USOO9642912B2

(12) United States Patent (10) Patent No.: US 9,642,912 B2 Kisak et al. (45) Date of Patent: *May 9, 2017

(54) TOPICAL FORMULATIONS FOR TREATING (58) Field of Classification Search SKIN CONDITIONS CPC ...... A61K 31f S7 (71) Applicant: Crescita Therapeutics Inc., USPC ...... 514/171 Mississauga (CA) See application file for complete search history.

(72) Inventors: Edward T. Kisak, San Diego, CA (56) References Cited (US); John M. Newsam, La Jolla, CA (US); Dominic King-Smith, San Diego, U.S. PATENT DOCUMENTS CA (US); Pankaj Karande, Troy, NY (US); Samir Mitragotri, Santa Barbara, 5,602,183 A 2f1997 Martin et al. CA (US); Wade A. Hull, Kaysville, UT 5,648,380 A 7, 1997 Martin 5,874.479 A 2, 1999 Martin (US); Ngoc Truc-ChiVo, Longueuil 6,328,979 B1 12/2001 Yamashita et al. (CA) 7,001,592 B1 2/2006 Traynor et al. 7,795,309 B2 9/2010 Kisak et al. (73) Assignee: Crescita Therapeutics Inc., 8,343,962 B2 1/2013 Kisak et al. Mississauga (CA) 8,513,304 B2 8, 2013 Kisak et al. 8,535,692 B2 9/2013 Pongpeerapat et al. (*) Notice: Subject to any disclaimer, the term of this 9,308,181 B2* 4/2016 Kisak ...... A61K 47/12 patent is extended or adjusted under 35 2002fOOO6435 A1 1/2002 Samuels et al. 2002fOO64524 A1 5, 2002 Cevc U.S.C. 154(b) by 204 days. 2005, OO 14823 A1 1/2005 Soderlund et al. This patent is Subject to a terminal dis 2005.00754O7 A1 4/2005 Tamarkin et al. claimer. 2005, 0196354 A1 9/2005 Soshinsky 2006/0229.364 A1 10/2006 Hobbs et al. (21) Appl. No.: 14/578,812 2008.0075793 A1 3/2008 Dunshee et al. 2011 0028460 A1 2/2011 Kisak et al. (22) Filed: Dec. 22, 2014 2013, OO79371 A1 3/2013 Sundberg et al. 2013,00794.04 A1 3/2013 Kisak et al. (65) Prior Publication Data 2013/O165504 A1 6/2013 Bancel et al. 2013/02599.24 A1 10/2013 Bancel et al. US 2015/0297723 A1 Oct. 22, 2015 FOREIGN PATENT DOCUMENTS Related U.S. Application Data GB 2008.946 6, 1979 (63) Continuation-in-part of application No. 13/791,460, WO WO 96/33706 10, 1996 filed on Mar. 8, 2013, now Pat. No. 9,308,181, which WO WO 2005/OO951O 2, 2005 is a continuation-in-part of application No. (Continued) 13/680,623, filed on Nov. 19, 2012, now Pat. No. 8,513.304, which is a continuation of application No. OTHER PUBLICATIONS 12/848,792, filed on Aug. 2, 2010, now Pat. No. 8.343.962, which is a continuation-in-part of PCT Application No. PCT/CA2014/051049: Filing date Oct. 31, application No. 12/281.561, filed as application No. 2014: Nuvo Research Inc.; International Search Report mailed Feb. PCT/IB2007/001983 on Mar. 6, 2007, now Pat. No. 10, 2015. 7,795,309. (Continued) (60) Provisional application No. 60/778,847, filed on Mar. 6, 2006. Primary Examiner — Raymond Henley, III (51) Int. Cl. (74) Attorney, Agent, or Firm — Thorpe North & A6 IK3I/56 (2006.01) Western, LLP A6 IK 47/8 (2017.01) A 6LX 3/573 (2006.01) A6 IK 47/4 (2017.01) (57) ABSTRACT A6 IK 47/12 (2006.01) A6 IK 9/00 (2006.01) The present disclosure is drawn to topical formulations and A6 IK 47/20 (2006.01) related methods. In one embodiment, a topical formulation A6 IK 9/06 (2006.01) is provided that includes at least one corticosteroid, a first A6DF 7/03 (2006.01) compound, and a second compound. The first compound and A6.1 F 7/O2 (2006.01) second compound are different and each is selected from the (52) U.S. Cl. group consisting of N-lauroyl sarcosine, sodium octyl Sul CPC ...... A61K 47/183 (2013.01); A61F 7/03 fate, methyl laurate, isopropyl myristate, oleic acid, glyceryl (2013.01); A61K 9/0014 (2013.01); A61K 9/06 oleate, and Sodium lauryl Sulfoacetate. (2013.01); A61 K3I/573 (2013.01); A61 K 47/12 (2013.01); A61K 47/14 (2013.01); A61 K 47/20 (2013.01); A61F 2007/0261 (2013.01) 46 Claims, 4 Drawing Sheets US 9,642.912 B2 Page 2

(56) References Cited

FOREIGN PATENT DOCUMENTS

WO WO 2005/O18530 3, 2005 WO WO 2013,106496 T 2013

OTHER PUBLICATIONS Teixeira, et al., “Local anesthetic-induced microscopic and mesoscopic effects in micelles. A fluorescence, spin label and SAXS”; 2001 Biochimica et Biophysica; ACTA 1510 (2001) pp. 93-105. * cited by examiner U.S. Patent May 9, 2017 Sheet 1 of 4 US 9,642,912 B2

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sF10 OF11 US 9,642,912 B2 1. 2 TOPCAL FORMULATIONS FOR TREATING molecules across the skin by, for example, disrupting the SKIN CONDITIONS lipid bilayers of the stratum corneum. Over 300 Substances have been identified as MPETMs but This application is a continuation-in-part of U.S. patent surprisingly few have been successfully developed into application Ser. No. 13/791,460 filed on Mar. 8, 2013 and commercial formulations. Many potent MPETMs are irritat issued as U.S. Patent No. 9.308,181, which is a continua ing to the cells of the epidermis which can limit both the tion-in-part of U.S. patent application Ser. No. 13/680,623. choice and concentration of MPETMs suitable for topical filed Nov. 19, 2012 and issued as U.S. Pat. No. 8,513,304, formulations. Discovery of new MPETMs to increase skin which was a continuation of U.S. patent application Ser. No. permeability is a highly desirable area and has had high 12/848,792, filed Aug. 2, 2010 and issued as U.S. Pat. No. 10 activity over the last 30 years. However, the number of 8.343.962, which was a continuation-in-part of U.S. patent substances identified to be penetration enhancers is still application Ser. No. 12/281.561, filed on Jan. 12, 2009 and relatively small when considering the more than 25,000,000 issued as U.S. Pat. No. 7,795,309, which was a national substances identified in the CAS registry (Chemical stage of PCT/IB2007/001983 filed on Mar. 6, 2007, which 15 Abstracts Service, Columbus, Ohio, www.cas.org). The claimed priority to U.S. Provisional Application Ser. No. number of candidate drugs suitable for topical and transder 60/788,847, each of which is incorporated herein by refer mal administration could be significantly increased with CCC. improved penetration enhancers. BACKGROUND SUMMARY Topical formulations for application to the skin can be With this background in mind, the present disclosure is useful in cosmetic applications, for treating conditions of the drawn to topical formulationstransdermal systems, and upper skin layers, and for transdermal administration of methods for treating skin conditions. In one embodiment, a active agents to the local tissue underlying the skin or into 25 topical formulation is provided that comprises (i) at least one the blood for systemic distribution. For example, using a corticosteroid, (ii) a first compound, and (iii) a second topical formulation of a pharmaceutical agent is advanta compound. The first compound and second compound are geous because it can avoid first-pass metabolism, circum different and each is selected from the group consisting of vent gastrointestinal (“GI) absorption, allow delivery of an N-lauroyl sarcosine, Sodium octyl sulfate, methyl laurate, active ingredient with a relatively short biological half-life 30 isopropyl myristate, oleic acid, glyceryl oleate, and sodium and/or a narrow therapeutic window, and facilitate uniform lauryl Sulfoacetate. plasma dosing of the active ingredient, and/or can improve In another embodiment, a method of treating a skin user compliance. condition Such as psoriasis or dermatitis can comprise In spite of the advantages, transdermal administration is topical or transdermal administration of a corticosteroid to a usually limited to about a dozen Small lipophilic drugs, 35 Subject. The formulation can comprise at least one corticos available in transdermal patch format (including scopol teroid, a first compound, and a second compound. The first amine, fentanyl, estradiol, nitroglycerine, nicotine, and tes compound and second compound are different and each is tosterone). Skin has evolved to impede the flux of exogenous selected from the group consisting of N-lauroyl sarcosine, molecules so as to provide a strong barrier to molecular Sodium octyl sulfate, methyl laurate, isopropyl myristate, delivery, particularly agents such as pharmaceutical agents. 40 oleic acid, glyceryl oleate, and sodium lauryl Sulfoacetate. In Transdermal drug administration is difficult because skin is one embodiment, the first and second compound can an excellent diffusion barrier. improve the flux and/or stability of the topical formulation Structurally, the skin consists of two principal parts: (i) a when compared to a comparative formulation devoid of the relatively thin outermost layer (the “epidermis'), and (ii) a first compound and the second compound and replaced with thicker inner region (the “dermis). The outermost layer of 45 an equivalent wt % of water. In another embodiment, the the epidermis (the “stratum corneum) consists of flattened first and second compound can improve the flux of the at dead cells which are filled with keratin. The region between least one corticosteroid into the skin Surface when compared the flattened dead cells of the stratum corneum is filled with to a comparative formulation devoid of the first compound lipids which form lamellar phases. The highly impermeable and the second compound and replaced with an equivalent nature of skin is due primarily to the stratum corneum. The 50 wt % of water. In a further embodiment, the first and second viable epidermis underlying the stratum corneum is akin to compound can improve the stability of the topical formula other living tissue. The dermis provides the skin's structural tion when compared to a comparative formulation devoid of strength as well as the nerve and vascular networks that the first compound and the second compound and replaced Support the epidermis. with an equivalent wt % of water. For example, the first and Delivering an active agent into or through the skin in 55 second compound can improve the amount of active deg Sufficient concentrations often utilizes some means for radation, change in Viscosity and/or change in pH over a reducing the stratum corneum’s hindrance of penetration. A period of time. number of methods for lowering the stratum corneum’s barrier properties have been developed, including electri BRIEF DESCRIPTION OF THE DRAWINGS cally assisted techniques such as iontophoresis or ultra 60 Sound, and bypassing the stratum corneum through Reference will now be made to the exemplary embodi microneedle arrays or ablation. ments illustrated, and specific language will be used herein Molecular or chemical penetration enhancers provide an to describe the same. It will nevertheless be understood that effective and inexpensive means of temporarily reducing no limitation of the scope of the invention is thereby skin resistance to the administration and passage of actives 65 intended. and other molecules. Molecular penetration enhancers or FIG. 1 is a plot of the pH of several exemplary embodi MPETMs can enhance the application to and/or diffusion of ments of formulations disclosed herein. US 9,642,912 B2 3 4 FIG. 2 is a plot of the viscosity of several exemplary The term “subject' as used herein includes all members of embodiments of formulations disclosed herein. the animal kingdom, including mammals, and most typi FIG. 3 is a plot of the active pharmaceutical ingredient cally, refers to humans. amount of several exemplary formulations over a three The term “topical administration is used in its conven month time span. 5 tional sense to mean delivery of a Substance, Such as a FIG. 4 is a plot of the permeation of the active ingredient therapeutically active agent, into the skin or a localized of several of the exemplary formulations through a region of the body. Topical administration of a drug may Durapore(R) membrane. often be advantageously applied in, for example, the treat ment of various skin disorders or conditions. DETAILED DESCRIPTION 10 As used herein the term “topical formulation” refers to a formulation that may be applied to skin or a mucosa. Topical Before particular embodiments of the present invention formulations may, for example, be used to confer therapeutic are disclosed and described, it is to be understood that this benefit to a patient or cosmetic benefits to a consumer. invention is not limited to the particular process and mate Topical formulations can be used for both topical and rials disclosed herein as Such may vary to Some degree. It is 15 transdermal administration of Substances. also to be understood that the terminology used herein is As used herein, the term “transdermal” means in the used for the purpose of describing particular embodiments broadest sense into or through the skin. Further the terms only and is not intended to be limiting, as the scope of the “transdermal” and “percutaneous” are used interchangeably present invention will be defined only by the appended throughout this specification. claims and equivalents thereof. 2O The term “transdermal administration' is used to mean In describing and claiming the present invention, the administration through the skin. Transdermal administration following terminology will be used. is often applied where systemic delivery of an active is The singular forms “a,” “an,” and “the include plural desired, although it may also be useful for delivering an referents unless the context clearly dictates otherwise. Thus, active to tissues underlying the skin with minimal systemic for example, reference to “a corticosteroid' includes refer- 25 absorption (i.e. localized delivery). ence to one or more of Such corticosteroids. The term “treating or “treatment” as used herein and as As used herein, the term “active agent' indicates a com is well understood in the art, means an approach for obtain pound or mixture of compounds, that when added to a ing beneficial or desired results, including clinical results. composition, tend to produce a particular therapeutic effect. Beneficial or desired clinical results can include, but are not As used herein, the term “comparative formulation' is a 30 limited to, alleviation or amelioration of one or more symp formulation that is compositionally identical with the excep toms or conditions, diminishment of extent of disease, tion that amounts (wt %) of the first compound and second stabilizing (i.e. not worsening) the state of disease, delaying compound are each replaced with the same amount (wt %) or slowing of disease progression, amelioration or palliation of water. of the disease state, diminishment of the reoccurrence of “Multiplexed molecular penetration enhancers' 35 disease, and remission (whether partial or total), whether (“MMPETM) as described herein include N-lauroyl sar detectable or undetectable. “Treating and “treatment can cosine, Sodium octyl sulfate, methyl laurate, isopropyl also mean prolonging Survival as compared to expected myristate, oleic acid, glyceryl oleate, and sodium lauryl Survival if not receiving treatment. In addition to being Sulfoacetate, and in accordance with examples described useful as methods of treatment, the methods described herein, typically they are used in combination, e.g., two or 40 herein may be useful for the prevention or prophylaxis of more. The use of a permeation enchancer(s) can be incor disease. porated in a topical formulation to facilitate administration The term “water as an ingredient in the compositions of of one or more active ingredients. The increased penetration the compositions of the present disclosure refers to pharma enhancement can also lead to a reduction in the amount of ceutically-acceptable water. skin irritants in a formulation. 45 As used herein, the term “about is used to provide The term “penetration enhancer is used herein to refer to flexibility to a numerical range endpoint by providing that a an agent that improves the transport of molecules such as an given value may be “a little above' or “a little below the active agent (e.g., a medicine) into or through the skin. endpoint. The degree of flexibility of this term can be Various conditions may occur at different sites in the body dictated by the particular variable and would be within the either in the skin or below creating a need to target delivery 50 knowledge of those skilled in the art to determine based on of compounds. For example, a psoriasis treatment may experience and the associated description herein. For benefit from delivery of therapeutic drug levels in the deeper example, in one embodiment, the degree of flexibility can be tissue. A penetration enhancer may be used to assist in the within about it 10% of the numerical value. In another delivery of an active agent directly to the skin or underlying embodiment, the degree of flexibility can be within about tissue or indirectly to the site of the disease through systemic 55 +5% of the numerical value. In a further embodiment, the distribution. A penetration enhancer may be a pure Substance degree of flexibility can be within about +2%, +1%, or or may comprise a mixture of different chemical entities. In +0.05%, of the numerical value. this specification the terms “penetration enhancer,” “chemi As used herein, a plurality of active agents and/or com cal penetration enhancer,” “multiplexed molecular penetra pounds may be presented in a common list for convenience. tion enhancer,” and “MMPETM can be used interchange- 60 However, these lists should be construed as though each ably. member of the list is individually identified as a separate and "Skin' is defined to include human skin (intact, diseased, unique member. Thus, no individual member of such list ulcerous, or broken) as well as mucosal Surfaces that are should be construed as a de facto equivalent of any other usually at least partially exposed to air such as lips, genital member of the same list solely based on their presentation in and anal mucosa, and nasal and oral mucosa. 65 a common group without indications to the contrary. As used herein, the term "skin contact region” refers to an Concentrations, amounts, and other numerical data may area wherein the topical formulation contacts the skin. be expressed or presented herein in a range format. It is to US 9,642,912 B2 5 6 be understood that such a range format is used merely for typically, the total concentration of the first compound and convenience and brevity and thus should be interpreted the second compound is in the range of from about 1 wt % flexibly to include not only the numerical values explicitly to about 25 wt %. Even more typically, the total concentra recited as the limits of the range, but also to include all the tion of the first compound and the second compound is in the individual numerical values or Sub-ranges encompassed 5 range of from about 1 wt % to about 20 wt %. Even more within that range as if each numerical value and Sub-range typically, the total concentration of the first compound and is explicitly recited. As an illustration, a numerical range of the second compound is in the range of from about 1 wt % to about 15 wt %. Even more typically, the total concentra “about 0.01 mm to 2.0 mm should be interpreted to include tion of the first compound and the second compound is in the not only the explicitly recited values of about 0.01 mm to range of from about 1 wt % to about 10 wt % per unit about 2.0 mm, but also include individual values and sub 10 volume of the formulation. Even more typically, the total ranges within the indicated range. Thus, included in this concentration of the first compound and the second com numerical range are individual values such as 0.5 mm, 0.7 pound is in the range of from about 1 wt % to about 7.5 wt mm, and 1.5 mm, and Sub-ranges such as from 0.5 mm to 1.7 %. In still another example, the total concentration of the mm, 0.7 mm to 1.5 mm, and from 1.0 mm to 1.5 mm, etc. first compound and the second compound are in the range of Furthermore, Such an interpretation should apply regardless 15 from about 1 wt % to about 5 wt % per unit volume of the of the breadth of the range or the characteristics being formulation. Within these ranges, it can in some cases, be described. Additionally, it is noted that all percentages are in desirable to have the total concentration of the first com weight, unless specified otherwise. pound and the second compound in the range of from about The present disclosure is drawn to various formulations 1.5 wt % to about 3 wt % per unit volume of the formulation. and methods in the area of topical and transdermal delivery. In one aspect of the present disclosure, as mentioned, the MMPETMs can be used to improve the administration and at least one active agent is a corticosteroid. Generally, any increase penetration of active agents, such as corticosteroids corticosteroid known in the art can be incorporated into into and through the skin. These compounds can thus act as topical formulations and systems disclosed herein. Non excellent penetration enhances, particularly when used in limiting examples of Such corticosteroids include alclom combination—i.e. two (or more) compounds are selected 25 etaSone dipropionate, amcinonide, beclomethasone dipropi from N-lauroyl sarcosine, sodium octyl sulfate, methyl Onate, betamethasone, betamethasone benzoate, laurate, isopropyl myristate, oleic acid, glyceryl oleate, or betamethasone dipropionate, betamethasone Valerate, budesonide, clobetasol propionate, desonide, desoximeta Sodium lauryl Sulfoacetate. Sone, dexamethasone, diflorasone diacetate, fludrocortisone Examples of combinations of compounds that can act to acetate, flunisolide, flurandrenolide, fluocinolone acetonide, improve penetration include the following: 30 fluocinonide, fluticaSone propionate, halcinonide, halobeta the first compound comprises methyl laurate and the Sol, halobetasol propionate, hydrocortisone, hydrocortisone second comprises isopropyl myristate; Valerate, methylprednisolone, mometaSone furoate, predni the first compound comprises methyl laurate and the Solone, prednisone, triamcinolone, triamcinolone acetonide, second comprises oleic acid; the first compound comprises or combinations thereof in another embodiment, the topical methyl laurate and the second comprises glyceryl oleate; 35 formulations comprises a corticosteroid and one or more the first compound comprises methyl laurate and the additional agents selected from retinoids (e.g. tretinoin, second comprises Sodium lauryl Sulfoacetate; adapalene, tazarotene, among others), Vitamin D and Vita the first compound comprises isopropyl myristate and the min analogs, JAK inhibitors, kinase inhibitors, phosphodi second compound comprises oleic acid; esterase inhibitors, coal tar and coal tar extracts, keratolytics the first compound comprises isopropyl myristate and the 40 and combinations thereof. second compound comprises glycerol oleate; The corticosteroid can be present in the formulation up to the first compound comprises isopropyl myristate and the about 20 wt %, e.g., 0.01 wt % to about 20 wt %, typically second compound comprises sodium lauryl Sulfoacetate; from about 0.05 wt % to about 10 wt %, and more typically the first compound comprises oleic acid and the second from about 0.05 wt % to about 5 wt %. In one embodiment, compound comprises glycerol oleate; 45 the corticosteroid can be a pharmaceutically acceptable salt the first compound comprises oleic acid and the second of a corticosteroid. In a further embodiment, the corticos compound comprises Sodium lauryl Sulfoacetate; and teroid can be a pharmaceutically acceptable base of a corticosteroid. In one embodiment, the corticosteroid can the first compound comprises glycerol oleate and the include clobetasol, halobetasol, betamethasone, triamcino second compound comprises sodium lauryl Sulfoacetate. lone acetonide and derivatives and combinations thereof. The first and second compounds can be present in the 50 topical formulation at a weight ratio of first compound to Most preferably the corticosteroid is halobetasol propionate, second compound of about 1:9 to about 9:1. In another see Formula I below. embodiment, the first and second compounds can be present in the topical formulation at a weight ratio of first compound to second compound of about 1:5 to about 5:1, about 1:4 to 55 about 4:1, about 1:3 to about 3:1, about 1:2 and about 2:1, and about 1:1. The first and second compound can collectively be pres ent in the composition in amounts up to about 50 wt %, e.g., 0.1 wt % to 50 wt %. More typically, the total concentration 60 of the first compound and the second compound is up to about 40 wt %, e.g., 0.1 wt % to 40 wt %. In another example, the total concentration of the first compound and the second compound is in the range of from about 1 wt % to about 35 wt %. Even more typically, the total concentra 65 tion of the first compound and the second compound is in the range of from about 1 wt % to about 30 wt %. Even more US 9,642,912 B2 7 8 In one embodiment, halobetasol propionate is used to increase in penetration of the corticosteroid can be at least treat a variety of skin conditions including but not limited to 5%, at least 10%, at least 20%, at least 30%, at least 40%, psoriasis, eczema, dermatitis, allergies, and skin rashes. In a at least 50%, at least 60%, at least 70%, at least 80%, at least preferred embodiment, the halobetasol propionate formula 90%, at least 100%, at least 250%, at least 500%, at least tion is used to treat psoriasis. In yet another embodiment, the 750%, at least 1,000%, at least 2,000%, at least 3,000%, at halobetasol propionate formulation is used to treat moderate least 4000% or even at least 8,000% greater than the to severe plaque psoriasis and is delivered into the Superfi penetration of the comparative formulation at a given period cial layers of the skin. of time during the application. Over the course of a thirty In one embodiment, the formulation comprises 0.05% hour application period, the increase in penetration of the w/w halobetasol propionate, 0.5% w/w methyl laurate, and 10 corticosteroid can be at least 800% greater, at least 900% 1% w/w isopropyl myristate, along with various solvents, greater, at least 1,000% greater, at least 1,250% greater, or emollients/surfactants, and preservatives. In another even at least 1,500% greater when compared to the com embodiment, the formulation comprises 0.05% w/w halo parative formulation. This increased penetration enhance betasol propionate, 0.5% w/w methyl laurate, and 1% w/w ment can also lead to a reduction in the total concentration oleic acid along with various solvents, emollients/surfac 15 of potential skin irritants in a formulation. It has been found tants, and preservatives. In yet another embodiment, the that the presence of the MMPETMs do not negatively affect formulation comprises 0.05% w/w halobetasol propionate, the stability of the active ingredient in the formulation or the 0.5% w/w methyl laurate, and 1% w/w glyceryl oleate, along physical stability of the formulation. with various solvents, emollients/surfactants, and preserva Alternatively, or in addition to the ability to improve the tives. In a further embodiment, the formulation comprises penetration of the corticosteroid through the skin when 0.05% w/w halobetasol propionate, 0.5% w/w methyl lau compared to a comparative formulation devoid of the rate, and 1% w/w Sodium lauryl Sulfoacetate, along with MMPETMs (with an equivalent wt % of water replacing the various solvents, emollients/surfactants, and preservatives. MMPETMs), the first and second compounds present in the In another embodiment, the formulation comprises 0.05% topical formulations may function to improve the stability of w/w halobetasol propionate, 1% w/w isopropyl myristate, 25 the formulation. and 1% w/w oleic acid, along with various solvents, emol Long storage periods can result in increased active deg lients/surfactants, and preservatives. In yet another embodi radation, changes in pH and changes in viscosity. One of the ment, the formulation comprises 0.05% w/w halobetasol benefits of the topical formulations disclosed herein is the propionate, 1% w/w isopropyl myristate, and 1% w/w improved physical and/or chemical stability of the formu glyceryl oleate, along with various solvents, emollients/ 30 lations when stored. In one embodiment, the formulation Surfactants, and preservatives. In a further embodiment, the comprising a first compound and a second compound may formulation comprises 0.05% w/w halobetasol propionate, have an enhanced physical stability. For example, in one 1% w/w isopropyl myristate, and 1% w/w sodium lauryl aspect, the topical formulation can have improved consis Sulfoacetate, along with various solvents, emollients/surfac tency of viscosity after being stored for 12 weeks, 6 months, tants, and preservatives. In another embodiment, the formu 35 12 months or 24 months at 25° C. compared to a compara lation comprises 0.05% w/w halobetasol propionate, 1% tive formulation devoid of the first compound and the W/w oleic acid, and 1% w/w glyceryl oleate, along with second compound (where the first and second compounds various solvents, emollients/surfactants, and preservatives. are replaced with a commensurate amount of water, i.e. In yet another embodiment, the formulation comprises equal weight percentage of water to replace the removed 0.05% w/w halobetasol propionate, 1% w/w oleic acid, and 40 first and second compounds). In still another embodiment, 1% w/w sodium lauryl sulfoacetate, along with various the topical formulation can have a viscosity that is at least Solvents, emollients/surfactants, and preservatives. In a fur 50% more, at least 25% more, or at least 10% more ther embodiment, the formulation comprises 0.05% w/w consistent with the formulations initial viscosity after 12 halobetasol propionate, 1% w/w glyceryl oleate, and 1% weeks, 6 months, 12 months or 24 months when stored at W/w Sodium lauryl Sulfoacetate, along with various solvents, 45 about 25°C. compared to a comparative formulation devoid emollients/surfactants, and preservatives. of the first compound and the second compound (again as in The combination of at least two MMPETMs in a corticos each of these examples, replacing the removed first and teroid containing formulation is shown herein to enhance second compounds with an equivalent amount of water). stability and/or penetration of the corticosteroid through the In addition to the improvements in physical stability, the skin. More specifically, the compounds act as excellent 50 topical formulations of the present invention may have penetration enhancers and are shown to have an amplified improvements in chemical stability, for example, decreased effect when used in a combination, i.e. two (or more) active degradation and/or improved pH stability. In one MMPETM compounds wherein the first compound and sec embodiment, the topical formulations disclosed herein can ond compound are each selected from the group of N-lau provide improved chemical stability after being stored for a royl sarcosine, sodium octyl sulfate, methyl laurate, isopro 55 period of 12 weeks, 6 months, 12 months or 24 months at pyl myristate, oleic acid, glyceryl oleate, and sodium lauryl 25° C. such that the formulation has less degradation of the Sulfoacetate. Again and in further detail, examples of com active ingredient as compared to a comparative formulation binations of first and second compounds that act as devoid of the first and second compound (again with an improved penetration enhancers can include: isopropyl equivalent amount of water added thereto to replace the first myristate and sodium lauryl Sulfoacetate, oleic acid and 60 and second compounds). In another embodiment, the topical Sodium lauryl Sulfoacetate; glyceryl oleate and sodium lau formulations disclosed herein can provide improved pH ryl Sulfoacetate; and methyl laurate and Sodium lauryl stability after being stored for 12 weeks, 6 months, 12 Sulfoacetate; to name a few. months or 24 months at 25° C. compared to a comparative The formulation can have increased penetration of the formulation devoid of the first compound and the second corticosteroid through the skin when compared to a com 65 compound (again with an equivalent amount of water added parative formulation devoid of the MMPETMs (with an thereto to replace the first and second compounds). For equivalent wt % of water replacing the MMPETMs). The example, the topical formulation can have a pH that is at US 9,642,912 B2 9 10 least 50% more, at least 25% more, or at least 10% more tical Excipients, 3rd Edition, Ed. Arthur H. Kibbe, American consistent with the formulations initial pH after 12 weeks, Pharmaceutical Association, Washington D.C. 2000. 6 months, 12 months or 24 months when stored at about 25° The topical formulations of the present disclosure may C. compared to a comparative formulation devoid of the first also include one or more skin care actives. "Skin care compound and the second compound stored under the same actives' means all compounds or substances now known or conditions for the same amount of time. later demonstrated to provide benefit when applied to skin Improved physical and/or chemical stability of topical and all compounds now claimed or in the future claimed to formulations may lead to increased commercial shelf life of provide benefit when applied to skin. Skin care actives may the system. In one embodiment, the topical formulation of provide benefits, or claimed benefits, in areas such as one or the invention can have an increased shelf life of about 3 10 more of wrinkle removal or wrinkle reduction, firming of months, about 6 months, about 9 months or about 12 months skin, exfoliation of skin, skin lightening, treatment of dan compared to a comparative formulation devoid of the first druff, treatment of acne, skin conditioning, development of compound and the second compound stored under the same tans and artificial tans, improvement of skin moisture con conditions. In another embodiment the shelf life of the tent, improvement of skin barrier properties, control of topical formulation can be at least about 27-months, at least 15 Sweat, anti-aging, reduction or avoidance of irritation, and about 30 months, at least about 33 months, or at least about reduction or avoidance of inflammation. Examples of skin 36 months. care actives include molecules Such as peptides, proteins, The topical formulations of the present disclosure may oligonucleotides, fullerenes as well as Small molecules. Skin also be formulated to include other chemical penetration care actives may be protease and/or enzyme inhibitors, enhancers which have significant ability to enhance trans anti-coenzymes, chelating agents, antibodies, antimicrobi port of the corticosteroid and/or other active agents present als, humectants, vitamins, skin protectants, antioxidants in the topical formulations. Such substances may have the and/or skin soothing agents, plant extracts and the like. character of Surfactants, aZone-like compounds, solvents, Examples of skin care actives include but are not limited to alcohols, fatty acids, fatty esters, aliphatic thiols, and the Vitamin C, Vitamin E (alpha tocopherol), retinoids, soy like. Examples of chemical penetration enhancers are 25 derivatives (e.g. isoflavones), green tea polyphenols, alpha reported in the paper of Santus et al. (Santus, C. G. and hydroxy acids (e.g. glycolic and lactic acids), beta hydroxy Baker, R. W., Transdermal enhancer patent literature. Jour acids (e.g. Salicylic acid), poly hydroxy acids, alpha lipoic nal of Controlled Release 1993.25:1-20.) The penetration acid, hemp oil (glycerides), niacinamide, dimethyl amino enhancing effect may be measured using techniques known ethanol, coenzyme Q10, kinetin (plant growth hormone), in the art. An example of one measurement method is 30 dimethyl sulfone, and botulinum toxin. Other examples of described in the Examples below. skin care actives may be found in The Perricone Prescription The topical formulations can also include other compo by Nicholas Perricone, Harper Collins Publishers Inc., New nents as well. Examples of additional compounds that can be York, 2002. included in the topical formulations include water, thicken The topical formulation of the present invention may be ing, gelling and/or solidifying polymers, emollients/surfac 35 formulated to be included in transdermal systems such as tants excipients, fatty acid esters, parabens, solvents, and/or those described above, the topical formulations of the pres the like. In one embodiment, the topical formulation can ent invention may be formulated by those skilled in the art include water, and in some case, the water can be the as liquids, Solutions, emulsions, creams, lotions, Suspen ingredient that is present at the single greatest concentration. sions, triturates, gels, jellies, foams, pastes, sprays, oint Other suitable carriers or excipients that may be used in 40 ments, shampoos, adhesives, traditional patches, or the like. the topical formulations discussed herein are known in the The present formulation provides an improved topical art and include, but are not limited to, solubilizers such as C. formulation for facilitating topical or transdermal adminis to Cs straight and branched chain alcohols, diols and triols, tration of at least one therapeutically active agent, which in moisturizers and humectants such as glycerine, amino acids accordance with examples herein, can be a corticosteroid. and amino acid derivatives, polyaminoacids and derivatives, 45 This enhanced effect is discussed further below and illus pyrrolidone carboxylic acids and their salts and derivatives, trated in embodiments of the formulations described in the Surfactants such as Sodium laureth Sulfate, Sorbitan mono Examples. In another example, the topical formulations laurate, emulsifiers such as di-isopropyl adipate, hexylene provide a means for targeting a therapeutically active agent glycol, cetyl alcohol, Stearyl alcohol, thickeners such as to a local tissue either in the skin or the underlying tissue. methyl cellulose, ethyl cellulose, hydroxymethylcellulose, 50 This latter embodiment may be particularly beneficially hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl applied for treatment of conditions such as psoriasis and alcohol, and acrylic polymers. The topical formulation may other dermatological conditions. The topical formulations include isopropyl alcohol. The isopropyl alcohol may be may be applied either occlusively or nonocclusively to the present in the formulation between about 1 wt % to about 40 skin. In a one embodiment, when the objective is transder wt %. Additionally the topical formulation may also include 55 mal administration, the topical formulation is applied to the di-isopropyl adipate and hexylene glycol. The di-isopropyl skin under occlusion in a transdermal patch. adipate may be present in the formulation between about 1 The present topical formulation may be applied to the skin wt % to about 10 wt %. The hexylene glycol may be present by any means known in the art including, but not limited to, in the formulation between about 1 wt % to about 15 wt %. by an aerosol, spray, pump-pack, brush, Swab, or other In addition the topical formulation may include polyoxyl 35 60 applicator. The applicator may provide either a fixed or castor oil. The polyoxyl 35 castor oil may be present in the variable metered dose application Such as a metered dose formulation from about 0 wt % to about 10 wt %. The aerosol, a stored-energy metered dose pump, or a manual formulation may also include at least one moisturizer/ metered dose pump. In this example, the topical formulation humectant. Other examples of Suitable excipients, such as can be applied to the skin of the human or animal covering binders and fillers are listed in Remington’s Pharmaceutical 65 a delivery surface area from about 5 cm to about 800 cm, Sciences, 18th Edition, Ed. Alfonso Gennaro, Mack Pub more typically from about 10 cm to about 400 cm, and in lishing Co. Easton, Pa., 1995 and Handbook of Pharmaceu another example, from about 10 cm to about 200 cm. The US 9,642,912 B2 11 12 application can be performed by means of a topical metered C-aryl alkanoic acids are chemical compounds having the dose spray combined with an actuator nozzle shroud which general structure of Formula II: together accurately control the amount and/or uniformity of the dose applied. One function of the shroud is to keep the noZZle at a pre-determined height above, and perpendicular 5 II to, the skin to which the drug delivery system is being applied. This function may also be achieved by means of a spacer-bar or the like. Another function of the shroud is to enclose the area above the skin in order to prevent or limit RI OH bounce-back and/or loss of the drug delivery system to the 10 Surrounding environment. The drug delivery system may be wherein Ar is an aryl group and R' is H or an alkyl group, a unit volume dispenser with or without a roll-on or other wherein aryl includes aromatic and heteroaromatic groups type of applicator. It may also be desirable to apply a number and alkyl includes acyclic and cyclic alkyl groups. The of dosages on untreated skin to obtain the desired result. While the present disclosure is directed primarily to the 15 C-aryl alkanoic acid may be an anti-inflammatory drug Such formulations and related methods utilizing corticosteroids as as a non-steroidal anti-inflammatory drug (NSAID) or an the pharmaceutically active agent (drug), in some aspects, it analagesic, specific examples of which are listed below. can be useful or desirable to include alternative or additional Preferably, the C-aryl alkanoic acids is selected from the pharmaceutically active compositions. Discussion of the group consisting of bromfenac, diclofenac, fenoprofen, flur various active agents that can be incorporated into the biprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, topical formulations, in addition to or instead of the corti naproxen, Sulindac and tolmetin, and pharmaceutically costeroids of the present disclosure, is provided below. acceptable salts and Solvates thereof, and mixtures thereof. In one aspect of the present invention, the at least one Structures for these C-aryl alkanoic acids, along with some active agent is an aryl alkanoic acid, such as an C-aryl common trade names, known to a person skilled in the art, alkanoic acid. As is known to a person skilled in the art, are shown in Table A. TABLE A

