WO2008115599A1

WO2008115599A1 - Apparatus and method for transdermal delivery of a 5-hydroxytrytamine antagonist

Info

Publication number: WO2008115599A1
Application number: PCT/US2008/003806
Authority: WO
Inventors: Frank Stonebanks
Original assignee: Alza Corporation
Priority date: 2007-03-21
Filing date: 2008-03-20
Publication date: 2008-09-25

Abstract

An apparatus and a method for transdermally delivering a 5-hydroxytrytamine (5-HT3) antagonist is described. The apparatus includes a microprojection member having a plurality of skin-piercing microprojections, adapted to pierce the stratum comeum of a subject.

Description

APPARATUS AND METHOD FOR TRANSDERMAL DELIVERY OF A 5-HYDROXYTRYTAMINE ANTAGONIST

TECHNICAL FIELD

[0001 ] The subject matter described herein relates generally to transdermal agent delivery systems and methods. More particularly, the subject matter relates to an apparatus and method for transdermal delivery of 5-hydroxytrytamine antagonists.

BACKGROUND OF THE INVENTION

[0002] Nausea and vomiting, also termed emesis, are associated with myriad causes and stimuli, ranging from motion sickness, mild gastrointestinal upset caused by infections, migraines, food poisoning, and adverse drug reactions, including cancer chemotherapy. Emesis also provides an elimination mechanism for ingested toxins and poisons. Colors, smells, tastes, and textures associated with potentially toxic compounds can result in a learned aversion to these substances, inducing emesis, and thus providing animals with a vital survival mechanism. Emesis symptoms can range from an unpleasant inconvenience to a debilitating condition causing sever dehydration, weight loss, fatigue, torn esophagus, and reopening of surgical wounds.

[0003] Nausea and vomiting remain common and feared side effects of treatment for cancer patients undergoing chemotherapy and/or radiation therapy. Uncontrolled emesis can adversely affect patient quality of life and impair compliance with treatment. Patents that are particularly adversely affected with emesis can become severely dehydrated and malnourished requiring parenteral fluid and dietary supplementation. As a result, many patents find that their life quality is so compromised that they voluntarily remove themselves from life saving chemotherapy. In other patients, the emesis is so severe that physicians must temporarily, or permanently discontinue treatments.

[0004] Emesis is a complex process involving many different neuroreceptors and the biochemical pathways that regulate emesis are varied and complex. Emesis-associated neuroreceptors include neurochemical receptors such as dopamine receptors, 5-hydτoxytrytamine (5-HT) receptors, aceytalcholine receptors, histamine receptors, opioid receptors, neurokinin (NKi) receptors, and cannabinoid receptors, as well as mechano-receptors.

[0005J There are four 5-HT receptors associated with emesis including 5-HT₃, 5-HT-,,,, 5-HT,_D) and 5-HT₊. Among the 5-HT receptors involved in emesis, the 5HT3 has been identified as involved in cancer therapy-related emesis. 5-HT₃ receptors are located in the central nervous system and peripherally in the gut mucosa, nerve endings, and primary afferent nerve fibers. Antagonism of the 5-HT₃ receptors can prevent emesis associated with increased local 5-HT concentrations. [0006] Significant progress has been made in developing more effective and better-tolerated measures to minimize emesis, particularly chemotherapy-induced nausea and vomiting. One of the more recent developments has been the introduction of selective 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists. This class of agents have become a cornerstone of antiemetic therapy (Oo, T. etal, Nat. CHn. Pract. Oncol, 2(4):195 (2005)).

[0007] Despite this progress, there remains a need for anti-emetic therapies that provide a rapid onset of action combined with an improved tolerability profile. Anti-emetic therapies administered intravenously or subcutaneously are undesirable because a skilled care giver is required for administration. Sublingual and oral tablets and nasal sprays provide rapid onset of action, but are associated with after-tastes that can worsen the problem or arc intolerable because of the difficulty in swallowing when nausea and vomiting aie present. Thus, there remains a need to identify effective new approaches to prevent or treat nausea and vomiting.

[0008] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.

SUMMARY OF THE INVENTION

[0009] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0010] In one aspect, a device for transdermally delivering a 5-hydroxytryptamine-3 (5-HT₃) antagonist is provided. The device is comprised of a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and a 5-HT₃ antagonist disposed on said microprojection member for communication with the plurality of microprojections.

