US 20070269379A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0269379 A1 Mitragotri et al. (43) Pub. Date: Nov. 22, 2007

(54) PENETRATION ENHANCER (52) U.S. Cl...... 424/9.2: 424/449; 435/40.52: COMBINATIONS FOR TRANSIDERMAL 436/149; 514/772; 514/777; DELIVERY 514/788: 514/789; 435/7.1 (76) Inventors: Samir Mitragotri, Goleta, CA (US); (57) ABSTRACT Pankaj S. Karande, Somerville, MA (US); Amit K. Jain, Redwood City, CA A high throughput Screening and isolation system identifies (US) rare enhancer mixtures from a candidate pool of penetration enhancer combinations. The combinations are screened for Correspondence Address: high penetration but low irritation potential using a unique Rober Berliner data mining method to find new potent and safe chemical Berliner & Associated penetration enhancer combinations. The members of a SSS. W. Fifth Street library of chemical penetration enhancer combinations are 31st Floor screened with a high throughput device to identify “hot Los Angeles, CA 90013 (US) spots”, particular combinations that show higher chemical penetration enhancement compared to neighboring compo (21) Appl. No.: 10/560,571 sitions. The irritation potentials of the hot spot combinations are measured to identify combinations that also show low (22) PCT Filed: Jul. 21, 2004 irritation potential. A active component, Such as a drug, is then combined with the combination in a formulation which (86). PCT No.: PCT/USO4/23634 is tested for the ability of the drug to penetrate into or through skin. It is then assessed whether the formulation can S 371(c)(1), deliver the quantity of drug required, and animal tests are (2), (4) Date: Feb. 2, 2007 conducted to confirm in vivo the ability of the chemical penetration enhancer combinations to facilitate transport of Related U.S. Application Data Sufficient active molecules across the skin to achieve thera (60) Provisional application No. 60/560,717, filed on Jul. peutic levels of the active molecule in the animals blood. 23, 2003. The invention provides specific unique and rare mixtures of chemical penetration enhancers that enhance skin perme Publication Classification ability to hydrophilic macromolecules by more than 50-fold without inducing skin irritation, such as combinations of (51) Int. C. Sodium laurel ether sulfate and 1-phenyl piperazine, and A6 IK 49/00 (2006.01) combinations of N-lauryl sarcosine and Span 20/sorbitan A 6LX 9/70 (2006.01) monolaurate.

116

SR 222222 H LLILL 112 110 120 Patent Application Publication Nov. 22, 2007 Sheet 1 of 18 US 2007/0269379 A1 10 -

Select penetration enhancers . 12 Design library of chemical penetration enhancer (CPE) 14 Combinations

Screen CPE Combinations for ability to increase skin permeability 16

Analyze skin permeability screening data for hot spots and 18 Select CPE Combinations for further analysis

Screen Selected CPE 20 combinations for irritation potential

Analyze irritation potential screening data and select CPE combinations for further analysis

Perform in vitro quantification of permeability of selected CPE 24 Combinations

Perform in vivo test of irritation, safety and efficacy of selected CPE Combinations

F.G. 1 Patent Application Publication Nov. 22, 2007 Sheet 2 of 18 US 2007/0269379 A1

116

108

22E T

112 12O 110

FIG. 2 Patent Application Publication Nov. 22, 2007 Sheet 3 of 18 US 2007/0269379 A1 Abbreviation Name

COCamidooroovl HvodroxVSultaine

Dodecyl PWridinium Chloride IM isopropyl Myristate Lauric Acid

Linoleic Acid

MP 1-Methyl-2-Pyrrolidone NLS N Laury Sarcosine (CAS number 137-16-6 often Called Sodium LauroV Sarcosinate icotine Sulfate leic Acid OTAB CtW Trimethyl Ammonium Bromide PEGE olyEthyleneGygol Dodecyl Ether 1-Pheny Piperazine Span 20/Sorbitan Monolaurate SLA Sodium Laury Ether Sulfate

SLS Sodium Dodecyl Sulfate So Sodium oleate Sos Sodium octylsulfate

Tween 20

FG. 3 Patent Application Publication Nov. 22, 2007 Sheet 4 of 18 US 2007/0269379 A1

LITETISTÆGTETLOEGTZB?GT? L57??TEBETET [×55????l Patent Application Publication Nov. 22, 2007 Sheet 5 of 18 US 2007/0269379 A1

8000 Š as 6000 Š 2 4000 S.

O S - 0-10 10-20 20-30 30-40 40-50 50-60 60-70 Conductivity Enhancement Ratio Range

F.G. 5 Patent Application Publication Nov. 22, 2007 Sheet 6 of 18 US 2007/0269379 A1

F.G. 6 Patent Application Publication Nov. 22. 2007 Sheet 7 of 18 US 2007/0269379 A1

v. C v coco o v Vr cy vs. n v

c witc. o v. Coo v- v- Q ld CNN cy w CO wr Y) rt V (r) v.

s e

O C O

v. Cric C. N. v crew

co cNvvco our verV cy) S8Ocy SSSSfood N. V.

2 C. e e CN

i | : ; i Patent Application Publication Nov. 22, 2007 Sheet 8 of 18 US 2007/0269379 A1

irritation Potential of Selected CPEs

70

60 345OOO

2O

10

O 10 20 30 40 50 60 70 80 90 100 irritation Potential

F.G. 8 Patent Application Publication Nov. 22, 2007 Sheet 9 of 18 US 2007/0269379 A1

CPE Combination

NLS S20 5 NLSMP 6 ITR Limonene

F.G. 9

CPE A

c CTAB (0.5%)

F CBOL (1.5%) G PEGE (0.5%) H S20 (1.5%) J M (1.5%) K Linolenic (0.5%) L CBCAS (2%)

R 2 O %

A (0.5%

Linoleic (1.0% FIG. 10 Patent Application Publication Nov. 22, 2007 Sheet 10 of 18 US 2007/0269379 A1 Potency Phase Map for SLAPP 2

0.5

O O.5 1 Weight fraction of SLA

F.G. 11 Patent Application Publication Nov. 22, 2007 Sheet 11 of 18 US 2007/0269379 A1 Potency Phase Map for NLS S20 2

0.5

O 0.5 1 Weight fraction of NLS FIG. 12

P a t e t A p p i C a ti O PU b C a tiO N OV 2 2, 2 O O7 S h e et 1. 4 Of 1. 8 US 2007/0269379 A1

7 O

6 O

5 O

4 O

3 O

2 O

10 P P O O 5 10 15 20 25 30 35 40 irritation potential (IP)

FIG. 15 Patent Application Publication Nov. 22, 2007 Sheet 15 of 18 US 2007/0269379 A1

1.OE-02

1.OE-04

1.OE-05

1.OE-06 1.OE+01 1.OE--O2 1.OE+03 1.OE-04 1.OE+05 Molecular Weight (Da) F.G. 16 Patent Application Publication Nov. 22, 2007 Sheet 16 of 18 US 2007/0269379 A1

O 5 10 15 20 25 Time (hours)

F.G. 17 Patent Application Publication Nov. 22, 2007 Sheet 17 of 18 US 2007/0269379 A1

Patent Application Publication Nov. 22, 2007 Sheet 18 of 18 US 2007/0269379 A1

3.OE-04

2.5E-04

2.OE-04 2

1 5 E O 4.

1.OE-04

5.0E-05

O.OE-00 O Z2 NLS S20 CONTROL F.G. 19 US 2007/0269379 A1 Nov. 22, 2007

PENETRATION ENHANCER COMBINATIONS and eventually disrupt viable epidermal cells thereby induc FORTRANSIDERMAL DELVERY ing irritation due to the interstitial release of cytokines and by triggering other inflammatory responses. Attempts have CROSS REFERENCE TO RELATED PATENT been made to engineer physico-chemical properties of CPE APPLICATIONS molecules to enhance potency without affecting irritancy, 0001. This application claims the benefit of Provisional but without much Success. Patent Application No. 60/560,717, filed Jul. 23, 2003. 0006. A number of approaches for improving the pen etration of drugs using liposomes and related systems have FIELD been pursued over the years and have recently been 0002 The invention includes compositions for the deliv reviewed by Hadgraft and further details may be found in the ery of active ingredients such as drugs into and through skin book of Williams, especially Chapter 5. Hadgraft (2003); and other tissues and related Screening methods. Williams (2003). Mezei and Gulasekharam in 1980 per formed early work to show the potential value of liposoma BACKGROUND lly encapsulated drugs for topical therapy. Mezei et al. (1980). U.S. Pat. Nos. 5,540,943 and 5,716,638 are said to 0003 Skin is the largest organ of the human body and describe ethosomes which are characterized as “soft' provides a painless and compliant interface for systemic vesicles formed from phospholipids in the presence of water drug administration. The transdermal route may provide and alcohol and sometimes glycols and contain claims advantages over injections and oral routes by increasing directed towards liposomal compositions for medical or patient compliance and avoiding first pass metabolism, and cosmetic use. U.S. Pat. No. 6,165,500 is said to describe the may also provide Sustained and controlled delivery over use of elastic, deformable mini-droplets called Transfer long times. However, after nearly four decades of extensive Somes for transporting medical agents through the skin of a studies, the Success of this technology remains stinted with mammal. U.S. Pat. Nos. 5,853,755 and 5,993,851 are said to only a limited number of transdermal products available in describe biphasic multilamellar lipid vesicles and contain the market, all of which are based on low-molecular weight claims directed towards liposomal compositions for topical lipophilic drugs. administration of compounds and methods for preparing 0004 Development of transdermal products for macro liposomes having a central core compartment containing an molecules is primarily hindered by low skin permeability. oil in water emulsion. However, liposomal formulations Evolved to impede the flux of toxins into the body, skin have yet to appear in FDA approved patch products for naturally offers a very low permeability to the movement of transdermal delivery of drugs, in spite of the fact that this foreign molecules across it. A unique hierarchical structure area has been under development for more than 20 years. of lipid-rich matrix with embedded keratinocytes in the Williams (2003). upper strata (15 um) of skin, the stratum corneum (SC), is 0007 Overcoming the SC barrier safely and reversibly is largely responsible for the barrier properties of skin. Several a fundamental problem that persists in the field of transder technological advances have been proposed in efforts to mal delivery. In the absence of fundamental knowledge of overcome this barrier. Examples include iontophoresis, these interactions, rapid methods to screen various enhanc Sonophoresis, and use of chemical penetration enhancers ers are of value. Most drugs bind strongly and selectively to (CPE). CPEs can provide advantages including design flex a target protein. Recent advances in biotechnology have ibility with formulation chemistry, possibility of patch appli allowed rapid screening of thousands of drugs for their cation over a large area (>10 cm) and ability to work ability to bind to such protein targets. Ng, et al. (1999); without external physical delivery mechanisms. Several Verdine, et al. (1996). Through the development of combi different classes of CPEs including surfactants, fatty acids natorial drug discovery, new drugs, including low-molecular and fatty esters have been studied in the literature and more weight analogs of proteins and peptides, are being continu than 250 chemicals have been identified as enhancers that ally developed. Zhang, et al., (1999). However, the ability to can increase skin permeability. However, only a few induce deliver these drugs is still evaluated by traditional experi a significant (therapeutic) enhancement of drug transport. ments. In these experiments, the biological membrane under Moreover, the permeability of skin to foreign molecules consideration, such as the skin for transdermal drug delivery shows a trend to decrease rapidly with the molecular weight or the intestine for oral drug delivery, is placed in a diffusion (MW) of the foreign molecule. Transdermal delivery of high cell and transport across this membrane is measured over molecular weight drugs is therefore especially difficult and several hours or days. Bronaugh, et al., (1985). In many all current drugs delivered with patch technologies have a cases, additional experiments are performed to try to assess molecular weight of less than 500 Daltons. Bos et al. (2000). the effect of the formulation on membrane permeability. The problem of development of transdermal approaches for During this process, various formulations are utilized in an drug delivery is further aggravated by the fact that potent effort to optimize drug bioavailability. The objective of this enhancers are usually also potent irritants to skin and are optimization is the identification of a formulation that can thus physiologically incompatible. deliver the required therapeutic dose into the body. This 0005 Pushing the envelope on enhancement efficiencies process is based on traditional experiments and is time with single enhancers inevitably leads to a compromise on consuming as well as expensive. Availability of a rapid safety issues. Potent CPEs usually enhance skin permeabil screening method to determine trans-membrane transport of ity by disrupting the SC lipid bilayers. Since the SC is drugs would greatly facilitate the development of drug comprised of non-viable, keratinized cells, disruption of its delivery systems. An ability to discover formulations that lipid bilayers is itself not sufficient to induce irritation. can deliver a much wider range of drugs transdermally with However, CPEs are usually not selective towards SC lipids low irritation would be very important, enabling the attrac US 2007/0269379 A1 Nov. 22, 2007

tive benefits of transdermal delivery to be realized for a 0012. The present invention employs, for example, a much wider range of therapeutics. system known as “in vitro skin impedance guided high 0008 Transdermal patches are often used in the delivery throughput” (INSIGHT) to perform high throughput experi of drugs through the skin. Patches can be categorized into mentation (HTE), allowing the identification of rare pen several types depending on how the drug is incorporated into etration enhancer mixtures from a colossal candidate pool. the device and include: (i) those in which the drug is in an INSIGHT uses high throughput skin impedance measure adhesive; (ii) those in which the drug is in a matrix; and (iii) ments (as described in Karande et al. (2002), and in Inter those in which the drug is in a reservoir. Williams (2003). national Publication Number WO 02/16941A2). A library of The formulations utilized in patch and topically applied CPE formulations are created by dissolving or dispersing medications contain multiple components and a typical drug CPEs in varying concentrations in one or more vehicles. The formulation may contain anywhere from 3-15 components, CPE formulations may be screened for high penetration including the drug. In order to optimize the concentration of enhancement but low irritation potential using a unique data these components of a formulation containing, for example mining method to identify or confirm new potent and safe six components, an experimental design is required that may penetration enhancers. include, for example, five levels of concentration of each 0013 In one embodiment of the invention, hot spots may component. In order to determine the optimal concentration be identified, which are places in compositional space of these components, 5' experiments are required; that is, (defined by varying the concentrations of a set of CPEs) about 15,000 experiments. Note that in a typical formulation within which pronounced penetration enhancement is found development project, testing a system containing more than as a consequence of a combination of constituent CPES in six components is not unusual. Thus, the number of experi the CPE formulation. ments required for optimization may be extremely large. Although reducing the parameter space by either eliminating 0014 Hot spots are regions in composition space of a CPE formulation where enhanced permeability of a mem Some of the components or by reducing the levels of each brane is observed as the concentrations of at least two component in the experimental design may lessen the num chemical penetration enhancers within the CPE formulation ber of experiments needed to be done, it greatly increases the are varied. Hot spots are associated with relatively sharp likelihood of missing other potentially important formula permeability maxima and by relatively large values com tions. A typical transdermal transport experiment lasts for at pared with the permeability produced by each of the indi least 24 hours and uses about a 2 cm piece of skin. It is vidual CPEs in isolation. Mathematically, a so-called syn customary to run about 15-20 transport experiments at a ergy value, S. may be calculated for a composition time. At this rate, it would take hundreds of days to screen containing at least two CPES, A and B, according to the all 15,000 combinations. following equation 0009 Most molecules known as potent chemical penetra tion enhancers in the literature are also potent irritants. Very few molecules that show therapeutically significant S = ERA-B (X, Y) enhancements enhancement of penetration are physiologi X. ERA (Y) + (1-X). ERB(Y) cally compatible. This is a limiting step in exploiting trans dermal delivery as an efficient delivery mode. Combinations of two or more penetration enhancers may also be used, and where ERACX,Y) is the enhancement ratio obtained with may be more effective in increasing transdermal transport the formulation containing CPEs A and B, Y stands for the compared to each of them alone. Mollgaard (1993). Several combined total concentration of A and B measured in wit/vol, amphiphilic molecules enhance skin permeability via tem X stands for the weight fraction of A calculated according to porary disruption of the lipid structure of the stratum cor the amount of A informulation (expressed in wit/vol) divided neum. However, they have found limited clinical acceptance by Y and ERA(Y) and ER(Y) are the enhancement ratios as they almost invariably induce skin irritation, given that obtained when the CPEs A and B are replaced in the the plasma membranes of live cells in the epidermis have formulation with pure components A and B, respectively at similar compositions to the lipid layers in the stratum concentration Y. Enhancement ratios and therefore synergy COC. values vary as a function of the time that a formulation has been in contact with a membrane and it is often convenient 0010. There is a need for new penetration enhancer to evaluate 24-hour synergy values computed by consider compositions that can extend the range of drugs that are ation of enhancement ratios observed after a formulation has suitable for delivery in topical and transdermal formats as been in contact with skin for 24 hours. Permeability maxima well as effective methods to identify mixtures of penetration in the two-dimensional concentration space of two penetra enhancers that significantly enhance skin permeability for a tion enhancers A and B with 24 hour S values of 2 or more, much broader range of active ingredients without inducing or more preferably 4 or more, can be used to identify hot skin irritation. spots. It is to be understood that in a system with N SUMMARY permeation enhancers there are N(N-1)/2 ways of forming binary A-B pairs of permeation enhancers. S values may be 0011. The inventions described and claimed herein have calculated by the above equation for each pair of CPEs in the many attributes and embodiments including, but not limited formulations and hot spots may be identified by varying the to, those set forth or described or referenced in this Sum mary. The inventions described and claimed herein are not concentrations of different pairs of CPEs in the formulation. limited to or by the features or embodiments identified in 00.15 Many hot spots represent rare mixtures of CPEs this Summary, which is included for purposes of illustration that exhibit potent ability to increase the permeability of the only and not restriction. stratum corneum. It has been discovered that some hot spots US 2007/0269379 A1 Nov. 22, 2007

also have low irritation potential. Without being bound by peutic levels of the drug in the animals blood. For theory, a possible explanation of this phenomenon is that the example, in vivo experiments in hairless rats can be hot spot formulations evolve into a relatively non-disruptive performed using leuprolide acetate as a model drug. formulation in the epidermis, perhaps due to differential 0027. The concept of selective testing of hot spots for low retention of the components in the CPE mixture in the irritation potential is a powerful tool for identifying combi stratum corneum versus the epidermis. The formulations nations of penetration enhancers that have the ability to that comprise a combination of CPEs associated with a hot rapidly penetrate the SC but which have low irritation spot and which induce no more than modest skin irritation potential. In prior screening methods, where single formu are referred to as “synergistic' combinations of penetration lations were tested, results were indicative only of the ability enhancers (SCOPE). Synergism may be seen but is not a of the formulation to penetrate the SC. It has surprisingly requirement of the invention. SCOPE formulations are con been found that hot spots identified from the evaluation of ceptually distinct from empirically formulated enhancer formulations containing CPEs not only identify strong SC combinations reported in the literature, which rarely have penetrators but sometimes also SC penetrator combinations enhanced penetration without inducing irritation. with low irritation potential. 0016. Another embodiment of the present invention pro 0028. The invention also provides combinations that can vides a methodology for identifying and for discovering hot be mixed with a selected drug or other active component to spots and SCOPE formulations. greatly facilitate its transport through the and into or through 0017. A further embodiment of the present invention the epidermis. provides a methodology for discovering SCOPE formula 0029. The methods of the present invention apply gen tions suitable for inter- or trans-dermal delivery of drugs. erally to the inter- or trans-dermal delivery of compounds. Thus, by way of example but not limitation, the present 0018. The method of the present invention provides a invention applies to the inter- and transdermal delivery of procedure comprising, for example, all or some of the Small molecule, lipophilic drugs, but of lipophilic drugs of following steps: a broad range of molecular weights, up to several thousand 0.019 (a) Obtaining a large diverse library of CPE Daltons and beyond, of non-lipophilic or hydrophilic drugs, combinations, which can be constructed, for example, also of a broad range of molecular weights, of molecular or by random selection of CPEs from known or other other ingredients for cosmetic application, of diagnostic CPES, selecting one or more vehicles and combining agents, of genetic material Such as DNA, of nanoparticulate the selected CPEs and vehicle in different ratios to materials, and the like. The present invention relates to make the diverse library; compounds to be delivered for the benefit of skin tissues, for example, Such as for dermatological, antibiotic, antifungal 0020 (b) Screening the elements of the library with a or cosmetic application, as well as to compounds to be HTE device for their ability to increase skin penetra delivered, for example, for systemic application. The present tion; invention is of particular benefit for routes for the delivery 0021 (c) Analyzing the skin penetration data for hot of compounds into and through skin, and the present inven spots to select CPE combinations for further analysis: tion is also of benefit for routes for the delivery of com pounds into or through tissues or other types, such as 0022 (d) Measuring the irritation potential of the hot mucosal tissue, as well as of synthetic membranes. As a spot CPE combinations. This can be done by any consequence the present invention also provides methods for known method. For example, hot spot CPE combina treating diseases. Further embodiments of the present inven tions can be placed, 24 at a time, on a culture of normal tion are transdermal patches containing formulations with human derived epidermal keratinocytes and the viabil potent ability to permeabilize skin and low irritation poten ity of the cells measured at the end of the study period, tial that may be used to deliver drugs or other active e.g., 4 to 24 hours, using a Mattek device (Mattek components. Corporation, 200 Homer Avenue, Ashland, Mass. 01721, www.mattek.com). 0030. Another embodiment of the invention provides specific SCOPE formulations, certain mixtures of penetra 0023 (e) Identifying from (d) those formulations that tion enhancers that enhance skin permeability to hydrophilic are SCOPE formulations, that is, that show low irrita macromolecules (MW-1 kDa-5 kDa) by more than 50-fold tion potential. without inducing skin irritation. These include combinations 0024 (f) Combining one or more identified formula of sodium laurel ether Sulfate and 1-phenyl piperazine, and tions with a selected drug and testing for penetration combinations of N-lauryl sarcosine and Span 20/sorbitan through skin. This can be done by any known method. monolaurate. For example, the drug-formulation combination can be BRIEF DESCRIPTION OF THE DRAWINGS placed on porcine or human skin and penetration of the 0031 FIG. 1 is a flow chart showing a sequence of steps drug through the skin can be measured after a period of useful for the identification of low irritation penetration 24 to 96 hours using Franz diffusion cells. enhancers according to a preferred embodiment of the 0025 (g) Determining whether the formulation can present invention; deliver the necessary drug amount, e.g., by comparison 0032 FIG. 2 is a schematic of a device that may be used with published data. for high throughput Screening of formulations. 0026 (h) Conducting animal testing to confirm the 0033 FIG. 3 is a table of chemical penetration enhancers ability of the enhancer combinations to deliver suffi that have been used to construct one library of penetration cient drug molecules across the skin to achieve thera enhancer combinations; US 2007/0269379 A1 Nov. 22, 2007

0034 FIG. 4 is a table that classifies the chemical pen 0048 FIG. 18 shows micrographs of hairless rat skin etration enhancers listed in the table in FIG.3 into 8 separate after application of patches containing a control formulation categories and shows how these chemical penetration based on PBS (FIG. 18 (A)), a SCOPE containing SLA and enhancers were divided into four blocks to assist in the PP (FIG. 18 (B)), and a formulation containing SLS (FIG. 18 construction of a library; (C)); and 0035 FIG. 5 is a histogram showing the frequency with 0049 FIG. 19 shows Franz diffusion cell measurement of which enhancement ratios in different ranges were observed the permeability of corticosterone across porcine skin uti in a data set containing over 20,000 conductivity enhance lizing a formulation based on NLS S20 compared to that ment ratios: achieved utilizing a formulation based on PBS. 0.036 FIG. 6 shows potency phase maps for six pairs of chemical penetration enhancers; DETAILED DESCRIPTION 0037 FIG. 7 is a table showing maximum conductivity 0050. The following terms have the following meanings enhancement ratios and maximum synergy ratios for 11 when used herein and in the appended claims. Terms not different combinations of chemical penetration enhancers; specifically defined herein have their art recognized mean ing. 0038 FIG. 8 shows a graph of irritation potential versus conductivity enhancement ratio for a series of individual 0051 “Active component’ means a substance or com chemical penetration enhancers and a series of chemical pound that imparts a primary utility to a composition or penetration enhancer combinations; formulation when the composition or formulation is used for its intended purpose. Examples of active components 0.039 FIG. 9 is a table showing a mapping between the include pharmaceuticals, vitamins, ultra violet (“UV) numeral symbols used to label data points in FIG. 8 and the radiation absorbers, cosmeceuticals, alternative medicines, chemical penetration enhancer combinations; skin care actives, and nutraceuticals. Active components 0040 FIG. 10 is a table showing a mapping between the can, by way of example but not limitation, be small mol letter symbols used to label data points in FIG. 8 and the ecules, proteins or peptides, genetic material. Such as DNA individual chemical penetration enhancers; or RNA, diagnostic or sensory compounds, agrochemicals, the active component of a consumer product formulation, or 0041 FIG. 11 shows a potency phase map of the chemi the active component of an industrial product formulation. cal penetration enhancer pair SLAPP, 0052 “Active component formulation” means a formu 0.042 FIG. 12 shows a potency phase map of the chemi lation which contains one or more active components. cal penetration enhancer pair NLS S20; 0053 “Array' or “sample array' means a plurality of 0.043 FIG. 13 shows a permeability enhancement ratio samples associated under a common experiment, or the for inulin measured with a Franz diffusion cell for the physical arrangement of a plurality of vessels used to chemical penetration enhancer pair NLS S20 and tape contain samples in a given experiment. stripped skin; 0054) “Automated” or “automatically” refers to the use of 0044 FIG. 14 shows the permeability enhancement ratio non-human means such as computer Software and robotics of inulin measured with a Franz diffusion cell for formula to achieve one or more operations such as adding, mixing, tions containing SLAPP. NLS S20 and tape stripped skin. In dispensing or analyzing the samples, components, and speci contrast to the data presented in FIG. 13, these data have not mens or diffusion products. been corrected for the amount of inulin that was trapped in the skin; 0055) "Body surface” refers to skin or mucosal tissue. 0045 FIG. 15 shows irritation potential versus conduc 0056 “Carriers” or equivalently “vehicles” as used tivity enhancement ratio for two SCOPE formulations based herein refer to carrier materials suitable for topical or on SLAPP and NLS S20 compared to that of formulations transdermal drug administration or for formulating samples containing the individual chemical penetration enhancers for use in high throughput experimentation. Carriers and SLA, PP, NLS and S20; vehicles useful herein include any Such material known in 0046 FIG. 16 shows Franz diffusion cell data on the the art that is generally nontoxic and does not interact with dependence on molecular weight of skin permeability for a other components of the composition in a deleterious or range of molecules. Open circles show permeability of unwanted manner. Vehicles may contain one or more excipi untreated skin reported in the literature to a variety of ents and may also contain one or more chemical penetration hydrophilic solutes. Open squares show skin permeability enhancers. Carriers and vehicles can be, for example, semi achieved for a range of test molecules utilizing formulations Solids, liquids, solvents, Solutions, gels, foams, pastes, oint containing SLA and PP. Closed circles show skin perme ments, triturates, Suspensions, or emulsions. ability for the same test molecules in the SLAPP formula 0057 "Component’ means any substance or compound. tion that have been corrected to account for the amount of A component can be active or inactive. test molecule that was trapped in the skin; 0058 “Enhancement ratio” or equivalently “skin conduc 0047 FIG. 17 shows the plasma concentration of leupro tivity enhancement ratio” means the ratio O/O, where O is lide as a function of time after placement of leuprolide an initial skin conductivity observed after a formulation has patches containing SLA:PP and hyaluronic acid (closed been brought into contact with skin and O, is skin conduc symbols) and control patches containing leuprolide and tivity observed after an incubation time t. The enhancement hyaluronic acid (open symbols) on the skin of hairless rats: ratio is a function of time and the term “t-hour enhancement US 2007/0269379 A1 Nov. 22, 2007

ratio' is understood to mean an enhancement ratio measured nents, such as cyclodextrins, albumin, Xanthan gum; and after an incubation time of thours, where thours may be any tonicity components, such as glycerol, dextrose, potassium period of time over which enhancement ratios may be chloride, and sodium chloride; and mixtures thereof. Excipi reasonably measured. As explained below enhancement ents include those that alter the rate of absorption, bioavail ratios can be conveniently measured using high throughput ability, or other pharmacokinetic properties of pharmaceu devices or Franz diffusion cells by measuring ratios in ticals, dietary Supplements, alternative medicines, or currents that flow across a skin Sample in response to an nutraceuticals. Other examples of Suitable excipients, such applied Voltage. It is understood that it may be necessary to as binders and fillers are listed in Remington's Pharmaceu repeat skin conductivity measurements on a number of tical Sciences, 18th Edition, Ed. Alfonso Gennaro, Mack separate skin samples to obtain a statistically meaningful Publishing Co. Easton, Pa., 1995 and Handbook of Phar result, due to experimental errors that may be introduced in maceutical Excipients, 3rd Edition, Ed. Arthur H. Kibbe, the measurement process, for example, as a consequence of American Pharmaceutical Association, Washington D.C. variability in skin samples used in the experiment. 2000, both of which are incorporated herein by reference. 0059) “Excipient” refers to inactive substances used to Excipients that are typically used in the formation of trans formulate pharmaceuticals as a result of processing or dermal delivery devices, and therefore particularly useful for manufacture or used by those of skill in the art to formulate formulation of the samples of the present invention, are pharmaceuticals, alternative medicines, cosmeceuticals, penetration enhancers, adhesives and solvents cosmetics, personal care products, dietary Supplements, and nutraceuticals for administration to animals or humans. 0061 “High throughput refers to the number of samples 0060 Preferably, excipients are approved for or consid generated or screened in a given time period as described ered to be safe for human and animal administration. herein, typically at least 10, more typically at least 50 to 100, Examples of suitable excipients include, but are not limited and preferably more than 1000 samples. The high through to, acidulents, such as lactic acid, hydrochloric acid, and put methods of the present invention can be performed using tartaric acid; solubilizing components, such as non-ionic various means and various forms of samples. Typically, the cationic, and anionic Surfactants; absorbents, such as ben methods are performed either with liquid samples or with tonite, cellulose, and kaolin; alkalizing components, such as Solid or semi-solid samples. diethanolamine, potassium citrate, and sodium bicarbonate; 0062 “Irritation antergy factor” between two CPEs in a anticaking components, such as calcium phosphate tribasic, formulation is calculated according to magnesium trisilicate, and talc; antimicrobial components, Such as benzoic acid, Sorbic acid, benzyl alcohol, benzetho nium chloride, bronopol, alkyl parabens, cetrimide, phenol, X. IPA (Y) + (1-X); IP (Y) phenylmercuric acetate, thimerosol, and phenoxyethanol: IPAB(X, Y) antioxidants, such as ascorbic acid, alpha tocopherol, propyl gallate, and Sodium metabisulfite; binders, such as acacia, alginic acid, carboxymethyl cellulose, hydroxyethyl cellu where IPACX,Y) is the irritation potential measured for the lose; dextrin, gelatin, guar gum, magnesium aluminum formulation containing CPES A and B, Y stands for the silicate, maltodextrin, povidone, starch, vegetable oil, and amount of the combination of A and B expressed in wit/vol Zein; buffering components, such as Sodium phosphate, and X stands for the amount of A in formulation (expressed malic acid, and potassium citrate; chelating components, in wit/vol) divided by Y. IPA(Y) and IP(Y) are measured by Such as EDTA, malic acid, and maltol; coating components, preparing formulations whose composition is the same as Such as adjunct Sugar, cetyl alcohol, poly-vinyl alcohol, that containing the CPES A and B except that CPEs A and B carnauba wax, lactose maltitol, titanium dioxide; controlled are replaced with either pure component A at a wit/vol of Y release vehicles, such as microcrystalline wax, white wax, or pure component Bata wt/vol of Y. IPA(Y) and IP(Y) are and yellow wax; desiccants, such as calcium sulfate; deter then the irritation potentials measured for the formulation in gents, such as Sodium lauryl Sulfate; diluents. Such as which A, but not B, is present and B, but not A, is present, calcium phosphate, Sorbitol, starch, talc, lactitol, poly respectively. Irritation potential can be measured according methacrylates, sodium chloride, and glyceryl palmitostear to a number of different methods and the calculated irritation ate; disintegrants, such as colloidal silicon dioxide, croscar antergy factor of a formulation will depend on which method mellose Sodium, magnesium aluminum silicate, potassium for measuring irritation potential is employed. Preferably, polacrilin, and sodium starch glycolate; dispersing compo irritation antergy factor is calculated using irritation poten nents, such as poloxamer 386, and polyoxyethylene fatty tials measured as an MTT 4-hour cell viability percentage. esters (polysorbates); emollients, such as cetearyl alcohol, lanolin, mineral oil, petrolatum, cholesterol, isopropyl 0063 “Irritation potential” means a numerical measure of myristate, and lecithin; emulsifying components, such as irritation of a formulation, which tends to increase in value anionic emulsifying wax, monoethanolamine, and medium as the degree of irritancy of the formulation increases. chain triglycerides; flavoring components, such as ethyl Irritation potential may be measured in vivo using animals maltol, ethyl Vanillin, fumaric acid, malic acid, maltol, and or humans. For example, in Vivo irritation potential in menthol; humectants, such as glycerin, propylene glycol, humans may be measured by the 21-day cumulative irrita Sorbitol, and triacetin, lubricants, such as calcium Stearate, tion test. Berger (1982). Irritation potential may also be canola oil, glyceryl palmitostearate, magnesium oxide, measured in vitro utilizing the methods discussed in more poloxymer, sodium benzoate, Stearic acid, and Zinc Stearate; detail below. In one approach to measurement of irritation Solvents, such as alcohols, benzyl phenylformate, vegetable potential, reconstructed human epidermis equivalents may oils, diethyl phthalate, ethyl oleate, glycerol, glycofurol, be employed such as EpiDermTM or EPISKINTM. Faller polyethylene glycol, tartazine, triacetin: Stabilizing compo (2002). US 2007/0269379 A1 Nov. 22, 2007

