58 Pharmaceutic& Technology NOVEMBER 1997
`
`Skin Penetration Enhancers
`Cited in the Technical Literature
`
`David W. Osborne* and Jill J. Henke
`
`D wring the development of a topical dosage form, it
`
`is often useful to know if solvents or excipients an-
`ticipated for use in the formulation have been listed
`in the literature as skin penetration enhancers. Al-
`though recent efforts in using chemical enhancers have fo-
`cused on substances categorized as generally recognized as
`safe (GRAS), early work included a wide range of materi-
`als. For this reason, a large number of excipients have been
`claimed to enhance skin penetration. Complete texts con-
`cerning pharmaceutical skin penetration enhancement are
`available and they provide excellent descriptions and criti-
`cal reviews of this subject (1,2).
`The pharmaceutical scientist developing topical products
`needs to have a quick reference summarizing the skin pene-
`tration literature. Topical products often contain many com-
`ponents that are considered inert excipients with respect to the
`pharmacology and delivery of the active ingredient. Solvents
`and cosolvents are used to alter drug solubility or ease of pro-
`cessing. Emulsifiers and gelling agents provide the consis-
`tency and properties expected of creams, lotions, and gels.
`Other additives such as antioxidants and preservatives are
`provided to extend shelf life or ensure quality. The formulator
`will know the intended use of the excipients present in the for-
`mulation, but it is also important to know whether the excip-
`lent is suspected of altering pharmacology or delivery. The
`goal of this review is to list the chemical substances reported
`in the technical literature to enhance skin permeation. The
`length of this list is surprising. In a review of the technical and
`patent literature up to 1996, more than 275 different chemi-
`cal compounds were found to be cited as skin penetration
`enhancers. Some of these compounds come from the patent
`literature in which a series of compounds of custom design
`were synthesized in hopes of commercializing the ideal
`chemical enhancer. However, most of the compounds are
`GRAS ingredients that would often be considered inert by the
`formulator. By providing this list of supposed penetration
`enhancers, the authors hope that the formulator will not be
`surprised by a group of references claiming their "inert" in-
`gredients to be skin penetration enhancers.
`It is very important to emphasize that this literature search
`attempts to be exhaustive in identifying chemical compounds
`
`AQUESTIVE EXHIBIT 1024 page 0001
`
`3M DRUG DELIVERY SYSTEMS
`
`A literature review found more than 275 chemical
`compounds cited as skin penetration enhancers.
`However, most of the compounds are generally
`recognized as safe (GRAS) ingredients that would
`often be considered inert by a formulator. This article
`lists the chemical substances reported in the technical
`literature to enhance skin permeation. The reader can
`view the reference list of more than 400 sources on the
`Pharmaceutical Technology Web site.
`
`David W. Osborne, PhD, is vice-president, research and develop-
`ment, and IN J. Henke is a former intern at ViroTex Corp., 4200
`Research Forest Drive, Suite 350, The Woodlands, TX 77381,
`tel. (281)298-6447, fax (281) 298-6474.
`
`*To whom all correspondence should be addressed.
`
`

`

`GO Pharmaceutical Technology NOVEMBER 1997
`
