(12) Patent Application Publication (10) Pub. No.: US 2010/0297032 A1 Setiawan Et Al
US 2010O297.032A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0297032 A1 Setiawan et al. (43) Pub. Date: Nov. 25, 2010
(54) TRANSDERMAL DELIVERY SYSTEM Publication Classification (75) Inventors: Kerrie Setiawan, Victoria (AU); (51) Eiki/12 2006.O1 Adam Watkinson, Victoria (AU) A6II 3/5685 ((2006.01) .01) Correspondence Address: A6II 3/566 (2006.01) FOLEY AND LARDNER LLP A63L/92 (2006.01) SUTESOO A 6LX 3/57 (2006.01) 3OOOK STREET NW A6II 3/196 (2006.01) WASHINGTON, DC 20007 US A6II 3/55 (2006.01) 9 (US) A6IP 25/24 (2006.01) A6IP5/00 (2006.01) (73)73) AssigneeA A X DDS Ptvy Ltd. A6IP 5/8 (2006.01) (21) Appl. No.: 12/740,663 A6M 35/00 (2006.01) (52) U.S. Cl...... 424/43; 514/170; 514/179; 514/182: (22) PCT Filed: Oct. 31, 2008 514/570; 514/567; 514/214.02: 604/310 (86). PCT No.: PCT/AUO8/O1614 (57) ABSTRACT S371 (c)(1) A transdermal delivery system comprising a composition (2), (4) Date. Aug. 9, 2010 comprising a physiologically active agent and a penetration s e 19 enhancer wherein the penetration enhancer comprises a com bination of (i) an ester of salicylic acid, preferably selected Related U.S. Application Data from the C to Coaliphatic ester of Salicylic acid and (ii) (60) Provisional application No. 60/984,787, filed on Nov. polyethylene glycol (PEG) of average molecular weight no 2, 2007. more than 300. Patent Application Publication Nov. 25, 2010 Sheet 1 of 10 US 2010/0297.032 A1
Formulations Contain 4.0 - 2.8% NETA, 0.55% E2, (O or 5)% OS, (0-10)% PEG200 in IPA With Out OS
E. With 5% OS 2 (?o 3.0 s E S. N 8 O 2.0 - cus as Old C. S. > d - it P 1.0 - c) O Cl
O. O O 5 1 O PEG200 Concentration (% w/v)
Figure 1: Norethisterone Acetate permeation obtained from the application of Compositions 2-5 compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 2 of 10 US 2010/0297.032 A1
Formulations contain 2.8% NETA, O.55% E2, (O or 5)9% OS, (O-10)% PEG200 in IPA 1.5 - Without OS
With 5% OS GN to 1.0 N. d) &us 5d 2 g 3 E O 5 O d O
OO - O 5 1 O PEG200 concentration (% w/v)
Figure 2: Estradiol permeation obtained from the application of Compositions 2-5 in accordance with the invention compared with application of control Composition 1. Patent Application Publication Nov. 25, 2010 Sheet 3 of 10 US 2010/0297.032 A1
3.0 -
2.5 -
2.0 -
15 -
10
OO 1.35% NES, 0.35% EE, 1.35% NES, 0.35% EE, 5%. OS in PA 5% OS, 5% PEG400 in PA (a) Figure 3a: Ethinylestradiol permeation obtained from the application of Composition 2 (not of the invention) compared against application of a control composition 1.
0.3
1.35% NES, 0.35% EE, 1.35% NES, 0.35% EE, 5% OS in IPA 5% OS, 5% PEG400 in IPA (b) Figure 3b: Nestorone permeation obtained from the application of Example 2 compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 4 of 10 US 2010/0297.032 A1
Formulations Contain 1.35% NES, 0.35% EE, (O or 5)% OS, (O - 10)% PEG200 in IPA
4.0 - without OS
With 5% OS
O O.5 l 2.5 5 1O PEG200 concentration (% w/v)
Figure 4: Nestorone permeation obtained from the application of Compositions 3 12 compared against application of the Composition 1 control. Patent Application Publication Nov. 25, 2010 Sheet S of 10 US 2010/0297.032 A1
Formulations CO ntain 1.35% NES, 0.35% EE, (O or 5)% OS, (O - 10% PEG200 in IPA
PEG200 concentration (% w/v)
Figure 5: Ethinylestradiol permeation obtained from the application of Compositions 3-12 compared against application of the Composition 1 control. Patent Application Publication Nov. 25, 2010 Sheet 6 of 10 US 2010/0297.032 A1
Formulations Contain 2% TES, 5% OS, (O-2.5)% PEG200, 2% PVP, 30% IPA in 95% ethanol 25. O -
1 5. O
1O.O -
5. O
O.O - O O.5 l 2.5 PEG200 concentration (% w/v)
Figure 6 (Comp 1): Testosterone permeation obtained from the application of Compositions 2-4 Compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 7 of 10 US 2010/0297.032 A1
Formulations Contain 2.0 - 5% TES, 5% OS, (O-2.5)% PEG200 in 95% ethanol
1 5
1.0 -
O 5
O.O - O 2.5 PEG200 concentration (% w/v)
Figure 7: Testosterone permeation obtained from the application of Compositions 2-3 Compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 8 of 10 US 2010/0297.032 A1
Figure8: Permeation of KETO transdermal spray in comparison with a commercially available gel. Formulations contain 5% KETO, 0 or 5% OS, O or 2.5% PEG 2 OO in PA.
25 - TNO Enhancer 2O OS PEG 200 15 - SOS - PEG 200
1 O
Commercially Available Gel 5%. KETO
Figure9: 2.5% KETO, 0 or 5% OS, 2.5% PEG 200 or PEG 4 OO in IPA
2 5 PEG 200 PEG 4OO
2 O
1 5
1 O
5
PEG PEG - OS Patent Application Publication Nov. 25, 2010 Sheet 9 of 10 US 2010/0297.032 A1
Figure10: Permeation of Diclofenac transdermal spray (2% DIC diethylamine, 0 or 5% OS, 0 or 2.5% PEG200 in IPA) vs. a commercially available gel 16 - 14 - No Enhancer OS 1O - PEG 200 8 - SOS - PEG 200
Commercially available gel 2%DC Patent Application Publication Nov. 25, 2010 Sheet 10 of 10 US 2010/0297.032 A1
Figure 11: DIC diethylamine from a transdermal spray formulation (1%DIC, O or 5%OS, O or 2.5% PEG400 in IPA)
No Enhancer OS PEG 4OO OS-PEG 4OO
Figure12: Effect of PEG200 or PEG 400 on Estradiol permeation. Formulations contain - - 0.25%E2, (O or 5)% OS, (O or 5)% (PEG200 or PEG400) in IPA 1.0 -
O. 6 -
O. 4 -
0.2 - S S S S O.O - S O.25% E2 in IPA O.25% E2, 5% OS 0.25% E2, 5% OS, 0.25% E2, 5% O.25%, 5% OS, (no enhancer) in IPA 5% PEG2OO in IPA PEG 4OO in IPA 5% PEG 4OO in IPA US 2010/0297.032 A1 Nov. 25, 2010
TRANSIDERMAL DELVERY SYSTEM dine and calcium thioglycolate have been reported as effec tive enhancers. However, difficulties remain with such dermal FIELD enhancers because the problem of irritation at the site of application has not been overcome. 0001. This invention relates to a transdermal delivery sys tem and to a method of transdermal delivery of a physiologi 0009. The most critical problem with these compounds cally active agent. however is their toxicity. If a compound when used as a dermal enhancer is toxic, irritating or allergenic, then that compound is unsuitable for application to the animal body. BACKGROUND Dimethyl acetamide is not clinically acceptable for these 0002 Administration of physiologically active agents reasons. Although Deet and AZones have lower reported tox through the skin (transdermal delivery) has received icities, their toxicity is still such that they are not widely used. increased attention because it not only provides a relatively It is possible that AZone and dimethyl sulfoxide may be simple dosage regime but it also provides a relatively slow employed as a dermal penetration enhancer if the amount and controlled route for release of a physiologically active applied is Sufficiently small so as not to be appreciably toxic, agent into the systemic circulation. However, transdermal irritating or allergenic to the animal. drug delivery is complicated by the fact that the skin behaves 0010. The compositions of the present invention are suit as a natural barrier and therefore transport of agents through able for use as vehicles for the topical application of specific the skin is a complex mechanism. compounds to the skin using pharmaceutical, nutraceutical, 0003 Structurally, the skin consists of two principle parts, cosmetic or veterinary preparations. Such topical application a relatively thin outermost layer (the epidermis) and a enables the specific compounds to penetrate the skin and thicker inner region (the dermis). The outermost layer of the enter the circulatory system thereby enabling the active com epidermis (the stratum corneum) consists of flattened dead pound (s) to have a systemic effect. The at least one active cells which are filled with keratin. The region between the compound may be a pharmacologically active compound. A flattened dead cells of the stratum corneum is filled with lipids “pharmacologically active compound is a compound that which form lamellar phases that are responsible for the natu has a therapeutic effect on the human or animal body in the ral barrier properties of the skin. treatment or prevention of a condition. 