0064 “MTT 4-hour cell viability percentage” means irri oxo-azepine-1-acetic acid esters, N-(2, Hydroxyethyl)-2- tation potential of a formulation as measured as a percentage pyrrolidone, 1-Laurylazacycloheptane, 2-(1-Nonyl)-1,3- of cell viability after 4 hours of contact with the formulation dioxolane, 1-N-Octylazacyclopentan-2-one, N-(1- on the EpiDermTM skin model (Mattek Corporation, Ash Oxododecyl)-hexahydro-1H-azepine, N-(1, Oxododecyl)- land, Mass. www.mattek.com) assayed using a methyl thia morpholines, 1-Oxohydrocarbyl-substituted Zol tetrazolium (MTT) uptake assay according to the pro azacyclohexanes, N-(1-Oxotetradecyl)-hexahydro-2-oxo tocol provided in the paper of Faller et al. Faller (2002). 1H-azepine, and N-(1 Thiododecyl)-morpholines. MTT 4-hour cell viability percentages are generally 0070 Solvents and related compounds: These molecules expected to fall in the range of 0-100%. are solubility enhancers. Some of them also extract lipids, 0065 “Mucosa” means a mucous membrane that covers thereby increasing skin permeability. Examples of Solvents the inside of a hollow organ Such as the membranes covering include Acetamide and derivatives, Acetone, n-Alkanes the oral cavity, the nasal cavity, the rectum and the vagina. (chain length between 7 and 16), Alkanols, diols, short-chain fatty acids, Cyclohexyl-1,1-dimethylethanol, Dimethyl 0066) “Library' means a plurality of samples. acetamide, Dimethyl formamide, Ethanol, Ethanol/D-li 0067 "Permeation enhancer' or, equivalently, “penetra monene combination, 2-Ethyl-1,3-hexanediol, Ethoxydigly tion enhancer.”“chemical penetration enhancer or “CPE col (transcutol), Glycerol, Glycols, Lauryl chloride, means a Substance used to modify, usually to increase, the Limonene, N-Methylformamide, 2-Phenylethanol, 3-Phe rate of permeation through skin or other tissue of one or nyl-1-propanol, 3-Phenyl-2-propen-1-ol, Polyethylene gly more products in a formulation, and includes all Such col, Polyoxyethylene sorbitan monoesters, Polypropylene substances now known or later developed or discovered. See glycol 425, Primary alcohols (tridecanol), Procter & Gamble Santus et al. (1993) and Williams (2003). Various enhancers system: Small polar solvents (1,2-propane diol, butanediol. are listed below. These enhancers are compiled from over C3-6 triols or their mixtures and a polar lipid compound 350 references and have been classified into several catego selected from C16 or C18 monounsaturated alcohol, C16 or ries and subcategories based on their structure or their effect C18 branched saturated alcohol and their mixtures), Span on permeability: 20, Squalene, Triacetin, Trichloroethanol, Trifluoroethanol, Trimethylene glycol, Xylene, DMSO and related com 0068 Surfactants: These are amphiphilic molecules with pounds. a hydrophilic head and a hydrophobic tail group. The tail length and the chemistry of the head group play an important 0071 Fatty alcohols, fatty acids, fatty esters, and related structures: These molecules are classic bilayer fluidizers. role in determining their effect on skin permeability. Sur Examples of these enhancers include Aliphatic alcohols, factants can be categorized into four groups, cationic, Decanol, Lauryl alcohol (dodecanol), Linolenyl alcohol, anionic, non-ionic, and Zwitterionic depending on the charge Nerolidol. 1-Nonanol, n-Octanol, Oleyl alcohol, Butyl on the head group. Prominent examples of Surfactants that acetate, Cetyl lactate, Decyl N,N-dimethylamino acetate, have been used for transdermal delivery include: Brij (vari Decyl N,N-dimethylamino isopropionate, Diethyleneglycol ous chain lengths), HCO-60 surfactant, Hydroxypoly oleate, Diethyl sebacate, Diethyl succinate, Diisopropyl ethoxydodecane, Lauryl sarcosine. Nonionic Surface active sebacate, Dodecyl N,N-dimethylamino acetate, Dodecyl agents, Nonoxynol, Octoxynol, Phenylsulfonate, Pluronic, (N,N-dimethylamino)-butyrate, Dodecyl N,N-dimethy Polyoleates (nonionic surfactants), Rewopal HV10, Sodium lamino isopropionate, Dodecyl 2-(dimethylamino)propi laurate, Sodium oleate, Sorbitan dilaurate, Sorbitan dioleate, onate, EO-5-oleyl ester, Ethyl acetate, Ethylaceto acetate, Sorbitan monolaurate, Sorbitan monooleates, Sorbitan Ethyl propionate, Glycerol monoethers, Glycerol monolau trilaurate, Sorbitan trioleate, Span 20, Span 40, Span 85, rate, Glycerol monooleate, Glycerol monolinoleate, Isopro Synperonic NP, Triton X-100. Tweens, Sodium alkyl sul pyl isoStearate, Isopropyl linoleate, Isopropyl myristate, fates, and alkyl ammonium halides. Isopropyl myristateffatty acid monoglyceride combination, 0069 AZone and related compounds: These compounds Isopropyl myristate/ethanol/L-lactic acid (87:10:3) combi are also amphiphilic and possess a nitrogen molecule in their nation, Isopropyl palmitate, Methyl acetate, Methyl caprate, head group (preferably in the ring). The presence of a Methyl laurate, Methyl propionate, Methyl Valerate, nitrogen atom in a ring creates a bulky polar head group with 1-Monocaproyl glycerol, Monoglycerides (medium chain the potential for strong disruption of stratum corneum. length), Nicotinic esters (benzyl), Octyl acetate, Octyl N,N- Examples of Such compounds include N-Acyl-hexahydro dimethylamino acetate, Oleyl oleate, n-Pentyl N-acetylpro 2-oxo-H-azepines, N-Alkyl-dihydro-1,4-oxazepine-5,7-di linate, Propylene glycol monolaurate, Sorbitan dilaurate, ones, N-Alkylmorpholine-2,3-diones, N-Alkylmorpholine Sorbitan dioleate, Sorbitan monolaurate, Sorbitan 3,5-diones, AZacycloalkane derivatives (-ketone, -thione), monooleates, Sorbitan trilaurate, Sorbitan trioleate, Sucrose Azacycloalkenone derivatives, 1-2-(Decylthio)ethylazacy coconut fatty ester mixtures. Sucrose monolaurate. Sucrose clopentan-2-one (HPE-101), N-(2.2), Dihydroxyethyl dode monooleate, Tetradecyl N,N-dimethylamino acetate, cylamine, 1-Dodecanoylhexahydro-1-H-azepine, 1-Dodecyl Alkanoic acids, Capric acid, Diacid, Ethyloctadecanoic acid, azacycloheptan-2-one (aZone or laurocapram), N-Dodecyl Hexanoic acid, Lactic acid, Lauric acid, Linoelaidic acid, diethanolamine, N-Dodecyl-hexahydro-2-thio-1H-azepine, Linoleic acid, Linolenic acid, Neodecanoic acid, Oleic acid, N-Dodecyl-N-(2-methoxyethyl)acetamide, N-Dodecyl-N- Palmitic acid, Pelargonic acid, Propionic acid, Vaccenic (2-methoxyethyl) isobutyramide, N-Dodecyl-piperidine-2- acid, C.-Monoglyceryl ether, EO-2-oleyl ether, EO-5-oleyl thione, N-Dodecyl-2-piperidinone, N-Dodecyl pyrrolidine ether, EO-10-oleyl ether, Ether derivatives of polyglycerols 3,5-dione, N-Dodecyl pyrrolidine-2-thione, N-Dodecyl-2- and alcohols (1-O-dodecyl-3-O-methyl-2-0-(29, 39-dihy pyrrolidone, 1-Farnesylazacycloheptan-2-one, droxypropyl)glycerol), L-O-amino-acids, Lecithin, Phos 1-Farnesylazacyclopentan-2-one, 1-Geranyl azacyclohep pholipids, Saponin/phospholipids, Sodium deoxycholate, tan-2-one, 1, Geranylazacyclopentan-2-one, Hexahydro-2- Sodium taurocholate, and Sodium tauroglycocholate. US 2007/0269379 A1 Nov. 22, 2007

0072 Others: Aliphatic thiols, Alkyl N,N-dialkyl-substi inhibitor; bronchodilator; cardiovascular agent; cholinergic; tuted amino acetates, Anise oil, Anticholinergic agent pre depressant; diagnostic aid; diuretic: dopaminergic agent; treatment, Ascaridole, Biphasic group derivatives, Bisab estrogen receptor agonist; fibrinolytic; fluorescent agent; olol, Cardamom oil, 1-Carvone, Chenopodium (70% free oxygen radical Scavenger, gastric acid suppressant; ascaridole), Chenopodium oil, 1.8 Cineole (eucalyptol), Cod gastrointestinal motility effector; glucocorticoid; hair liver oil (fatty acid extract), 4-Decyloxazolidin-2-one, Dicy growth stimulant; hemostatic; histamine H2 receptor clohexylmethylamine oxide, Diethyl hexadecylphospho antagonists; hormone; hypocholesterolemic; hypoglycemic, nate, Diethyl hexadecylphosphoramidate, N,N-Dimethyl hypolipidemic; hypotensive; imaging agent; immunizing dodecylamine-N-oxide, 4.4-Dimethyl-2-undecyl-2-oxazo line, N-Dodecanoyl-L-amino acid methyl esters, 1,3-Diox agent; immunomodulator, immunoregulator, immunostimu acycloalkanes, (SEPAs), Dithiothreitol, Eucalyptol (cin lant; immunosuppressant, keratolytic; LHRH agonist; mood eole), Eucalyptus oil, Eugenol. Herbal extracts, Lactam regulator, mucolytic; mydriatic; nasal decongestant; neuro N-acetic acid esters, N-Hydroxyethalaceamide, 2-Hydroxy muscular blocking agent; neuroprotective; NMDA antago 3-oleoyloxy-1-pyroglutamyloxypropane, Menthol, Men nist; non-hormonal sterol derivative; plasminogen activator; thone, Morpholine derivatives, N-Oxide, Nerolidol, Octyl platelet activating factor antagonist, platelet aggregation B-D-(thio)glucopyranosides, Oxazolidinones, piperazine inhibitor, psychotropic; radioactive agent; scabicide; scle derivatives, Polar lipids, Polydimethylsiloxanes, Poly rosing agent; sedative; sedative-hypnotic; selective adenos 2-(methylsulfinyl)ethyl acrylate). Polyrotaxanes, Polyvi ine Al antagonist, serotonin antagonist; serotonin inhibitor; nylbenzyldimethylalkylammonium chloride, Poly(N-vinyl serotonin receptor antagonist; Steroid; thyroid hormone; N-methyl acetamide), Prodrugs, Saline, Sodium pyro thyroid inhibitor; thyromimetic, tranquilizer; amyotrophic glutaminate, Terpenes and azacyclo ring compounds, lateral Sclerosis agent; cerebral ischemia agent, Paget’s Vitamin E (C-tocopherol), Ylang-ylang oil, N-Cyclohexyl disease agent; unstable angina agent; vasoconstrictor; 2-pyrrolidone, 1-Butyl-3-dodecyl-2-pyrrolidone, 1,3-Dim vasodilator, wound healing agent, Xanthine oxidase inhibi ethyl-2-imidazolikinone, 1.5 Dimethyl-2-pyrrolidone, 4.4- tOr. Dimethyl-2-undecyl-2-oxazoline, 1-Ethyl-2-pyrrolidone, 1-Hexyl-4-methyloxycarbonyl-2-pyrrolidone. 1-Hexyl-2- 0075 Specific examples of pharmaceuticals that may be pyrrolidone, 1-(2 Hydroxyethyl)pyrrolidinone, 3-Hydroxy included within formulations of the invention, both alone or N-methyl-2-pyrrolidinone, 1-Isopropyl-2-undecyl-2-imida in combination, include but are not limited to: Zoline, 1-Lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-Methyl-2-pyrrolidone, Poly(N-vinylpyrrolidone), Pyro 0076 Adrenergic: Adrenaline; Amidephrine Mesylate: glutamic acid esters, Acid phosphatase, Calonase, Orgelase, Apraclonidine Hydrochloride; Brimonidine Tartrate; Papain, Phospholipase A-2, Phospholipase C and Triacylg Dapiprazole Hydrochloride; Deterenol Hydrochloride: lycerol hydrolase. Dipivefrin; Dopamine Hydrochloride; Ephedrine Sulfate: 0073. “Penetration enhancement’ means a measure of the Epinephrine: Epinephrine Bitartrate; Epinephryl Borate; degree to which a formulation is successful in increasing the Esproquin Hydrochloride; Etafedrine Hydrochloride: permeability of skin, mucosa or a test membrane. Hydroxyamphetamine Hydrobromide: Levonordefrin; Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline 0074 "Pharmaceutical' or, used interchangeably, "drug’ Hydrochloride; Naphazoline Hydrochloride; Norepineph means any Substance or compound that has a therapeutic, rine Bitartrate; Oxidopamine; Oxymetazoline Hydrochlo disease preventive, diagnostic, or prophylactic effect when ride; Phenylephrine Hydrochloride; Phenylpropanolamine administered to an animal or a human. The term pharma Hydrochloride; Phenylpropanolamine Polistirex: Prenalterol ceutical includes prescription drugs and over the counter Hydrochloride; Propylhexedrine: Pseudoephedrine Hydro drugs. The molecular structures of drugs can often be chloride; Tetrahydrozoline Hydrochloride; Tramazoline characterized as Small molecules, peptides, proteins and Hydrochloride; Xylometazoline Hydrochloride. antibodies although other structures also include, for example, oligonucleotides and polysaccharides. Pharmaceu 0077 Adrenocortical steroid: Ciprocinonide; Desoxycor ticals suitable for use in the invention include those now ticosterone Acetate; Desoxycorticosterone Pivalate; Dexam known or later developed. Examples of pharmaceuticals for ethasone Acetate; Fludrocortisone Acetate; Flumoxonide; use with SCOPE formulations include, but are not limited to, Hydrocortisone Hemisuccinate; Methylprednisolone drugs of the following types: adrenergic agent; adrenocor Hemisuccinate; Naflocort; Procinonide; Timobesone tical steroid; adrenocortical Suppressant; aldosterone antago Acetate; Tipredane. nist; amino acid; anabolic; analeptic; analgesic; anesthetic; anorectic; anti-acne agent; anti-adrenergic; anti-allergic; 0078. Adrenocortical suppressant: Aminoglutethimide: anti-amebic; anti-anemic; anti-anginal; anti-arthritic; anti Trilostane. asthmatic; anti-atherosclerotic; antibacterial; anticholin ergic; anticoagulant; anticonvulsant; antidepressant; antidia 0079 Alcohol deterrent: Disulfuram. betic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; 0080 Aldosterone antagonist: Canrenoate Potassium; antifibrinolytic; antifungal; antihemorrhagic; antihistamine; Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate antihyperlipidemic; antihypertensive; antihypotensive; anti Potassium; Spironolactone. infective; anti-inflammatory; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, 0081 Amino acid: Alanine; Arginine: Aspartic Acid: antineutropenic, antiparasitic; antiproliferative; antipsy Carnitine: Cysteine Hydrochloride: Cystine; Glycine: His chotic; antirheumatic; antiseborrheic; antisecretory; antis tidine; Isoleucine; Leucine; Lysine; Lysine Acetate; Lysine pasmodic; antithrombotic; antiulcerative; antiviral; appetite Hydrochloride; Methionine; Phenylalanine: Proline: Serine; Suppressant; blood glucose regulator, bone resorption Threonine: Tryptophan; Tyrosine; Valine. US 2007/0269379 A1 Nov. 22, 2007

0082 Ammonia detoxicant: Arginine Glutamate; Argin Tramadol Hydrochloride; Trefentanil Hydrochloride; Trola ine Hydrochloride. mine: Veradoline Hydrochloride: Verilopam Hydrochloride; Volazocine: Xorphanol Mesylate; Xylazine Hydrochloride; 0.083 Amyotrophic lateral sclerosis agents: Riluzole. Zomepirac Sodium, Zucapsaicin. 0084 Anabolic: Bolandiol Dipropionate; Bolasterone: 0087 Androgen: Fluoxymesterone; Mesterolone; Meth Boldenone Undecylenate; Bolenol; Bolmantalate; Ethyl yltestosterone; Nandrolone Decanoate; Nandrolone Phen estrenol; Methenolone Acetate; Methenolone Enanthate: propionate; Nisterime Acetate; Oxandrolone; Mibolerone; Nandrolone Cyclotate; Norbolethone; Pizoty Oxymetholone; Silandrone; Stanozolol; Testosterone; Test line; Quinbolone; Stenbolone Acetate; Tibolone; Zeranol. osterone Cypionate; Testosterone Enanthate; Testosterone Ketolaurate; Testosterone Phenylacetate; Testosterone Pro 0085 Analeptic: Modafinil. pionate; Trestolone Acetate. 0.086 Analgesic: Acetaminophen; Alfentanil Hydrochlo 0088 Anesthesia, adjunct to: Sodium Oxybate. ride; Aminobenzoate Potassium; Aminobenzoate Sodium; Amidoxime; Anileridine; Anileridine Hydrochloride; Anilo 0089 Anesthetic: Aliflurane; Benoximate Hydrochloride: pam Hydrochloride; Anirolac, Antipyrine; Aspirin; Benox Benzocaine; Biphenamine Hydrochloride; Bupivacaine aprofen; Benzydamine Hydrochloride; Biciifadine Hydro Hydrochloride; Butamben; Butamben Picrate; Chlorop chloride; Brifentanil Hydrochloride; Bromadoline Maleate; rocaine Hydrochloride: Cocaine; Cocaine Hydrochloride; Bromfenac Sodium: Buprenorphine Hydrochloride: Butace Cyclopropane; Desflurane; Dexivacaine; Diamocaine tin; Butixirate; Butorphanol; Butorphanol Tartrate; Carbam Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclo azepine; Carbaspirin Calcium; Carbiphene Hydrochloride: nine Hydrochloride; Enflurane; Ether; Ethyl Chloride: Eti Carfentanil Citrate: Ciprefadol Succinate; Ciramadol; Cira docaine; Etoxadrol Hydrochloride; Euprocin Hydrochlo madol Hydrochloride; Clonixeril; Clonixin: Codeine; ride; Fluoroxene; Halothane; Isobutamben; Isoflurane; Codeine Phosphate: Codeine Sulfate; Conorphone Hydro Ketamine Hydrochloride; Levoxadrol Hydrochloride: chloride: Cyclazocine; Dexoxadrol Hydrochloride; Dex Lidocaine; Lidocaine Hydrochloride; Mepivacaine Hydro pemedolac, Dezocine; Diflunisal; Dihydrocodeine Bitar chloride; Methohexital Sodium; Methoxyflurane: Mida trate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Zolam Hydrochloride: Midazolam Maleate; Minaxolone: Drinidene: Enadoline Hydrochloride: Epirizole; Ergotamine Norflurane; Octodrine; Oxethazaine; Phencyclidine Hydro Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; chloride; Pramoxine Hydrochloride; Prilocalne Hydrochlo Fenoprofen; Fenoprofen Calcium: Fentanyl Citrate: Floc ride; Procaine Hydrochloride; Propanidid; Proparacaine tafenine: Flufenisal; Flunixin: Flumixin Meglumine: Flupir Hydrochloride; Propofol; Propoxycaine Hydrochloride; Pyr tine Maleate: FluproduaZone: Fluradoline Hydrochloride; rocaine: Risocaine; Rodocaine; Roflurane; Salicyl Alcohol: Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: Sevoflurane; Teflurane; Tetracaine; Tetracaine Hydrochlo Indoprofen; Ketazocine; Ketorfanol: Ketorolac ride; Thiamylal; Thiamylal Sodium; Thiopental Sodium; Tromethamine: Letimide Hydrochloride; Levomethadyl Tiletamine Hydrochloride; Zolamine Hydrochloride. Acetate; Levomethadyl Acetate Hydrochloride; Levonant radol Hydrochloride; Levorphanol Tartrate; Lofemizole 0090 Anorectic compounds including: Dexfenfluramine. Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxi 0091 Anorexic agents: Aminorex: Amphecloral; Chlor cam: Magnesium Salicylate; Mefenamic Acid; Menabitan phentermine Hydrochloride; Clominorex; Clortermine Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Diethylpropion Hydrochloride: Fenflu Hydrochloride; Methadone Hydrochloride; Methadyl ramine Hydrochloride; Fenisorex: Fludorex: Fluminorex: Acetate; Methopholine; Methotrimeprazine; Metkephamid Levamfetamine Succinate; Mazindol; Mefenorex Hydro Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo chloride; Phemnetrazine Hydrochloride; Phentermine: ride; MolinaZone: Morphine Sulfate; Moxazocine; Nabitan Sibutramine Hydrochloride. Hydrochloride; Nalbuphine Hydrochloride; Nalmexone 0092 Antagonist: Atipamezole; Atosiban; Bosentan; Hydrochloride: Namoxyrate; Nantradol Hydrochloride: Cimetidine: Cimetidine Hydrochloride; Clentiazem Male Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro ate; Detirelix Acetate; Devazepide; Donetidine: Etintidine chloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Famotidine: Fenmetozole Hydrochloride: Hydrochloride; Ocfentanil Hydrochloride; Octazamide: Flumazenil; Icatibant Acetate: Icotidine; Isradipine; Metia Olvanil; Oxetorone Fumarate; Oxycodone: Oxycodone mide: Nadide; Nalmefene; Naloxone Hydrochloride; Naltr Hydrochloride: Oxycodone Terephthalate: Oxymorphone exone; Nilvadipine; Oxilorphan: Oxmetidine Hydrochlo Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; ride; Oxmetidine Mesylate; Quadazocine Mesylate: Pentazocine Hydrochloride: Pentazocine Lactate; Ranitidine: Ranitidine Bismuth Citrate; Ranitidine Hydro Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo chloride; Sufotidine; Teludipine Hydrochloride; Tiapamil ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Hydrochloride; Tiotidine: Vapiprost Hydrochloride; Zalti Piroxicam Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol Hydrochloride; Propiram Fuma dine Hydrochloride. rate; Propoxyphene Hydrochloride; Propoxyphene Napsy 0093 Anterior pituitary activator: Epimestrol. late: Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyrroliphene Hydrochloride: Remifentanil Hydrochloride: 0094) Anterior pituitary suppressant: Danazol. Salcolex: Salicylamide: Salicylate Meglumine; Salsalate: 0095 Anthelmintic: Albendazole; Anthelmycin; Bro Sodium Salicylate: Spiradoline Mesylate: Sufentanil; Sufen moxanide; Bunamidine Hydrochloride: Butonate; Cam tanil Citrate; Talmetacin; Talniflumate; Talosalate; Tazad bendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel: olene Succinate; Tebufelone; Tetrydamine; Tifurac Sodium; Cyclobendazole; Dichlorvos; Diethylcarbamazine Citrate; Tilidine Hydrochloride; Tiopinac; Tonazocine Mesylate: Dribendazole; Dymanthine Hydrochloride: Etibendazole; US 2007/0269379 A1 Nov. 22, 2007

Fenbendazole; Furodazole: Hexylresorcinol; Mebendazole; Sodium; Enofelast; Isamoxole; Ketotifen Fumarate; Levcro Morantel Tartrate; Niclosamide: Nitramisole Hydrochloride: makalim; Lodoxamide Ethyl, Lodoxamide Tromethamine; Nitrodan: Oxantel Pamoate; Oxfendazole; Oxibendazole; Montelukast Sodium; Ontazolast: Oxarbazole; Oxatomide: Parbendazole; Piperamide Maleate; piperazine; piperazine Piriprost: Piriprost Potassium; Pirolate: Pobilukast Edamine: Citrate; piperazine Edetate Calcium; Proclonol; Pyrantel QuaZolast; Ritolukast; Sulukast; Tiaramide Hydrochloride: Pamoate: Pyrantel Tartrate; Pyrvinium Pamoate; Rafox Tibenelast Sodium; Tomelukast; Tranilast; Verlukast; Ver anide; Stilbazium Iodide; Tetramisole Hydrochloride; Thia ofylline Zarirlukast. bendazole; Ticarbodine: Tioxidazole; Triclofenol pipera 0106 Anti-atherosclerotic: Mifobate; Timefuronc. Zine; Vincofos; Zilantel. 0.107 Antibacterial: Acedapsone; Acetosulfone Sodium; 0.096 Anti-acne: Adapalene; Erythromycin Salnacedin; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil, Inocoterone Acetate. Amicycline; Amifioxacin; Amifloxacin Mesylate; Amika 0097 Anti-adrenergic: Acebutolol; Alprenolol Hydro cin; Amikacin Sulfate; Aminosalicylate Sodium; Aminosali chloride: Atenolol; Bretylium Tosylate: Bunolol Hydrochlo cylic acid; Amoxicillin; Amphomycin; Ampicillin; Ampicil ride; Carteolol Hydrochloride: Celiprolol Hydrochloride; lin Sodium; Apalcillin Sodium; Apramycin; Aspartocin, Cetamolol Hydrochloride: Cicloprolol Hydrochloride; Dex Astromicin Sulfate, Avilamycin; Avoparcin, Azithromycin; propranolol Hydrochloride; Diacetolol Hydrochloride; Azlocillin: Azlocillin Sodium; Bacampicillin Hydrochlo Dihydroergotamine Mesylate; Dilevalol Hydrochloride: ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci Esmolol Hydrochloride; Exaprolol Hydrochloride: Fen tracin Zinc: Bambermycins; Benzoylpas Calcium: Betami spiride Hydrochloride; Flestolol Sulfate; Labetalol Hydro cin Sulfate; Biapenem; Biniramycin; Bispyrithione chloride; Levobetaxolol Hydrochloride; Levobunolol Magsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sul Hydrochloride; Metalol Hydrochloride; Metoprolol; Meto fate; Carbadox; Carbenicillin Disodium; Carbenicillin Inda prolol Tartrate; Nadolol; Pamatolol Sulfate; Penbutolol Sul nyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin fate; Phentolamine Mesylate: Practolol; Propranolol Hydro Potassium; Carumonam Sodium; Cefaclor, Cefadroxil, chloride; Proroxan Hydrochloride; Solypertine Tartrate; Cefamandole; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Sotalol Hydrochloride; Timolol; Timolol Maleate; Tipre Cefazolin Sodium; CefbuperaZone; Cefdinir, Cefepime: nolol Hydrochloride; Tolamolol; Zolertine Hydrochloride. Cefepime Hydrochloride: Cefetecol; Cefixime; Cef 0.098 Anti-allergic: Amlexanox; Astemizole; Azelastine menoxime Hydrochloride; Cefnmetazole; Cefnmetazole Hydrochloride; EclaZolast; Minocromil Nedocromil Sodium; Cefonicid Monosodium; Cefonicid Sodium; Nedocromil Calcium; Nedocromil Sodium; Nivinedone CefoperaZone Sodium; Ceforanide; Cefotaxime Sodium; Sodium; Pemirolast Potassium Pentigetide; Pirquinozol; Cefotetan: Cefotetan Disodium; Cefotiam Hydrochloride: Poisonoak Extract; Probicromil Calcium; ProXicromil: Cefoxitin: Cefoxitin Sodium; Ce?pimizole; Ce?pimizole Repirinast; Tetrazolast Meglumine: Thiazinamium Chlo Sodium; Ce?piramide; Ce?piramide Sodium; Ce?pirome Sul ride; Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; fate; Cefpodoxime Proxetil: Cefprozil; Cefroxadine: Cefsu TixanoX. lodin Sodium; Ceftazidime; Ceftibuten; Ceftiroxime Pivox 0099 Anti-amebic: Berythromycin; Bialamicol Hydro etil: Ceftizoxime Sodium; Ceftriaxone Sodium; chloride; Chloroquine; Chloroquine Hydrochloride; Chloro Cefuroxime; Cefuroxime Axetil: Cefuroxime Sodium; quine Phosphate; Clamoxyquin Hydrochloride; Clioquinol; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochlo Emetine Hydrochloride: Iodoquinol; Paromomycin Sulfate: ride; Cephaloglycin; Cephaloridine; Cephalothin Sodium; Quinfamide: Symetine Hydrochloride; Teclozan; Tetracy Cephapirin Sodium; Cephradine; Cetocycline Hydrochlo cline; Tetracycline Hydrochloride. ride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex: 0100 Anti-androgen: Benorterone: Cioteronel; Cyproter Chloramphenicol Sodium Succinate; Chlorhexidine Phos one Acetate; Delmadinone Acetate; Oxendolone; Topterone: phanilate; Chloroxylenol; Chlortetracycline Bisulfate; Chlo Zanoterone. rtetracycline Hydrochloride; Cinoxacin: Ciprofloxacin: 0101 Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Ciprofloxacin Hydrochloride: Cirolemycin; Clarithromycin; Sulfate, Dried; Leucovorin Calcium. Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride: 0102) Anti-anginal: Amlodipine Besylate: Amlodipine Clindamycin Phosphate; Clofazimine; Cloxacillin Benza Maleate; Betaxolol Hydrochloride; Bevantolol Hydrochlo thine; Cloxacillin Sodium; Cloxyquin; Colistimethate ride; Butoprozine Hydrochloride; Carvedilol; Cinepazet Sodium; Colistin Sulfate; Coumermycin; Coumermycin Maleate; Metoprolol Succinate; Molsidomine; Monatepil Sodium; Cyclacillin: Cycloserine; Dalfopristin; Dapsone; Maleate; Primidolol; Ranolazine Hydrochloride; Tosifen; Daptomycin; Demeclocycline; Demeclocycline Hydrochlo Verapamil Hydrochloride. ride; Demecycline; Denofingin: Diaveridine; Dicloxacillin; 0103 Anti-anxiety agent: Adatanserin Hydrochloride: Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipy Alpidem; Binospirone Mesylate: Bretazenil; Glemanserin; rithione; Dirithromycin; Doxycycline; Doxycycline Cal Ipsapirone Hydrochloride; Mirisetron Maleate; Ocinaplon; cium; Doxycycline Fosfatex: Doxycycline Hyclate; Droxa Ondansetron Hydrochloride; Panadiplon; Pancopride; Pazi cin Sodium: Enoxacin; Epicillin: Epitetracycline naclone; Serazapine Hydrochloride; Tandospirone Citrate; Hydrochloride; Erythromycin; Erythromycin Acistrate; Zalospirone Hydrochloride. Erythromycin Estolate; Erythromycin Ethylsuccinate: Erythromycin Gluceptate; Erythromycin Lactobionate: 0104 Anti-arthritic: Lodelaben. Erythromycin Propionate; Erythromycin Stearate; Etham 0105 Anti-asthmatic: Ablukast; Ablukast Sodium; butol Hydrochloride; Ethionamide: Fleroxacin; Floxacillin; Bunaprolast; Cinalukast; Cromitrile Sodium; Cromolyn Fludalanine: Flumequine; Fosfomycin; Fosfomycin US 2007/0269379 A1 Nov. 22, 2007