`Fatty alcohols, fatty acids, and related structures
`
`Fatty alcohols
`Aliphatic alcohols (17, 18, 263, 299, 303)
`Decanol (88, 128, 177, 239, 303)
`Lauryl alcohol (dodecanol) (88, 128, 148, 177, 266, 281, 286,
`288, 299, 309, 315, 320, 355)
`Linolenyl alcohol (299, 346)
`Nerolidol (402)
`1-Nonanol (239, 242, 298)
`n-Octanol (234, 299, 303)
`()ley' alcohol (31, 97, 98, 155, 199, 246, 381)
`
`Fatty acid esters
`Butyl acetate (175, 192)
`Cetyl lactate (58)
`Decyl N,N-dimethylamino acetate (312, 315)
`Decyl N,N-dimethylamino isopropionate (313)
`Diethyleneglycol oleate (69)
`Diethyl sebacate (68)
`Diethyl succinate (192)
`Diisopropyl sebacate (70)
`Dodecyl N,N-dimethylamino acetate (148, 286, 288, 299, 312,
`315, 318, 320, 333)
`Dodecyl (N,N-dimethylarnino)-butyrate (313)
`Dodecyl N,N-dimethylamino isopropionate (313, 320)
`Dodecyl 2-(dimethylamino)propionate (148, 280, 284)
`EO-5-oleyl ester (199)
`Ethyl acetate (175, 192, 193, 194, 246, 252, 279)
`Ethylaceto acetate (192)
`Ethyl propionate (192)
`Glycerol monoethers (394)
`Glycerol monolaurate (93, 94, 350, 351, 388)
`Glycerol monooleate (90-94, 388)
`Glycerol monolinoleate (387, 388)
`Isopropyl isostearate (353)
`Isopropyl linoleate (381)
`Isopropyl myristate (46, 101-107, 234, 246, 311, 326, 353)
`Isopropyl myristatelfatty acid monoglyceride combination
`(391)
`Isopropyl rnyristate/ethanol/L-lactic acid (87:10:3) combination
`(404)
`Isopropyl palmitate (353)
`Methyl acetate (192, 385)
`Methyl caprate (299)
`Methyl laurate (117, 374, 375, 384)
`Methyl propionate (192)
`Methyl valerate (192)
`1-Monocaproyl glycerol (311)
`
`Monoglycerides (medium chain length) (119)
`Nicotinic esters (benzyl) (129, 130)
`Octyl acetate (252)
`Octyl N,N-dimethylarnino acetate (312)
`()ley' oleate (326)
`n-Pentyl N-acetylprolinate (235, 251)
`Propylene glycol monolaurate (374, 375)
`Sorbitan dilaurate (388)
`Sorbitan dioleate (388)
`Sorbitan monolaurate (388)
`Sorbitan monooleates (48, 50, 346, 388)
`Sorbitan trilaurate (388)
`Sorbitan trioleate (388)
`Sucrose coconut fatty ester mixtures (165, 384)
`Sucrose monolaurate (165)
`Sucrose monooleate (163, 164)
`Tetradecyl N,N-dimethylamino acetate (312)
`
`Fatty acids
`Alkanoic acids (55, 230, 263, 273, 315, 347)
`Capric acid (57, 299)
`Diacid (262)
`Ethyloctadecanoic acid (401)
`Hexanoic acid (I03)
`Lactic acid (109, 110)
`Lauric acid (55, 111, 178, 218, 220, 299, 309)
`Linoelaidic acid (55)
`Linoleic acid (55, 299, 381)
`Linolenic acid (55)
`Neodecanoic acid (55)
`Oleic acid (3, 11, 31, 55, 92, 97, 118, 137, 148, 152, 153, 154,
`178, 199, 200, 210, 211, 216, 218, 219, 228, 231, 234, 243,
`246, 265, 266, 271, 275, 283, 294-296, 299, 305, 307-309,
`320, 323, 333, 341, 344, 346, 356-358, 376, 381)
`Palmitic acid (55)
`Pelargonic acid (55)
`Propionic acid (103)
`Vaccenic acid (88, 128, 177)
`
`Fatty alcohol ethers
`et-Monoglyceryl ether (23)
`EO-2-oleyl ether (199)
`EO-5-oleyl ether (199)
`E0-10-okyl ether (199)
`Ether derivatives of polyglycerols and alcohols (1-0-dodecy1-3-
`0-methy1-2-0-(2', 3 `-dihydroxypropyl)glycerol) (85)
`
`cited as penetration enhancers. For compounds with multiple lit-
`erature citations, such as axone and oleic acid, a representative
`sampling of the literature rather than an exhaustive or critical
`listing is provided. Thus, this is not a critical review, but a listing
`of at least one reference of the chemical compounds cited in
`the technical or patent literature as skin penetration enhancers.