NSAID TRADE NAME STRUCTURE

Diclofenac Voltaren, Pennsaid C

NH

C OH

Indomethacin Indocin H3CO

OH

C

Sulindac Clinoril F

OH US 9,642,912 B2

TABLE A-continued

NSAID TRADE NAME STRUCTURE Tolimetin Tollectin R \, OH & J

Naproxen Naprosyn, Aleve E -- OH

O H3CO Ibuprofen Advil, Brufen, Motrin OH

O

Flurbiprofen Ansaid, Flurwood, Froben OH

O

F

Ketoprofen Orudis O

OH

O

Ketorolac Acular, Toradol O

N OH

O Fenoprofen Nalfon Ol O

O OH

Bromfenac Xibrom O NH2

OH

Br

More preferably the C-aryl alkanoic acid is selected from the include acetaminophen (paracetamol), aspirin, celecoxib, group consisting of diclofenac, ibuprofen, and ketoprofen, diflunisal, etodolac, etoricoxib, meclofenamic acid, mefe and pharmaceutically acceptable salts and Solvates thereof, namic acid, meloxicam, nabumetone, Oxaprozin, piroxicam, and mixtures thereof. Other NSAIDs that are not C-aryl alkanoic acids, as well as other compounds having anti Salsalate, and rofecoxib. Structures for these compounds pyretic and analgesic actions are also included in the scope along with some common trade names, known to a person of the present invention. Examples of Such compounds skilled in the art, are shown in Table B. US 9,642,912 B2 15 16 TABLE B

