TW200820996A - Transdermal method and patch for emesis - Google Patents

Abstract

Provided, among other things, is a method of treating acute, delayed or anticipatory emesis for a sustained period in an individual, which involves applying to a portion of intact skin on the individual a composition of i. an antiemetically effective amount of a 5-HT3 receptor antagonist; ii. a permeation enhancing amount of permeation enhancer comprising 0.5% to 15% by weight of the skin-contacting layer; and iii. an adhesive.

Description

200820996 IX. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to transdermal delivery devices and methods for treating nausea and vomiting, and more particularly to the treatment of nuisances over a sustained period of time. A transdermal administration method, composition and device containing a 5-HT3 receptor antagonist. [Prior Art] Most patients who have undergone anticancer chemotherapy or radiation therapy have suffered from therapeutic side effects such as nausea and vomiting (a common condition of a patient). In order to prevent the side effects of such anti-cancer treatments or to minimize the side effects of such anti-cancer treatments, antagonists of 5-hydroxytryptamine subtype 3 (herein referred to as "serotonin") have been widely administered, such as Ondansetron, granisetr〇n, tropisetron, dolasetron, hydrodolasetron, azasetr〇n ), ramosetron, ierisetr〇n, indisetron, itassetron〇, piperonosetron, ramosetron (1 face osetrcm), allosetron (allosetron) and mixtures thereof (known as serotonin receptor antagonists or 5_HT3 ? stylistic antagonists)' are administered parenterally or orally for many days. • Heart and vomiting can also occur for other reasons, such as after surgery, motion sickness, or as a side effect of other medications taken by the patient. Examples of drugs that can cause side effects of nausea and vomiting are certain antibacterial and antiviral agents, bioactive agents that control glucose levels, such as insulin and amylm or its natural and synthetic analogs, and cardiolipase inhibition. Agent, sulfonate 116268.doc 200820996 meglitinide, thiazolidine dione, biguanide, double PPARa/γ agonist, ρρΑΚγ agonist and insulin secretagogue. The nausea or vomiting of unknown etiology, including periodic vomiting syndrome, can also weaken an individual. In periodic vomiting syndrome (cvs), people experience a sustained or frequent nausea and vomiting, and often - and alternate with longer asymptomatic periods. Each episode is similar to the previous one. Attacks - tend to start at about the same time on the mother's day, last for the same length of time and exhibit the same symptoms at the same intensity. Symptoms before the onset can predict the oncoming _ _ and defined as, prodromal symptoms. In any situation where the patient's k π nausea and vomiting, oral administration of antiemetics is irritating and causes the patient to produce more More discomfort. Intravenous (Iv) or intramuscular (IM) administration is generally not practical for home use. Although these routes of administration provide fluctuating antiemetic plasma levels, patients must be administered orally in multiple doses over time. IM and IV doses to achieve continuous antiemetic benefits. In addition, because nausea and vomiting are irritating reversal, antiemetics are most effective if used prophylactically. In chemotherapy, radiation therapy, taking drugs In the case of vomiting or CVS prodromal period, this prophylaxis is quite important when nausea and vomiting can be expected in advance. 'To solve these problems, an attempt has been made to formulate an antiemetic composition in the form of a patch so that it can be administered percutaneously. Evacuation attempts to develop antiemetics for transdermal administration have caused other problems. For example, certain penetration enhancers (e.g., terpenoids) used in transdermal compositions induce skin irritation. Alcohols, which are often required for the dissolution of transdermal agents, are also irritating to the skin. Because the alcohol is rapidly depleted, it is difficult to achieve sustained delivery over a period of several hours 116268.doc 200820996. When (iv) consists of a low viscosity solution The transdermal administration of the composition 'the blood content of the music can be easily reduced below the effective level, thus reducing the desired pharmacological effect. Other efforts to administer the antiemetic agent percutaneously have included complex application devices or techniques, such as supplemental energy to Enhancing the percutaneous penetration of drugs. The current techniques for describing transdermal drug antiemetic treatment are often focused on imitating σ or ιv agents to obtain therapeutic sputum content. These agents have been tried using a salt-formed drug that retains the active agent. Typical delivery 'However, the salt form antiemetic has a relatively low: skin permeability' and it is difficult to achieve a therapeutic blood aggregation level for a sustained period of time. Usually * consider using a free form because it may be irritating or think it Unstable in the dosage form. / It is therefore desirable to provide a transdermal administration composition of an antiemetic which is simple to use, non-irritating to the skin' and which is connectable Positioning remains on the skin for two days, three days or longer and effectively prevents, improves or treats heart and vomiting. In addition, moderate but functionally significant concentrations of active agents and penetration enhancers make use of the current It is possible to deploy a patch that delivers an antiemetic agent during an extremely substantial period of time, and the blood content is measured to indicate that it remains transmitted even after removal of the composition. Incremental delivery of blood has been reported, and lack of use has been reported. Percutaneous delivery device for permeation enhancers. See 〇 2〇〇4/〇69141. According to the present invention, a significant sustained delivery can be achieved in the presence of a functionally significant concentration of penetration enhancer. The lack of penetration enhancers limits instability and irritation. The lack of penetration enhancers limits the maximum plasma concentration and total delivery of the active moiety. On the other hand, the inclusion penetration enhancer results in an irritating combination 116268.doc 200820996. Surprisingly, the therapeutic plasma levels are achieved and maintained using the teachings of the present invention, but using an appropriate amount of a functionally significant concentration of the penetration enhancer to render the final product non-irritating and stable. SUMMARY OF THE INVENTION In Example k, a method for treating acute, delayed, or expected vomiting in a subject for a sustained period of time, the method comprising: applying a composition to the intact skin or mucosal portion of the individual for 24 hours or longer The composition comprises: * i. an antiemetic effective amount of a 5·ΗΤ3 receptor antagonist; u·of the skin contact layer 〇·5 wt% to 15 wt❶/. An osmotic enhancing amount of the osmotic stimulating agent; and iii. an adhesive, wherein the plasma concentration of the 5-HT3 receptor antagonist is within a therapeutically effective range from the start time to 12 hours or more after the removal of the composition. In some of the examples, the second composition is applied to one body after removing the composition for 2 hours or more, wherein from the start time to 12 hours or more after the second composition is removed The plasma concentration of the 5_HT3 receptor antagonist is provided within a therapeutically effective range. In