`Throughout this introduction we have used the terms sup-
`posed and cited as skin penetration enhancers. The literature
`cited in this review often contains reports in which a chemical
`substance added to the formulation alters delivery, but the in-
`
`vestigators do not sufficiently characterize a mechanism to es-
`tablish that the substance is a chemical skin penetration en-
`hancer. By definition, a chemical skin penetration enhancer in-
`creases skin permeability by reversibly damaging or by altering
`the physiochemical nature of the stratum corneum to reduce
`its diffusional resistance (3). Although there are many strate-
`gies to enhance skin penetration, only some of them include the
`use of chemical skin penetration enhancers. Additives that en-
`hance skin delivery by altering solubility of the active ingredi-
`ent in the formulation (including supersaturation) or by opti-
`
`AQUESTIVE EXHIBIT 1024 page 0002
`
`

`

`62 Pharmaceutical Technology NOVEMBER 1997
`
`Miscellaneous compounds and groups
`
`Biologics
`L-a-amino-acids (108, 346)
`Lecithin (112, 229, 258, 346, 352)
`Phospholipids (403)
`Saponin/phospholipids (161)
`Sodium deoxycholate (285)
`Sodium taurocholate (285)
`Sodium tauroglycocholate (285)
`
`Enzymes
`Acid phosphatase (332)
`Calonase (310)
`Orgelase (310)
`Papain (346)
`Phospholipase A-2 (332)
`Phospholipase C (332)
`Triacylglycerol hydrolase (332)
`
`Amines and amides (not placed in previous categories)
`Acetarnide derivatives (16)
`Acyclic amides (290)
`N-Adamantyl n-alkanamides (408)
`Clofibric acid amides (321, 342)
`N,N-Didodecyl acetamide (16)
`Di-2-ethylhexylamine (66)
`Diethyl methyl benzamide (39)
`N,N-Diethyl-m-toluamide (68, 131-133, 218, 299, 326)
`N,N-Dimethyl-m-toluamide (309)
`Ethomeen S12 [bis-(2-hydroxyethyl)oleylamine] (86, 87, 299,
`346)
`Hexamethykne lauramide (95)
`Lauryl-amine (dodecylamine) (240, 299, 346)
`Octyl amide (233)
`Oleylamine (240)
`Unsaturated cyclic ureas (61, 62, 293, 299)
`Urea (43, 109, 172, 185, 256, 285, 299, 304, 346)
`
`Comptexing agents
`13- and y-cyclodextrin complexes (52, 53)
`Hydroxypropyl methylcellulose (Carbapol 934) (91, 100)
`Liposomes (113, 195)
`Naphthalene diamide diirnide (398)
`Naphthalene diester diimide (398)
`
`MaCreCyClICS
`Macrocyclic lactones, ketones, and anhydrides (optimum ring-
`16) (114, 346)
`Unsaturated cyclic areas (61, 62, 293, 299)
`
`Classical surfactants
`Brij 30 (201. 202)
`Brij 36T (207, 216, 307, 346)
`Brij 35 (204, 209)
`Brij 52 (207)
`Brij 56 (207, 208)
`Brij 58 (203, 207, 208)
`Brij 72 (208)
`Brij 76 (207)
`Brij 78 (208)
`
`Brij 92 (209)
`Brij 96 (206, 207)
`Brij 98 (208)
`Cetyl trimethyl ammonium bromide (218, 299, 346)
`Empicol ML261F (299)
`HCO-60 surfactant (59)
`Hydroxypolyethoxydodecane (99)
`Ionic surfactants (ROONa, ROSO3Na, RNH3C1, R = 8-16) (79)
`Lauroyl sarcosine (334)
`Nonionic surface active agents (134)
`Nonoxynol (386)
`Octoxynol (386)
`Phenylsulfonate CA (299)
`Pluronic F68 (201, 207, 285)
`Pluronic F127 (285)
`Pluronic L62 (201, 207)
`Polyoleates (nonionic surfactants) (92, 135)
`Rewopal HV10 (207)
`Sodium karate (346)
`Sodium lauryl sulfate (sodium dodecyl sulfate) (56, 59, 60, 126,
`269, 295, 299, 335, 346)
`Sodium oleate (326, 335)