[0011] In one embodiment, the 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microprojections.

[0012] In another embodiment, the 5-HT₃ antagonist is contained in a reservoir in contact with said microprojection member.

[0013] In still another embodiment, the plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

[0014] In another embodiment, the 5-HT₃ antagonist is selected from the group consisting of ondasetron, granisetron, tropisetron, dolasetron, and paloαosetron.

[0015] In another aspect, a method for transdermally delivering a 5-HT₃ antagonist is described. A microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient is provided, and applying the member to a skin site on a patient, whereby the plurality of microprojections pierce the stratum-comeum for delivery of the 5 -HT₃ antagonist.

[0016] In one embodiment, the member is applied to a patient prior to, during, or after chemotherapy or radiation therapy.

[0017] In another embodiment, the member is applied to a patient before, during, or after surgery.

[0018] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Fig. 1 is a perspective view of a portion of one example of a microprojection member;

[0020] Fig. 2 is a perspective view of a microprojection member where a coating is deposited on the outer surface of each micToprojectiott in the array;

[0021] Fig. 3 is a side sectional view of a microprojection member having a drug reservoir and an adhesive backing;

[0022] Fig. 4 is a perspective view of a microprojection having a standard hollow needle-like configuration, where the interior and/or exterior of the micropτojections include an agent for delivery;

[0023] Fig. 5 A is an exploded perspective view of a microprojection member enclosed in a retainer and an applicator; [0024] Fig. 5B is a side sectional view of a retainer having a microprojection member disposed therein. (0025] Fig. 6 is a graph of Mean Granisetron Concentration. [0026] Fig. 7 is a graph of Individual Granisetron Concentrations.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0027] Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified materials, methods or structures as such may, of course, vary. Thus, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

[0028] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0030] Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0031] Finally, as used in this specification and the appended claims, the singular forms "a, "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an active agent" includes two or more such agents; reference to "a microprojection" includes two or more such microprojections and the like.

[0032] The term "transdermal", as used herein, means the delivery of an agent into and/or through the skin for local or systemic therapy.

[0033] The term "transdermal flux", as used herein, means the rate of transdermal delivery.

[0034] The term "5-hydroxytrytaphamiπe antagonist" ("5-HT₃ antagonist") intends an agent that acts by blocking 5-HT₃ receptors and preventing or reducing the initiation of the emetic response. Examples of 5-HT₃ antagonists include, without limitation, ondasetron, granisetron, tropisetron, dolasetron, and palonosetron. It will be appreciated that the term is intended to encompass the agent in any form, including, but not limited to, a free base, a free acid, a salt, or as a component of a complex. It is also to be understood that more than one 5-HT₃ antagonist agent can be incorporated into the agent source, reservoirs, and/or coatings described hereinbelow, and that the use of the term "5-HT₃ antagonist" in no way excludes the use of two or more such agents.

[0035] The term "microprojections", as used herein, refers to piercing elements which are adapted to pierce or cut through die stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a mammal and more particularly a human.

II. Apparatus for Delivery

[0036] In one embodiment, a device for delivery of a 5-HT₁ antagonist is provided. The device includes a plurality of microprojections (or array thereof) that are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers. A portion of such an array from an exemplary deyice is shown in Fig. 1. A microprojection member 10 is comprised of an array of microprojections, such as microprojections 12, 14. The microprojections extend at a substantially 90° angle from a substrate 16 having openings, such as openings 18, 20. The microprojections typically have a length of less than about 1000 microns, and preferably a length of less than about 500 microns, more preferably, less than about 250 microns The width (designated "W" m Fig 1) of each microprojection is typically in the range of approximately 25 - 500 microns and the thickness of each microprojection is generally in the range of approximately 10 - 100 microns The microprojections may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof [0037] The microprojection member can be formed by etching or punching a plurality of microprojections from a sheet or substrate, such as substrate 16, and folding or bending the microprojections out of the plane of the sheet The microprojection member can also be formed in other known manners, such as by forming one or more strips having microprojections along an edge of each of the stπp(s) as disclosed in U S Patent No 6,050,988, which is hereby incorporated by reference in its entirety [0038] In one embodiment, the microprojection member is constructed out of stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials In another embodiment, the microprojection member is constructed out of a non-conductive material, such as a polymeric material The microprojection member when formed from a conductive material can be coated with a non-conductive material, such as Parylene^®, or a hydrophobic material, such as Teflon^®, silicon, or the like [0039] The microprojection member, in one embodiment, has a microprojection density of at least approximately 10 microprojections/cnr², more preferably, in the range of at least approximately 200 - 2000 microprojections/cm²