0004 For effective transdermal delivery of a physiologi 0011. The discussion of documents, acts, materials, cally active agent that is applied to the Surface of the skin devices, articles and the like is included in this specification (topical application), the agent must partition firstly from solely for the purpose of providing a context for the present the vehicle into the stratum corneum, it must typically then invention. It is not suggested or represented that any or all of diffuse within the stratum corneum before partitioning from these matters formed part of the prior art base or were com the stratum corneum to the viable epidermis. mon general knowledge in the field relevant to the present 0005 To overcome some of the problems with transder invention as it existed before the priority date of each claim of mal delivery that are associated with transport across the this application. dermal layers (percutaneous absorption), physiologically active agents are commonly formulated with dermal penetra tion enhancers (Finnin and Morgan, J. Pharm. Sci., Vol 88, SUMMARY No. 10, October 1999, pp. 955-958) which are often lipophilic chemicals that readily partition into the stratum corneum 0012. The invention provides a transdermal delivery sys whereupon they exert their effects on improving the transport tem comprising composition comprising a physiologically of drugs across the skin barrier. active agent and a penetration enhancer wherein the penetra 0006. A transdermal “patch' typically consists of a matrix tion enhancer comprises a combination of (i) an ester of or reservoir containing the drug to be administered, together salicylic acid, preferably selected from the C to Coaliphatic with a backing layer, an adhesive and a protective release ester of salicylic acid and (ii) polyethylene glycol of average liner. Release membranes may also be incorporated. The molecular weight no more than 300. delivery of drugs through these systems is either through 0013. In a further aspect the invention provides a method passive diffusion, controlled by a semi-permeable release of transdermal administration of an active agent to an animal membrane, or is controlled by the adhesive/adhesive matrix. Subject, including a human, comprising application to dermal The system may also incorporate drug penetration enhancers surface of the animal of the above described transdermal to increase the flux of the drug through the skin. delivery system. 0007. One of the drawbacks of the current approaches is 0014. In yet another aspect the invention provides use of that the formulations are typically in continuous contact with (i) an ester of salicylic acid, preferably selected from the C to the skin. Creams and ointments or adhesives used in patches Coaliphatic ester of Salicylic acid and (ii) polyethylene gly can cause skin irritation and sensitisation. A significant pro col (of average molecular weight no more than 300) in manu portion of patch users Suffer from skin irritation and sensiti facture of a medicament with a physiologically active agent sation due to adhesives used in the patch. for transdermal administration of the physiologically active 0008. The rate of drug delivery across a dermal surface can agent to an animal by application of the medicament to an be increased by dermal penetration enhancers. The problem area of the skin Surface of the animal. with most known dermal penetration enhancers is that they 0015. In a further aspect the invention provides a method are often toxic, irritating or allergenic. These enhancers tend of preparing a transdermal delivery system for administration to be proton accepting solvents such as dimethylsulfoxide to an area of dermal Surface of an animal the method com and dimethyacetamide. More recently, 2-pyrrolidine, N.N prising combining the physiologically active agent and a first diethyl-m-toluamide (Deet), 1-dodecal-azacycloheptane-2- penetration enhancer component of an ester of salicylic acid, one (AZone), N, N dimethylformamide, N-methyl-2-pyrroli preferably selected from the C to Coaliphatic ester of sali US 2010/0297.032 A1 Nov. 25, 2010
cylic acid and a second penetration enhancer component of 0023 Steroids vary by the functional groups attached to polyethylene glycol of average molecular weight no more these rings and the oxidation state of the rings. The steroid than 300. may be in the form of the active drug or may be a prodrug 0016. In a further embodiment the invention comprises a steroid which in vivo provides a more active form of the transdermal delivery system comprising a spray apparatus steroid. The steroids include drugs and prodrugs which pro comprising a container for a transdermal composition a spray vide eutrogenic, androgenic glucocorticoid, adrenocortoid, noZZle and an actuator for delivering a metered dose of spray anabolic or birth control activity. Examples of steroids from the container via the nozzle, wherein the transdermal include, for example, dexamethasone, dexamethasone composition comprises a physiologically active agent and a acetate, dexamethasone sodium phosphate, cortisone, corti first penetration enhancer component of an ester of salicylic Sone acetate, hydrocortisone, hydrocortisone acetate, hydro acid, preferably selected from the C to Coaliphatic ester of cortisone cypionate, hydrocortisone sodium phosphate, salicylic acid, and a second penetration enhancer component hydrocortisone sodium Succinate, prednisone, prednisolone, of polyethylene glycol of average molecular weight no more prednisolone acetate, prednisolone sodium phosphate, pred than 300. nisolone tebutate, prednisolone pivalate, triamcinolone, tri 0017. The transdermal delivery system will preferably be amcinolone acetonide, triamcinolone hexacetonide, triamci applied in a dose sufficient to provide an effective amount of nolone diacetate, methylprednisolone, methylprednisolone the physiologically active agent in the bloodstream of the acetate, methylprednisolone sodium Succinate, flunsolide, animal. beclomethasone dipropionate, betamethasone sodium phos 0018 Preferably the animal is a human but the invention phate, betamethasone, Vetamethasone disodium phosphate, also extends to the treatment of non-human animals. Vetamethasone sodium phosphate, betamethasone acetate, Definitions betamethasone disodium phosphate, chloroprednisone 0019. It will be understood by those skilled in the art that acetate, corticosterone, desoxycorticosterone, desoxycorti the term polyethylene glycol does not include diethylene costerone acetate, desoxycorticosterone pivalate, des glycol (although diethylene glycol may if desired be present Oximethasone, estradiol, fludrocortisone, fludrocortisone as an additional component). Polyethylene glycol of average acetate, dichlorisone acetate, fluorohydrocortisone, fluo molecular weight no more than 300 includes polyethylene rometholone, fluprednisolone, paramethasone, parametha glycol of nominal average molecular weight 200 and 300 Sone acetate, androsterone, fluoxymesterone, aldosterone, wherein the average molecular weight is not more than 110% methandrostenolone, methylandrostenediol, methyl test and not less than 90% (preferably not more than 105% and not osterone, norethandrolone, testosterone, testosterone enan less than 95%) of the nominated value. Polyethylene glycol is thate, testosterone propionate, equilenin, equilin, estradiol of formula H IOCH2CH, OH. An average molecular benzoate, estradiol dipropionate, estriol, estrone, estrone ben weight of no more than 300 means the average value of n is at Zoate, acetoxypregnenolone, anagestone acetate, chlormadi least 3 and is generally from 3 to 6 such as 3, 4, 5 or 6 none acetate, flurogestone acetate, hydroxymethyl progester (although the average need not be an integer) and more pref One, hydroxymethylprogesterone acetate, erably 3 to 5. Polyethylene glycol (PEG) is widely available hydroxyprogesterone, hydroxyprogesterone acetate, hydrox from commercial Suppliers in pharmaceutical grades and is yprogesterone caproate, melengestrol acetate, normethister sold in specified nominal molecular weights which generally one, pregnenolone, progesterone, ethynyl estradiol, mestra signify that the average molecular weight is not more than nol, dimethisterone, ethisterone, ethynodiol diacetate, 105% and not less than 95% of the nominated value. The norethindrone, norethindrone acetate, norethisterone, fluoci Viscosities and methods for molecular weight determination nolone acetonide, flurandrenolone, hydrocortisone sodium are disclosed in USPNF Official Compendium of Standards Succinate, methylprednisolone sodium Succinate, predniso Volume 11180-1182 2007 Edition. lone phosphate sodium, triamcinolone acetonide, hydroxydi 0020. The term “physiologically active agent' is used one sodium, Spironolactone, Oxandrolone, oxymetholone, herein to refer to a broad class of useful chemical and thera prometholone, testosterone cypionate, testosterone pheny peutic agents. lacetate, estradiol cypionate, and norethynodrel. 0021. The term “physiologically active' in describing the 0024. A "prodrug is a pharmaceutically active agent agents contemplated herein is used in a broad sense to com which is administered in an inactive or less active form and is prehend not only agents having a direct pharmacological metabilised into an active form. The prodrug itself may have effect on the host, but also those having an indirector observ little or none of the desired activity until it interacts with the able effect which is useful in the medical arts. The term systems of the body Such as the skin or circulatory systems. physiologically active agent includes prodrugs of the agent Nonetheless a pharmaceutically active agent used in the which in vivo exerts the physiological effect. transdermal delivery system of the invention include agents 0022 Steroids encompass compounds having the general which are prodrugs which on administration form a more cyclopentanoperhydrophenanthrene ring system of formula: active agent in vivo during or after the process of transdermal administration.