certain embodiments, the 5-HT3 receptor antagonist is administered in combination with another antiemetic, or in the same agent as the separate administration form. Further provided is an antiemetic composition for transdermal administration comprising a skin contact composition comprising: L an antiemetically effective amount of a 5-HT3 receptor antagonist; Η·occupying a skin contact layer 5 5% by weight a penetration enhancement amount of up to 15% by weight, 116268.doc 200820996, a permeation enhancer; and m. an adhesive, wherein the composition is applied to the entire skin portion of the individual for 24 hours (or longer) and then moved In addition, it provides the plasma concentration of the 5-HT3 receptor antagonist within the therapeutically effective range of the individual from the start time to 12 hours or longer after removal of the composition. Further providing a transdermal delivery device for preventing, ameliorating or treating nausea and vomiting in a subject, comprising a patch comprising 0) a carrier layer; and (b) a skin φ contact layer comprising: i An anti-emetically effective amount of a 5-HT3 receptor antagonist; u. an osmotic enhancer in an amount of 5 to 15% by weight of the skin contact layer; and

Hi. Adhesive, wherein when the device is applied to the entire skin site of an individual for 24 hours (or longer) and subsequently removed, it is surprisingly from the start time to 12 hours after removal of the device The plasma concentration of the 5-HT3 receptor antagonist in the individual therapeutically effective range is provided for a longer period of time. In a preferred embodiment, the formulation surprisingly exhibits minimal irritation despite the presence of the penetration enhancer and the active ingredient. After the first application, the stimuli are less than 1.0. Further provided is a transdermal administration device for preventing, ameliorating or treating nausea and vomiting' which can be applied 30 to 36 hours (e.g., 2-36 hours, 12 hours, 24 hours, etc.) prior to the expected or expected nausea and vomiting. In one embodiment, the composition exhibits one or more of the following adult in vivo 116268.doc 200820996 mean plasma profile: i. transdermal administration of the composition throughout the 6 to 24 hour period after patch application, or in patch application Provides a plasma concentration of 1 ng/ml or more than 1 ng/ml (such as 2 ng/ml or more) after the entire 6 to 36 hours; ii. The transdermal composition provides a significantly lower level of sputum than the same HT3 is a plasma antagonist obtained from a standard parenteral dose of a rapid non-successful administration (eg, ϊν, injection); iii. Transdermal composition (eg, granisetron at 15 to 25 mg 5 ) - ΗΤ3 to be applied by the antagonist antagonist) to provide the same ΗΤ3 receptor antagonist (in single or divided doses) for oral administration for 3 days of wearing the patch for 4 days, or for wearing the patch for 4 days. The total daily exposure (as defined by granisetron is 2 mg per day) is 75% or more of the total exposure (as defined by the area under the curve). Iv. Plasma concentration of 5-HT3 receptor antagonist provided by transdermal compositions (such as granisetron) · (i) 6 hours (or 12 hours, or 18 hours) after application to 96 hours after application ( Or 120 hours, or 144 hours), 1 call / ❿丨 to 12 ng / ml (or to 10 ng / ml); (ii) 1 ng / ml according to the situation 18 hours after application to 96 hours after application ( Or 2 ng/ml ' or 3 ng/ml) to 12 ng/ml (or to 10 ng/ml); (iii) 24 hours (or 18 hours) after application to application - after 120 hours for 2 hours Ng/ml (or 3 ng/ml) to 12 ng/ml (or to 1 ng/ml) 实施 [Embodiment] The term "5-HT3 receptor antagonist" is used herein as A hydroxytryptamine receptor antagonist is any type of drug that provides an individual with anti-nausea and anti-vomiting effects. 116268.doc -11- 200820996 Improving or treating the evil of the individual The term "antiemetic" as used herein refers to the prevention of heart and vomiting. The term "anti-emetic effective amount" as used herein means the dose or blood of an antiemetic agent that provides (4) and _ mitigation (including improvement). Content (depending on the context). In the case of blood levels, if the content is properly continued, it provides a relief (including improvement) in body and area. The dosage is the amount that is expected to be effective for the target patient population segment' and may be an amount that is divided by a reasonable number of delivery devices or vehicles. For the purposes of this patent, the enumeration of blood concentrations and other blood kinetic parameters measured by blood measurements are based on the study of the mean of the first-world Western population (18_65). For example, cancer patients are expected to exhibit a higher blood concentration, possibly at a higher concentration of almost 1 > 5 to 3 times. The results may vary depending on the subgroup (such as different races), metabolic profile, other regimens, or the like. The term "individual" as used herein refers to a living mammal and includes (not limited to) humans and other primates, such as livestock and sports animals of cattle, pigs and horses, and pets such as cats and dogs. The term "starting time" as used herein refers to the time during which an individual obtains an antiemetic effective amount in a blood of a subject after application of the transdermal delivery device or composition. As used herein, the term "infiltration enhanced" means that the permeability of the skin to the therapeutic agent in the presence of the penetration enhancer is enhanced by the penetration of the same therapeutic agent by the skin in the absence of the penetration enhancer. 116268.doc - 12-200820996 The term "permeation enhancer" as used herein, is a drug or mixture of agents that is used to increase the permeability of the skin to a therapeutic agent. The term "infiltration enhancement is used herein. "孙社普& t _ 曰 55 refers to the amount of penetration enhancer that provides penetration enhancement throughout the substantive portion of the administration period. The phrase "complete skin area" as used herein refers to intact intact skin or mucosal tissue. Define the area. This area will typically be in the range of about $ coffee 2 to about (10) cm2. The term "salt" as used herein refers to, but is not limited to, a pharmaceutically acceptable #organic or inorganic salt. Typical inorganic salts include functional hydrogen such as hydrogen chloride, carbonates, phosphates, sulfates, hydrogen sulfate. Salts, hydrobromides, sulphates and sulfides. Organic salts include, but are not limited to, acid addition salts, including, for example, acetic acid, mayonic acid, maleic acid, propionic acid, succinic acid, anti Salts of monoterpicic acid and polycarboxylic acid of succinic acid, succinic acid, benzene f acid, cinnamic acid, tartaric acid and the like. ~ The phrase "duration" as used herein refers to about 24 hours or more. Long time, and will generally mean a period of time ranging from about 48 or 72 hours to 168 hours. The term "transdermal administration" as used herein refers to both transdermal and transmucosal administration, that is, a drug such as an antiemetic agent, such as intact skin or intact: non-destructive mucosal tissue of the body surface or membrane. Enter the systemic circulation. : The phrase "percutaneous delivery device wear time" or "slice wear time" as used herein refers to the time interval in which the transdermal delivery device is positioned to remain in the skin or mucosal portion of an individual. The term &quot used herein. "Transdermal absorbability" refers