID in Formulation surements were made in five-fold replicates for each formu 30 lation. 5 was higher than that achieved by either of Formulation 6 or The concentration of diclofenac in the samples was mea Formulation 7 in spite of the fact that the total concentration sured using HPLC analysis. Specifically, HPLC was carried of the molecular penetration enhancers in Formulation 5 was out with C18 column and using acetonitrile and water as the lower that that in Formulation 6 and Formulation 7. mobile phase. Flux rates were calculated using standard equa 35 Example 3 tions based on the total transference of diclofenac across the skin after 46 hours. Thus, flux rates, F, were computed In this Example, sodium octyl sulfate (SOS) and oleic acid according to (OA) were added to the base formulation. The details of each formulation and the results of the Franz diffusion cell experi 40 ments are set out in Table 5. Da V With reference to Table 5, it can be seen that Formulation 8 t: A (containing a mixture of SOS and OA each at a concentration 1.5% wt/vol and 3.5% wt/vol, respectively) was more effec wherein: D is the concentration of the drug in the receptor tive at enhancing diclofenac sodium flux rate through the skin well after incubation time t, V is the volume of the receptor 45 when compared to either of Formulation 9 (containing 5% well and A is the surface are of skin. wt.?vol OA and no SOS) or Formulation 10 (containing 5% Individual penetration enhancers in the Examples dis wt.?vol SOS and no OA). cussed below were obtained from the following sources: Example 4 glyceryl oleate (glycerol monooleate) from TCI (VWR), product code TCG0082 50 In this Example, glyceryl oleate (GO) and sodium octyl isopropyl myristate from Sigma product code M0757 sulfate (SOS) were added to the base formulation. The details methyl laurate from Chem Service product code CSO426 of each formulation and the results of the Franz diffusion cell N-lauroyl sarcosine from Sigma product code L5000 experiments are set out in Table 6. oleic acid (octadecenoic acid) from Mallinckroft (VWR) With reference to Table 6, it can be seen that Formulation product code MK274.404 55 11 (containing a mixture of GO and SOS each at a concen sodium lauryl sulfoacetate from Stepan (65-72%) product tration 1.5% wt/vol.) was approximately as effective at code Lathanol LAL enhancing diclofenac sodium flux rate through the skin as sodium octyl sulfate from Alfa Aesar (VWR) product code Formulation 12 (containing 5% wt./vol GO and no SOS) and AA43750-06 was substantially improved over that of Formulation 13 (con The base composition used for each formulation of a car 60 taining 5% wt./vol SOS and no GO). rier composition comprising isotonic PBS, ethanol, propy lene glycol and propylene glycol 300 in a volume ratio of Example 5 2:2:1:1. The base formulation further comprised diclofenac sodium in a concentration of 1.5 wt.% per unit volume of the In this Example, glyceryl oleate (GO) and methyl laurate base composition. In the Examples below, various combina 65 (ML) were added to the base formulation. The details of each tions of the MPETMs detailed below were added to the base formulation and the results of the Franz diffusion cell experi composition. ments are set out in Table 7. US 8,343,962 B2 37 38 With reference to Table 7, it can be seen that Formulation prevent skin degradation). Care was taken to ensure all 14 (containing a mixture of GO and ML each at a concentra bubbles are removed from the receptor solution. The skin was tion 2.5% wt/vol.) was more effective at enhancing diclofenac allowed to pre-hydrate for 20 minutes before the formulations sodium flux rate through the skin when compared to either of were applied to the skin. Formulation 15 (containing 5% wt./vol GO and no ML) or 5 Diffusion cell testing: After the skin was prehydrated, 40 ul Formulation 16 (containing 5% wt./vol ML and no GO). of the test formulation was applied to the skin with a positive displacement pipettor and the applied dose then rubbed gen Example 6 tly across the skin with a glass stir rod. Once the formulation was applied, a stir bar was added to the receptor well. The receptor well was maintained at 32° C. and continuously methylIn this laurate