0025. In yet another preferred embodiment, a prodrug or a composition of prodrug mixed with the parent composition has a permeation rate that is faster or slower than an identical composition having a pharmacologically equivalent amount of the parent drug. In still another preferred embodiment, the composition has a duration of the therapeutic effect that is longer or shorter than a composition having a pharmacologi cally equivalent amount of the parent drug alone. In another preferred embodiment, the prodrug is more lipophilic than the parent drug and the prodrug has a greater permeation rate US 2010/0297.032 A1 Nov. 25, 2010 through the skin. Generally prodrugs are variations orderiva across the skin for use and delivery of active agents to organ tives of the parent drugs which have groups cleavable under isms such as animals, whether it be for local application or metabolic conditions. Prodrugs become the parent drugs systemic delivery. which are pharmaceutically active or more active in Vivo, 0028. The term “non-occlusive' is used herein in its when they undergo Solvolysis under physiological conditions broadest sense to refer to not trapping or closing the skin to or undergo enzymatic degradation. Prodrugs commonly the atmosphere by means of a patch device, fixed reservoir, application chamber, tape, bandage, Sticking plaster, or the known in the art include acid esters prepared by reaction of like which remains on the skin at the site of application for a the parent acids or alcohol with a suitable alcohol or acid prolonged length of time. It is particularly preferred that the respecctively, or amides prepared by reaction of the parent transdermal delivery system of the invention is non-occlu acid or amine compound with an amine or acid respectively, sive. or basic groups reacted to form an acylated base derivative. 0029. The term “stratum corneum” is used herein in its Examples of prodrugs are discussed in, Bundgard, Design of broadest sense to refer to the outer layer of the skin, which is Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985: Silver comprised of (approximately 15) layers of terminally differ man, The Organic Chemistry of Drug Design and Drug entiated keratinocytes made primarily of the proteinaceous Action, pp. 352-401, Academic Press, San Diego, Calif., material keratin arranged in a brick and mortar fashion with 1992 and Burger's Medicinal Chemistry and Drug Chemistry, the mortar being comprised of a lipid matrix made primarily Fifth Ed., Vol. 1, pp. 172-178,949-982 (1995). The other from cholesterol, ceramides and long chain fatty acids. The method for controlling the blood plasma profile of subject is stratum corneum creates the rate limiting barrier for diffusion in the selection of the prodrug, such as based on its molecular of the active agent across the skin. weight or polarity. By increasing the molecular weight of the 0030 The term “skin-depot’ is used herein in its broadest prodrug, the time to the onset of permeation of effective sense to refer to a reservoir or deposit of active agent and amounts of the prodrug will increase relatives to the parent dermal penetration enhancer within the stratum corneum, drug. One example of this effect is in the use of norethindrone whether it be intra-cellular (within keratinocytes) or inter and norethindrone acetate. The permeation rate of norethin cellular. drone rapidly peaks after application, whereas norethindrone 0031. The term “volatile:non-volatile liquid vehicle' is acetate having a higher molecular weight reaches a maximum used in the art to refer to a liquid pharmaceutical vehicle comprising a volatile liquid mixed with a non-volatile liquid after the norethindrone permeation rate begins to decline. vehicle. Such as a dermal penetration enhancer. A system or steroids having a free hydroxy group at a position on the vehicle comprising a volatile liquid mixed with a non-volatile steroid ring, Such as the 17-position, the 3-position, or at the dermal penetration enhancer when described herein is used in 11-position on the fused ring. Particularly preferred are ste its broadest sense to include those systems known as Volatile: roidal hormones such as estrogens, progestins, and andro non-volatile liquid vehicles. gens. The corresponding steroid prodrug (prosteroid) is 0032. The term “aliphatic' includes straight chain, defined as a corresponding structure to the Steroid where the branched chain and cyclic aliphatic and may be saturated free hydroxy at the 3.11 or 17 position has been reacted with alkyl groups or unsaturated aliphatic containing from 1 to 3 an alcohol reactive moiety. Particularly preferred are steroid unsaturated groups particularly 1 to 3 double bonds. derivatives acylated at the 17 position hydroxyl for example 0033. The transdermal drug delivery system of the present by a C1-C12 alkanoyl group. Regardless of whether the ste invention enables a wide range of physiologically active roid or the corresponding prosteroid derivative is incorpo agents to be delivered through the skin to achieve a desired rated in the carrier composition as the dominant drug, each systemic effect. The drug delivery system preferably com provides a source of steroid in the bloodstream to achieve the prises the active agent intimately mixed with a non-volatile intended physiological effect which, in the case of the corre dermal penetration enhancer and a volatile liquid. Where the sponding prosteroid, occurs through metabolic conversion of drug delivery system is applied to the skin, the active agent the derivative. A steroid ester is the corresponding structure to and non-volatile liquid are thermodynamically driven into the the steroid where the free hydroxy group on the ring has been skin as the volatile liquid evaporates. Once within the skin the esterified. Examples of a steroid and its corresponding ester non-volatile liquid may either disrupt the lipid matrix and/or include estradiol and estradiol benzoate, estradiol 17-beta act as a solubilizer to allow an enhanced penetration rate of cypionate, estradiol 17 propionate, estradiol hemisuccinate the active agent through the skin and into the Subject being (eutocol), estradiol enanthate, estradiol undecylate, estradiol treated. In this way, the dermal penetration enhancer acts as a acetate, and estradiol proprionate, etc. Another example is vehicle and many systemic active agents are able to be trans testosterone and its corresponding ester of testosterone Such dermally administered to an animal. as 17 beta-cypionate, testosterone enanthate, testosterone 0034. A “nutraceutically active compound is a com nicotinate, testosterone phenylacetate, testosterone proprion pound, derived from a natural origin (animal or vegetable) ate, etc. Also included are non-esters that have groups on the that has a beneficial and/or therapeutic effect on the human or 17 position such as testosterone 17-chloral hemiacetal, or animal body in the treatment of a condition. Such compounds ethers that have groups on the 3-position Such as estradiol may be regarded as nutrients. 3-methyl ether. 0035. Throughout the description and the claims of this 0026. The terms “percutaneous” and “transdermal are specification the word “comprise' and variations of the word, used herein in the broadest sense to refer to being able to pass Such as "comprising and "comprises is not intended to through unbroken skin. exclude other additives, components, integers or steps. 0027. The term “dermal penetration enhancer is used DETAILED DESCRIPTION herein in its broadest sense to refer to an agent which 0036. The present inventors have found that the use of a improves the rate of percutaneous transport of active agents penetration enhancer which is a combination of (i) an ester of US 2010/0297.032 A1 Nov. 25, 2010
salicylic acid, preferably selected from the C to Coaliphatic of non-volatile penetration enhancers other than PEG of esters of Salicylic acid and (ii) polyethylene glycol (of aver molecular weight of no more than 300 and salicylic acid age molecular weight no more than 300) shows a synergistic esterS. improvement in penetration enhancement. 0044) The volatile solvent is preferably present in the com position of the invention in an amount in the range of from 40 0037. The weight ratio of ester of salicylic acid to poly to 95% by weight of the composition and more preferably ethylene glycol (of average molecular weight no more than from 50 to 95%, still more preferably from 60 to 95% by 300) is preferably in the range of from 95 : 5 to 5:95 and weight such as 65% to 95% by weight 70% to 95%, 70 to 90% preferably from to 1:10 to 10:1 such as 1:10 to 5:1 and 1:5 to and 75 to 90% by weight of the total composition. 2:1. The optimal ratio may vary depending on the nature and 0045. The composition of the invention may if desired concentration of the active agent and the concentration of the contain one or more additional adjuvants such as those penetration enhancer combination. selected from the group consisting of penetration enhancers, 0038. The ester of salicylic acid is preferably a C to Cs Surfactants, thickeners and solvents. Examples of Suitable aliphatic ester, more preferably a C to Calkyl ester and still thickeners include polyacrylic acids; and acylic acid copoly more preferably is C alkyl and most preferably is 2-ethyl mers agor, carrageenan, food Starch, gelatins, germ Arabic, hexylester known by the common name Octyl salicylate or guorgem, hydroxyethyl cellulose hydroxypropymethylcellu simply Octisalate. lose, protein and polyvinyl pyrrolidone. The content of thick 0039 Typically the ester of salicylic acid will be present in ener may be from 0 to 5%. It is however a particularly pre ferred aspect of the invention that the composition consists an amount of from 0.1 to 10% by weight of the total trans essentially of dermal composition of the invention and more preferably 0046 (i) an physiolocically active agent component from 0.5 to 5% such as 0.5,0.7, 0.8, 0.9, 1.0, 1.2, 1.5, 1.7, 2.0, which may include one or more physiologically active 3.0, 3.5, 4.0, 4.5 and 5.0. agents; 0040 Typically the PEG of average molecular weight less 0047 (ii) a penetration enhancer component consisting than 300 will be present in an amount in the range of from 0.1 of an ester of salicylic acid and a polyethylene glycol of to 40%by weight of the total composition and preferably from average molecular weight no more than 300; 0.5 to 20% such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 0.048 (iii) a volatile solvent consisting of one or more of 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, ethanol and isopropanol; and 17%, 18%, 19%, 20%. 0049 (iv) optionally a propellant. 