Treatment of vomiting and nausea with minimum doses of olanzapine

Abstract

Emesis and nausea are treated with a minimum dose of olanzapine. Compositions, devices and methods for the transdermal administration of olanzapine, and uses thereof, for example, for the treatment of nausea and vomiting.

Description

[0001] This application is a divisional application of the PCT international application PCT / US2021 / 013272 with a priority date of January 13, 2020, an application date of January 13, 2021, an invention name of "Treating vomiting and nausea with minimal doses of olanzapine", which entered the Chinese national stage on June 29, 2022 and has an application number of 202180007819.9.

[0002] Related Applications

[0003] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 960,582 and U.S. Provisional Patent Application No. 62 / 960,611, both filed on January 13, 2020, the entire contents of each of which are hereby incorporated by reference for all purposes. Technical Field

[0004] The subject matter described herein relates to pharmaceutical compositions comprising olanzapine and oleic acid, and their uses, for example, in methods of treating vomiting (emesis) and nausea. background

[0006] Olanzapine (2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine), whose chemical structure is shown below, is an antipsychotic used to treat schizophrenia and bipolar disorder. It is generally classified as an atypical antipsychotic, a newer generation of antipsychotics. It has been approved by the FDA for the treatment of schizophrenia and bipolar mania in tablet form under the brand name ZYPREXA®. Olanzapine has also been studied as an antiemetic, at oral doses of 10 mg and 5 mg a day, generally in combination with one or more additional agents, for example to treat nausea and vomiting following administration of the chemotherapeutic agent cisplatin.

[0007]

[0008] Olanzapine

[0009] Because of the side effects associated with transdermal administration of olanzapine, such as fatigue and sedation, it is important to determine the minimum effective dose of olanzapine and to find improved compositions, devices, patches, systems and methods for transdermal delivery of olanzapine and uses thereof, for example to treat nausea and vomiting.

[0010] Brief description

[0011] The following aspects and embodiments thereof described and illustrated below are intended to be exemplary and illustrative, not limiting in scope.

[0012] In one aspect, a method for reducing vomiting in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0013] In another aspect, a method for reducing the frequency of vomiting (emesis) in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0014] In another aspect, a method for reducing the intensity of vomiting (emesis) in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0015] In each of the foregoing aspects, the amount of olanzapine greater than about 4 mg and less than about 8 mg refers to a daily amount.

[0016] In another aspect, a method of ameliorating nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0017] In another aspect, a method of reducing the frequency of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0018] In another aspect, a method of reducing the intensity of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0019] In another aspect, a method for reducing the frequency of nausea in a subject in need thereof and for reducing the intensity of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0020] In another aspect, a method of treating nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0021] In each of the foregoing aspects, the amount of olanzapine greater than about 2 mg and less than about 6 mg refers to a daily amount.

[0022] In another aspect, a method of preventing chemotherapy-related nausea and / or vomiting in a subject in need thereof is provided. The method comprises administering olanzapine in an amount greater than about 2 mg and less than about 8 mg or instructing administration of olanzapine in an amount greater than about 2 mg and less than about 8 mg, wherein sedation resulting from said administration is substantially unchanged relative to an oral dose of about 2 mg of olanzapine.

[0023] In another aspect, a method of reducing chemotherapy-related nausea and / or vomiting in a subject in need thereof is provided. The method comprises administering olanzapine in an amount greater than about 2 mg and less than about 8 mg or instructing administration of olanzapine in an amount greater than about 2 mg and less than about 8 mg, wherein sedation resulting from said administration is substantially unchanged relative to an oral dose of about 2 mg of olanzapine.

[0024] In each of the foregoing aspects, the amount of olanzapine greater than about 2 mg and less than about 8 mg refers to a daily amount.

[0025] In another aspect, a method of treating nausea and / or vomiting induced by a PARP inhibitor in a subject in need thereof is provided. The method comprises administering a therapeutically effective amount of a PARP inhibitor to a subject in need thereof, administering olanzapine to the subject in an amount greater than about 2 mg and less than about 8 mg, greater than about 4 mg and less than about 8 mg, or greater than about 2 mg and less than about 6 mg per day or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 8 mg, greater than about 4 mg and less than about 8 mg, or greater than about 2 mg and less than about 6 mg per day, wherein the administration of the PARP inhibitor and olanzapine is performed as part of a co-administration regimen. In further embodiments, the co-administration regimen is characterized by administering olanzapine about 1 to about 24 hours prior to the administration of the PARP inhibitor. In other embodiments, the co-administration regimen is characterized by co-administering olanzapine and the PARP inhibitor within a time window of 1 hour or less.