COMPOUND TRADE NAME STRUCTURE Acetaminophen Tylenolyleno NH

O HO Aspirin CO2H N O

Celecoxib Celebrex

e CF N/N

H2NNs OIN

Diflunisal Dolobid CO2H F OH

F

Etoricoxib Arcoxia

Piroxicam Feldane,(C86. RROX8. 21 O OH

N N N 21 H 1. Ns /MV \, Rofecoxib Vioxx \

o O US 9,642,912 B2 17 18 TABLE B-continued

COMPOUND TRADE NAME STRUCTURE

Salsalate Disalcid, Monogesic, OH O OH Salflex, Salcitab O

O

Meloxicam Mobic W O OH --> 21 1. Ns MV O O

Etodolac Lodine OH H N o

Oxaprozin Daypro

/ O 2 OH N O

Nabumetone Relafen O

OH

Mefenamic acid Ponstel

NH OH O HC CH

Meclofenamic Acid Meclofen, Meclomen O OH C H

c C US 9,642,912 B2 19 20 In another aspect of the present invention, the at least one anorectic; anti-acne agent; anti-adrenergic; anti-allergic; active agent is a phenethylamine, for example, a pheneth anti-amebic; anti-anemic; anti-anginal; anti-arthritic; anti ylamine that is an antidepressant, anti-anxiety agent, anti asthmatic; anti-atherosclerotic; antibacterial; anticholin cholinergic agent, cholinergic, dopaminergic, stimulant, ergic; anticoagulant; anticonvulsant; antidepressant; antidi serotonin antagonist, serotonin inhibitor, anti-emetic, anti abetic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; histamine and/or antipsychotic, specific examples of which antifibrinolytic; antifungal; antihemorrhagic; antihistamine; are listed below. As is known to a person skilled in the art, antihyperlipidemia; antihypertensive; antihypotensive; anti phenethylamines are chemical compounds having the gen infective; anti-inflammatory; antimicrobial; antimigraine; eral core structure of Formula III: antimitotic; antimycotic, antinauseant, antineoplastic, anti 10 neutropenic, antiparasitic; antiproliferative; antipsychotic; antirheumatic; antiseborrheic; antisecretory; antispasmodic; III antithrombotic; antiulcerative; antiviral; appetite Suppres Sant; blood glucose regulator, bone resorption inhibitor; bronchodilator, cardiovascular agent; cholinergic; depres 15 Sant; diagnostic aid; diuretic; dopaminergic agent; estrogen receptor agonist, fibrinolytic; fluorescent agent; free oxygen radical Scavenger; gastric acid suppressant, gastrointestinal wherein the phenyl ring, ethylene chain and nitrogen can be motility effector; glucocorticoid; hair growth stimulant; Substituted. The phenethylamine may be a psychoactive hemostatic; histamine H2 receptor antagonists; hormone; agent that exerts its effect through a monoamine neurotrans hypocholesterolemic; hypoglycemic, hypolipidemic; mitter system, for example dopamine, serotonin and/or norepinephrine receptors. Examples of phenethylamines, hypotensive; imaging agent; immunizing agent; immuno include, for example, bupropion, amphetamine, hydroxyam modulator; immunoregulator, immunostimulant; immuno phetamine, dextroamphetamine, methamphetamine, ephed Suppressant, keratolytic; LHRH agonist; mood regulator; 25 mucolytic, mydriatic; nasal decongestant; neuromuscular rine, epinephrine, pseudoephedrine, dopamine, epinephryl blocking agent; neuroprotective; NMDA antagonist; non borate, etafedrine, norepinephrine and oxidopamine, and hormonal sterol derivative; plasminogen activator; platelet pharmaceutically acceptable salts and Solvates thereof, and activating factor antagonist; platelet aggregation inhibitor; mixtures thereof. Preferably the phenethylamine is bupro psychotropic; radioactive agent; Scabicide; sclerosing agent; pion, or a pharmaceutically acceptable salt or Solvate sedative; sedative-hypnotic; selective adenosine A1 antago thereof, such as bupropion hydrochloride. The structure of nist; Serotonin antagonist; serotonin inhibitor, serotonin bupropion, known to a person skilled in the art, is: receptor antagonist; steroid; thyroid hormone; thyroid inhibitor; thyromimetic, tranquilizer, amyotrophic lateral Sclerosis agent; cerebral ischemia agent; Paget’s disease IV 35 agent; unstable angina agent; vasoconstrictor, Vasodilator; wound healing agent; Xanthine oxidase inhibitor; and the like. Specific examples of pharmaceutical agents that may be included within the present topical formulation, both alone 40 or in combination, include but are not limited to: Adrenergic: Adrenalone; Amidephrine Mesylate; Apra circ clonidine Hydrochloride: Brimonidine Tartrate; Dapiprazole Hydrochloride; Deterenol Hydrochloride; Dipivefrin; Dop In another aspect of the present invention, the at least one amine Hydrochloride; Ephedrine Sulfate: Epinephrine: Epi active agent is a steroid, other than coriticosteriods, for 45 nephrine Bitartrate: Epinephryl Borate; Esprocquin Hydro example, Steroids that are hormones, glucosteroids, andro chloride; Etafedrine Hydrochloride; Hydroxyamphetamine gens, anabolics, estrogens and/or progestin, specific Hydrobromide; Levonordefrin; Mephentermine Sulfate: examples of which are listed below. Preferably the steroid is Metaraminol Bitartrate; Metizoline Hydrochloride; Nap testosterone, or a pharmaceutically acceptable salt or Solvate hazoline Hydrochloride; Norepinephrine Bitartrate; Oxido thereof. 50 pamine: Oxymetazoline Hydrochloride; Phenylephrine Other suitable active agents include those in the class of Hydrochloride; Phenylpropanolamine Hydrochloride; Phe COX-2 inhibitors such as celecoxib, rofecoxib, Valdecoxib, nylpropanolamine Polistirex: Prenalterol Hydrochloride; lumiracoxib, etoricoxib: Antifungals such as tolnaftate, Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahy econazole, ciclopiroX; Antibiotics such as clindamycin; drozoline Hydrochloride; Tramazoline Hydrochloride; and Musculoskeletal agents such as dantrolene: Retinoids Such 55 Xylometazoline Hydrochloride. as isotretinoin, Antivirals such as acyclovir, Vasodilating Adrenocortical steroid: Ciprocinonide; Desoxycorticos agents such as nitroglycerine, papaverine; Hormones and terone Acetate; Desoxycorticosterone Pivalate; Dexametha synthetic Substitutes Such as androgens, estrogens, insulin; sone Acetate; Fludrocortisone Acetate; Flumoxonide; Opiate agonists such as fentanyl, oxycodone, hydromor Hydrocortisone Hemisuccinate; Methylprednisolone phone; Local Anaesthetics such as lidocaine, tocainide and 60 Hemisuccinate; Naflocort; Procinonide; Timobesone mexiletine and butyl-para-aminobenzoate: NMDA receptor Acetate; and Tipredane. antagonists such as ketamine, dextromethorphan and aman Adrenocortical Suppressant: Aminoglutethimide; and tadine. Trilostane. Examples of other therapeutically active agents that may Alcohol deterrent: Disulfiram. be used include the following: adrenergic agent, adrenocor 65 Aldosterone antagonist: Canrenoate Potassium, Can tical steroid; adrenocortical Suppressant; aldosterone antago renone; Dicirenone; Mexrenoate Potassium; Prorenoate nist; amino acid; anabolic; analeptic; analgesic; anesthetic; Potassium; and Spironolactone. US 9,642,912 B2 21 22 Amino acid: Alanine; Arginine; Aspartic Acid; Carnitine; Trefentanil Hydrochloride; Trolamine: Veradoline Hydro Cysteine Hydrochloride: Cystine; Glycine. Histidine: Iso chloride: Verilopam Hydrochloride; Volazocine: Xorphanol leucine; Leucine; Lysine; Lysine Acetate; Lysine Hydro Mesylate; Xylazine Hydrochloride; Zomepirac Sodium; and chloride; Methionine; Phenylalanine: Proline: Serine; Zucapsaicin. Threonine: Tryptophan: Tyrosine; and Valine. Androgen: Fluoxymesterone; Mesterolone; Methyltestos Ammonia detoxicant: Arginine Glutamate; and Arginine terone; 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 onate; Testosterone Enanthate; Testosterone Ketolaurate; enone Undecylenate; Bolenol; Bolmantalate: Ethylestrenol; 10 Testosterone Phenylacetate; Testosterone Propionate; and Methenolone Acetate; Methenolone Enanthate; Mibolerone; Nandrolone Cyclotate; Norbolethone; Pizotyline; Quinbo Trestolone Acetate. lone; Stenbolone Acetate; Tibolone; and Zeranol. Anesthesia (adjunct to): Sodium Oxybate. Analeptic: Modafinil. Anesthetic: Aliflurane; Benoximate Hydrochloride; Ben Analgesic: Acetaminophen; Alfentanil Hydrochloride; 15 Zocaine; Biphenamine Hydrochloride; Bupivacaine Hydro Aminobenzoate Potassium; Aminobenzoate Sodium; Ani chloride; Butamben; Butamben Picrate; Chloroprocaine doxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopro Hydrochloride; Anirolac, Antipyrine; Aspirin; Benoxapro pane; Desflurane; Dexivacaine; Diamocaine Cyclamate; fen; Benzydamine Hydrochloride; Biciifadine Hydrochlo Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydro ride; Brifentanil Hydrochloride: Bromadoline Maleate; Bro chloride; Enflurane; Ether; Ethyl Chloride; Etidocaine; mfenac Sodium: Buprenorphine Hydrochloride: Butacetin: Etoxadrol Hydrochloride; Euprocin Hydrochloride: FluroX Butixirate; Butorphanol; Butorphanol Tartrate; Carbam ene: Halothane: Isobutamben; Isoflurane; Ketamine Hydro azepine; Carb aspirin Calcium; Carbiphene Hydrochloride: chloride; Levoxadrol Hydrochloride; Lidocaine; Lidocaine Carfentanil Citrate: Ciprefadol Succinate; Ciramadol; Cira Hydrochloride; Mepivacaine Hydrochloride; Methohexital madol Hydrochloride; Clonixeril; Clonixin: Codeine; 25 Sodium; Methoxyflurane: Midazolam Hydrochloride; Mida Codeine Phosphate: Codeine Sulfate; Conorphone Hydro Zolam Maleate; Minaxolone; Norflurane; Octodrine; Oxet chloride: Cyclazocine; Dexoxadrol Hydrochloride; Dex hazaine; Phencyclidine Hydrochloride; Pramoxine Hydro pemedolac, Dezocine; Diflunisal; Dihydrocodeine Bitar chloride; Prilocaine Hydrochloride; Procaine trate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Hydrochloride; Propanidid; Proparacaine Hydrochloride: Drinidene: Enadoline Hydrochloride: Epirizole; Ergotamine 30 Propofol; Propoxycaine Hydrochloride: Pyrrocaine: Riso Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; caine; Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane: Fenoprofen; Fenoprofen Calcium: Fentanyl Citrate: Floc Teflurane: Tetracaine: Tetracaine Hydrochloride; Thiamylal; tafenine: Flufenisal; Flunixin: Flumixin Meglumine: Flupir Thiamylal Sodium; Thiopental Sodium; Tiletamine Hydro tine Maleate: FluproduaZone: Fluradoline Hydrochloride; chloride; and Zolamine Hydrochloride. Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: 35 Anorectic compound: Dexfenfluramine. Indoprofen; Ketazocine; Ketorfanol; Ketorolac Trometh Anorexic agents: Aminorex: Amphecloral; Chlorphenter amine; Letimide Hydrochloride; Levomethadyl Acetate; mine Hydrochloride; Clominorex: Clortermine Hydrochlo Levomethadyl Acetate Hydrochloride; Levonantradol ride; Diethylpropion Hydrochloride; Fenfluramine Hydro Hydrochloride; Levorphanol Tartrate; Lofemizole Hydro chloride; Fenisorex: Fludorex: Fluminorex; Levamfetamine chloride; Lofentanil Oxalate; Lorcinadol; Lornoxicam, 40 Succinate; Mazindol; Mefenorex Hydrochloride; Phemn Magnesium Salicylate; Mefenamic Acid; Menabitan Hydro etrazine Hydrochloride; Phentermine; and Sibutramine chloride; Meperidine Hydrochloride; Meptazinol Hydro Hydrochloride. chloride; Methadone Hydrochloride; Methadyl Acetate; Antagonist: Atipamezole; Atosiban; Bosentan, Cimeti Methopholine; Methotrimeprazine; Metkephamid Acetate; dine, Cimetidine Hydrochloride; Clentiazem Maleate; Mimbane Hydrochloride; Mirfentanil Hydrochloride; Moli 45 Detirelix Acetate; Devazepide; Donetidine: Etintidine naZone: Morphine Sulfate; Moxazocine; Nabitan Hydro Hydrochloride; Famotidine: Fenmetozole Hydrochloride: chloride; Nalbuphine Hydrochloride; Nalmexone Hydro Flumazenil; Icatibant Acetate: Icotidine; Isradipine; Meti chloride: Namoxyrate; Nantradol Hydrochloride; Naproxen; amide; Nadide; Nalmefene; Naloxone Hydrochloride; Nal Naproxen Sodium; Naproxol; Nefopam Hydrochloride; trexone; Nilvadipine; Oxilorphan: Oxmetidine Hydrochlo Nexeridine Hydrochloride; Noracymethadol Hydrochloride; 50 ride; Oxmetidine Mesylate; Quadazocine Mesylate: Ocfentanil Hydrochloride; Octazamide; Olvanil; Oxetorone Ranitidine: Ranitidine Bismuth Citrate; Ranitidine Hydro Fumarate; Oxycodone; Oxycodone Hydrochloride: Oxyco chloride; Sufotidine; Teludipine Hydrochloride; Tiapamil done Terephthalate: Oxymorphone Hydrochloride; Pemed Hydrochloride; Tiotidine: Vapiprost Hydrochloride; and olac, Pentamorphone: Pentazocine; Pentazocine Hydrochlo Zaltidine Hydrochloride. ride; Pentazocine Lactate; Phenazopyridine Hydrochloride; 55 Anterior pituitary activator: Epimestrol. Phenyramidol Hydrochloride; Picenadol Hydrochloride: Anterior pituitary Suppressant: DanaZol. Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Maleate: Prodilidine Hydrochloride; Profadol Hydrochlo Bunamidine Hydrochloride: Butonate; Cambendazole; Car ride; Propiram Fumarate; Propoxyphene Hydrochloride; bantel Lauryl Sulfate; Clioxanide; Closantel: Cyclobenda Propoxyphene Napsylate: Proxazole; Proxazole Citrate; 60 Zole; Dichlorvos; Diethylcarbamazine Citrate; Dribenda Proxorphan Tartrate: Pyrroliphene Hydrochloride: Remifen Zole; Dymanthine Hydrochloride; Etibendazole; tanil Hydrochloride; Salcolex: Salicylamide: Salicylate Fenbendazole; Furodazole: Hexylresorcinol; Mebendazole; Meglumine; Salsalate: Sodium Salicylate: Spiradoline Morantel Tartrate; Niclosamide: Nitramisole Hydrochloride: Mesylate: Sufentanil; Sufentanil Citrate; Talmetacin; Talni Nitrodan: Oxantel Pamoate; Oxfendazole; Oxibendazole; flumate; Talosalate; Tazadolene Succinate; Tebufelone; Tet 65 Parbendazole; Piperamide Maleate; Piperazine; Piperazine rydamine; Tifurac Sodium; Tilidine Hydrochloride; Tiopi Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel nac; Tonazocine Mesylate: Tramadol Hydrochloride; Pamoate: Pyrantel Tartrate: Pyrvinium Pamoate; Rafox US 9,642,912 B2 23 24 anide; Stilbazium Iodide; Tetramisole Hydrochloride; Thi micin Sulfate; A villamycin; A Voparcin, Azithromycin; abendazole; Ticarbodine; Tioxidazole; Triclofenol Pipera Azlocillin: Azlocillin Sodium; Bacampicillin Hydrochlo Zine; Vincofos; and Zilantel. ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci Anti-acne: Adapalene; Erythromycin, Salnacedin, and tracin Zinc: Bambermycins; Benzoylpas Calcium: Betami Inocoterone Acetate. cin Sulfate; Biapenem; Biniramycin; Bispyrithione Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride: Magsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sul Atenolol; Bretylium Tosylate; Bunolol Hydrochloride; Car fate; Carbadox; Carbenicillin Disodium; Carbenicillin Inda teolol Hydrochloride: Celiprolol Hydrochloride; Cetamolol nyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Hydrochloride: Cicloprolol Hydrochloride; Dexpropranolol Potassium; Carumonam Sodium; Cefaclor, Cefadroxil, Hydrochloride; Diacetolol Hydrochloride; Dihydroergot 10 Cefamandole; Cefamandole Nafate; Cefamandole Sodium; amine Mesylate; Dilevalol Hydrochloride; Esmolol Hydro Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; chloride; Exaprolol Hydrochloride: Fenspiride Hydrochlo Cefazolin Sodium; CefbuperaZone; Cefdinir, Cefepime: ride; Flestolol Sulfate; Labetalol Hydrochloride; Cefepime Hydrochloride; Cefetecol; Cefixime; Cefnmenox Levobetaxolol Hydrochloride; Levobunolol Hydrochloride: ime Hydrochloride: Cefnmetazole; Cefnetazole Sodium; Metalol Hydrochloride; Metoprolol; Metoprolol Tartrate; 15 Cefonicid Monosodium; Cefonicid Sodium; CefoperaZone Nadolol; Pamatolol Sulfate; Penbutolol Sulfate; Phen Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan: Cefo tolamine Mesylate; Practolol; Propranolol Hydrochloride; tetan Disodium; Cefotiam Hydrochloride; Cefoxitin: Proroxan Hydrochloride; Solypertine Tartrate; Sotalol Cefoxitin Sodium; Ce?pimizole; Ce?pimizole Sodium; Cef Hydrochloride; Timolol; Timolol Maleate; Tiprenolol piramide: Ce?piramide Sodium; Ce?pirome Sulfate; Ce?po Hydrochloride; Tolamolol; and Zolertine Hydrochloride. doxime Proxetil: Cefprozil; Cefroxadine; Cefsulodin Anti-allergic: Amlexanox; Astemizole; AZelastine Hydro Sodium; Ceftazidime; Ceftibuten; Ceftiroxime Pivoxetil: chloride; EclaZolast; Minocromil Nedocromil Nedocromil Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Calcium; Nedocromil Sodium; Nivinedone Sodium; Pemi Cefuroxime Axetil: Cefuroxime Sodium; Cephacetrile rolast Potassium Pentigetide; Pirquinozol; Poisonoak Sodium; Cephalexin; Cephalexin Hydrochloride; Cephalo Extract; Probicromil Calcium; Proxicromil: Repirinast: Tet 25 glycin; Cephaloridine; Cephalothin Sodium; Cephapirin razolast Meglumine: Thiazinamium Chloride; Tiacrilast; Sodium; Cephradine; Cetocycline Hydrochloride; Ceto Tiacrilast Sodium; Tiprinast Meglumine; and Tixanox. phenicol; Chloramphenicol; Chloramphenicol Palmitate; Anti-amebic: Berythromycin; Bialamicol Hydrochloride: Chloramphenicol Pantothenate Complex: Chloramphenicol Chloroquine; Chloroquine Hydrochloride; Chloroquine Sodium Succinate; Chlorhexidine Phosphanilate; Chlorox Phosphate: Clamoxyquin Hydrochloride: Clioquinol: 30 ylenol; Chlortetracycline Bisulfate; Chlortetracycline Emetine Hydrochloride: Iodoquinol; Paromomycin Sulfate: Hydrochloride: Cinoxacin: Ciprofloxacin: Ciprofloxacin Quinfamide: Symetine Hydrochloride; Teclozan: Tetracy Hydrochloride: Cirolemycin; Clarithromycin; Clinafloxacin cline; and Tetracycline Hydrochloride. Hydrochloride; Clindamycin; Clindamycin Hydrochloride: Anti-androgen: Benorterone; Cioteronel, Cyproterone Clindamycin Palmitate Hydrochloride; Clindamycin Phos Acetate; Delmadinone Acetate; Oxendolone; Topterone; and 35 phate; Clofazimine; Cloxacillin Benzathine; Cloxacillin Zanoterone. Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sul Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate, fate; Coumermycin; Coumermycin Sodium; Cyclacillin; Dried; and Leucovorin Calcium. Cycloserine; Dalfopristin; Dapsone; Daptomycin; Demeclo Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; cycline; Demeclocycline Hydrochloride; Demecycline: Betaxolol Hydrochloride; Bevantolol Hydrochloride; Buto 40 Denofungin: Diaveridine; Dicloxacillin; Dicloxacillin prozine Hydrochloride; Carvedilol; Cinepazet Maleate; Sodium; Dihydrostreptomycin Sulfate; Dipyrithione: Metoprolol Succinate; Molsidomine; Monatepil Maleate; Dirithromycin; Doxycycline; Doxycycline Calcium; Doxy Primidolol; Ranolazine Hydrochloride; Tosifen; and Vera cycline Fosfatex: Doxycycline Hyclate; Droxacin Sodium; pamil Hydrochloride. Enoxacin; Epicillin: Epitetracycline Hydrochloride; Eryth Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; 45 romycin; Erythromycin Acistrate; Erythromycin Estolate: Binospirone Mesylate: Bretazenil; Glemanserin; Ipsapirone Erythromycin Ethylsuccinate; Erythromycin Gluceptate; Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondanse Erythromycin Lactobionate; Erythromycin Propionate: tron Hydrochloride; Panadiplon; Pancopride; Pazinaclone: Erythromycin Stearate; Ethambutol Hydrochloride; Ethio Serazapine Hydrochloride; Tandospirone Citrate; and namide: Fleroxacin; Floxacillin: Fludalanine: Flumequine; Zalospirone Hydrochloride. 50 Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Anti-arthritic: Lodelaben. Furazolium Chloride; Furazolium Tartrate; Fusidate Anti-asthmatic: Ablukast; Ablukast Sodium: Bunaprolast; Sodium; Fusidic Acid, Gentamicin Sulfate; Gloximonam, Cinalukast; Cromitrile Sodium; Cromolyn Sodium; Gramicidin; Haloprogin: Hetacillin: Hetacillin Potassium; Enofelast; Isamoxole; Ketotifen Fumarate; Levcromakalim, Hexedine; Ibafloxacin; Imipenem, Isepamicin; Isoconazole; Lodoxamide Ethyl; Lodoxamide Tromethamine; Montelu 55 Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; kast Sodium; Ontazolast: Oxarbazole; Oxatomide: Piriprost; Levofuraltadone; Levopropylcillin Potassium; Lexithromy Piriprost Potassium; Pirolate: Pobilukast Edamine; Quazo cin; Lincomycin; Lincomycin Hydrochloride; Lomefloxa last; Ritolukast; Sulukast; Tiaramide Hydrochloride: cin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate: Tibenelast Sodium; Tomelukast; Tranilast; Verlukast; and Loracarbef: Mafenide; Meclocycline: Meclocycline Sulfos Verofylline Zarirlukast. 60 alicylate; Megalomicin Potassium Phosphate; Mequidox; Anti-atherosclerotic: Mifobate; and Timefuronc. Meropenem; Methacycline; Methacycline Hydrochloride: Antibacterial: Acedapsone; Acetosulfone Sodium; Ala Methenamine; Methenamine Hippurate; Methenamine mecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Ami Mandelate; Methicillin Sodium; Metioprim; Metronidazole cycline; Amifioxacin; Amifloxacin Mesylate; Amikacin; Hydrochloride; Metronidazole Phosphate; Mezlocillin; Amikacin Sulfate; Aminosalicylate sodium; Aminosalicylic 65 Mezlocillin Sodium; Minocycline; Minocycline Hydrochlo acid; Amoxicillin; Amphomycin; Ampicillin; Ampicillin ride; Mirincamycin Hydrochloride; Monensin; Monensin Sodium; Apalcillin Sodium; Apramycin; Aspartocin, Astro Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic US 9,642,912 B2 25 26 Acid; Natamycin; Nebramycin; Neomycin Palmitate; Neo Bromide: Cyclopentolate Hydrochloride; Dexetimide; Dicy mycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; clomine Hydrochloride; Dilhexy verine Hydrochloride: Neutramycin; Nifarthiazole; Nifuradene; Nifuraldezone: Domazoline Fumarate; Elantrine; Elucaine; Ethybenz Nifuratel; Nifuratrone; Nifurdazil; Nifurimide: Nifurpirinol: tropine: Eucatropine Hydrochloride; Glycopyrrolate: Het Nifurcquinazol; Nitrocycline; Nitrofurantoin: Nitromide: eronium Bromide; Homatropine Hydrobromide: Homatro Norfloxacin; Novobiocin Sodium; Ofloxacin; Onnetoprim; pine Methylbromide: Hyoscyamine: Hyoscyamine Oxacillin Sodium; Oximonam, Oximonam Sodium; OXo Hydrobromide; Hyoscyamine Sulfate; Isopropamide Iodide: linic Acid: Oxytetracycline; Oxytetracycline Calcium; Mepenzolate Bromide: Methylatropine Nitrate; Meto Oxytetracycline Hydrochloride; Paldimycin; Parachloro quizine: Oxybutynin Chloride; Parapenzolate Bromide: Pen phenol; Paulomycin; Pefloxacin: Pefloxacin Mesylate: Pena 10 tapiperium Methylsulfate; Phencarbamide: Poldine Methyl mecillin, Penicillin G BenZathine; Penicillin G Potassium; sulfate; Proglumide: Propantheline Bromide: Propenzolate Penicillin G Procaine; Penicillin G Sodium; Penicillin V: Hydrochloride; Scopolamine Hydrobromide: Tematropium Penicillin V Benzathine: Penicillin V Hydrabamine; Peni Methylsulfate; Tiquinamide Hydrochloride; Tofenacin cillin V Potassium; Pentizidone Sodium; Phenyl Amin Hydrochloride; Toquizine; TriampyZine Sulfate; Trihexy osalicylate; Piperacillin Sodium; Pirbenicillin Sodium; 15 phenidyl Hydrochloride; and Tropicamide. Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicil Anticoagulant: Ancrod; Ardeparin Sodium, Bivalirudin; lin Hydrochloride; Pivampicillin Pamoate: Pivampicillin Bromindione; Dalteparin Sodium Desirudin; Dicumarol; Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin: Lyapolate Sodium; Nafamo.stat Mesylate; Phenprocoumon; Pyrazinamide: Pyrithione Zinc: Quindecamine Acetate; Qui Tinzaparin Sodium; and Warfarin Sodium. nupristin: Racephenicol; Ramoplanin; Ranimycin; Relomy Anticoccidal: Maduramicin. cin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rif Anticonvulsant: Albutoin: Ameltolide; Atolide; Bura amide; Rifampin; Rifapentine; Rifaximin; Rolitetracycline: mate; Cinromide: Citenamide; Clonazepam, Cyheptamide; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Dezinamide; Dimethadione; Divalproex Sodium: Eterobarb: Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Ethosuximide: Ethotoin: Flurazepam Hydrochloride: Fluzi Phosphate; Rosaramicin Stearate; Rosoxacin; Roxarsone; 25 namide; Fosphenytoin Sodium; Gabapentin; Ilepcimide; Roxithromycin; Sancycline: Sanfetrinem Sodium; Sarmoxi Lamotrigine; Magnesium Sulfate; Mephenytoin: Mephobar cillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sul bital; Methetoin: MethSuximide: Milacemide Hydrochlo fate; Sparfloxacin; Spectinomycin Hydrochloride: Spiramy ride; Nabazenil; Nafimidone Hydrochloride; Nitrazepam; cin; Stallimycin Hydrochloride; Steflimycin; Streptomycin Phenacemide; Phenobarbital; Phenobarbital Sodium; Phen Sulfate: Streptonicozid; Sulfabenz; Sulfabenzamide: Sulfac 30 suximide; Phenytoin: Phenytoin Sodium; Primidone: Proga etamide: Sulfacetamide Sodium; Sulfacytine; Sulfadiazine: bide; Ralitoline; Remacemide Hydrochloride; Ropizine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamera Sabeluzole; Stiripentol; Sulthiame: Topiramate: Trimethadi Zine; Sulfameter, Sulfamethazine; Sulfamethizole; Sulfame one; Valproate Sodium; Valproic Acid; Vigabatrin: Zonicl thoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate eZole Hydrochloride; and Zonisamide. Zinc, Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiaz 35 Antidepressant: Adinazolam; Adinazolam Mesylate: ole: Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl: Alaproclate; Aletamine Hydrochloride; Amedalin Hydro Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultami chloride; Amitriptyline Hydrochloride: Aptazapine Maleate; cillin; Suncillin Sodium; Talampicillin Hydrochloride; Tei AZaloxan Fumarate; AZepindole; AZipramine Hydrochlo coplanin; Temafloxacin Hydrochloride; Temocillin; Tetracy ride; Bipenamol Hydrochloride: Bupropion Hydrochloride; cline Phosphate Complex; Tetroxoprim; Thiamphenicol; 40 Butriptyline Hydrochloride; Caroxazone; Cartazolate: Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticar Ciclazindol; Cidoxepin Hydrochloride: Cilobamine Mesy cillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodo late; Clodazon Hydrochloride; Clomipramine Hydrochlo nium Chloride; Tobramycin; Tobramycin Sulfate; Tosu ride; Cotinine Fumarate; Cyclindole: Cypenamine Hydro floxacin: Trimethoprim; Trimethoprim Sulfate; chloride; Cyprolidol Hydrochloride; Cyproximide: Trisulfapyrimidines; Troleandomycin; Trospectomycin Sul 45 Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol fate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride: Maleate; Dazepinil Hydrochloride: Desipramine Hydro Virginiamycin; and Zorbamycin. chloride; Dexamisole; Deximafen; Dibenzepin Hydrochlo Anti-cancer Supplementary potentiating agents: Amitryp ride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride; tyline, Amoxapine; Amphotericin B; Antiarrhythmic drugs Doxepin Hydrochloride; Duloxetine Hydrochloride: Eclan (e.g., Quinidine); Antihypertensive drugs (e.g., Reserpine); 50 amine Maleate; Encyprate; Etoperidone Hydrochloride: Ca++ antagonists (e.g., Verapamil; Calmodulin inhibitors Fantridone Hydrochloride: Fenmetramide; Fezolamine (e.g., Prenylamine; Caroverine); Citalopram); Clomip Fumarate: Fluotracen Hydrochloride: Fluoxetine: Fluox ramine; Clomipramine); Desipramine; Doxepin; Maproti etine Hydrochloride: Fluparoxan Hydrochloride; Gamfex line); Nifedipine; Nitrendipine; Non-tricyclic anti-depres ine; Guanoxyfen Sulfate: Imafen Hydrochloride: Imiloxan sant drugs (e.g., Sertraline; Nortriptyline: Protriptyline: 55 Hydrochloride: Imipramine Hydrochloride; Indeloxazine Sulfoximine) and Multiple Drug Resistance reducing agents Hydrochloride; Intriptyline Hydrochloride; Iprindole: Iso such as Cremaphor EL: Thiol depleters (e.g., Buthionine: carboxazid; Ketipramine Fumarate; Lofepramine Hydro Trazodone; Tricyclic anti-depressant drugs (e.g., Imip chloride; Lortalamine: Maprotiline: Maprotiline Hydrochlo ramine; Trifluoroperazine; Trimipramine; and Triparanol ride; Melitracen Hydrochloride; Minaprine Hydrochloride; analogues (e.g., Tamoxifen). 60 Mirtazapine; Moclobemide: Modaline Sulfate; Napactadine Anticholelithic: Monoctanoin. Hydrochloride; Napamezole Hydrochloride: Nefazodone Anticholelithogenic: Chenodiol; Ursodiol. Hydrochloride; Nisoxetine; Nitrafudam Hydrochloride: Anticholinergic: Alverinc Citrate; Anisotropine Methyl Nomifensine Maleate; Nortriptyline Hydrochloride; Octrip bromide: Atropine; Atropine Oxide Hydrochloride; Atropine tyline Phosphate; Opipramol Hydrochloride: Oxaprotiline Sulfate; Belladonna; Benapryzine Hydrochloride; Ben 65 Hydrochloride: Oxypertine; Paroxetine; Phenelzine Sulfate: Zetimide Hydrochloride; Benzilonium Bromide: Biperiden; Pirandamine Hydrochloride; Pridefine Hydrochloride; Pro Biperiden Hydrochloride; Biperiden Lactate; Clidinium lintane Hydrochloride; Protriptyline Hydrochloride; Qui US 9,642,912 B2 27 28 pazine Maleate; Rolicyprine; Seproxetine Hydrochloride; acetin: Triafungin: Undecylenic Acid; Viridofulvin; Zinc Sertraline Hydrochloride; Sulpiride: Suritozole; Tametraline Undecylenate; and Zinoconazole Hydrochloride. Hydrochloride; Tampramine Fumarate; Tandamine Hydro Antiglaucoma agent: AlprenoXime Hydrochloride; Col chloride; Thiazesim Hydrochloride; Thozalinone; Tomox forsin; Dipivefrin Hydrochloride; Naboctate Hydrochloride: etine Hydrochloride; Trazodone Hydrochloride; Trebenzo Pilocarpine; and Pirnabine. mine Hydrochloride; Trimipramine Maleate; Venlafaxine Antihemorrhagic: Poliglusam. Hydrochloride; Viloxazine Hydrochloride; Zimeldine Antihemorrheologic: Phentoxifylline. Hydrochloride; and Zometapine. Antihistaminic: Acrivastine; Antazoline Phosphate: AZa Antidiabetic: Acetohexamide; Buformin; Butoxamine tadine Maleate; Barmastine; Bromodiphenhydramine Hydrochloride; Camighbose; Chlorpropamide: Ciglitazone: 10 Hydrochloride; Brompheniramine Maleate; Carbinoxamine Englitazone Sodium: Etoformin Hydrochloride; Gliamilide; Maleate; Cetirizine Hydrochloride; Chlorpheniramine Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide: Maleate; Chlorpheniramine Polistirex: Cirmarizine; Clem Glucagon; Glyburide; Glyhexamide: Glymidine Sodium; astine; Clemastine Fumarate; Closiramine Aceturate; Cyc Glyoctamide; Glyparamide; Insulin; Insulin Human; Insulin liramine Maleate; Cyclizine; Cyproheptadine Hydrochlo Human Zinc, Insulin Human Zinc, Extended; Insulin 15 ride; Dexbrompheniramine Maleate; Dexchlorpheniramine Human, Isophane; Insulin Lispro; Insulin Zinc, Insulin Zinc, Maleate; Dimethindene Maleate; Diphenhydramine Citrate; Extended; Insulin Zinc, Prompt; Insulin, Dalanated; Insulin, Diphenhydramine Hydrochloride; Dorastine Hydrochloride: Isophane; Insulin, Neutral; Linogliride; Linogliride Fumar Doxylamine Succinate; Ebastine; Fexofenadine HCI: Levo ate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium; cabastine Hydrochloride; Loratadine: Mianserin Hydrochlo Pioglitazone Hydrochloride; Pirogliride Tartrate; Proinsulin ride; Noberastine; Orphenadrine Citrate: Pyrabrom: Pyril Human; Seglitide Acetate; Tolazamide; Tolbutamide: amine Maleate: Pyroxamine Maleate; Rocastine Tolpyrramide; TroglitaZone; and Zopolrestat. Hydrochloride; Rotoxamine; Tazifylline Hydrochloride: Antidiarrheal: Diphenoxylate Hydrochloride; Methyl Temelastine; Terfenadine; Tripelennamine Citrate; prednisolone; Metronidazole; and Rolgamidine. Tripelennamine Hydrochloride; and Triprolidine Hydro Antidiuretic: Argipressin Tannate; Desmopressin Acetate; 25 chloride. and Lypressin. Antihyperlipidemic: Cholestyramine Resin; Clofibrate; Antidote: Dimercaprol: Edrophonium Chloride: Colestipol Hydrochloride: Crilvastatin: Dalvastatin: Dextro Fomepizole; Levoleucovorin Calcium; Methylene Blue; and thyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Lec Protamine Sulfate. imibide; Lovastatin; Niacin; Pravastatin Sodium; Probucol, Antidyskinetic: Selegiline Hydrochloride. 30 Simvastatin; Tiqueside; and Xenbucin. Anti-emetic: Alosetron Hydrochloride; Batanopride Antihyperlipoproteinemic: Acifran; Beloxamide: Bezafi Hydrochloride: Bemesetron; Benzquinamide; Chlorpromaz brate; Boxidine; Cetaben Sodium: Ciprofibrate: Gemcadiol: ine; Chlorpromazine Hydrochloride; Clebopride: Cyclizine Halofenate: Lifibrate; Meglutol; Nafenopin: Pimetime Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Theofibrate; Tilbric Acid; and Treloxinate. Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate: 35 Antihypertensive: Alfuzosin Hydrochloride; Alipamide: Domperidone; Dronabinol; Flumeridone; Galdansetron Althiazide; Amiquinsin Hydrochloride; Anaritide Acetate; Hydrochloride; Granisetron; Granisetron Hydrochloride: Atiprosin Maleate; Belfosdil: Bemitradine; Bendacalol Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopr Mesylate; Bendroflumethiazide; Benzthiazide: Bethanidine amide Hydrochloride; Metopimazine: Prochlorperazine: Sulfate; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Prochlorperazine Edisylate: Prochlorperazine Maleate; Pro 40 Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthi methazine Hydrochloride; Thiethylperazine; Thiethylpera azide: Candoxat rilat; Candoxatril; Captopril; Ceronapril; zine Malate: Thiethylperazine Maleate; Trimethobenzamide Chlorothiazide Sodium: Cicletanine: Cilazapril; Clonidine: Hydrochloride; and Zacopride Hydrochloride. Clonidine Hydrochloride; Clopamide: Cyclopenthiazide: Anti-epileptic: Felbamate; Iamotrigine; LorecleZole; and Cyclothiazide: Darodipine; Debrisoquin Sulfate; Delapril Tolgabide. 45 Hydrochloride; Diapamide: Diazoxide; Diltiazem Hydro Anti-estrogen: Clometherone; Nafoxidine Hydrochloride: chloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate: Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Ecadotril: Enalapril Maleate; Enalaprilat; Enalkiren: Citrate; Toremifene Citrate; and Trioxifene Mesylate. Endralazine Mesylate: Epithiazide: Eprosartan; Eprosartan Antifibrinolytic: Nafamostat Mesylate. Mesylate: Fenoldopam Mesylate: Flavodilol Maleate; Antifungal: Acrisorcin; Ambruticin; AZaconazole; AZa 50 Flordipine; Flosequinan; Fosinopril Sodium; Fosinoprilat; serine; Basifungin: Bifonazole; Butoconazole Nitrate; Cal Guanabenz: Guanabenz, Acetate; Guanacline Sulfate; Gua cium Undecylenate; Candicidin; Carbol-Fuchsin; Chlordan nadrel Sulfate; Guancvdine; Guanethidine Monosulfate; toin: Ciclopirox: Ciclopirox Olamine: Cilofungin; Guanethidine Sulfate; Guanfacine Hydrochloride; Guaniso Cisconazole; Clotrimazole; Cuprimyxin; Doconazole; quin Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride: Econazole; Econazole Nitrate; Enilconazole; Ethonam 55 Guanoxabenz: Guanoxan Sulfate; GuanoXVfen Sulfate; Nitrate: Fenticonazole Nitrate; Filipin; Fluconazole: Flucy Hydralazine Hydrochloride; Hydralazine Polistirex; Hydro tosine; Fungimycin; Griseofulvin; Hamycin, Itraconazole; flumethiazide; Indacrinone Indapamide: Indolapril Hydro Kalafungin; Ketoconazole; Lomoftmgin; Lydimycin; chloride; Indoramin; Indoramin Hydrochloride; Indorenate Mepartricin; Miconazole; Miconazole Nitrate; Monensin; Hydrochloride; Lacidipine; Leniquinsin; Lisinopril; Lofexi Monensin Sodium; Naftifine Hydrochloride; Nifuratel 60 dine Hydrochloride; Losartan Potassium; Losulazine Hydro Nifurmerone; Nitralamine Hydrochloride; Nystatin: chloride; Mebutamate; Mecamylamine Hydrochloride: Octanoic Acid, Orconazole Nitrate; Oxiconazole Nitrate; Medroxalol; Medroxalol Hydrochloride; Methalthiazide Oxifungin Hydrochloride; Parconazole Hydrochloride; Par Methyclothiazide Methyldopa; Methyldopate Hydrochlo tricin; Potassium Iodide; Pyrrolnitrin; Rutamycin; Sangui ride; Metipranolol; Metolazone Metoprolol Fumarate; narium Chloride; Saperconazole: Selenium Sulfide: Sine 65 Metyrosine; Minoxidil; Muzolimine; Nebivolol; Nifidipine; fungin; Sulconazole Nitrate; Terbinafine; Terconazole; Ofornine: Pargyline Hydrochloride; Pazoxide; Pelanserin Thiram; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Tri Hydrochloride; Perindopril Erbumine; Phenoxybenzamine US 9,642,912 B2 29 30 Hydrochloride; Pinacidil: Pivopril; Polythiazide; Prazosin RomaZarit; Salnacedin; SeclaZone; Sermetacin; Sudoxicam, Hydrochloride; Prizidilol Hydrochloride; Quinapril Hydro Sulindac: Suprofen; Talniflumate; Tenidap: Tenidap chloride; Quinaprilat; Quinazosin Hydrochloride; Quinelo Sodium; Tenoxicam, Tesicam, Tesimide; Tixocortol Piva rane Hydrochloride: Quinpirole Hydrochloride; Quinuclium late; Tolimetin; Tolimetin Sodium; Triclonide; Triflumidate; Bromide: Ramipril; Rauwolfia Serpentina; Reserpine; and Zidometacin. Saprisartan Potassium; Saralasin Acetate; Sodium Nitrop Antikeratinizing agent: Doretinel; Linarotene; and Pelre russide; Sulfinalol Hydrochloride; Tasosartan; Temocapril tin. Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tia Antimalarial: Amodiaquine Hydrochloride; Amquinate; menidine; Tiamenidine Hydrochloride; Ticrynafen; Tinabi Artefiene; Chloroquine; Chloroquine Hydrochloride; nol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethi 10 Cycloguanil Pamoate; Enpiroline Phosphate: Halofantrine azide; Trimazosin Hydrochloride; Trimethaphan Camsylate: Hydrochloride; Hydroxychloroquine Sulfate; Mefloquine Trimoxamine Hydrochloride; Tripamide; Xipamide: Hydrochloride; Menoctone; Primaquine Phosphate: Zankiren Hydrochloride; and Zofenoprilat Arginine. Pyrimethamine; Quinine Sulfate; and Tebuquine. Antihypotensive: Ciclafrine Hydrochloride; and Mido Antimicrobial: Aztreonam; Chlorhexidine Gluconate; drine Hydrochloride. 15 Imidurea; Lycetamine; Nibroxane: Pirazmonam Sodium; Anti-infective: Acyclovir; Difloxacin Hydrochloride: Propionic Acid; Pyrithione Sodium; and Tigemonam Dicho Integrase Inhibitors of HIV and other retroviruses: Lauryl line. Isoquinolinium Bromide; Moxalactam Disodium: Ornida Antimigraine: Naratriptan Hydrochloride: Sergolexole Zole; Pentisomicin; Protease inhibitors of HIV and other Maleate: Sumatriptan Succinate; and Zatosetron Maleate. retroviruses; and Sarafloxacin Hydrochloride. Antimitotic: Podofilox. Anti-infective (topical): Alcohol; Aminacrine Hydrochlo Antimycotic: Amorolfine. ride; Benzethonium Chloride; Bithionolate Sodium; Bro Antinauseant: Buclizine Hydrochloride; and Cyclizine mchlorenone; Carbamide Peroxide; Cetalkonium Chloride; Lactate. Cetylpyridinium Chloride; Chlorhexidine Hydrochloride: Antineoplastic: Acivicin, Aclarubicin; Acodazole Hydro Domiphen Bromide: Fenticlor: Fludazonium Chloride: 25 chloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Fuchsin, Basic; Furazolidone; Gentian Violet; Halquinols: Ambomycin; Ametantrone Acetate; Amsacrine; Anastro Hexachlorophene; Hydrogen Peroxide: Ichthammol: Imide Zole; Anthramycin; Asparaginase; Asperlin; AZacitidine; cyl Iodine: Iodine: Isopropyl Alcohol; Mafenide Acetate; AZetepa, Azotomycin; Batimastat; BenZodepa; Bicaluta Meralein Sodium; Mercufenol Chloride; Mercury, Ammo mide: Bisantrene Hydrochloride; Bisnafide Dimesylate: niated; Methylbenzethonium Chloride: Nitrofarazone: 30 Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirim Nitromersol; Octenidine Hydrochloride: Oxychlorosene: ine; BuSulfan; Cactinomycin, Calusterone; Caracemide; Oxychlorosene Sodium; Parachlorophenol, Camphorated: Carbetimer; Carboplatin: Carmustine: Carubicin Hydro Potassium Permanganate; Povidone-Iodine; Sepazonium chloride; Carzelesin; Cedefingol: Chlorambucil; Cisplatin: Chloride; Silver Nitrate; Sulfadiazine, Silver; Symclosene: Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytara Thimerfonate Sodium; Thimerosal; and Troclosene Potas 35 bine; Dacarbazine; Dactinomycin; Daunorubicin Hydro sium. chloride; Decitabine; Dexorinaplatin: Dezaguanine; Deza Anti-inflammatory: Alclofenac; Alclometasone Dipropi guanine Mesylate; Diaziquone; Docetaxel, Doxorubicin; onate; Algestone Acetonide; Alpha Amylase; Amcinafal; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Cit Amcinafide: Amfenac Sodium; Amiprilose Hydrochloride; rate; DromoStanolone Propionate; DuaZomycin; Edatrexate; Anakinra, AnitraZafen; Apazone; Balsalazide Disodium; 40 Eflornithine Hydrochloride; Elsamitrucin; Enloplatin: Bendazac. Bromelains; Broperamole; Budesonide; Carpro Enpromate: Epipropidine: Epirubicin Hydrochloride; Erbu fen: Cicloprofen; Cintazone; Cliprofen; Clobetasol Propi lozole; Esorubicin Hydrochloride; Estramustine; Estramus onate; Clobetasone Butyrate; Clopirac; Cloticasone Propi tine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; onate; Cormethasone Acetate; Cortodoxone; Deflazacort; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Desonide; DeSoximetasone; Dexamethasone Dipropionate; 45 Hydrochloride; Fazarabine; Fenretinide; Floxuridine: Flu Diclofenac Potassium; Diclofenac Sodium; Diflorasone darabine Phosphate: Fluorouracil; Flurocitabine; Fosqui Diacetate; Diflumidone Sodium; Difluprednate; Diftalone: done; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydro Dimethyl Sulfoxide: Drocinonide; Endrysone; Enlimomab: chloride; Gold Au 198: Hydroxyurea; Idarubicin, Enolicam Sodium; Etodolac, Felbinac; Fenamole: Fen Hydrochloride: Ifosfamide: Ilmofosine; Interferon Alfa-2a: bufen: Fenclofenac; Fenclorac; Fendosal: Fenpipalone: Fen 50 Interferon Alfa-2b: Interferon Alfan3; Interferon Alfa-nl, tiazac, Flazalone; Fluazacort; Flufenamic Acid, Flumizole; Interferon Beta-I a: Interferon Garmna-Ib, Iproplatin; Iri Flunisolide Acetate: Fluocortin Butyl; Fluorometholone notecan Hydrochloride: Isotretinoin; Lanreotide Acetate; Acetate; FluquaZone: Fluretofen; Fluticasone Propionate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride: Furaprofen; Furobufen; Halcinonide; Halobetasol Propi Lometrexol Sodium; Lomustine; Losoxantrone Hydrochlo onate; Halopredone Acetate; Ibuprofen; Ibuprofen Alumi 55 ride; Masoprocol; Maytansine; Mechlorethamine Hydro num; Ibuprofen Piconol; Ilonidap: Indomethacin Sodium; chloride; Megestrol Acetate; Melengestrol Acetate; Mel Indomethacin; Indoprofen Indoxole; Intrazole; Isoflupre phalan; Menogaril; Mercaptopurine; Methotrexate: done Acetate; Isoxepac; Isoxicam, Ketoprofen; Lomoxicam, Methotrexate Sodium; Metoprine; Meturedepa; Mitindo Loteprednol Etabonate; Meclofenamate Sodium; Meclofe mide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin: namic Acid; Meclorisonc Dibutyrate; Mesalamine; Mese 60 Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochlo clazone; Methylprednisolone Suleptanate; Morniflumate: ride; Mycophenolic Acid; Nocodazole; Nogalamvcin: Nabumetone; Nimazone; Olsalazine Sodium; Orgotein; Ormaplatin: Oxisuran; Paclitaxel; Pegaspargase; Peliomy Orpanoxin: Oxaprozin: Oxyphenbutazone: Paranyline cin; Pentamustine: Peplomycin Sulfate; Perfosfamide; Pipo Hydrochloride; Pentosan Polysulfate Sodium; Phenbuta broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy Zone Sodium Glycerate; Piroxicam, Piroxicam Cinnamate: 65 cin; Plomestane; Porfimer Sodium; Prednimustine; Pirprofen; Prednazate: Prednisolone Sodium Phosphate: Procarbazine Hydrochloride; Puromycin; Puromycin Prifelone: Prodolic Acid; ProquaZone; Rimexolone: Hydrochloride: Pyrazofurin; Riboprine; Rogletimide: Safin US 9,642,912 B2 31 32 gol Safingol Hydrochloride: Semustine; SimtraZene; Spar philic Disaccharide Peptide; Lipophilic Platinum Com fosate Sodium; Sparsomycin; Spiro germanium Hydrochlo pounds; Lissoclinamide 7: Lobaplatin; Lombricine; Lom ride, Spiromustine; Spiroplatin; Streptonigrin: Streptozocin, etrexol; Lonidamine; Losoxantrone; Lurtotecan; Lutetium Strontium Chloride Sr 89: Sulofenur; Talisomycin; Taxane: Texaphyrin; Lysofylline; Lytic Peptides; Maitansine: Man Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydro nostatin A; Marimastat; Maspin; Matrilysin Inhibitors: chloride; Temoporfin; Teniposide; Teroxirone; Testolactone: Matrix Metalloproteinase Inhibitors; Merbarone; Meterelin; Thiamiprine: Thioguanine: Thiotepa; TiaZofarin; Tira Methioninase; Metoclopramide: MIF Inhibitor; Mifepris pazamine; Topotecan Hydrochloride; Triciribine Phosphate: tone; Miltefosine; Mirimostim; Mismatched Double Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubu Stranded RNA; MitoguaZone; Mitolactol; Mitomycin ana lozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide: 10 Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vin logues; Mitonafide: Mitotoxin Fibroblast Growth Factor desine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Saporin; Mitoxantrone: Mofarotene; Monoclonal Antibody, Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosi Human Chorionic Gonadotrophin; Monophosphoryl Lipid dine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin: A+Myobacterium Cell Wall Sk; Mopidamol; Multiple Drug Zinostatin; and Zorubicin Hydrochloride. 15 Resistance Gene Inhibitor: Multiple Tumor Suppressor Anti-neoplastic compounds (additional): 20-epi-1.25 I-Based Therapy: Mustard Anticancer Agent; Mycaperoxide Dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Acyl B: Mycobacterial Cell Wall Extract; Myriaporone; NAcetyl fulvene, Adecypenol; ALL-TK Antagonists; Ambamustine; dinaline; Nafarelin; Nagrestip; Naloxone--Pentazocine; Amidox: Amifostine; Aminolevulinic Acid, Amrubicin; Napavin; Naphterpin; Nartograstim; Nedaplatin: Nemoru Anagrelide; Andrographolide; Angiogenesis Inhibitors; bicin; Neridronic Acid; Neutral Endopeptidase; Nilutamide: Antagonist D. Antagonist G.; Antarelix; Antiandrogen, Pro Nisamycin; Nitric Oxide Modulators; Nitroxide Antioxi static Carcinoma; Anti-Dorsalizing Morphogenetic Protein dant; Nitrullyn; N-Substituted Benzamides; 06-Benzylgua I; Antiestrogen; Antineoplaston; Antisense Oligonucle nine; Okicenone; Oligonucleotides; Onapristone; Ondanse otides: Aphidicolin Glycinate: Apoptosis Gene Modulators: tron: Oracin; Oral Cytokine Inducer: Osaterone; Oxaliplatin: Apoptosis Regulators: Apurinic Acid; Ara-CDP-DL-PTBA: 25 Oxaunomycin; Paclitaxel Analogues: Paclitaxel Deriva Arginine Deaminase; ASulacrine; AtameStane; Atrimustine; tives: Palauamine: Palmitoylrhizoxin; Pamidronic Acid; Axinastatin 1: Axinastatin 2: Axinastatin 3; AZasetron; AZa Panaxytriol; Panomifene: Parabactin; Pazelliptine: toxin; AZatyrosine; Baccatin III Derivatives; Balanol; BCR/ Peldesine; Pentostatin: Pentrozole; Perflubron: Perillyl ABL Antagonists; BenZochlorins; BenZoylstaurosporine; Alcohol; Phenazinomycin; Phenylacetate; Phosphatase Beta Lactam Derivatives: Beta-Alethine: Betaclamycin B; 30 Inhibitors; Picilbanil; Pilocarpine Hydrochloride: Pirarubi Betulinic Acid; bFGF Inhibitor; Bisantrene; Bisaziridinyl cin; Piritrexim; Placetin A; Placetin B: Plasminogen Acti spermine; Bisnafide: Bistratene A: Breflate: Budotitane: vator Inhibitor: Platinum Complex: Platinum Compounds: Buthionine Sulfoximine; Calcipotriol: Calphostin C; Camp Platinum-Triamine Complex: Propyl Bis-Acridone; Prosta tothecin Derivatives; Canarypox IL-2; Capecitabine; Car glandin J2: Proteasome Inhibitors: Protein A-Based Immune boxamide-Amino-Triazole; Carboxyamidotriazole; CaRest 35 Modulator; Protein Kinase C Inhibitor; Protein Kinase C MI; CARN 700, Cartilage Derived Inhibitor; Casein Kinase Inhibitors, Microalgal; Protein Tyrosine Phosphatase Inhibi Inhibitors (ICOS); Castanospermine; Cecropin B; Cetrore tors; Purine Nucleoside Phosphorylase Inhibitors; Pur lix; Chlorins; Chloroquinoxaline Sulfonamide: Cicaprost; purins; Pyrazoloacridine: Pyridoxylated Hemoglobin Poly Cis-Porphyrin; Clomifene analogues; Collismycin A; Col oxyethylene Conjugate; Raf Antagonists; Raltitrexed: lismycin B; Combretastatin A4; Combretastatin Analogue; 40 Ramosetron; Ras Famesyl Protein Transferase Inhibitors: Conagenin; Crambescidin 816: Crisinatol; Cryptophycin 8: Ras Inhibitors; Ras-GAP Inhibitor: Retelliptine Demethyl Cryptophycin A Derivatives; Curacin A; Cyclopentanthra ated; Rhenium, Re 186 Etidronate; Rhizoxin; Ribozymes: quinones; Cycloplatam; Cypemycin; Cytarabine Ocfosfate; Rh Retinamide: Rohitukine; Romurtide; Roquinimex: Cytolytic Factor; Cytostatin: Dacliximab: Dehydrodidenmin Rubiginone B 1: Ruboxyl; Safingol: Saintopin; SarCNU; B: Dexifosfamide: DexVerapamil: Didemnin B: Didox; 45 Sarcophytol A; Sdi 1 Mimetics; Senescence Derived Inhibi Diethylnorspennine; Dihydro AZacytidine; 9-Dihydrotaxol; tor 1: Sense Oligonucleotides; Signal Transduction Inhibi Dioxamycin; Diphenyl Spiromustine; Docosanol; Dolas tors; Signal Transduction Modulators; Single Chain Antigen etron; Doxifluridine; Duocarmycin SA; Ebselen; Ecomus Binding Protein; Sizofiran; Sobuzoxane: Sodium Boroc tine; Edelfosine; Edrecolomab, Eflomithine; Elemene; aptate; Sodium Phenylacetate; Solverol: Somatomedin Emitefur, Epirubicin; Estramustine Analogue; Estrogen 50 Binding Protein; Sonermin; Sparfosic Acid; Spicamycin D; Agonists; Estrogen Antagonists; Exemestane; Fadrozole; Splenopentin; Spongistatin 1: Squalamine: StemCell Inhibi Fiezelastine: Flavopiridol; Fluasterone: Fludarabine; Fluo tor; Stem-Cell Division Inhibitors: Stipiamide: Stromelysin rodaunorunicin Hydrochloride; Forfenimex: Formestane: Inhibitors; Sulfinosine: Superactive Vasoactive Intestinal Fostriecin; Fotemustine; Gadolinium Texaphyrin; Gallium Peptide Antagonist; Suradista; Suramin; Swainsonine; Syn Nitrate; Galocitabine; Ganirelix; Gelatinase Inhibitors; Glu 55 thetic Glycosaminoglycans; Tallimustine; Tamoxifen tathione Inhibitors; Hepsulfam; Heregulin: Hexamethylene Methiodide; Tauromustine; Tellurapyrylium; Telomerase Bisacetamide: Hypericin; Ibandronic acid; Idarubicin; Idox Inhibitors; Temozolomide; Tetrachlorodecaoxide; TetraZom ifene; Idramantone; Ilomastat, Imidazoacridones; Immuno ine: Thaliblastine: Thalidomide: Thiocoraline: Thrombopoi stimulant Peptides; Insulin-Like Growth Factor-1 Receptor etin: Thrombopoietin Mimetic: Thymalfasin; Thymopoietin Inhibitor; Interferon Agonists; Interferons; Interleukins: 60 Receptor Agonist; Thymotrinan; Thyroid Stimulating Hor Iobenguane; Iododoxorubicin: 4-Ipomeanol; Irinotecan; Iro mone; Tin Ethyl Etiopurpurin; Titanocene Dichloride; Topo plact; Irsogladine; IsobengaZole; Isohomohalicondrin B; tecan; Topsentin; Toremifene: Totipotent Stem Cell Factor; Itasetron; Jasplakinolide: Kahalalide F. Lamellarin-N Triac Translation Inhibitors; Triacetyluridine; Triciribine; Tropise etate; Lanreotide; Leinamycin; Lentinan Sulfate; Leptolsta tron: Turosteride; Tyrosine Kinase Inhibitors: Tyrphostins: tin, Leukemia Inhibiting Factor; Leukocyte Alpha Inter 65 UBC Inhibitors: Ubenimex: Urogenital Sinus-Derived feron; Leuprolide--Estrogen--Progesterone; Leuprorelin; Growth Inhibitory Factor: Urokinase Receptor Antagonists: Levamisole; Liarozole; Linear Polyamine Analogue; Lipo Variolin B; Vector system, Erythrocyte Gene Therapy: US 9,642,912 B2 33 34 Velaresol; Veramine; Verdins; Vinorelbine; Vinxaltine; Antischistosomal: Becanthone Hydrochloride; Hycan Vitaxin, Zilascorb; and Zinostatin Stimalamer. thone; Lucanthone Hydrochloride; Niridazole: Oxam Antineutropenic: Filgrastim; Lenograstim; Molgra niquine; Pararosaniline Pamoate; and Teroxalene Hydro mostim; RegramoStim; and Sargramostim. chloride. Antiobsessional agent: Fluvoxamine Maleate. Antiseborrheic: Chloroxine; Piroctone; Piroctone Antiparasitic: Abamectin; ClorSulon; and Ivermectin. Olamine; and Resorcinol Monoacetate. Antiparkinsonian: Benztropine Mesylate; Biperiden; Antisecretory: Arbaprostil; Deprostil: Fenoctimine Sul Biperiden Hydrochloride; Biperiden Lactate; Carbidopa fate; Octreotide; Octreotide Acetate; Omeprazole Sodium; Levodopa; Carmantadine: Ciladopa Hydrochloride; Dopa Rioprostil; Trimoprostil. mantine; Ethopropazine Hydrochloride; Lazabemide: 10 Antispasmodic: Stilonium Iodide; Tizanidine Hydrochlo Levodopa; Lometraline Hydrochloride; Mofegiline Hydro ride. chloride; N axagolide Hydrochloride; Pareptide Sulfate: Antithrombotic: Anagrelide Hydrochloride; Dalteparin Procyclidine Hydrochloride; Ropinirole Hydrochloride; and Sodium; Danaparoid Sodium; Dazoxiben Hydrochloride: Tolcapone. Efegatran Sulfate; Enoxaparin Sodium: Ifetroban: Ifetroban 15 Sodium; and Trifenagrel. Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; Antitussive: BenZonatate; Butamirate Citrate; Fluperamide; Lidamidine Hydrochloride; Loperamide Chlophedianol Hydrochloride: Codeine Polistirex: Codox Hydrochloride; Malethamer; Nufenoxole; Paregoric. ime; Dextromethorphan: Dextromethorphan Hydrobromide: Antipneumocystic: Atovaquone. Dextromethorphan Polistirex: Ethyl Dibunate; Guaiapate: Antiproliferative agent: Piritrexim Isethionate. Hydrocodone Bitartrate; Hydrocodone Polistirex; Levo Antiprostatic hypertrophy: Sitogluside. propoxyphene Napsylate: Noscapine; Pemerid Nitrate; Antiprotozoal: Amodiaquine; AZanidazole; Banmidazole; Pipazethate; and Suxemerid Sulfate. Camidazole; Chlortetracycline Bisulfate Chlortetracycline Anti-ulcerative: Aceglutamide Aluminum; CadeXomer Hydrochloride: Flubendazole: Flunidazole; Halofuginone Iodine; Cetraxate Hydrochloride; Enisoprost: Isotiquimide: Hydrobromide: Imidocarb Hydrochloride; Ipronidazole; 25 Lansoprazole; Lavoltidine Succinate; Misoprostol; Nizati Misonidazole; Moxinidazole; Nitarsone; Ronidazole; Sul dine; Nolinium Bromide; Pantoprazole; Pifarnine: nidazole; and Tinidazole. Pirenzepine Hydrochloride; Rabeprazole Sodium; Remipro Antipruritic: Methdilazine; Methdilazine Hydrochloride: stol; Roxatidine Acetate Hydrochloride; Sucralfate; Sucro and Trimeprazine Tartrate. sofate Potassium; and Tolimidone. 30 Anti-urolithic: Cysteamine: Cysteamine Hydrochloride; Antipsoriatic: Acitretin: Anthralin; Azaribine; Calcipot and Tricitrates. riene; Cycloheximide: Enazadrem Phosphate; Etretinate; Antiviral: Acemannan: Acyclovir; Acyclovir Sodium; LiaroZole Fumarate; Lonapalene; and Tepoxalin. Adefovir. Alovudine; Alvircept Sudotox: Amantadine Antipsychotic: Acetophenazine Maleate; Alentemol Hyd Hydrochloride; Aranotin: Arildone: Atevirdine Mesylate: robromide: Alpertine; Azaperone; Batelapine Maleate; Ben 35 Avridine; Cidofovir, Cipamfylline; Cytarabine Hydrochlo peridol; BenZindopyrine Hydrochloride; Brofoxine; Bro ride; Delavirdine Mesylate: Desciclovir; Didanosine; Dis mperidol; Bromperidol Decanoate: Butaclamol oxaril: Edoxudine; Enviradene; Enviroxime; Famciclovir, Hydrochloride; Butaperazine; Butaperazine Maleate; Car Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari phenazine Maleate; Carvotroline Hydrochloride; Chlorpro late; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir, thixene; Cinperene; Cintriamide: Clomacran Phosphate: 40 Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Clopenthixol; Clopimozide; Clopipazan Mesylate; Clorop Lobucavir; Memotine Hydrochloride; Methisazone; Nevi erone Hydrochloride; Clothiapine; Clothixamide Maleate; rapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Clozapine; Cyclophenazine Hydrochloride; Droperidol; Hydrochloride; Saquinavir Mesylate: Somantadine Hydro Etazolate Hydrochloride: Fenimide: Flucindole: FlumeZap chloride; Sorivudine; Statolon; Stavudine; Tilorone Hydro ine: Fluphenazine Decanoate: Fluphenazine Enanthate: Flu 45 chloride; Trifluridine; Valacyclovir Hydrochloride: Vidara phenazine Hydrochloride: Fluspiperone: Fluspirilene: Flu bine; Vidarabine Phosphate: Vidarabine Sodium Phosphate: troline; Gevotroline Hydrochloride; Halopemide: Viroxime; Zalcitabine; Zidovudine; and Zinviroxime. Haloperidol; Haloperidol Decanoate: Iloperidone: Imidoline Appetite suppressant: Dexfenfluramine Hydrochloride; Hydrochloride; Lenperone; Mazapertine Succinate: Phendimetrazine Tartrate; and Phentermine Hydrochloride. Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper 50 Benign prostatic hyperplasia therapy agent: Tamsulosin one; Milipertine; Molindone Hydrochloride: Naranol Hydrochloride. Hydrochloride: Neflumozide Hydrochloride: Ocaperidone: Blood glucose regulators: Acetohexamide and Glipizide; Olanzapine; Oxiperomide: Penfluridol; Pentiapine Maleate; Chloropropamide; and Human insulin. Perphenazine: Pimozide; Pinoxepin Hydrochloride; Pipam Bone resorption inhibitor: Alendronate Sodium: Etidro 55 nate Disodium; and Pamidronate Disodium. perone; Piperacetazine; Pipotiazine Palmitate; Piquindone Bronchodilator: Albuterol; Albuterol Sulfate; AZanator Hydrochloride; Promazine Hydrochloride: Remoxipride: Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate: Remoxipride Hydrochloride; Rimcazole Hydrochloride: Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydro Seperidol Hydrochloride: Sertindole: Setoperone; Spiper chloride; Colterol Mesylate; Doxaprost; Doxofylline; Dyph one. Thioridazine: Thioridazine Hydrochloride; Thiothix 60 yline; Enprofylline: Ephedrine; Ephedrine Hydrochloride; ene: Thiothixene Hydrochloride; Tioperidone Hydrochlo Fenoterol: Fenprinast Hydrochloride; Guaithylline: Hexo ride; Tiospirone Hydrochloride: Trifluoperazine prenaline Sulfate; Hoquizil Hydrochloride; Ipratropium Hydrochloride; Trifluperidol; Triflupromazine; Triflupro Bromide: Isoetharine: Isoetharine Hydrochloride; Isoetha mazine Hydrochloride; and Ziprasidone Hydrochloride. rine Mesylate: Isoproterenol Hydrochloride: Isoproterenol Antirheumatic: Auranofin, Aurothioglucose: Bindarit; 65 Sulfate; Metaproterenol Polistirex: Metaproterenol Sulfate; Lobenzarit Sodium; Phenylbutazone; Pirazolac, Prinomide Nisbuterol Mesylate: Oxtriphylline; Picumeterol Fumarate; Tromethamine; and Seprilose. Piquizil Hydrochloride; Pirbuterol Acetate; Pirbuterol US 9,642,912 B2 35 36 Hydrochloride; Procaterol Hydrochloride; Pseudoephedrine Diagnostic aid: Aminohippurate Sodium; Anazolene Sulfate; QuaZodine; Quinterenol Sulfate; Racepinephrine; Sodium; Arclofenin; Bentiromide: Benzylpenicilloyl Racepinephrine Hydrochloride; Reproterol Hydrochloride: Polylysine; Butedronate Tetrasodium: Butilfenin; Coccidioi Rimiterol Hydrobromide: Salmeterol: Salmeterol Xinafoate: din; Corticorelin Ovine Triflutate; Corticotropin Zinc Soterenol Hydrochloride; Sulfonterol Hydrochloride: Hydroxide: Corticotropin, Repository; Diatrizoate Meglu Suloxifen Oxalate; Terbutaline Sulfate; Theophylline: Xan mine; Diatrizoic Acid; Diphtheria Toxin for Schick Test: oxate Sodium; Zindotrine; and Zinterol Hydrochloride. Disofenin; Ethiodized Oil: Etifenin; Exametazime; Ferris Carbonic anhydrase inhibitor: Acetazolamide: Acetazol tenc; Ferumoxides; Ferumoxsil; Fluorescein; Fluorescein amide Sodium; Dichlorophenamide: Dorzolamide Hydro Sodium; Gadobenate Dimeglumine; Gadodiamide; Gado chloride; Methazolamide; and Sezolamide Hydrochloride. 10 pentetate Dimegiumine; Gadoteridol; Gadoversetamide; Cardiac depressant: Acecainide Hydrochloride: Acetyl Histoplasmin: Impromidine Hydrochloride; Indigotindisul choline Chloride; Actisomide; Adenosine; Amiodarone; fonate Sodium; Indocyanine Green: Iobenguane Sulfate I Aprindine: Aprindine Hydrochloride; Artilide Fumarate; 123: Iobenzamic Acid, Iocarmate Meglumine; Iocarmic Azimilide Dihydrochloride; Bidisomide; Bucainide Acid, Iocetamic Acid, Iodamide; Iodamide Megilumine; Maleate; Bucromarone; Capobenate Sodium; Capobenic 15 Iodipamide Meglumine; Iodixanol; Iodoxamate Meglumine; Acid; Cifenline; Cifenline Succinate; Clofilium Phosphate: Iodoxamic Acid, Ioglicic Acid, Ioglucol, Ioglucomide; Disobutamide: Disopyramide: Disopyramide Phosphate: Ioglycamic Acid, Iogulamide: Iohexol; Iomeprol; Iopami Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosy dol; Iopentol; Iophendylate; Ioprocemic Acid, Iopronic late: Encainide Hydrochloride; Flecainide Acetate; Ibutilide Acid, Iopydol; Iopy done; Iosefamic Acid, Ioseric Acid; Fumarate; Indecainide Hydrochloride: Ipazilide Fumarate; IoSulamide Meglumine; IoSumetic Acid; Iotasul; Iotetric Lorajmine Hydrochloride; Lorcainide Hydrochloride: Acid; Iothalamate Meglumine; Iothalamate Sodium; Iotha Meobentine Sulfate; Mexiletine Hydrochloride: Modecain lamic Acid; Iotrolan; Iotroxic Acid, Ioversol, Ioxagiate ide: Moricizine; Oxiramide: Pirmenol Hydrochloride: Piro Sodium; Ioxaglate Meglumine; Ioxaglic Acid, Ioxilan, IoXo lazamide; Pranolium Chloride: Procainamide Hydrochlo trizoic Acid; Ipodate Sodium; Iprofenin; Isosulfan Blue; ride; Propafenone Hydrochloride; Pyrinoline; Quindonium 25 Leukocyte Typing Serum; Lidofenin; Mebrofenin; Meglu Bromide: Quinidine Gluconate; Quinidine Sulfate: mine; Metrizamide: Metrizoate Sodium; Metyrapone Tar Recainam Hydrochloride; Recainam Tosylate: Risotilide trate; Mumps Skin Test Antigen; Pentetic Acid; Propy Hydrochloride; Ropitoin Hydrochloride: Sematilide Hydro liodone; Quinaldine Blue: Schick Test Control; Sermorelin chloride; Suricainide Maleate: Tocainide; Tocainide Hydro Acetate; Sodium Iodide I 123: Sprodiamide: Stannous Pyro chloride; and Transcainide. 30 phosphate: Stannous Sulfur Colloid; Succimer: Teriparatide Cardioprotectant: Dexrazoxane; and Draflazine. Acetate; Tetrofosmin, Tolbutamide Sodium; Tuberculin; and Cardiotonic agent: Actodigin; Amrinone; Bemoradan; Xylose. Butopamine; CarbaZeran; Carsatirin Succinate; Deslanoside; Diuretic: Ambuphylline; Ambuside; Amiloride Hydro Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine chloride; Azolimine; AZosemide; Brocrinat: Bumetanide; Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar 35 Chlorothiazide; Chlorthalidone; Clazolimine; Clorexolone; trate; Enoximone: Imazodan Hydrochloride; Indolidan; Iso Ethacrynate Sodium: Ethacrynic Acid; Etozolin; Fengui mazole Hydrochloride; Levdobutamine Lactobionate; Lix Zone; Furosemide; Hydrochlorothiazide: Isosorbide; Man azinone Sulfate; Medorinone; Milrinone; Pelrinone nitol Mefruside; Ozolinone; Piretanide; Spiroxasone; Hydrochloride: Pimobendan; Piroximone; Prinoxodan; Torsemide; Triamterene; Triflocin, and Urea. Proscillaridin; Quazinone; Tazolol Hydrochloride; and 40 Dopaminergic agent: Ibopamine. Vesnarinone. Ectoparasiticide: Nifluridide; Permethrin. Cardiovascular agent: Dopexamine; and Dopexamine Emetic: Apomorphine Hydrochloride. Hydrochloride. Enzyme inhibitor: 30 Polignate Sodium: Acetohy Cerebral ischemia Dextrorphan Hydrochloride. droxamic Acid; Alrestatin Sodium; Aprotinin; Benazepril Choleretic: Dehydrocholic Acid: Fencibutirol; Hymec 45 Hydrochloride; Benazeprilat; Benurestat; Bromocriptine: romone; Piprozolin; Sincalide; Tocamphyl. Bromocriptine Mesylate: Cilastatin Sodium; Flurofamide: Cholinergic: Aceclidine: Bethanechol Chloride; Carba Lergotrile; Lergotrile Mesylate; Levcycloserine: Liben chol; Demecarium Bromide; Dexpanthenol; Echothiophate Zapril; Pentopril; Pepstatin: Perindopril; Sodium Amylosul Iodide: Isoflurophate; Methacholine Chloride; Neostiamine fate: Sorbinil; Spirapril Hydrochloride; Spiraprilat; Talera Methylsulfate; Neostigmine Bromide; Physostigmine; Phys 50 nol; Teprotide; Tolfamide; and Zofenopril Calcium. ostigmine Salicylate: Physostigmine Sulfate; Pilocarpine Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbe Nitrate; and Pyridostigmine Bromide. strol; Diethylstilbestrol Diphosphate: Equilin; Estradiol; Cholinergic agonist. Xanomeline; and Xanomeline Tar Estradiol Cypionate; Estradiol Enanthate; Estradiol Undecy trate. late; Estradiol Valerate; EstraZinol Hydrobromide: Estriol: Cholinesterase Deactivator: Obidoxime Chloride; Prali 55 Estrofurate; Estrogens, Conjugated; Estrogens, Esterified; doxime Chloride; Pralidoxime Iodide; and Pralidoxime Estrone; Estropipate; Ethinyl Estradiol: Fenestrel; Mestra Mesylate. nol; Nylestriol; and Quinestrol. Coccidiostat: Arprinocid; Narasin; Semduramicin; and Fibrinolytic: Anistreplase; Bisobrin Lactate; and Brino Semduramicin Sodium. lase. Cognition adjuvant: Ergoloid Mesylates; Piracetam; 60 Free oxygen radical scavenger: Pegorgotein. Pramiracetam Hydrochloride; Pramiracetam Sulfate; and Gastric Acid Suppressant: Lansoprazole, Pantoprazole Tacrine Hydrochloride. and Omeprazole. Cognition enhancer: Besipirdine Hydrochloride: Linopir Gastrointestinal Motility agents: Cisapride. dine; and Sibopirdine. Glucocorticoid: Amcinonide; Beclomethasone Dipropi Contrast Media: Barium Sulfate; Diatrizoate Sodium; 65 onate; Betamethasone; Betamethasone Acetate. Betametha Erythrosine Sodium; Iopanoic Acid; Ipodate Calcium; sone Benzoate: Betamethasone Dipropionate; Betametha Metyrapone; and Tyropanoate Sodium. sone Sodium Phosphate: Betamethasone Valerate; US 9,642,912 B2 37 38 Carbenoxolone Sodium; Clocortolone Acetate; Clocor Immunoregulator: Azarole; Fanetizole Mesylate; Frenti tolone Pivalate: Cloprednol; Corticotropin; Cortisone Zole: Oxamisole Hydrochloride: Ristianol Phosphate; Thy Acetate; Cortivazol: Descinolone Acetonide; Dexametha mopentin; and Tilomisole. sone; Dexamethasone Sodium Phosphate; Diflucortolone: Immunostimulant: Loxoribine; and Teceleukin. Diflucortolone Pivalate: Flucloronide; Flumethasone; Flu Immunosuppressant: Azathioprine; Azathioprine Sodium; methasone Pivalate: Flunisolide; Fluocinolone Acetonide; Cyclosporine; Daltroban: Gusperimus Trihydrochloride: Fluocinonide; Fluocortolone: Fluocortolone Caproate: Fluo Sirolimus; and Tacrolimus. rometholone: Fluperolone Acetate: Fluprednisolone: Flu Impotence therapy adjunct: Delequamine Hydrochloride. prednisolone Valerate: Flurandrenolide; Formocortal: Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Hydrocortisone; Hydrocortisone Acetate; Hydrocortisone 10 Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel; Buteprate; Hydrocortisone Butyrate; Hydrocortisone Docebenone: Epoprostenol; Epoprostenol Sodium; Epris Sodium Phosphate; Hydrocortisone Sodium Succinate; teride; Finasteride: Flurbiprofen Sodium; Furegrelate Hydrocortisone Valerate; Medrysone; Methylprednisolone Sodium; Lufironil; Miglitol; Orlistat; Pimagedine Hydro Acetate; Methylprednisolone Sodium Phosphate; Methyl 15 chloride; Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Ben prednisolone Sodium Succinate; Nivazol; Paramethasone Zathine; Sulbactam Pivoxil; Sulbactam Sodium; Suronacrine Acetate; Prednicarbate; Prednisolone; Prednisolone Acetate; Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine Prednisolone Hemisuccinate; Prednisolone Sodium Succi Hydrochloride; Tirilazad Mesylate: Tolrestat; Velnacrine nate; Prednisolone Tebutate; Prednisone; Prednival; Maleate; Zifrosilone; and Zileuton. Ticabesone Propionate; Tralonide; Triamcinolone; Triamci Keratolytic: Alcloxa; Aldioxa; Dibenzothiophene; Etaro nolone Acetonide; Triamcinolone Acetonide Sodium; Tri tene: Motretinide-I Picotrin Diolamine; Salicylic Acid; amcinolone Diacetate; and Triamcinolone Hexacetonide. Sumarotene; Tazarotene; Tetroquinone; and Tretinoin. Gonad-stimulating principle: Buserelin Acetate; Clomi LHRH agonist: Deslorelin; Goserelin; Histrelin; Lutrelin phene Citrate; Ganirelix Acetate; Gonadorelin Acetate; Acetate; and Nafarelin Acetate. Gonadorelin Hydrochloride; Gonadotropin, Chorionic; and 25 Liver disorder treatment: Malotilate. Menotropins. Luteolysin: Fenprostalene. Hormone: 17 Alpha Dihydroequilenin; 17 Alpha Dihy Memory adjuvant: Dimoxamine Hydrochloride; and Rib droequilin; 17 Alpha Estradiol; 17 Beta Estradiol; 17 aminol. Hydroxy Progesterone; Androstenedione; Clomiphene: Mental performance enhancer: Aniracetam. Cosyntropin: Dehydroepiandrosterone; Dihydroestosterone: 30 Mood regulator: Fengabine. Equilenin; Ethyndiol; Follicle Regulatory Protein; Follicle Mucolytic: Acetylcysteine; Carbocysteine; and Domi Stimulating Hormone: Folliculostatin: Gonadoctrinins: odol. Gonadorelin; Gonadotropins; Han Memopausal Gonadotro Mucosal Protective agents: Misoprostol (Cytotec). pins; Human Chorionic Gonadotropin; Insulin Growth Fac Mydriatic: Berefrine. tor; Leuprolide; Levonorgestrel; Luteinizing hormone; 35 Nasal decongestant: Nemazoline Hydrochloride; Pseu Luteinizing Hormone Releasing Hormone and Analogs; doephedrine Polistirex. Medroxyprogesterone: Megestrol; Metogest; Norethin Neuroleptic: Duoperone Fumarate; and Risperidone. drone; Norethynodrel; Norgestrel; Oocyte Maturation Neuromuscular blocking agent: Atracurium Besylate: Inhibitor; Oxytocin; Pituitary, Posterior; Progesterone: Cisatracurium Besylate; Doxacurium Chloride; Gallamine Relaxin; Seractide Acetate. Somalapor. Somatrem: Soma 40 Triethiodide; Metocurine Iodide; Mivacurium Chloride; tropin; Somenopor: Somidobove: Tamoxifen; Urofollitro Pancuronium Bromide; Pipecuronium Bromide: Rocuro pin; and Vasopressin. nium Bromide: Succinylcholine Chloride; Tubocurarine Hypocholesterolemic: Lifibrol. Chloride; and Vecuronium Bromide. Hypoglycemic: DarglitaZone Sodium; and Glimepiride. Neuroprotective: Dizocilpine Maleate. Hypolipidemic: AzalanstatDihydrochloride; Colestolone; 45 NMDA antagonist: Selfotel. Surfomer; and Xenalipin. Non-hormonal sterol derivative: Pregnenolone Succinate. Hypotensive: Viprostol. Oxytocic: Carboprost; Carboprost Methyl: Carboprost Immunizing agent: Antirabies Serum; Antivenin; Anti Tromethamine; Dinoprost: Dinoprost Tromethamine; Dino venin (Crotalidae) Polyvalent; BCG Vaccine; Botulism prostone; Ergonovine Maleate; Meteneprost; Methylergon Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphthe 50 ovine Maleate; and Sparteine Sulfate. ria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Paget’s disease agents: Tiluldronate Disodium. Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Progestin: Algestone Acetophenide; Amadinone Acetate; Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine Anagestone Acetate; Chlormadinone Acetate; Cingestol; Live: Meningococcal Polysaccharide Vaccine Group A: Clogestone Acetate; Clomegestone Acetate; Desogestrel; Meningococcal Polysaccharide Vaccine Group C; Mumps 55 Dimethisterone; Dydrogesterone; Ethynerone; Ethynodiol Virus Vaccine Live: Pertussis Immune Globulin; Pertussis Diacetate; Etonogestrel; Flurogestone Acetate; Gestaclone; Vaccine: Pertussis Vaccine Adsorbed; Plague Vaccine; Gestodene; Gestonorone Caproate; Gestrinone; Haloproges Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live terone; Hydroxyprogesterone Caproate; Lynestrenol; Oral; Rabies Immune Globulin; Rabies Vaccine; Rho(D) Medrogestone; Medroxyprogesterone Acetate; Methynodiol Immune Globulin; Rubella Virus Vaccine Live: Smallpox 60 Diacetate; Norethindrone Acetate; Norgestimate; Norges Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; tomet, Oxogestone Phenpropionate; Quingestanol Acetate; Tetanus Toxoid: Tetanus Toxoid Adsorbed; Typhoid Vac Quingestrone; and Tigestol. cine; Vaccinia Immune Globulin; VaricellaZoster Immune Prostaglandin: Cloprostenol Sodium; Fluprostenol Globulin; and Yellow Fever vaccine. Sodium; Gemeprost; Prostalene; and Sulprostone. Immunomodulator: Dimepranol Acedoben; Imiquimod: 65 Prostate growth inhibitor: Pentomone. Interferon Beta-1b: Lisofylline: Mycophenolate Mofetil: Prothyrotropin: Protirelin. and Prczatide Copper Acetate. Psychotropic: Minaprine. US 9,642,912 B2 39 40 Radioactive agent: Fibrinogen I 125: Fludeoxyglucose F Serotonin inhibitor: Cinanserin Hydrochloride: Fenclo 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; Ioben nine; Fonazine Mesylate; and Xylamidine Tosylate. guane I 123: Iodipamide Sodium I 131; Iodoantipyrine I Serotonin receptor antagonist: Tropanserin Hydrochlo 131; Iodocholesterol I 131; Iodohippurate Sodium I 123; ride. Iodohippurate Sodium I 125; Iodohippurate Sodium I 131; Steroid: Dexamethasone Acefurate; and Mometasone Iodopyriacet I 125; Iodopyracet I 131; Iofetamine Hydro Furoate. chloride I 123: Iomethin I 125; Iomethin I 131; Iothalamate Stimulant: Amfonelic Acid; Amphetamine Sulfate; Sodium I 125; Iothalamate Sodium I 131; Iotyrosine I 131; AmpyZine Sulfate; Arbutamine Hydrochloride; Azabon: Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Caffeine; Ceruletide; Ceruletide Diethylamine; Dazopride 10 Fumarate; Dextroamphetamine; Dextroamphetamine Sul Hg 197; Merisoprol Acetate Hg 203: Merisoprol Hg 197: fate; Difluanine Hydrochloride; Dimefline Hydrochloride: Selenomethionine Se 75; Technetium Tc 99m Antimony Doxapram Hydrochloride; Ethamivan; Etryptamine Acetate; Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Fenethylline Hydrochloride: Flubanilate Hydrochloride: Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne Flurothyl; Histamine Phosphate: Indriline Hydrochloride: tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, 15 Mefexamide; Methamphetamine Hydrochloride; Methyl Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid phenidate Hydrochloride; Pemoline: Pyrovalerone Hydro ofenin; Technetium Tc 99m Mebrofenin; Technetium Tc chloride; Xamoterol; and Xamoterol Fumarate. 99m Medronate; Technetium Tc 99m Medronate Disodium; Suppressant: Amflutizole; Colchicine; Tazofelone. Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidro Symptomatic multiple Sclerosis: Fampridine. nate; Technetium Tc 99m Pentetate; Technetium Tc 99m Synergist: Proadifen Hydrochloride. Pentetate Calcium Trisodium; Technetium Tc 99m Sesta Thyroid hormone: Levothyroxine Sodium; Liothyronine mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m Sodium; and Liotrix. Succimer; Technetium Tc 99m Sulfur Colloid; Technetium Thyroid inhibitor: Methimazole; and Propylthiouracil. Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin, Thyromimetic: Thyromedan Hydrochloride. Technetium Tc 99m Tiatide; Thyroxine I 125; Thyroxine 25 Tranquilizer: Bromazepam; Buspirone Hydrochloride: 1131; Tolpovidone 1131; Triolein 1125; and Triolein 1131. Chlordiazepoxide: Clazolam; Clobazam; Clorazepate Dipo Regulator: Calcifediol; Calcitonin; Calcitriol: Clodronic tassium; CloraZepate Monopotassium; Demoxepam, Dex Acid; Dihydrotachysterol: Etidronic Acid: Oxidronic Acid; medetomidine: Enciprazine Hydrochloride; Gepirone Piridironate Sodium; Risedronate Sodium; and Secalciferol. Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro Relaxant: Adiphenine Hydrochloride; Alcuronium Chlo 30 chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, ride; Aminophylline: Azumolene Sodium; Baclofen; Ben LorZafone; Loxapine; Loxapine Succinate; Medazepam Zoctamine Hydrochloride: Carisoprodol; Chlorphenesin Hydrochloride; Nabilone; Nisobamate: Oxazepam; Penta Carbamate; ChlorZoxazone; Cinflumide: Cinnamedrine; bamate; Pirenperone; Ripazepam, Rolipram; Sulazepam, Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene: Taciamine Hydrochloride; Temazepam; Triflubazam; Dantrolene Sodium; Fenalamide: Fenyripol Hydrochloride: 35 Tybamate; and Valnoctamide. Fetoxylate Hydrochloride: Flavoxate Hydrochloride; Fle Unstable angina agents: Tirofiban Hydrochloride. tazepam; Flumetramide: Hexafluorenium Bromide: Isom Uricosuric: BenZbromarone; Irtemazole; Probenecid; ylamine Hydrochloride; Lorbamate; Mebeverine Hydro Sulfinpyrazone. chloride; Mesuprine Hydrochloride; Metaxalone; Vasoconstrictor: Angiotensin Amide: Felypressin; Methy Methixene Hydrochloride; Methocarbamol; Nafomine 40 sergide; and Methysergide Maleate. Malate: NeleZaprine Maleate; Papaverine Hydrochloride: Vasodilator: Alprostadil; AZaclorzine Hydrochloride; Pipoxolan Hydrochloride: Quinctolate: Ritodrine: Ritodrine Bamethan Sulfate; Bepridil Hydrochloride; Buterizine: Hydrochloride; Rolodine: Theophylline Sodium Glycinate: Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Thiphenamil Hydrochloride; and Xilobam. Dipyridamole; Droprenilamine; Erythrity1 Tetranitrate; Repartitioning agent: Cimaterol. 45 Felodipine: Flunarizine Hydrochloride; Fostedil; Hexoben Scabicide: Amitraz: Crotamiton. dine; Inositol Niacinate; Iproxamine Hydrochloride; Isosor Sclerosing agent: Ethanolamine Oleate; Morrhuate bide Dinitrate; Isosorbide Mononitrate; Isoxsuprine Hydro Sodium; Tribenoside. chloride; Lidoflazine; Mefenidil; Mefenidil Fumarate; Sedative: Propiomazine. Mibefradil Dihydrochloride; Mioflazine Hydrochloride: Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam: 50 Mixidine; Nafronyl Oxalate; Nicardipine Hydrochloride: Amobarbital Sodium; Bentazepam; Brotizolam: Butabarbi Nicergoline; Nicorandil; Nicotinyl Alcohol; Nimodipine; tal; Butabarbital Sodium: Butalbital; Capuride; Carbocloral; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; Pen Chloral Betaine; Chloral Hydrate; Chlordiazepoxide Hydro taerythritol Tetranitrate; Pentoxifylline; Pentrinitrol; Per chloride; Cloperidone Hydrochloride; Clorethate: Cypraze hexiline Maleate; Pindolol; Pirsidomine; Prenylamine: Pro pam; Dexclamol Hydrochloride; Diazepam; Dichloral 55 patyl Nitrate; Suloctidil; Terodiline Hydrochloride; phenazone; Estazolam Ethchlorvynol; Etomidate: Fenobam; Tipropidil Hydrochloride; Tolazoline Hydrochloride; and Flunitrazepam, Fosazepam, Glutethimide; Halazepam, Lon Xanthinol Niacinate. netazepam, Mecloqualone; Meprobamate; Methaqualone; Wound healing agent: ErSofermin. Midaflur: Paraldehyde; Pentobarbital; Pentobarbital Xanthine oxidase inhibitor: Allopurinol; and Oxypurinol. Sodium; Perlapine; Prazepam, Quazepam, Reclazepam, 60 Other active agents include: 16-Alpha Fluoroestradiol; Roletamide: Secobarbital; Secobarbital Sodium; Supro 16Alpha-Gitoxin; 16-Eplestriol; 17 Alpha Estradiol; 17Beta clone; Tracazolate: Trepipam Maleate; Triazolam; Tricet Estradiol; 1 Alpha-Hydroxyvitamin D2: 1-Decpyrrolidi amide; Triclofos Sodium; Trimetozine: Uldazepam; Zale none: 1-Dodecpyrrolidinone; 22-Oxacalcitriol: 2CVV: plon; Zolazepam Hydrochloride; and Zolpidem Tartrate. 2'-Nor-cGMP; 3-Isobutyl GABA: 6-FUDCA: 7-Methoxyta Selective adenosine A1 antagonist: Apaxifylline. 65 crine; Abacavir Sulfate; Abanoquil; Abecarnil; Acadesine: Serotonin antagonist: Altanserin Tartrate; Amesergide; Acamprosate; Acebutolol Hydrochloride; Aceclofenac: Ketanserin; and Ritanserin. Acetomepregenol; Acetrizoate Sodium, Acetylcysteine, N-: US 9,642,912 B2 41 42 Acetyldigitoxin; Acetyl-L-carnitine, Acetylmethadol; Acipi Cevimeline Hydrochloride; Chlormerodrin, Hg-197; Chlo moX; Acitemate; Aclatonium; Aconiazide; Acrivastinet; rmezanone; Chloroorienticin A; Chloroorienticin B: Chole Adafenoxate; Adatanserin; Adefovir Dipivoxil; Adelmidrol; calciferol: Cholestyramine; Choriogonadotropin Alfa: Chro Ademetionine; Adiposin; Adrafinil; Alacepril; Aladapcin; mic Phosphate, P-32; Chymopapain; Chymotrypsin; Alaptide; Alatrofloxacin Mesylate; Albolabrin; Albumin 5 Cibenzoline: Ciclesonide: Cicloprolol; Cilansetron: Cilni Chromated Cr-51 Serum; Albumin Human; Albumin Iodi dipine: Cilobradine: Cilostazol; Cimetropiurn Bromide: nated I-125 Serum; Albumin Iodinated 1-131 Serum; Alde Cinitapride; Cinolazepam: Ciprostene: Cisapride Monohy calmycin; Alendronic Acid; Alentemol; Alfacalcidol; Alfu drate; Cisatracurium, Besilate: Cistinexine: Citalopram; Cit Zosin; Alglucerase; Alinastine; Alitretinoin, Alkavervir, allopram Hydrobromide: Citicoline; Citreamicin Alpha; Allopurinol Sodium; Almotriptan Malate; Alosetron: Alpha 10 Clausenamide; Clidinium Bromide; Clinafloxacin; Clom Idosone: Alpha-Tocopherol; Alpha-Tocopherol Acetate; ethiazole; Clopidogrel; Clopidogrel Bisulfate; Cobalt Chlo Alseroxylon; Altromycin B; Amantadine-HCl, ride, Co-57; Cobalt Chloride, Co-60; Colesevelam Hydro Ambenonium Chloride; Amelometasone; Amezinium Metil chloride; Colestimide: Colfosceril Palmitate; Complestatin: sulfate; Amfebutamone; Amifloxacin; Aminolevulinic Acid Contignasterol; Contortrostatin: Corticotropin Zinc Hydrox Hydrochloride; Aminosalicylic Acid Resin Complex: Amio 15 ide: Cosalane; Costatolide; Cotinine; Cournermycin AI; darone Hydrochloride; Amisulpride; Amlodipine: Ammo Cryptenamine Acetates; Cryptenamine Tannates: Cucumari nium Lactate; Amphetamine Adipate; Amphetamine Aspar osid; Curdlan Sulfate; Curiosin; Cyanocobalamin; Cyano tate; Amphetamine Resin Complex: Ampiroxicam, cobalamin, Co-57: Cyanocobalamin, Co-58: Cyanocobala Amprenavir, Amylin; Amythiamicin; Ananain; Anaritide; min, Co-60; Cyclazosin; Cyclic HPMPC: Cyclobenzaprine; Anileridine Phosphate: Anisindione; Anordrin; Apadoline; Cyclobut A: Cyclobut G: Cyclocapron; Cyclosin; Cycloth Apafant; Apraclonidine; Aprepitant; Aprosulate Sodium; ialidine: Cyclothiazomycin; Cycrimine Hydrochloride: Aprotinin Bovine; Aptiganel; Aranidipine; Arbekacin; Arbi Cyproterone: Cysteamine Bitartrate; Cytochalasin B; Dac dol; Arbutamine: Arecatannin B 1: Argatroban; Aripiprazol; timicin; Daidzein; Daidzin; Danaparoid; Daphnodorin A; Aripiprazole; Arotinolol; Articaine Hydrochloride: Ascorbic Dapiprazole; Dapitant: Darifenacin; Darlucin A; Darsidom Acid, Asimadoline; Aspalatone; Asperfuran; Aspoxicillin; 25 ine; Daunorubicin Citrate; DdUTP, Decamethonium Bro Atazanavir Sulfate; Atenolol, S-: Atevirdine: Atomoxetine mide; Deferiprone; Deferoxamine Mesylate: Dehy Hydrochloride; Atpenin B; Atrinositol; Aureobasidin A; drodidemnin B; Delapril: Delequarnine; Delfaprazine: AVobenzone; Azadirachtine, AZelaic Acid, AZelastine, AZel Delmopinol; Delphinidin; Deoxypyridinoline; Deprodone: nidipine; Azimilide; Azithromycin Dihydrate; Aztreonwn; Depsidomycinderamciclane; Dermatan Sulfate; Deserpi Baccatin III; Bacoside A: Bacoside B: Bactobolamine; 30 dine; Desirudin: Desloratadine; Desmopressin, DeSoxoami Balazipone; Balhimycin; Balofloxacin; Balsalazide; Bam odarone; Desoxyribonuclease; Detajrniurn Bitartrate; buterol; Baohuoside 1: Barnidipine: Batebulast; Beauveri Dexketoprofen; Dexloxiglumide: Dexmethylphenidate cin; Becaplermin; Becliconazole; Beclomethasone Dipropi Hydrochloride; Dexrazoxane Hydrochloride; Dexsotalol; Onate Monohydrate; Befloxatone; Bellenamine; Dextrin 2-Sulphate: Dextroamphetamine Adipate; Dextro Benflumetol; Benidipine; Bentoquatam; Benzisoxazole; 35 amphetamine Resin Complex; Dextroamphetamine Saccha Benzoidazoxan; Benzoyl Peroxide; Benzphetamine Hydro rate; Dextrose; Diclofenac Digolil; Dicranin; Dienogest: chloride; Benzquinamide Hydrochloride; Benztropine; Ben Diethylhomospennine; Diethylnorspermine; Difenoxin Zyl Benzoate; Benzyl Penicilloyl-Polylysine: Bepridil; Hydrochloride; Dihydrexidine; Diltiazeim; Dimethyl Pros Beractant; Beraprost; Berlafenone; Bertosamil: Besipirdine: taglandin A1; Dimethylhomospermine; Dimiracetarn; Beta-Carotene; Betaine, Anhydrous; Betamipron: Betaxolol; 40 Dimyristoyl Lecithin; Diphemanil Methylsulfate; Diphen Betazole Hydrochloride; Bevantolol; Bexarotene; Bife cyprone; Diphenylpyraline Hydrochloride; Diprafenone; melane; Bimakalim; Bimatoprost; Bimithil; Binospirone: Dipropylnorspermine; Discodermolide; Divalproex: Docar Biotin: Bioxalomycin Alpha2: Biriperone; Bisaramil: parnine; Docosanol, 1-; Dolasetron Mesylate Monohydrate; Bisaziridinylspermine; Bis-Benzimidazole A; Bis-Benzimi Domitroban; Donepezil Hydrochloride; Dorzolamide: Dos dazole B: Bismuth Subsalicylate; Bistramide D: Bistramide 45 malfate; Dotarizine; Doxazosin; Doxercalciferol: Draculin; K; Boldine; Bopindolol; Bortezomib: Brefeldin; Brimoni Drosperidone; Drospirenone; Drotaverine Acephyllinate: dine: Brinzolamide: Bromfenac; Bucindolol; Budipine; Droxicam; Dutasteride; Ebiratide: Ebrotidine; Ecabapide: Bunazosin; Butenafine; Butenafine Hydrochloride: Butixo Ecabet; Ecdisteron; Echicetin; Echistatin; Ecteinascidin cort Propionate; Cabergoline; Caffeine Citrate; Calanolide 722; Ecteinascidin 729; Ecteinascidin 743; Edaravone; Ede A; Calcitonin Human; Calcitonin, Salmon; Calcium; Cal 50 tate Calcium Disodium; Edetate Disodium; Edobacomab, cium Acetate; Calcium Gluceptate; Calcium Metrizoate: Edrecolornab: Efavirenz: Efegatran; Efonidipine; Egualen; Califactant; Camonagrel; Candesartan; Candesartan Cilex Elcatonin; Eletriptan; Eletriptan Hydrobromide: Elgodipine; etil: Candoxatrilat; Capromab; Capsaicin; Carbarnazepine; Eliprodil; Eltenac; Emakalim; Emedastine; Emedastine Carbazomycin C; Carbetocin; Carbidopa/Levodopa; Carbo Difumarate; Emiglitate; Emoctakin; Emtricitabine: Enal vir; Carboxymethylated Beta-1,3-Glucan: Carperitide; Car 55 april, EnaZadrem, Enfluvirtide; EnglitaZone; Entacapone; teolol, Carumonam, Carvotroline; Caspofungin Acetate; Entero statin: Eplerenone; Epoxymexrenone; Eptastigmine; Cebaracetam; Cefadroxil; Cefadroxil Hemihydrate; Cef Eptifibatide; Erdosteine; Ergocalciferol; Ersentilide; capene Pivoxil; Cefdaloxime Pentexil Tosilate: Cefditoren Ertapenem Sodium; Erythritol; Escitalopram Oxalate: Pivoxil; Cefepime Hydrochloride (Arginine Formulation); Esomeprazole Magnesium: Estazolam, Estradiol Acetate; Cefetamet; Cefetamet Pivoxil; Ceffietazole; Cefluprenam; 60 Esuprone; Etanterol: Ethacizin; Ethchlorvynol; Ethinamate: Cefninox; Cefodizime; Cefoselis; Cefotiam; Cefotiam Ethinylestradiol; EthoXZolamide: Etidocaine Hydrochloride: Hexetil: Cefozopran; Ce?pirome; Cefsulodin; Ceftazidime Etizolam; Etrabamine; Eveminomicin; Examorelin; (Arginine Formulation); Ceftazidime Sodium; Cefteram; EZetimibe; Faerieftmgin; Fantofarone; Farnciclovir, Faro Ceftibuten Dihydrate; Ceftriaxone; Celastrol: Celecoxib; penem; Fasidotril; Fasudil; Fedotozine; Felbarnate: Fenofi Celikalim; Celiprolol; Cellulose Sodium Phosphate; Cepaci 65 brate; Fenoldopam; Fenspiride; Fentanyl: Fenticonazole; dine A; Cericlamine; Cerivastatin: Cerivastatin Sodium; Fepradinol; Ferpifosate Sodium; Ferristene; Ferrixan: Fer Certoparin Sodium; Cetiedil; Cetirizine; Cetyl Alcohol: rous Citrate, Fe-59; Fexofenadine Hydrochloride; Fibrino US 9,642,912 B2 43 44 gen, 1-125; Fibrinolysin; Flecainide; Flerobuterol; Fle Lintitript; Lintopride; Lipase: Lirexapride; Lithium Carbon sinoxan; Flezelastine; Flobufen, Flomoxef Florfenicol; ate; Lithium Citrate; Lodoxamide; Lomerizine; Lonazolac, Florifenine: Flornastat; Flosatidil; Fludeoxyglucose, F-18: Lopinavir, Lorglumide; Losartan; Losigamone; Lotepred Flumecinol; Flunarizine; Fluocalcitriol; Fluoxetine, R-. Flu nol; Loviride; Loxapine Hydrochloride: LpdR; Lubeluzole; oxetine, S-; Fluparoxan; Flupirtine: Flurbiprofen Axetil: Lutetium: Luzindole; Lydicamycin; Lysostaphin, Magainin Flurithromycin; Flutamide: Flutrimazole: Fluvastatin: Flu 2 Arnide; Magnesium Acetate; Magnesium Acetate Tetra voxamine; Folic Acid; Follitropin Alfa: Follitropin Alfa/ hydrate; Magnolol; Malathion; Mallotochromene; Malloto Beta; Fomivirsen Sodium; Fondaparinux Sodium; Forasar japonin; Mangafodipir; Mangafodipir Trisodium; Mani tan; Formoterol; Formoterol Fumarate; Formoterol, R.R; dipine; Maniwamycin A; Mannitol; Manurnycin E: Fosinopril; Fosphenytoin: Frovatriptan Succinate; Fulves 10 Manurnycin F; Mapinastine; Martek 8708; Martek 92211; trant. Furosernide; Gadobenic Acid, Gadobutrol; Gadodi Massetolide; Meglumine Metrizoate; Meloxicam; Mel amide-EOB-DTPA; Gadopentetate Dimeglumine; Gadoteric phalan Hydrochloride; Menadiol Sodium Diphosphate: Acid; Galantamine; Galantamine Hydrobromide; Galdanse Menadione; Meprednisone; Mequinol; Mersalyl Sodium; tron; Gallopamil: Gamolenic Acid; Gatifloxacin; Gefitinib; Mesna; Metformin Hydrochloride; Methantheline Bromide: Gemifloxacin Mesylate: Gemtuzumab OZogamicin; 15 Metharbital; Methoxamine Hydrochloride; Methoxatone: Gepirone; Girisopam; Glaspimod: Glatiramer Acetate; Methoxsalen: Methscopolamine Bromide: Methyclothiaz Glaucocalyxin A; Glucagon Hydrochloride; Glucagon ide; Methyldopa; Methylhistamine, R-alpha; Methylinosine Hydrochloride Recombinant: Glucagon Recombinant: Glu Monophosphate; Methylprednisolone Aceponate; Methy conolactone; Glutapyrone: Glutathione Disulfide: Glyco prylon; Metiparinide; Metipranolol Hydrochloride; Metola pine; Glycopril; Goserelin Acetate; Grepafloxacin; Grepa Zone: Metoprolol Fumarate; Metoprolol, S-; Metoprotol floxacin Hydrochloride; Guaifenesin; Guanidine Tartrate; Metrifonate; Metrizoate Magnesium; Metrizoic Hydrochloride; Halichondrin B; Halofantrine: Halomon; Acid; Mezlocillin Sodium Monohydrate; Michellarnine B: Haloperidol Lactate; Halopredone; Hatomarubigin C: Microcolin A; Midodrine; Miglustat; Milacernide; Milarne Hatornambigin D; Hatornamicin; Hatornarubigin A: Hator line: Mildronate; Milnacipran; Milrinone Lactate; narubigin B; Heparin Calcium; Heparin Sodium; Hexocyc 25 Miokarnycin; Mipragoside; Mirfentanil; MivaZerol; Mixan lium Methylsulfate: Hexylcaine Hydrochloride: Histrelin pril; Mizolastine: Mizoribine: Moexipril: Moexipril Hydro Acetate; Hyaluronidase; Hydrocortamate Hydrochloride; chloride; Mofezolac, Mometasone; Mometasone Furoate Hydrocortisone Cypionate; Hydrocortisone Probutate; Hyd Monohydrate; Monobenzone: Montirelin; Moracizine: roquinone; Hydroxocobalamin; Hydroxypropyl Cellulose; Moricizine Hydrochloride: Mosapramine; Mosapride: Hydroxy stilbamidine Isethionate; Ibandronate Sodium; Ibo 30 Motilide; Moxifloxacin Hydrochloride; Moxiraprine; Mox gaine; Ibudilast, Ibuprofen Potassium, Icodextrin; Illimaqui onidine: Mupirocin; Mupirocin Calcium; Mycophenolate none; Iloprost: Imatinib Mesylate: Imidapril: Imidazenil; Mofetil Hydrochloride: Nadifloxacin: Nadroparin Calcium: Imiglucerase, Imipramine Pamoate; Inamrinone Lactate; Nafadotride; Nafamostat; Naftopidil; Naglivan; Nalmefene Indapamide: Indinavir, Indinavir Sulfate; Indium In-Ill Oxy Hydrochloride; Naltrexone Hydrochloride; Napadisilate: quinoline; Indium In-Ill Pentetate Disodium; Indium In-Ill 35 Napsagatran; Naratriptan; Nasaruplase; Nateglinide; Pentetreotide Kit; Indometacin; Indometacin Farnesil; Indo Nateplasel; Nelfinavir Mesylate; Nesiritide; Niacinamide: methacin Sodium; Inocoterone; Inogatran; Inolimomab; Nicotine; Nicotine Polacrilex; Niperotidine; Niravoline; Insulin Aspart; Insulin Aspart Protamine; Insulin Glargine; Nisin; Nitazoxanide; Nitecapone; Nitisinone; Nitrendipine, Insulin Lispro Protamine; Interferon Alfa: Interferon Alfa S-; Nitrofurantoin Monohydrate; Nitrofurantoin Sodium; NI; Interferon Beta; Interferon Beta-lal; Interferon Gamma-I 40 Nitrofurantoin, Macrocrystalline; Nitrofurazone; Nitroglyc A: Interferon Gamma-I B; Interferon Omega; Interferon, erin; Nonoxynol-9; Norelgestromin; Octyl Methoxycinna Consensus; interleukin-3; Interleukin-1, Interleukin-I Beta; mate; Olmesartan Medoxomil; Olopatadine; Olopatadine Interleukin-10; Interleukin-11; Interleukin-12; Interleukin Hydrochloride; Olprinone; Olsalazine: Omeprazole Magne 15: Interleukin-2: Interleukin-4; Interleukin-5; Interleukin sium, Ondansetron, R-; Oral Hypoglyceremics; 7: Interleukin-8: Interleukinl Alpha; Intrinsic Factor; Inulin; 45 Orphenadrine Hydrochloride; Oseltamivir Phosphate: Oten Invert Sugar, Iobenguane Sulfate I 131; Iobitridol; Iodamide Zepad: Oxamisole; Oxaprozin Potassium, Oxcarbazepine; Meglumine: Iodipamide Sodium; Iodoamiloride; Iodohip Oxiconazole; Oxiracetam; Oxodipine: Oxybenzone: Oxy purate Sodium, 1-123: Iodohippurate Sodium, 1-131; Iofe butynin. Oxyphencyclimine Hydrochloride: Oxyphenonium tamine Hydrochloride 1-123: Iofratol; Iopromide: Iopyrol: Bromide: OZagrel; Palauarnine: Palinavir, Palonosetron Iorneprol; Iothalamate Sodium, 1-125; Iotriside; Ioxaglate 50 Hydrochloride; Pamaparin Sodium; Panamesine; Pancreli Sodium; Ipazilide; Ipenoxazone; Ipidacrine; Ipomeanol. 4; pase; Panipenem; Panipenum; Pannorin; Panornifene; Pan Ipriflavone; Ipsapirone; Irbesartan; Irloxacin; Iron Dextran; tethine; Pantoprazole Sodium; Pantothenic Acid; Parameth Iron Sucrose; Irternazole; Isalsteine; Isbogrel, Iseparnicin; adione; Paricalcitol; Parnaqueside; Parnicogrel; Paroxetine Isofloxythepin; Isopropyl Unoprostone; Itameline; Itopride; Hydrochloride; Paroxetine Mesylate; Parthenolide; PaZu Ketoprofen, R-; Ketoprofen, S-; Ketorolac, Lactitol; Lac 55 floxacin; Pegademase Bovine; Pegvisomant; Pemirolast; tivicin; Lactulose; Laennec; Lafutidine; Lanoconazole; Lan Pemirolast Potassium; Penciclovir Sodium; Penicillamine; perisone; Larnifiban; Larnotrigine; Latanoprost; Lateritin; Pentafuside; Pentagastrin; Pentamidine; Pentamidine Ise Laurocaprarn, Leflunomide; Lemefloxacin, Leminoprazole; thionate; Pentetate Calcium Trisodium Yb-169; Pentigetide; Lenercept; Lepirudin; Leptin; Lercanidipine; Lerisetron; Pentolinium Tartrate; Pentosan; Perflexane: Perfluoropoly Lernildipine; Lesopitron: LetraZuril; Leucomyzin, Leval 60 methylisopropyl Ether; Perflutren: Pergolide; Pergolide buterol Hydrochloride; Levallorphan Tartrate; Levamisole Mesylate: Perindoprilat; Pernedolac: Perospirone; Phenari Hydrochloride; Levetiracetam; Levobetaxolol; dine; Phenindione; Pheniramine Maleate; Phenmetrazine Levobunolol; Levobupivacaine; Levobupivacaine Hydro Hydrochloride; Phenotoxifvline; Phenserine; Phensuccinal; chloride; Levocabastine; Levocarnitine; Levodropropizine; Phentermine Resin Complex; Phentolamine Mesilate; Phe Levofloxacin; Levopropoxyphene Napsylate, Anhydrous; 65 nylalanyl Ketoconazole; Phenylephrine Bitartrate; Pheny Levormeloxifene; Levornoprolol; Levosimendan; Levo toin Sodium, Extended; Phenytoin Sodium, Prompt; Phos Sulpiride; Lindane; Linezolid; Linotroban; Linsidormine; phoric Acid; Phytonadione: Picenadol; Picroliv; US 9,642,912 B2 45 46 Picumeterol; Pidotimod: Pilsicainide; Pimagedine: Pime HCl; Treprostinil Sodium; Tretinoin Tocoferil: Triarntevene: crolimus: Pimilprost; Pinocebrin; Pioglitazone: Piperonyl Tricaprilin; Trichohyalin; Trichosanthin, Alpha; Triclosan; Butoxide: Pirlindole; Pirmenol; Pirodornast; Polyestradiol Tridihexethyl Chloride; Trientine; Trientine Hydrochloride: Phosphate: Polyethylene Glycol 3350; Polytetrafluoroethyl Triflavin; Trimegestone; Trimethoprim Hydrochloride; Tri ene: Poractant Alfa: Potassium Chloride; Pramipexole Dihy oxsalen; Triptorelin Pamoate; Trolamine Polypeptide Oleate drochloride; Praziquantel; Prazosin; Prilocaine; Procaine Condensate; Trombodipine; Trometarnol; Tromethamine: Merethoxylline: Proguanil Hydrochloride: Propagerma Tropine Ester; Trospectomycin; Trovafloxacin; Trovafloxa nium; Propentofylline: Propiolactone; Propiomazine Hydro cin Mesylate; Trovirdine; Tucaresol; Tulobuterol; Tylo chloride; Propionylcamitine, L-; Propiram; Propiram--Par genin; Tyloxapol: Undecoylium Chloride; Undecoylium acetarnol; Propiverine; Prostratin: Protegrin: Protein 10 Chloride Iodine Complex: Unoprostone Isopropyl; Urapidil; Hydrolysate: Protokylol Hydrochloride; Protosufloxacin: Urea, C-13: Urea, C-14; Uridine Triphosphate; Valaciclovir; Prulifloxacin; Pyrethrins; Pyridoxine: Pyridoxine Hydro Valdecoxib; Valganciclovir Hydrochloride; Valproate Mag chloride: Quazeparn; Quetiapine; Quetiapine Fumarate; nesium; Valproate Semisodium; Valrubicin; Valsartan; Quiflapon; Quinagolide; Quinapril; QuinethaZone; Quini Vamicamide: Vanadeine; Vaninolol, Vasopressin Tannate; dine Polygalacturonate; Raloxifene: Ramatroban; Ranelic Venlafaxine: Verapamil, (S); Veratrum Viride: Veroxan; Acid; Ranolazine; Rapacuronium Bromide; Recainarn; 15 Vexibinol; Vinburnine Citrate; Vinburnine Resinate; Vin Regavirumab. Repaglinide; Rescinnamine; Resinferatoxin; conate; Vinpocetine; Vinpocetine Citrate; Vintoperol; Vio Reticulon; Reviparin Sodium; Revizinone: Riboflavin; mycin Sulfate; Vitamin A; Vitamin A Palmitate; Vitamin E: Riboflavin Phosphate Sodium; Ricasetron; Rilopirox, Rim Vitamin K. Voriconazole; Voxergolide; Warfarin Potassium; antadine; Rimexolone; Rimoprogin; Riodipine; Ripisartan; Xemilofiban; Ximoprofen; Yangarnbin: Zabicipril; Zaco Risedronic Acid; Rispenzepine; Ritipenem Acoxil; Ritipen pride; Zacopride, R-; Zafirlukast; Zalospirone; Zaltoprofen; ern; Ritonavir; Rivastigmine Tartrate; Rizatriptan Benzoate: Zanamivir; Zanarnivir, Zankiren, Zatebradine; Zatosetron; Rnibefradil; Rnivacurium Chloride; Rofecoxib; Rokitamy Zenarestat; Zinostatin Stimalarner, Ziprasidone; Ziprasi cin; Ropinirole; Ropivacaine; Ropivacaine Hydrochloride done Mesylate; Zoledronic Acid; Zolmitriptan; Zolpidem; Monohydrate; Roquinirnex: Rose Bengal Sodium, 1131; Zopiclone; Zopiclone, S-; Zopolrestat; and Zotepine. Still Rosiglitazone Maleate; Roxatidine; Roxindole; Rubidium 25 other examples of therapeutically active agents are listed in Chloride Rb-82; Rufloxacin; Rupatidine. Ruzadolane; Sac 2000 MedAd News 19:56-60 and The Physicians Desk rosidase; Safflower Oil: Safironil; Salbutarnol, R-; Salnace Reference, 53rd. Edition, pages 792-796, Medical Econom din, R-; Samarium Sm 153 Lexidronam Pentasodium; San ics Company (1999). fetrinem; Saprisartan; Sapropterin; Saquinavir, Sarcophytol Embodiments of the present disclosure will be described A SargramoStim; Sarneridine, Sarnpatrilat, Sarpogrelate; with reference to the following Examples which are pro Saruplase; Saterinone; Satigrel; Satumomab Pendetide; Sco 30 polamine; Secretin: Selenomethionine, Se-75; Sematilide; vided for illustrative purposes only and should not be used Sermorelin; Sernotiadil Sertaconazole; Sertraline: Sertra to limit the scope of or construe the invention. line-HCl; Setiptiline; Sevelamer Hydrochloride: Sevirurnab: Sezolamide: Sildenafil Citrate; Silipide: Silteplase; Silver EXAMPLES Sulfadiazine; Simendan; Simethicone; Simethicone-Cellu 35 lose: Sinitrodil; Sinnabidol; Sipatrigine; Sirnvastatin: Example 1 Somatomedin C; Somatropin Recombinant; Sorbitol; Sor natomedin B: Sornatrem: Somatropin; Sotalol; Stauro Transdermal/Topical Delivery Formulations sporine; Stepronin; Stobadine: Strontium Chloride, Sr-89: Succibun; Sulfanilamide: Sulfaphenazole; Sulfapyridine: Several formulations were prepared according to embodi Sulfoxamine; Sulfoxone Sodium; Sulfur, Sultamicillin; Sul 40 ments of the present disclosure utilizing the compositional topride: Sumatriptan; Sutilains: Symakalim; Talbutal; Tan components set forth in Tables 1A and 1B. Each of the dospirone; Tannic Acid; Tapgen; Taprostene; Tartaric Acid; formulations was prepared in a batch at a batch size of 2 kg. Tazanolast: Tegaserod Maleate; Telenzepine; Telmesteine: All raw materials were stored at ambient conditions prior to Telmisartan; Temocapril; Tenofovir Disoproxil Fumarate; manufacturing of the formulations. Generally, all formula Tenosal; Tepirindole; Terazosin; Terbinafine Hydrochloride: 45 tions were manufactured as described below. Terflavoxate; Terguride; Terlipressin; Terodiline; Tertatolol; The organic phase, containing isopropyl alcohol, di-iso Testosterone Buciclate: Thallous Chloride, T1-201; Thia propyl adipate, hexylene glycol, halobetasol propionate was mine; Thiamine Hydrochloride; Thiofedrine; Thiomarinol: added into an aqueous phase containing purified water, Thioperamide: Thiosemicarbazone; Thonzonium Bromide: anhydrous citric acid, di-hydrate Sodium citrate, and if Thyroglobulin; Thyrotropin; Thyrotropin Alfa; Tiagabine; 50 present in the formulation SLSA. This mixture was then Tiagabine Hydrochloride; Tianeptine; Tiapafant; Ticlopi combined with any other MMPETMs found in the formula dine: Tienoxolol; Tilisolol; Tilnoprofen Arbamel: Tiludronic tion and if present in the formulation polyoxyl 35 castor oil. Acid; Tiopronin; Tiotropium Bromide; Tirandalydigin; Tiri A bench top mixer was used to ensure complete dissolution lazad: Tirofiban; Tiropramide: Tocopherol Acetate; Tolt after each component addition. The order of ingredients erodine Tartrate; Torasemide: Trafennin; Trandolapril; Tra combined may vary depending on the preparation of labo nylcypromine Sulfate; Travoprost; Traxanox; Trazodone ratory vs. GMP batches. TABLE 1A Example Formulations Control and Fl-F6 (wt %