0041. The composition of the invention preferably com 0050. It will be understood by those skilled in the art that prises PEG 200 in an amount in the range of from 0.1 to 40% alcohols and polyols contain a certain amount of water. Typi by weight of the total composition and preferably from 0.5 to cally the total water content of the composition is less than 20% such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 6%, 20% by weight and preferably less than 10% by weight of the 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, total composition. 18%, 19%, 20%. 0051. The composition of the invention may be in a range 0042. The composition of the invention may and prefer of forms from a liquid, cream, paste, gel, lotion, patch (matrix ably will contain a volatile solvent. Preferably the volatile and reservoir), tape, plaster or film former. In the more pre Solventhas a vapour pressure above 35mm Hg at atmospheric ferred embodiment the transdermal delivery system is in the pressure and normal skin temperature of 32 degrees Celsius. form of a liquid for application to a defined area of skin. In a particularly preferred form of the invention the solvent 0.052 The compositions of the present invention may be in preferably a C to Calkanol and more preferably is ethanol any form suitable for topical application to the skin. Suitable or isopropanol, or a mixture thereof. forms include sprayable liquids; gels; liquids that may be 0043 Known dermal penetration enhancers may also be applied using a roll-on device; lacquers; and Sustained release employed in the transdermal drug delivery system. The use of matrices of transdermal delivery devices Such as patches. The known dermal penetration enhancers include laurocapram compositions are usually administered alone but, under some (AZone.RTM.) and laurocapram derivatives, such as those circumstances, administration may be further modified by 1-alkylazacycloheptan-2-ones specified in U.S. Pat. No. using other delivery mechanisms such as iontophoresism, 5,196,410, and oleic acid and its ester derivatives, such as ultrasound and microneedles to enhance penetration. Non methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmo occlusive application and in particular Spray application are nooleate, and Sorbitan esters such as Sorbitan monolaurate preferred. and Sorbitan monooleate, and other fatty acid esters such as 0053 Suitable pharmacologically active compounds may isopropyl laurate, isopropyl myristate, isopropyl palmitate, be selected from: diisopropyl adipate, propylene glycol monolaurate and pro 0054 Alimentary System Antidiarrhoeals such as diphe pylene glycol monooleate, and long chain alkyl esters of noxylate, loperamide andhyoscyamine; 2-pyrrolidone, particularly the 1-lauryl, 1-hexyl and 1-(2- 0055 Cardiovascular system agents including: ethylhexyl) esters of 2-pyrollidone and those dermal penetra 0056 Antihypertensives such as hydralazine, minoxidil, tion enhancers given in U.S. Pat. No. 5,082,866, particulary captopril, enalapril, clonidine, praZosin, debrisoquine, diaz dodecyl (N,N-dimethylamino) acetate and dodecyl (N.N- oxide, guanethine, methyldopa, reserpine, trimetaphan; dimethylamino) propionate and in U.S. Pat. No. 4,861,764, 0057 Calcium channel blockers such as diltiazem, felo particularly 2-n-nonyl-1-3-dioxolane. Preferably the compo dopine, amlodipine, nitrendipine, nifedipine and Verapamil; sition will comprise no more than 5% by weight of the non 0.058 Proton pump inhibitors such as lansoprazole; ome volatile penetration enhancers other than PEG and the sali prazole; and pantaprazole; cylic acid esters more preferably no more than 1% and most 0059 Antiarrhyrithmics such as amiodarone, flecainide, preferably no more than 0.5% by weight of the composition disopyramide, procainamide, mexiletene and quinidine; US 2010/0297.032 A1 Nov. 25, 2010
0060 Antiangina agents such as glyceryl trinitrate, eryth covalent complexes, chelates, hydrates, crystalline or amor ritol tetranitrate, pentaerythritol tetranitrate, mannitol hexani phous forms thereof. trate, perhexilene, isosorbide dinitrate and nicorandil; 0077 CNS stimulants such as caffeine. 0061 Beta-adrenergic blocking agents such as alprenolol. 0078 Anti-alzheimer's agents such as tacrine. atenolol, bupranolol, carteolol, labetalol, metoprolol, nad 0079 Antiparkinson agents such as amantadine, benser olol, nadoxolol, oXprenolol, pindolol, propranolol, Sotalol, azide, carbidopa, levodopa,benztropine, biperiden, ben timolol and timolol maleate; Zhexol, procyclidine and dopamine-2 agonists such as S(-)- 0062 Cardiotonic glycosides such as digoxin and other 2-(N-propyl-N-2thienylethylamino)-5-hydroxytetralin cardiac glycosides and theophylline derivatives; (N-0923). 0063 Adrenergic stimulants such as adrenaline, ephe 0080 Lipid regulating drugs such as statins. drine, fenoterol, isoprenaline.orciprenalihe, rimeterol, Salb I0081. Drugs affecting bone metabolism such as calcitonin utamol, salmeterol, terbutaline, dobutamine, phenylephrine, and bisphosphonates. phenylpropanolamine, pseudoephedrine and dopamine; I0082 Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and car 0064 Vasodilators such as cyclandelate, isoxsuprine, bamazepine, ethoSuximide, methSuximide, phensuximide, papaverine, dipyrimadole, isosorbide dinitrate, phentola Sulthiame and clonazepam. mine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyc I0083 Antiemetics, antinauseants such as the phenothiaz eryl trinitrate, pentaerythritol tetranitrate and Xanthinol; and ines, prochloperazine, thiethylperazine and 5HT3 receptor 0065 Antimigraine preparations such as ergotamine, antagonists Such as ondansetron and granisetron and others dihydroergotamine, methysergide, pizotifen and Sumatrip Such as dimenhydrinate, diphenhydramine, metoclopramide, tan. domperidone, hyoscine, hyoscine hydrobromide, hyoscine 0066 Drugs affecting blood and haemopoietic tissues hydrochloride, clebopride and brompride. including: I0084. Musculoskeletal system drugs: 0067. Anticoagulants and thrombolytic agents such as I0085. Non-steroidalanti-inflammatory agents including warfarin, dicoumarol, low molecular weight heparins such as their racemic mixtures or individual enantiomers where enoxaparin; streptokinase and its active derivatives. applicable, such as ibuprofen, flurbiprofen, ketoprofen, 0068 Haemostatic agents such as aprotinin, tranexamic aclofenac, diclofenac, aloXiprin, aproxen, aspirin, diflunisal, acid and protamine. fenoprofen, indomethacin, mefenamic acid, naproxen, phe 0069 Drugs affecting the Central Nervous System includ nylbutaZone, piroXicam, Salicylamide, salicylic acid, Sulin 1ng: dac, desoxysulindac, tenoxicam, tramadol and ketoralac; 0070 Analgesics; I0086. Additional non-steroidal antiinflammatory agents 0071 antipyretics including the opiod analgesics such as which can be formulated in combination with the dermal buprenorphine, dextromoramide, dextropropoxyphene, fen penetration enhancers include Salicylamide, salicylic acid, tanyl, alfentanil, Sufentanil, hydromorphone, methadone, flufenisal, Salsalate, triethanolamine salicylate, aminopyrine, morphine, oxycodone, papaveretum, pentazocine, pethidine, antipyrine, oxyphenbutaZone, apaZone, cintaZone, flufe phenoperidine, codeine and dihydrocodeine. Others include namic acid, clonixeril, clonixin, meclofenamic acid, flunixin, acetylsalicylic acid (aspirin), paracetamol, and phenaZone; colchicine, demecolcine, allopurinol, oxypurinol, benzy damine hydrochloride, dimefadane, indoxole, intrazole, 0072 Hypnotics and sedatives such as the barbiturates, mimbane hydrochloride, paranylene hydrochloride, tetry amylobarbitone, butobarbitone and pentobarbitone and other damine, benzindopyrine hydrochloide, fluprofen, ibufenac, hypnotics and sedatives such as choral hydrate, chlormethia naproXol, fenbufen, cinchophen, diflumidone sodium, fen Zole, hydroxy Zine and meprobamate; and amole, flutiazin, metaZamide, letimide hydrochloride, nexeri 0073 Antianxiety agents such as the benzodiazepines, dine hydrochloride, octaZamide, molinazole, neocinchophen, alprazolam, bromazepam, chlordiazepoxide, clobazam, chlo nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and razepate, diazepam, flunitrazepam, flurazepam, lorazepam, triflumidate; nitrazepam, oxazepam, temazepam and triazolam. I0087 Antirheumatoid agents such as penicillamine, 0074 Agents to treat food allegies such as sodium cro aurothioglucose, Sodium aurothiomalate, methotrexate and moglicate. auranofin, 0075 Neuroleptic and antipsychotic drugs such as the I0088 Muscle relaxants such as baclofen, diazepam, phenothiazines, chlorpromazine, fluphenazine, pericyazine, cyclobenzaprine hydrochloride, dantrolene, methocarbamol. perphenazine, promazine, thiopropazate, thioridazine and tri orphenadrine and quinine; and fluoperazine and the butyrophenones, droperidol and halo I0089 Agents used in gout and hyperuricaemia such as peridol and the other antipsychotic drugs such as pimozide, allopurinol, colchicine, probenecid and Sulphinpyrazone. thiothixene and lithium. 0090 Hormones and Steroids including: 0076 Antidepressants such as the tricyclic antidepres 0091 Estrogens such estradiol, estriol, estradiol benzoate, sants amitryptyline, clomipramine, desipramine, dothiepin, estradiol 17.beta.-cypionate, estradiol enanthate, estradiol doxepin, imipramine, nortriptyline, opipramol, protriptyline propionate, estrone, ethinylestradiol, Fosfestrol, Dienestrol and trimipramine; tetracyclic antidepressants such as mestranol, stilboestrol, dienoestrol, epioestriol, estropipate mianserin; monoamine oxidase inhibitors such as isocarbox Diethylstilbestrol, Chlorotrianisene, conjugated estrogenic azid, phenelizine, tranylcypromine and moclobemide; selec hormones, Polyestradiol phosphate and Zeranol and mixtures tive serotonin re-uptake inhibitors such as fluoxetine, paroX thereof; etine,titalopram, fluvoxamine and Sertraline; and tetracyclic 0092 Progesterone and progestins such as norethisterone, antidepressants such as mirtazapine and any metabolites, norethisterone acetate, gestodene, levonorgestrel, allylestre salts enantiomers (including esmirtazapine), solvents, non nol, anagestone, desogestrel, dimethisterone, dydrogester US 2010/0297.032 A1 Nov. 25, 2010 one, ethisterone, ethynodiol, Ethynodiol diacetate, 0100 Hypoglycaemic agents such as insulin, chlorpropa Etonogestrel, gestodene, ethinylestradiol, haloprogesterone, mide, glibenclamide, gliclazide, glipizide, tolaZamide, tolb 17-hydroxy-16-methylene-progesterone, 17.alpha.