[0026] In another aspect, a composition for transdermal delivery is provided, wherein the composition comprises an adhesive matrix, wherein the adhesive matrix comprises olanzapine, oleic acid, and one or more of a fatty acid, a fatty alcohol, and a fatty ester.

[0027] In another aspect, a composition for transdermal delivery is provided, comprising a binder, olanzapine, oleic acid, and one or more of fatty acids, fatty alcohols, and fatty esters.

[0028] In one embodiment, the composition does not include another acid (organic or inorganic, which is not a polymer or oligomer) having a pKa lower than the pKa of oleic acid. Such another acid includes acetic acid and trifluoroacetic acid.

[0029] In one embodiment, olanzapine and oleic acid form an association complex via proton transfer.

[0030] In one embodiment, the composition further comprises an emulsifier or a penetration enhancer.

[0031] In one embodiment, the emulsifier is a glyceride.

[0032] In one embodiment, the glyceride is selected from glyceryl monooleate, glyceryl monotolate and glyceryl trioleate.

[0033] In one embodiment, the penetration enhancer is selected from dimethyl sulfoxide and n-dodecyl caprolactam (Azone).

[0034] In one embodiment, the molar amount of olanzapine corresponds to a therapeutically effective amount.

[0035] In one embodiment, the therapeutically effective amount is about 2-50 mg of olanzapine.

[0036] In one embodiment, the molar amount of olanzapine is selected to deliver 1-20 mg, such as 1-12 mg olanzapine within 24 hours when the composition is applied to the skin.

[0037] In one embodiment, the molar ratio of oleic acid to olanzapine is about 0.5:1 to 5:1, such as 1:1 to 3:1.

[0038] In one embodiment, the molar ratio of oleic acid to olanzapine is about 1:1 to 3:1.

[0039] In one embodiment, the molar ratio of oleic acid to olanzapine is about 1:1 to 2.7:1.

[0040] In one embodiment, the molar ratio of oleic acid to olanzapine is about 1.2:1 to 2.6:1.

[0041] In one embodiment, the adhesive matrix comprises fatty alcohols and fatty esters.

[0042] In one embodiment, the fatty alcohol is myristyl alcohol.

[0043] In one embodiment, the fatty ester is isopropyl palmitate.

[0044] In one embodiment, the adhesive matrix comprises polyvinylpyrrolidone.

[0045] In one embodiment, the polyvinylpyrrolidone is selected from cross-linked polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone.

[0046] In one embodiment, the copolymer of polyvinyl pyrrolidone is a vinyl pyrrolidone-vinyl acetate copolymer.

[0047] In one embodiment, the adhesive matrix comprises silica.

[0048] In one embodiment, the binder matrix comprises ethylcellulose.

[0049] In one embodiment, the adhesive matrix further comprises a pressure sensitive adhesive.

[0050] In one embodiment, the pressure sensitive adhesive is an acrylate copolymer.

[0051] In another aspect, a composition for transdermal delivery is provided. The composition comprises (i) at least about 40% by weight of a pressure-sensitive adhesive; (ii) about 3-15% by weight of a fatty acid ester; (iii) about 1-20% by weight, such as 5-20% by weight, of olanzapine; and (iv) about 8-25% by weight of oleic acid; and wherein the amount of olanzapine is sufficient to deliver 1-20 mg, such as 1-12 mg of olanzapine within 24 hours when the composition is applied to the skin.

[0052] In one embodiment, the pressure sensitive adhesive is an acrylate copolymer.

[0053] In one embodiment, the fatty acid ester is isopropyl palmitate.

[0054] In one embodiment, the molar ratio of oleic acid to olanzapine is about 1.2:1 to 2.7:1.