to the ability of a drug to enter the circulatory system through the surface of the body or the sputum, such as intact skin or mucosal tissue, when formulated in a transdermal delivery device of the present invention. The term "acute nausea and vomiting" as used herein refers to an individual's nausea and vomiting that lasts for 24 hours after receiving an chemotherapeutic, radiation or medical treatment. It is also related to postoperative cardiac and sigma vomiting and motion sickness. To the heart and sing. The term "late nausea and vomiting" as used herein relates to nausea and vomiting that occurs within 5 days after an individual receives/sputum radiotherapy, post-operative, or drug treatment. The term "expected nausea and vomiting" as used herein relates to an individual who experiences nausea and vomiting after receiving chemotherapy, radiation, or medication, if the individual desires to be treated as a result of treatment or if the individual experiences nausea and diarrhea as a result of prior treatment. Individual conditions of vomiting. Expected nausea and vomiting can also be experienced after surgery or as a result of motion sickness. The term "skin contact layer" as used herein, is a transdermal delivery device used to contact the skin or mucosal layer. The "flux rate" used in this article is applied to the human cadaver skin. The present invention relates to a method for preventing, ameliorating or treating nausea and vomiting for a sustained period of time by percutaneous orbital reversal with an antiemetic agent. The antiemetic agent used in the present invention is percutaneously administered. In the drug device, the free base is tested as a 5_ΗΤ3 receptor antagonist, and its examples include ondansetron, granise, tropisetron, dolasetron, hydrogen dolasetron, azasetron. , Ramo. ^ ^ ^ JJong, Lai Siqiong, Di Diqiqiong, Itzaqiong, Piperonstron, Remo ^ Yu Zhiyao - JJong, Jurassic and their mixtures. The antagonist will then form a chewable salt or metabolite, as provided by the administration of other administration devices or salt forms of 116268.doc-14, 200820996. The invention also relates to devices and combinations for use in the methods of the invention. The method of the present invention is due to prevention, improvement or treatment due to chemical treatment. Radiation therapy, other medications, motion sickness, hyperemesis or postoperative nausea and vomiting are effective. Because this method involves transdermal administration of antiemetics over several days, it is a continuation of prevention, improvement or treatment. Pain and vomiting are effective over time. Other benefits of the present invention include improved patient compliance, as the method involves placement of a transdermal delivery device, in some embodiments its retention 2, 3, 4, 5, 6, 7 days or longer, protect the patient from the time the device is applied until it is removed or after its removal (such as 6, 9, 2, i 8 or 24 hours or more) Nausea and vomiting; increase the confidence of patients to leave the hospital or doctor's office after chemotherapy, know that the device will prevent or reduce nausea and vomiting. In addition, the device can keep the content of antiemetics in the therapeutic effective range until It is removed. In certain embodiments, the device is worn for 24 hours or more (or 36 hours or more, or 48 hours or more, or 72 hours or more, or 96 hours or more). Long _ time, Or I20 hours or more) after the removal of the blood content (such as 6, 9, 12, 18 or 24 hours or more) is maintained within the therapeutic range of effectiveness. Because the device is controlled The rate delivers the antiemetic agent, so the blood r concentration does not have, for example, a starting spike upon IV administration of the agent; thus the method reduces side effects such as headache and constipation that other administration forms sometimes experience. In certain embodiments The therapeutically effective blood content of the 5-HT3 receptor antagonist is achieved within 24 hours of application, within 18 hours of application, within 12 hours of application, or within 9 hours, or within 8 hours, or within 7 hours, or Within 6 hours 116268.doc -15 - 200820996 reached. This initial phase will vary with the 5-HT3 receptor antagonist and the particular skin contact layer formulation. In certain embodiments, the patch provides 24 hours or more, 48 hours or more, or 72 hours or more, or 96 hours or more, or 120 hours or more after the initial period. Flux rate of 5-ΗΤ3 receptor antagonists at time, or 144 hours or longer, or 168 hours or longer, between ^^/(^2/1ΐΓ or above (such as between 1 and 25 pg/cmVhr) In certain embodiments, the patch provides an initial period of 24 hours or more, 48 hours • or longer, or 72 hours or more, or 96 hours or more, or 120 hours or 5-HT3 receptor antagonists for longer periods of time, or 144 hours or longer, or 168 hours or longer, between 2 pg/cm2/hr or more (such as between 2 and 1 〇pg/cm2/hr) Flux rate. In certain embodiments, the patch is from start time to 24 hours or longer, 48 hours or longer, or 72 hours or longer, or 96 hours or longer, or 120. 10 hours or more, or 144 hours or more, or 168 hours or more, 10 (micrograms per day) or more per day (10 hours or more) The 5-HT3 receptor antagonist of 〇〇〇Pg) is delivered to the individual every day. In some embodiments, the patch is from the start time to 24 hours or longer: between 48 hours or 20 pg per day for a longer time, or 72 hours or longer, or 96 hours r or longer, or 120 hours or longer, or 144 hours or longer, or 168 hours or longer ( Micrograms per day or more, or 50 pg or more per day, 1 week or more per day, 2 weeks or more per day, 500 pg or more per day, 1, 〇〇〇pg or more per day, 2,000 pg or more per day, 5,000 pg or more per day, 6,000 pg per day or 5 ΗΤ3 receptor antagonist on 116268.doc -16-200820996. It is understood that the amount of the attempted delivery will vary with the 5_ΗΤ3 receptor antagonist. The dose of ondansetron can be higher than granisetron. The permeation enhancer used in the device of the present invention can be used to increase the permeability of the skin to the 5-ΗΤ3 receptor antagonist in the skin contact layer. In general, the penetration enhancer The higher the amount, the more the permeability of the skin increases; however, the penetration enhances When the amount of the agent is high, the adhesive can be cold-flowed and the transdermal patch must be removed prematurely. The cold flow is a phenomenon in which the reservoir material flows laterally from under the substrate layer or the like. When the amount of the penetration enhancer is high, the 5-ΗΤ3 receptor antagonist can also crystallize from the matrix, thus limiting its permeability. Therefore, it is desirable to use an amount of the penetration enhancer to reliably enhance the permeability of the drug while limiting or preventing Adhesive cold flow and drug crystallization. In embodiments of the device of the invention, the amount of penetration enhancer is 15% or less by weight of the skin contact layer (or composition) (or about 14% or less, or about 13% or Hereinafter, or about 12% or less, or about 11% or less, or about 10% or less, or about 9% or less) to enhance the permeability of the drug without causing significant adhesive cold flow or drug crystallization. The osmotic increase _ strong agent is present in an amount that enhances penetration. The penetration enhancer can, for example, be about 0.5% or more (or about 1% or more, or about 2 or more, or about 3 Λ or more, or about 4% or more, by weight of the skin contact layer (or composition), Or a dose of about $%: or above, or about 7% or