C1 Ingredient Control F1 F2 F3 F4 F5 F6

Halobetasol Propionate O.OS O.OS O.OS O.OS O.OS O.OS O.OS Isopropyl Alcohol (IPA) 3S.O 3S.O 3S.O 3SO 3S.O 3S.O 3S.O Di-Isopropyl Adipate (DIA) 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Hexylene Glycol 7.5 7.5 7.5 7.5 7.5 7.5 7.5 US 9,642,912 B2 47 48 TABLE 1 A-continued Example Formulations Control and F1-F6 (wt % C1 Ingredient Control F1 F2 F3 F4 F5 F6 Citric Acid, anhydrous O.09 O.O9 O.O9 O.O9 O.09 0.09 O.09 Sodium Citrate, dihydrate O.O7 O.O7 O.O7 O.O7 O.O7 O.O7 O.O7 Purified Water 54.29 47.79 47.79 47.79 S2.79 47.29 47.29 Polyoxyl 35 Castor Oil S.O S.O S.O O S.O S.O Methyl Laurate (ML) O.S O.S O.S O.S Isopropyl Myristate (IM) 1.O 1.O 1.O Oleic Acid (OA) — 1.0 — — 1.0 — Glyceryl Oleate (GO) 1.O 1.O Sodium Lauryl Sulfoacetate (SLSA) 1.O

15 TABLE 1B The phase separation for each of the formulations is provided in Table 2. None of the formulations experienced Example Formulations F7-F11 (wt % any visible phase separation during the testing period. Ingredient F7 F8 F9 F10 F11 2O TABLE 2 Halobetasol Propionate O.OS O.OS O.OS O.OS O.OS Isopropyl Alcohol (IPA) 3SO 3S.O 3S.O 3SO 3S.O Phase Separation (ml Di-Isopropyl Adipate (DIA) 3.0 3.0 3.0 3.0 3.0 Hexylene Glycol 7.5 7.5 7.5 7.5 7.5 Citric Acid, anhydrous O.09 0.09 O.O9 O.O9 O.O9 Week Control F1 F2 F3 F4 FS F6 F7 F8 F9 F10 F11 Sodium Citrate, dihydrate O.O7 O.O7 O.O7 O.O7 O.O7 25 Purified Water 47.29 47.29 47.29 47.29 47.79 Polyoxyl 35 Castor Oil S.O S.O S.O S.O S.O Methyl Laurate (ML) O.S Isopropyl Myristate (IM) 1.O Oleic Acid (OA) 1.O 1.O Glyceryl Oleate (GO) 1.O 1.O 30 Sodium Lauryl Sulfoacetate (SLSA) 1.O 1.O 1.O 1.O Example 3 Example 2 35 pH of the Formulations of Example 1 Physical Stability of the Formulations of Example Each of the formulations and the control described in 1 Example 1 were stored at ambient conditions (25°C.). The Each of the formulations and the control described in pH of each of the formulations was tested following U.S. 40 Pharmacopeial Convention (USP) procedure 791 as of the Example 1 were stored at ambient conditions (25°C.). The date of the present patent application filing. The pH of each physical stability (i.e. the phase separation of the formula of the formulations was tested at Zero, four, eight, and twelve tions) of each of the formulations was tested at weeks one, weeks. The pH for each of the formulations are provided in two, three, four, eight, and twelve. The phase separation was Table 3 and graphed in FIG. 1. All test formulations (F1 to measured by placing each of the formulations in a 10 ml F11) showed improved pH stability over the control formu graduated glass container. The cylinders were stopped and 45 lation following 12 weeks of storage. The improvement in the phase separation was measured in terms of millimeters pH stability over the control formulation may become more at the indicated time intervals. The containers were not pronounced for the test formulations at extended time inter moved during the course of this study. vals e.g. 6 months, 12 months, 24 months. TABLE 3

pH

Week Control

4.74 4.98 4.86 5.07 4.78 4.91 5.07 4.90 4.92 4.84 4.93 4.92 4 4.75 4.95 4.91 S.09 4.79 4.91 S.O6 4.91 4.95 4.83 4.92 4.90 4.73 S.O2 4.90 5.07 4.79 4.93 S.O7 4.89 4.95 4.84 4.93 4.90 12 4.8O S.O2 4.91 S.O6 4.79 4.90 S.O7 4.88 4.95 4.83 4.94 4.90 Total O.O6 O.04 O.OS O.O1 O.O1 O.O1 O O.O2 O.O3 O.O1 O.O1 O.O2 Change

*Calculated as change in pH between 0-week timepoint and 12-week timepoint, US 9,642,912 B2 49 50 Example 4 Viscosity of the Formulations of Example 1 Each of the formulations and the control described in 5 Example 1 were stored at ambient conditions (25°C.). The viscosity of each of the formulations was tested following U.S. Pharmacopeial Convention (USP) procedure 911 as of the date of the present patent application filing. The Viscosity of each of the formulations was tested at Zero, four, eight, 10 and twelve weeks. The viscosity for each of the formulations is provided in Table 4. TABLE 4

viscosity (cps)

Week Control F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11

O 4.11 5.61 5.49 5.94 4.26 6.51 6.21 5.94 5.94 5.76 S.76 S.46 3.96 S.64 S.76 S.82 3.99 S.61 S.S8 S.28 S.85 5.61 5.70 5.55 8 3.90 S.64 6.39 S-67 3.69 6.39 S.70 S.64 S.94 S.28 S.73 S.34 12 3.72 5.13 5.04 5.19 3.57 5.91 5.79 5.55 5.64 5.34 S.64 S.31 Total O.39 O48 0.45 0.75 O.69 O.60 0.42 0.39 O.30 O42 (0.12 O.15 Change