[0055] In one embodiment, the composition further comprises one or more of polyvinylpyrrolidone, ethylcellulose, and silicon dioxide.

[0056] In another aspect, a composition for transdermal delivery is provided. The composition consists essentially of: (i) at least about 40% by weight of a pressure-sensitive adhesive; (ii) optionally about 0.1-25%, such as 3-10% by weight, of polyvinyl pyrrolidone, ethyl cellulose or silica or a stabilizer; (iii) about 3-15% by weight of isopropyl palmitate; (iv) about 6-15% by weight of olanzapine; and (v) about 8-20% by weight of oleic acid; and wherein the amount of olanzapine is sufficient to deliver 1-20 mg, such as 1-12 mg of olanzapine within 24 hours when the composition is applied to the skin.

[0057] In another aspect, a transdermal device comprises any of the compositions described herein.

[0058] In another aspect, a transdermal device for systemic delivery of olanzapine is provided. The transdermal device comprises a drug matrix comprising an acrylate polymer binder, a fatty ester, oleic acid, and olanzapine, and wherein the transdermal device, when applied to the skin, (i) delivers an amount of olanzapine effective to relieve nausea, vomiting, or both within a first period of about 4-8 hours, and (ii) delivers an amount of olanzapine effective to relieve nausea, vomiting, or both for a sustained period of about 1-7 days.

[0059] In one embodiment, the transdermal device has a pH of at least about 4 µg / cm2 over a sustained period of time when applied in vitro to (human cadaver) skin. 2 Average flux of hr.

[0060] In one embodiment, the sustained period is about 2-7 days or 2-5 days.

[0061] In one embodiment, the amount of olanzapine delivered during the first period and the ongoing period is at least 3 mg per day.

[0062] In one embodiment, the amount of olanzapine delivered during the first period and the sustained period is about 1-20 mg per day, such as 3-6 mg per day.

[0063] In one embodiment, the drug matrix comprises about 1-20% by weight, such as 5-20% by weight, of olanzapine.

[0064] In another aspect, a transdermal device for delivering olanzapine is provided. The transdermal device comprises a drug matrix comprising an acrylate polymer binder, a fatty ester, oleic acid, and olanzapine, and wherein the transdermal device has a flux profile when applied to the skin in vitro, wherein (i) a maximum flux rate is achieved within about 36-54 hours, (ii) about 65-80% of the maximum flux rate is achieved within about 18-36 hours, and (iii) at least about 3 µg / cm2 is achieved over a period of about 1-7 days. 2Average flux rate in hr.

[0065] In one embodiment, the average flux rate is for a period of about 1-3 days or 1-5 days.

[0066] In one embodiment, the flux profile provides an amount of olanzapine effective to relieve nausea, vomiting, or both over the time period.

[0067] In one embodiment of the transdermal device, olanzapine and oleic acid form an association complex via proton transfer.

[0068] In one embodiment of the transdermal device, the drug matrix further comprises an emulsifier or a penetration enhancer.

[0069] In one embodiment of the transdermal device, the emulsifier is a glyceride.

[0070] In one embodiment of the transdermal device, the glyceride is selected from the group consisting of glyceryl monooleate, glyceryl monotolate, and glyceryl trioleate.

[0071] In one embodiment of the transdermal device, the drug matrix further comprises a fatty alcohol, such as myristyl alcohol.

[0072] In one embodiment of the transdermal device, the penetration enhancer is selected from dimethyl sulfoxide and n-dodecyl caprolactam (Azone).

[0073] In one embodiment of the transdermal device, the molar amount of olanzapine corresponds to a therapeutically effective amount.

[0074] In one embodiment of the transdermal device, the therapeutically effective amount is about 2-50 mg olanzapine.

[0075] In one embodiment of a transdermal device, the molar amount of olanzapine is selected to deliver 1-20 mg, such as 1-12 mg olanzapine within 24 hours when the composition is applied to the skin.

[0076] In one embodiment of the transdermal device, the molar ratio of oleic acid to olanzapine is about 0.5:1 to 5:1, such as 1:1 to 3:1.

[0077] In one embodiment of the transdermal device, the molar ratio of oleic acid to olanzapine is about 1:1 to 3:1.