more). The 5-ΗΤ3 receptor antagonist 1 can, for example, vary from one of the lower limits (excluding the limit or exclusion endpoint) to one of the upper limits (except or included). The lower limit is 0.1%, 〇_2%, 1% '2%, 3% or 4% by weight of the skin contact layer or composition. The upper limit is 116268.doc • 17 - 200820996 15%, 14%, 13%, 12%, ι1%, 1%, 9%, 8%, 7% or 6% by weight of the skin contact layer or composition. Moreover, such doses may additionally vary with a particular 5-HT3 receptor antagonist. Embodiments of the device of the present invention are applied to a transdermal patch of an individual's skin or mucosa. The patch has a skin or mucous contact layer (abbreviated as "skin contact layer") laminated or otherwise attached to the carrier layer. Typically, the skin contact layer is covered with a removable release liner to protect the skin contacting surface and keep it clean until it is applied to the skin or mucosa. The carrier layer acts as a carrier for the skin contact layer and provides a barrier layer to prevent the loss of drug into the environment in the skin contact layer. The carrier should be compatible with the adhesive, drug, and penetration enhancer and should have the lowest permeability for any patch component. The carrier can be opaque to protect the matrix patch component from degradation by UV exposure. In addition, the carrier should be capable of bonding and supporting the adhesive layer and should be bendable to accommodate the movement of the patch user. Suitable carrier materials include metal rims, metallized multilayer foils, composite foils or films containing polyesters such as polyethylene terephthalate, polyester or aluminized p〇lyester, polytetrafluoroethylene, poly Ether block decylamine copolymer, polymethyl methacrylate styrene copolymer, polyurethane, polydivinylidene, nylon, polyoxoelastomer, rubber-based polyisobutylene, benzene Ethylene, styrene-butylene and stupid ethylene-isoprene copolymer, polyethylene and polypropylene. For example, a thickness of about 0.0005 to 0.01 Å can be used. The release liner can be made from the same material as the carrier or other suitable release surface coated film. Suitable adhesives include acrylic polymers (for example, polyacrylates including acetoin), polyvinyl acetate, natural and synthetic rubbers, and ethylene 116268.doc -18 - 200820996 olefin-vinyl acetate copolymers. Polyoxyalkylene 'polyurethane, plasticized polyether block amide copolymer, plasticized styrene-butadiene rubber block copolymer and mixtures thereof. For example, the polyacrylate can be 〇111*〇-丁&1<:87-4098, Duro_Tak 87-2052, Duro-Tak 387_2353 (or Duro_Tak 87-2353), Duro-Tak 387-2287 (or Duro-Tak) 87-2287), Duro_Tak 387.2516 (or Duro-Tak 87-2516) (all from National Starch & Chemical, Briden, NJ) or mixtures thereof. For example, the 'styrene-butadiene rubber pressure-sensitive adhesive may be the adhesive Durq_ 10 TAK® 87-6173 (National Starch & Chemical). As already in the art, the adhesive monomer may include a formic acid moiety (or a salt thereof) and/or other functional groups such as a via group. Alternatively, the adhesive monomer may have no functional monomers (e.g., a synthesizer, such as to ensure no substantial ester bond hydrolysis). Adhesive polymers are often crosslinked to some extent, such as by the use of crosslinking monomers. The osmotic resilience agent, if present, is typically a fatty acid ester of a fatty thiol chain of length Cl2_Ci8. The alcohol component of the ester is typically Cl_C6 or C2_c4, such as isopropyl alcohol. In addition to adhesives, antiemetics, and penetration enhancers, the patch may additionally contain various additives. Such additives are generally pharmaceutically acceptable. They are well known in the art of drug delivery technology and, more specifically, are well known in the art of transdermal delivery of music. Non-limiting examples of additive ingredients include diluents, excipients, emollients, plasticizers, skin irritation reducers (which may also include agents that reduce mucosal irritation), carriers, and mixtures of such materials. For example, suitable diluents can include mineral oils, low molecular weight, plasticizers, and the like. A variety of transdermal drug delivery formulations: 116268.doc •19- 200820996 There is a tendency to cause irritation after long-term exposure to the skin or mucous membranes, so the addition of a stimulating agent helps to obtain a better skin or mucosal tolerance group. The subject, however, does not even have a stimulating lowering agent, and some embodiments of the present transdermal compositions are now non-irritating. In the grass, every time you stay; in the K example, the average cumulative stimulus score (as measured in Example 4) is less than 2, 岑4 is at 1 · 5, or less than 1 · 2 ' or lower than 1 · 1. Or less than 1. 〇. For the delivery of antiemetics according to an embodiment of the present invention, a patch device containing a (four) agent, a 5-ΗΤ3 receptor antagonist, and an infiltration enhancer is used to contact the skin or mucous membrane in a selected intact skin or mucosa portion. And being held by the adhesive. In some implementations, the ecdysone composition (before application to a patient) is substantially free of water. In certain embodiments, the transdermal compositions are substantially free of tetraethylene glycol (also known as tetrahydrofuran polyglycol ether). In certain embodiments, the transdermal compositions are substantially free of hydrophilic organic solvents, including substantially free of ethanol, isopropanol, butanol, benzyl alcohol, propylene glycol, glycerol, having a weight of 600 or less. Molecular weight polyethylene glycol, diethylene glycol monoethyl ether, diacetin, hydrazine-methylpyrrolidone, 2-pyrrolidine, dimethyl lime, mercaptomethyl sulfoxide, dioxane, Lactone or a mixture thereof. For the purposes previously described, "a hydrophilic organic solvent, excluding fatty acid esters of a fatty sulfhydryl chain of length Ci2_Cu. It will be appreciated that when the transdermal compositions are substantially free of nominal amounts of components The components may be present in an amount consistent with the process parameters, however, the amount present is not materially affected by certain factors that are important to function, processing, storage, or effective use or sale of the transdermal delivery device. In one embodiment, the invention provides a combination of a 5-HT3 receptor antagonist 116268.doc-20-200820996 by a transdermal administration of a 5-HT3 receptor antagonist (wherein a 5-HT3 receptor antagonist is combined with another antiemetic (eg, a corticosteroid) Administration (eg, oral, injection (such as Iv, IP, IM, sc), transdermal I)) or hunting the same or different 5-HT3 receptor antagonists administered by separate routes of administration to prevent, ameliorate or treat Attributable to chemotherapy, radiation therapy, other medications, motion sickness or post-operative response. Methods of nausea and vomiting. If appropriate for a given dosage form, the second administration form can be administered in a single dose schedule. Known peers vote with 5-HT3 Body antagonists and corticosteroids are used to treat heartbeat and sing. For example, 'US 5,929, (4) (Sanger et al.) discloses a method for treating and/or preventing nausea and vomiting, which comprises granisetron and a steroid (such as a celite). Dexamethasone or a pharmaceutically acceptable salt or ester thereof is administered to a human or animal subject. Sanger et al. additionally disclose that the two components can be administered orally, rectally, parenterally or orally. Oral administration is preferred.