*Calculated as change in cps between 0-week timepoint and 12-week timepoint,

30 The viscosity at 25°C. for each of the formulations is plotted The API assay results for each of the formulations is plotted and shown in FIG. 2. Formulations F8, F10 and F11 showed and shown in FIG. 3. Formulations F1, F2, F3, F4, F5, F8, improved consistency of Viscosity over the control formu F10 and F11 showed reduced active degradation over the lation following 12 weeks of storage. The consistency of control formulation following 12 weeks of storage. The Viscosity over the control formulation may become more 35 reduction in degradation of API over the control formulation pronounced for certain test formulations at extended periods may become more pronounced in certain test formulations at of time, e.g. 6 months, 12 months, 24 months. extended periods of time, e.g. 6 months, 12 months, 24 months. Example 5 40 Example 6 Active Pharmaceutical Ingredient Assay of the Formulations of Example 1 Delivery through Durapore(R) Membrane of the Formulations of Example 1 Each of the formulations and the control described in Example 1 were stored at ambient conditions (25° C.). An 4s Select formulations and the control described in Example active pharmaceutical ingredient (API) assay for each of the 1 were tested for penetration through the Durapore(R) mem formulations was tested using High Performance Liquid brane. A total of 10 formulations were tested. The Chromatography (HPLC) equipped with a SynergiTM Durapore(R) membrane is a hydrophilic polyvinylidene fluo Hydro-RP (4 um, 100x3.0 mm) column. The API of each of ride membrane with a 0.45 um pore size. The amount of the formulations was tested at Zero, four, eight, and twelve so halobetasol propionate that diffused through the Durapore weeks. The API assay results for each of the formulations are membrane into the receptor fluid was quantified at hours 2, provided in Table 5. 4, 6, 8, 10, 24, and 30. The results are included in Table 6A. TABLE 5 Active Pharmaceutical Ingredient (API) (%)

Week Control F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11

O 102.5 102.3 102.2 102.4 102.4 101.5 101.6 101.1 102.2 101.9 101.3 101.3 4 99.8 100.3 10OS 10O.S 1 OOO 100.4 100 99.1 100.1 100.3 100.1 98.9 8 102.6 102.2 101.4 102.1 102.O. 101.8 101.9 100.5 102.3 102.2 101.9 101.7 12 101.0 101.5 101.1 101.3 101.1 101.2 98.8 98.0 101.0 99.3 1OO.S 100.3 Total 1.5 O.8 11 1.1 13 O.3 2.8 3.1 1.2 2.6 O.8 1 Change

*Calculated as change in API between 0-week timepoint and 12-week timepoint, US 9,642,912 B2 51 52 TABLE 6A Diffusion of Halobetasol Propionate through Durapore B Membrane Time (hours) Control F1 F2 F3 F4 F5 F7 F9 F10 F11 2 16.65 228.81 128.1 1O.S6 57.22 15.26 46.74 58.38 218.01 786.64 4 15.39 S4473 261.09 135.37 131.91 72.88 735.87 183.14 655.06 1392.31 6 SO.64 1048.57 774.24 404.35 229.19 343.75 1923.86 1414.31 1813.25 2009.S 8 156.67 1654.93 1475.49 1OO1.02 336.98 1034.7 3.325.24 3219.19 326S.42 2917.09 10 231.19 2296.47 2116.4 3664.81. 415.6 3668.02 4528.02 4941.46 S142.33 3797.72 24 348.98 3828.18 3757.6 4295.24 S26.23 45O1.34 SO28.3 S853.46 S648.37 4216.92 30 S1922 3916.49 3823.7S 4395.79 S11.34 4536.92 SO85.83 S874.12 5509.76 4211.38

Total 1338.73 13518.18 12336.67 13907.13 220846 14172.86 2O673.8S 21S44.07 22252.19 19331.57

15 The total amount of halobetosal propionate delievered The concentration of diclofenac in the samples was mea during the treatment period and percent increase compared sured using HPLC analysis. Specifically, HPLC was carried to the control is included in Table 6B. The presence of the MMPETMs in the test formulations improved penetration of out with C18 column and using acetonitrile and water as the the halobetasol propionate by as much as 1,600%. mobile phase. Flux rates were calculated using standard TABLE 6B Percent Increase of Total Diffusion During the Testing Period Control F1 F2 F3 F4 F5 F7 F9 F10 F11

Amount 1338.73 13518.18 12336.67 13907.13 2208.46 14172.86 20673.8S 21S44.07 222S2.19 19331.57 %. Increase 1009.78 921.52 1038.83 164.97 1058.68 1544.29 1609.29 1662.19 1444.02

30 Examples 7-14 equations based on the total transference of diclofenac across the skin after 46 hours. Thus, flux rates, F, were Materials and Methods for Examples 7-14 computed according to

A number of formulations (described in Examples 7-14 35 below) containing diclofenac sodium (a non-steroidal anti inflammatory drug or NSAID) were tested for permeation D: W through porcine skin using the Franz diffusion cells as t: A generally described in Franz T J. Percutaneous absorption. On the relevance of in vitro data. J. Invest Dermatol 1975; 40 wherein: D is the concentration of the drug in the receptor 64:190-195. well after incubation time t, Vis the volume of the receptor More specifically, Franz cells with a 5 ml receptor well well and A is the surface area of skin. Volume were used in conjunction with full-thickness porcine skin harvested at Perry Scientific (San Diego, Calif.). The Individual penetration enhancers in the Examples discussed porcine skin was shaved free of hair, washed with water and 45 below were obtained from the following sources: subcutaneous fat was removed. The donor well had an area glyceryl oleate (glycerol monooleate) from TCI (VWR), of ~0.5 cm. Receptor wells were filled with isotonic phos product code TCG0082 phate buffered saline (PBS) doped with 0.01% sodium azide. isopropyl myristate from Sigma product code M0757 The flanges of the Franz cell were coated with vacuum grease to ensure a complete seal and were clamped together 50 methyl laurate from Chem Service product code CSO426 with uniform pressure using a pinch clamp (SS #18 VWR N-lauroyl sarcosine from Sigma product code L5000 80073-350). After the Franz cells were assembled, the porcine skin oleic acid (octadecenoic acid) from Mallinckroft (VWR) was allowed to pre-hydrate for 45 minutes with isotonic product code MK274.404 PBS. Isotonic PBS was then removed and 200 ml of the 55 sodium lauryl sulfoacetate from Stepan (65-72%) product formulation was applied to the donor well. Receptor wells of code Lathanol LAL the Franz cells were maintained at 37° C. (temperature on sodium octyl sulfate from Alfa Aesar (VWR) product the surface of the skin is -30°C.) in a stirring block with code AA43750-06 continual agitation via a stir bar. The flux rates were calculated by assuming a radius of 0.4 60 The base composition used for each formulation of a cm in the donor well (i.e., an area of 0.503 cm). The HPLC carrier composition comprised isotonic PBS, ethanol, pro calibration curve for diclofenac was determined to have a pylene glycol and propylene glycol 300 in a Volume ratio of slope of 115.6 AUC/(ug diclofenac/ml). 2:2:1:1. The base formulation further comprised diclofenac Samples were drawn from the receptor wells at t=24 hours sodium in a concentration of 1.5 wt % per unit volume of the and t=46 hours for all formulations. Franz diffusion cell 65 base composition. In the Examples below, various combi measurements were made in five-fold replicates for each nations of the MMPETMs detailed below were added to the formulation. base composition. US 9,642,912 B2 53 Example 7 TABLE 9 Formu- SOS + OA Weight Flux NLS and IM lation (wt %ivol) Ratio of (ughr/cm) 5 H S.O 3:7 4.73 In this Example, N-lauroyl sarcosine (NLS) and isopropyl I S.O 1:O 2.70 myristate (IM) were added to the base formulation. The J S.O O:1 O.O2 details of each formulation and the results of the Franz diffusion cell experiments are set out in Table 7 below. With reference to Table 9, it can be seen that Formulation 10 H (containing a mixture of SOS and OA each at a concen TABLE 7 tration 1.5% wt/vol and 3.5% wt/vol, respectively) was more Formu- NLS + IM Weight Ratio Flux effective at enhancing diclofenac sodium flux rate through lation (wt %/vol) of NLSIM (ughr/cm) the skin when compared to either of Formulation I (con A. 3.0 1:1 3.80 taining 5% wt/vol OA and no SOS) or Formulation J B S.O 1:1 O.S3 15 (containing 5% wt/vol SOS and no OA). C S.O 1:O O.26 D S.O O:1 O.O2 Example 10 With reference to Table 7, it can be seen that Formulation In this Example, glyceryl oleate (GO) and sodium octyl B (containing a mixture of NLS and IM each at a concen sulfate (SOS) were added to the base formulation. The tration 2.5% wt/vol) was more effective at enhancing details of each formulation and the results of the Franz diclofenac sodium flux rates through the skin when com diffusion cell experiments are set out in Table 10. pared to either of Formulation C (containing 5% wt/vol NLS and no IM) or Formulation D (containing 5% wt/vol IM and TABLE 10 no NLS). Further and surprisingly, Formulation A (contain 25 ing a mixture of NLS and IM each at a concentration of 1.5% Formu- GO + SOS) Weight Flux wit/vol) was approximately seven times more effective at lation (wt %ivol) Ratio of (Igl/hr/cm) enhancing the flux rate of the diclofenac sodium when K 3.0 1:1 O.30 compared to Formulation B. L S.O 1:O O.34 30 M S.O O:1 O.O2 Example 8 With reference to Table 10, it can be seen that Formulation In this Example, N-lauroyl sarcosine (NLS) and oleic acid K (containing a mixture of GO and SOS each at a concen (OA) were added to the base formulation. The details of each 35 tration 1.5% wt/vol) was approximately as effective at formulation and the results of the Franz diffusion cell enhancing diclofenac sodium flux rate through the skin as experiments are set out in Table 8. Formulation L (containing 5% wt/vol GO and no SOS) and was substantially improved over that of Formulation M TABLE 8 (containing 5% wt/vol SOS and no GO). 40 Formu- NLS + OA Weight Ratio Flux Example 11 lation (wt %/vol) of NLS:OA (ughr/cm) E 3.0 1:1 3.29 In this Example, glyceryl oleate (GO) and methyl laurate F S.O 1:O O.26 (ML) were added to the base formulation. The details of G S.O O:1 2.70 45 each formulation and the results of the Franz diffusion cell experiments are set out in Table 11. With reference to Table 8, it can be seen that Formulation E (containing a mixture of NLS and OA each at a concen TABLE 11 tration 1.5% wt/vol) was more effective at enhancing 50 Formu- GO + ML Weight Flux diclofenac sodium flux rate through the skin when compared lation (wt %ivol) Ratio of (ughr/cm) to either of Formulation F (containing 5% wt/vol NLS and N S.O 1:1 O.S4 no OA) or Formulation G (containing 5% wt/vol OA and no O S.O 1:O O.34 NLS). P S.O O:1 O.32 It is notable that the flux rate of the NSAID in Formula tion E was higher than that achieved by either of Formula 55 tion F or Formulation G in spite of the fact that the total With reference to Table 11, it can be seen that Formulation concentration of the molecular penetration enhancers in N (containing a mixture of GO and ML each at a concen Formulation E was lower than that in Formulation F and tration 2.5% wt/vol) was more effective at enhancing Formulation G. diclofenac sodium flux rate through the skin when compared 60 to either of Formulation O (containing 5% wt/volGO and no ML) or Formulation P (containing 5% wt/vol ML and no Example 9 GO). In this Example, sodium octyl sulfate (SOS) and oleic Example 12 acid (OA) were added to the base formulation. The details of 65 each formulation and the results of the Franz diffusion cell In this Example, sodium lauryl sulfoacetate (SLSA) and experiments are set out in Table 9. methyl laurate (ML) were added to the base formulation. US 9,642,912 B2 55 56 The details of each formulation and the results of the Franz rubbed gently across the skin with a glass stir rod. Once the diffusion cell experiments are set out in Table 12. formulation was applied, a stir bar was added to the receptor well. The receptor well was maintained at 32° C. and TABLE 12 continuously agitated throughout the experiment. Sample aliquots were drawn from the receptor well at varying time Formu- SLSA + ML Weight Ratio Flux points and replaced with fresh PBS buffer. Sample aliquots lation (wt %ivol) of SLSA:ML (g/hr/cm) were filtered and analyzed for concentration of the active Q S.O 3:7 O.S2 using HPLC analysis. Measurements for each formulation R S.O 1:O O.22 were carried out in six-fold replicates. S S.O O:1 O.32 The individual penetration enhancers used in Example 7 10 are provided in the following table along with their abbre viation (Abbr) and Chemical Abstract Service (CAS) regis With reference to Table 12, it can be seen that Formulation try number: Q (containing a mixture of SLSA and ML each at a con centration 2.5% wt/vol) was more effective at enhancing diclofenac sodium flux rate through the skin when compared 15 Abbr. Chemical CAS No. to either of Formulation R (containing 5% wt/vol SLSA and IM Isopropyl Myristate 110-27-0 no ML) or Formulation S (containing 5% wt/vol ML and no SLSA Sodium Lauryl Sulfoacetate 1847-58-1 SLSA). OA Oleic Acid 112-801-1 ML Methyl Laurate 111-82-0 GO Glyceryl Monooleate 31566-31-1 Example 13 NLS N-lauroyl Sarcosine 97-78-9 In this Example, sodium lauryl sulfoacetate (SLSA) and isopropyl myristate (IM) were added to the base formula Numerous formulations were prepared with the tion. The details of each formulation and the results of the MMPETMs used in conjunction with varying active agents. Franz diffusion cell experiments are set out in Table 13. 25 MMPETMs tested were SLSA/IM, SLSA/ML, IM/NLS, GO/ML, and NLS/OA in a hydroalcoholic solution. These MMPETMs were tested with the active agents ibuprofen, TABLE 13 buproprion HCl, ketoprofen, and testosterone. Tables 14A Formu- SLSA + IM] Weight Ratio Flux 14J list the MMPETMs that showed a significant increase in lation (wt %ivol) of SLSA:IM (Lig/hr/cm) flux when compared to flux from the analogous formulations 30 containing only one of the MMPETMs. T S.O 1:1 O.S2 U S.O 1:O O.22 V S.O O:1 O.O2 TABLE 14A Formu- Ibuprofen SLSA IM Flux With reference to Table 13, it can be seen that Formulation 35 lation (wt wt %) (wt wt %) (wt %?wt %). (ughr/cm) T (containing a mixture of SLSA and IM each at a concen W 5 3 42.1 tration 2.5% wt/vol) was more effective at enhancing X 5 3 28.5 diclofenac sodium flux rate through the skin when compared Y 5 1.5 1.5 66.5 to either of Formulation U (containing 5% wt/vol SLSA and no IM) or Formulation V (containing 5% wt/vol IM and no 40 SLSA). TABLE 1.4B Materials and Methods for Example 14 Using methodology similar to that described in Examples Formu- Ibuprofen SLSA ML Flux 8-13, a number of formulations containing other active lation (wt %?wt %). (wt %wt %). (wt %wt %). (g/hr/cm) 45 agents (as described in greater detail below) were tested for Z. 5 3 42.1 permeation through porcine skin using Franz diffusion cells. AA 5 3 25.2 Franz Cell Guidelines: BB 5 1.5 1.5 53.9 Skin Preparation: Porcine skin was sourced from Lampire Biological Laboratories (Pipersville, Pa.). The skin was then dermatomed in house to a set thickness. 50 Diffusion Cell Assembly: Diffusion cells were assembled TABLE 14C using dermatomed porcine skin as the Substrate. Cell assem Formu- Ibuprofen IM NLS Flux bly was carried out by clamping the skin between a donor lation (wt %?wt %). (wt %wt %). (wt %wt %). (g/hr/cm) well (the flange was coated with a thin coating of vacuum CC 5 3 28.5 grease to ensure a proper seal) and a receptor well. The wells 55 DD 5 3 1O.O were clamped together and held in place using a spring EE 5 1.5 1.5 31.0 clamp. The receptor wells had a volume of 3.3 ml and the clamped skin had an available surface area of -0.55 cm for the diffusion study. Once the cell was assembled, the recep TABLE 1.4D tor well was filled with PBS containing 0.01 wt % NaNs (to 60 help prevent skin degradation). Care was taken to ensure all Formu- Ibuprofen GO ML Flux bubbles are removed from the receptor solution. The skin lation (wt %?wt %). (wt %wt %). (wt %wt %). (g/hr/cm) was allowed to pre-hydrate for 20 minutes before the FF 5 3 14.4 formulations were applied to the skin. GG 5 3 25.2 Diffusion Cell Testing: After the skin was prehydrated, 40 65 HH 5 1.5 1.5 S3.6 ul of the test formulation was applied to the skin with a positive displacement pipettor and the applied dose then US 9,642,912 B2 58 TABLE 14E 2. The topical formulation of claim 1, wherein the first compound and the second compound are each selected from Bupropion the group consisting of methyl laurate, isopropyl myristate, Formu- HCI NLS OA Flux lation (wt %?wt %). (wt %/wt %). (wt %wt %). (g/hr/cm) oleic acid, glyceryl oleate, and sodium lauryl Sulfoacetate. 3. The topical formulation of claim 1, wherein the at least II 5 3 14.3 JJ 5 3 9.1 one corticosteroid is a pharmaceutically acceptable salt of a KK 5 1.5 1.5 18.8 corticosteroid. 4. The topical formulation of claim 1, wherein the at least one corticosteroid is a pharmaceutically acceptable base of 10 a corticosteroid. TABLE 14F 5. The topical formulation of claim 1, wherein the at least Bupropion one corticosteroid is selected from the group consisting of Formu- HCI SLSA IM Flux lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (Lig/hr/cm) clobetasol, halobetasol, betamethasone, triamcinolone 15 acetonide, and combinations thereof. LL 5 3 34.3 6. The topical formulation of claim 1, wherein the at least MM 5 3 14.5 one corticosteroid is halobetasol propionate. NN 5 1.5 1.5 45.6 7. The topical formulation of claim 6, wherein the halo betasol propionate is present at about 0.01 wt % to about 20 wt % of the formulation. TABLE 1.4G 8. The topical formulation of claim 7, wherein the halo Bupropion betasol propionate is present at about 0.05 wt % of the Formu- HCI SLSA ML Flux formulation. lation (wt %?wt %). (wt %/wt %). (wt %wt %). (g/hr/cm) 9. The topical formulation of claim 1, wherein the first 25 OO 5 3 34.3 compound comprises methyl laurate and the second com PP 5 3 14.8 pound comprises isopropyl myristate. QQ 5 1.5 1.5 51.3 10. The topical formulation of claim 1, wherein the first compound comprises methyl laurate and the second com pound comprises oleic acid. 30 11. The topical formulation of claim 1, wherein the first TABLE 14H compound comprises methyl laurate and the second com Bupropion pound comprises glyceryl oleate. Formu- HCI IM NLS Flux 12. The topical formulation of claim 1, wherein the first lation (wt %?wt %). (wt %/wt %). (wt %wt %). (g/hr/cm) compound comprises methyl laurate and the second com RR 5 3 14.5 35 pound comprises sodium lauryl Sulfoacetate. SS 5 3 14.3 13. The topical formulation of claim 1, wherein the first TT 5 1.5 1.5 55.9 compound comprises isopropyl myristate and the second compound comprises oleic acid. 14. The topical formulation of claim 1, wherein the first 40 compound comprises isopropyl myristate and the second TABLE 1.4 compound comprises glyceryl oleate. Formu- Ketoprofen NLS OA Flux 15. The topical formulation of claim 1, wherein the first lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (Lig/hr/cm) compound comprises isopropyl myristate and the second UU 5 3 14.3 compound comprises Sodium lauryl Sulfoacetate. VV 5 3 9.1 45 16. The topical formulation of claim 1, wherein the first WW 5 1.5 1.5 18.8 compound comprises oleic acid and the second compound comprises glyceryl oleate. 17. The topical formulation of claim 1, wherein the first TABLE 1.4 compound comprises oleic acid and the second compound 50 comprises sodium lauryl Sulfoacetate. Formu- Testosterone SLSA IM Flux 18. The topical formulation of claim 1, wherein the first lation (wt %/wt %). (wt %/wt %). (wt %/wt %). (Lig/hr/cm) compound comprises glyceryl oleate and the second com XX 5 3 14.3 pound comprises sodium lauryl Sulfoacetate. YY 5 3 9.1 19. The topical formulation of claim 1, further comprising ZZ 5 1.5 1.5 18.8 55 one or more biologically acceptable excipients. 20. The topical formulation of claim 19, further compris ing polyoxyl 35 castor oil. What is claimed is: 21. The topical formulation of claim 1, wherein the 1. A topical formulation, comprising: formulation further comprises water. at least one corticosteroid, 60 22. The topical formulation of claim 1, wherein the total a first compound, and concentration of the first compound and the second com a second compound, pound is in the range from about 1 wt % to about 5 wt %, wherein the first compound and the second compound are per unit volume of the formulation. different, and each is selected from the group consisting of 23. The topical formulation of claim 1, wherein the total N-lauroyl sarcosine, Sodium octyl sulfate, methyl laurate, 65 concentration of the first compound and the second com isopropyl myristate, oleic acid, glyceryl oleate, and sodium pound is up to about 10 wt %, per unit volume of the lauryl Sulfoacetate. formulation. US 9,642,912 B2 59 60 24. The topical formulation of claim 1, wherein the weight 33. The method of claim 30, wherein the first compound ratio of the first compound to the second compound is in the comprises methyl laurate and the second compound com range from about 1:9 to about 9:1. prises isopropyl myristate. 25. The topical formulation of claim 1, wherein the weight 34. The method of claim 30, wherein the first compound ratio of the first compound to the second compound is in the comprises methyl laurate and the second compound com range of from about 1:3 to about 3:1. prises oleic acid. 26. The topical formulation of claim 1, wherein the weight 35. The method of claim 30, wherein the first compound ratio of the first compound to the second compound is in the comprises methyl laurate and the second compound com range of from about 1:2 to about 2:1. prises glyceryl oleate. 27. The topical formulation of claim 1, wherein the weight 10 36. The method of claim 30, wherein the first compound ratio of the first compound to the second compound is about comprises methyl laurate and the second compound com 1:1. prises sodium lauryl Sulfoacetate. 28. The topical formulation of claim 1, wherein the topical 37. The method of claim 30, wherein the first compound formulation provides for improved flux of the drug as comprises isopropyl myristate and the second compound compared to a comparative formulation devoid of the first 15 compound and the second compound and replaced with an comprises oleic acid. equivalent wt % of water. 38. The method of claim 30, wherein the first compound 29. The topical formulation of claim 1, wherein the topical comprises isopropyl myristate and the second compound formulation has improved chemical and/or physical stability comprises glyceryl oleate. as compared to a comparative formulation devoid of the first 39. The method of claim 30, wherein the first compound compound and the second compound and replaced with an comprises isopropyl myristate and the second compound equivalent wt % of water. comprises sodium lauryl Sulfoacetate. 40. The method of claim 30, wherein the first compound 30. A method of treating a skin condition, comprising: comprises oleic acid and the second compound comprises applying a topical formulation of a corticosteroid to a skin glyceryl oleate. Surface of a subject at a site of the skin condition, said 25 formulation comprising: 41. The method of claim 30, wherein the first compound at least one corticosteroid, comprises oleic acid and the second compound comprises a first compound, and Sodium lauryl Sulfoacetate. a second compound, wherein the first compound and 42. The method of claim 30, wherein the first compound second compound are different and each is selected 30 comprises glyceryl oleate and the second compound com from the group consisting of N-lauroyl sarcosine, prises sodium lauryl Sulfoacetate. sodium octyl sulfate, methyl laurate, isopropyl 43. The method of claim 30, wherein the formulation myristate, oleic acid, glyceryl oleate, and sodium further comprises polyoxyl 35 castor oil. lauryl Sulfoacetate. 44. The method of claim 30, wherein the skin condition is 31. The method of claim 30, wherein the at least one 35 caused by eczema, dermatitis, allergy, or a skin rash. corticosteroid is selected from the group consisting of a 45. The method of claim 30, wherein the skin condition is clobetasol, halobetasol, betamethasone, triamcinolone caused by psoriasis. acetonide, and combinations thereof. 46. The method of claim 30, wherein the skin condition is 32. The method of claim 30, wherein the at least one plaque psoriasis. corticosteroid is halobetasol propionate.