[0040] The device is designed for transdermal delivery of a 5-HT₃ antagonist, which is administered to a subject desirous of emesis control The antagonist is administered into the underlying epidermis layer, or epidermis and dermis layers, of a subject via slits or cuts made by the microprojections through the stratum comeum The 5-HT₃ antagonist is disposed on the device in a way that permits delivery of the agent from the device into the slits made in the stratum corneum For example, in one embodiment shown in Fig 2, each microprojection, such as microprojections 24, 26, in an array 28 can be coated with a biocompatible coating 30 The biocompatible coating may partially or completely cover the microprojections and may be applied to the microprojections before or after the microprojections are formed

[0041] The coating 30 on the microprojections can be formed by a variety of known methods One such method is dip-coating, where the microprojections are partially or totally immersed into a formulation containing a 5-HT₃ antagonist For example, a coating solution containing a suitable solvent (aqueous or nonaqueous), a 5-HT₃ antagonist, and any additional solution components, is prepared and applied to the microprojections Alternatively, the entire device can be immersed into the coating solution An apparatus for coating a microprojection array is descπbed in U S Publication No 2002/0132054, coating methods are also taught in U S 2004/0062813, both of which is incorporated by reference herein in its entirety The coating device applies the coating solution only to the microprojections and not upon the substrate/sheet from which the microprojections project Other coating techniques such as microfluidic spray or printing techniques can be used to precisely deposit a coating on the tips of the microprojections The microprojections may further include means adapted to receive and/or increase the volume of the coating such as apertures, grooves, surface irregularities, or similar modifications, wherein the means provides increased surface area upon which a greater amount of coating may be deposited A coating solution can also be applied to the microprojections by spraying Spraying can encompass formation of an aerosol suspension of the coating composition, where droplets having a size of about 10 to about 200 picoliters is sprayed onto the microprojections and then dried

[0042] The coating formulation includes a 5-HT₃ antagonist in any desired amount The coating formulation is applied to the microprojections to obtain a dry solid, biocompatible coating that contains in the range of between about 1 μg -1000 μg, even more preferably, in the range of 10 — 100 ug, of the 5-HT₃ antagonist The coating thickness is dependent upon the density of the microprojections per unit area, the viscosity and concentration of the coating formulation, as well as the coating method. In general, coating thickness less than 50 micrometers are desired, and a preferred average coating thickness is less than about 30 micrometers, as measured perpendicularly from the microprojecrkm surface.

[0043] Another embodiment of a microprojection device is shown in cross-sectional view in Fig. 3. In this embodiment, device 40 includes a microprojection member 42 comprised of a plurality of microprojections, such as microprojections 44, 46. The microprojections extend from a substrate 48, which is in contact with a reservoir 50 containing a 5-HT₃ antagonist. Reservoir 50 is in fluid communication with openings between and adjacent the microprojections, such as openings 52, 54. Preferably, the number of openings per unit area through which the agent passes is at least approximately 10 openings/cm and less than about 2000 openings/cm². Agent in reservoir 50 is delivered through the openings and into the slits in the stratum comeum of a subject formed upon piercing with the array of microprojections. A backing layer 56 is disposed on the skin proximal side of the agent reservoir, and can additionally include an adhesive (not shown) for adhering the device to the skin.