-hydrox utamide and metformin; yprogesterone, lynestrenol, medroxyprogesterone, 0101 Thyroid hormones such as calcitonin, thyroxine and melengestrol, norethindrone, norethynodrel, norgesterone, liothyronine and antithyroid agents such as carbimazole and Gestonorone, Norethisterone, norgestimate, norgestrel, propylthiouracil; and Levonorgestrel, norgestrienone, norvinisterone, pentag 0102 Other miscellaneous hormone agents such asoct estrone, MENT (7-methyl-19-testosterone); Norelgestromin, reotide. and trimigestone Drospirenone, Tibolone, and megestrol and 0103 Pituitary inhibitors such as bromocriptine. mixtures thereof; 0104 Ovulation inducers such as clomiphene. 0093 Antiandrogens such as cyproterone acetate and 0105 Genitourinary system including: danazol; 0106 Diuretics such as the thiazides, related diuretics and 0094. Antiestrogens such as tamoxifen and epitiostanol loop diuretics, bendrofluazide, chlorothiazide, chlorthali and the aromatase inhibitors, exemestane and 4-hydroxy done, dopamine, cyclopenthiazide, hydrochlorothiazide, androstenedione and its derivatives; indapamide, mefruside, methycholthiazide, metolaZone, 0095 Androgens and anabolic agents such as androisox quinethaZone, bumetanide, ethacrynic acid and frusemide azole, androstenediol, bolandiol, bolasterone, clostebol, eth and pottasium sparing diuretics, spironolactone, amiloride ylestrenol. formyldienolone, 4-hydroxy-19-nortestosterone, and triamterene. methandriol, methenolone, methyltrienolone, nandrolone, 0107 Antidiuretics such as desmopressin, lypressin and norbolethone, oxymesterone, Stenbolone and trenbolone. vasopressin including their active derivatives or analogs. Androgenic steroids can include boldenone, fluoxymester 0.108 Obstetric drugs including agents acting on the one, mestanolone, mesterolone, methandrostenolone, 17-me uterus Such as ergometrine, oxytocin and gemeprost. thyltestosterone, 17.alpha.-methyltestosterone 3-cyclopentyl 0109 Prostaglandins such as alprostadil (PGEi), prosta enol ether, norethandrolone, normethandrone, Oxandrolone, cyclin (PGI2), dinoprost (prostaglandin F2-alpha) and miso oxymesterone, oxymetholone, prasterone, Stanlolone, stano prostol. Zolol, testosterone, testosterone 17-chloral hemiacetal, test 0110 Antimicrobials including: osterone proprionate, testosterone enanthate tiomesterone 0111 Antimicrobials including the cephalosporins such dehydroepiandrosterone (DHEA), androstenedione (Andro): ascephaiexin, cefoxytin and cephalothin; an androstenediol, androsterone, dihydrotestosterone (DHT) 0112 Penicillins such as amoxycillin, amoxycillin with and androstanolone and derivatives thereof; clavulanic acid, amplicillin, bacampicillin, benzathine peni 0096 5-alpha reductase inhibitors such as finasteride, cillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, turosteride, LY-191704 and MK-306; phenethicillin, phenoxymethylpenicillin, flucloxacillin, 0097 Corticosteroids such as betamethasone, betametha meZlocillin, piperacillin, ticarcillin and azlocillin; Sone Valerate, cortisone, dexamethasone, dexamethasone 0113 Tetracyclines such as minocycline, chlortetracy 21-phosphate, fludrocortisone, flumethasone, fluocinonide, cline, tetracycline, demeclocycline, doxycycline, methacy fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, cline and oxytetracycline and other tetracycline-type antibi hydrocortisone 17-valerate, hydrocortisone 17-butyrate, otics; hydrocortisone 21-acetate methylprednisolone, predniso 0114 Aminoglycosides such as amikacin, gentamicin, lone, prednisolone 21-phosphate, prednisone, triamcinolone, kanamycin, neomycin, netilmicin and tobramycin; triamcinolone acetonide; 0115 Antifungals such as amorolfine, isoconazole, clot 0098. Further examples of steroidal antiinflammatory rimazole, econazole, miconazole, nystatin, terbinafine, agents for use in the instant compositions include include bifonazole, amphotericin, griseofulvin, ketoconazole, flu cortodoxone, fluoracetonide, fludrocortisone, difluorSone conazole and flucytosine, Salicylic acid, fezatione, ticlatone, diacetate, flurandrenolone acetonide, medrysone, amcinafel, tolnaftate, triacetin, Zinc, pyrithione and Sodium pyrithione; amcinafide, betamethasone and its other esters, chloropred 0116 Quinolones Such as nalidixic acid, cinoxacin, cipro nisone, clorcortelone, descinolone, desonide, dichlorisone, floxacin, enoxacin andnorfloxacin; difluprednate, flucloronide, flumethasone, flunisolide, flucor 0117 Sulphonamides such as phthalylsulphthiazole, sul tolone, fluoromethalone, fluperolone, fluprednisolone, fadoxine, Sulphadiazine, Sulphamethizole and Sulpha meprednisone, methylmeprednisolone, paramethasone, cor methoxazole; tisone acetate, hydrocortisone cyclopentylpropionate, corto 0118 Sulphones such as dapsone; and doxone, flucetonide, fludrocortisone acetate, flurandrenolone 0119. Other miscellaneous antibiotics such as chloram acetonide, medrysone, amcinafal, amcinafide, betametha phenicol, clindamycin, erythromycin, erythromycin ethyl Sone, betamethasone benzoate, chloroprednisone acetate, carbonate, erythromycin estolate, erythromycin glucepate, clocortolone acetate, descinolone acetonide, desoximeta erythromycin ethylsuccinate, erythromycin lactobionate, sonedichlorisone acetate, difluprednate, flucloronide, flu roXithromycin, lincomycin, natamycin, nitrofurantoin, spec methasone pivalate, flunisolide acetate, fluperolone acetate, tinomycin, Vancomycin, aztreonam, colistin IV, metronida fluprednisolone Valerate,paramethasone acetate, prednisola Zole, tinidazole, fusidic acid and trimethoprim; 2-thiopyri mate, prednival, triamcinolone hexacetonide, cortivaZol, for dine N-oxide; halogen compounds, particularly iodine and mocortal and nivaZol; iodine compounds such as iodine-PVP complex andd 0099 Pituitary hormones and their active derivatives or iiodohydroxyquin; hexachlorophene; chlorhexidine, chloro analogs such as corticotrophin, thyrotropin, follicle stimulat amine compounds; benzoylperoxide. ing hormone (FSH), luteinising hormone (LH) and gonadot I0120 Antituberculosis drugs such as ethambutol, iso rophin releasing hormone (GnRH): niazid, pyrazinamide, rifampicin and clofazimine. US 2010/0297.032 A1 Nov. 25, 2010
0121 Antimalarials such as primaquine, pyrimethamine, tamins such as vitamins A, C, D and E. Rosmarinic acid; chloroquine, hydroxychloroquine, quinine, mefloquine and Honokiol; Magnolol; Chlorogenic acid; Oleuropein; Methyl halofantrine. sulphonylmethane (“MSM'); Collagen and Chondroitin; 0122 Antiviral agents such as acyclovir and acyclovir Boswellin and boswellic acid; prodrugs, famciclovir, Zidovudine, didanosine, stavudine, 014.4 Keratolytics Such as the alpha-hydroxy acids, gly lamivudine, Zalcitabine, saquinavir, indinavir, ritonavir, collic acid and Salicylic acid. indocosanol, tromantadine and idoxuridine. 0145 Psychicenergisers, such as 3-(2-aminopropyl) 0123 Anthelmintics such as mebendazole, thiabendazole, indole, 3-(2-aminobutyl)indole, and the like. niclosamide, praziquantel, pyrantel embonate and diethylcar 014.6 Anti-acne agents such as isotretinoin, tretinoin and bamazine. benzoyl peroxide. 0124 Cytotoxic agents such as plicamycin, cyclophos 0147 Anti-psoriasis agents such as etretinate, cyclosporin phamide, dacarbazine, fluorouracil and its prodrugs de and calcipotriol. scribed, for example, in international Journal of Pharmaceu 0.148 Anti-itchagents such as capsaicinand its derivatives tics 111, 223-233 (1994), methotrexate, procarbazine, Such as nonivamide Tsai, et al. Drug. DeV. Ind. Pharm., 6-mercaptopurine and mucophenolic acid. 20(4), 719, 1994). 0.125 Metabolism agents including: 0149 Anticholinergic agents, which are effective for the 0126. Anorectic and weight reducing agents including inhibition of axillary sweating and for the control of prickly dexfenfluramine, fenfluramine, diethylpropion, mazindol heat. The antiperspirrant activity of agents such as methatro and phentermine; and pine nitrate, propantheline bromide, Scopolamine, methsco 0127 Agents used in hypercalcaemia Such as calcitriol, polamine bromide, and the new class of soft antiperspirants, dihydrotachysterol and their active derivatives or analogs; quaternary acyloxymethylammnonium salts described, for 0128 Respiratory system agents including: example, by Bodor et al., J. Med... chem. 23, 474 (1980) and 0129. Antitussives such as ethylmorphine, dextromethor also in United Kingdom Specification No. 2010270, pub phan and pholcodine; lished 27 Jun. 1979. 0130 Expectorants such as acetylcysteine, bromhexine, 0150. The optimal ratio of penetration enhancer to active emetine, guaiphenesin, ipecacuanha ans Saponins: will differ depending on the nature of the active and the 0131 Decongestants such as phenylephrine, phenylpro specific identity and composition of the combination which panolamine ans pseudoephedrine; and makes up the penetration enhance. Typically the weight ratio (0132 Bronchospasm relaxants such as ephedrine, fenot of penetration enhancer to active will be in the range of from erol, orciprenaline, rimiterol, Salbutamol, Sodium cromogly 1000:1 to 1:1000 and preferably from 500:1 to 1:10 and most cate, cromoglycic acid and its prodrugs (described, for preferably from 20:1 to 1:1. example, in International Journal of Pharmaceutics 7, 63-75 0151. The penetration enhancer of the invention is particu (1980), terbutaline, ipratropium bromide, salmeterol and larly useful in transdermal administration of antidepressants, theophylline and theophylline derivatives. women's health actives and hormones. Hormones that may be 0133 Allergy and immune system agents including: used in the drug delivery system of the present invention 0134) Antihistamines such as meclozine, cyclizine, chlo include systemically active hormones which can be delivered rcyclizine, hydroxy Zine, brompheniramine, chlorphe through the skin with the assistance of the dermal penetration niramine, clemastine, cyproheptadine, dexchlorpheniramine, enhancer to achieve a desired effect. diphenhydramine, diphenylamine, doxylamine, mebhydro 0152 Suitable hormones include: lin, pheniramine, tripolidine, azatadine, diphenylpyraline, 0153 androgens such as: methdilazine, terfenadine, astemizole, loratidine and cetiriz 0154 testosterone. dehydroepiandrosterone (DHEA), 1C. androstenedione (Andro): an androstenediol, androsterone, 0135 Local anaesthetics such as bupivacaine, ame dihydrotestosterone (DHT) androstanolone, fluoxymester thocaine, lignocaine, cinchocaine, dibucaine, mepivacaine, one, mesterolone, methyltestosterone and derivatives thereof. prilocaine and etidocaine. 0155 estrogens such as: 0.136 Stratum corneum lipids, such as ceramides, choles 0156 Estradiol, Estriol, Estrone, Chlorotrianisene, terol and free fatty acids, for improved skin barrier repair Dienestrol, Diethylstilbestrol, Ethinylestradiol, Fosfestrol, Man, et al. J. Invest. Dennatol., 106(5), 1096, 1996. Mestranol, Polyestradiol phosphate. 0.137 H2-receptor antagonists such as cimetidine; and 0157 Selective estrogen receptor modulators such as: ranitidine; 0158 Bazedoxifene, Clomifene, Fulvestrant, Lasofox 0138 Neuromuscular blocking agents such assuxametho ifene, Raloxifene, Tamoxifen, Toremifene nium, alcuronium, pancuronium, atracurium, gallamine, tub 0159. Aromatase inhibitor such as: ocurarine and vecuronium. 0160 Aminogluthetimide, Anastrozole, Exemestane, 0139 Smoking cessation agents such as nicotine, bupro Formestane, Letrozole and Vorozole. pion and ibogaine. 0.161 Gonadotropins such as: 0140 Insecticides and other pesticides which are suitable 0162 Clomifene and Urofollitropin. for local or systemic application. 0163 Progestogens such as: 0141 Dermatological agents, such as vitamins A and E. 0164 progesterone; vitamin E acetate and vitamin E sorbate. 0.165 progestins such as: 0142. Allergens for desensitisation such as house dust 0166 those selected from the group consisting of mite allergen. Desogestrel, Drospirenone, Dydrogesterone, Ethister 0143 nutraceutically active compounds include caro one, Etonogestrel, Ethynodiol diacetate, Gestodene, tenoids such as lycopene, lutein, astaxanthin and beta-caro Gestonorone, Levonorgestrel, Lynestrenol, MedroX tene; glucosamine or N-acylglucosamine; ubiquinone; Vi yprogesterone, Megestrol, Norelgestromin, Norethister US 2010/0297.032 A1 Nov. 25, 2010