`Sorbitan dilaurate (388)
`Sorbitan dioleate (388)
`Sorbitan monolaurate (388)
`Sorbitan monooleates (48, 50, 346, 388)
`Sorbitan trilaurate (388)
`Sorbitan trioleate (388)
`Span 20 (134)
`Span 40 (201, 203)
`Span 85 (206)
`Synperonic NP (299)
`Triton X-100 (207)
`Tween 20 (32, 102, 134, 147)
`Tween 40 (201, 203)
`Tween 60 (147)
`Tween 80 (147, 170, 346, 396)
`Tween 85 (206)
`
`Others
`Aliphatic thiols (316)
`Alkyl N,N-dialkyl-substituted amino acetates (22)
`Anise oil (232)
`Anticholinergic agent pretreatment (149)
`Ascaridole (241, 299)
`Biphasic group derivatives (54)
`Bisabolol (299, 306, 339, 346)
`Cardamom oil (405)
`l-Carvone (382)
`Chenopodium (70% ascaridole) (241, 299)
`Chenopodium oil (232, 299)
`1,8 Cineole (eucalyptol) (83, 197, 234, 237, 241, 299, 326, 345,
`346, 402)
`Cod liver oil (fatty acid extract) (236)
`4-Decyloxazolidin-2-one (297)
`Dicyclohexylmethylamine oxide (67)
`Diethyl hexadecylphosphonate (329)
`Diethyl hexadecylphosphoramidate (329)
`N,N-Dimethyl dodecylamine-N-oxide (335, 346)
`
`AQUESTIVE EXHIBIT 1024 page 0003
`
`

`

`64 Pharmaceutical Technology NOVEMBER 1997
`
`Miscellaneous compounds and groups, continued
`
`4, 4-Dimethyl-2-undecyl-2-oxazoline (7)
`N-Dodecanoyl-L-amino acid methyl esters (410)
`1,3-Dioxacycioalkanes (SEPAs) (346)
`Dithiothreitol (26)
`Eucalyptol (cineole) (83, 197, 234, 237, 241, 299, 326, 345,
`346, 402)
`Eucalyptus oil (232, 299)
`Eugenol (383)
`Herbal extracts (337)
`Lactam N-acetic acid esters (407)
`N-Hydroxyethalaceamide (299)
`2-Hydroxy-3-oleoyloxy-l-pyroglutamyloxypropane (12)
`Menthol (115, 237, 253, 271, 299, 348, 349)
`Menthone (380)
`Morpholine derivatives (120)
`N-Oxide (389)
`Nerolidol (402)
`
`N-methyl pyrrolidone and related compounds
`
`N-Cyclohexy1-2-pyrrolidone (250)
`1-Butyl-3-dodecyl-2-pyrrolidone (330)
`1,3-Dimethyl-2-imidazolikinone (62, 184)
`1,5 Dimethyl-2-pyrrolidone (299, 309)
`4,4-Ditnethy1-2-undecy1-2-oxazoline (7)
`1-Ethyl-2-pyrrolidone (299, 309)
`1-11exy1-4-methyloxycarbony1-2-pyrrolidone (331)
`1-Hexy1-2-pyrrolidone (324, 325, 346)
`1-(2-Hydroxyethyl)pyrrolidinone (3)
`
`Octy1-13-D-(thio)glucopyranosides (136, 277)
`Oxa2olidinones (406)
`Piperazine derivatives (120)
`Polar lipids (123, 143)
`Polydimethylsiloxanes (338)
`Poly [2-(methylsulfinyl)ethyl acrylate] (145)
`Polyrotaxanes (400)
`Polyvinyibenzyldimethylalkylammoniurn chloride (257)
`Poly(N-vinyl-N-methyl acetamide) (145)
`Prodrugs (142, 151, 399)
`Saline (skin hydration) (160)
`Sodium pyroglutaminate (299)
`Terpenes and azacyclo ring compounds (15, 127, 196, 215,
`231, 237, 238, 241, 242, 249, 253, 270, 273, 299, 306, 345,
`346, 395)
`Vitamin E (ix-tocopherol) (255)
`Ylang-ylang oil (232, 299)
`
`3-Hydroxy-N-methyl-2-pyrrolidinone (317)
`1-Isopropyl-2-undecyl-2-imidazoline (7)
`1-Laury1-4-methyloxycarbony1-2-pyrrolidone (331)
`N-Methyl-2-pyrrolidone (110, 121-125, 218, 234, 247, 259, 265,
`276, 283, 299-301, 309, 317, 324-326, 354, 381)
`Poly(N-vinylpyrrolidone) (145, 392)
`Pyroglutamic acid esters (156, 157, 360, 372, 373)
`2-Pyrrolidone (2-pyrrolidinone) (247, 264, 295, 299, 301, 309,
`330)
`
`Ionic compounds
`
`Dimethyl sulfoxide and related compounds
`
`Ascorbate (26)
`"Amphoteric cations and anions" (25)