Tromethamine; Fumoxicillin; Furazolium Chloride; Furazo Trisulfapyrimidines; Troleandomycin; Trospectomycin Sul lium Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin fate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride: Sulfate: Gloximonam; Gramicidin; Haloprogin: Hetacillin; Virginiamycin; Zorbamycin. Hetacillin Potassium: Hexedine; Ibafloxacin: Imipenem: 0.108 Anti-cancer Supplementary potentiating agents: Isepamicin; Isoconazole; Isoniazid; Josamycin; Kanamycin Amitryptyline; Amoxapine; Amphotericin B; Antiarrhyth Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin mic drugs (e.g., Quinidine); Antihypertensive drugs (e.g., Potassium; Lexithromycin; Lincomycin; Lincomycin Reserpine); Ca++ antagonists (e.g., Verapamil; Calmodulin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochlo inhibitors (e.g., Prenylamine; Caroverine); Citalopram); ride; Lomefloxacin Mesylate: Loracarbef: Mafenide; Meclo Clomipramine; Clomipramine); Desipramine; Doxepin; cycline; Meclocycline Sulfosalicylate; Megalomicin Potas Maprotiline); Nifedipine; Nitrendipine; Non-tricyclic anti sium Phosphate; Mequidox: Meropenem; Methacycline: depressant drugs (e.g., Sertraline; Nortriptyline; Protrip Methacycline Hydrochloride; Methenamine; Methenanine tyline; Sulfoximine) and Multiple Drug Resistance reducing Hippurate; Methenamine Mandelate; Methicillin Sodium; agents such as Cremaphor EL. Thiol depleters (e.g., Metioprim; Metronidazole Hydrochloride; Metronidazole Buthionine; Trazodone; Tricyclic anti-depressant drugs Phosphate: Mezlocillin: Mezlocillin Sodium; Minocycline: (e.g., Imipramine; Trifluoroperazine; Trimipramine; Tripara Minocycline Hydrochloride; Mirincamycin Hydrochloride: nol analogues (e.g., Tamoxifen). Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate 0109) Anticholelithic: Monoctanoin. Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomy cin Palmitate; Neomycin Sulfate; Neomycin Undecylenate: 0110 Anticholelithogenic: Chenodiol; Ursodiol. Netilmicin Sulfate; Neutramycin; Nifarthiazole; 0.111) Anticholinergic: Alverinc Citrate; Anisotropine Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone; Methylbromide: Atropine; Atropine Oxide Hydrochloride: Nifuirdazil; Nifurimide: Nifurpirinol; Nifurcquinazol; Nitro Atropine Sulfate; Belladonna; Benapryzine Hydrochloride; cycline; Nitrofurantoin: Nitromide: Norfloxacin; Novobio Benzetimide Hydrochloride; Benzilonium Bromide: cin Sodium; Ofloxacin: Onnetoprim: Oxacillin Sodium; Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Cli Oximonam. Oximonam Sodium; Oxolinic Acid: Oxytetra dinium Bromide: Cyclopentolate Hydrochloride; Dexetim cycline; Oxytetracycline Calcium; Oxytetracycline Hydro ide; Dicyclomine Hydrochloride; Dilhexy verine Hydrochlo chloride; Paldimycin; Parachlorophenol; Paulomycin; ride; Domazoline Fumarate; Elantrine; Elucaine; Pefloxacin: Pefloxacin Mesylate: Penamecillin: Penicillin G Ethybenztropine; Eucatropine Hydrochloride; Glycopyrro BenZathine; Penicillin G Potassium; Penicillin G Procaine; late: Heteronium Bromide: Homatropine Hydrobromide: Penicillin G Sodium; Penicillin V: Penicillin V BenZathine; Homatropine Methylbromide; Hyoscyamine; Hyoscyamine Penicillin V Hydrabamine: Penicillin V Potassium; Pentizi Hydrobromide; Hyoscyamine Sulfate; Isopropamide Iodide: done Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; Mepenzolate Bromide: Methylatropine Nitrate; Meto quizine: Oxybutynin Chloride; Parapenzolate Bromide: Pen Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin tapiperium Methylsulfate; Phencarbamide: Poldine Methyl Hydrochloride: Pivampicillin Hydrochloride: Pivampicillin sulfate; Proglumide: Propantheline Bromide: Propenzolate Pamoate: Pivampicillin Probenate; Polymyxin B Sulfate: Hydrochloride; Scopolamine Hydrobromide: Tematropium Porfiromycin; Propikacin; Pyrazinamide: Pyrithione Zinc; Methylsulfate; Tiquinamide Hydrochloride; Tofenacin Quindecamine Acetate; Quinupristin, Racephenicol; Hydrochloride; Toquizine; TriampyZine Sulfate; Trihex Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabu yphenidyl Hydrochloride; Tropicamide. tin; Rifametane; Rifamexil; Rifamide: Rifampin; Rifapen tine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; 0112 Anticoagulant: Ancrod; Ardeparin Sodium; Biva Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propi lirudin; Bromindione; Dalteparin Sodium Desirudin; Dicu onate; Rosaramicin Sodium Phosphate; Rosaramicin Stear marol; Lyapolate Sodium; Nafamo.stat Mesylate; Phenproc ate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; oumon; Tinzaparin Sodium; Warfarin Sodium. Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafun 0113 Anticoccidal: Maduramicin. gin, Sisomicin; Sisomicin Sulfate; Sparfloxacin; Spectino mycin Hydrochloride: Spiramycin; Stallimycin Hydrochlo 0.114) Anticonvulsant: Albutoin: Ameltolide: Atolide; ride; Steflimycin; Streptomycin Sulfate; Streptonicozid: Buramate; Cinromide, Citenamide; Clonazepam; Cyhepta mide; Dezinamide: Dimethadione; Divalproex Sodium; Sulfabenz; Sulfabenzamide; Sulfacetamide; Sulfacetamide Eterobarb; Ethosuximide: Ethotoin: Flurazepam Hydrochlo Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; ride; Fluzinamide; Fosphenyloin Sodium; Gabapentin; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sul Ilepcimide; Lamotrigine; Magnesium Sulfate; Mepheny famethazine; Sulfamethizole; Sulfamethoxazole; Sulfa loin; Mephobarbital; Methetoin: Methsuximide: Milace monomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanit mide Hydrochloride; Nabazenil; Nafimidone Hydrochlo ran, Sulfasalazine; Sulfasomizole; Sulfathiazole; ride; Nitrazepam; Phenacemide: Phenobarbital; Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisox Phenobarbital Sodium; Phensuximide; Phenyloin; Pheny azole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; loin Sodium; Primidone; Progabide; Ralitoline; Remace Suncillin Sodium; Talampicillin Hydrochloride; Teicopla mide Hydrochloride; Ropizine: Sabeluzole; Stiripentol; nin; Temafloxacin Hydrochloride; Temocillin; Tetracycline Sulthiame: Topiramate; Trimethadione; Valproate Sodium; Phosphate Complex; Tetroxoprim; Thiamphenicol; Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticar Zonisamide. cillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodo nium Chloride; Tobramycin; Tobramycin Sulfate; Tosu 0115) Antidepressant: Adinazolam; Adinazolam Mesy floxacin: Trimethoprim; Trimethoprim Sulfate; late: Alaproclate: Aletamine Hydrochloride; Amedalin US 2007/0269379 A1 Nov. 22, 2007

Hydrochloride; Amitriptyline Hydrochloride: Aptazapine promazine; Chlorpromazine Hydrochloride; Clebopride; Maleate; AZaloxan Fumarate; AZepindole; AZipramine Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Hydrochloride; Bipenamol Hydrochloride; Bupropion Diphenidol Hydrochloride; Diphenidol Pamoate; Dolas Hydrochloride; Butriptyline Hydrochloride; Caroxazone: etron Mesylate; Domperidone; Dronabinol; Flumeridone: Cartazolate: Ciclazindol; Cidoxepin Hydrochloride: Cilo Galdansetron Hydrochloride; Granisetron; Granisetron bamine Mesylate; Clodazon Hydrochloride; Clomipramine Hydrochloride: Lurosetron Mesylate; Meclizine Hydrochlo Hydrochloride; Cotinine Fumarate; Cyclindole; Cype ride; Metoclopramide Hydrochloride; Metopimazine; namine Hydrochloride: Cyprolidol Hydrochloride; Cyprox Prochlorperazine: Prochlorperazine Edisylate: Prochlor imide; Daledalin Tosylate; Dapoxetine Hydrochloride: perazine Maleate; Promethazine Hydrochloride; Thiethylp Dazadrol Maleate; Dazepinil Hydrochloride: Desipramine erazine; Thiethylperazine Malate: Thiethylperazine Male Hydrochloride; Dexamisole; Deximafen; Dibenzepin ate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydro Hydrochloride. chloride; Doxepin Hydrochloride; Duloxetine Hydrochlo ride; Eclanamine Maleate; Encyprate; Etoperidone Hydro 0.122 Anti-epileptic: Felbanate; lamotrigine; Lore chloride; Fantridone Hydrochloride: Femmetramide: clezole; Tolgabide. Fezolamine Fumarate: Fluotracen Hydrochloride: Fluoxet 0123 Anti-estrogen: Clometherone; Nafoxidine Hydro ine: Fluoxetine Hydrochloride: Fluparoxan Hydrochloride: chloride; Nitromifene Citrate; Raloxifene Hydrochloride: Gamfexine; Guanoxyfen Sulfate: Imafen Hydrochloride: Tamoxifen Citrate; Toremifene Citrate; Trioxifene Mesylate. Imiloxan Hydrochloride: Imipramine Hydrochloride; Inde 0.124 Antifibrinolytic: Nafamostat Mesylate. loxazine Hydrochloride; Intriptyline Hydrochloride; Iprin dole; Isocarboxazid; Ketipramine Fumarate; Lofepramine 0.125 Antifungal: Acrisorcin; Ambruticin; AZaconazole; Hydrochloride; Lortalamine: Maprotiline: Maprotiline AZaserine; Basifungin: Bifonazole; Butoconazole Nitrate; Hydrochloride; Melitracen Hydrochloride; Minaprine Calcium Undecylenate; Candicidin; Carbol-Fuchsin; Chlo Hydrochloride; Mirtazapine: Moclobemide: Modaline Sul rdantoin: Ciclopirox: Ciclopirox Olamine: Cilofungin; fate; Napactadine Hydrochloride; Napamezole Hydrochlo Cisconazole; Clotrimazole; Cuprimyxin; Doconazole; ride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam Econazole; Econazole Nitrate; Enilconazole; Ethonam Hydrochloride: Nomifensine Maleate; Nortriptyline Hydro Nitrate: Fenticonazole Nitrate; Filipin: Fluconazole: Flucy chloride; Octriptyline Phosphate; Opipramol Hydrochlo tosine; Fungimycin; Griseofulvin; Hamycin, Itraconazole; ride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Kalafungin; Ketoconazole; Lomoftmgin; Lydimycin; Phenelzine Sulfate; Pirandamine Hydrochloride: Pridefine Mepartricin; Miconazole; Miconazole Nitrate; Monensin; Hydrochloride; Prolintane Hydrochloride: Protriptyline Monensin Sodium; Naftifine Hydrochloride; Nifuratel Hydrochloride: Quipazine Maleate; Rolicyprine; Seproxet Nifurmerone; Nitralamine Hydrochloride; Nystatin: ine Hydrochloride: Sertraline Hydrochloride: Sulpiride: Octanoic Acid, Orconazole Nitrate; Oxiconazole Nitrate; Suritozole; Tametraline Hydrochloride; Tampramine Fuma Oxifingin Hydrochloride; Parconazole Hydrochloride; Par rate; Tandamine Hydrochloride; Thiazesim Hydrochloride; tricin; Potassium Iodide; Pyrrolnitrin; Rutamycin; Sangui Thozalinone; Tomoxetine Hydrochloride; Trazodone narium Chloride; Saperconazole: Selenium Sulfide: Sinef Hydrochloride; Trebenzomine Hydrochloride; Trimi ingin: Sulconazole Nitrate; Terbinafine; Terconazole; pramine Maleate; Venlafaxine Hydrochloride; Viloxazine Thiram; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Tri Hydrochloride; Zimeldine Hydrochloride; Zometapine. acetin: Triafungin: Undecylenic Acid; Viridofulvin; Zinc 0116. Antidiabetic: Acetohexamide: Buformin; Butox Undecylenate; Zinoconazole Hydrochloride. amine Hydrochloride; Camighbose; Chlorpropamide: Cigli 0.126 Antiglaucoma agent: Alprenoxime Hydrochloride: taZone; Englitazone Sodium; Etoformin Hydrochloride; Colforsin; Dipivefrin Hydrochloride; Naboctate Hydrochlo Gliamilide; Glibomuride; Glicetanile Sodium; Gliflumide: ride; Pilocarpine; Pimabine. Glipizide. Glucagon; Glyburide; Glyhexamide: Glymidine 0.127) Antihemorrhagic: Poliglusam. Sodium; Glyoctamide: Glyparamide: Insulin; Insulin Human; Insulin Human Zinc, Insulin Human Zinc, 0.128 Antihemorrheologic: Phentoxifylline. Extended; Insulin Human, Isophane; Insulin Lispro; Insulin 0129. Antihistaminic: Acrivastine; Antazoline Phos Zinc: Insulin Zinc, Extended; Insulin Zinc, Prompt; Insulin, phate: AZatadine Maleate; Barmastine; Bromodiphenhy Dalanated; Insulin, Isophane; Insulin, Neutral; Linogliride; dramine Hydrochloride; Brompheniramine Maleate; Carbi Linogliride Fumarate; Metformin; Methyl Palmoxirate; Pal noxamine Maleate; Cetirizine Hydrochloride: moxirate Sodium; Pioglitazone Hydrochloride; Pirogliride Chlorpheniramine Maleate; Chlorpheniramine Polistirex: Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide: Cirmarizine; Clemastine; Clemastine Fumarate; Closir Tolbutamide; Tolpyrramide; Troglitazone; Zopolrestat. amine Aceturate; Cycliramine Maleate; Cyclizine; Cypro 0117 Antidiarrheal: Diphenoxylate Hydrochloride: heptadine Hydrochloride; Dexbrompheniramine Maleate; Methylprednisolone; Metronidazole; Rolgamidine. Dexchlorpheniramine Maleate; Dimethindene Maleate; 0118 Antidiuretic: Argipressin Tannate; Desmopressin Diphenhydramine Citrate; Diphenhydramine Hydrochlo Acetate; Lypressin. ride; Dorastine Hydrochloride; Doxylamine Succinate; Ebastine; Fexofenadine HCl; Levocabastine Hydrochloride: 0119) Antidote: Dimercaprol; Edrophonium Chloride: Loratadine: Mianserin Hydrochloride; Noberastine: Fomepizole; Levoleucovorin Calcium; Methylene Blue: Orphenadrine Citrate; Pyrabrom: Pyrilamine Maleate; Protamine Sulfate. Pyroxamine Maleate; Rocastine Hydrochloride; Rotoxam 0120 Antidyskinetic: Selegiline Hydrochloride. ine: Tazifylline Hydrochloride; Temelastine; Terfenadine: 0121 Anti-emetic: Alosetron Hydrochloride; Batano Tripelennamine Citrate; Tripelennamine Hydrochloride: pride Hydrochloride: Bemesetron; Benzquinamide; Chlor Triprolidine Hydrochloride. US 2007/0269379 A1 Nov. 22, 2007

0130 Antihyperlipidemic: Cholestyramine Resin; Clofi 0.135 Anti-infective, topical: Alcohol; Aminacrine brate; Colestipol Hydrochloride; Crilvastatin: Dalvastatin: Hydrochloride; Benzethonium Chloride; Bithionolate Dextrothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Sodium; Bromchlorenone; Carbamide Peroxide; Cetalko Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Probu nium Chloride; Cetylpyridinium Chloride; Chlorhexidine col; Simvastatin; Tiqueside; Xenbucin. Hydrochloride; Domiphen Bromide: Fenticlor: Fludazo 0131) Antihyperlipoproteinemic: Acifran; Beloxamide: nium Chloride; Fuchsin, Basic; Furazolidone; Gentian Vio Bezafibrate; Boxidine; Cetaben Sodium: Ciprofibrate; Gem let; Halquinols: Hexachlorophene; Hydrogen Peroxide: Ich cadiol; Halofenate; Lifibrate; Meglutol; Nafenopin; Pimet thammol: Imidecyl Iodine: Iodine: Isopropyl Alcohol: ine Hydrochloride; Theofibrate; Tibric Acid; Treloxinate. Mafenide Acetate; Meralcin Sodium; Mercufenol Chloride; 0132) Antihypertensive: Alfuzosin Hydrochloride; Alipa Mercury, Ammoniated; Methylbenzethonium Chloride: mide: Althiazide; Amiquinsin Hydrochloride; Anaritide Nitrofarazone; Nitromersol; Octenidine Hydrochloride; Acetate; Atiprosin Maleate; Belfosdil; Bemitradine; Benda Oxychlorosene: Oxychlorosene Sodium; Parachlorophenol, calol Mesylate; Bendroflumethiazide; Benzthiazide: Camphorated; Potassium Permanganate; Povidone-Iodine: Bethanidine Sulfate; Biclodil Hydrochloride; Bisoprolol; Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupico Symclosene: Thimerfonate Sodium; Thimerosal; Troclosene mide: Buthiazide: Candoxat rilat; Candoxatril; Captopril; Potassium. Ceronapril; Chlorothiazide Sodium: Cicletanine: Cilazapril; Clonidine; Clonidine Hydrochloride; Clopamide: Cyclo 0.136 Anti-inflammatory: Alclofenac; Alclometasone penthiazide: Cyclothiazide; Darodipine; Debrisoquin Sul Dipropionate; Algestone Acetonide; Alpha Amylase; fate; Delapril Hydrochloride; Diapamide: Diazoxide; Dilt Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose iazem Hydrochloride; Diltiazem Malate; Ditekiren: Hydrochloride; Anakinra; Anitrazafen; Apazone; Bal Doxazosin Mesylate; Ecadotril: Enalapril Maleate; Enalap salazide Disodium; Bendazac. Bromelains; Broperamole; rilat; Enalkiren: Endralazine Mesylate: Epithiazide: Eprosa Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; rtan; Eprosartan Mesylate: Fenoldopam Mesylate: Fla Clobetasol Propionate; Clobetasone Butyrate; Clopirac: vodilol Maleate: Flordipine: Flosequinan; Fosinopril Cloticasone Propionate; Cormethasone Acetate; Cortodox Sodium; Fosinoprilat; Guanabenz: Guanabenz. Acetate; one; Deflazacort; Desonide; Desoximetasone; Dexametha Guanacline Sulfate; Guanadrel Sulfate; Guancvdine; sone Dipropionate; Diclofenac Potassium; Diclofenac Guanethidine Monosulfate; Guanethidine Sulfate; Guanfa Sodium; Diflorasone Diacetate; Diflumidone Sodium; Dif cine Hydrochloride; Guanisoquin Sulfate; Guanoclor Sul luprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; fate; Guanoctine Hydrochloride; Guanoxabenz: Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride: Endrysone; Enlimomab: Enolicam Sodium; Etodolac; Fel Hydralazine Polistirex; Hydroflumethiazide; Indacrinone binac; Fenamole: Fenbufen, Fenclofenac; Fenclorac, Fen Indapamide: Indolapril Hydrochloride; Indoramin; dosal: Fenpipalone: Fentiazac. Flazalone: Fluazacort: Flufe Indoramin Hydrochloride; Indorenate Hydrochloride: Laci namic Acid, Flumizole; Flunisolide Acetate; Fluocortin dipine; Leniquinsin; Lisinopril; Lofexidine Hydrochloride; Butyl; Fluorometholone Acetate: FluquaZone: Fluretofen; Losartan Potassium; Losulazine Hydrochloride; Meb Fluticasone Propionate; Furaprofen; Furobufen; Halcinon utamate; Mecamylamine Hydrochloride; Medroxalol; ide; Halobetasol Propionate; Halopredone Acetate; Ibupro Medroxalol Hydrochloride; Methalthiazide Methyclothiaz fen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap: ide Methyldopa; Methyldopate Hydrochloride; Metipra indomethacin Sodium; Indomethacin; Indoprofen Indoxole; nolol; Metolazone Metoprolol Fumarate; Metyrosine; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Keto Minoxidil; Muzolimine; Nebivolol; Nifidipine; Oformine: profen; Lomoxicam; Loteprednol Etabonate; Meclofe Pargyline Hydrochloride; Pazoxide: Pelanserin Hydrochlo namate Sodium; Meclofenamic Acid; Meclorisonc Dibu ride; Perindopril Erbumine; Phenoxybenzamine Hydrochlo tyrate; Mesalamine: Meseclazone; Methylprednisolone ride; Pinacidil: Pivopril; Polythiazide; Prazosin Hydrochlo Suleptanate; Morniflumate; Nabumetone; Nimazone: ride; Prizidilol Hydrochloride: Quinapril Hydrochloride; Olsalazine Sodium; Orgotein; Orpanoxin: Oxaprozin; Quinaprilat; Quinazosin Hydrochloride: Quinelorane Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Hydrochloride: Quinpirole Hydrochloride: Quinuclium Bro Polysulfate Sodium; Phenbutazone Sodium Glycerate; mide: Ramipril; Rauwolfia Serpentina; Reserpine; Saprisar Piroxicam, Piroxicam Cinnamate; Pirprofen; Prednazate: tan Potassium; Saralasin Acetate; Sodium Nitroprusside; Prednisolone Sodium Phosphate: Prifelone; Prodolic Acid: Sulfinalol Hydrochloride; Tasosartan; Temocapril Hydro ProquaZone: Rimexolone; Romazarit; Salnacedin; Secla chloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine: Zone: Sermetacin; Sudoxicam; Sulindac: Suprofen; Talni Tiamenidine Hydrochloride; Ticrynafen; Tinabinol; Tioda flumate; Tenidap; Tenidap Sodium, Tenoxicam, Tesicam, Zosin; Tipentosin Hydrochloride; Trichlormethiazide; Tri mazosin Hydrochloride; Trimethaphan Camsylate: Trimox Tesimide; Tixocortol Pivalate; Tolimetin; Tolimetin Sodium; amine Hydrochloride; Tripamide; Xipamide: Zankiren Triclonide; Triflumidate; Zidometacin. Hydrochloride; Zofenoprilat Arginine. 0.137 Antikeratinizing agent: Doretinel; Linarotene: Pel 0.133 Antihypotensive: Ciclafrine Hydrochloride; Mido retin. drine Hydrochloride. 0.138 Antimalarial: Amodiaquine Hydrochloride: 0134) Anti-infective: Acyclovir; Difloxacin Hydrochlo Amquinate; Artefiene; Chloroquine; Chloroquine Hydro ride; Integrase Inhibitors of HIV and other retroviruses: chloride: Cycloguanil Pamoate; Enpiroline Phosphate: Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Halofantrine Hydrochloride; Hydroxychloroquine Sulfate: Ornidazole; Pentisomicin; Protease inhibitors of HIV and Mefloquine Hydrochloride: Menoctone: Primaquine Phos other retroviruses; Sarafloxacin Hydrochloride. phate: Pyrimethamine; Quinine Sulfate; Tebuquine. US 2007/0269379 A1 Nov. 22, 2007

0139 Antimicrobial: Aztreonam; Chlorhexidine Glucon Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubu ate, Imidurea; Lycetamine; Nibroxane: PiraZmonam lozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide: Sodium; Propionic Acid; Pyrithione Sodium; Tigemonam Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vin Dicholine. desine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosi 0140 Antimigraine: Naratriptan Hydrochloride: Sergo dine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin: lexole Maleate; Sumatriptan Succinate; Zatosetron Maleate. Zinostatin: Zorubicin Hydrochloride. 0141 Antimitotic: Podofilox. 0145 Anti-neoplastic compounds, additional: 20-epi-1, 0142 Antimycotic: Amorolfine. 25 Dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone: Acylfulvene; Adecypenol; ALL-TK Antagonists; Ambam 0143 Antinauseant: Buclizine Hydrochloride: Cyclizine ustine; Amidox: Amifostine; Aminolevulinic Acid, Amrubi Lactate. cin; Anagrelide; Andrographolide; Angiogenesis Inhibitors; 0144 Antineoplastic: Acivicin; Aclarubicin; Acodazole Antagonist D. Antagonist G.; Antarelix; Antiandrogen, Pro Hydrochloride: Acronine; Adozelesin; Aldesleukin; Altre static Carcinoma; Anti-Dorsalizing Morphogenetic Protein tamine; Ambomycin; Ametantrone Acetate; Amsacrine; 1; Antiestrogen; Antineoplaston; Antisense Oligonucle AnastroZole; Anthramycin; Asparaginase; Asperlin, AZaciti otides: Aphidicolin Glycinate: Apoptosis Gene Modulators: dine; AZetepa, Azotomycin; Batimastat; BenZodepa; Apoptosis Regulators: Apurinic Acid; Ara-CDP-DL-PTBA: Bicalutamide: Bisantrene Hydrochloride; Bisnafide Dime Arginine Deaminase; ASulacrine; AtameStane; Atrimustine; sylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Axinastatin 1: Axinastatin 2: AXinastatin 3: AZasetron; AZa Bropirimine; BuSulfan; Cactinomycin; Calusterone; Carace toxin; AZatyrosine; Baccatin III Derivatives; Balanol; BCR/ mide: Carbetimer; Carboplatin: Carmustine; Carubicin ABL Antagonists; BenZochlorins; Benzoylstaurosporine; Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cis Beta Lactam Derivatives: Beta-Alethine; Betaclamycin B; platin: Cladribine; Crisinatol Mesylate: Cyclophosphamide: Betulinic Acid; bFGF Inhibitor; Bisantrene; Bisaziridinyl Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin spermine; Bisnafide; Bistratene A; Breflate; Budotitane: Hydrochloride; Decitabine; Dexorinaplatin: Dezaguanine: Buthionine Sulfoximine; Calcipotriol: Calphostin C; Camp Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubi tothecin Derivatives; Canarypox IL-2; Capecitabine; Car cin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene boxamide-Amino-Triazole; Carboxyamidotriazole; CaRest Citrate; Dromostanolone Propionate; Duazomycin; Edatrex MI; CARN 700, Cartilage Derived Inhibitor; Casein Kinase ate: Eflornithine Hydrochloride; Elsamitrucin: Enloplatin: Inhibitors (ICOS); Castanospermine; Cecropin B; Enpromate: Epipropidine: Epirubicin Hydrochloride; Erbu Cetrorelix; Chlorins; Chloroquinoxaline Sulfonamide: Cica lozole; Esorubicin Hydrochloride; Estramustine; Estramus prost; Cis-Porphyrin, Clomifene analogues; Collismycin A; tine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Collismycin B: Combretastatin A4; Combretastatin Ana Etoposide; Etoposide Phosphate; Etoprine; Fadrozole logue; Conagenin; Crambescidin 816: Crisinatol; Cryptophy Hydrochloride; Fazarabine; Fenretinide; Floxuridine: Flu cin 8: Cryptophycin A Derivatives; Curacin A; Cyclopen darabine Phosphate: Fluorouracil; Fluorocitabine; Fosqui tanthraquinones; Cycloplatam; Cypemycin; Cytarabine done; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydro Ocfosfate; Cytolytic Factor; Cytostatin: Dacliximab: Dehy chloride; Gold Au 198: Hydroxyurea; Idarubicin drodidenmin B: Dexifosfamide; DexVerapamil: Didemnin Hydrochloride: Ifosfamide: Ilmofosine; Interferon Alfa-2a: B: Didox; Diethylnorspennine; Dihydro AZacytidine; Dihy Interferon Alfa-2b: Interferon Alfa-n3; Interferon Alfa-n1; drotaxol. 9-; Dioxamycin; Diphenyl Spiromustine: Interferon Beta-Ia, Interferon Gamma-Ib; I proplatin; Irino Docosanol; Dolasetron; Doxifluridine; Duocarmycin SA: tecan Hydrochloride; Isotretinoin; Lanreotide Acetate; Ebselen; Ecomustine; Edelfosine; Edrecolomab, Eflomith Letrozole; Leuprolide Acetate; Liarozole Hydrochloride: ine; Elemene; Emitefur; Epirubicin; Estramustine Analogue: Lometrexol Sodium; Lomustine; Losoxantrone Hydrochlo Estrogen Agonists; Estrogen Antagonists; Exemestane; ride; Masoprocol; Maytansine; Mechlorethamine Hydro Fadrozole; Fiezelastine: Flavopiridol; Fluasterone: Fludara chloride; Megestrol Acetate; Melengestrol Acetate; Mel bine; Fluorodaunorunicin Hydrochloride; Forfenimex: phalan; Menogaril; Mercaptopurine; Methotrexate: Formestane; Fostriecin; Fotemustine; Gadolinium Texaphy Methotrexate Sodium; Metoprine; Meturedepa; Mitindo rin; Gallium Nitrate; Galocitabine; Ganirelix; Gelatinase mide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin: Inhibitors; Glutathione Inhibitors; Hepsulfam; Heregulin; Mitomycin; Mitosper; Mitotane: Mitoxantrone Hydrochlo Hexamethylene Bisacetamide: Hypericin; Ibandronic acid; ride; Mycophenolic Acid; Nocodazole; Nogalamvcin: Idarubicin; Idoxifene; Idramantone; Ilomastat; Imidazoacri Ormaplatin: Oxisuran; Paclitaxel; Pegaspargase; Peliomy dones; Immunostimulant Peptides; Insulin-Like Growth cin; Pentamustine: Peplomycin Sulfate; Perfosfamide; Pipo Factor-1 Receptor Inhibitor; Interferon Agonists; Interfer broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy ons; Interleukins; Iobenguane; Iododoxorubicin; Ipomeanol, cin; Plomestane; Porfimer Sodium; Prednimustine; 4-; Irinotecan; Iroplact; Irsogladine; IsobengaZole; Isohomo Procarbazine Hydrochloride; Puromycin; Puromycin halicondrin B; Itasetron: Jasplakinolide; Kahalalide F: Hydrochloride: Pyrazoftrin; Riboprine; Rogletimide: Safin Lamellarin-N Triacetate; Lanreotide; Leinamycin; Lentinan gol Safingol Hydrochloride: Semustine; SimtraZene; Spar Sulfate; Leptolstatin: Leukemia Inhibiting Factor; Leuko fosate Sodium; Sparsomycin; Spirogermanium Hydrochlo cyte Alpha Interferon; Leuprolide+Estrogen--Progesterone; ride, Spiromustine; Spiroplatin; Streptonigrin: Streptozocin, Leuprorelin; Levamisole; Liarozole; Linear Polyamine Ana Strontium Chloride Sr 89: Sulofenur; Talisomycin; Taxane: logue; Lipophilic Disaccharide Peptide; Lipophilic Platinum Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydro Compounds; Lissoclinamide 7: Lobaplatin; Lombricine; chloride; Temoporfin; Teniposide; Teroxirone; Testolactone: Lometrexol; Lonidamine; Losoxantrone; Lurtotecan; Lute Thiamiprine: Thioguanine: Thiotepa; Tiazofarin; Tira tium Texaphyrin; Lysofylline; Lytic Peptides; Maitansine; pazamine; Topotecan Hydrochloride; Triciribine Phosphate: Mannostatin A; Marimastat; Maspin; Matrilysin Inhibitors: US 2007/0269379 A1 Nov. 22, 2007