Example, (ML) sodiumwere added lauryl to thesulfoacetate base formulation. (SLSA) Theand '' agitated throughout the experiment. Sample aliquots were details of each formulation and the results of the Franz diffu- drawn from the receptor Well at Varying time points and sion cell experiments are set out in Table 8. replaced with fresh PBS buffer. Sample aliquots were filtered With reference to Table 8, it can be seen that Formulation and analyzed for concentration of the active using HPLC 17 (containing a mixture of SLSA and ML each at a concen- analysis. Measurements for each formulation were carried tration 2.5% wit/vol.) was more effective at enhancing 15 out in six-fold replicates. diclofenac sodium flux rate through the skin when compared The individual penetration enhancers used in Example 8 to either of Formulation 18 (containing 5% wt.?vol SLSA and are provided in the following table along with their abbrevia no ML) or Formulation 19 (containing 5% wt./vol ML and no tion (Abbr) and Chemical Abstract Service (CAS) registry SLSA). number: Example 7 2O In this Example, sodium lauryl sulfoacetate (SLSA) and Abbr Chemical CAS isopropyl myristate (IM) were added to the base formulation. IM Isopropyl Myristate 110-27-O The details of each formulation and the results of the Franz SLSA Sodium Lauryl Sulfoacetate 1847-58-1 diffusion cell experiments are set out in Table 9. 25 OA Oleic Acid 112-801-1 With reference to Table 9, it can be seen that Formulation ML Methyl Laurate 111-82-O 20 (containing a mixture of SLSA and IM each at a concen- GO Glyceryl Monooleate 31566-31-1 tration 2.5% wt/vol.) was more effective at enhancing NLS N-lauroyl Sarcosine 97-78-9 diclofenac sodium flux rate through the skin when compared to either of Formulation 21 (containing 5% Wt.?volSLSA and 30 Numerous formulations were prepared with the MMPETMs no IM) or Formulation 22 (containing 5% wt./vol IM and no used in conjunction with varying active agents. MMPETMs SLSA). tested were SLSA/IM, SLSA/ML, IM/NLS, GO/ML, and NLS/OAinahydroalcoholic solution. These MMPETMs were Materials and Methods for Example 8 tested with the active agents ibuprofen, buproprion HCl, keto 35 profen and testosterone. Tables 10-19 list the MMPETMs that Using methodology similar to that described in Examples showed a significant increase in flux when compared to flux 1-7, a number of formulations containing other active agents from the analogous formulations containing only one of the (as described in greater detail below) were tested for perme- MPETMs. ation through porcine skin using Franz diffusion cells. While this invention has been described with reference to Franz Cell Guidelines: illustrative embodiments and examples, the description is not Skin preparation: Porcine skin was sourced from Lampire " intended to be construed in a limiting sense. Thus, various Biological Laboratories (Pipersville, Pa.). The skin was then modifications of the illustrative embodiments, as well as dermatomed in house to a set thickness. other embodiments of the invention, will be apparent to per Diffusion cell assembly: Diffusion cells were assembled sons skilled in the art upon reference to this description. It is using dermatomed porcine skin as the Substrate. Cell assem- therefore contemplated that the appended claims will cover bly was carried out by clamping the skin between a donor well 45 any such modifications or embodiments. Further, all of the (the flange was coated with a thin coating of vacuum grease to claims are hereby incorporated by reference into the descrip ensure a proper seal) and a receptor well. The wells were tion of the preferred embodiments. clamped together and held in place using a spring clamp. All publications, patents and patent applications referred to The receptor wells had a volume of 3.3m1 and the clamped herein are incorporated by reference in their entirety to the skin had an available surface area of -0.55 cm for the diffu- so same extent as if each individual publication, patent or patent sion study. Once the cell was assembled, the receptor well application was specifically and individually indicated to be was filled with PBS containing 0.01 wt % NaNs (to help incorporated by reference in its entirety. TABLE 1.