one, Norethynodrel, Norgestimate, Norgestrel, Norg second penetration enhancer component of polyethylene gly estrienone, ethinylestradiol, Tibolone, megestrol and col of average molecular weight no more than 300. MENT (7-methyl-19-testosterone): 0181. The transdermal delivery system will preferably be 0167 Selective progesterone receptor modulators such as: applied in a dose sufficient to provide an effective amount of (0168 Asoprisnil, CDB-4124 the physiologically active agent in the bloodstream of the 0169. Antiprogestogen such as Mifepristone; animal. 0170 Antigonadotropins such as: 0182 Preferably, the applicator provides a metered dose 0171 Danazol and Gestrinone; and application Such as a metered dose aerosol, a stored-energy 0172 GnRH:(receptor) agonis such as: metered dose pump or a manual metered dose pump. Prefer 0173 Buserelin, Goserelin, Histrelin, Leuprorelin, ably the drug delivery system is applied to the skin of the Nafarelin and Triptorelin. animal covering a delivery surface area between about 10 and 0.174 GnRH antagonist: Abarelix, Cetrorelix and Ganire 800 cm, more preferably between about 10 and 400, and lix. most preferably between about 10 and 200 cm. The applica 0175 Compositions of the invention may include a plural tion is most preferably performed by means of a topical ity of hormones from one or more of these groups. For metered dose spray combined with an actuator nozzle shroud example it may be desirable for contraceptive formulations to which together accurately control the amount and/or unifor comprise one or more estrogens and one or more progestins. mity of the dose applied. One function of the shroud is to keep 0176 The treatment system may be used for local or sys the nozzle at a pre-determined height above, and perpendicu temic administration in an effective amount. In one embodi lar to, the skin to which the drug delivery system is being ment the transdermal delivery system is administered to pro applied. This function may also be achieved by means of a vide a pharmaceutically effective amount of the active in the spacer-bar or the like. Another function of the shroud is to systemic circulation. In one preferred form of the invention enclose the area above the skin in order to prevent or limit the drug delivery system comprises on a weight basis from bounce-back and/or loss of the drug delivery system to the about 0.1 to about 10% of active agent (partially a hormone), Surrounding environment. Preferably the area of application from about 0.1 to 12% of the at least one dermal penetration defined by the shroud is substantially circular in shape. enhancer and from about 78 to 99.8% ethanol, isopropanol or 0183. The invention will now be described with reference mixture thereof. to the following examples. It is to be understood that the 0177. In another preferred form of the invention the drug examples are provided by way of illustration of the invention delivery system comprises, on a weight basis, from about 1 to and that they are in no way limiting to the scope of the 3% of a hormone, from about 1 to 15% of the dermal pen invention. etration enhancer combination, from about 45 to 90% etha nol, isopropanol or mixture thereof, 5 to 45% water. Examples 0.178 Another group of preferred drugs are antidepres 0.184 The compositions of the Examples and their perfor sants including noradrenergic and specific serotonergic anti mance are compared with reference to the drawings. depressants (NSSA); more preferably tetracyclic antidepres sants and most preferably mirtazapine and any metabolites, BRIEF DESCRIPTION OF DRAWINGS salts, enantiomers (including eSmirtazapine), Solvants, non covalent complexes, chelates, hydrates, crystalline or amor 0185. In the drawings: phous forms thereof. 0186 FIG. 1 is a column chart comparing the permeation 0179 Diseases or conditions that may be treated by using of a progestin from a control with progestin transdermal the drug delivery system and methods of the present invention delivery composition of the invention of Example 1. include, but are not limited to, male hormone replacement in 0187 FIG. 2 is a column chart comparing the permeation testosterone deficient hypogonadal men, female hormone of an estrogen from a control with a transdermal delivery replacement therapy for postmenopausal women using for composition of the invention of Example 1. example estradiol, androgen replacement therapy for females 0188 FIGS. 3a and 3b are column charts showing the lacking libido and/or to treat depression using an androgen effect on progestin permeation of comparative transdermal Such as testosterone, male contraception (for example using a compositions containing different progestins and PEG400 progestin Such etonogestrel optionally with testosterone) and rather than PEG 200 as described in Example 2. female contraception (for example using a progestin option 0189 FIG. 4 is a column chart comparing the permeation ally in combination with an estrogen). Steroidal hormones of a progestin from a control composition with a transdermal particularly estrogens may be used to treal premenstrual Syn delivery compositions of the invention containing PEG200 drome (PMS) symptoms in women for example estradiol. pursuant to Example 2. PMS symptoms include (but are not limited to) abdominal 0.190 FIG. 5 is a column chart comparing the permeation bloating, abdominal cramps, headache or migraine, breast of an estrogen from transdermal delivery compositions 2 to 7 tenderness or Swelling, anxiety, insomnia, joint or muscle of the invention with the control composition of 1 of Example pain and mood Swings. 2. 0180. In one embodiment the transdermal delivery system 0191 FIG. 6 is a column chart comparing the effect of comprises a spray apparatus comprising a container for a PEG200 on permeation of an androgen from transdermal transdermal composition, a spray nozzle and an actuator for delivery compositions 1 to 4 of Example 3. delivering a metered dose of spray from the container via the 0.192 FIG. 7 is a column chart comparing permeation of noZZle, wherein the transdermal composition comprises a an androgen from transdermal delivery compositions 2 to 3 physiologically active agent and a first penetration enhancer with the control composition 1 of Example 4. component of an ester of salicylic acid, preferably selected 0193 FIGS. 8 and 9 are column charts comparing perme from the C to Coaliphatic ester of Salicylic acid, and a ation of the non-steroidal anti-inflamatory drug (NASAID) US 2010/0297.032 A1 Nov. 25, 2010 ketoprofen from a commercial product with transdermal estradiol through human epidermis in vitro. Permeation of delivery spray compositions containing each of OS and PEG NETA is compared in FIG. 1 and permeation of estradiol is alone and in combination (in accordance with the invention) compared in FIG. 2. as described in Example 5. 0194 FIGS. 10 and 11 are column charts comparing per Example 2 meation of the non-steroidal anti-inflamatory drug (NA SAID) diclofenac from a commercial product with transder (0208 Investigation into the Effect of PEG200 and mal delivery spray compositions containing each of OS and PEG400 on Cumulative Nestorone & Ethinylestradiol Per PEG200 and PEG 400 alone and OS in combination with the meation Through Human Skin In Vitro different PEG compositions as described in Example 6. 0.195 FIG. 12 is a column chart which compares the effect Methods: of each of PEG 200 and PEG 400 on the permeation of the 0209 Finite-dose in vitro diffusion studies were under estrogen estradiol from compositions containing OS penetra taken using dermatomed human female abdominal skin (500 tion enhancer as described in Example 7. Lm). 0210. These experiments were performed over 24 hours Example 1 using stainless steel, flow through diffusion cells based on (0196) Investigation of the Effect of PEG200 on Cumula those described previously (Cooper, E. R. J. Pharm. Sci. tive Norethisterone Acetate and Estradiol Permeation 1984, 73, 1153-1156) except that the cell was modified to Through Human Skin In Vitro increase the diffusion area to 1.0 cm2. The formulations were applied using a finite dose technique (Franz, T. J. Curr. Probl. Methods: Dermatol., 1978, 7, 58-68) to mimic clinical dosing condi tions at an applied dose Volume of 3.6 L/cm2. A piece of 0197) Finite-dose in vitro diffusion studies were under stainless steel wire mesh was placed directly below the skin in taken using dermatomed human female abdominal skin (500 the receptor chamber of the of the diffusion cell to maintain a Lm). turbulent flow of receptor solution below the skin. The diffu 0198 These experiments were performed over 24 hours sion cells were maintained at a flow rate of approximately 0.5 using Franz-type cells. Pre-cut skin membranes were mL/hr by a microcassette peristaltic pump (Watson Marlow mounted as a barrier between the halves of greased (high 505S UK). The cells were kept at 32+0.5° C. by a heater bar vacuum grease, BDH) horizontal Franz-type permeation and the samples were collected into appropriately sized glass cells in the middle of the receptor chamber of the cell with the vials for a period of 24hr. The receptor solutions (Phosphate stratum corneum facing the donor chamber. The area avail Buffered Saline pH7.4) maintained sink conditions below the able for permeation was approximately 0.925 cm2. The skin. receptor chambers of the permeation cells were filled with the 0211. The formulations consisted of: receptor phase (Phosphate Buffered Saline pH 7.4) and 0212 Composition (Comp) 1 (Control): 1.35% Nestor capped. The permeation cells were immersed in a constant one (NES), 0.35% Ethinylestradiol (EE), 5% Octyl Sali temperature water bath such that the receptor chambers were cylate (OS) in Isopropyl Alcohol (IPA) maintained at 35° C. Receptor chamber contents were con 0213 Comp 2: 1.35% NES, 0.35% EE, 5% OS, 5% tinuously agitated by small PTFE-coated magnetic stirrer Polyethylene glycol 400 (PEG400) in IPA bars driven by submersible magnetic stirrers. The skin was 0214 Comp 3: 1.35% NES, 0.35% EE, 0.5% Polyeth allowed to equilibrate to temperature with receptor solution ylene glycol (PEG200) in IPA for 1 h in the water bath prior to dosing. 