Matrix Metalloproteinase Inhibitors; Merbarone; Meterelin; 0146 Antineutropenic: Filgrastim; Lenograstim; Mol Methioninase; Metoclopramide: MIF Inhibitor; Mifepris gramostim; RegramoStim; Sargramostim. tone; Miltefosine; Mirimostim; Mismatched Double Stranded RNA; MitoguaZone; Mitolactol; Mitomycin ana 0147 Antiobsessional agent: Fluvoxamine Maleate. logues; Mitonafide: Mitotoxin Fibroblast Growth Factor 0.148 Antiparasitic: Abamectin; Clorsulon; Ivermectin. Saporin; Mitoxantrone: Mofarotene; Monoclonal Antibody, 0.149 Antiparkinsonian: Benztropine Mesylate: Human Chorionic Gonadotrophin; Monophosphoryl Lipid Biperiden; Biperiden Hydrochloride; Biperiden Lactate; A+Myobacterium Cell Wall Sk; Mopidamol; Multiple Drug Carbidopa-Levodopa; Carmantadine: Ciladopa Hydrochlo Resistance Gene Inhibitor: Multiple Tumor Suppressor ride; Dopamantine; Ethopropazine Hydrochloride: Lazabe 1-Based Therapy: Mustard Anticancer Agent; Mycaperoxide mide: Levodopa; Lometraline Hydrochloride: Mofegiline B: Mycobacterial Cell Wall Extract; Myriaporone: Hydrochloride: Naxagolide Hydrochloride; Pareptide Sul N-Acetyldinaline; Nafarelin; Nagrestip; Naloxone--Pentazo fate: Procyclidine Hydrochloride; Ropinirole Hydrochlo cine; Napavin; Naphterpin; Nartograstim; Nedaplatin: ride; Tolcapone. Nemorubicin; Neridronic Acid; Neutral Endopeptidase; Nilutamide: Nisamycin; Nitric Oxide Modulators; Nitroxide 0150 Antiperistaltic: Difenoximide Hydrochloride: Antioxidant; Nitrullyn; N-Substituted Benzamides: Difenoxin: Fluperamide: Lidamidine Hydrochloride; Lop O6-Benzylguanine; Okicenone; Oligonucleotides; Onapris eramide Hydrochloride; Malethamer; Nufenoxole; Parego tone; Ondansetron; Oracin; Oral Cytokine Inducer: Osater ric. one; Oxaliplatin: Oxaunomycin; Paclitaxel Analogues; Antipneumocystic: Atovaquone. Paclitaxel Derivatives; Palauamine; Palmitoylrhizoxin; 0151) Pamidronic Acid; Panaxytriol; Panomifene; Parabactin; 0152) Antiproliferative agent: Piritrexim Isethionate. Pazelliptine: Peldesine: Pentostatin: Pentrozole; Perflubron; Perillyl Alcohol; Phenazinomycin; Phenylacetate; Phos O153) Antiprostatic hypertrophy: Sitogluside. phatase Inhibitors: Picibanil; Pilocarpine Hydrochloride; 0154 Antiprotozoal: Amodiaquine; Azanidazole; Banmi Pirarubicin; Piritrexim; Placetin A: Placetin B: Plasminogen dazole; Camidazole; Chlortetracycline Bisulfate Chlortetra Activator Inhibitor; Platinum Complex: Platinum Com cycline Hydrochloride: Flubendazole: Flunidazole; pounds; Platinum-Triamine Complex: Propyl Bis-Acridone; Halofuginone Hydrobromide: Imidocarb Hydrochloride: Prostaglandin J2; Proteasome Inhibitors; Protein A-Based Ipronidazole; Misonidazole; Moxinidazole; Nitarsone: Immune Modulator; Protein Kinase C Inhibitor; Protein Ronidazole; Sulnidazole; Tinidazole. Kinase C Inhibitors, Microalgal; Protein Tyrosine Phos phatase Inhibitors; Purine Nucleoside Phosphorylase Inhibi O155 Antipruritic: Methdilazine; Methdilazine Hydro tors; Purpurins; Pyrazoloacridine: Pyridoxylated Hemoglo chloride; Trimeprazine Tartrate. bin Polyoxyethylene Conjugate; Raf Antagonists; 0156 Antipsoriatic: Acitretin: Anthralin; Azaribine; Cal Raltitrexed; Ramosetron; Ras Farnesyl Protein Transferase cipotriene; Cycloheximide: Enazadrem Phosphate; Etreti Inhibitors; Ras Inhibitors: Ras-GAP Inhibitor; Retelliptine nate; Liarozole Fumarate; Lonapalene; Tepoxalin. Demethylated; Rhenium, Re 186 Etidronate; Rhizoxin; Ribozymes; R1H Retinamide; Rohitukine: Romurtide: 0157 Antipsychotic: Acetophenazine Maleate; Alente Roquinimex: Rubiginone B1; Ruboxyl; Safingol: Saintopin: mol Hydrobromide: Alpertine; Azaperone; Batelapine Male SarCNU; Sarcophytol A; Sdi 1 Mimetics; Senescence ate; Benperidol; BenZindopyrine Hydrochloride; Brofoxine: Derived Inhibitor 1: Sense Oligonucleotides; Signal Trans Bromperidol; Bromperidol Decanoate; Butaclamol Hydro duction Inhibitors: Signal Transduction Modulators; Single chloride; Butaperazine; Butaperazine Maleate; Carphena Chain Antigen Binding Protein; Sizofuran; Sobuzoxane: zine Maleate; Carvotroline Hydrochloride; Chlorprothixene; Sodium Borocaptate; Sodium Phenylacetate; Solverol; Cinperene; Cintriamide: Clomacran Phosphate; Clo Somatomedin Binding Protein; Sonermin; Sparfosic Acid; penthixol; Clopimozide; Clopipazan Mesylate; Cloroperone Spicamycin D: Splenopentin; Spongistatin 1; Squalamine; Hydrochloride; Clothiapine; Clothixamide Maleate; Cloza Stem Cell Inhibitor; Stem-Cell Division Inhibitors; Stipi pine; Cyclophenazine Hydrochloride; properidol; Etazolate amide: Stromelysin Inhibitors; Sulfinosine; Superactive Hydrochloride: Fenimide: Flucindole: Flumezapine; Vasoactive Intestinal Peptide Antagonist; Suradista; Fluphenazine Decanoate: Fluphenazine Enanthate: Suramin; Swainsonine; Synthetic Glycosaminoglycans; Tal Fluphenazine Hydrochloride: Fluspiperone: Fluspirilene: limustine; Tamoxifen Methiodide; Tauromustine; Tellurapy Flutroline; Gevotroline Hydrochloride; Halopemide: Halo rylium; Telomerase Inhibitors; Temozolomide; Tetrachloro peridol; Haloperidol Decanoate; Iloperidone: Imidoline decaoxide; Tetrazomine; Thaliblastine; Thalidomide: Hydrochloride; Lenperone; Mazapertine Succinate: Thiocoraline: Thrombopoietin: Thrombopoietin Mimetic: Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper Thymalfasin; Thymopoietin Receptor Agonist; Thymotri one: Milipertine; Molindone Hydrochloride: Naranol nan; Thyroid Stimulating Hormone; Tin Ethyl Etiopurpurin; Hydrochloride: Neflumozide Hydrochloride: Ocaperidone: Titanocene Dichloride; Topotecan; Topsentin; Toremifene: Olanzapine; Oxiperomide: Penfluridol; Pentiapine Maleate; Totipotent Stem Cell Factor; Translation Inhibitors; Tri Perphenazine: Pimozide; Pinoxepin Hydrochloride; Pipam acetyluridine; Triciribine; Tropisetron; Turosteride; Tyrosine perone; Piperacetazine: Pipotiazine Palmitate; Piquindone Kinase Inhibitors; Tyrphostins; UBC Inhibitors: Ubenimex: Hydrochloride; Promazine Hydrochloride: Remoxipride: Urogenital Sinus-Derived Growth Inhibitory Factor: Uroki Remoxipride Hydrochloride; Rimcazole Hydrochloride: nase Receptor Antagonists; Variolin B; Vector system, Seperidol Hydrochloride: Sertindole: Setoperone; Spiper Erythrocyte Gene Therapy; Velaresol; Veramine: Verdins: one: Thioridazine: Thioridazine Hydrochloride; Thiothix Vinorelbine; Vinxaltine; Vitaxin: Zilascorb; Zinostatin Sti ene: Thiothixene Hydrochloride; Tioperidone Hydrochlo malamer. ride; Tiospirone Hydrochloride; Trifluoperazine US 2007/0269379 A1 Nov. 22, 2007

Hydrochloride; Trifluperidol; Triflupromazine; Triflupro 0170 Blood glucose regulators: Acetohexamide and mazine Hydrochloride; Ziprasidone Hydrochloride. Glipizide; Chloropropamide: Human insulin. 0158 Antirheumatic: Auranofin: Aurothioglucose: Bin 0171 Bone resorption inhibitor: Alendronate Sodium; darit; Lobenzarit Sodium; Phenylbutazone; Pirazolac. Pri Etidronate Disodium; Pamidronate Disodium. nomide Tromethamine; Seprilose. 0172 Bronchodilator: Albuterol; Albuterol Sulfate; Aza 0159 Antischistosomal: Becanthone Hydrochloride: nator Maleate; Bamifylline Hydrochloride; Bitolterol Mesy Hycanthone; Lucanthone Hydrochloride; Niridazole; late: Butaprost; Carbuterol Hydrochloride; Clorprenaline Oxamniquine; Pararosaniline Pamoate; Teroxalene Hydro Hydrochloride; Colterol Mesylate; Doxaprost; Doxofylline: chloride. Dyphylline; Enprofylline; Ephedrine; Ephedrine Hydro 0160 Antiseborrheic: Chloroxime; Piroctone; Piroctone chloride: Fenoterol: Fenprinast Hydrochloride; Guaithyl Olamine; Resorcinol Monoacetate. line: Hexoprenaline Sulfate; Hoquizil Hydrochloride; Ipra 0161 Antisecretory: Arbaprostil; Deprostil: Fenoctimine tropium Bromide: Isoetharine: Isoetharine Hydrochloride; Sulfate; Octreotide; Octreotide Acetate: Omeprazole Isoetharine Mesylate: Isoproterenol Hydrochloride; Isopro Sodium; Rioprostil; Trimoprostil. terenol Sulfate; Metaproterenol Polistirex: Metaproterenol Sulfate; Nisbuterol Mesylate: Oxtriphylline; Picumeterol 0162 Antispasmodic: Stilonium Iodide; Tizanidine Fumarate; Piquizil Hydrochloride; Pirbuterol Acetate: Pir Hydrochloride. buterol Hydrochloride; Procaterol Hydrochloride; Pseu 0163 Antithrombotic: Anagrelide Hydrochloride; Dalte doephedrine Sulfate; QuaZodine; Quinterenol Sulfate: parin Sodium; Danaparoid Sodium; Dazoxiben Hydrochlo Racepinephrine: Racepinephrine Hydrochloride; Reproterol ride; Efegatran Sulfate; Enoxaparin Sodium: Ifetroban: Hydrochloride; Rimiterol Hydrobromide: Salmeterol: Sal Ifetroban Sodium; Trifenagrel. meterol Xinafoate: Soterenol Hydrochloride: Sulfonterol Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate: 0164 Antitussive: Benzonatate; Butamirate Citrate; Theophylline; Xanoxate Sodium; Zindotrine; Zinterol Chlophedianol Hydrochloride: Codeine Polistirex: Hydrochloride. Codoxime; Dextromethorphan: Dextromethorphan Hydro bromide: Dextromethorphan Polistirex: Ethyl Dibunate; 0173 Carbonic anhydrase inhibitor: Acetazolamide: Guaiapate; Hydrocodone Bitartrate; Hydrocodone Polis Acetazolamide Sodium; Dichlorphenamide; Dorzolamide tirex; Levopropoxyphene Napsylate: Noscapine; Pemerid Hydrochloride; Methazolamide: Sezolamide Hydrochloride. Nitrate; Pipazethate: Suxemerid Sulfate. 0.174 Cardiac depressant: Acecamide Hydrochloride: 0165 Anti-ulcerative: Aceglutamide Aluminum: Cadex Acetylcholine Chloride; Actisomide: Adenosine; Amio omer Iodine; Cetraxate Hydrochloride; Enisoprost: Iso darone; Aprindine; Aprindine Hydrochloride; Artilide tiquimide; Lansoprazole; LaVoltidine Succinate; Misopros Fumarate; Azimilide Dihydrochloride: Bidisomide; Bucam tol; Nizatidine: Nolinium Bromide; Pantoprazole; Pifamine; ide Maleate; Bucromarone; Capobenate Sodium; Capobenic Pirenzepine Hydrochloride; Rabeprazole Sodium; Remi Acid; Cifenline; Cifenline Succinate; Clofilium Phosphate: prostol; Roxatidine Acetate Hydrochloride: Sucralfate; Disobutamide: Disopyramide: Disopyramide Phosphate: Sucrosofate Potassium; Tolimidone. Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosy 0166 Anti-urolithic: Cysteamine: Cysteamine Hydro late: Encamide Hydrochloride; Flecamide Acetate; Ibutilide chloride; Tricitrates. Fumarate; Indecamide Hydrochloride: Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcamide Hydrochloride: 0167 Antiviral: Acemannan: Acyclovir. Acyclovir Meobentine Sulfate; Mexiletine Hydrochloride: Modecam Sodium; Adefovir; Alovudine; Alvircept Sudotox: Amanta dine Hydrochloride; Aranotin: Arildone: Atevirdine Mesy ide: Moricizine; Oxiramide: Pirmenol Hydrochloride: Piro late: Avridine: Cidofovir, Cipamfylline; Cytarabine Hydro lazamide: Pranolium Chloride: Procainamide Hydrochlo chloride; Delavirdine Mesylate: Desciclovir; Didanosine: ride; Propafenone Hydrochloride: Pyrinoline; Quindonium Disoxaril: Edoxudine; Enviradene; Enviroxime; Famciclo Bromide: Quinidine Gluconate; Quinidine Sulfate: vir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosa Recainam Hydrochloride: Recainam Tosylate: Risotilide rilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir, Hydrochloride; Ropitoin Hydrochloride: Sematilide Hydro Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; chloride; Suricamide Maleate: Tocamide: Tocamide Hydro Lobucavir; Memotine Hydrochloride; Methisazone; Nevi chloride; Transcamide. rapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate: Somantadine Hydro 0.175 Cardioprotectant: Dexrazoxane: Draflazine. chloride; Sorivudine; Statolon; Stavudine; Tilorone Hydro 0176 Cardiotonic: Actodigin; Aminone; Bemoradan; chloride; Trifluridine; Valacyclovir Hydrochloride: Vidara Butopamine; Carbazeran; Carsatirin Succinate; Deslanoside; bine; Vidarabine Phosphate: Vidarabine Sodium Phosphate: Digitalis; Digitoxin; Digoxin; Dobutanine; Dobutanine Viroxime; Zalcitabine; Zidovudine; Zinviroxime. Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar 0168 Appetite suppressant: Dexfenfluramine Hydro trate; Enoximone: Imazodan Hydrochloride; Indolidan; Iso chloride; Phendimetrazine Tartrate; Phentermine Hydro mazole Hydrochloride; Levdobutamine Lactobionate; Lix chloride. azinone Sulfate; Medorinone; Milrinone; Pelrinone Hydrochloride: Pimobendan; Piroximone: Prinoxodan; 0169 Benign prostatic hyperplasia therapy agent: Tam Proscillaridin; Quazinone; Tazolol Hydrochloride: Sulosin Hydrochloride. Vesnarinone. US 2007/0269379 A1 Nov. 22, 2007

0177 Cardiovascular agent: Dopexamine; Dopexamine 0188 Diuretic: Ambuphylline; Ambuside; Amiloride Hydrochloride. Hydrochloride: Azolimine: Azosemide: Brocrinat; Bumeta mide; Chlorothiazide; Chlorthalidone; Clazolimine; Clorex 0178 Cerebral ischemia agents: Dextrorphan Hydrochlo olone; Ethacrynate Sodium: Ethacrynic Acid; Etozolin: Fen ride. quizone; Furosemide; Hydrochlorothiazide: Isosorbide: 0179 Choleretic: Dehydrocholic Acid: Fencibutirol; Mannitol Mefruside; Ozolinone; Piretamide: Spiroxasone: Hymecromone; Piprozolin; Sincalide; Tocamphyl. Torsemide; Triamterene; Triflocin, Urea. 0180 Cholinergic: Aceclidine: Bethanechol Chloride: 0189) Dopaminergic agent: Ibopamine. Carbachol; Demecarium Bromide: Dexpanthenol; Ectoparasiticide: Nifluridide; Permethrin. Echothiophate Iodide; Isofluorophate; Methacholine Chlo 0.190) ride; Neostiamine Methylsulfate; Neostigmine Bromide: 0191) Emetic: Apomorphine Hydrochloride. Physostigmine; Physostigmine Salicylate; Physostigmine 0.192 Enzyme inhibitor: 30 Polignate Sodium: Acetohy Sulfate; Pilocarpine Nitrate; Pyridostigmine Bromide. droxamic Acid; Alrestatin Sodium; Aprotinin; Benazepril 0181 Cholinergic agonist: Xanomeline; Xanomeline Tar Hydrochloride; Benazeprilat; Benurestat; Bromocriptine: trate. Bromocriptine Mesylate: Cilastatin Sodium; Fluorofamide: Lergotrile; Lergotrile Mesylate; Levcycloserine; Libenza 0182 Cholinesterase Deactivator: Obidoxime Chloride: pril; Pentopril: Pepstatin: Perindopril; Sodium Amylosul Pralidoxime Chloride; Pralidoxime Iodide; Pralidoxime fate: Sorbinil; Spirapril Hydrochloride; Spiraprilat; Talera Mesylate. nol; Teprotide; Tolfamide: Zofenopril Calcium. 0183 Coccidiostat: Arprinocid; Narasin: Semduramicin; 0193 Estrogen: Chlorotrianisene; Dienestrol; Diethyl Semduramicin Sodium. stilbestrol; Diethylstilbestrol Diphosphate: Equilin; Estra 0184 Cognition adjuvant: Ergoloid Mesylates; Pirac diol; Estradiol Cypionate; Estradiol Enanthate; Estradiol etam; Pramiracetam Hydrochloride; Pramiracetam Sulfate: Undecylate; Estradiol Valerate; EstraZinol Hydrobromide: Tacrine Hydrochloride. Estriol, Estrofurate; Estrogens, Conjugated; Estrogens, Esterified; Estrone; Estropipate; Ethinyl Estradiol: Fenes 0185. Cognition enhancer: Besipirdine Hydrochloride: trel; Mestranol; Nylestriol: Quinestrol. Linopirdine: Sibopirdine. 0194 Fibrinolytic: Anistreplase; Bisobrin Lactate; Brino 0186 Contrast Media: Barium Sulfate; Diatrizoate lase. Sodium; Erythrosine Sodium; lopanoic Acid; Ipodate Cal cium; Metyrapone; Tyropanoate Sodium. 0.195 Free oxygen radical scavenger: Pegorgotein. 0187 Diagnostic aid: Aminohippurate Sodium; Ana 0.196 Gastric Acid Suppressant: Omeprazole. Zolene Sodium; Arclofenin; Bentiromide: Benzylpenicilloyl 0.197 Gastrointestinal Motility agents: Cisapride. Polylysine; Butedronate Tetrasodium; Butilfenin; Coccidioi 0198 Glucocorticoid: Amcinonide; Beclomethasone din; Corticorelin Ovine Triflutate; Corticotropin Zinc Dipropionate; Betamethasone; Betamethasone Acetate; Hydroxide; Corticotropin, Repository; Diatrizoate Meglu Betamethasone Benzoate: Betamethasone Dipropionate: mine; Diatrizoic Acid; Diphtheria Toxin for Schick Test; Betamethasone Sodium Phosphate: Betamethasone Valer Disofenin; Ethiodized Oil: Etifenin; Exametazime; Ferris ate; Carbenoxolone Sodium; Clocortolone Acetate; Clocor tenc; Ferumoxides; Ferumoxsil; Fluorescein; Fluorescein tolone Pivalate; Cloprednol; Corticotropin; Cortisone Sodium; Gadobenate Dimeglumine; Gadodiamide; Gado Acetate; Cortivazol: Descinolone Acetonide; Dexametha pentetate Dimeglumine; Gadoteridol; Gadoversetamide; sone; Dexamethasone Sodium Phosphate; Diflucortolone: Histoplasmin: Impromidine Hydrochloride; Indigotindisul Diflucortolone Pivalate: Flucloronide; Flumethasone; Flu fonate Sodium; Indocyanine Green: Iobenguane Sulfate I methasone Pivalate: Flunisolide; Fluocinolone Acetonide; 123: Iobenzamic Acid, Iocarmate Meglumine; Iocarmic Fluocinonide; Fluocortolone: Fluocortolone Caproate: Fluo Acid, Iocetamic Acid, Iodamide; lodamide Megilumine; rometholone: Fluperolone Acetate: Fluprednisolone: Flu Iodipamide Meglumine; Iodixanol; Iodoxamate Meglumine; prednisolone Valerate: Flurandrenolide; Formocortal: Iodoxamic Acid; loglicic Acid, loglucol; Ioglucomide; Hydrocortisone; Hydrocortisone Acetate; Hydrocortisone Ioglycamic Acid, Iogulamide; lohexyl, lomeprol; Iopami Buteprate; Hydrocortisone Butyrate; Hydrocortisone dol; Iopentol; Iophendylate, Ioprocemic Acid, Iopronic Sodium Phosphate; Hydrocortisone Sodium Succinate; Acid, Iopydol; lopy done; Iosefamic Acid, Ioseric Acid; Hydrocortisone Valerate; Medrysone; Methylprednisolone loSulamide Meglumine; IoSumetic Acid; lotasul; lotetric Acetate; Methylprednisolone Sodium Phosphate; Methyl Acid; lothalamate Meglumine; Iothalamate Sodium; Iotha lamic Acid; Iotrolan, lotroxic Acid, IoverSol; Ioxagiate prednisolone Sodium Succinate; Nivazol; Paramethasone Sodium; Ioxaglate Meglumine; Ioxaglic Acid, Ioxilan, IoXo Acetate; Prednicarbate; Prednisolone; Prednisolone Acetate; trizoic Acid; Ipodate Sodium; Iprofenin; Isosulfan Blue; Prednisolone Hemisuccinate; Prednisolone Sodium Succi Leukocyte Typing Serum; Lidofenin; Mebrofenin: Meglu nate; Prednisolone Tebutate; Prednisone; Prednival; Ticabe mine; Metrizamide: Metrizoate Sodium; Metyrapone Tar sone Propionate; Tralonide; Triamcinolone; Triamcinolone trate; Mumps Skin Test Antigen; Pentetic Acid; Propyli Acetonide; Triamcinolone Acetonide Sodium; Triamcino odone; Quinaldine Blue: Schick Test Control; Sermorelin lone Diacetate; Triamcinolone Hexacetonide. Acetate; Sodium Iodide I 123: Sprodiamide: Stannous Pyro 0199 Gonad-stimulating principle: Buserelin Acetate; phosphate: Stannous Sulfur Colloid; Succimer: Teriparatide Clomiphene Citrate; Ganirelix Acetate; Gonadorelin Acetate; Tetrofosmin, Tolbutamide Sodium; Tuberculin; Acetate; Gonadorelin Hydrochloride; Gonadotropin, Chori Xylose. onic; Menotropins. US 2007/0269379 A1 Nov. 22, 2007

0200 Hair growth stimulant: Aminocaproic Acid: Furegrelate Sodium; Lufironil; Miglitol; Orlistat; Pimage Minoxidil Hemostatic: Oxamarin Hydrochloride; Sulmarin; dine Hydrochloride; Pirmagrel; Ponalrestat; Ridogrel; Sul Thrombin; Tranexamic Acid. bactam BenZathine; Sulbactam Pivoxil; Sulbactam Sodium; 0201 Hormone: 17 Alpha Dihydroequilenin; 17 Alpha Suronacrine Maleate; Tazobactam, Tazobactam Sodium; Dihydroequilin; 17 Alpha Estradiol; 17 Beta Estradiol; 17 Ticlopidine Hydrochloride; Tirilazad Mesylate; Tolrestat; Hydroxy Progesterone; Androstenedione; Clomiphene: Velnacrine Maleate; Zifrosilone; Zileuton. Cosyntropin: Dehydroepiandrosterone; Dihydroestosterone: Equilenin; Ethyndiol; Follicle Regulatory Protein; Follicle 0213 Keratolytic: Alcloxa; Aldioxa; Dibenzothiophene: Stimulating Hormone; Folliculostatin: Gonadoctrinins: Etarotene: Motretinide-I Picotrin Diolamine; Salicylic Acid: Gonadorelin; Gonadotropins; Han Memopausal Gonadotro Sumarotene; Tazarotene; Tetroquinone; Tretinoin. pins; Human Chorionic Gonadotropin; Insulin Growth Fac tor; Leuprolide; Levonorgestrel; Luteinizing hormone; 0214. LHRH agonist: Deslorelin; Goserelin; Histrelin; Luteinizing Hormone Releasing Hormone and Analogs; Lutrelin Acetate; Nafarelin Acetate. Medroxyprogesterone: Megestrol; Metogest; Norethin 0215 Liver disorder treatment: Malotilate. drone; Norethynodrel; Norgestrel; Oocyte Maturation Inhibitor; Oxytocin; Pituitary, Posterior; Progesterone: 0216 Luteolysin: Fenprostalene. Relaxin; Seractide Acetate. Somalapor. Somatrem: Somat ropin; Somenopor: Somidobove: Tamoxifen; Urofollitropin: 0217 Memory adjuvant: Dimoxamine Hydrochloride: Vasopressin. Ribaminol. 0202 Hypocholesterolemic: Lifibrol. 0218 Mental performance enhancer: Aniracetam. 0203 Hypoglycemic: Darglitazone Sodium; Glime 0219 Mood regulator: Fengabine. piride. 0220 Mucolytic: Acetylcysteine; Carbocysteine; Domi 0204 Hypolipidemic: Azalanstat Dihydrochloride; odol. Colestolone; Surfomer, Xenalipin. 0205 Hypotensive: Viprostol. 0221 Mucosal Protective agents: Misoprostol (Cytotec). 0206. Immunizing agent: Antirabies Serum; Antivenin; 0222 Mydriatic: Berefrine. Antivenin (Crotalidae) Polyvalent; BCG Vaccine; Botulism Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphthe 0223 Nasal decongestant: Nemazoline Hydrochloride: ria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Pseudoephedrine Polistirex. Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine 0224) Neuroleptic: Duoperone Fumarate; Risperidone. Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine Live: Meningococcal Polysaccharide Vaccine Group A: 0225. Neuromuscular blocking agent: Atracurium Besy Meningococcal Polysaccharide Vaccine Group C; Mumps late: Cisatracurium Besylate; Doxacurium Chloride; Gal Virus Vaccine Live: Pertussis Immune Globulin; Pertussis lamine Triethiodide; Metocurine Iodide; Mivacurium Chlo Vaccine: Pertussis Vaccine Adsorbed; Plague Vaccine; ride; Pancuronium Bromide: Pipecuronium Bromide: Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Rocuronium Bromide: Succinylcholine Chloride; Tub Oral; Rabies Immune Globulin; Rabies Vaccine; Rho(D) ocurarine Chloride; Vecuronium Bromide. Immune Globulin; Rubella Virus Vaccine Live: Smallpox Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin; 0226) Neuroprotective: Dizocilpine Maleate. Tetanus Toxoid: Tetanus Toxoid Adsorbed; Typhoid Vac cine; Vaccinia Immune Globulin; Varicella-Zoster Immune 0227 NMDA antagonist: Selfotel. Globulin; Yellow Fever vaccine. 0228 Non-hormonal sterol derivative: Pregnenolone 0207 Immunomodulator: Dimepranol Acedoben: Imi Succinate. quimod: Interferon Beta-1b: Lisofylline: Mycophenolate 0229. Oxytocic: Carboprost; Carboprost Methyl: Carbo Mofetil: Prozatide Copper Acetate. prost Tromethamine; Dinoprost; Dinoprost Tromethamine; 0208 Immunoregulator: Azarole; Fanetizole Mesylate: Dinoprostone; Ergonovine Maleate; Meteneprost; Methyl Frentizole: Oxamisole Hydrochloride: Ristianol Phosphate: ergonovine Maleate; Sparteine Sulfate. Thymopentin; Tilomisole. 0230 Paget’s disease agents: Tiludronate Disodium. 0209) Immunostimulant: Loxoribine; Teceleukin. 0231 Progestin: Algestone Acetophenide; Amadinone 0210 Immunosuppressant: Azathioprine; Azathioprine Acetate; Anagestone Acetate; Chlormadinone Acetate; Sodium; Cyclosporine; Daltroban; Gusperimus Trihydro Cingestol; Clogestone Acetate; Clomegestone Acetate; chloride; Sirolimus; Tacrolimus. Desogestrel; Dimethisterone; Dydrogesterone; Ethynerone: Impotence therapy adjunct: Delequamine Hydro Ethynodiol Diacetate; Etonogestrel; Fluorogestone Acetate; 0211 Gestaclone; Gestodene; Gestonorone Caproate: Gestrinone; chloride. Haloprogesterone; Hydroxyprogesterone Caproate; 0212. Inhibitor: Acarbose; Atorvastatin Calcium; Benser Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; azide: Brocresine; Carbidopa; Clavulanate Potassium; Methynodiol Diacetate; Norethindrone Acetate; Norgesti DaZmegrel; Docebenone; Epoprostenol; Epoprostenol mate; Norgestomet, Oxogestone Phenpropionate; Sodium; Epristeride; Finasteride: Flurbiprofen Sodium; Quingestanol Acetate; Quingestrone; Tigestol. US 2007/0269379 A1 Nov. 22, 2007

0232 Prostaglandin: Cloprostenol Sodium; Fluprostenol ride; Clorethate: Cyprazepam: Dexclamol Hydrochloride; Sodium; Gemeprost; Prostalene; Sulprostone. Diazepam; Dichloralphenazone; Estazolam Ethchlorvynol: Etomidate: Fenobam; Flunitrazepam; Fosazepam; Glute 0233 Prostate growth inhibitor: Pentomone. thimide; Halazepam; Lon-netazepam, Mecloqualone; Mep 0234) Prothyrotropin: Protirelin. robamate; Methaqualone; Midaflur. Paraldehyde; Pentobar bital; Pentobarbital Sodium; Perlapine; Prazepam; 0235 Psychotropic: Minaprine. Quazepam. Reclazepam; Roletamide: Secobarbital; Seco 0236 Radioactive agent: Fibrinogen I 125: Fludeoxyglu barbital Sodium; Suproclone: Tracazolate: Trepipam Male cose F 18: Fluorodopa F 18: Insulin I 125; Insulin I 131: ate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Iobenguane I 123; lodipamide Sodium I 131; Iodoantipyrine Uldazepam; Zaleplon; Zolazepam Hydrochloride; Zolpidem I 131; Iodocholesterol I 131; Iodohippurate Sodium I 123; Tartrate. Iodohippurate Sodium I 125; Iodohippurate Sodium I 131; Iodopyriacet I 125; Iodopyracet I 131; Iofetamine Hydro 0244. Selective adenosine Al antagonist: Apaxifylline. chloride I 123: Iomethin I 125; Iomethin I 131; Iothalamate 0245 Serotonin antagonist: Altanserin Tartrate; Ameser Sodium I 125; lothalamate Sodium I 131; Iotyrosine I 131; gide; Ketanserin; Ritanserin. Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Hg 197; Merisoprol Acetate Hg 203: Merisoprol Hg 197: 0246 Serotonin inhibitor: Cinanserin Hydrochloride: Selenomethionine Se 75; Technetium Tc 99m Antimony Fenclonine; Fonazine Mesylate: Xylamidine Tosylate. Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium 0247 Serotonin receptor antagonist: Tropanserin Hydro Tc 99m Disofenin; Technetium Tc 99m Etidronate; Techne chloride. tium Tc 99m Exametazime; Technetium Tc 99m Furifosmin, Technetium Tc 99m Gluceptate; Technetium Tc 99m Lid 0248 Steroid: Dexamethasone Acefurate; Mometasone ofenin; Technetium Tc 99m Mebrofenin; Technetium Tc Furoate. 99m Medronate; Technetium Tc 99m Medronate Disodium; 0249 Stimulant: Amfonelic Acid; Amphetamine Sulfate: Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidr AmpyZine Sulfate; Arbutamine Hydrochloride; Azabon: onate; Technetium Tc 99m Pentetate; Technetium Tc 99m Caffeine; Ceruletide; Ceruletide Diethylamine; Dazopride Pentetate Calcium Trisodium; Technetium Tc 99m Sesta Fumarate; Dextroamphetamine; Dextroamphetamine Sul mibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m fate; Difluanine Hydrochloride; Dimefline Hydrochloride: Succimer; Technetium Tc 99m Sulfur Colloid; Technetium Doxapram Hydrochloride; Ethamivan; Etryptamine Acetate; Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin, Fenethylline Hydrochloride: Flubanilate Hydrochloride: Technetium Tc 99m Tiatide; Thyroxine I 125; Thyroxine I Fluorothyl; Histamine Phosphate; Indriline Hydrochloride: 131; Tolpovidone I 131; Triolein I 125: Triolein I 131. Mefexamide; Methamphetamine Hydrochloride; Meth 0237 Regulator: Calcifediol; Calcitonin; Calcitriol: Clo ylphenidate Hydrochloride; Pemoline: Pyrovalerone Hydro dronic Acid; Dihydrotachysterol: Etidronic Acid: Oxidronic chloride; Xamoterol: Xamoterol Fumarate. Acid, Piridironate Sodium; Risedronate Sodium; Secalcif 0250 Suppressant: Amflutizole; Colchicine; Tazofelone. erol. 0251 Symptomatic multiple sclerosis: Fampridine. 0238 Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Aminophylline; AZumolene Sodium; Baclofen; 0252) Synergist: Proadifen Hydrochloride. Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin 0253) Thyroid hormone: Levothyroxine Sodium; Liothy Carbamate; ChlorZoxazone; Cinflumide: Cinnamedrine; ronine Sodium; Liotrix. Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene: Dantrolene Sodium; Fenalamide: Fenyripol Hydrochloride: 0254 Thyroid inhibitor: Methimazole; Propylthiouracil. Fetoxylate Hydrochloride: Flavoxate Hydrochloride; Fle 0255 Thyromimetic: Thyromedan Hydrochloride. tazepam; Flumetramide: Hexafluorenium Bromide: Isomy 0256 Tranquilizer: Bromazepam; Buspirone Hydrochlo lamine Hydrochloride; Lorbamate; Mebeverine Hydrochlo ride; Chlordiazepoxide; Clazolam; Clobazam; Clorazepate ride; Mesuprine Hydrochloride; Metaxalone; Methixene Dipotassium; CloraZepate Monopotassium; Demoxepam, Hydrochloride; Methocarbamol; Nafomine Malate; Nelleza Dexmedetomidine: Enciprazine Hydrochloride; Gepirone prine Maleate; Papaverine Hydrochloride; Pipoxolan Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro Hydrochloride: Quinctolate; Ritodrine; Ritodrine Hydro chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, chloride; Rolodine: Theophylline Sodium Glycinate: LorZafone; Loxapine; Loxapine Succinate; Medazepam Thiphenamil Hydrochloride; Xilobam. Hydrochloride; Nabilone; Nisobamate: Oxazepam; Pent 0239 Repartitioning agent: Cimaterol. abamate; Pirenperone; Ripazepam, Rolipram; Sulazepam, Taciamine Hydrochloride; Temazepam; Triflubazam; 0240 Scabicide: Amitraz: Crotamiton. Tybamate; Valnoctamide. 0241 Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium; Tribenoside. 0257 Unstable angina agents: Tirofiban Hydrochloride. 0258 Uricosuric: Benzbromarone; Irtemazole; 0242 Sedative: Propiomazine. Probenecid; Sulfinpyrazone. 0243 Sedative-hypnotic: Allobarbital; Alonimid; Alpra 0259 Vasoconstrictor: Angiotensin Amide: Felypressin: Zolam; Amobarbital Sodium; Bentazepam; Brotizolam: But Methysergide; Methysergide Maleate. abarbital; Butabarbital Sodium: Butalbital; Capuride; Car bocloral; Chloral Betaine; Chloral Hvdrate; 0260 Vasodilator: Alprostadil; AZaclorzine Hydrochlo Chlordiazepoxide Hydrochloride; Cloperidone Hydrochlo ride; Bamethan Sulfate; Bepridil Hydrochloride: Buterizine; US 2007/0269379 A1 Nov. 22, 2007

Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Benzoidazoxan; Benzoyl Peroxide; Benzphetamine Hydro Dipyridamole; proprenilamine; Erythrity1 Tetranitrate; Fello chloride; Benzquinamide Hydrochloride; Benztropine; Ben dipine: Flunarizine Hydrochloride; Fostedil: Hexobendine: Zyl Benzoate; Benzyl Penicilloyl-Polylysine: Bepridil; Inositol Niacinate; Iproxamine Hydrochloride: Isosorbide Beractant; Beraprost; Berlafenone; Bertosamil: Besipirdine: Dinitrate; Isosorbide Mononitrate; IsoxSuprine Hydrochlo Beta-Carotene: Betaine, Anhydrous; Betamipron: Betaxolol; ride; Lidoflazine; Mefenidil; Mefenidil Fumarate; Milbe Betazole Hydrochloride; Bevantolol; Bexarotene; Bife fradil Dihydrochloride; Mioflazine Hydrochloride: Mixi melane; Bimakalim; Bimatoprost; Bimithil; Binospirone: dine; Nafronyl Oxalate: Nicardipine Hydrochloride: Biotin: Bioxalomycin Alpha2: Biriperone; Bisaramil: Nicergoline; Nicorandil; Nicotinyl Alcohol; Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; Pen Bisaziridinylspermine; Bis-Benzimidazole A; Bis-Benzimi taerythritol Tetranitrate; Pentoxifylline; Pentrinitrol; Per dazole B: Bismuth Subsalicylate; Bistramide D: Bistramide hexyline Maleate; Pindolol; Pirsidomine: Prenylamine; Pro K; Boldine; Bopindolol; Bortezomib: Brefeldin; Brimoni patyl Nitrate; Suloctidil; Terodiline Hydrochloride; dine: Brinzolamide: Bromfenac; Bucindolol; Budipine; Tipropidil Hydrochloride; Tolazoline Hydrochloride; Xan Bunazosin; Butenafine; Butenafine Hydrochloride; Butixo thinol Niacinate. cort Propionate; Cabergoline; Caffeine Citrate; Calanolide A; Calcitonin Human; Calcitonin, Salmon; Calcium; Cal 0261 Vulnerary: Allantoin. cium Acetate; Calcium Gluceptate; Calcium Metrizoate: Califactant; Camonagrel, Candesartan; Candesartan Cilex 0262 Wound healing agent: Ersofermin. etil, Candoxatrilat; Capromab, Capsaicin; Carbamazepine; 0263 Xanthine oxidase inhibitor: Allopurinol; Oxypu Carbazomycin C; Carbetocin; Carbidopa/Levodopa; Carbo rinol. vir; Carboxymethylated Beta-1,3-Glucan: Carperitide; Car teolol, Carumonam, Carvotroline; Caspofungin Acetate; 0264. Other pharmaceuticals include: 16-Alpha Fluo Cebaracetam; Cefadroxil/Cefadroxil Hemihydrate; Cefcap roestradiol; 16 Alpha-Gitoxin; 16-Eplestriol; 17 Alpha Estra ene Pivoxil; Cefdaloxime Pentexil Tosilate; Cefditoren Piv diol; 17Beta Estradiol; 1 Alpha-Hydroxyvitamin D2: oxil; Cefepime Hydrochloride (Arginine Formulation); 1-Decpyrrolidinone: 1-Dodecpyrrolidinone; 22-Oxacal Cefetamet; Cefetamet Pivoxil; Ceffietazole; Cefluprenam; citriol: 2CVV; 2'-Nor-cGMP;3-Isobutyl GABA; 6-FUDCA: Cefininox; Cefodizime; Cefoselis; Cefotiam; Cefotiam Hex 7-Methoxytacrine; Abacavir Sulfate; Abanoquil; Abecarnil; etil: Cefozopran; Ce?pirome; Cefsulodin; Ceftazidime Acadesine; Acamprosate; Acebutolol Hydrochloride; Ace (Arginine Formulation); Ceftazidime Sodium; Cefteram; clofenac; Acetomepregenol; Acetrizoate Sodium: Acetyl Ceftibuten Dihydrate; Ceftriaxone: Celastrol: Celecoxib: cysteine, N-; Acetyldigitoxin; Acetyl-L-carnitine; Acetyl Celikalim; Celiprolol; Cellulose Sodium Phosphate; Cepa methadol; Acipimox, Acitemate; Aclatonium; Aconiazide; cidine A; Cericlamine; Cerivastatin: Cerivastatin Sodium; Acrivastinet; Adafenoxate; Adatanserin: Adefovir Dipiv Certoparin Sodium; Cetiedil; Cetirizine; Cetyl Alcohol: oxil; Adelmidrol; Ademetionine: Adiposin; Adrafinil; Ala Cevimeline Hydrochloride; Chlormerodrin, Hg-197; Chlo cepril; Aladapcin; Alaptide; Alatrofloxacin Mesylate; Albo rmezanone; Chloroorienticin A; Chloroorienticin B: Chole labrin; Albumin Chromated Cr-51 Serum; Albumin Human; calciferol: Cholestyramine; Choriogonadotropin Alfa: Chro Albumin Iodinated I-125 Serum; Albumin Iodinated I-131 mic Phosphate, P-32; Chymopapain; Chymotrypsin; Serum; Aldecalmycin; Alendronic Acid; Alentemol; Alfa Cibenzoline: Ciclesonide: Cicloprolol; Cilansetron: Cilnid calcidol; AlfuZosin; Alglucerase; Alinastine; Alitretinoin, ipine: Cilobradine: Cilostazol; Cimetropiurn Bromide: Cini Alkavervir; Allopurinol Sodium; Almotriptan Malate; Alos tapride: Cinolazepam: Ciprostene: Cisapride Monohydrate; etron: Alpha Idosone: Alpha-Tocopherol; Alpha-Tocopherol Cisatracurium, Besilate: Cistinexine; Citalopram; Citalo Acetate; Alseroxylon; Altromycin B; Amantadine-HCl; pram Hydrobromide: Citicoline; Citreamicin Alpha; Clause Ambenonium Chloride; Amelometasone; Amezinium Metil namide; Clidinium Bromide: Clinafloxacin; Clomethiazole; sulfate; Amfebutamone; Amifloxacin; Aminolevulinic Acid Clopidogrel; Clopidogrel Bisulfate; Cobalt Chloride, Co-57; Hydrochloride; Aminosalicylic Acid Resin Complex: Amio Cobalt Chloride, Co-60; Colesevelam Hydrochloride: darone Hydrochloride; Amisulpride: Amlodipine; Ammo Colestimide: Colfosceril Palmitate; Complestatin: Contign nium Lactate; Amphetamine Adipate; Amphetamine Aspar asterol; Contortrostatin: Corticotropin-Zinc Hydroxide: tate; Amphetamine Resin Complex: Ampiroxicam, Cosalane; Costatolide; Cotinine: Cournermycin AI: Crypte Amprenavir, Amylin; Amythiamicin; Ananain; Anaritide; namine Acetates; Cryptenamine Tannates: Cucumariosid: Anileridine Phosphate: Anisindione; Anordrin; Apadoline; Curdlan Sulfate; Curiosin; Cyanocobalamin; Cyanocobal Apafant; Apraclonidine; Aprepitant; Aprosulate Sodium; amin, Co-57; Cyanocobalamin, Co-58: Cyanocobalamin, Aprotinin Bovine; Aptiganel; Aranidipine; Arbekacin; Arbi Co-60; Cyclazosin: Cyclic HPMPC: Cyclobenzaprine: dol; Arbutamine; Arecatannin B1; Argatroban; Aripiprazol; Cyclobut A: Cyclobut G: Cyclocapron; Cyclosin: Cyclothia Aripiprazole; Arotinolol; Articaine Hydrochloride: Ascorbic lidine; Cyclothiazomycin; Cycrimine Hydrochloride: Acid, Asimadoline; Aspalatone; Asperfuran; Aspoxicillin; Cyproterone: Cysteamine Bitartrate; Cytochalasin B; Dac Atazanavir Sulfate; Atenolol, S-: Atevirdine: Atomoxetine timicin; Daidzein; Daidzin; Danaparoid; Daphnodorin A; Hydrochloride; Atpenin B; Atrinositol; Aureobasidin A; Dapiprazole; Dapitant: Darifenacin; Darlucin A; Darsidom AVobenzone; Azadirachtine, AZelaic Acid, AZelastine; ine; Daunorubicin Citrate; DdUTP, Decamethonium Bro AZelnidipine: Azimilide: Azithromycin Dihydrate; Aztre mide; Deferiprone; Deferoxamine Mesylate; Dehydrodi onwn; Baccatin III; Bacoside A: Bacoside B: Bactobola demnin B; Delapril; Delequamine; Delfaprazine: mine; Balazipone; Balhimycin; Balofloxacin; Balsalazide: Delmopinol; Delphinidin; Deoxypyridinoline; Deprodone: Bambuterol; Baohuoside 1: Barnidipine; Batebulast; Beau Depsidomycinderamciclane; Dermatan Sulfate; Deserpi vericin; Becaplermin; Becliconazole; Beclomethasone dine; Desirudin: Desloratadine; Desmopressin, DeSoxoami Dipropionate Monohydrate; Befloxatone; Bellenamine: odarone; Desoxyribonuclease; Detajrniurn Bitartrate; Benflumetol; Benidipine; Bentoquatam; Benzisoxazole; Dexketoprofen; Dexioxiglumide: Dexmethylphenidate US 2007/0269379 A1 Nov. 22, 2007 20

Hydrochloride; Dexrazoxane Hydrochloride; Dexsotalol; Hydroxy stilbamidine Isethionate; Ibandronate Sodium; Dextrin 2-Sulphate; Dextroamphetamine Adipate; Dextro Ibogaine; Ibudilast; Ibuprofen Potassium: Icodextrin; Illi amphetamine Resin Complex; Dextroamphetamine Saccha maquinone; Iloprost, Imatinib Mesylate: Imidapril, Imida rate; Dextrose; Diclofenac Digolil; Dicranin; Dienogest; Zenil, Imiglucerase: Imipramine Pamoate; Inaminone Lac Diethylhomospennine; Diethylnorspermine; Difenoxin tate; Indapamide; Indinavir; Indinavir Sulfate; Indium Hydrochloride; Dihydrexidine; Diltiazeim; Dimethyl Pros In-111 Oxyquinoline; Indium In-111 Pentetate Disodium; taglandin Al; Dimethylhomospermine; Dimiracetam; Indium In-111 Pentetreotide Kit; Indometacin; Indometacin Dimyristoyl Lecithin; Diphemanil Methylsulfate; Diphen Farnesil; Indomethacin Sodium; Inocoterone; Inogatran; cyprone; Diphenylpyraline Hydrochloride; Diprafenone; Inolimomab, Insulin Aspart; Insulin Aspart Protamine; Insu Dipropylnorspermine; Discodermolide; Divalproex: Docar lin Glargine; Insulin Lispro Protamine; Interferon Alfa: pamine; Docosanol, 1-, Dolasetron Mesylate Monohydrate; Interferon Alfa-NI; Interferon Beta; Interferon Beta-lal; Domitroban; Donepezil Hydrochloride; Dorzolamide: Dos Interferon Gamma-I A: Interferon Gamma-I B; Interferon malfate; Dotarizine; Doxazosin; Doxercalciferol: Draculin; Omega; Interferon, Consensus; Interleukin-3; Interleukin-1; Drosperidone; Drospirenone; Drotaverine Acephyllinate: Interleukin-I Beta; Interleukin-10; Interleukin-1, Interleu Droxicam; Dutasteride; Ebiratide: Ebrotidine; Ecabapide: kin-12; Interleukin-15; Interleukin-2: Interleukin-4; Inter Ecabet; Ecdisteron; Echicetin; Echistatin; Ecteinascidin leukin-5; Interleukin-7: Interleukin-8: Interleukin I Alpha; 722; Ecteinascidin 729; Ecteinascidin 743; Edaravone; Ede Intrinsic Factor; Inulin; Invert Sugar; lobenguane Sulfate I tate Calcium Disodium; Edetate Disodium; Edobacomab, 131; lobitridol; Iodamide Meglumine; lodipamide Sodium; Edrecolomab: Efavirenz; Efegatran; Efonidipine; Egualen; Iodoamiloride: Iodohippurate Sodium, I-123: Iodohippurate Elcatonin; Eletriptan; Eletriptan Hydrobromide: Elgodipine; Sodium, I-131; Iofetamine Hydrochloride I-123: Iofratol; Eliprodil; Eltenac; Emakalim; Emedastine; Emedastine Iopromide; lopyrol: Iomeprol; lothalamate Sodium, I-125; Difumarate; Emiglitate; Emoctakin; Emtricitabine: Enala Iotriside; Ioxaglate Sodium; Ipazilide; Ipenoxazone; Ipida pril: EnaZadrem, Enfluvirtide; EnglitaZone; Entacapone; crine; Ipomeanol. 4; priflavone; Ipsapirone; Irbesartan; Enterostatin; Eplerenone; EpoxymeXrenone; Eptastigmine; Irloxacin; Iron Dextran; Iron Sucrose; Irtemazole; Isalsteine; Eptifibatide; Erdosteine; Ergocalciferol; Ersentilide; Ertap Isbogrel, Isepamicin; Isofloxythepin; Isopropyl Unopros enem Sodium; Erythritol; Escitalopram Oxalate; Esomepra tone; Itameline; Itopride; Ketoprofen, R-; Ketoprofen, S-: Zole Magnesium: EstaZolam, Estradiol Acetate; ESuprone; Ketorolac, Lactitol; Lactivicin; Lactulose; Laennec; Lafuti Etanterol: Ethacizin; Ethchlorvynol; Ethinamate; Ethi dine; Lanoconazole; Lanperisone; Larnifiban; Larnotrigine; nylestradiol: EthoXZolamide: Etidocaine Hydrochloride: Latanoprost; Lateritin: Laurocaprarn: Leflunomide: Leme Etizolam; Etrabamine; Eveminomicin; Examorelin; floxacin: Leminoprazole; Lenercept; Lepirudin; Leptin; Ler EZetimibe; Faerieftmgin; Fantofarone; Farnciclovir, Faro canidipine; Lerisetron; Lemildipine; Lesopitron; LetraZuril; penem; Fasidotril; Fasudil; Fedotozine: Felbamate; Fenofi Leucomyzin; Levalbuterol Hydrochloride; Levallorphan brate; Fenoldopam; Fenspiride: Fentanyl: Fenticonazole; Tartrate; Levamisole Hydrochloride; Levetiracetam; Levo Fepradinol; Ferpifosate Sodium; Ferristene; Ferrixan: Fer betaxolol; Levobunolol; Levobupivacaine; Levobupiv rous Citrate, Fe-59; Fexofenadine Hydrochloride; Fibrino acaine Hydrochloride; Levocabastine; Levocarnitine; Levo gen, I-125; Fibrinolysin; Flecamide: Flerobuterol; Flesi dropropizine; Levofloxacin; Levopropoxyphene Napsylate, noxan; Flezelastine; Flobufen, Flomoxef Florfenicol; Anhydrous; Levormeloxifene; Levornoprolol; Levosimen Florifenine: Flornastat; Flosatidil; Fludeoxyglucose, F-18: dan; LevoSulpiride; Lindane; Linezolid; Linotroban; Linsi Flumecinol; Flunarizine; Fluocalcitriol; Fluoxetine, R-. Flu dormine; Lintitript; Lintopride; Lipase; Lirexapride; Lithium oxetine, S-; Fluparoxan; Flupirtine: Flurbiprofen Axetil: Carbonate; Lithium Citrate; Lodoxamide; Lomerizine; Flurithromycin; Flutamide: Flutrimazole: Fluvastatin: Flu Lonazolac, Lopinavir, Lorglumide: Losartan; Losigamone; voxamine; Folic Acid; Follitropin Alfa: Follitropin Alfa/ Loteprednol; Loviride; Loxapine Hydrochloride; LpdR; Beta; Fomivirsen Sodium; Fondaparinux Sodium; Forasar Lubeluzole; Lutetium, Luzindole; Lydicamycin; Lysos tan; Formoterol; Formoterol Fumarate; Formoterol, R.R-. taphin; Magainin 2 Amide: Magnesium Acetate; Magnesium Fosinopril; Fosphenyloin. Frovatriptan Succinate; Fulves Acetate Tetrahydrate; Magnolol; Malathion; Malloto trant. Furosernide; Gadobenic Acid, Gadobutrol; Gadodia chromene; Mallotojaponin; Mangafodipir, Mangafodipir mide-EOB-DTPA; Gadopentetate Dimeglumine; Gadoteric Trisodium; Manidipine: Maniwamycin A; Mannitol; Manu Acid; Galantamine; Galantamine Hydrobromide: mycin E: Manumycin F: Mapinastine; Martek 8708; Martek Galdansetron; Gallopamil: Gamolenic Acid; Gatifloxacin: 92211; Massetolide; Meglumine Metrizoate; Meloxicam; Gefitinib; Gemifloxacin Mesylate: Gemtuzumab Ozogami Melphalan Hydrochloride; Menadiol Sodium Diphosphate: cin, Gepirone; Girisopam; Glaspimod: Glatiramer Acetate; Menadione; Meprednisone; Mequinol; Mersalyl Sodium; Glaucocalyxin A; Glucagon Hydrochloride; Glucagon Mesna; Metformin Hydrochloride; Methantheline Bromide: Hydrochloride Recombinant: Glucagon Recombinant: Glu Metharbital; Methoxamine Hydrochloride; Methoxatone: conolactone; Glutapyrone: Glutathione Disulfide: Glyco Methoxsalen: Methscopolamine Bromide: Methyclothiaz pine; Glycopril; Goserelin Acetate; Grepafloxacin; Grepa ide; Methyldopa; Methylhistamine, R-alpha; Methylinosine floxacin Hydrochloride; Guaifenesin; Guanidine Monophosphate; Methylprednisolone Aceponate; Meth Hydrochloride; Halichondrin B; Halofantrine: Halomon; yprylon; Metipamide: Metipranolol Hydrochloride; Metola Haloperidol Lactate; Halopredone; Hatomarubigin C: Zone: Metoprolol Fumarate; Metoprolol, S-; Metoprotol Hatomambigin D; Hatomamicin; Hatornarubigin A; Hator Tartrate; Metrifonate; Metrizoate Magnesium; Metrizoic narubigin B; Heparin Calcium; Heparin Sodium; Hexocyc Acid; Mezlocillin Sodium Monohydrate; Michellamine B: lium Methylsulfate: Hexylcaine Hydrochloride: Histrelin Microcolin A; Midodrine; Miglustat; Milacemide: Milarne Acetate; Hyaluronidase; Hydrocortamate Hydrochloride; line: Mildronate; Milnacipran; Milrinone Lactate; Hydrocortisone Cypionate; Hydrocortisone Probutate; Hyd Miokarnycin; Mipragoside; Mirfentanil; MivaZerol; Mixan roquinone; Hydroxocobalamin; Hydroxypropyl Cellulose; pril; Mizolastine: Mizoribine: Moexipril: Moexipril Hydro US 2007/0269379 A1 Nov. 22, 2007

chloride: Mofezolac; Mometasone: Mometasone Furoate Rokitamycin; Ropinirole; Ropivacaine; Ropivacaine Hydro Monohydrate; Monobenzone: Montirelin; Moracizine; chloride Monohydrate; Roquinimex: Rose Bengal Sodium, Moricizine Hydrochloride; Mosapramine; Mosapride; I-131; Rosiglitazone Maleate; Roxatidine; Roxindole; Motilide; Moxifloxacin Hydrochloride; Moxiraprine; Mox Rubidium Chloride Rb-82; Rufloxacin; Rupatidine, Ruza onidine; Mupirocin; Mupirocin Calcium; Mycophenolate dollane; Sacrosidase; Safflower Oil: Safironil; Salbutamol. Mofetil Hydrochloride; Nadifloxacin; Nadroparin Calcium; R-; Salnacedin, R-; Samarium Sm 153 Lexidronam Penta Nafadotride; Nafamostat; Naftopidil; Naglivan; Nalmefene sodium; Sanfetrinem; Saprisartan; Sapropterin; Saquinavir, Hydrochloride; Naltrexone Hydrochloride; Napadisilate; Sarcophytol A Sargramostim; Sameridine; Sampatrilat; Sar Napsagatran; Naratriptan; Nasaruplase; Nateglinide; pogrelate: Saruplase; Saterinone; Satigrel; Satumomab Pen detide; Scopolamine; Secretin: Selenomethionine, Se-75; Nateplasel; Nelfinavir Mesylate; Nesiritide; Niacinamide: Sematilide: Sermorelin; Semotiadil; Sertaconazole; Sertra Nicotine; Nicotine Polacrilex: Niperotidine; Niravoline; line: Sertraline-HCl; Setiptiline: Sevelamer Hydrochloride: Nisin; Nitazoxanide: Nitecapone: Nitisinone; Nitrendipine, Sevirurnab: Sezolamide: Sildenafil Citrate; Silipide; S-: Nitrofurantoin Monohydrate; Nitrofurantoin Sodium; Silteplase; Silver Sulfadiazine; Simendan; Simethicone; Nitrofurantoin, Macrocrystalline; Nitrofurazone; Nitroglyc Simethicone-Cellulose: Sinitrodil; Sinnabidol; Sipatrigine; erin: Nonoxynol-9; Norelgestromin; Octyl Methoxycin Sirnvastatin: Somatomedin C; Somatropin Recombinant; namate; Olmesartan Medoxomil; Olopatadine; Olopatadine Sorbitol; Somatomedin B: Sornatirem: Sornatropin; Sotalol; Hydrochloride; Olprinone; Olsalazine; Omeprazole Magne Staurosporine; Stepronin; Stobadine; Strontium Chloride, sium: Ondansetron, R-: Oral Hypoglyceremics; Sr-89: Succibun; Sulfanilamide: Sulfaphenazole; Sulfapyri Orphenadrine Hydrochloride; Oseltamivir Phosphate, Oten dine: Sulfoxamine; Sulfoxone Sodium; Sulfur, Sultamicil Zepad: Oxamisole; Oxaprozin Potassium; Oxcarbazepine; lin; Sultopride; Sumatriptan; Sutilains; Symakalim; Talb Oxiconazole; Oxiracetam; Oxodipine: Oxybenzone: Oxy utal; Tandospirone; Tannic Acid; Tapgen; Taprostene; butynin. Oxyphencyclimine Hydrochloride; Oxyphenonium Tartaric Acid; Tazanolast: Tegaserod Maleate; Telenzepine; Bromide: Ozagrel; Palauamine: Palinavir, Palonosetron Telmesteine; Telmisartan; Temocapril; Tenofovir Disoproxil Hydrochloride; Pamaparin Sodium; Panamesine; Pancreli Fumarate; Tenosal; Tepirindole; Terazosin; Terbinafine pase; Panipenem; Panipenum; Pannorin; Panornifene, Pan Hydrochloride; Terflavoxate; Terguride; Terlipressin; tethine; Pantoprazole Sodium; Pantothenic Acid; Terodiline; Tertatolol; Testosterone Buciclate: Thallous Paramethadione; Paricalcitol; Pamaqueside; Pamicogrel; Chloride, TI-201: Thiamine: Thiamine Hydrochloride: Paroxetine Hydrochloride; Paroxetine Mesylate; Partheno Thiofedrine: Thiomarinol; Thioperamide; Thiosemicarba lide; PaZufloxacin: Pegademase Bovine; Pegvisomant; Zone: Thonzonium Bromide; Thyroglobulin; Thyrotropin: Pemirolast; Pemirolast Potassium; Penciclovir Sodium; Thyrotropin Alfa; Tiagabine; Tiagabine Hydrochloride; Penicillamine: Pentafuside; Pentagastrin; Pentamidine; Pen Tianeptine; Tiapafant; Ticlopidine; Tienoxolol; Tilisolol; tamidine Isethionate; Pentetate Calcium Trisodium Yb-169; Tilnoprofen Arbamel: Tiludronic Acid; Tiopronin; Tiotro Pentigetide; Pentolinium Tartrate; Pentosan; Perflexane: pium Bromide; Tirandalydigin; Tirilazad; Tirofiban; Tiro Perfluoropolymethylisopropyl Ether; Perflutren: Pergolide; pramide: Tocopherol Acetate; Tolterodine Tartrate; Pergolide Mesylate: Perindoprilat; Pemedolac, Perospirone; Torasemide: Trafennin; Trandolapril; Tranylcypromine Sul Phenaridine; Phenindione; Pheniramine Maleate; Phenme fate: Travoprost; Traxanox; Trazodone-HCl; Treprostinil trazine Hydrochloride; Phenotoxifvline; Phenserine; Phen Sodium; Tretinoin Tocoferil; Triarntevene; Tricaprilin; Tri succinal; Phentermine Resin Complex; Phentolamine Mesi chohyalin; Trichosanthin, Alpha; Triclosan; Tridihexethyl late; Phenylalanyl Ketoconazole; Phenylephrine Bitartrate; Chloride; Trientine; Trientine Hydrochloride; Triflavin; Tri Phenyloin Sodium, Extended; Phenyloin Sodium, Prompt; megestone; Trimethoprim Hydrochloride; Trioxsalen; Trip Phosphoric Acid; Phytonadione: Picenadol; Picroliv; Picu torelin Pamoate; Trolamine Polypeptide Oleate Condensate; meterol; Pidotimod: Pilsicamide: Pimagedine: Pimecroli Trombodipine; Trometarnol; Tromethamine; Tropine Ester; mus: Pimilprost; Pinocebrin; Pioglitazone; Piperonyl Butox Trospectomycin; Trovafloxacin; Trovafloxacin Mesylate; ide: Pirlindole: Pirmenol; Pirodomast; Polyestradiol Trovirdine: Tucaresol; Tulobuterol; Tylogenin; Tyloxapol: Phosphate: Polyethylene Glycol 3350; Polytetrafluoroethyl Undecoylium Chloride: Undecoylium Chloride Iodine Com ene: Poractant Alfa: Potassium Chloride; Pramipexole Dihy plex: Unoprostone Isopropyl; Urapidil; Urea, C-13; Urea, drochloride; Praziquantel; Prazosin; Prilocalne; Procaine C-14; Uridine Triphosphate; Valaciclovir; Valdecoxib; Val Merethoxyline: Proguanil Hydrochloride; Propagerma ganciclovir Hydrochloride; Valproate Magnesium; Val nium; Propentofylline; Propiolactone; Propiomazine Hydro proate Semisodium; Valrubicin; Valsartan; Vamicamide; chloride: Propionylcamitine, L-: Propiram; Propiram+ Vanadeine; Vaninolol; Vasopressin Tannate; Venlafaxine; Paracetamol; Propiverine; Prostratin: Protegrin: Protein Verapamil, (S); Veratrum Viride; Veroxan: Vexibinol; Vin Hydrolysate: Protokylol Hydrochloride; Protosufloxacin: bumine Citrate; Vinbumine Resinate; Vinconate; Vinpocet Prulifloxacin: Pyrethrins; Pyridoxine: Pyridoxine Hydro ine; Vinpocetine Citrate; Vintoperol; Viomycin Sulfate; chloride: Quazepam; Quetiapine; Quetiapine Fumarate: Vitamin A; Vitamin A Palmitate; Vitamin E: Vitamin K: Quiflapon; Quinagolide; Quinapril; QuinethaZone; Quini Voriconazole; Voxergolide; Warfarin Potassium; dine Polygalacturonate; Raloxifene: Ramatroban; Ranelic Xemilofiban: Ximoprofen; Yangambin: Zabicipril; Acid; Ranolazine: Rapacuronium Bromide: Recainarn; Zacopride; Zacopride, R-; Zafirlukast; Zalospirone; Zalto Regavirumab: Repaglinide; Rescinnamine; Resinferatoxin; profen; Zanamivir; Zanamivir, Zankiren; Zatebradine; Reticulon; Reviparin Sodium; Revizinone; Riboflavin; Zatosetron: Zenarestat; Zinostatin Stimalamer, Ziprasidone: Riboflavin Phosphate Sodium; Ricasetron; Rilopirox: Ziprasidone Mesylate; Zoledronic Acid; Zolmitriptan; Rimantadine; Rimexolone; Rimoprogin; Riodipine; Ripisar Zolpidern; Zopiclone; Zopiclone, S-: Zopolrestat; Zotepine. tan; Risedronic Acid; Rispenzepine; Ritipenem Acoxil, Riti penern; Ritonavir; Rivastigmine Tartrate; Rizatriptan Ben 0265 Still other examples of pharmaceuticals are listed Zoate; Rnibefradil; Rnivacurium Chloride; Rofecoxib; in 2000 MedAdNews 19:56-60 and The Physicians Desk US 2007/0269379 A1 Nov. 22, 2007 22