NSAID TRADE NAME STRUCTURE

Diclofenac Voltaren, Pennsaid C

NH

C OH US 8,343,962 B2 39 40 TABLE 1-continued

NSAID TRADENAME STRUCTURE

Indomethacin Indocin

Sulindac Clinoril F

OH

O

S-CH3 O Tolimetin Tollectin R \, OH & J

Naproxen Naprosyn, Aleve

Ibuprofen Advil, Brufen, Motrin OH

O

Flurbiprofen Ansaid, Flurwood, Froben OH

O

F

Ketoprofen Orudis O

OH

O US 8,343,962 B2 41 42 TABLE 1-continued

NSAID TRADENAME STRUCTURE

Ketorolac Acular, Toradol O

OH Fenoprofen Nalfon O-Ol. Bromfenac Xibrom O NH2 OH

Br

TABLE 2

COMPOUND TRADENAME STRUCTURE Acetaminophen Tylenol Hs HO O O

Aspirin CO2H N O

Celecoxib Celebrex

e CF N-4N

H2N- S

OIN

Diflunisal Dolobid CO2H F OH US 8,343,962 B2 43 44 TABLE 2-continued

COMPOUND TRADENAME STRUCTURE Etoricoxib Arcoxia O O

V/ 1. S

Piroxicam Feldane, Roxam O O OH

H s 1NsN C / \, Rofecoxib Vioxx S O

Salsalate Disalcid, Monogesic, Salflex, OH O OH Salcitab

O

O

Meloxicam Mobic -(i.--- O OH H N 1. Ns /MV \,

Etodolac Lodine OH

H N o

Oxaprozin Daypro

/ O e OH

US 8,343,962 B2 47 48 TABLE 11 TABLE 1.8

Formu- Ketoprofen NLS OA Flux Formu Ibuprofen SLSA ML Flux lation (wt %/wt %l). (wt %/wt %). (wt %/wt %l). (g/hr/cm) lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (ughr/cm) 5 47 5 3 14.3 48 5 3 9.1 26 3 42.1 49 5 1.5 1.5 18.8 27 3 25.2 28 1.5 1.5 53.9 10 TABLE 19

Formu- Testosterone SLSA IM Flux lation (wt %/wt%). (wt %/wt %). (wt %/wt %). (g/hr/cm) TABLE 12 50 5 3 14.3 15 51 5 3 9.1 Formu Ibuprofen IM NLS Flux 52 5 1.5 1.5 18.8 lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (g/hr/cm)