[0044] Another embodiment of a microprojection for use in a device for delivery of a 5-HT₃ antagonist to a subject is shown in Fig. 4. In this embodiment, a device as described above, includes an array of microprojections, where each microprojection is in the shape of a hollow needle, like needle 60 shown in Fig. 4. Needle 60 has an exterior surface 62, an interior surface 64, and a skin-piercing distal tip 66. The interior surface 64 of the microprojection is coated with a coating formulation to form a solid, dry coating 68. When the microprojection is inserted into the skin, interstitial fluid from the surrounding tissue can come in contact with the coating 68, thereby dissolving the coating and releasing the 5-HT₃ antagonist incorporated into the solid coating, hi alternative embodiments, not shown here but detailed in U.S. Publication No. 2005/0031676 Al, incorporated by reference herein, the needle includes slits, perforations, or other openings, and/or is formed of a porous material to facilitate entry of interstitial fluid and dissolution of the 5-HT₃ antagonist. [0045] Figs. 5A-5B show an embodiment of a microprojection member 70 suspended in a retainer ring 72 by adhesive tab 76, as described in detail in U.S. Publication No. 2002/0091357 Al, which is incorporated by reference herein in its entirety. In use, the retainer ring is placed against the skin and the microprojection member 70 is downwardly displaced for contact with patient's skin. Preferably, the microprojection member is applied to the patient's skin using an impact applicator 78, such as shown in Fig. 5A, and described in U.S. Publication No. 2002/0123675 Al, which is incorporated by reference herein in its entirety.

[0046] Alternative embodiments of microprojection members that can be employed for delivery of the 5-HT₃ antagonist can also include, but are not limited to, the members disclosed in U.S. Patent Nos. 6,083,196, 6,050,988, and 6,091,975, which are incorporated by reference herein in their entirety.

[0047] Other microprojection members that can be employed include members formed by etching silicon using silicon chip etching techniques or by molding plastic using etched micro-molds, such as the members disclosed U.S. Patent No. 5,879,326, which is incorporated by reference herein in its entirety.

[0048] An apparatus designed to cause the microprojections to impact the stratum comeum with an impact power of at least 0.05 joules per cm² in 10 milliseconds or less is described in U.S. Publication No. 2005/0234401 Al, which is incorporated by reference herein. The apparatus includes an applicator device for repeatable impact application of a microprotrusion array, to achieve predefined and consistent penetration of the microprotrusions into the skin. [0049] In the embodiments described with respect to Figs. 2-4, a biocompatible, solid dry coating containing the 5-HT3 antagonist is formed on the microprojections. As briefly described above, the solid coating is deposited from a coating formulation that can contain various additional components, now to be described.

|0050] In one embodiment, the coating formulation includes at least one buffer. Examples of such buffers include, without limitation, ascorbic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fiimaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, citramalic acid, dimethylolpropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, β-hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and mixtures thereof.

[0051] In another embodiment, the coating formulation includes at least one antioxidant, which can be a sequestering agent, such sodium citrate, citric acid, EDTA (ethylene-dinitrilo-tetraacetic acid) or free radical scavengers such as ascorbic acid, methionine, sodium ascorbate and the like. Preferred antioxidants comprise EDTA and methionine. The concentration of the antioxidant is in the range of approximately 0.01-20 wt. % of the coating formulation. Preferably the antioxidant is in the range of approximately 0.03-10 wt. % of the coating formulation.

[0052] The coating formulation can additionally include at least one surfactant, which can be zwitterionic, amphoteric, cationic, anionic, or nonionic, including, without limitation, sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbates, such as Tween 20 and Tween 80, other sorbitan derivatives, such as sorbitan laurate, alkoxylated alcohols, such as laureth-4 and polyoxyethylene castor oil derivatives, such as Cremophor^®. The concentration of the surfactant is in the range of approximately 0.01-20 wt. % of the coating formulation. Preferably the surfactant is in the range of approximately 0.05- 1 wt. % of the coating formulation.

[0053] The coating formulation can also include at least one polymeric material or polymer that has amph philic properties, which can comprise, without limitation, cellulose derivatives, such as hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxy-ethylcellulose (EHEC), as well as a Pluronic™. The concentration of the polymer presenting amphiphilic properties in the coating formulation is preferably in the range of approximately 0.01-20 wt. %, more preferably, in the range of approximately 0.03-10 wt. % of the coating formulation.