However, as previously described herein, oral administration of an anti-vomiting compound can be irritating and can result in greater discomfort to the patient. In addition, oral, parenteral (e.g., IV, IM), transrectal, and oral administration of the active ingredient produces fluctuations in the plasma levels of the active ingredient. Because of sputum, 5_HT3 receptor antagonist is administered transdermally to prevent, ameliorate or treat nausea and vomiting, and followed by an antiemetic effective amount of an antiemetic corticosteroid which enhances the antiemetic properties of 5-HT3 receptor antagonists. It is advantageous. The administration of an antiemetic corticosteroid can be initiated at the same time as the transdermal administration of the 5-HT3 receptor antagonist, or the SHI receptor antagonist has been administered for 1 hour or longer, 12 hours or longer, or 24 hours. Start after a longer time. Dosing can be kept for 12 hours or longer, or at 116268.doc -21 - 200820996 or longer, 48 hours or longer, 72 hours or longer, 96 hours or longer, 120 hours or Longer time, 144 hours or more, or 168 hours or more. Administration of corticosteroids can occur in a single dose or at an optional interval. Suitable routes of administration include, for example, oral or parenteral routes.

Antiemetic corticosteroids suitable for use in this embodiment of the invention include, for example, dexamethasone, methylprednis®, prednisolone, physiologically acceptable salts or esters thereof, Or a combination thereof. Dexamethasone can be administered in the form of dexamethasone or a pharmaceutically acceptable salt or ester. Suitable salts and esters include acetate, isonicotinic acid ester, phenylpropionate, pivalate, tert-butyl acetate, trioxyundecanoate, disodium meta-benzoate and Disodium phosphate. The dose of steroid (such as dexamethasone) used in the method according to this embodiment of the invention may, for example, be in the range of 〇.5 to 2〇111§ per dosage unit. Unit dose (1) can be administered per day. However, the precise dose will depend on the route of administration and the condition being treated, and it should be understood that the dosage will generally vary depending on the age and weight of the patient and the nature and severity of the condition being treated. Compositions for oral administration of dexamethasone (such as tablets and capsules) can be prepared by conventional equipment and pharmaceutically acceptable excipients, such as binders (eg, pregelatinized corn starch, polyethylene) *Slightly decyl propyl group: cellulose), filler (such as lactose, microcrystalline cellulose or hydrogen phosphate), lubricants (such as magnesium stearate, talc, and others), disintegrant (for example, horse starch starch or sodium starch glycolate) or wet fine, ΔW ^ (for example, sodium lauryl sulfate). Tablets can be coated with a coating which is well known in the art. Oral administration of H6268.doc -22- 200820996 Liquid preparations may be taken, for example, in the form of hydrazine, lysate, syrup or suspension, or as a liquid before use, such as... Anhydrous articles of other suitable vehicle construction are present. The liquid preparations can be prepared by using a fungicide equipment and a pharmaceutically acceptable additive, such as Suspension Ik, L & 心 (heart) such as mountain I alcohol syrup, cellulose derivative or hydrogenated edible fat), γ # such as egg% fat or gum arabic), non-aqueous agents (such as almond oil, oil secret ^ (1) ^ raw oysters, ethyl yeast or branch vegetable oil) and preservatives

(eg methyl or propyl-p-- mei 杂 Miscellaneous A native I or sorbic acid). These preparations are also

It may contain a suitable buffer, this h w M deodorant, a coloring agent and a sweetener. Oral administration of corticosteroids 丨 /, IΜ! ▲ formulated to provide controlled release of the active ingredient. For parenteral injection, the composition may be suitable for rapid injection or continuous administration. The main formulation may be present as a unit dosage form (eg, syringe, ampoule or multiple dose container) with preservative added. The composition may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain, for example, a suspending, stabilizing and/or dispersing agent, and the other active ingredient may be before use. In powder form constructed with a suitable t-agent (eg, sterile pyrogen-free water). In certain embodiments of the invention, the transdermal patch has a skin contact layer comprising: 1 beta antiemetic An effective amount of a free base of a 5_ΗΤ3 receptor antagonist; 1 a penetration enhancing dose of a penetration enhancer selected from the group consisting of isopropyl myristate, isopropyl palmitate or a fatty sulfhydryl chain of fatty thiol chain of length Cl2_Ci8 Group; and

Hi. Adhesive, selected from the group consisting of acrylic poly 116268.doc -23- 200820996 (including polyacrylates of alkyl acrylic polymers), polyvinyl acetate vinegar, natural and synthetic rubber , ethylene-vinyl acetate copolymer, polyoxynitride, polyurethane, plasticized polyether block phthalamide copolymer, plasticized styrene-butadiene rubber block copolymer and mixtures thereof; Transdermal patches are applied to the skin or mucosa of an individual in need of anti-emetic treatment or prevention. After p-passing, an antiemetic effective amount of systemic corticosteroid is administered orally to the individual to enhance the antiemetic effect of the 5-HT3 receptor antagonist. • In another embodiment, the transdermal delivery device is provided in conjunction with a systemic corticosteroid (such as dexamethasone) in the form of a kit. In another embodiment, the present invention provides for the prevention, amelioration (including improvement of subsequent symptoms after prophylactic administration) by transdermal administration of a 5-HT3 receptor antagonist in combination with an oral or injection-administered antiemetic agent. Treatment is due to nausea and vomiting in chemotherapy, radiation therapy, other medications, motion sickness, or post-operative response. The antiemetic agent can be selected from the group consisting of 5_ΗΤ3 receptor antagonists, cannabis test, receptor antagonists, dopamine buckling agents, corticosteroids or any other known antiemetic agent. In certain embodiments, the antiemetic agent is administered to the corpus callosum while the transdermal delivery device is applied to the skin of the individual. In other embodiments, other antiemetic agents are administered at selective timing: to provide a phasing of transdermal administration to the initial delivery of plasma. In one embodiment, the transdermal delivery device has an antiemetic in the form of a kit. In another embodiment, the kit includes a label describing the administration of the antiemetic agent to the individual while the transdermal delivery device is applied to the individual's skin. Examples of the second component include those comprising the same or different antiemetic agents as the first transdermal drug delivery device 116268.doc -24-200820996. For example, the second dosage form can be administered orally, via injection (such as ιν, ιρ, IM, SC), transdermally, orally, rectally, or the like. In another embodiment, the transdermal delivery device is applied to the skin of the individual (e.g., for up to 24 hours) before the individual will experience an event of developing a risk of vomiting. Today's events include the administration of pharmaceutical compounds that are