`Calcium thioglycolate (56, 346)
`Cetyl trimethyl ammonium bromide (218, 299)
`3,5-Diiodosalicylate sodium (15)
`Ionic surfactants (ROONa, ROSO3Na, RNH3C1) (79)
`Lauroylcholine iodide (200)
`5-Methoxysalicylate sodium (15)
`Monoalkyl phosphates (378, 379)
`2-PAM chloride, 4-PAM chloride (derivatives of N-methyl
`picolinium chloride) (14)
`Sodium carboxylate (289)
`Sodium hyaluronate (39)
`Sodium lauryl sulfate (sodium dodecyl sulfate) (56, 59, 60,
`126, 269, 295, 299, 335, 346)
`
`Cyclic sulfoxides (328)
`Decylmethyl sulfoxide (31, 46, 63-65, 118, 163, 191, 216, 227,
`234, 250, 295, 299, 300, 302, 304, 305, 307-309, 311, 335,
`346)
`Dimethyl sulfoxide (66, 72-74, 77, 78, 80, 81, 126, 138, 144,
`170, 186, 191, 218, 249, 259-261, 263, 274, 285, 295, 299,
`309, 311, 317, 323, 346)
`2-Hydroxyundecyl methyl sulfoxide (13)
`
`AQUESTIVE EXHIBIT 1024 page 0004
`
`

`

`66 Pharmaceutical Technology NOVEMBER 1997
`
`Solvents and related compounds
`
`Acetamide and derivatives (16)
`Acetone (263, 299)
`n-Alkanes (chain length between 7 and 16) (239, 242, 298,
`315)
`Alkanols, dials, short-chain fatty acids (18-21, 217, 230, 239,
`299, 347, 381)
`Cyclohexy1-1,1-dimethylethanol (17)
`Dimethyl acetamide (71, 72, 218, 274, 275, 295, 299, 309)
`Dimethyl fonnamide (72, 75-82, 138, 144, 185, 191, 218, 246,
`264, 274, 275, 285, 299, 309)
`Ethanol (17, 18, 32, 63, 83, 84, 213, 238, 252, 263, 275, 279,
`283, 291, 295, 299, 309, 343, 350, 351)
`Ethanalld-lirnonene combination (409)
`2-Ethyl-1,3-hexanediol (11, 346, 356-358)
`Ethoxydiglycol (transcutol) (374, 375)
`Glycerol (304)
`Glycols (24, 32, 77, 299, 346)
`Lauryl chloride (323)
`Limonene (291, 299, 346)
`N-Methylformamide (299)
`2-Phenylethanol (411)
`3-Phenyl-l-propanal (411)
`3-Phenyl-2-propen-l-al (411)
`Polyethylene glycol (74, 78, 80, 146, 170, 299)
`Polyoxyethylene sorbitan monoesters (147, 346)
`Polypropylene glycol 425 (230)
`Primary alcohols (tridecanol) (150)
`Procter & Gamble system: small polar solvent (1,2-propane
`diol, butanediol, C3-6 triols or their mixtures and a polar lipid
`compound selected form C16 or C18 monounsaturated alco-
`hol, C16 or C18 branched saturated alcohol and their mix-
`tures) (20, 336)
`Propylene glycol (20, 31-33, 46, 63, 68, 69, 74, 77, 88, 89, 91,
`92, 97, 98, 101, 109, 117, 118, 123, 124, 130, 131, 135, 140,
`141, 143, 147, 152-155, 170, 173, 174, 176, 212, 231, 243,
`252, 261, 263, 275, 294, 295, 299, 304, 305, 308, 309, 346,
`353, 377)
`Span 20 (134)
`Squalene (252)
`Triacetin (393)
`Trichloroethanol (168, 169)
`Trifluaroethanol (168, 169)
`Trimethylene glycol (32)
`Tween 20 (32, 102, 134, 147)
`Tween 80 (147, 170)
`Xylene (66)
`
`mizing the ionization state of the drug are not necessarily
`chemical skin penetration enhancers.
`Also, many of these studies used in vitro permeation tech-
`niques completed on excised animal skin. Depending on the
`species used and the experimental design, the significant en-
`hancement found in vitro may not translate into improved clin-
`ical delivery in humans. Thus, even though a compound is cited
`as a skin penetration enhancer, it is the responsibility of the for-
`mulator to critically evaluate the validity of this assessment.