[0054] The coating formulation can optionally include a hydrophilic polymer selected from the following group: hydroxyethyl starch, carboxymethyl cellulose and salts of, dextran, poly( vinyl alcohol), poly(ethylene oxide), poly(2- hydroxyethylmethacrylate), poly(n- vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers. In a preferred embodiment, the concentration of the hydrophilic polymer in the coating formulation is in the range of approximately 1-30 wt. %, more preferably, in the range of approximately 1-20 wt. % of the coating formulation. [0055] The coating formulation can optionally include a biocompatible carrier, which can comprise, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffϊnose, stachyose, mannitol, and other sugar alcohols. Preferably, the concentration of the biocompatible carrier in the coating formulation is in the range of approximately 2-70 wt. %, more preferably, in the range of approximately 5-50 wt. % of the coating formulation. [0056] The coating formulation can also include a stabilizing agent, which can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar. Suitable non-reducing sugars for use in the methods and compositions of the invention include, for example, sucrose, trehalose, stachyose, oτ rafϊϊnose. Suitable polysaccharides for use in the methods and compositions of the invention include, for example, dextran, soluble starch, dextrin, and insulin. Suitable reducing sugars for use in the methods and compositions of the invention include, for example, monosaccharides such as, for example, apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; and disaccharides such as, for example, primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose, and turanose, and the like. Preferably, the concentration of the stabilizing agent in the coating formulation is at ratio of approximately 0.1 -2.0: 1 with respect to the 5-HT₃ antagonist, more preferably, approximately 0.25-1.0: 1 with respect to the 5-HTj antagonist.

[0057] In another embodiment, the coating formulation includes a vasoconstrictor, which can comprise, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, omipressin, oxymethazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline and the mixtures thereof. The most preferred vasoconstrictors include epinephrine, naphazoline, tetrahydrozoline indanazoline, metizoline, tramazoline, tymazoline, oxymetazoline and xylometazoline. As will be appreciated by one having ordinary skill in the art, the addition of a vasoconstrictor to the coating formulations and, hence, solid biocompatible coatings is particularly useful to prevent bleeding that can occur following application of the microprojection member or array and to prolong the pharmacokinetics of the 5-HT₃ antagonist through reduction of the blood flow at the application site and reduction of the absorption rate from the skin site into the system circulation. The concentration of the vasoconstrictor, if employed, is preferably in the range of approximately 0.1 wt. % to 10 wt. % of the coating formulation. [0058] In another embodiment, the coating formulation includes at least one "pathway patency modulator", which can comprise, without limitation, osmotic agents (e.g., sodium chloride), zwitterionic compounds (e.g., amino acids), and antiinflammatory agents, such as betamethasone 21 -phosphate disodium salt, triamcinolone acetonide 21 -disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21 -phosphate disodium salt, methylprednisolone 21 -phosphate disodium salt, methylprednisolone 21-succinaate sodium, salt, paramethasone disodium phosphate and prednisolone 21 -succinate sodium salt, and anticoagulants, such as citric acid, citrate salts (e.g., sodium citrate), dextrin sulfate sodium, aspirin and EDTA. [0059] In yet another embodiment, the coating formulation includes a solubilising/complexing agent, which can comprise alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydτoxypropyl-beta- cyclodextrin, 2-hydroxypropyl-garnma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfoburylether-gamma-cyclodextrin. Most preferred solubilising/complexing agents are beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, and sulfobutylether7 beta-cyclodextrin. The concentration of the sohibilising/complexing agent, if employed, is preferably in the range of approximately 1 wt. % to 20 wt. % of the coating formulation.

[0060] In another embodiment, the coating formulation includes at least one nόn-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethysulfoxide, glycerin, N,N-dimethylformamide and polyethylene glycol 400. Preferably, the non-aqueous solvent is present in the coating formulation in the range of approximately 1 wt. % to 50 wt. % of the coating formulation.

[0061] Other known formulation adjuvants can also be added to the coating formulations provided they do not adversely affect the necessary solubility and viscosity characteristics of the coating formulation and the physical integrity of the dried coating. Preferably, the coating formulations have a room temperature (about 20-25⁰C) viscosity less than approximately 500 centipoise and greater than 3 centipoise.

III. Methods of Use

[0062] In another aspect, a method for administering a 5-HT₃ antagonist to a subject is provided. In the method, a device as described above in provided. The microprojection member is initially applied to the patient's skin to cause the microprojections to pierce the stratum corneum. The microprojection member is preferably left on the skin for a period lasting from 5 seconds to 24 hours. Following the desired wearing time, the microprojection member is removed. [0063] Preferably, the amount of 5-HT₃ antagonist contained in the biocompatible coating (i.e., dose) or in a reservoir in communication with the microprojections is in the range of approximately 1 micrograms -1000 micrograms, more preferably, in the range of approximately 10-200 micrograms. Even more preferably, the amount of 5-HT₃ antagonist contained in the biocompatible coating is in the range of approximately 10-100 micrograms per device.