Reference, 53rd. Edition, pages 792-796, Medical Econom development of tans and artificial tans, improvement of skin ics Company (1999), both of which are incorporated herein moisture content, improvement of skin barrier properties, by reference. control of Sweat, anti-ageing, reduction or avoidance of irritation and reduction or avoidance of inflammation. Skin 0266 Examples of suitable veterinary pharmaceuticals care actives can be molecules such as protease and/or other for used with SCOPE formulations include, but are not enzyme inhibitors, anti-coenzymes, chelating agents, anti limited to, Vaccines, antibiotics, growth enhancing compo bodies, antimicrobials, humectants, vitamins, skin pro nents, and dewormers. Other examples of suitable veterinary tectants and/or skin soothing agents, plant extracts and the pharmaceuticals are listed in The Merck Veterinary Manual, like. Examples of skin care actives include but are not 8th Edition, Merck and Co., Inc., Rahway, N.J., 1998: limited to vitamin C. vitamin E (alpha tocopherol), retinoids, (1997); The Kirk-Othmer Encyclopedia of Chemical Tech Soy derivatives (e.g. isoflavones), green tea polyphenols, nology, Volume 24 Kirk-Othmer (4th Edition at page 826); alpha hydroxy acids (e.g. glycolic and lactic acid), beta and Veterinary Drugs by A. L. Shore and R. J. Magee, hydroxy acids (e.g. salicylic acid), polyhydroxy acids, alpha American Cyanamid Co. in The Encyclopedia of Chemical lipoic acid, hemp oil (glycerides), niacinamide, dimethyl Technology 2nd. Edition, Volume 21, all of which are aminoethanol, coenzyme Q10, kinetin (plant growth hor incorporated herein by reference. mone), dimethyl sulfone and botulinum toxin. 0267 "Potency phase map” means a plot of the magni 0272 "Solvent” means a fluid in which a component such tude of penetration enhancement as a function of two or as an active component, carrier, or adhesive will dissolve. more compositional variables. Solvents are selected based on the solubility of the compo 0268 “Sample' or equivalently “formulation' means a nent to be dissolved, chemical compatibility, biocompatibil component or a mixture of a plurality of components. A ity and other factors. Aqueous solvents can be used to make sample typically contains at least one active component and matrices formed of water soluble polymers. Organic sol at least one inactive component, although this is not a vents will typically be used to dissolve hydrophobic and requirement. For example, approximate measurements of Some hydrophilic components. Preferred organic solvents penetration enhancement may be made on samples contain are volatile or have a relatively low boiling point or can be ing a chemical penetration enhancer or a combination of removed under vacuum and which are acceptable for admin chemical penetration enhancers, usually with a solvent, but istration to humans in trace amounts, such as methylene without an active component. Samples and formulations can chloride. Other solvents, such as ethyl acetate, ethanol, take many forms, which include, without limitation, solids, methanol, dimethyl formamide (DMF), acetone, acetoni semisolids, liquids, solutions, emulsions, suspensions, tritu trile, tetrahydrofuran (THF), acetic acid, dimethylsulfoxide rates, gels, films, foams, pastes, ointments, adhesives, highly (DMSO) and chloroform, and combinations thereof, also Viscoelastic liquids and any of the foregoing having solid may be utilized. Preferred solvents are those rated as class particulates dispersed therein. 3 residual solvents by the Food and Drug Administration, as published in the Federal Register vol. 62, number 85, pp. 0269. When performing high throughput experimenta 24301-24309 (May 1997), incorporated herein by reference. tion on samples it is preferred that the samples are placed in Solvents for drugs will typically be distilled water, phos an array format. Samples in a sample array may each phate buffered saline (“PBS”), Lactated Ringer's or some comprise a different composition, or the sample array may other pharmaceutically acceptable carrier. contain replicate samples, standards and/or blanks. A sample can be present in any container or holder or in or on any 0273 "Synergy value” between two CPEs, A and B, in a material or surface. Preferably, the samples are located at formulation is calculated using the following equation: separate sites. Preferably, where samples are in an array format, samples are contained an array of sample wells, for example, a 24, 36, 48.96,384 or 1,536 well plate array. The ERA, B (X, Y) sample can comprise less than about 100 milligrams of an * x. ERy) (1 x). ERy). active component, preferably, less than about 1 milligram, more preferably, less than about 100 micrograms, and even more preferably, less than 100 nanograms. Preferably, the where ERAL(X,Y) is the enhancement ratio obtained with sample has a total volume of about 1-200ul, more preferably the formulation containing CPEs A and B, Y stands for the about 5-150 ul, and most preferably about 10-100 ul. combined amount of A and B expressed in wit/vol and X stands for the weight fraction of A computed as the amount 0270 "Skin' means the tissue layer forming the external of A in formulation (expressed in wit/vol) divided by Y. covering of the body of a human or animal, which is in turn ERACY) and ER(Y) are measured by preparing formula characterized by a number of sub-layers such as the dermis, tions whose composition is the same as that containing the the epidermis and the stratum corneum. CPEs A and B except that CPEs A and B are replaced with 0271 "Skin care actives” means all compounds or sub either pure component A at a wit/vol of Y or pure component stances now known or later demonstrated to provide benefit B at a wt/vol of Y. ERACY) and ER(Y) are then the when applied to the skin of patients or consumers and all enhancement ratios measured for the formulation in which compounds now claimed or in the future claimed to provide A, but not B, is present and B, but not A, is present, benefit when applied to the skin of patients or consumers. respectively. Enhancement ratios, and as a consequence Skin care actives may provide benefits, or claimed benefits, Synergy values, are a function of time and it is understood in areas such as wrinkle removal or wrinkle reduction, that the enhancement ratios in the above equation should be firming of skin, exfoliation of skin, skin lightening, treat measured at equal times. The term “t-hour synergy value' is ment of dandruff, treatment of acne, skin conditioning, understood to mean the synergy value calculated using US 2007/0269379 A1 Nov. 22, 2007

t-hour enhancement ratios, where thours may be any period 21-day cumulative irritation test described by Berger and of time over which enhancement ratios may be reasonably Bowman (1982). The 21-day cumulative irritation test score measured. is a measure of irritation potential and acceptable variations 0274 “Test membrane' means a membrane that is suit and modifications thereof. able for use in a diffusion cell experiment. A test membrane may be natural or synthetic skin or related tissue Such as 0280 For a rapid assessment of combinations of penetra mucosal tissue, preferably stratum corneum or skin tissue, tion enhancers, a high throughput experimentation system Such as hairless mouse skin, porcine skin, guinea pig skin, has been developed. Karande et al. (2002), and International or human skin. If human cadaver skin is to be used, one Application Number PCT/US01/26473 entitled “A Combi known method of preparing the test membrane entails heat natorial Method For Rapid Screening Of Drug Delivery stripping by keeping it in water at 60° C. for two minutes Formulations”, published under International Publication followed by the removal of the epidermis, and storage at 4 Number WO 02/16941 A2. The HTE system provides an C. in a humidified chamber, a piece of epidermis is taken out efficient method to monitor the depletion of a test substance from the humidified chamber prior to the experiments and from a donor well, the migration of the test Substance into optionally supported by a porous Support Such as Nylon a test membrane, and/or the migration of the test Substance mesh (available from Sefar America Inc. (Tetko Inc.) of through a test membrane into a receptor well. A test mem Depew, N.Y.: www.sefaramerica.com, or Fisher Scientific of brane is secured to a donor plate having a plurality of Pittsburgh, Pa.; www.fishersci.com) to avoid damage and to through holes forming donor wells. Formulations are intro mimic the fact that the skin in Vivo is Supported by mechani duced into donor wells and a characteristic of the test cally strong dermis. Other types of tissues may also be used, Substance that remains in the donor well or migrates into the including living tissue explants, any of a number of endot test membrane is evaluated. A receptor plate can be provided helial or epithelial cell culture barriers, such as those that is formed with receptor wells that correspond to the described in Audus, et al., animal tissue (e.g. rodent, bovine or Swine) or engineered tissue-equivalents. Audus et al. donor wells, the test membrane being secured between the (1990). Examples of a suitable engineered tissues include donor plate and the receptor plate. The device can further DERMAGRAFTR, a human fibroblast-derived dermal Sub include electrodes to measure current across the test mem stitute (available from Smith & Nephew, Inc. of Largo Fla.: brane. www.dermagraft.com) and those taught in U.S. Pat. No. 0281 Transdermal and Topical Drug Delivery: Transder 5,266,480, which is incorporated herein by reference. A synthetic membrane. Such as an elastomeric membrane, may mal drug delivery can be used to circumvent first pass also be used. The nature of the test membrane is membrane metabolism and provide a Sustained drug release for a is preferably chosen based in the desired application. prolonged period of time. Topical drug delivery allows a Screening of formulations for transdermal delivery is pref. drug to be applied directly to the surface of area to be erably conducted using pigskin; whereas to Screen formu treated, which can be useful to localize the treatment and minimize side effects. Evolved to impede the flux of toxins lations for buccal, vaginal, nasal drug delivery and the like, into the body, skin however offers a very low permeability mucosal membrane might be used, and so forth. to the movement of foreign molecules across it. The stratum 0275 “Therapeutically effective amount’ means a suffi corneum is responsible for this barrier. It possesses a unique cient amount of a drug to provide the desired therapeutic hierarchical structure of lipid rich matrix with embedded effect or other desired effect, for example, a prophylactic keratinocytes in the upper strata (15um) of skin. Bouwstra effect. (1997). Overcoming this barrier safely and reversibly is a 0276 “Transdermal drug delivery' or “transdermal drug fundamental problem that persists today in the field of administration” refers to administration of a drug to the skin transdermal delivery. Although more than two hundred and Surface of an individual so that the drug passes through the fifty chemical enhancers including Surfactants, aZone and skin tissue and into the individual’s blood stream. The term related chemicals, fatty acids, fatty alcohols, fatty esters, and “transdermal' is intended to include “transmucosal” drug organic solvents have been tested to increase transdermal administration, i.e., administration of a drug to the mucosal drug transport, only a handful are actually used in practice. (e.g., Sublingual, buccal, vaginal, rectal) surface of an indi Berti et al. (1995). This discrepancy results from the fact that vidual so that the drug passes through the mucosal tissue and among all the enhancers that have been used, only a few into the individual’s blood stream. induce a significant (therapeutic) enhancement of drug trans 0277 “Topical drug delivery' or “topical drug adminis port, Walters (1989); Finnin (1999). Furthermore skin irri tration' is used in its conventional sense to mean delivery of tation and safety issues limit the applications of several a topical drug of a pharmacologically active agent to the skin enhancers. These limitations are overcome by the invention or mucosa, as in, for example, the treatment of various skin and the use of special combinations of chemical penetration disorders. Topical drug administration, in contrast to trans enhancers. dermal administration, is often used to provide a local rather 0282 Most molecules known as potent enhancers in the than a systemic effect. literature are also potent irritants. Very few molecules that 0278 “21-day cumulative irritation test” refers to the show therapeutically significant enhancements are physi 21-day patch test described by Berger and Bowman (1982) ologically compatible. This remains a limiting step in entitled “A reappraisal of the 21-day cumulative irritation exploiting transdennal delivery as an efficient delivery test in man,” and acceptable variations and modifications mode. By combining two or more penetration enhancers, the thereof. concentration of each enhancer required to achieve desired 0279) “21-day cumulative irritation test score” means the enhancements may be lower than that required if any one of score achieved by a formulation on the 630 point scale of the the enhancers was used individually. There is limited litera US 2007/0269379 A1 Nov. 22, 2007 24 ture data available on combinations of chemical enhancers. The first step, 12, is to select individual penetration enhanc Mollgaard (1993); Funke et al. (2002); Karande et al. ers. Then, if desired, a library of CPE combinations is (2000). designed, at 14. One or more combinations or a library may 0283. In screening as contemplated herein a large diverse be screened, at 16, for the ability of the CPE combinations library of component combinations, for example, is selected to increase skin permeability. The Screening data may be from the above categories of enhancers, either randomly or analyzed, at 18, for hot spots and selected CPE combinations based on knowledge about the mechanism of action of the may be selected for further analysis and measurement of enhancers. If individual enhancers increase transdermal irritation potential, at 20. The irritation potential data may be transport via different mechanisms, their combination can be analyzed, at 22, and a refined list of CPE combinations more effective than either of them alone. Chemical penetra developed for further analysis. The selected CPE combina tion enhancers increase skin permeability by reversibly tions may be combined with a selected drug and in vitro disrupting or by altering the physiochemical nature of the quantification performed, at 24. Finally, candidate combi stratum corneum to reduce its diffusional resistance. Typi nations may be selected from, for example, the in vitro cally a penetration may enhancer increase SC penetrability quantification data and in vivo tests are performed, at 26, for by any of the following mechanisms, for example (Shah, et irritation, safety and efficacy. al. (1993)): 0293. It can be seen that the sequence of steps provided in FIG. 1 provides a procedure whereby a pool of candidate 0284 fluidizing the crystalline structure of SC by formulations may be progressively narrowed to Smaller incorporating itself in the lipid bilayer; Subsets of the initial pool. The formulations remaining under 0285) dissolving skin lipids by forming mixed aggre investigation may tend to become, on average, better Suited gates with lipid molecules; to the task of delivering active components in topical or transdermal products with each narrowing step of the pro 0286 acting as a co-solvent for the drug, thereby cess. It is understood that if any narrowing step in the work driving more drug into the solvent phase; flow causes all the formulations in the pool to be removed, the procedure may be restarted by returning to 14 and 0287 increasing the partition coefficient of drug in generating a new library of formulations containing com skin and thus increasing its distribution in the lipid positions that have not been previously studied or, alterna matrix; and/or tively, returning to step 12 and selecting a different set of 0288 altering polar or non-polar pathways in the mul chemical penetration enhancers with which to work. tilaminate lipid matrix. 0294 More particularly, a set of CPEs may be chosen, for 0289. A combination of two molecules chosen from two example by selecting compounds from the list of enhancers independent categories above may better than either of them introduced previously. CPEs may also be selected from alone. An enhancer A that fluidizes the bilayer and an compounds that are analogs of the previously introduced enhancer B that forms mixed aggregates with the skin lipids enhancers, or that may be generally classified as, for may work, for example, in either of the following ways: example, Surfactants, aZones, Solvents, fatty alcohols, fatty acids or fatty esters or selected from compounds that are 0290 component A fluidizes the bilayer, facilitating dis related to compounds in these classes. The CPEs may also solution of lipid molecules in the bilayer by component B; be selected from other compounds that have previously been and/or component B dissolves the bilayer thus facilitating found to impact skin penetration, or that are related to Such incorporation of component A into the bilayer. compounds. Referring to FIG. 3 a list of CPEs from 0291. In either case, or for other reasons, the combination Example 1 is provided along with their abbreviated names of A and B may work better than A or B by itself. An (as used in this specification). example of this possibility is provided by the work of 0295). In another embodiment of the present invention a Karande et al., where high throughput Screening experi library of CPE formulations is designed. In practical appli ments revealed that mixtures of sodium lauryl sulfate and cations CPES may comprise only a fraction of the compo dodecyl pyridinium chloride are significantly more effective sition that is used in a product and it is therefore advanta in enhancing transdermal transport compared to each of geous to select one or more vehicles to which the CPEs are them alone. Karande et al. (2000). It might be thought that added to create the CPE formulation as part of a formulation the enhancement of penetration by formulations containing preparation or library design process. The vehicles may be A and B would vary in a gradual fashion as the concentration single Substances such as, for example, water, an alcohol or of A and B are varied and that the irritation potential of other single Substance solvent, or may include several Sub highly penetrating formulations will be tend to be higher stances Such as, for example, phosphate buffered saline than the irritation potential of less penetrating formulations. (PBS) and mixtures of PBS with solvents such as EtOH. The Surprisingly, however it has been discovered that a combi vehicle may also include complex materials designed to nation of penetration enhancers can yield sharp maxima mimic the actual use of the CPEs in commercial products about which the penetration rates varies rapidly with the Such as the matrices used in patch devices, formulations concentration of constituent CPEs. A further surprise is that used for cosmetics products and the like. In a preferred compositions in the vicinity of these maxima in composition embodiment, to assist in later detection of hot spots, the space showing exceptional penetration enhancement can library is designed to include scans over a grid of compo also on occasion have exceptionally low irritation potential. sitions where the relative concentration of pairs of CPEs are 0292 FIG. 1 is a flow chart 10 showing in general terms, varied, while other compositional variables are held con a sequence of steps that may be applied to identify SCOPE stant. The library may include members that contain, for compositions according to one embodiment of the invention. example, 0, 1, 2, 3, 4, 5 or more different CPEs. Active US 2007/0269379 A1 Nov. 22, 2007

components that it is desired to deliver topically or trans 102 in this example contains 100 donor holes 108. When the dermally may be either present or absent from members of device is assembled, one end of the donor holes is sealed by the library. A practical example of library design is provided a test membrane 106 to form a series of donor wells also in Example 1 below where the set of CPEs introduced in called donor compartments. In typical operation a plurality FIG. 3 is divided into subsets, according to their chemical of samples 114 to be screened is introduced into the donor character. Referring to FIG. 4, the CPEs listed in the table in holes. In the example device presented in FIG. 2 the test FIG. 3 are classified into 8 Separate categories, each cat membrane 106 is supported by a receptor plate 104 which egory being divided into four blocks to construct the library. may also be called a receiver plate. The receptor plate 104 The categories are cationic Surfactants, anionic Surfactants, in turn contains a plurality of receptor wells 110 which may Zwitterionic Surfactants, nonionic Surfactants, fatty acids, also be called receptor compartments, receiver wells or fatty esters, aZone-like chemicals, and other. receiver compartments. In normal operation the receiver compartments 110 are filled with a fluid 112. While the use 0296. The fabrication of formulations or libraries may be of a receiver plate is generally preferred in Such high accomplished entirely manually or with the assistance of throughput screening devices the receiver plate is not nec automated fluid dispensing systems which are available essary and other geometries without receiver plates may be from a wide range of suppliers (e.g. MultiPROBER II and utilized, as explained in International Publication Number MultiPROBER EX, available from PerkinElmer Life and WO 02/16941 A2. The donor plate 102, receiver plate 104 Analytical Sciences, Inc. of Boston, Mass. (las. Derkinelm and test membrane in the device shown in FIG. 2 are secured er.com), the Multiple Probe 215 and ConstellationTM 1200 by means of bolts 116 and wing nuts 118. Where skin available from Gilson, Inc. of Middleton, Wis. (www.gilson conductivity is utilized to monitor changes in the perme .com), the Microlab STAR available from Hamilton Com ability of the test membrane the device may be further pany of Reno, Nev. (www.hamiltoncomp.com), the Syn provided with one or more electrodes (shown as a single QUAD available from Genomic Solutions (Cartesian electrode 124 in FIG. 2) for contacting with the samples 114 Technologies) of Irvine Calif. (www.cartesiantech.com), the together with a signal generator 120) and a device 122 for Tango TM available from Matrix Technologies Corp. (Rob measuring electrical signals, such as for example a digital bins Scientific) of Sunnyvale Calif. (www.robsci.com), and multimeter. the Genesis and Genesis NPS, available from Tecan, head quartered in Mannedorf near Zurich, Switzerland (www.te 0300. In a particularly preferred embodiment of the can.com)). In a preferred embodiment of the invention the present invention porcine skin may be used as a model for CPE formulations are fabricated in a sequenced fashion to the screening or HTE studies. The donor and receiver plates support screening of the CPE formulations. may be conveniently constructed from materials such as polycarbonate or Teflon and may be approximately one half 0297. The CPE combinations are subjected to screening, inch thick. A device, suitable for use in the present invention, for example, HTE screening for a rapid assay of their may be constructed by drilling 100 holes (each of diameter enhancement potentials. Traditional methods of formulation 3 mm) in the donor and receiver plates to act as the donor testing (Franz diffusion cells) rely on steady-state measure and receptor compartments, respectively. Phosphate buff ments of drug transport across the skin. Bronaugh, 1989. ered saline (PBS) may be utilized to fill the receptor com These methods, though useful for quantifying the drug dose partments and the skin may be clamped between the two delivered across the skin, are not suitable for HTE screening plates with the stratum corneum facing the donor plate. Care due to: a) inefficient utilization of skin area, b) low time should be taken to ensure that there are no bubbles between efficiency due to elaborate sample collection and handling, the donor plate and the skin sample, so as to avoid experi and c) long time periods required to obtain steady state. The mental error in later measurements of penetration rates. The HTE method and allied high throughput devices address donor chambers are used to contain the CPE formulations to these challenges. Karande et al. (2002). Other high through be tested. put devices and methods for screening of formulations against skin are set forth in U.S. Pat. No. 5.490.415 and 0301 There are a number of measurements that can be International Application Number PCT/US01/22167 pub utilized to determine the effect of chemical enhancers on lished under International Publication Number WO skin permeability. These measurements generally involve O2/O6518 A1. contacting the formulation to be tested with skin or other suitable test membrane for a suitable incubation time. The 0298. In a preferred embodiment of the invention HTE or incubation time is preferably in the range of 2-96 hours and other screening is accomplished with a high throughput more preferably in the range of 4-24 hours. Measurements device comprising a donor plate, a receiver plate between that may be taken include, for example: which is sandwiched a test membrane which mimics the penetration properties of skin in a living Subject. The test 0302) (i) Measurement of solute penetration into the membrane may, for example, be human cadaver skin or skin: In this approach the ability of a solute or test porcine skin. It may also be a skin model Such as the Substance to penetrate into the skin is monitored. Solute EpiDermTM skin model available from Mattek Corporation, diffusion in the SC may be described by Fick's law. The Ashland, Mass. (www.mattek.com). The donor plate and solute concentration in the SC measured at short times receptor plate have a series of holes that form donor and is a function of its steady-state permeability. Accord receiver compartments for performing measurements of skin ingly, the amount of test Substance delivered into the penetration. skin can be measured at short times, for example, to Screen the efficacy of the enhancers or putative enhanc 0299 FIG. 2 provides plan and crossectional views an ers and formulations containing combinations thereof. example of a device that may be utilized for high throughput The amount of test substance delivered across the skin screening. In the plan view at the top of FIG. 2, a donor plate can also be measured to directly determine the effec US 2007/0269379 A1 Nov. 22, 2007 26

tiveness of enhancers or putative enhancers and for with high synergy values in the potency phase maps (con mulations containing combinations thereof. The test centration of other components being held approximately Substance may take many forms, the only requirement constant). An example of a potency phase map is provided being the availability of a method to measure the in FIG. 11 (for further discussion see Example 1). amount of the test Substance that penetrates into the 0307 Measure the irritation potential: A further step is skin or test membrane. For example, the test Substance measurement of irritation potential of the hot spot CPE may be a dye in which case colorimetric measurements combinations, which can be done by any known method. A can be used to assess the amount of the test molecule variety of in vitro skin corrosion test methods have been penetrating the skin. Alternatively, if test Substance developed and several have Successfully passed initial inter concentration can be assessed by HPLC the skin may national validation. Robinson et al. (2000). These have be solubulized after the incubation period and the included skin or epidermal equivalent assays that have been resulting solution subjected to HPLC analysis. In yet shown to distinguish corrosive from noncorrosive chemi another embodiment the HTE method follows the cals. These skin/epidermal equivalent assays have also been transport of a radiolabeled molecule, for example, modified and used to assess skin irritation potential relative mannitol, into the skin. to existing human exposure test data. The data show good 0303 (ii) Skin conductivity: In a preferred embodi correlation between the in vitro assay data so developed and ment of the invention, electrical conductance may be different types of human skin irritation data for both chemi used to determine skin permeability. Transepidermal cals and consumer products. The effort to eliminate animal current is mediated by the movement of charge carry tests has also led to the development of a novel human patch ing ions and is thus related to the permeability of these test for assessment of acute skin irritation potential. A case ions. The ion flux across the skin can be treated in the study shows the benefits of in vitro and human skin irritation same way as the flux of Solute molecules across the tests compared to the animal tests they seek to replace, and skin. Formal relationships relating ionic conductivity to strategies now exist to adequately assess human skin irrita permeability can be developed using Nemst-Planck tion potential without the need to rely on animal test flux equations and the Nemst-Einstein relations for methods. ideal solutions. Dugard et al. (1973); Srinivasan et al. 0308 Formulations represented by a hot spot can be (1965). Such relations become significant if one were placed, 24 at a time, on a culture of human skin cells and the to precisely estimate skin permeability based on con viability of the cells measured at the end of the study period, ductivity. However, for screening purposes it is suffi e.g., 4 to 24 hours, using a Mattek device (Mattek Corpo cient to know that skin possessing higher electrical ration, 200 Homer Avenue, Ashland, Mass. 01721, www conductivity exhibits higher permeability to polar sol mattek.com). Human skin constitutes the first immune utes. Accordingly, the electrical conductivity of skin defense barrier and serves as the interface between the exposed to various compositions is monitored to iden internal milieu and the external environment. Any attempt of tify the ones most efficient in increasing skin perme using this interface to deliver a formulation is a naturally ability, specifically to determine the “hot spots” as undesirable perturbation. Cutaneous irritation and corrosion described herein. are the main adverse reactions encountered during exposure 0304 (iii) Concentration changes: The concentrations of skin to a Xenobiotic or other external physical agent. of compounds in either the donor and/or receptor wells Acute irritation can be defined as “a non-immunological, may be monitored as function of time, by periodically inflammatory, reversible reaction following the applications sampling of materials from the wells. Changes in of a chemical Substance to an identical cutaneous site'. concentration as a function of time may be related to Manifestations include inflammation, redness, Swelling and the permeability of the sample. pain among other physiological responses. Marzuli et al. (1975); Judge et al. (1996) Wilhelmet al. (2001). Cumula 0305. In a preferred embodiment of the invention, skin tive irritation results from repeated or continued exposure to conductivity is used as endpoints to determine the effect of materials that do not themselves cause acute irritation. formulations on skin permeability: Current may, for Corrosion on the other hand may be defined as “a direct example, be measured periodically over 24 hrs across the chemical action on skin that results in its disintegration and skin at 143 mV peak to peak and 100 Hz frequency. The irreversible alteration at the site of contact. Manifestations conductivity enhancement ratio (ER) at time t is calculated include ulceration, necrosis, and, in time, the formation of as ER=I/I, where I, is the current measured at time t and scar tissue. Roguet (1999). While the types of cells involved Io is the current measured at time Zero (0). Skin Samples and the clinical aspects of these two reactions are similar, the occasionally contain defects. It is preferred that precautions underlying biological mechanisms are different. Schmitt are taken to avoid including ER values from wells with (1999); Schroder (1995). defective skin. A simple precaution that may be applied with 0309. Other tools are also available and may be used for the setup described here, when porcine skin is used as the determining the irritation potential of the hot spot including, test membrane, is to eliminate all ER values for which I>3 for example, irritation measurements using laser Doppler LA. perfusion imaging, laser Doppler flowmetry, transepidermal 0306 In a preferred embodiment of the invention the data water loss, visual scoring, colorimetric measurements, mex collected from screening or high throughput screening ameter Hb Scale and capacitance measurements. Fluhr et al experiments is analyzed for the presence of hot spots. This (2001); Zuanget al. (1999); Ollmaretal (1995). In vitro skin can be accomplished, for example, by generating potency irritation screens and computational approaches have been phase maps, showing skin permeability as the concentra used an in vitro testing models have been developed using tions of two CPEs are varied and looking for sharp maxima human or animal skin, 3-D skin “equivalent” culture sys US 2007/0269379 A1 Nov. 22, 2007 27 tems derived from human skin cells, or non-cellular “biobar the paper of Berger and Bowman, based on the earlier work rier systems. Medina et al. (2000) Lee (2000); Jung et al. of Lanman et al. Berger et al. (1982); Lanman et al. (1968). (1999); Augustin et al. (1997). A principal computational In this system test formulations are applied to the skin of the approach to predicting skin irritation has been “Ouantitative backs of a panel of human Volunteers over a 21-day period Structure Activity Relationship' (QSAR) methodology. and 21-day cumulative irritation test score computed by Kodithala et al. (2002); Smith et al. (2000); Hayashi et al. grading reactions to test materials and effects on Superficial (1999). QSAR is based on the evaluation of physicochemi layers of the skin on a daily basis. The 21-day cumulative cal properties of chemical compounds and an attempt to irritation test score measured according to Berger and Bow relate these properties to their biological activities. These man's system can have a value from 0-630. Test scores can methods however have been plagued with limitations. Ani be interpreted as follows: mal and human skin can be difficult to obtain. The equivalent cultures are more permeable to chemicals in absence of the 0314 0-49 indicates a mild material (no experimental natural pre-epidermal barrier. Bronaugh et al. (1985); Frais irritation); sinette et al. (1999). On the other hand QSAR methods are 0315 50-199 indicates a material is probably mild in effectively limited to dealing with analog structure-activity normal use; training sets while most structure activity data sets consist of structurally diverse compounds. Kodithala et al. (2002). In 0316 200-449 indicates a material that is possibly mild in light of this knowledge and given the low throughput and normal use; high expense of irritation potential measurement, methods 0317 450-580 indicates a material is an experimental that make efficient use of irritation potential measurement cumulative irritant; data are highly desired. 0318 581-630 indicates a material is an experimental 0310. In a preferred embodiment of the invention, in vitro primary irritant. quantification of permeability is performed with respect to formulations that show high penetration ability and low 03.19 Tests with very similar structure have been pro irritation potential. Each identified formulation may be vided as guidance to industry by the United States Food and combined with a selected drug or active (if actives are not Drug Administration for the irritation testing of generic already present in the library) and each combination may be transdermal drug products. (“Guidance for industry: Skin tested for penetration through skin. This can be done by any irritation and sensitization testing of generic transdermal known method. For example, a drug-formulation combina drug products.” U.S. Department of Health and Human tion can be placed on porcine or human skin and penetration Services, Food and Drug Administration, Center for Drug of the drug through the skin can be measured after a period Evaluation and Research, December 1999, available from of 24 to 96 hours using Franz diffusion cells (FDC). These http://www.fda.gov/cder/guidance/index.htm) results may then compared with published or otherwise 0320 Use of SCOPE Formulations. SCOPE composi available data to determine whether the drug-enhancer for tions can be utilized in a variety of ways. A SCOPE mulation can deliver the necessary drug amount. composition containing the active component of interest 0311. In vitro quantification of permeability may, for may be applied directly to the body surface. Alternatively, example, be accomplished by means of a vertical Franz two or even more compositions can be applied to the body diffusion cell with a receptor volume of approximately 12 ml surface and allowed to mix either passively by diffusion or and an area of about 1.7 cm. In such an embodiment 10 by means of mechanical agitation to create a SCOPE for uCi/mL radiolabeled mannitol may be used as an exemplary mulation in situ on the body surface. SCOPE formulations tracer Solute in transport experiments. The skin is incubated may be applied to a predetermined area of the skin or other with the formulations in the FDC assembly. At the end of the tissue for a period of time sufficient to provide the desired incubation period the skin is removed and rinsed gently and local or systemic effect. The method may involve direct the concentration of radiolabelled mannitol is measured application of the SCOPE formulation(s) as an ointment, using a liquid Scintilation counter. Enhancement of trans gel, cream, or the like, or may involve use of a drug delivery dermal mannitol transport may be calculated as Er=M/M. device such as a “patch.” Example 3, below, provides one where M is the amount of mannitol transported after a illustration of how a SCOPE formulation can be developed suitable incubation time in the formulation that showed high into a gel and utilized in a patch type of device. SCOPE penetration ability and Mo is the amount of mannitol trans formations may also be used in combination with other ported in the same incubation time in a control formulation approaches for permeabilizing skin including, for example, Such as PBS. techniques such as Sonophoresis, iontophoresis and elec troporation. Mitragotri, 2000, "Synergistic effect . . . . 0312 Animal testing may also be conducted to confirm the ability of the enhancer combinations to deliver sufficient 0321) Suitable SCOPE formulations for delivery of drug or other active across the skin to achieve therapeutic active components include ointments, creams, gels, lotions, levels of the drug in the animals blood. For example, in vivo pastes, and the like. Ointments, as is well known in the art experiments in hairless rats can be performed using leupro of pharmaceutical formulation, are semisolid preparations lide acetate as a model drug. that typically may be based on petrolatum or other petro leum derivatives. The specific ointment base to be used, as 0313 Products embodying a SCOPE composition will will be appreciated by those skilled in the art, is one that will normally be subject to testing in humans, including irritation provide for optimum drug delivery, and, preferably, will and sensitization testing, before being brought to market. provide for other desired characteristics as well, e.g., emol One procedure that may be followed for irritation testing is liency or the like. As with other carriers or vehicles, an provided by the standardized system described in detail in ointment base should preferably be inert, stable, nonirritat US 2007/0269379 A1 Nov. 22, 2007 28 ing and nonsensitizing. As explained in Remington: The Depending on the nature of the base, pastes are often divided Science and Practice of Pharmacy, 19th Edition ointment between fatty pastes or those made from a single-phase bases may be grouped in four classes: oleaginous bases; aqueous gels. The base in a fatty paste is generally petro emulsifiable bases; emulsion bases; and water-soluble bases. latum or hydrophilic petrolatum or the like. The pastes made Gennaro (1995). Oleaginous ointment bases include, for from single-phase aqueous gels generally incorporate car example, vegetable oils, fats obtained from animals, and boxymethylcellulose or the like as a base. semisolid hydrocarbons obtained from petroleum. Emulsi 0326 Various additives, known to those skilled in the art, fiable ointment bases, also known as absorbent ointment may be included in topical formulations. For example, bases, contain little or no water and include, for example, Solvents, including relatively small amounts of alcohol, may hydroxy Stearin Sulfate, anhydrous lanolin and hydrophilic be used to solubilize certain drug substances. Other optional petrolatum. Emulsion ointment bases are either water-in-oil additives include opacifiers, antioxidants, fragrance, colo (W/O) emulsions or oil-in-water (O/W) emulsions, and rant, gelling agents, thickening agents, stabilizers, Surfac include, for example, cetyl alcohol, glyceryl monostearate, tants and the like. Other agents may also be added, such as lanolin and Stearic acid. antimicrobial agents, to prevent spoilage upon storage, e.g., 0322 Creams, also well known in the art, are generally to inhibit growth of microbes such as yeasts and molds. Viscous liquids or semisolid emulsions, usually either oil Suitable antimicrobial agents are typically selected from the in-water or water-in-oil. Cream bases are water-washable, group consisting of the methyl and propyl esters of p-hy and contain an oil phase, an emulsifier and an aqueous droxybenzoic acid (e.g., methyl and propyl paraben), phase. The oil phase, also sometimes called the “internal Sodium benzoate, Sorbic acid, imidurea, and combinations phase, is generally comprised of petrolatum and a fatty thereof. alcohol Such as cetyl or Stearyl alcohol. The aqueous phase 0327. The concentration of the drug or other active usually, although not necessarily, exceeds the oil phase in component in the formulation can vary a great deal, and will Volume, and generally contains a humectant. The emulsifier depend on a variety of factors, including the disease or in a cream formulation is generally a nonionic, anionic, condition to be treated, the nature and activity of the active cationic or amphoteric Surfactant. agent, the desired effect, possible adverse reactions, the 0323. As will be appreciated by those working in the field ability and speed of the active agent to reach its intended of pharmaceutical formulation, gels are generally semisolid, target, and other factors within the particular knowledge of Suspension-type systems. Single-phase gels contain organic the patient and physician. Preferred formulations will typi macromolecules distributed substantially uniformly cally contain on the order of about 0.001 wt.% to 50 wt.%. throughout the carrier liquid, which is typically aqueous, but often about 0.01 wt.% to 1.0 wt.%, active component. also, preferably, contain an alcohol and, optionally, an oil. 0328. An alternative and preferred method of utilizing Preferred "organic macromolecules, i.e., gelling agents, are SCOPE compositions involves the use of a drug delivery crosslinked acrylic acid polymers such as the “carbomer' system, e.g., a topical or transdermal “patch, wherein the family of polymers, e.g., carboxypolyalkylenes that may be active agent is contained within a laminated structure that is obtained commercially under the Carbopol.R trademark. to be affixed to the skin. Williams (2003). In such a structure, Also preferred are hydrophilic polymers such as polyethyl the drug composition is contained in a layer, or “reservoir.” ene oxides, polyoxyethylene-polyoxypropylene copolymers underlying an upper backing layer. The laminated structure and polyvinylalcohol; cellulosic polymers such as hydrox may contain a single reservoir, or it may contain multiple ypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl reservoirs. methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and Xanthan 0329. In one embodiment, the reservoir comprises a gum, Sodium alginate; and gelatin. In order to prepare a polymeric matrix of a pharmaceutically acceptable adhesive uniform gel, dispersing agents such as alcohol or glycerin material that serves to affix the system to the skin during can be added, or the gelling agent can be dispersed by drug delivery; typically, the adhesive material is a pressure trituration, mechanical mixing or stirring, or combinations sensitive adhesive (PSA) that is suitable for long-term skin thereof. contact, and which should be physically and chemically compatible with the drug or other active agent, chemical 0324 Lotions, which are typically preferred for delivery penetration enhancers, and any carriers, vehicles or other of cosmetic agents, are preparations to be applied to the skin additives that are present. Examples of suitable adhesive Surface with low friction, and are typically liquid or semi materials include, but are not limited to, the following: liquid preparations in which solid particles, including the polyethylenes; polysiloxanes; polyisobutylenes; polyacry active agent, are present in a water or alcohol base. Lotions lates; polyacrylamides; polyurethanes; plasticized ethylene are usually suspensions of Solids. Lotions are preferred vinyl acetate copolymers; and tacky rubbers such as poly formulations for treating large body areas, because of the isobutene, polybutadiene, polystyrene-isoprene copolymers, ease of applying a more fluid composition. In general the polystyrene-butadiene copolymers, and neoprene(polychlo insoluble matter in a lotion is finely divided. Lotions will roprene). Preferred adhesives are polyisobutylenes. typically contain Suspending agents to produce better dis persions as well as compounds useful for localizing and 0330. The backing layer functions as the primary struc holding the active agent in contact with the skin, e.g., tural element of the transdermal system and provides the methylcellulose, sodium carboxymethylcellulose, or the device with flexibility and, preferably, occlusivity. The like. material used for the backing layer should be inert and incapable of absorbing the drug or other active component 0325 Pastes are generally semisolid dosage forms in or other components of the SCOPE formulation contained which the active agent is suspended in a Suitable base. within the device. The backing is preferably comprised of a US 2007/0269379 A1 Nov. 22, 2007 29 flexible elastomeric material that serves as a protective include polyolefins such as polyethylene and polypropylene, covering to prevent loss of the active component and/or polyamides, polyesters, ethylene-ethacrylate copolymer, vehicle via transmission through the upper Surface of the ethylene-Vinyl acetate copolymer, ethylene-vinyl methylac patch, and will preferably impart a degree of occlusivity to etate copolymer, ethylene-vinyl ethylacetate copolymer, eth the system, such that the area of the body surface covered by ylene-vinyl propylacetate copolymer, polyisoprene, poly the patch becomes hydrated during use. The material used acrylonitrile, ethylene-propylene copolymer, and the like. for the backing layer is typically constructed to permit the device to follow the contours of the skin and be worn 0335 Generally, the underlying surface of the transder comfortably on areas of skin Such as at joints or other points mal device, i.e., the skin contact area, has an area in the of flexure, that are normally Subjected to mechanical strain range of about 5 cm to 200 cm, preferably 5 cm to 100 with little or no likelihood of the device disengaging from cm, more preferably 20 cm to 60 Cm. That area will vary, the skin due to differences in the flexibility or resiliency of of course, with the amount of drug to be delivered and the the skin and the device. Examples of materials useful for the flux of the drug through the body Surface. Larger patches backing layer are polyesters, polyethylene, polypropylene, will be necessary to accommodate larger quantities of drug, polyurethanes and polyether amides. while Smaller patches can be used for Smaller quantities of drug and/or drugs with SCOPE compositions that exhibit a 0331. During storage and prior to use, the laminated relatively high permeation rate. structure includes a release liner. Immediately prior to use, this layer is removed from the device so that the system may 0336 Such drug delivery systems may be fabricated be affixed to the skin. The release liner should be made from using conventional coating and laminating techniques a drug/vehicle impermeable material, and is a disposable known in the art. For example, adhesive matrix systems can element that serves to protect the device prior to application. be prepared by casting a fluid admixture of adhesive, the Typically, the release liner is formed from a material imper active component, chemical penetration enhancers and a meable to the active component and other components of the suitable vehicle onto the backing layer in order to form a SCOPE formulation, followed by lamination of the release SCOPE formulation, and which is easily stripped from the liner. Similarly, the adhesive mixture may be cast onto the transdermal patch prior to use. release liner, followed by lamination of the backing layer. 0332. In another embodiment, the drug and SCOPE Alternatively, the drug reservoir may be prepared in the containing reservoir and skin contact adhesive are present as absence of drug or excipient, and then loaded by “soaking separate and distinct layers, with the adhesive underlying the in a drug/SCOPE formulation mixture. In general, transder reservoir. In Such a case, the reservoir may be a polymeric mal systems of the invention are fabricated by solvent matrix as described above. Alternatively, the reservoir may evaporation, film casting, melt extrusion, thin film lamina be comprised of a liquid or semisolid formulation contained tion, die cutting, or the like. in a closed compartment or “pouch,” or it may be a hydrogel reservoir, or may take some other form. Hydrogel reservoirs 0337 As with the topically applied formulations of the are particularly preferred. As will be appreciated by those invention, the SCOPE composition containing the active skilled in the art, hydrogels are macromolecular networks agent within the drug reservoir(s) of these laminated systems that absorb water and thus swell but do not dissolve in water. may contain a number of components and generally the drug That is, hydrogels contain hydrophilic functional groups that or other active component will be dissolved, dispersed or provide for water absorption, but the hydrogels are com Suspended together with the synergistic combination of prised of crosslinked polymers that give rise to aqueous chemical penetration enhancers in a suitable pharmaceuti insolubility. Generally, then, hydrogels are comprised of cally acceptable vehicle, typically a solvent or gel. Other crosslinked hydrophilic polymers such as a polyurethane, a components which may be present include preservatives, polyvinyl alcohol, a polyacrylic acid, a polyoxyethylene, a stabilizers, and the like. polyvinylpyrrolidone, a poly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixture thereof. Particu EXAMPLE 1. larly preferred hydrophilic polymers are copolymers of 0338 A library of CPE combinations was developed HEMA and polyvinylpyrrolidone. using the thirty-two individual CPEs listed in the right hand 0333 Additional layers, e.g., intermediate fabric layers column of the table shown in FIG. 3. The thirty-two CPEs and/or rate-controlling membranes, may also be present in listed in FIG.3 are referred to as “library CPEs” in Example any of these drug delivery systems. Fabric layers may be 1. Example 2. Example 3 and Example 4. Each of the library used to facilitate fabrication of the device, while a rate CPEs was assigned an abbreviated name as shown in the left controlling membrane may be used to control the rate at hand column of the table in FIG. 3, to facilitate tracking and which one or more components permeates out of the device. analysis of data. The library CPEs were assigned to one of The one or more components may be a drug, a SCOPE eight general categories, with four of the CPEs in each. The formulation, one or more components of a SCOPE formu eight categories and their CPES were: (i) cationic Surfactants lation, one or more penetration enhancers, or Some other (cetyl trimethyl ammonium bromide, dodecyl pyridinium component(s) contained in the drug delivery system. chloride, benzyl dimethyl dodecyl ammonium chloride, octyl trimethyl ammonium bromide); (ii) anionic Surfactants 0334] A rate-controlling membrane, if present, will be (sodium dodecyl sulfate, n-lauryl sarcosine (CAS number included in the system on the skin side of one or more of the 137-16-6 also called sodium lauroyl sarcosinate), sodium drug reservoirs. The materials used to form Such a mem octyl sulfate, sodium lauryl ether sulfate), (iii) Zwitterionic brane are selected to limit the flux of one or more compo Surfactants (hexadecyl trimethyl ammoniopropane Sul nents contained in the drug formulation. Representative fonate, cocamidopropyl betaine, cocamidopropyl hydrox materials useful for forming rate-controlling membranes ySultaine, oleyl betaine); (iv) nonionic Surfactants (Tween US 2007/0269379 A1 Nov. 22, 2007 30