`Editor's note: Because of space constraints, it is impossible to
`print the extensive reference list here. However, the list can be
`
`Azone and related compounds (see Patents, refer-
`ences 361-371)
`
`N-Acyl-hexahydro-2-oxo-1H-azepines (254)
`N-Alkyl-clihydro-1,4-oxazepine-5,7-diones (254)
`N-Alkylmorpholine-2,3-diones (254)
`N-Alkylmorpholine-3,5-diones (254)
`Azacycloalkane derivatives (-ketone, -thione) (29, 30)
`Azacycloalkenone derivatives (127, 179)
`1-[2-(Decylthio)ethyl] azacyclopentan-2-one (HPE-101)
`(327, 340)
`N-(2,2-Dihydroxyethyl)dodecylamine (314)
`1-Dadecanoylhexahydro-l-H-azepine (4)
`1-Dodecyl azacycloheptan-2-one (atone or laurocapram)
`(6, 31-50, 118, 141, 148, 167, 176, 180-184, 186-190,
`198, 214, 218, 224, 225, 233-235, 244, 245, 247-249,
`256, 259, 261, 266-268, 271, 272, 274, 275, 278, 281,
`282, 286-288, 290, 292, 293, 295, 299, 305, 308, 309,
`311, 314, 315, 318, 320, 322, 326, 327, 333, 359, 376,
`381, 402)
`N-Dodecyl diethanolamine (397)
`N-Dodecyl-hexahydro-2-thio-1H-azepine (247)
`N-Dodecyl-N-(2-methoxyethyl)acetamide (314, 397)
`N-Dodecyl-N-(2-methoxyethyl)isobutyramide (397)
`N-Dodecyl-piperidine-2-thione (247)
`N-Dodecyl-2-piperidinone (247, 248, 268, 314, 397)
`N-Dodecyl pyrrolidine-3,5-dione (254)
`N-Dodecyl pyrrolidine-2-thione (247)
`N-Dodecyl-2-pyrrolidone (247, 248, 267, 268, 299, 314, 324,
`325, 331, 346, 397)
`l-Farnesylazacycloheptan-2-one (6, 127, 244)
`l-Farnesylazacyclopentan-2-one (6, 127)
`1-Geranylazacycloheptan-2-one (6, 127, 221-223, 226, 244)
`1-Geranyla.zacyclopentan-2-one (244)
`Hexahydro-2-oxo-azepine-1-acetic acid esters (254)
`N-(2-Hydroxyethyl)-2-pyrrolidone (319)
`1-Laurylazacycloheptane (8)
`2-(1-Nony1)-1,3-diaxolane (314, 390, 397)
`1-N-Octylazacyclopentan-2-one (9)
`N-(1-Oxododecy1)-hexahydro-111-azepine (247)
`N-(1-0xododecy1)-morpholines (247, 248)
`1-Oxohydrocarbyl-substituted azacyclohexanes (10)
`N-( I-Oxatetradecy1)-hexahydro-2-oxo-1H-azepine (248)
`N-(1-"Iliododecy1)-morpholines (247)
`
`viewed on the Pharmaceutical Technology Web site
`(www.pharmtech.com). Access the list by clicking on the No-
`vember Table of Contents or on the Technical Resources link on
`our home page. Readers are encouraged to notify the author to
`report recent publications that they believe should be added to
`the reference list.
`
`REFERENCES
`1. Pharmaceutical Skin Penetration Enhancement, K.A. Walters and
`.1. Hadgraft, Eds. (Dekker, New York, 1993).
`2. Drug Permeation Enhancement: Theory and Applications, D.S.
`Hseih, Ed. (Dekker, New York, 1994).
`3. V,P. Shah, C.C. Peck, and R.L. Williams, "Skin Penetration En-
`hancement: Clinical Pharmacological and Regulatory Considera-
`tions," in Pharmaceutical Skin Penetration Enhancement, K.A.
`Walters and J. Hadgraft, Eds, (Dekker, New York, 1993).El
`
`AQUESTIVE EXHIBIT 1024 page 0005
`
`

`

`PENETRATION ENHANCERS: REFERENCES
`
`1 (cid:9)
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`2.
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`3.
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`4.
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`5.
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`6.
`
`7.
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`8.
`
`9.
`
`Pharmaceutical Skin Penetration Enhancement, K.A. Walters and J. Hadgraft, Eds.,
`Marcel Dekker, New York, 1993; Drug Permeation Enhancement: Theory and
`Applications, D.S. Hsieh, Ed., Marcel Dekker, New York, 1994.
`
`V.P. Shah, C.C. Peck, and R.L. Williams. Skin Penetration Enhancement: Clinical
`Pharmacological and Regulatory Considerations. Pharmaceutical Skin Penetration
`Enhancement . K. A. Walters and J. Hadgraft, Eds. (Marcel Dekker 1993). pp. 417-427.
`
`E. R. Cooper. Penetrating Topical Pharmaceutical Compositions Containing N-(2-
`hydroxyethyl)pyrrolidone. Eur. Pat. Appl. EP 129285 A2, 27 Dec 1984; Appl.
`84/200823,12 Jun 1984; US Appl. 506273, 21 Jun 1983.
`
`Rajadhyaksha, V. J., PCT Int. Appl. WO 87/1935 Al, 9 Apr 1987; App1.86/US2052, 1
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