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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/172603 Al 5 October 2017 (05.10.2017) P O P C T (51) International Patent Classification: c/o Tioga Research, Inc., 6330 Nancy Ridge Drive, Suite A61K 31/197 (2006.01) A61K 31/00 (2006.01) 102, San Diego, California 92121 (US). A61K 9/00 (2006.01) A61K 31/195 (2006.01) (74) Agents: TANNER, Lorna L. et al; SHEPPARD MUL- A61K 9/06 (2006.01) LIN RICHTER & HAMPTON LLP, 379 Lytton Avenue, (21) International Application Number: Palo Alto, California 94301-1479 (US). PCT/US20 17/024281 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 27 March 2017 (27.03.2017) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (30) Priority Data: MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, 62/390,369 28 March 2016 (28.03.2016) US NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (71) Applicant: TIOGA RESEARCH, INC. [US/US]; 6330 RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, Nancy Ridge Drive, Suite 102, San Diego, California TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, 9212 1 (US). ZA, ZM, ZW. (72) Inventors: KISAK, Edward T.; c/o Tioga Research, Inc., (84) Designated States (unless otherwise indicated, for every 6330 Nancy Ridge Drive, Suite 102, San Diego, California kind of regional protection available): ARIPO (BW, GH, 9212 1 (US). NEWSAM, John M.; c/o Tioga Research, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Inc., 6330 Nancy Ridge Drive, Suite 102, San Diego, Cali TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, fornia 92121 (US). BUYUKTIMKIN, Servet; c/o Tioga TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Research, Inc., 6330 Nancy Ridge Drive, Suite 102, San DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Diego, California 92121 (US). BUYUKTIMKIN, Nadir; LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [Continued on nextpage] (54) Title: TOPICAL FORMULATION (57) Abstract: Provided herein are top ical formulations. The topical formula tion may comprise: (i) pregabalin, (ii) water, (iii) DMSO, (iv) a keto acid, and (v) and/or a fatty alcohol. The topical formulation may also comprise (i) pregabalin, (ii) DMSO, (iii) a keto acid and (iv) a fatty acid ester. It has been discovered that the combinations of DMSO with a keto acid such as levulinic acid and/or and a fatty acid ester such as lauryl lactate, or combina tions of DMSO with a keto acid such as levulinic acid and/or with a fatty al I cohol such as oleyl alcohol are excel ■ lent penetration enhancers and, as such, can be incorporated in a skin-applied formulation to facilitate administration of pregabalin. 1 1 w o 2017/172603 Illlll II Hill lllll Hill llll III III Hill lllll Hill lllll Hill llll limn i i llll SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Published: GW, KM, ML, MR, NE, SN, TD, TG). — with international search report (Art. 21(3)) Declarations under Rule 4.17: — before the expiration of the time limit for amending the — as to the applicant's entitlement to claim the priority of claims and to be republished in the event of receipt of the earlier application (Rule 4.17(Hi)) amendments (Rule 48.2(h)) TOPICAL FORMULATION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application 62/390,369, filed March 28, 2016, which is hereby incorporated by reference in its entirety. FIELD [0002] The present disclosure relates to a topical formulation of a pharmaceutical agent comprising multiplexed molecular penetration enhancers. BACKGROUND [0003] The administration of a drug through the skin for systemic distribution, that is transdermally, can provide compelling advantages relative to other modes of administration. Transdermal administration circumvents potential complications in the gastrointestinal ("GI") tract, avoids first-pass metabolism in the liver, can allow delivery of an active ingredient with a relatively short biological half-life or a narrow therapeutic window, facilitates uniform plasma dosing of the active ingredient, and, as above, is broadly preferred from a user compliance perspective. [0004] In spite of the advantages, transdermal administration is limited to only a small number of drugs. For example, a transdermal patch format is currently limited to some thirty drugs (including scopolamine, fentanyl, estradiol, nitroglycerin, nicotine, testosterone, selegiline and methyl phenidate). The reason for the paucity of transdermal products to treat serious pain conditions is that the skin presents a formidable barrier. [0005] Structurally, the skin consists of two principle layers: (i) the epidermis, the outermost layer, which varies in thickness from 0.05 mm on the eyelids to 1.5 mm on the palms and soles of the feet but which typically averages 80 µπ , and (ii) the 'dermis,' the inner region, ranges in thickness from 0.4 to 4mm, with a typical average of 2mm. The outermost layer of the epidermis (the 'stratum corneum') comprises corneocytes (flattened dead cells which are filled with keratin), interconnected by corneodesmosomes and surrounded by lipids which form lamellar phases. The highly impermeable nature of skin is due primarily to the stratum corneum. The viable epidermis underlying the stratum corneum is akin to other living tissue. The dermis provides the skin's structural strength as well as the nerve and vascular