20, Span 20/sorbitan monolaurate, polyethyleneglycol dode second electrode was placed sequentially by hand into each cyl ether, Triton); (v) fatty acids (oleic acid, linoleic acid, donor compartment. An AC signal, 143 mV peak to peak at lauric acid, linolenic acid); (vi) fatty esters (tetracaine, 100 Hz, was applied across the skin with a waveform isopropyl myristate, Sodium oleate, methyl laurate); (vii) generator (Agilent 33 120A, Palo Alto, Calif.). Conductivity aZone-like chemicals (1-dodecyl pyrrolidone, dodecyl measurements were performed using a multimeter (Fluke amine, nicotine Sulfate, 1-phenyl piperazine); and (viii) 189, Everett, Wash.) with a resolution of 0.01 LA. Current other (menthol, 1-methyl-2-pyrrolidone, cineole, limonene). measurements were performed at two time points, time t=0 The classification of the library CPEs into the eight catego (Io) and time t=24 hrs (I2). The AC signal was only applied ries is shown in the table in FIG. 4, using the abbreviated while conductivity measurements were being made. The names for the CPES introduced in FIG. 3. conductivity enhancement ratio (ER) for each formulation was then calculated by taking the ratio of skin conductivities 0339) A library of CPE combinations was constructed at 24 and 0 hours. The enhancement ratio obtained for each from the thirty-two individual CPEs as follows. The CPEs formulation was assigned a unique integer experiment index were first divided into four blocks (labeled Block 1, Block for Subsequent tracking and analysis purposes. In addition, 2, Block 3 and Block 4) such that each block had one representative from each of eight categories. The assignment data points from individual wells where the initial current of individual CPEs into the blocks is shown in FIG. 4. The was greater than 31A were assumed to indicate that the skin CPEs within each block were then paired to generate all area between the donor and receptor wells was defective. possible distinct binary combinations (yielding 28 binary These data points were discarded and not used in Subsequent combinations per block and providing a total of 4x28=112 analysis. Additional experiments were performed when data combinations in the entire library). A compositional grid was points were discarded to ensure that there were at least 4 then constructed for each pair of CPEs. For each pair of good values of ER available for each formulation. CPEs four different total concentrations of 0.5, 1.0, 1.5 and 0342 FIG. 5 shows a histogram for over 20,000 separate 2.0% weight/volume were selected. At each total concen 24-hour conductivity enhancement ratios that were obtained tration the weight fraction of one enhancer was varied from using the high throughput experimentation approach. 0 to 1 in steps of 0.1. Thus for each enhancer pair 44 test Enhancement ratio ranges are plotted horizontally, while the formulations were generated yielding a total library contain vertical axis shows the frequency with which each given ing over 4,000 formulations. All formulations were prepared range of enhancement ratios was observed. It can be seen in a vehicle consisting of 1:1 PBS:EtOH. The PBS solution that the frequency with which each range of ER values is was 0.01M calcium phosphate, 0.027M potassium phos observed falls of rapidly as the ER range increases. How phate and 0.137M sodium chloride. Formulations were ever, with this large data set very high values of ER are prepared by hand without the use of a robot. occasionally observed. 0340 Members of the library were screened for their 0343. The enhancement ratios for the repeat measure ability to enhance the penetration of skin in a series of ments that were made on each formulation were averaged experiments as follows. Porcine skin was used as a model before further analysis and errors in the conductivity for skin in all the experiments. Skin was harvested from enhancement ratio computed using standard statistical for Yorkshire pigs and was stored at -70° C. immediately after mulae. procurement until the time of experiments using the methods described in Mitragotri et al., 2000. A high throughput 0344) The 44 averaged enhancement ratios generated screening device of the type described in International from each binary combination of CPEs were used to gen Publication Number WO 02/16941 A2 was utilized to Screen erate two-dimensional contour maps, which may be termed the formulations. The apparatus consisted of a polycarbon potency phase maps. The six panels in FIG. 6 show potency ate plate that served as the donor plate and a Teflon plate that phase maps for the following pairs of library CPEs: (A) served as the receptor plate. Each plate was 12.7 mm thick. Azone HPS, (B) MP DPC(C)NS LA, (D) IM Linoleic, (E) The donor contained a square matrix of 100 wells (each 3 SLATR and (F) CBC ML (using the abbreviated chemical mm in diameter) that served as individual donor compart names introduced in the table in FIG. 3). In each potency ments. The center-to-center distance between the donor phase map the vertical axis scans the total concentration of compartments was 6 mm. A matching matrix of 100 wells in library chemical penetration enhancer in units of% weight/ the Teflon plate served as individual receptors. The receptor volume. The horizontal axis scans the weight fraction of the wells were filled with PBS to keep the skin hydrated over the first named library CPE in the legend below the potency entire duration of the experiment (24 hrs). Skin was thawed phase map. Thus the left and right hand axes of FIG. 6 (A) at room temperature prior to each experiment. The skin was provides information about the penetration enhancement then placed between the two plates with the stratum cor effects of HPS in the absence of AZone and AZone in the neum facing the donor plate. Donor and receptor plates were absence of HPS, respectively. The contour levels show clamped together using 4 screws. The skin was incubated interpolated values of the enhancement ratio based on the 44 with 85 uL of each test formulation in the donor wells for a data points available for each sample according to the scale period of 24 hrs with each formulation being repeated in at inset on the right hand side of FIG. 6. least four wells. 0345 A range of different interaction behaviors between 0341 The skin penetration enhancement achieved by the library CPEs was observed by analyzing the screening each formulation was assayed using skin conductivity fol data using potency phase maps. For example, in FIG. 6 (A) lowing the methods disclosed in International Publication and FIG. 6 (B) generally positive synergy can be seen in the Number WO 02/16941 A2. Skin impedance in each well was potency phase maps; most combinations of AZone HPS and recorded using two electrodes. One electrode was inserted MP DPC give enhancement ratios that are higher than the into the dermis and served as a common electrode while the enhancement ratios obtained from the individual end mem US 2007/0269379 A1 Nov. 22, 2007

ber CPEs of the formulation at the same total concentration. assay. The cell cultures were rinsed clear of the test formu FIG. 6 (C) and FIG. 6 (D) show examples of generally lations using PBS and incubated with 300 uL of MTT negative synergy. In these measurements the enhancement reagent (Mattek Co., MA, USA) for 3 hrs at 37° C. and 5% ratio of combinations of CPEs was usually lower than that CO. At the end of the incubation period the cell cultures obtained by using the pure end member CPEs at the same were treated with 2 ml of extracting media (provided by concentration. FIG. 6 (E) and FIG. 6 (F) show examples MatTek Co) for 2 hrs. 200 uL of this extraction media was where little synergy is seen between the CPEs. then sampled and its optical density (or absorbence) was measured at 570 nm wavelength. The optical absorbance 0346) The data were further analyzed to select promising data was then used to calculate the percentage cell viability CPE combinations for further analysis. For each formulation as recommended in the MTT-ET-50 protocol. Based on the a synergy value, S, was cell viability, the irritation potential (IP) may be defined as follows: ° x . ER(y).ERA-B (X, X).Y) ER(y) % cell viability with the formulation IP = 10 (1 maximum.9%NTEN" cell viability where ERACX,Y) is the enhancement ratio obtained with the formulation containing CPEs A and B, Y stands for the total concentration of A and B (wt/vol), X stands for the The vehicle of 1:1 EtOH:PBS was used as negative control amount of A in formulation (expressed in wit/vol) divided by and 1% Triton X-100 was used as the positive control. Y and ERACY) and ER(Y) are the enhancement ratios obtained with pure components A and B at concentration Y 0348 Results obtained in the screening experiments are (wt/vol) in the vehicle of 1:1 PBS:EtOH, respectively. The reported in FIG. 8. The values of IP are plotted on the data were analyzed to determine the highest observed values horizontal axis, while 24-hour ER values are plotted verti of S and the highest observed value of ER for each binary cally. Solid circles are used for data from formulations combination of penetration enhancers in the study. CPE containing binary pairs of library CPEs. The library CPEs combinations that give rise to high sharp maxima in the ER for each data point may be found by reference to the table in the potency phase maps have been discovered to produce given in FIG. 9. Also plotted on FIG. 8, using open diamond compositions with low irritation potential. CPE combina symbols, are 24-hour ER and IP values of a number of tions showing high maximum values of ER are expected to formulations containing a single library CPE, each labeled be the most promising increasing the permeability of skin. with a single letter. The composition of the formulations CPE combinations with a tendency to fit these hot spot containing a single library CPE may be found by reference attributes were selected by choosing formulations that to the table in FIG. 10. showed (i) large maximum value of ER (ii) large maximum 0349. It can be seen that high values of enhancement ratio value of S and (iii) Small distance in composition space of the formulations containing a single library CPE shown in between the maximum value of ER and the maximum value FIG. 8 have a tendency to be associated with high values of of S. Eleven formulations containing library CPE pairs that irritation potential. Formulations representing hot spots were selected for further analysis are shown in FIG. 7. The selected for analysis following the method of the present left hand column lists the binary pairs CPEs. The columns invention generally provided higher enhancement ratios and headed Max Enhancement report the position in composi lower irritation potential than the formulations containing a tion space, observed ER and S value at the maximum ER single library CPE. In certain rare cases, such as points 3 and position in the potency phase map for each pair of library 4 on the chart (corresponding to formulations containing CPES. The composition position is given as the weight SLAPP and NLS S20, respectively), high ER values and fraction (column headed wit Fr) of the first library CPE to be low IP values were achieved simultaneously by the formu listed in the first column of the table and a total concentra lations. These formulations were found to have IP values tion of the two library CPEs (column headed Tot Conc) below 10% and ER values above 50. The IP values of these expressed in percent weight/volume. Similarly, the columns formulations lie below those of 1.5% oleic acid wit/vol in a headed Max Synergy report the position in composition vehicle of 1:1 PBS:EtOH, which was measured to have an space, observed ER and S value at the maximum S position IP value of 14.5%. Oleic acid under these conditions is in the potency phase map for each pair of CPEs. generally recognized as safe and is used in commercial 0347 Experiments to assess irritation potential were per estradiol patches. formed on the binary pairs of library CPEs at the composi 0350. The potency phase map that was measured for SLA tions that yielded the maximum ER value in the screening PP is shown in FIG. 11 below. A very high sharp maximum, experiments using the methyl thiazol tetrazolium (MTT) corresponding to a hot spot, can be seen in the potency phase uptake assay. Irritation potential was estimated using Epi map. The potency phase map that was measured for NLS DermTM (Mattek Co., MA, USA, www.mattek.com), a cell S20 is provided in FIG. 12. culture of normal human derived epidermal keratinocytes. EpiDermTM cultures were stored and handled according to 0351. As discussed previously, without being bound by the standard protocol MTT-ET-50 (Mattek Co., MA, USA, theory, the low irritation of SCOPE formulations containing www.mattek.com). To study the effect of the test formula binary pairs of library CPEs compared to their formulations tions on cell viability, cell cultures were exposed to 10 ul of containing the individual library CPEs may be based on their each test formulation for 4 hrs. Each test formulation was relative dynamics in stratum corneum. Due to differential analyzed in duplicate. At the end of 4 hrs the assay medium retention of various components in the SC, every stratum in was removed and stored aside at -70° C. for Interleukin-1C. the skin exposed to the formulation experiences a different US 2007/0269379 A1 Nov. 22, 2007 32 composition of enhancers. For example, in vitro experiments penetration enhancement ratio derived from the FDC mea performed using EpiDermTM and two model enhancers surements plotted vertically. It was found that the NLS S20 Sodium Lauryl Sulfate (SLS) and Oleic acid (Oleic) in a hot spot combination was very effective in improving the vehicle, revealed that the ratio of Oleic: SLS in the epidermis transport of inulin across the stratum corneum, improving is about 10-times smaller than that in the formulation that the permeability by more than 50 fold compared with a was contacted with the SC. sample which omitted the CPES. In addition it was found 0352. In vitro quantification of the absolute permeability that performance of the NLS S20 formulation is about 50% of NLS S20 was confirmed using a Franz diffusion cell of that obtained with tape stripped skin, which models the (FDC). Bronaugh (1989). Penetration experiments were performance of a CPE combination that is 100% effective in performed using H labeled inulin, (American Radiolabeled removing the penetration barrier of the stratum corneum. Chemicals, St. Louis, Mo.) as a model permeate. FDCs (16 mm diameter, 12 ml receptor Volume) were used to assess 0355 Further FDC measurements on porcine skin to flux of the radiolabeled inulin across skin. Simultaneous measure transport of radiolabeled inulin were also taken on conductivity measurements were performed in the FDC to the NLS S20 combination and the SLAPP combination validate the results from HTS. A small stir bar and an Ag/AgCl disk electrode (E242, InVivo Metric, Ukiah, using a 1:1 PBS:EtOH vehicle using the methods outlined in Calif.) were added to the receptor chamber. The conductivity the previous paragraphs. The NLS S20 formulation utilized measurement assembly used was the same as that used in the a total concentration of library CPE of 1% wt/vol with an case high throughput Screening experiments except that an NLS library CPE weight fraction of 0.6. The SLA PP Ag/AgCl electrode was used in the receptor compartment formulation utilized a total concentration of library CPE of instead of inside the skin. The electrical resistance of the 0.5% wit/vol with an SLA library CPE weight fraction of 0.7. electrodes used in both the systems was verified to be Also tested was the case of tape stripped skin in the presence similar. The receptor chamber was filled with PBS. Pigskin of inulin in a PBS vehicle. Radiolabeled inulin was added to was thawed and was mounted on the diffusion cell using a all formulations to a level of 10 uCi/ml. Results are reported clamp with the stratum corneum side facing the donor. Before each experiment the structural integrity of the skin in FIG. 14. The permeability enhancement ratio was com sample was confirmed by measuring its conductivity using puted in each case by comparisons with the flux rate of the methods set out in Mitragotri et al. (1996). Skin samples inulin in a vehicle consisting of PBS only through intact with a resistivity of less that 20 kS2 cm were assumed to be skin. In contrast to the results shown in FIG. 13, the data in defective and were not used. FIG. 14 does not include corrections for the amount of inulin deposited into the skin. The hot-spot formulations contain 0353. An NLS S20 formulation was prepared in PBS ing SLA PP and NLS S20 are both highly effective in (omitting any EtOH) and radiolabled inulin (10 uCi/ml) promoting the transport of inulin across skin. In the case of using the concentration and weight fractions of NLS and S20 that were found to give the maximum ER value in the SLAPP the permeability enhancement ratio is about 80% of earlier high throughput screening experiments. The perfor the value observed with tape stripped skin. mance of the formulation was compared against a control 0356. Finally, the irritation potential and conductivity containing just PBS and radiolabeled inulin a molecule with enhancement ratio of the SLAPP and NLS S20 hot-spot a molecular weight of about 5,000 Daltons. In addition, formulations are shown in FIG. 15 together with conduc experiments were performed using a formulation consisting tivity enhancement ratios and irritation potentials of formu of PBS and inulin, where the stratum corneum of the skin lations containing constituent CPEs. All formulations uti sample had been removed by tape stripping. See generally, lized a vehicle of 1:1 PBS:EtOH. The points in FIG. 15 are Bronauch and Maibach (1989). labeled according to the library CPEs contained within each 0354 Skin was incubated with radiolabeled test formu formulation. The concentrations of library CPE of each of lation (10 uCi/ml) in the donor for a period of 96 hrs during the labeled points in the FIG. 15 are as follows: SLA:PP which time the receptor compartment was sampled periodi SCOPE formulation, total library CPE concentration 0.5% cally. Concentration of radiolabeled solute was measured wit/vol, SLA weight fraction 0.7: SLA, total library CPE using a scintillation cocktail and a Scintillation counter concentration 0.5% wit/vol; PP, total library CPE concentra (Packard Tri-Carb 2100 TR, Meriden, Conn.). Skin perme tion 0.5% wit/vol; NLS:S20 SCOPE formulation, total ability was calculated using the standard equations. Perme abilities were corrected to take account of the amount of library CPE concentration 1% wt/vol, NLS weight fraction drug deposited in the skin. The amount of inulin in each skin 0.6: NLS, total library CPE concentration 1% wt/vol; S20, specimen was measured by gently washing the skin at the total library CPE concentration 1% wt/vol. It can be seen conclusion of the FDC experiment, dissolving the skin that the conductivity enhancement of the SCOPE formula specimen in SolvableTM, a tissue solubilizer, held at about tions is substantially enhanced compared with the formula 60° C. for about 12 hours and measuring the concentration tions containing a single library CPE, reflecting the previ of radiolabeled molecules in the resulting solution. Enhance ously discussed synergies in penetration enhancement ment of permeability was calculated by determining the ratio produced by the library CPEs. In the case of the NLS:S20 of permeabilities obtained in the presence and absence of SCOPE formulation the irritation potential of the formula NLS S20. In addition the enhancement of permeability tion was substantially reduced when compared to that of the achieved by tape stripping the skin was also computed by formulations containing the individual library CPEs at the determining the ratio of permeabilities obtained from PBS same total library CPE concentration. In the case of the and inulin from tape stripped and intact skin samples. NLS:S20 SCOPE formulation the irritation antergy factor, Results are shown in FIG. 13 as a bar chart with the A, defined through US 2007/0269379 A1 Nov. 22, 2007 33

specimen in SolvableTM, a tissue solubilizer, held at about 60° C. for about 12 hours and measuring the concentration X. IPA (Y) + (1-X). Pe (Y) of radiolabled molecules in the resulting solution. - IPA, B (X, Y) 0358. In order to confirm that detected radioactivity was a result of transport of the test molecules and not from is substantially greater than 1 (symbols in this equation tritiated water that may have resulted from tritium exchange, having the meanings provided earlier in the definition of receiver samples were desiccated and analyzed for radioac antergy factor). For the case of the NLS:S20 SCOPE for tivity. No substantial differences in radioactivity were mulation the irritation antergy factor, using values of irrita observed between native and desiccated receiver samples. tion potential measured using the MTT uptake assay as 0359 The measured skin permeabilities as measured in the FDC experiments are shown graphically with the open explained above, is calculated to be 4.2. square symbols in the log-log plot in FIG. 16. The closed EXAMPLE 2 circles show the permeabilities corrected for amounts of the test molecules deposited in the skin. In the case of ODN, the 0357. In vitro FDC experiments were performed to evalu majority of the oligonucleotides were trapped in the skin and ate the ability of formulations containing an SLA:PPSCOPE only the permeability value calculated based on amounts formulation to enhance the delivery of test molecules with a deposited in the skin is reported. The open circles in FIG. 16 range of molecular weights across the stratum corneum. Test show permeability of untreated skin reported in the literature molecules whose transport properties were measured were for a variety of hydrophilic solutes. Mitragotri (2003). It can mannitol (MWs 180 Da, a small molecule), methotrexate be seen that the SLA:PP SCOPE formulation produces (MWs454 Da, a small molecule), luteinizing hormone substantial increases in the permeability of skin for the test releasing hormone (LHRH, MWs 1.2 kDa, a peptide), inulin molecules compared to that usually observed for hydrophilic (MW=5 kDa, a polysaccharide), low molecular weight hep molecules. In addition it can be seen from the present arin (LMWH, MWs 10 kDa, a polysaccharide) and an oli example that the SCOPE formulation containing SLA and gonucleotide (ODN, MWs-15 kDa). Concentration changes PP at relatively low concentration is able to deliver not only of the molecules due to transport were measured using small molecule drugs but also larger molecules with the radiolabeled chemicals. H-labeled forms of the test mol character of peptides, oligonucleotides and polysaccharides. ecules were obtained from the following sources: mannitol, Moreover, it should also be noted that the test molecules of methotrexate, inulin and LMWH were acquired from Ameri the present example are hydrophilic in character, which are can Radiolabeled Chemicals of St. Louis, Mo. (www.arc traditionally the most difficult to deliver across the skin inc.com); LHRH was obtained from NEN, now part of barrier. Perkin Elmer, Wellesley, Mass. (www.Derkinelmer.com); ODN was provided by ISIS Pharmaceuticals of Carlsbad, EXAMPLE 3 Calif. (www.isispharm.com). Each radiolabeled test mol 0360. In vivo experiments were performed using hairless ecule was directly added to formulation containing the CPEs rats (250-280 gm) from Charles River Laboratories, Wilm SLA and PP in a vehicle of 1:1 PBS:EtOH at a concentration ington, Mass. (www.criver.com). All experiments on the of 10 uCi/ml. The total concentration of the library CPEs in animals were performed according to institutionally the SCOPE formulation was 0.5% wit/vol, the SLA weight approved protocols at the University of California, Santa fraction of library CPE being 0.7. The resulting formulations Barbara. Animals were anesthetized using isofluorane (1.25 were placed in the donor well of Franz cells and the contents 3% isofluorane in oxygen). 1 gm of a either a control gel of the receiver wells were sampled periodically for a period containing leuprolide or a gel containing the CPES SLA and of 96 hours to monitor transport. FDCs utilized in the PP and the drug leuprolide was applied to the lateral side of experiments had a diameter of 16 mm and receiver Volume the rat above the left hind leg over a skin area of 9 cm. The of 12 ml. Small stir bars and Ag/AgCl disk electrodes control gel utilized 2 mg/ml leuprolide dissolved in PBS (model number E.242 acquired from In Vivo Metric, Healds containing 1.8% wt/vol hyaluronic acid. The second gel. burg, Calif. (www.invivometric.com)) were added to the based on the SLA PP SCOPE formulation discovered in receiver chamber, the disk electrode allowing skin conduc Example 1, contained 2 mg/ml leuprolide, 0.35% wit/vol tivity to be measured as the experiment proceeded. The FDC SLA, 0.15% wit/vol PP and 1.8% wt/vol hyaluronic acid in receiver chambers were filled with PBS and adequate mea 1:1 PBS:EtOH. A thin polymer sheet was placed on the gel sures were taken to prevent inclusion of air in the receiver patches and the edges sealed with a cyanoacrylate adhesive. chamber. Thawed pig skin, harvested from Yorkshire pigs The animals were allowed to recover from anesthesia after and stored at -70° C. immediately after procurement until 2 hrs. Blood samples were collected from the jugular vein the time of experiments using the methods described by over a period of 24 hrs and plasma concentration of the Mitragotri et al. was mounted on the diffusion cell using a leuprolide measured using ELISA (using product number clamp with the stratum corneum side facing the donor well. S-1159 from Bachem Bioscience, Bubendorf, Switzerland Mitragotri et al. (2000). The concentration of the radiola (www.bachem.com). The results of the experiment are beled test molecule was measured using a Packard Tri-Carb shown in the graph in FIG. 17 with plasma concentration of 2100 TR scintillation counter. FDC measurements were leuprolide plotted on the vertical axis and time plotted repeated several times for each test molecule to ensure horizontally. Solid and open symbols provide results for statistically meaningful results. In addition permeabilities plasma concentration of the SLAPP-containing formulation were corrected to take account of the amount of drug and control formulation, respectively. deposited in the skin. The amount of test molecule in each 0361) The skin of the rats was observed throughout the skin specimen was measured by gently washing the skin at experiments. The skin appeared normal throughout the the conclusion of the FDC experiment, dissolving the skin experiment and no erythema was observed at any time. US 2007/0269379 A1 Nov. 22, 2007 34