at risk of vomiting, such as chemotherapeutic agents for anti-cancer treatments and surgical or other medical procedures that produce a risk of vomiting. In another embodiment, the transdermal delivery device is 0.5 hours or longer (1 hour or longer, or 2 hours or longer, or 4 hours or longer before the event that the individual will be at risk of developing vomiting) The time, or 8 hours or more, or ίο hours or longer, or 12 hours or more, or 24 hours or more, or 36 hours or more, is applied to the skin of the individual. In other transdermal delivery devices suitable for providing long-term granisetron delivery, the long-term delivery is achieved by the use of a penetration enhancer. The present invention provides a device that includes the enhancer but does not provide long term delivery, (4) avoids the money associated with the enhancer. In some embodiments, the current device based on the standardized area of the device provides a stronger method for providing plasma to the plasma by peak plasma content or auc (area under the curve) compared to the device with the permeation enhancer in all of the corresponding shirts. Leather delivery. In some embodiments, the transfer 24, 48, 72, 96 or 12 after the device is measured as 1.5 times or more 'or < times or more, or 2 times or more. Example 1: Preparation of Adhesive Mixture and Transdermal Delivery Device 116268.doc -25- 200820996 Table 1 e ί»--乂一:-t= :--乙 It ;7-:,观•继' — ^ r " ^ϊ.'· - _ κ --__ Jane-face reading-'two:, one /: two ^ one 兮 γ \ ' ^ film and: only two sides of the brain, ' ~ ^ - --. _ Every 顾顾_· Ί古计的目目: 樨Γ dose two / ^ - _ - two "- - V: il; Ζ; rfl-g £ ::, ... - two 匕 '...d two one - * ft 三二"广ΐ;-- 5 Ο Λ _ ••2~3〆士_嫉嫉; ^mrnmrn^ 乂' - : 1 % Λ -yv ^ , X v _ - _ styrene-butyl Diene Rubber Pressure Sensitive Adhesive 44.04 -- Acrylic Acid Vinyl Acetate Pressure Sensitive Adhesive -- 43.8 Isopropyl octanoate 3.01 4.07 Granisetron 3.05 3.05 Polyester Release Lining 35.8 3 5.8 Polyester Substrate 13.3 13.3 Component Formulation A and Formulation B were prepared using the amounts of the components shown in Table 1 above. The styrene-butadiene rubber pressure sensitive adhesive used in the examples herein was purchased from National Starch and Chemical in Bridgewater, NJ's DURO-TAK® 87-6137 adhesive. The acrylic acid-vinyl acetate pressure sensitive adhesive used in the examples herein was purchased from National Starch and Chemical in Bridgewater, NJ's DURO-ΊΓΑΚ® 87-2516 adhesive. The isopropyl myristate used in the examples herein is of the NF grade. The polyester release liner used in the examples herein was purchased from Loparex, Inc., and the polyester substrate used in the examples herein was purchased from 3M at 2610F. 116268.doc -26- 200820996 Process The granisetron base is dissolved in a suitable solvent such as toluene and mixed with a selective adhesive. This is followed by the addition of isopropyl sulfonate to the mixture to mix the contents until a homogeneous solution is obtained. The homogeneous solution is applied to the desired/thickness on the deuterated surface of the polyester release liner. The coated release liner is then passed through a drying oven until the solvent is evaporated. The dried adhesive coated release liner was removed from the oven and subsequently laminated with a polyester backing layer. The multilayer laminate is cut by stamping into a desired size and geometry unit for delivery of each desired target dose, or it can be rolled into a roll for storage or transport to other locations. The web laminate is then unrollable and cut into units of desired size and geometry by stamping. The stamping units are then placed in respective bags and sealed for later use as a patch. Stimulation Data Formulation A was tested in the Rex Rabbit Stimulation Test, the Guinea Pig Sensitivity Test, the Dog Toxicity Kinetics, and the Human Stimulation Test and found to be non-irritating and non-toxic. Example 2 · Grastron flux test for transdermal drug delivery device Process 2 Cut the hot-separated human cadaver skin to the desired size and adhere it to

Franz diffusion unit. Release the release liner from the above example! The patch produced by the described formulation B is peeled off. Place the patch on the skin and hold the patch together with the skin. The receptor solution was added to the diffusion unit and the set was maintained at 32 °C. Aliquots of the receptor solution were sampled at periodic time points (24 hours, 48 hours, 72 hours, 96 116268.doc -27-200820996 hours and 120 hours). The granisetron concentration in the receptor solution was measured at each time point and the flux rates in Examples A and B were calculated. The information obtained is illustrated in Figure 1. The cumulative delivery of granisetron during the indicated time is also calculated from the concentration of glassum at various time points in the receptor solution and is illustrated in Figure 2. Example 3: Stability of granisetron in an illustrative example Table 2 Composition; :, :Γ调=配物〇〆' Formulation D, 二,,,一^ -1,于,今v _ &gt ; —— "圏_议_____||||||111_||1_|#| 1 round_discussion|1110|1811____11111111111 Π \ ^ - X , * ~ £ dryness % _ dry: degree % ' , ' - ,:' ' Styrene-butadiene rubber pressure sensitive adhesive 49.88% - Acrylic acid-vinyl acetate pressure sensitive adhesive - 43.77% Isopropyl urate - 5.09% Grastron test * 1.02 % 2.04% Polyester Release Lining 35.8% 35.8% Polyester Substrate 13.3% 13.3% The patch was made according to the formulation described in Example 1 above using the formulation shown in Table 2. The granisetron stability in the patch was then tested using the method described below. The patch samples were stored at 50 ° C for up to 2 months. The stability of the product was evaluated by periodically testing the granisetron content and the total amount of impurities using high performance liquid chromatography. The results are shown in Table 3 below. 116268.doc -28 - 200820996 Table 3

The data in Table 3 shows that granisetron is stable in the example composition of the present invention at 50 C, and it is stable until February, and the efficiency of granisetron in the starting time is almost lossless and the formulation is The related impurities are low in quality. Example 4: The sample patch of the in vivo test was made according to the above method using the ingredients shown in Table 4 and the respective amounts to make the 0 ingredient. / Cylinder. : 3⁄4 Prayer ___ " 'C w ^ A Qin-Fun beer · Face Love stepping face difficult granstron test 0.75 2.54 18.75 isopropyl myristate 1.20 4.06 3 〇〇〇 acrylic adhesive 13.05 44.13 326.25 total 15.00 50.73 375.00 polyester substrate 3.91 13.22 97.75 release liner 10.66 36.05 266.50 Total weight 29.57 100.00 739.25 The acrylic adhesive used in Example 4 was purchased from Nati〇nal Starch and Chemical in Bridgewater, NJ, DURO-TAK® 87-2516. Randomized cross-clinical studies were conducted among anonymous individuals who received a transdermal patch or IV solution of glisal. Dispense each 25 cm2 patch to deliver 116 mg.doc -29- 200820996 2 mg of granisetron per day. The 25 cm2 patch of Example 4 was applied to individual skin and left for 96 hours, at which time it was removed. This is followed by a 1 day washout period followed by the same individual receiving a single daily dose of 2 mg daily dose of granules. Individuals receiving the "treatment" in the first phase received a transdermal patch during the cross-treatment. During the 96-hour period of wearing the patch and administering