[0078] In one embodiment of the transdermal device, the molar ratio of oleic acid to olanzapine is about 1:1 to 2.7:1.

[0079] In one embodiment of the transdermal device, the molar ratio of oleic acid to olanzapine is about 1.2:1 to 2.6:1.

[0080] In one embodiment of the transdermal device, the fatty ester is isopropyl palmitate.

[0081] In one embodiment of the transdermal device, the drug matrix further comprises polyvinylpyrrolidone.

[0082] In one embodiment of the transdermal device, the polyvinylpyrrolidone is selected from cross-linked polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone.

[0083] In one embodiment of the transdermal device, the copolymer of polyvinyl pyrrolidone is a vinyl pyrrolidone-vinyl acetate copolymer.

[0084] In one embodiment of the transdermal device, the drug matrix comprises silicon dioxide.

[0085] In one embodiment of the transdermal device, the drug matrix comprises ethylcellulose.

[0086] In one embodiment of the transdermal device, the drug matrix comprises butylated hydroxytoluene (BHT).

[0087] In another aspect, a method for treating nausea and / or vomiting in a subject in need thereof is provided. The method comprises transdermally administering olanzapine to the subject at a dose ranging from 2.0 mg to 6.0 mg per day. The dose can be determined as an "apparent daily dose", which as used in this application refers to the difference between the drug load on the transdermal device before administration and the residual drug on the transdermal device obtained after administration, divided by the number of days the transdermal device is applied to the subject.

[0088] In another aspect, a method of treating nausea and / or vomiting in a subject in need thereof is provided. The method comprises transdermally administering olanzapine to the subject, wherein the method achieves an AUC of olanzapine in the range of 1000 to 2500 μg / L / h.

[0089] In another aspect, a method of treating nausea and / or vomiting in a subject in need thereof is provided. The method comprises transdermally administering olanzapine to the subject, wherein the method achieves a mean Cmax in the range of 5 to 20 μg / L.

[0090] In another aspect, a method of treating nausea and / or vomiting in a subject in need thereof is provided. The method comprises transdermally administering olanzapine to the subject, wherein the method achieves an AUC of olanzapine that is 20% to 80% of the AUC achieved by a standard of care treatment.

[0091] In each of the foregoing aspects, olanzapine is administered in the form of a composition or transdermal device disclosed herein.

[0092] In some embodiments of each of the aforementioned aspects, the nausea and / or vomiting is induced by chemotherapy or a PARP inhibitor, wherein the chemotherapy or the PARP inhibitor may be administered before, after, or simultaneously with the administration of olanzapine. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 Computer modeling showing olanzapine plasma levels over a 7-day dosing interval reaching steady state at daily oral doses of 10 mg, 5 mg, and 2.5 mg, with planned patch plasma level targets to mimic each specific oral dose.

[0095] Figure 2 Shown are olanzapine plasma levels per oral dose obtained in the Phase 1 study.

[0096] Figure 3 Shows the severity of nausea following an apomorphine challenge.

[0097] Figure 4 Nausea scores after apomorphine challenge are shown.

[0098] Figure 5 Shown are sedation scores by dose after taking oral olanzapine on the same day.

[0099] Figure 6 The blood drug target for the olanzapine patch was modeled to simulate a 6 mg daily dose, with error bars for a 4 mg dose.

[0100] Figure 7 In vitro flux of olanzapine through human cadaver skin is shown versus time.

[0101] Figure 8 The plasma levels of olanzapine were compared in three dosing groups: Group 1 - 10 mg olanzapine, orally once daily; Group 2 - 1 x 35 cm 2 Patches containing olanzapine; and Set 3 - 2 x 35 cm 2 A patch containing olanzapine.

[0102] Fig. 9 Shown is the mean cumulative sum of hunger intensity scores for two groups given one or two olanzapine-containing transdermal patches and one group given olanzapine orally in one study.

[0103] Fig.10 Shown is the mean cumulative sum of sedation intensity scores for two groups given one or two olanzapine-containing transdermal patches and one group given olanzapine orally in one study.

[0104] Details

[0105] I. definition

[0106] Various aspects will now be described more fully below. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete and fully convey its scope to those skilled in the art.