[0064] In one embodiment, the 5-HT₃ antagonist is delivered to the patient on a daily basis, or as needed to control emesis. For patients undergoing chemotherapy and/or radiation, the antagonist is delivered prior to, during, and/or after the chemotherapy or radiation, again as needed to control emesis. In one embodiment, delivery of the 5-HT₃ antagonist transdermally using the apparatus described herein provides beneficial pharmacokinetics, as evidenced by a larger area under the curve and longer blood circulation lifetime, when compared to the same dose administered subcutaneously. [0065] It will be appreciated by one having ordinary skill in the art that in order to facilitate drug transport across the skin barrier, the present device can also be employed in conjunction with a wide variety of iontophoresis or elecrrotransport systems. Illustrative electrotransport drug delivery systems are disclosed in U.S. Pat. Nos.5,147,296, 5,080,646, 5,169,382 and 5,169,383, the disclosures of which are incorporated by reference herein in their entirety.

IV. Examples

[0066] The following examples are illustrative in nature and are in no way intended to be limiting.

EXAMPLE l

ADMINISTRATION OF GRANISERON TO ANIMALS

[0067] Bolus delivery of the 5-HTj antagonist granisetron from a microprojection member is evaluated using a hairless guinea pig (HGP) model. A microprojection device is formed via photo/chemical etching to have an area of 2 cm², a microprojection density with 1450 microprojections/cm², and a projection length of 225 μm.

[0068] The microprojections are coated with a 33.3% aqueous solution of granisetron, 12.4% citric acid, and 0.2% polysorbate at 287 drug ± 10 μg per 2 cm² array, with a solid coating limited to the first 150 μm of the microprojections. The coated microprojection array is attached to a flexible polymeric adhesive backing and then assembled onto a retainer ring. The assembly is then loaded on a reusable impact applicator at the time of application to the HGP. [0069] The device is applied to an area of skin on each anesthetized HGP (n=5) and the microprojections are caused to pierce the skin. The device is left in place for one hour. At various time intervals following patch application, blood samples are taken for determination of plasma granisetron levels. Figures 6 and 7 show the mean and individual pharmacokinetic (PK) profile of granisetron administered with the microprojections, respectively. Delivery of peak granisetron concentrations was rapid with T_m2x achieved by 7 (SD=4.5) minutes after patch application.

[0070] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

Claims

WHAT IS CLAIMED IS:

1. A device for transdeπnally delivering a 5-hydroxytryptamiiie-3 (5-HT₃) antagonist, comprising: a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and a 5-HT₃ antagonist disposed on said microprojection member for communication with the plurality of microprojections.

2. The device of claim 1, wherein said 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microprojections.

3. The device of claim 1 , wherein said 5-HT₃ antagonist is contained in a reservoir in contact with said microprojection member.

4. The device of claim 1, wherein said plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

5. The device of claim I₁ wherein said 5-HT₃ antagonist is selected from the group consisting of ondasetron, granisetron, tropisetron, dolasetron, and palonosetron.

6. A method for transdermally delivering a 5-HT₃ antagonist, comprising: providing a microprojection member having a plurality of microprojections adapted to pierce the stratum comeum of a patient, and applying said member to a skin site on a patient, whereby said plurality of microprojections pierce the stratum corneum for delivery of the 5-HT₃ antagonist.

7. The method of claim 6, wherein said applying comprises applying to a patient prior to, during, or after chemotherapy or radiation therapy.

8. The method of claim 6, wherein said applying comprises applying to a patient before, during, or after surgery.

9. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microproj ections .

10. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said 5-HT₃ antagonist is contained in a reservoir in contact wiΛ said microprojection member.

11. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the 5-HT₃ antagonist is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.

12. The method of claim 6, wherein said providing comprises providing a microprojection member wherein said 5-HT₃ antagonist is selected from the group consisting of ondasetron, granisetron, tropisetron, dolasetron, and palonosetron.