the IV dose, and removing the patch and interrupting the IV administration for an additional 2 days after the cycle Sex measurement of granisetron plasma levels in all tested individuals. , , , σ fruit (Figure 3) indicates that individuals receiving granisetron IV experienced spikes in plasma content of granisetron after administration of rapid IV _ 1, and plasma The content decreased extremely rapidly. On the other hand, the plasma content of granisetron in the individual wearing the patch increased steadily and reached a level of 96 hours after the patch was removed, at which time the plasma content was slowly and steadily decreased while removing the patch. After staying in the therapeutically effective range for more than 24 hours, the typical wear time and the typical plasma content of granisetron in the range of 〇1_25 ng/mi for the other 2 days after the patch removal were observed, so the patch of this example Provides all patch wear time and patch shift _ plasma content within the therapeutic range of more than 24 hours after the removal. Different pharmacokinetic profiles can be seen from different patient subgroups, as from Aya It is not clear whether the results reflect genetic changes, health conditions, eating habits, health status, antagonistic drug therapy or other factors. Example 5: Stimulation test - Patch made according to the formulation of Table 4. The cumulative stimulation study was also tested in 193 healthy volunteers. The active agent was applied to the spine of each healthy volunteer with the placebo patch (Beizhan tablets instead of the active agent) 116268.doc 200820996 Side area. Replace the patches with a new set of patches after 5 days. The application is performed four times in total. The table below shows the single and cumulative stimulus scores for the test. According to the 7-point scale and the descriptive elements The letter grade ranks the patch area. The letter score is converted to a digital score and added to the digital scale for final evaluation. Surprisingly, despite the presence of the active agent, the average cumulative stimulus score of the active patch is still lower. Placebo (0.66 vs. 83). Also as indicated in the table below, in the first application representing typical use, the active patch has a significantly larger number of subjects, and the score is higher. Low consolation. Application ~~~' 1 2 3 4 Conversion score N % N % N % N % A-Grastron TDS 0 139 72.02 115 59.59 105 54.40 80 41.45 1 31 16.06 42 21.76 55 28.50 53 27.46 2 20 10.36 33 17.10 29 15.03 47 24.35 3 3 1.55 3 1.55 4 2.07 13 6.74 193 100.00 193 100.00 193 100.00 193 100.00 B-Placebo 0 80 41.45 98 50.78 91 47.15 74 3834 1 76 39.38 57 29.53 61 31.61 65 33.68 2 30 15.54 29 15.03 31 16.06 40 20.73 3 7 3.63 9 4.66 10 5.18 14 7.25 193 100.00 193 100.00 193 100.00 193 100.00 116268.doc -31- 200820996 Publications and references cited in this monthly book (including but not limited to patents and patent applications) The entire disclosure of the present disclosure is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety herein The present application is hereby incorporated by reference in its entirety in its entirety in its entirety in the the the the the the the the the The present invention has been described with emphasis on certain embodiments, and those skilled in the art will appreciate that the preferred apparatus and method can be varied and the present invention is intended to be practiced otherwise. Accordingly, the present invention includes all modifications within the spirit and scope of the invention as defined by the scope of the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the in vitro flux of granisetron on human cadaver skin using an embodiment of the device of the present invention. Figure 2 is a graph showing the in vitro cumulative transfer of granisetron through human cadaver skin using an embodiment of the device of the present invention. Figure 3 shows a pharmacokinetic profile obtained using the device of the invention. 116268.doc -32-

Claims (1)

200820996 X. Patent Application Range: L · The use of a composition for the preparation of a medicament comprising: 1. an antiemetic effective amount of a 5-HT3 receptor antagonist; a skin contact layer 5 5 wt% to 15 wt% Penetration enhancing amount of penetration enhancer; and iii. Adhesive agent, the music (four) material in the continuous period of cardiac therapy (four) acute, delayed or pre-supplied! · raw area spit' wherein the agent is applied to the individual's intact skin or mucous membrane The moiety lasts for 24 hours or more and has one or more of the following applications: a. The agent provides 5_Ht3 receptor antagonism within a therapeutically effective range from the start time to 12 hours or more after removal of the composition. Plasma concentration; or b. The agent provides 75% or more than 75% of the area under the curve achieved by oral administration of the same 5-HT3 receptor antagonist (single or divided d) for 3 days; or The agent provides 75% or more of the area under the curve achieved by oral administration of the same 5-HT3 receptor antagonist (single or divided dose) for 3 days, and provides an average of less than 2 Cumulative stimulation score; or the agent provides a plasma concentration of 5 ng/ml to 12 ng/ml of 5_HT3 receptor antagonist from 6 hours after administration to 12 hours after administration, and from 24 hours after administration to 96 hours after administration. Called to the plasma concentration of 5-HT3 receptor antagonist in ng/ml; or plasma 116268.doc 200820996 concentration of j ng/ml or higher throughout the 6 to 24 hours after patch administration. 2 · If the request item 1 Xitian, Jin, Yi reverse, remove the agent for 12 hours or more minutes, / two of the agent is applied to the individual's intact skin or mucosa ± from the beginning to the removal The 12-hour or longer day of the second agent provides a plasma concentration of the 5·ΗΤ3 % body antagonist in the beta target. : Use of claim 1 'One of the antiemetic effective amounts of corticosteroids is co-administered with the agent. 4. If the use of sputum i is used, one of the second doses of antiemetic and an antiemetic agent is co-administered with the agent. 5. The use according to claim 4, wherein the co-administrator is a 5-11 receptor antagonist and provides an immediate plasma content of the 5-HT3 receptor antagonist, and the transdermal administration agent and the second dosage form Oral, IV, 1] or sc administration should also be used according to claim 1, wherein the serotonin 5-HT3 receptor antagonist is selected from the group consisting of: Ondansetron , granisetron, tropisetron, dolasetron, hydrodolasetron, azasetron, ramosetron, come Lerisetron, INDisetron, itasetron, palonosetron, lamosetron, allosetron, and mixtures thereof . 7. The use of claim 1, wherein the 5-HT3 receptor antagonist is granisetron 0 116268.doc 200820996 8. The use of the drug according to claim 7, wherein the plasma concentration of the agent is avoided with oral and intravenous Peak and valley values associated with internal administration. 9. The use of claim 7, wherein the agent provides a cumulative stimulus score of less than 2.0. For example, the use of the item 7 is one of an antiemetic effective amount of corticosteroid co-administered with the agent. U' </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> wherein the permeation enhancer is substantially composed of fatty acid esters of 15% or less of a Ci2_Ci8 fat sulfhydryl linkage or a mixture thereof in the weight of the skin contact layer . 