29 5 3 28S 30 3 1O.O What is claimed is: 31 1.5 1.5 31.0 20 1A topical formulation comprising: (i) at least one active agent, (ii) a first compound, and (iii) a second compound, wherein the first compound and second compound are differ TABLE 13 ent, and each is selected from the group consisting of N-lau 25 royl sarcosine, Sodium octylsulfate, methyl laurate, isopropyl Formu Ibuprofen GO ML lation ( Ren) myristate, oleic acid, glyceryl oleate and sodium lauryl Sul (wt %/wt %). (wt %/wt %). (wt %/wt %). 19. foacetate. 32 5 3 14.4 2. The topical formulation of claim 1, wherein the first 33 5 3 S3.625.2 compound comprises sodium lauryl Sulfoacetate and the sec 34 5 1.5 1.5 30 ond compound comprises isopropyl myristate. 3. The topical formulation of claim 1, wherein the first compound comprises sodium lauryl sulfoacetate and the sec TABLE 1.4 ond compound comprises methyl laurate. Formu Bupropion HCl NLS OA Flux 4. The topical formulation of claim 1, wherein the first lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (g/hr/cm’) 35 compound comprises isopropyl myristate and the second 35 5 3 14.3 compound comprises N-lauryl sarcosine. 36 5 3 9.1 5. The topical formulation of claim 1, wherein the first 37 5 1.5 1.5 18.8 compound comprises glyceryl monooleate and the second compound comprises methyl laurate. '' 6. The topical formulation of claim 1, wherein the first TABLE 1.5 compound comprises N-lauroyl sarcosine and the second compound comprises oleic acid. Formu Bupropion HCl SLSA IM Flux 7. The topical formulation of claim 1, wherein the first lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (ughricm?) 45 compound comprises sodium octyl sulfate and the second 38 5 3 34.3 compound comprises oleic acid. 39 5 3 ... 8. The topical formulation of claim 1, wherein the first 40 5 1.5 1.5 compound comprises glyceryl oleate and the second com pound comprises sodium octyl Sulfate. so 9. The topical formulation of claim 1, further comprising a TABLE 16 biologically acceptable excipient. Formu Bupropion HCl SLSA ML Flux 10. The topical formulation of claim 1, wherein the total lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (g/hr/cm) concentration of the first compound and the second com 41 5 3 pound is up to about 50 wt.%, 40 wt.%, 35 wt.%, 30 wt.%, 42 5 3 ss 25 wt %, 20 wt.%, 15 wt.%, 10 wt.%, 7.5 wt.% or 5 wt.%, 43 5 1.5 1.5 51.3 per unit volume of the formulation. 11. The topical formulation of claim 1, wherein the total concentration of the first compound and the second com pound is in the range of from about 2 wt.% to about 5 wt %, TABLE 17 60 per unit volume of the formulation. Formu IM NLS Flux 12. The topical formulation of claim 1, wherein the total lation (wt %/wt %). (wt %/wt %). (Lig/hr/cm) concentration of the first compound and the second com 44 5 3 pound is in the range of from about 2 wt.% to about 4 wt %, 45 5 3 per unit volume of the formulation. 46 5 1.5 1.5 55.9 65 13. The topical formulation of claim 1, wherein the weight ratio of the first compound to the second compound is in the range of from about 1:9 to about 9:1. US 8,343,962 B2 49 50 14. The topical formulation of claim 1, wherein the weight meloxicam, nabumetone, Oxaprozin, piroxicam, Salsalate, ratio of the first compound to the second compound is in the and rofecoxib, and pharmaceutically acceptable salts and Sol range of from about 1:4 to about 4:1. vates thereof, and mixtures thereof. 15. The topical formulation of claim 1, wherein the weight 23. The topical formulation of claim 1, wherein the at least ratio of the first compound to the second compound is in the one active agent is a phenethylamine. range of from about 1:3 to about 3:1. 24. The topical formulation of claim 23, wherein the phen 16. The topical formulation of claim 1, wherein the weight ethylamine is selected from the group consisting of antide ratio of the first compound to the second compound is in the pressants, anti-anxiety agents, anticholinergic agents, cholin range of from about 1:2 to about 2:1. ergics, dopaminergics, stimulants, serotonin antaogonists, 10 serotonin inhibitors, anti-emetics, antihistamines and/or 17. The topical formulation of claim 1, wherein the weight antipsychotics. ratio of the first compound to the second compound is about 25. The topical formulation of claim 24, wherein the phen 1:1. ethylamine is selected from the group consisting of bupro 18. The topical formulation of claim 1, wherein the at least pion, amphetamine, hydroxyamphetamine, dextroamphet one active agent is an O-aryl alkanoic acid. 15 amine, methamphetamine, ephedrine, epinephrine, 19. The topical formulation of claim 18, wherein the C-aryl pseudoephedrine, dopamine, epinephryl borate, etafedrine, alkanoic acid is an anti-inflammatory drug, Such as a non norepinephrine and oxidopamine, and pharmaceutically steroidal anti-inflammatory drug (NSAID), or an analgesic. acceptable salts and Solvates thereof, and mixtures thereof. 20. The topical formulation of claim 18, wherein the C-aryl 26. The topical formulation of claim 25, wherein the phen alkanoic acid is selected from the group consisting of bro ethylamine is bupropion or a pharmaceutically acceptable mfenac, diclofenac, fenoprofen, flurbiprofen, ibuprofen, salt or solvate thereof. indomethacin, ketoprofen, ketorolac, naproxen, Sulindac and 27. The topical formulation of claim 1, wherein the at least tolimetin, and pharmaceutically acceptable salts and Solvates one active agent is a steroid. thereof and mixtures thereof. 28. The topical formulation of claim 27, wherein the ste 21. The topical formulation of claim 20, wherein the C-aryl 25 roid is selected from the group consisting of hormones, glu alkanoic acid is selected from the group consisting of costeroids, androgens, adrenocortical Steroids, anabolics, diclofenac, ibuprofen and ketoprofen, and pharmaceutically estrogens and/or progestin. acceptable salts and Solvates thereof, and mixtures thereof. 29. The topical formulation of claim 27, wherein the ste 22. The topical formulation of claim 1, wherein the at least roid is testosterone or a pharmaceutically acceptable salt or one active agent is acetaminophen or an NSAID selected 30 solvate thereof. from the group consisting of aspirin, celecoxib, diflunisal, etodolac, etoricoxib, meclofenamic acid, mefenamic acid,