0215 Comp 4: 1.35% NES, 0.35% EE, 5% OS, 0.5% 0199 The formulations were applied to the skin at a dose PEG2OO in IPA of 3.6 L/cm2. The applied formulation was spread over the skin area using an Eppendorf positive displacement pipette 0216 Comp 5: 1.35% NES, 0.35% EE, 1% PEG200 in tip without breaking the skin membrane. IPA 0200. The formulations consisted of: 0217. Comp 6: 1.35% NES, 0.35% EE, 5% OS, 1% 0201 Comparison composition 1:2.8% Norethisterone PEG2OO in IPA Acetate (NETA), 0.55% Estradiol (E2), 5% Octyl Sali 0218 Comp 7: 1.35% NES, 0.35% EE, 2.5% PEG200 cylate (OS) in IPA (0202 Composition 2: 2.8% NETA, 0.55% E2, 5% 0219) Comp 8: 1.35% NES, 0.35% EE, 5% OS, 2.5% Polyethylene Glycol 200 (PEG200) PEG2OO in IPA 0203 Composition 3: 2.8% NETA, 0.55% E2, 5% OS, 0220 Comp 9: 1.35% NES, 0.35% EE, 5% PEG200 in 5% PEG2OO IPA (0204 Composition 4: 2.8% NETA, 0.55% E2, 10% 0221) Comp 10: 1.35% NES, 0.35% EE, 5% OS, 5% PEG2OO PEG2OO in IPA 0205 Composition 5:2.8% NETA, 0.55% E2, 5% OS, 0222 Comp 11: 1.35% NES, 0.35% EE, 10% PEG200 10% PEG2OO in IPA 0206. The amount of active that permeated the skin was 0223 Comp 12: 1.35% NES, 0.35% EE, 5% OS, 10% quantified using validated HPLC methods PEG2OO in IPA 0207 FIG. 1 compares the penetration of comparative 0224. The amount of active that permeated the skin was composition 1 with compositions 2-5 relating to invention. quantified using validated HPLC methods PEG200 in combination with OS was found to significantly 0225. The effect of PEG400 on permeation of NES and EE enhance the permeation of both Norethisterone Acetate and is shown in FIGS.3a and 3b respectively. PEG200 in combi US 2010/0297.032 A1 Nov. 25, 2010
nation with OS was found to enhance the permeation of both 0241 These experiments were performed over 24 hours Nestorone and Ethinylestradiol through human epidermis in using stainless steel, flow through diffusion cells based on vitro. those described previously (Cooper, E. R. J. Pharm. Sci. 0226. The addition of PEG400 to the formulation did not have a significant effect (enhancing or inhibitory) on the 1984, 73, 1153-1156) except that the cell was modified to permeation of Nestorone through human epidermis in vitro. increase the diffusion area to 1.0 cm2. The formulations were PEG400 was found to inhibit the permeation of ethinylestra applied using a finite dose technique (Franz, T. J. Curr. Probl. diol through human epidermis in vitro. Dermatol., 1978, 7, 58-68) to mimic clinical dosing condi 0227. The effect of PEG 200 in compositions 3 to 12 on tions at an applied dose Volume of 3.6 L/cm2. A piece of permeation of NES is compared with the Composition 1 stainless steel wire mesh was placed directly below the skin in control (containing no PEG200) in FIG. 4. the receptor chamber of the of the diffusion cell to maintain a 0228. The effect of PEG200 in compositions 3 to 12 on turbulent flow of receptor solution below the skin. The diffu permeation of EE is compared with the Composition 1 con sion cells were maintained at a flow rate of approximately 1.0 trol in FIG. 5. mL/hr by a microcassette peristaltic pump (Watson Marlow Example 3 505S UK). The cells were kept at 32+0.5° C. by a heater bar 0229 Investigation Into the Effect of PEG200 on Cumu and the samples were collected into appropriately sized glass lative Testosterone Permeation Through Human Skin. In vials for a period of 24hr. The receptor solutions (0.002% w/v. Vitro. NaN3) maintained sink conditions below the skin. Methods: 0242. The formulations consisted of: 0230 Finite-dose in vitro diffusion studies were under 0243 Comp 1: 5% Testosterone (TES), 5% Octyl Sali taken using dermatomed human female abdominal skin (500 cylate (OS) in ethanol (95%) Lm). 0244 Comp 2: 5% TES, 5% OS, 1.0% polyethylene 0231. These experiments were performed over 24 hours glycol 200 (PEG200) in ethanol (95%) using stainless steel, flow through diffusion cells based on those described previously (Cooper, E. R. J. Pharm. Sci. 0245 Comp3:5%TES, 5% OS, 2.5% PEG200 in etha 1984, 73, 1153-1156) except that the cell was modified to nol (95%) increase the diffusion area to 1.0 cm2. The formulations were 0246 The amount of active that permeated the skin was applied using a finite dose technique (Franz, T. J. Curr. Probl. quantified using validated HPLC methods Dermatol., 1978, 7, 58-68) to mimic clinical dosing condi 0247. The effect of the combination of PEG200 and OS in tions at an applied dose Volume of 15 LL/cm2. A piece of Compositions 2 and 3 is compared with a control Composi stainless steel wire mesh was placed directly below the skin in tion 1 in FIG. 7. As shown in FIG. 7, PEG200 in combination the receptor chamber of the of the diffusion cell to maintain a with OS was found to significantly enhance the permeation of turbulent flow of receptor solution below the skin. The diffu Testosterone through human epidermis in vitro. sion cells were maintained at a flow rate of approximately 1.0 mL/hr by a microcassette peristaltic pump (Watson Marlow Example 5 505S UK). The cells were kept at 32+0.5° C. by a heater bar and the samples were collected into appropriately sized glass 0248 Ketoprofen Transdermal Spray: Investigation into vials for a period of 24hr. The receptor solutions (0.002% w/v. the Effect of PEG200 and PEG 400 on Ketoprofen Perme NaN3) maintained sink conditions below the skin. ation through Human Skin In Vitro 0232. The formulations consisted of: 0233 Comp 1: 2% Testosterone (TES), 5% Octyl Sali Methods: cylate (OS), 2% polyvinyl pyrrolidine (PVP), 30% iso propyl alcohol (IPA) in ethanol (95%) 0249 Finite-dose in vitro diffusion studies were under 0234 Comp 2: 2% TES, 5% OS, 2% PVP, 30% IPA, taken dermatomed skin (Padgett Model B or S electric der 0.5% polyethylene glycol 200 (PEG200) in ethanol matome set at 500 um) prepared from excised female, (95%) abdominal skin. 0235 Comp 3: 2% TES, 5% OS, 2% PVP, 30% IPA, 0250. These experiments were conducted over 24 hours 1.0% PEG200 in ethanol (95%) using flow-through systems with a 1-cm2 administration 0236 Comp 4: 2% TES, 5% OS, 2% PVP, 30% IPA, area. A piece of stainless steel wire mesh was placed directly 2.5% PEG200 in ethanol (95%) below the skin in the receptor chamber of the of the diffusion 0237. The amount of active that permeated the skin was cell to maintain a turbulent flow of receptor solution below the quantified using validated HPLC methods skin. The diffusion cells were maintained at a flow rate of 0238. The effect on permeation of TES from using the approximately 0.5 mL/hr by a peristaltic pump (Watson Mar composition as shown in FIG. 6. PEG200 in combination low 520S Peristaltic Pump with 313A adaptor and 308MC 8 with OS was found to significantly enhance the permeation of roller pump-head; Stauff Corporation, Australia). The cells Testosterone through human epidermis in vitro. were kept at 32+0.5°C. by a heater bar and the samples were Example 4 collected into appropriately sized glass vials for a period of 24 0239 Investigation Into the Effect of PEG200 on Cumu hr lative Testosterone Permeation Through Human Skin InVitro 0251. Following a 2-h equilibration of the skin with the receptor solution (RS) of 0.002% sodium azide (NaN3), the Methods: stratum corneum surface was dosed with a volume of 3.6 0240 Finite-dose in vitro diffusion studies were under LL/cm2 (unless otherwise indicated) of a test formulation taken using dermatomed human female abdominal skin (500 using a positive displacement pipette. The formulation was Lm). spread evenly over the skin area using the pipette tip. US 2010/0297.032 A1 Nov. 25, 2010 11
0252. The Ketoprofen Transdermal Spray formulations kept at 32+0.5° C. by a heater bar and the samples were were as follows: collected into appropriately sized glass vials for a period of 24 (0253) 5.0% Ketoprofen (KETO) in Isopropyl alcohol hr. (IPA) no enhancer 0265 Following a 2-h equilibration of the skin with the 0254 5.0% KETO, 5% Octyl Slaicylate (OS) in IPA receptor solution (RS) of phosphate-buffered saline (PBS) pH OS 7.4, the stratum corneum surface was dosed with a volume of 3.6L/cm (unless otherwise indicated) of a test formulation 0255 5.0% KETO, 2.5% Polyethylene glycol 200 using a positive displacement pipette. The formulation was (PEG 200) in IPAPEG 200 spread evenly over the skin area using the pipette tip. 0256 5.0% KETO, 5% OS, 2.5% PEG 200 in IPA OS 0266 The Diclofenac Transdermal Spray formulations +PEG 200 were as follows: 0257. A commercially available ketoprofen gel (approxi 0267 0.1-2.0% Diclofenac (DIC) diethylamine in Iso mately 5 mg/cm2) was used as a control. The commercially propyl alcohol (IPA) no enhancer available gel was applied using a solid cap to simulate the 0268 0.1-2.0% DIC diethylamine, 5% Octyl Salicylate rubbing action required when using the product. Approxi (OS) in IPA OS alone mately 7 mg gel was applied to the circular Surface of a black 0269 0.1-2.0% DIC diethylamine, 2.5% Polyethylene polypropylene cylindrical cap (Alltech catalogue # 98105. glycol 200 (PEG 200) in IPA PEG 200 alonel diameter 11 mm). The cap was weighed before the gel was 0270 0.1-2.0% DIC diethylamine, 5% OS, 2.5% PEG rubbed onto the surface of the skin. The gel was rubbed on for 200 in IPA OS+PEG 200 30 seconds (s) and the cap was left on the skin for a further 1 0271. A commercially available Diclofenac gel (approxi minute with a 3.5 g weight on top. The cap was then re mately 5 mg/cm2) was used as a control. The commercially weighed to determine the actual amount of gel applied. The available gel was applied using a solid cap to simulate the actual weights of the commercially available gel were used to rubbing action required when using the product. Approxi adjust the permeation data to the levels that would have been mately 7 mg gel was applied to the circular Surface of a black achieved with 5 mg/cm2 of KETO applied. polypropylene cylindrical cap (Alltech catalogue #98105. 