networks that support the epidermis. [0006] Various factors can affect the skin absorption rates and penetration depths of a drug molecule applied in a formulation to the skin, including the nature of the active ingredient, the nature of the vehicle, the pH, and the relative solubility of the active in the vehicle versus the skin. More specifically, drug attributes such as solubility, size and charge, melting point as well as vehicle attributes such as the drug solubility and dissolution rate, ability to alter the membrane permeability, spreadability and adhesion can each have significant effects on permeability. [0007] Delivering an active agent into or through the skin in sufficient concentrations usually requires some means for reducing the stratum corneum's hindrance to ingress of the active agent. A number of physical methods for lowering the stratum corneum's barrier properties have been developed including electrically assisted techniques such as iontophoresis or electroporation, ultrasound, heat, puncturing the stratum corneum with microneedle arrays, or ablation. Even for a single, non-repeated application such physical methods have limitations, leading to very restricted use by patients in practice. SUMMARY [0008] Some embodiments provide for a topical formulation comprising multiplexed molecular penetration enhancers for topical or transdermal administration of a zwitterionic pharmaceutical agent. In some embodiments, the present disclosure relates to a topical formulation comprising multiplexed molecular penetration enhancers for topical or transdermal administration of a gabapentinoid. In some embodiments, the present disclosure relates to a topical formulation comprising multiplexed molecular penetration enhancers for topical or transdermal administration of pregabalin. [0009] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) a keto acid, and (iv) a fatty acid ester. [0010] In another of its aspects, the present disclosure provides a topical formulation comprising: (i) at least one active agent, (ii) water, (iii) dimethyl sulfoxide ("DMSO"), (iv) a keto acid, and (v) an ester of a fatty alcohol and an a-hydroxy acid, an ester of a fatty acid and an alcohol, or a mixture thereof. [0011] In another of its aspects, the present disclosure provides a topical formulation comprising: (i) at least one active agent, (ii) water, (iii) DMSO, (iv) a keto acid, and (v) a fatty alcohol. [0012] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) levulinic acid, and (iv) lauryl lactate. [0013] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) a keto acid, (iv) a fatty acid ester, and (v) a polyalkylene glycol alkyl ether. [0014] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) levulinic acid, (iv) lauryl lactate, and (v) a polyethylene glycol alkyl ether. [0015] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) levulinic acid, (iv) lauryl lactate, and (v) dimethyl isosorbide. [0016] In another of its aspects, the present disclosure provides a topical formulation for use in topical or transdermal administration of a substance comprising: (i) at least one active agent, (ii) DMSO, (iii) a fatty alcohol or a fatty acid ester, and (iv) a polyalkylene glycol alkyl ether.
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    Gabapentinoids: Pharmacokinetics, Pharmacodynamics and Considerations for Clinical Practice

    912496BJP British Journal of PainChincholkar Special Issue Article British Journal of Pain 1 –11 Gabapentinoids: pharmacokinetics, © The British Pain Society 2020 Article reuse guidelines: sagepub.com/journals-permissions pharmacodynamics and considerations DOI:https://doi.org/10.1177/2049463720912496 10.1177/2049463720912496 for clinical practice journals.sagepub.com/home/bjp Mahindra Chincholkar Abstract The gabapentinoids are often recommended as first-line treatments for the management of neuropathic pain. The differing pharmacodynamic and pharmacokinetic profiles can have implications for clinical practice. This article has summarised these key differences. In addition to their use in managing neuropathic pain, gabapentinoids are increasingly being used for off-label conditions despite the lack of evidence. Prescription rates for off-label conditions have overtaken that for on-label use. Similarly, the use of gabapentinoids in the perioperative period is now embedded in clinical practice despite conflicting evidence. This article summarises the risks associated with this increasing use. There is increasing evidence of the potential to cause harm in vulnerable populations such as the elderly and increasing prevalence of abuse. The risk of respiratory depression in combination with opioids is of particular concern in the context of the current opioid crisis. This article describes the practical considerations involved that might help guide appropriate prescribing practices. Keywords Gabapentin, pregabalin, pain management, adverse effects, pharmacology Introduction movement, sleep disorders, headaches, alcohol with- drawal syndrome, chronic back pain, fibromyalgia, vis- The gabapentinoid drugs gabapentin and pregabalin ceral pain and acute postoperative pain.4,5 The rate of are antiepileptic drugs that are considered as first-line new prescriptions is increasing and tripled in England 1 treatments for the management of neuropathic pain.