0362 Skin conductance was measured during the course solution. The permeability enhancement ratio obtained in of the experiment to assess skin permeabilization and recov this manner was computed to be 30. FIG. 19 depicts the flux ery. The SLAPP SCOPE formulation caused a roughly rate of corticosterone across porcine skin in the NLS:S20 20-fold increase in skin conductance during the 24 hrs that formulation and the PBS formulation. the formulation was in contact with the skin. The skin 0366 Much evidence points to the fact that molecules conductance fell back to 20% of the peak value within 12 hrs with molecular weight greater than 500 Da do not pass after removal of the formulation. through the stratum corneum in significant amounts. Bos et 0363. In some animals the skin exposed to the SLAPP al., (2000). The molecular weights of virtually all common SCOPE formulation and the control formulation was excised contact allergens, most commonly used pharmacological and fixed in 10% vol/vol formalin immediately after remov agents applied in topical dermatotherapy, and all drugs ing the patch. The skin was sectioned and stained with presently available in FDA-approved transdermal patches hematoxylin and cosin by Mass Histology Service, War are less than 500 Da. The lack of effective CPEs has largely wick, R1 (www.masshistology.com). Histological studies restricted pharmaceutical development of new innovative showed the stratum corneum of the skin exposed to the products to those containing drugs with a MW of less than SLAPP formulation to be normal and no structural differ 500 Da when topical dernatological therapy or percutaneous ences were observed in the skin compared with controls. systemic therapy or vaccination is the objective. A predictive There were no signs of inflammation in the histological rule of thumb that has been applied in the field of transder sections and the presence of inflammatory cells was not mal drug delivery is that the maximum flux of drug through detected. FIG. 18 (A) is a micrograph of skin section the skin decreases by a factor of 5 for an increase of 100 Da obtained from a hairless rat after application of the PBS/ in MW. Finnin et al. (1999). Moreover, drugs that are hyaluronic acid based control patch, while FIG. 18 (B) is a normally considered suitable for transdermal drug delivery micrograph of a skin section from a rat that had received the should be lipophilic with log K in the range of 1-3. Finnin SLA:PP-containing patch. In addition, patches were also et al. (1999). In contrast, the examples presented here serve applied to hairless rats utilizing a formulation containing to illustrate that transport of drugs and other active compo 10% wt/vol SLS, 1.8% wt/vol hyaluronic acid and 2 mg/ml nents can be achieved without these restrictions by the use leuprolide made up in a 1:1 PBS:EtOH vehicle, as a positive of formulations containing rare combinations of chemical control. A typical micrograph of the skin section obtained penetration enhancers. The data in Example 1 demonstrates after applying this formulation in a patch to a hairless rat, that inulin (a 5,000 Da molecule) is transported well across according to the protocol outlined previously, is provided in the Stratum corneum using formulations containing low FIG. 18 (C). It can be seen that the stratum corneum of the concentrations of NLS and S20, and SLA and PP. Example rathas completely detached from the lower lying skin layers, 2, demonstrates that a range of hydrophilic molecules, in contrast to what was observed in FIG. 18 (A) and FIG. 18 spanning molecular weight range from 180 Da ~15,000 Da. (B), where the skin remains intact. can be delivered across skin utilizing SCOPE formulations. Moreover, in FIG. 16 it can be seen that the usual rule that 03.64 Experiments were also performed on hairless rats a decrease of skin penetration by a factor of 5 occurs for each utilizing a formulation consisting of 2 mg/ml leuprolide, 100 Da increase in molecular weight no longer holds with 0.35% wit/vol SLA, 0.15% wit/vol PP and 1.5% wit/vol SCOPE formulations. SCOPE formulations also overcome hydroxypropyl cellulose MF in 1:1 PBS:EtOH. The perfor the restrictions limiting transdermal delivery of lipophilic mance of patches utilizing this formulation were very simi molecules (log K in the range of 1-3) as illustrated, for lar to those obtained with the formulation containing SLA, example, by the data presented on exemplary test molecules PP. leuprolide and hyaluronic acid described previously. such as mannitol (log K=-3.1) and inulin (log K=-3) in Example 2. Example 4 on the other hand, illustrates that EXAMPLE 4 SCOPE formulations may also be used greatly enhance the 0365. In vitro FDC experiments were performed to com transport of corticosterone, a low molecular weight lipo pare the flux of corticosterone, a lipophilic molecule (Log philic drug (MW =346.5 Da, log K = 1.94), and therefore K=1.94), across porcine skin using a SCOPE formulation that SCOPE formulations also have utility in improved containing NLS S20 in a 1:1 PBS:EtOH vehicle against that delivery of molecules that would conventionally be consid obtained with a PBS-based formulation. The total concen ered candidates for topical and transdermal delivery. tration of NLS and S20 in the SCOPE formulation was 1.0% wit/vol and the library CPE weight fraction of NLS was 0.6. 0367 From the foregoing, it will be appreciated that, Radiolabeled corticosterone was acquired from NEN (now although specific embodiments of the invention have been part of Perkin Elmer, Wellesley, Mass. www.perkinelmer described herein for the purpose of illustration, various .com) and added to the two formulations at a concentration modifications may be made without deviating from the spirit of 10 uCi/ml. FDC experiments were conducted as and scope of the invention. Accordingly, the present inven described in Example 2 using porcine skin. Samples were tion is not limited except as by the appended claims. obtained periodically from FDCs over the entire duration of 0368 All patents, patent applications, publications, sci 96 hrs period in which the skin was exposed to the test entific articles, web sites, and other documents and materials formulations. Concentration of radiolabeled solute in these referenced or mentioned herein are indicative of the levels of samples was measured with a Scintillation counter and the skill of those skilled in the art to which the invention molecular flux and skin permeability were calculated using pertains, and each Such referenced document and material is standard equations as described previously. A permeability hereby incorporated by reference to the same extent as if it enhancement ratio was calculated by taking the ratio of skin had been incorporated by reference in its entirety individu permeability to corticosterone at 96 hrs obtained with the ally or set forth herein in its entirety. Additionally, all claims SCOPE formulation to that obtained with the PBS based in this application, and all priority applications, including US 2007/0269379 A1 Nov. 22, 2007 but not limited to original claims, are hereby incorporated in removing any Subject matter from the genus, regardless of their entirety into, and form a part of the written description whether or not the excised material is specifically recited of the invention. Applicants reserve the right to physically herein. incorporate into this specification any and all materials and information from any Such patents, applications, publica 0372 Other embodiments are within the following tions, scientific articles, web sites, electronically available claims. In addition, where features or aspects of the inven information, and other referenced materials or documents. tion are described in terms of Markush groups, those skilled Applicants reserve the right to physically incorporate into in the art will recognize that the invention is also thereby any part of this document, including any part of the written described in terms of any individual member or subgroup of description, the claims referred to above including but not members of the Markush group. limited to any original claims. Citations 0369 The specific methods and compositions described 0373) Audus, K. L., Bartel, R. L., Hidalgo, I. J. and herein are representative of preferred embodiments and are Borchardt, R. T., The use of cultured epithelial and exemplary and not intended as limitations on the scope of endothelial cells for drug transport and metabolism stud the invention. Other objects, aspects, and embodiments will ies. Pharm Res. 1990 7(5): p. 435-51. occur to those skilled in the art upon consideration of this specification, and are encompassed within the spirit of the 0374. Augustin, C; Colombel, C. Damour, O. Use of in invention as defined by the scope of the claims. It will be vitro dermal equivalent and skin equivalent kits for evalu readily apparent to one skilled in the art that varying ating cutaneous toxicity of cosmetic products. In vitro Substitutions and modifications may be made to the inven Toxicology 1997. 10 p. 23-31. tion disclosed herein without departing from the scope and 0375 Berger, R. S. and Bowman, J. P. A reappraisal of spirit of the invention. The invention illustratively described the 21-day cumulative irritation test in man. J. Toxicol.- herein Suitably may be practiced in the absence of any Cut. & Ocular Toxicol. 1982 1(2) p. 109-115. element or elements, or limitation or limitations, which is not specifically disclosed herein as essential. Thus the terms 0376 Berti, J. and Lipsky J. J., Transcutaneous drug “comprising”, “including, containing, etc. are to be read delivery: A practical review. Mayo Clinical Proceedings, expansively and without limitation. The methods and pro 1995. 70: p. 581-586. cesses illustratively described herein suitably may be prac 0377 Bos J. D., Meinardi M. M. H. M., The 500 Dalton ticed in differing orders of steps, and that they are not rule for the skin penetration of chemical compounds and necessarily restricted to the orders of steps indicated herein drugs. Exp. Dermatol. 2000. 9 p. 165-169. or in the claims. It is also that as used herein and in the appended claims, the singular forms “a,'an,” and “the 0378 Bouwstra, J. A., The skin, a well organized mem include plural reference unless the context clearly dictates brane. Colloids and Surfaces. A 1997. 123-124: p. 403 otherwise. Thus, for example, a reference to “a host cell 413. includes a plurality (for example, a culture or population) of 0379 Bronauch R. L. and Maibach H. I., Percutaneous Such host cells, and so forth. Under no circumstances may Absorption: Mechanisms-Methodology-Drug Delivery, the patent be interpreted to be limited to the specific Marcel Dekker Inc.: New York, Basel, 1989. examples or embodiments or methods specifically disclosed herein. Under no circumstances may the patent be inter 0380 Bronaugh, R. L., and Stewart, R. F., Methods for in preted to be limited by any statement made by any Examiner vitro percutaneous studies absorption studies IV: The flow or any other official or employee of the Patent and Trade through diffusion cell. Journal of Pharmaceutical Science, mark Office unless such statement is specifically and without 1985.74: p. 64-67. qualification or reservation expressly adopted in a respon 0381 Bronaugh, R. L., Determination of Percutaneous sive writing by Applicants. Absorption by In vitro Techniques. In Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, 0370. The terms and expressions that have been employed are used as terms of description and not of R. L. Bronaugh, Maibach, H. I., Editor, Marcel Dekker limitation, and there is no intent in the use of such terms and Inc.: New York, Basel, 1989. expressions to exclude any equivalent of the features 0382 Dugard, P. H. and Scheuplien, R.J., Effects of ionic reported and described or portions thereof, but it is recog Surfactants on the permeability of human epidermis: An nized that various modifications are possible within the electrometric study. Journal of Investigative Dermatol scope of the invention as claimed. Thus, it will be under ogy, 1973. 60: p. 263-269. stood that although the present invention has been specifi cally disclosed by preferred embodiments and optional 0383 Finnin, C. B. and Morgan, T. M., Transdermal features, modification and variation of the concepts herein penetration enhancers: Applications, limitations and disclosed may be resorted to by those skilled in the art, and potential. Journal of Pharmaceutical Sciences, 1999.88: that such modifications and variations are considered to be p. 955-958. within the scope of this invention as defined by the appended 0384 Fluhr, J. L., et al., Testing for irritation with a claims. multifactorial approach: comparison of eight non-inva 0371 The invention has been described broadly and sive measuring techniques on five different irritation generically herein. Each of the narrower species and Sub types. British Journal of Dermatology, 2001. 145: p. generic groupings falling within the generic disclosure also 696-703. form part of the invention. This includes the generic descrip 0385) De Brugerolle de Fraisinette, A. et al., Predictivity tion of the invention with a proviso or negative limitation of an in vitro model for acute and chronic skin irritation US 2007/0269379 A1 Nov. 22, 2007 36

(SkinEthic) applied to the testing of topical vehicles. Cell 0400 Mitragotri, S., et al., Transdermal drug delivery Biology and Toxicology, 1999. 15: p. 121-135. using low-frequency Sonophoresis. Pharmaceutical 0386 Faller, C., Bracher, M., Dami, N. and Roguet, R., Research, 1996. 13: p. 411-420. Predictive ability of reconstructed human epidermis 0401 Mitragotri, S., Synergistic effect of enhancers for equivalents for the assemssment of skin irritation of transdermal drug delivery. Pharmaceutical Research, cosmetics. Toxicology in vitro, 2002. 16: p. 557-572. 2000. 17: p. 1354-1359. 0387 Funke, A. P. Schiller, R., Motzkus, H. W., Günther, 0402 Mitragotri, S., et al., Determination of the threshold C., Müller, R. H. and Lipp, R., Transdermal delivery of energy dose for ultra-sound-induced transdermal drug highly lipophilic drugs: In vitro fluxes of antiestrogens, delivery. J. Control. Release 63:41-52 (2000). permeation enhancers, and solvents from liquid formula 0403 Mitragotri, S. Modeling skin permeability to tions. Pharmaceutical Research 2002. 19: p. 661-668. hydrophilic and hydrophobic solutes based on four per 0388 Gennaro, A. R., editor. Remington: The Science meation pathways. J. Control. Release 86:69-92 (2003). and Practice of Pharmacy. 19th edition. Pennsylvania: 0404 Mollgaard, B., Synergistic effects in percutaneous Mack Publishing Company; 1995 enhancement. Pharmaceutical Skin Penetration Enhanc 0389 Hadgraft, J. Trans(dermal) delivery, present and ers, ed. K. Walters and J. Hadgraft. 1993, New York, future perspectives. The Drug Delivery Companies Basel, Hong Kong: Marcel Dekker. 229-242. Report Spring/Summer 2003, published by PharmaVen tures Ltd. see http://www.iirusa.com/docs/P0950 04.05 Ng, S., Goodson, B., Ehrardt, R., Moos, W. H., Hadgraft.pdf. Siani, M. and Winter, J., Combinatorial Discovery Pro cess Yields Antimicrobial Peptides. Prog. Med. Chem. 7: 0390 Hayashi, M., et al., A quantitative relationship 1781-5 (1999). study of the skin irritation potential of phenols. Toxicol 0406 Ollmar, S., et al., Electrical impedance for estima ogy In vitro, 1999. 13(6): p. 915-922. tion of irritation in oral mucosa and skin. Medical 0391) Judge, M. R., et al., Variation in response of human Progress Through Technology, 1995. 21 (1): p. 29-37. skin to irritant challenge. Contact Dermatitis, 1996. 34: p. 115-117. 04.07 Mak, V. H. W. and Francoeur, M. L., Diffusion test apparatus and method. U.S. Pat. No. 5,490,415. Date of 0392 Jung, S., et al., Skin organ culture for cutaneous Patent: Feb. 13, 1996. irritancy screening. In vitro and molecular toxicology, 1999. 12(2): p. 77-82. 0408 Robinson M. K., Osborne R. and Perkins M. A. In vitro and human testing strategies for skin irritation. Ann 0393 Karande, P. S., and Mitragotri, S., High Throughput NY Acad. Sci. (2000) 919:192-204. Screening of transdermal formulations. Pharmaceutical Research, 2002. 19: p. 655-660. 04.09 Roguet, R., Use of skin cell cultures for in vitro assessment of corrosion and cutaneous irritancy. Cell 0394 Kodithala, K., et al., Prediction of skin irritation Biology and Toxicology, 1999. 15: p. 63-75. from organic chemicals using membrane-interaction QSAR analysis. Toxicological Sciences, 2002. 66: p. 0410 Santus, C. G. and Baker, R. W., Transdermal 336-346. enhancer patent literature. Journal of Controlled Release 0395 Lanman, B. M., Elvers, E. B. and Howard C. J., 1993. 25: p. 1-20. The role of human patch testing in a product development 0411 Schmitt, D., Immune functions of the human skin. program. Joint Conference on Cosmetic Sciences, The Models of in vitro studies using Langerhans cells. Cell Toilet Goods Association (currently The Cosmetic, Toi Biology and Toxicology, 1999. 15: p. 41-45. letry and Fragrance Association), Washington D.C., Apr. 0412 Schroder, J. M., Cytokine networks in the skin. 21-23, 1968. Journal of Investigative Dermatology, 1995. 105(1): p. 0396 Lee, J. K. In vitro cytotoxicity tests on cultured S2O-S24. human skin fibroplasts to predict skin irritation potential of surfactants. Toxicology In vitro, 2000. 14(4): p. 345 0413 Shah, V. P. Peck, C. C. and Williams, R. L., Skin 349. Penetration Enhancement: Clinical pharmacological and regulatory considerations. Pharmaceutical skin penetra 0397) Marzuli, F. N. and Maibach, H. I. The rabbit as a tion enhancement, ed. K. Walters. 1993, New York, Basel, model for evaluating skin irritants: a comparison of Hong Kong: Marcel Dekker. 417-427. results obtained on animals and man using repeated skin exposure. Food Cosmetology and Toxicology, 1975. 13: 0414 Smith, J. S., et al., Experimental Validation of a p. 533-540 structure-activity relationship model of skin irritation by esters. Quantitative structure activity relationships, 2000. 0398 Medina, J., et al., Use of human skin equivalent 19(5): p. 467-474. Apligraf for in vitro assessment of cumulative skin irri tation potential of topical products. Toxicology and 0415 Srinivasan, V. and Higuchi, W. I. A model for Applied Pharmacology, 2000. 164: p. 38-45. iontophoresis incorporating the effect of convective sol 0399 Mezei, M. and Gulasekharam, V., Liposomes—a vent flow. International Journal of Pharmaceutics, 1965. selective drug delivery system for the topical route of 60: p. 133-138. administration. Lotion dosage form. Life Sci. 1980. 0416 Verdine, G. L., The Combinatorial Chemistry of 26(18): p. 1473-1477. Nature. Nature. 384: 11-13 (1996). US 2007/0269379 A1 Nov. 22, 2007 37

0417 Walters, K. A., Penetration enhancers and their use (d) evaluating the amount of the test Substance in each in transdermal therapeutic systems. Transdermal Drug donor hole that migrates through the test membrane Delivery. Developmental Issues and Research Initiatives, into the receiver well corresponding to said donor hole. ed. J. Hadgraft and R. H. Guy. 1989, New York: Marcel 4. The method of claim 1 wherein the test membrane is Dekker. 197-233. mammalian skin or mucosa. 0418 Wilhelm, K. P. Bottjer, B. and Siegers, P. C., 5. The method of claim 1 wherein the abilities of the Quantitative assessment of primary skin irritants in vitro samples to increase the permeability of the test membrane in a cytotoxicity model: comparison with in vivo human are measured by making a plurality of electrical conductivity irritation tests. British Journal of Dermatology, 2001. 145: measurementS. 6. The method of claim 1 in which each of a plurality of p. 709-715. the samples comprises three chemical penetration enhanc 0419 Williams AC, Transdermal and topical drug deliv CS. ery: From theory to clinical practice. Pharmaceutical 7. The method of claim 1 in which each of a plurality of Press London, Chicago, 2003. the samples comprises four chemical penetration enhancers. 0420 Zhang, B., et al., Discovery of a Small Molecule 8. The method of claim 1 in which each of a plurality of Insulin Mimetic with Antidiabetic Activity in Mice. Sci the samples comprises more than four chemical penetration ence. 284: 974-7 (1999). enhancers. 9. The method of claim 1 in which the library contains 0421 Zuang, V., et al., Detection of skin irritation poten more than 1,000 samples. tial of cosmetics by non-invasive measurements. Skin 10. The method of claim 1 in which the library contains Pharmacology and Applied Skin Physiology, 2000. 13(6): more than 10,000 samples. p. 358-371. 11. The method of claim 1 in which the library contains 1. A method for selecting compositions having potent more than 1,000,000 samples. ability to increase the permeability of a body surface as 12. The method of claim 1 in which the library contains candidates for further testing for low irritation potential, more than 10,000,000 samples. comprising the following steps: 13. The method of claim 1 in which one or more of the chemical penetration enhancers are selected from the group (a) providing a library, said library comprising a plurality consisting of N-Acyl-hexahydro-2-oxo-1H-azepines, of samples, each sample comprising at least two chemi N-Alkyl-dihydro-1,4-oxazepine-5,7-diones, N-Alkylmor cal penetration enhancers; pholine-2,3-diones, N-Alkylmorpholine-3,5-diones, AZacy (b) measuring with a high throughput device the abilities cloalkane derivatives (-ketone, -thione), AZacycloalkenone of the samples to increase the permeability of a test derivatives, 1-2-(Decylthio)ethylazacyclopentan-2-one membrane; and (HPE-101), N-(2.2), Dihydroxyethyl) dodecylamine, 1-Dodecanoylhexahydro-1-H-azepine, 1-Dodecyl azacyclo (c) analyzing the measurements to select compositions heptan-2-one (aZone or laurocapram), N-Dodecyl diethano having potent ability to increase the permeability of lamine, N-Dodecyl-hexahydro-2-thio-1H-azepine, N-Dode said body Surface. cyl-N-(2-methoxyethyl)acetamide, N-Dodecyl-N-(2- 2. The method of claim 1 in which the abilities of the methoxyethyl) isobutyramide, N-Dodecyl-piperidine-2- samples to increase the permeability of the test membrane thione, N-Dodecyl-2-piperidinone, N-Dodecyl pyrrolidine are measured by a method comprising: 3,5-dione, N-Dodecyl pyrrolidine-2-thione, N-Dodecyl-2- (a) securing the test membrane to a device comprising a pyrrolidone, 1-Farnesylazacycloheptan-2-one, donor plate, the donor plate including a plurality of 1-Farnesylazacyclopentan-2-one, 1-Geranyl azacyclohep donor holes passing through the donor plate; tan-2-one, 1, Geranylazacyclopentan-2-one, Hexahydro-2- oxo-azepine-1-acetic acid esters, N-(2, Hydroxyethyl)-2- (b) introducing the samples into donor holes, each sample pyrrolidone, 1-Laurylazacycloheptane, 2-(1-Nonyl)-1,3- including a test Substance; and dioxolane, 1-N-Octylazacyclopentan-2-one, N-(1- (c) evaluating the amount of the test Substance that Oxododecyl)-hexahydro-1H-azepine, N-(1, Oxododecyl)- remains in the donor holes or that migrates into the test morpholines, 1-Oxohydrocarbyl-substituted membrane after a suitable incubation time. azacyclohexanes, N-(1-Oxotetradecyl)-hexahydro-2-oxo 3. The method of claim 1 in which the abilities of the 1H-azepine, N-(1 Thiododecyl)-morpholines, Acetamide samples to increase the permeability of the test membrane and derivatives, Acetone, n-Alkanes (chain length between 7 and 16), Alkanols, diols, short-chain fatty acids, Cyclo are measured by a method comprising: hexyl-1,1-dimethylethanol, Dimethyl acetamide, Dimethyl (a) securing the test membrane to a device comprising a formamide, Ethanol, Ethanol/d-limonene combination, donor plate, the donor plate including a plurality donor 2-Ethyl-1,3-hexanediol, Ethoxydiglycol (transcutol), Glyc holes passing through the donor plate; erol, Glycols, Lauryl chloride, Limonene, N-Methylforma mide, 2-Phenylethanol, 3-Phenyl-1-propanol, 3-Phenyl-2- (b) securing the test membrane to a receiver plate Such propen-1-ol, Polyethylene glycol, Polyoxyethylene sorbitan that the test membrane is disposed between the donor monoesters, Polypropylene glycol 425, Primary alcohols plate and the receiver plate, said receiver plate includ (tridecanol), Procter & Gamble system: small polar solvent ing a plurality of receiver wells corresponding to the (1,2-propane diol, butanediol, C3-6 triols or their mixtures donor holes and said receiver wells containing a liquid; and a polar lipid compound selected form C16 or C18 (c) introducing the samples into donor holes, each sample monounsaturated alcohol, C16 or C18 branched saturated including a test Substance; and alcohol and their mixtures), Span 20, Squalene, Triacetin, US 2007/0269379 A1 Nov. 22, 2007

Trichloroethanol, Trifluoroethanol, Trimethylene glycol, Poly(N-vinylpyrrolidone), Pyroglutamic acid esters, Acid Xylene, DMSO, Aliphatic alcohols, Decanol, Lauryl alcohol phosphatase, Calonase, Orgelase, Papain, Phospholipase (dodecanol), Linolenyl alcohol, Nerolidol, 1-Nonanol, A-2, Phospholipase C, and Triacylglycerol hydrolase. n-Octanol, Oleyl alcohol, Butyl acetate, Cetyl lactate, Decyl 14. The method of claim 1 wherein the step of measuring N,N-dimethylamino acetate, Decyl N,N-dimethylamino iso the abilities of samples to increase the permeability of a test propionate, Diethyleneglycol oleate, Diethyl sebacate, membrane is accomplished by making a plurality of elec Diethyl succinate, Diisopropyl sebacate, Dodecyl N,N-dim trical conductivity measurements and the step of analyzing ethylamino acetate Dodecyl (N,N-dimethylamino)-butyrate, the measurements is assisted by considering synergy values Dodecyl N,N-dimethylamino isopropionate, Dodecyl between chemical penetration enhancers in said samples. 2-(dimethylamino)propionate, EO-5-oleyl ester, Ethyl 15. The method of claim 1 wherein at least one of the acetate, Ethylaceto acetate, Ethyl propionate, Glycerol selected compositions contains a pair of chemical penetra monoethers, Glycerol monolaurate, Glycerol monooleate, tion enhancers with a synergy value of 2 or more. Glycerol monolinoleate, Isopropyl isostearate, Isopropyl 16. The method of claim 1 wherein at least one of the linoleate, Isopropyl myristate, Isopropyl myristate/fatty acid selected compositions contains a pair of chemical penetra monoglyceride combination, Isopropyl myristate/ethanol/L- tion enhancers with a synergy values of 4 or more. lactic acid (87:10:3) combination, Isopropyl palmitate, 17. The method of claim 1 wherein the step of analyzing Methyl acetate, Methyl caprate, Methyl laurate, Methyl the measurements is assisted by considering one or more propionate, Methyl Valerate, 1-Monocaproyl glycerol, potency phase maps. Monoglycerides (medium chain length), Nicotinic esters 18. The method of claim 1 wherein the step of analyzing (benzyl), Octyl acetate, Octyl N,N-dimethylamino acetate, the measurements is assisted by considering synergy values Oleyl oleate, n-Pentyl N-acetylprolinate, Propylene glycol between one or more pairs of chemical penetration enhanc monolaurate, Sorbitan dilaurate, Sorbitan dioleate, Sorbitan ers in the samples. monolaurate, Sorbitan monooleates, Sorbitan trilaurate, Sor 19. The method of claim 1 including the step of deter bitan trioleate. Sucrose coconut fatty ester mixtures. Sucrose mining the irritation potential of the selected compositions monolaurate. Sucrose monooleate, Tetradecyl N,N-dimethy whereby to identify one or more compositions having potent lamino acetate, Alkanoic acids, Capric acid, Diacid, Ethy ability to increase the permeability of a body surface and low loctadecanoic acid, Hexanoic acid, Lactic acid, Lauric acid, irritation potential. Linoelaidic acid, Linoleic acid, Linolenic acid, Neodecanoic 20. The method of claim 19 in which the determination of acid, Oleic acid, Palmitic acid, Pelargonic acid, Propionic irritation potential is accomplished with an in vitro mea acid, Vaccenic acid, a-Monoglyceryl ether, EO-2-oleyl ether, Surement. EO-5-oleyl ether, EO-10-oleyl ether, Ether derivatives of 21. The method of claim 19 in which the determination of polyglycerols and alcohols (1-O-dodecyl-3-O-methyl-2-0- irritation potential is accomplished with an in vivo measure (29.39-dihydroxypropyl)glycerol), L-O-amino-acids, Leci ment. thin, Phospholipids, Saponin/phospholipids, Sodium deoxy 22. The method of claim 19 in which the determination of cholate, Sodium taurocholate, Sodium tauroglycocholate irritation potential is accomplished using an interleukin-1C. (285), Aliphatic thiols, Alkyl N,N-dialkyl-substituted amino assay. acetates, Anise oil, Anticholinergic agent pretreatment, 23. The method of claim 19 in which the determination of Ascaridole, Biphasic group derivatives, Bisabolol, Carda irritation potential is accomplished using a methyl thiazol mom oil, 1-Carvone, Chenopodium (70% ascaridole), Che tetrazolium assay. nopodium oil, 1.8 Cineole (eucalyptol), Cod liver oil (fatty acid extract), 4-Decyloxazolidin-2-one, Dicyclohexylm 24. The method of claim 19 in which irritation potential ethylamine oxide, Diethyl hexadecylphosphonate, Diethyl is measured using a 21-day cumulative irritation test. hexadecylphosphoramidate, N,N-Dimethyl dodecylamine 25. The method of claim 19 including the step of com N-oxide, 4,4-Dimethyl-2-undecyl-2-oxazoline, N-Dode bining each identified composition with a selected active canoyl-L-amino acid methyl esters, 1,3-Dioxacycloalkanes, component to form one or more candidate active component (SEPAs), Dithiothreitol, Eucalyptol (cineole), Eucalyptus formulations. oil, Eugenol, Herbal extracts, Lactam N-acetic acid esters, 26. The method of claim 25 including the step of testing N-Hydroxyethalaceamide, 2-Hydroxy-3-oleoyloxy-1-pyro each candidate active component formulation for the pen glutamyloxypropane, Menthol, Menthone, Morpholine etration of the active component into or through skin or derivatives, N-Oxide, Nerolidol, Octyl-b-D-(thio)glucopy COSa. ranosides, Oxazolidinones, piperazine derivatives, Polar lip 27. The method of claim 26 in which the candidate active ids, Polydimethylsiloxanes, Poly 2-(methylsulfinyl)ethyl component formulation is placed on porcine or human skin acrylate), Polyrotaxanes, Polyvinylbenzyldimethylalky and penetration of the active component through the skin is lammonium chloride, Poly(N-vinyl-N-methyl acetamide), measured after a suitable incubation time. Prodrugs, Saline, Sodium pyroglutaminate, Terpenes and 28. The method of claim 27 in which penetration of the azacyclo ring compounds, Vitamin E (C-tocopherol), Ylang active component through the skin is measured using a ylang oil, N-Cyclohexyl-2-pyrrolidone, 1-Butyl-3-dodecyl Franz diffusion cell. 2-pyrrolidone, 1,3-Dimethyl-2-imidazolikinone, 1.5 Dim 29. The method of claim 26 including the step of deter ethyl-2-pyrrolidone, 4.4-Dimethyl-2-undecyl-2-oxazoline, mining whether the tested candidate active component for 1-Ethyl-2-pyrrolidone, 1-Hexyl-4-methyloxycarbonyl-2- mulation can deliver the necessary active component pyrrolidone. 1-Hexyl-2-pyrrolidone, 1-(2 Hydroxyeth amount through the skin. yl)pyrrolidinone, 3-Hydroxy-N-methyl-2-pyrrolidinone, 30. The method of claim 29 in which the capacity of the 1-Isopropyl-2-undecyl-2-imidazoline, 1-Lauryl-4-methy tested candidate active component formulation to deliver the loxycarbonyl-2-pyrrolidone, N-Methyl-2-pyrrolidone, necessary active component amount through the skin is US 2007/0269379 A1 Nov. 22, 2007 39 determined by comparing penetration of the candidate active component formulation with published data. 31. The method of claim 25 wherein the active component ERAB (X, Y) is a drug and further including the step of conducting animal * x. ER(y) (1 x). ER(y) testing to confirm the ability of an active component for mulation to deliver Sufficient drug across the skin to achieve where ERACX,Y) is the 24-hour enhancement ratio therapeutic levels of the drug in the blood of animals. obtained with said formulation, A stands for said first 32. The method of claim 31 in which the animal testing chemical penetration enhancer, B stands for said second comprises in vivo experiments on hairless rats performed penetration enhancer, Y stands for the combined total con using leuprolide acetate as a model active component. centration of said first and second chemical penetration 33. A composition identified by the method of claim 19 enhancer in said formulation measured in weight/volume, X having potent ability to increase the permeability of skin and stands for the weight fraction said first chemical penetration pharmaceutically acceptable irritation potential. enhancer in the formulation divided by Y, and ERACY) and ER(Y) are the 24-hour enhancement ratios obtained with a 34. A method for identifying active component formula second and third formulation where the chemical penetration tions comprising a plurality of chemical penetration enhanc enhancers A and B are replaced in said formulation with pure ers having potent ability to increase the permeability of a components A and B, respectively, each at concentration Y body Surface and low irritation potential, comprising: weight/volume. (a) providing a library, said library comprising a plurality 38. The formulation of claim 36 in which the 24-hour of samples comprising at least two chemical penetra synergy value is 4 or more. tion enhancers; 39. A formulation comprising a first and second chemical penetration enhancer with potent ability to increase the (b) screening the library with a high throughput device by permeability of skin showing Sufficient partitioning of com a method comprising (i) securing mammalian skin or ponents of said formulation between the stratum corneum of mucosa to a device comprising a donor plate, the donor skin and other layers of skin to exhibit low irritation poten plate including a plurality of donor holes passing tial. through the donor plate, (ii) introducing said samples 40. The formulation of claim 39 wherein the 21-day into the donor holes, and (iii) measuring the abilities of cumulative irritation test score of said formulation is less the samples to increase the permeability of said mam than about 199. malian skin or mucosa by making a plurality of elec 41. A composition comprising a first and second chemical trical conductivity measurements; penetration enhancer having potent ability to increase the permeability of skin and low irritation potential to enable (c) analyzing said electrical conductivity measurements to transdermal delivery of a drug having a molecular weight of Select compositions having high synergy values and at least 500 Da with pharmaceutically acceptable irritation potent ability to increase the permeability of said body potential. Surface; 42. A composition comprising sodium laurel ether Sulfate (d) determining the irritation potential of the selected and 1-phenylpiperazine having potent ability to increase the compositions whereby to identify one or more compo permeability of skin and low irritation potential. sitions having potent ability to increase the permeabil 43. A composition comprising N-lauryl sarcosine and ity of a body surface and low irritation potential; Sorbitan monolaurate having potent ability to increase the permeability of skin and low irritation potential. (e) combining the identified compositions with a selected active component to form one or more candidate active 44. A formulation for topical and/or transdermal admin component formulations; istration of a drug, comprising: (a) a therapeutically effective amount of said drug; (f) testing the candidate active component formulations for penetration of said active component through a (b) a pharmaceutically acceptable vehicle suitable for body surface; topical or transdermal drug administration; (g) analyzing the results of the tests of penetration of said (c) a first and second chemical penetration enhancer, the active component through said body Surface to select synergy value between said first and second chemical an active component formulation having potent ability penetration enhancer being at least about 2: to increase the permeability of said body surface and wherein said formulation has a pharmaceutically accept low irritation potential. able irritation potential and the skin conductivity 35. An active component formulation with potent ability enhancement ratio of the formulation is at least about to increase the permeability of a body surface and low 3O. irritation potential selected according to the method of claim 45. A composition comprising a first and second chemical 34. penetration enhancer wherein the 24-hour synergy value 36. A formulation comprising a first and second chemical between said first and second chemical penetration enhancer penetration enhancer having a 24-hour synergy value of 2 or is at least about 2 and wherein the irritation antergy factor O. between said first and second chemical penetration enhancer 37. The combination of chemical penetration enhancers of is at least about 2, said irritation antergy factor being claim 36 in which the synergy value is calculated according computed using the MTT 4-hour cell viability percentage to the following equation measure of irritation potential. US 2007/0269379 A1 Nov. 22, 2007 40

46. The formulation of claim 44 wherein said chemical 51. A method for screening for formulations providing penetration enhancers are selected from the group consisting potent ability to increase the permeability of skin and low of Surfactants, aZone and related compounds, solvents and irritation potential, comprising: related compounds, fatty alcohols, fatty esters and fatty (a) providing a library of samples, a plurality of said acids. samples comprising at least two chemical penetration 47. A method for treating a disease that is responsive to enhancers; administration of a drug comprising applying the formula tion of claim 44 to a patient’s body Surface. (b) using a high throughput device to assay the abilities of 48. A system for topical or transdermal administration of said samples to permeabilize skin; a drug, comprising: (c) analyzing the results of the assay to identify the presence hot spots or Suspected hot spots to select one (a) the formulation of claim 44; or more compositions for irritation potential measure (b) at least one drug reservoir, said reservoir containing ment; and said formulation; (e) measuring the irritation potential of the selected com (c) means for securing said system to a body Surface. positions; 49. A transdermal patch comprising the formulation of whereby formulations providing potent ability to increase claim 44. the permeability of skin and low irritation potential 50. A method for delivering an active component, com may be efficiently discovered. prising applying a formulation to the skin of a mammal said 52. A method for making a formulation providing potent formulation comprising: ability to deliver an active component and low irritation potential, comprising: (a) an effective amount of said active component; (a) providing at least two materials wherein in aggregate (b) a cosmetically or pharmaceutically acceptable vehicle: the components of said at least two materials comprise (c) a first chemical penetration enhancer; and a first and second chemical penetration enhancer, an active component and a vehicle: (d) a second chemical penetration enhancer, (b) combining said at least two materials in a predeter wherein said formulation has an irritation potential that is mined ratio: less than that of 1.5% wt/vol oleic acid in a vehicle whereby a formulation is made, said formulation having consisting of phosphate buffered saline, the 24-hour a 24-hour porcine skin conductivity enhancement ratio synergy value between the first and second chemical penetration enhancer is at least about 2, and the 24-hour of at least about 30 and an MTT 4-hour cell viability conductivity enhancement ratio of said formulation percentage of less than about 15%. measured with porcine skin is at least about 30. k k k k k