0258. The amount of active that permeated the skin was diameter 11 mm). The cap was weighed before the gel was quantified using validated HPLC methods. rubbed onto the surface of the skin. The gel was rubbed on for 0259 FIG. 8 compares the permeation of ketoprofen from 30 seconds (s) and the cap was left on the skin for a further 1 a commercially available transdermal gel with the above minute with a 3.5 g weight on top. The cap was then re spray formulations containing 5% ketoprofen 0 or 5% OS and weighed to determine the actual amount of gel applied. The 0 or 2.5% PEG200 in isopropyl alcohol. actual weights of the commercially available gel were used to 0260 FIG. 9 compares the transdermal permeation of adjust the permeation data to the levels that would have been 2.5% ketoprofen composition where the penetration achieved with 5 mg/cm of DIC applied. enhancer is PEG200 or PEG400 and where PEG200 and 0272. The amount of active that permeated the skin was PEG400 are used in combination with OSAL (2' and 3 quantified using validated HPLC methods. columns). 0273 FIG. 10 compares diclofenac DIC permeation from a commercially available gel with compositions containing Results: 2% DIC diethylamine with each of 0% enhancer, 5% OS, 2.5% PEG 200 and 5% OS plus 2.5% PEG 200 (each in 0261 PEG200 in combination with OS was found to sig isopropylamine (IPA)). nificantly enhance the permeation of KETO through human (0274 FIG. 11 comprises the effect of PEG 400 on epidermis in vitro. PEG 400, either alone or in combination enhancement with OS. with OS, did not enhance the permeation of KETO. Results: Example 6 (0275 PEG200 in combination with OS was found to sig 0262 Diclofenac Transdermal Spray: Investigation into nificantly enhance the permeation of DIC through human the Effect of PEG200 and PEG 400 on Diclofenac Permeation epidermis in vitro. PEG 400, either alone or in combination through Human Skin In Vitro with OS, was found to decrease the DIC permeation. Methods: Example 7 0263 Finite-dose in vitro diffusion studies were under 0276 Estradiol Spray: Investigation into the Effect of taken dermatomed skin (Padgett Model B or S electric der PEG200 and PEG 400 on Estradiol Permeation Through matome set at 500 um) prepared from excised female, Human Skin. In Vitro abdominal skin. Methods: 0264. These experiments were conducted over 24 hours using flow-through systems with a 1-cm administration area. 0277 Finite-dose in vitro permeation studies were under A piece of stainless steel wire mesh was placed directly below taken using dermatomed skin (Padgett Model B or Selectric the skin in the receptor chamber of the of the diffusion cell to dermatome set at 500 um) prepared from excised female, maintain a turbulent flow of receptor solution below the skin. abdominal skin. The diffusion cells were maintained at a flow rate of approxi 0278. These experiments were conducted over 24 hours mately 0.5 mL/hr by a peristaltic pump (Watson Marlow 520S (h) using flow-through systems with a 1-cm2 administration Peristaltic Pump with 313A adaptor and 308MC 8 roller area. A piece of stainless steel wire mesh was placed in the pump-head; Stauff Corporation, Australia). The cells were receptor chamber of the of each permeation cell to support the US 2010/0297.032 A1 Nov. 25, 2010
skin and to maintain a turbulent flow of receptor solution 31. A transdermal delivery system according to claim 23 below the skin. The receptor solution was maintained at a wherein the composition consists essentially of: nominal flow rate of 0.5 mL/h by a peristaltic pump (Watson (i) the physiolocically active agent component which may Marlow 520S Peristaltic Pump with 313A adaptor and include one or more physiologically active agents; 308MC 8 roller pump-head; Stauff Corporation, Australia). (ii) the penetration enhancer component consisting of a C The cells were placed on a heater bar to keep the temperature to C alkyl ester of salicylic acid and a polyethylene of the skin at 321° C. glycol of average molecular weight no more than 300; 0279. Following a 2-h equilibration of the skin with the (iii) a volatile solvent consisting of one or more of ethanol receptor solution (RS; 0.002% sodium azide), the stratum and isopropanol; and corneum surface was dosed with 3.6 uL/cm of an Estradiol (iv) optionally a propellant. Transdermal Spray formulation using a positive displacement 32. A transdermal delivery system according to claim 23 pipette. The formulation was spread evenly over the skin area wherein the total water content of the composition is less than using the pipette tip. Permeation samples were collected into 10% by weight of the total composition. appropriately sized glass vials for a period of 24 h. 33. A transdermal delivery system according to claim 23 0280. The Estradiol transdermal spray formulations con which is non-occlusive. tained: 34. A transdermal delivery system according to claim 23 0281 Estradiol (E2)+Octyl Salicylate (OS) in Isopro wherein the weight ratio of penetration enhancer to active is pyl Alcohol IPA in the range of from 500:1 to 1:10. (0282 E2+OS+Polyethylene glycol (PEG200) in Iso 35. A transdermal delivery system according to claim 23 propyl Alcohol IPA wherein the physiologically active agent comprises one or (0283 E2+OS+Polyethylene glycol 400 (PEG400) in more selected from the group consisting of antidepressants; IPA women's health actives and hormones. 0284. The amount of active that permeated the skin was 36. A transdermal delivery system according to claim 23 quantified using validated HPLC methods. wherein the physiologically active agent comprises one or 0285 FIG. 12 shows the effect of PEG200 and PEG400 on more of mirtazapine, metabolites, salts, enantiomers (includ estradiol permeation. ing esmirtazapine), solvents, non-covalent complexes, che lates, hydrates, crystalline or amorphous forms thereof. Results: 37. A transdermal delivery system according to claim 23 0286 PEG200 combined with OS synergistically wherein the physiologically active agent comprises one or enhanced the permeation of estradiol through human skin in more hormones selected from the group consisting of andro vitro. PEG400 had no significant effect on the permeation of gens, estrogens, selective estrogen receptor modulators, aro Estradiol when compared with the control formulation this matase inhibitors, gonadotropins, progesterone, progestins, was true for formulations containing PEG400 alone and selective progesterone receptor modulators, antiprogestogen, PEG4OO-OS. antigonadotropins, GnRH:(receptor) agonists, antidiarrhoe 1-22. (canceled) als, cardiovascular system agents, antihypertensives, calcium 23. A transdermal delivery system comprising a composi channel blockers, proton pump inhibitors, antiarrhyrthmics, tion comprising a physiologically active agent and a penetra antiangina, beta-adrenergic blocking agents, cardiotonic gly tion enhancer wherein the penetration enhancer comprises a cosides, adrenergic stimulants, vasodilators, antimigraine combination of (i) an ester of salicylic acid, and (ii) polyeth preparations, anticoagulants, haemostatic agents, analgesics, ylene glycol (PEG) of average molecular weight no more than antipyretics, hypnotics, antianxiety, neuroleptic and antipsy 3OO. chotic drugs, antidepressants, CNS Stimulants such as caf 24. A transdermal delivery system according to claim 23 feine, anti-alzheimer's agents, antiparkinson agents, lipid wherein the ester of salicylic acid is a C to C2 alkyl ester. regulating drugs, anticonvulsants, antiemetics, antinauseants, 25. A transdermal delivery system according to claim 23 non-steroidal antiinflammatory agents, antirheumatoid, wherein the ester of salicylic acid is ethylhexylester. muscle relaxants, agents used in gout and hyperuricaemia, 26. A transdermal delivery system according to claim 23 diuretics, antidiuretics, obstetric drugs, prostaglandins, anti wherein the ester of Salicylic acid is present in an amount of microbials, antituberculosis drugs, antimalarials, antiviral from 0.1 to 10% by weight of the total transdermal composi agents, anthelmintics, cytotoxic agents, anorectics, agents tion. used in hypercalcaemia, antitussives, expectorants, decon 27. A transdermal delivery system according to claim 23 gestants, bronchospasm relaxants, antihistamines, local wherein the PEG of average molecular weight of no more anaesthetics, stratum corneum lipids, H2-receptor antago than 300 is present in an amount in the range of from 0.1 to nists, neuromuscular blocking agents, Smoking cessation 40% by weight of the total composition. agents, insecticides and other pesticides, dermatological 28. A transdermal delivery system according to claim 23 agents, allergens, nutraceutically active compounds, kera wherein the weight ratio of ester of salicylic acid to polyeth tolytics, psychicenergisers, anti-acne agents, anti-psoriasis ylene glycol of average molecular weight no more than 300 is agents, anti-itch agents, anticholinergic agents, and mixtures in the range of from to 1:10 to 10:1. thereof. 29. A transdermal delivery system according to claim 23 38. A transdermal delivery system according to claim 36 wherein the composition comprises a solvent selected from comprising a plurality of hormones from one or more of these C. to Calkanol. groups preferably a contraceptive active agent comprising 30. A transdermal delivery system according to claim 29 one or more estrogens and one or more progestins. wherein the volatile solvent is preferably present in the com 39. A transdermal delivery system according to claim 37 position in an amount in the range of from 70% to 95% by wherein the drug delivery system comprises on a weight basis weight of the total composition. from about 0.1 to about 10% of the hormone, from about 0.1 US 2010/0297.032 A1 Nov. 25, 2010
to 12% of the penetration enhancer and from about 70 to pausal women, androgen replacement therapy for females 99.8% ethanol, isopropanol or mixture thereof. lacking libido using an androgen Such as testosterone, male 40. A method of transdermal administration of an active contraception and female contraception. agent to an animal Subject comprising application to dermal 42. A transdermal delivery system according to claim 23 Surface of the animala transdermal system according to claim further comprising a spray apparatus comprising a container 23. containing the transdermal composition a spray nozzle and an 41. A method of transdermal administration according to actuator for delivering a metered dose of spray from the claim 40 wherein the animal subject is in need of male hor container via the nozzle. mone replacement in testosterone deficient hypogonadal men, female hormone replacement therapy for postmeno c c c c c