12. The use of spray i, wherein the agent is used in combination with the application, in combination with a drug or procedure that produces vomiting or unknown etiology or the risk of expected vomiting of hyperemesis. 13. The use of claim 12, wherein the application occurs prior to the vomiting risk or procedure or before the vomiting due to (1) unknown etiology or (p) vomiting. 14. A composition for use in a meal and an antiemetic comprising a skin contact composition comprising: a skin contact composition comprising: an antiemetic effective amount of a 5_HT3 receptor antagonist; U• accounting for a skin contact layer 0.5% to 15% by weight of a penetration enhancing amount of a penetration enhancer; and iii. an adhesive having one or more of the following applications: a. The composition is from the start time to 12 hours after the removal of the composition or The 5-HT3 receptor antagonist plasma 116268.doc 200820996 concentration is provided for a long period of time within a therapeutically effective range; or b. The composition provides oral administration by the same 5 Qiu receptor antagonist (single or divided dose) 3 75% or more of the area under the curve achieved by the standard of the day; or c. The composition provides a standard for oral administration of the same 5_ΗΤ3 receptor antagonist (single or divided dose) for 3 days. 75% or more of the area under the curve' and provide an average cumulative stimulation score of less than 2; or • d. The composition provides 1 ng/ml to 12 calls/ml from 6 hours after administration to 120 hours after administration. 5-HT3 receptor antagonist plasma concentration, and 24 hours after administration 96 hours after administration to provide 2 ng / m] ^ i2 ng / mi of the 5-HT3 receptor antagonist plasma concentrations; plasma concentrations during the whole 6-24 hours after administration of the patch or e · 1 ng / ml or more of. 15. A device for transdermal administration for preventing, ameliorating or treating nausea and vomiting in an individual, comprising a patch comprising: ❿ a_ - a carrier layer; and b. - a skin contact layer comprising : : i. an antiemetically effective amount of a 5-HT3 receptor antagonist; • a permeation enhancer in an amount of 5 to 15% by weight of the skin contact layer; and iii. an adhesive having One or more of the following applications: a. The composition provides a therapeutically effective range of 5 _HT]receptor antagonist plasma concentrations from the start time to 12 hours after the removal of the composition or 116268.doc 200820996. b. The composition provides 75% or more of the area under the curve achieved by oral administration of the same 5-HT3 receptor antagonist (single or divided dose) for 3 days; or c. Provides 75% or more of the area under the curve achieved by oral administration of the same %hr receptor antagonist (single or divided dose) for 3 days, and provides an average cumulative thorn of 10 below 2 a score; or d. the composition is applied 6 hours after application to 2 after application Plasma concentration of 5·ΗΤ3 receptor antagonist from j ng/ml to 12 ng/ml is provided, and 5 ng/mm ng/ml of 5-HT3 receptor antagonist plasma is provided from 24 hours after administration to 9 施用 after administration. Concentration; or e. plasma concentration of (f) or higher throughout the 6 to 24 hours after patch administration. If the device of claim 15 wherein the device is applied to the intact skin of the individual for a period of 48 hours and subsequently removed, it is provided from the start time to 12 hours or more after removal of the device The plasma concentration of the 5-HT3 receptor antagonist within the effective therapeutic range of the individual. The device of claim 15 wherein the device comprises a free base selected from the group consisting of a free base comprising an antiemetic agent and a dosage form comprising a corticosteroid as claimed in claim 15. A kit comprising the device of claim 18, and a dosage form comprising an antiemetic agent suitable for oral administration or in the form of a primary injection. 2. A kit according to claim 19, wherein the agent of the dosage form is a 5-HT3 receptor antagonist, a nicotinic base, an NK! receptor antagonist, a dopamine antagonist, a corticosteroid or a mixture thereof. 21. The device of claim 15, wherein the 5-HT3 receptor antagonist is selected from the group consisting of: dandans, granisetron, torpexon, dolasetron, hydrogen Dorastron, azasetron, Ramostron, lystron, sedative, itastron, piperonone, ramosetron, errosone and mixtures thereof. The device of claim 15, wherein the 5-HT3 receptor antagonist is a device of claim 15, wherein the permeation enhancer is substantially 15% by weight of the skin contact layer Or a lower length fatty acid ester of a fatty thiol chain of c12-Ci8 or a mixture thereof. 24. The device of claim 15, further comprising a package instruction label describing the application of the 4 device to the individual in combination with one or both of the following: (a) administering to the individual a drug that produces a risk of chewing, Or (b) performing an operation or other medical procedure to the individual at risk of vomiting, or (c) expected vomiting due to unknown etiology. The device of claim 24, wherein the label is described in the administration of the device for vomiting or for administration or for 30 minutes or more. 26. The device of claim 15, wherein the device is applied to a portion of human cadaver skin for a period of 168 hours or more, which provides a flux rate between 1 and 25 pg/cm /hr, The flux rate is maintained between 1 and 25 116268.doc 200820996 Kg/cm2/hr for ι 68 hours or longer. 27. The device of claim 15 wherein when the device is applied to a portion of the individual's intact skin for 168 hours, it is passed between 10 and 1 〇, 〇00 ang/day after the initial period. 5_ΗΤ3 receptor antagonist to the individual. The device of claim 15, wherein when the device is applied to the individual's intact, one part of the skin for a period of 24 hours to 144 hours and then removed, 'from the initial period until 12 hours after removal, A 5-HT3 receptor antagonist between 1 〇 and 10,000 Å/day is delivered to the individual daily. 29. The device of claim 15 which avoids peaks and troughs associated with oral and parenteral administration. 30. The device of claim 15 which provides a cumulative stimulation score of less than 2 当 when administered to an individual. 3 1. A device for transdermal administration to prevent, ameliorate or treat nausea and vomiting in an individual, comprising a patch comprising: a•-carrier layer; and a b--skin contact layer, It comprises: i. an antiemetically effective amount of a 5-HT3 receptor antagonist free base; an iL penetration enhancing dose permeation enhancer, the permeation enhancer being substantially 0.5% or higher by weight of the skin contact layer And 15% or a lower length of a fatty acid ester of a fatty thiol chain of c12-C18 or a mixture thereof; and 111. an adhesive agent selected from the group consisting of: an acrylic polymer (including burning) Acrylic polymer based polyacrylic acid 116268.doc 200820996 ester), polyvinyl acetate, natural and synthetic rubber, ethylene-vinyl acetate copolymer, polyoxyalkylene, polyurethane, plasticized polyether Blocked decylamine copolymers, plasticized styrene-butadiene rubber block copolymers, and mixtures thereof. 116268.doc