[0107] The compositions, devices and methods described herein are not limited to the specific polymers, excipients, cross-linking agents, additives, manufacturing methods or adhesive products described herein. It will be understood that specific terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0108] Where a numerical range is provided, it is intended that each intervening value between the upper and lower limits of that range and any other stated or intervening value in that stated range be included in the disclosure. For example, if a range of 1 μm to 8 μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm and 7 μm, as well as a numerical range greater than or equal to 1 μm and a numerical range less than or equal to 8 μm are also expressly disclosed.

[0109] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more of the same or different polymers, reference to "a solvent" includes a single solvent as well as two or more of the same or different solvents, and so forth.

[0110] The term fatty alcohol refers to compounds having the formula ROH, wherein R is C 2-30 Alkyl or C containing one, two, three or four double bonds 3-30 Alkenyl.

[0111] The term fatty ester refers to an ester produced by the combination of a fatty acid and an alcohol, wherein the fatty acid and the alcohol are of the formula RCOOH and R(OH), respectively. 1-3 A compound wherein R is C 1-30 Alkyl (hydrocarbon) or C containing one, two, three or four double bonds 3-30Exemplary fatty acids include, but are not limited to, capric acid, lauric acid, palmitic acid, stearic acid, elaidic acid (C18:1), gondoic acid (C20:1), erucic acid (C22:1), nervonic acid (C24:1), and ximenic acid (C26:1), hexadecatrienoic acid (16:3), linoleic acid (C18:2), alpha-linolenic acid (C18:3), gamma-linolenic acid (C18:3), calendic acid (C18:3), stearidonic acid (C18:4), mead acid (C20:3), eicosadienoic acid (C20:3), eicosatrienoic acid (C20:3), and eicosatrienoic acid (C20:4). acid) (C20:3), dihomo-γ-linolenic acid (C20:3), arachidonic acid (C20:4) and docosadienoic acid (C22:2).

[0112] As used herein, the term "active agent" refers to a chemical substance or compound suitable for topical or transdermal administration, and which induces a desired effect. The term includes agents that are therapeutically effective, prophylactically effective, and cosmetically effective agents. The terms "active agent," "drug," and "therapeutic agent" are used interchangeably herein.

[0113] As used herein, "adhesive matrix" includes matrices that are made in one piece, such as via solvent casting or extrusion, as well as matrices that are formed in two or more parts that are then pressed or joined together.

[0114] As used herein, "PARP" refers to a group of poly(ADP-ribose) polymerases (PARPs). PARP enzymes are activated by DNA damage, particularly PARP1 and PARP2 enzymes. These enzymes promote DNA repair in pathways involving single-strand breaks (SSBs) and base excision repair (BER). It is generally believed that all PARP inhibitors inhibit both PARP1 and PARP2. Inhibition of the catalytic activity of PARP prevents the formation of poly(ADP-ribose) polymers and blocks the binding of NAD+ at sites of DNA damage, ultimately impairing the ability of cells to overcome DNA-dependent damage.

[0115] As used herein, "PARP inhibitors" refers to chemical compounds that block an enzyme in cells called poly (ADP-ribose) polymerase (PARP). The PARP enzyme helps repair DNA after it has been damaged. DNA damage can be caused by a variety of things including exposure to ultraviolet light, radiation, certain anti-cancer drugs, or other substances in the environment. Many PARP inhibitors share certain structural commonalities and typically contain a benzamide moiety or a benzamide derivative moiety and have found use as chemotherapeutic agents that target cancers that have defective DNA damage repair. Blocking PARP prevents cancer cells from repairing their damaged DNA, causing them to die.

[0116] Examples of PARP inhibitors include, for example, olaparib (AZD-2281, Lynparza® by Astra Zeneca) for breast, ovarian, colorectal or prostate cancer, rucaparib (PF-01367338, Rubraca® by Clovis Oncology) for metastatic breast and ovarian cancer, niraparib (MK-4827, Zejula® by Tesaro) for epithelial ovarian, fallopian tube and primary peritoneal cancer, talazoparib (BMN-673, originally developed by BioMarin Pharmaceutical Inc. and currently developed by Pfizer) for advanced hematological malignancies and for advanced or recurrent solid tumors and for metastatic germline BRCA-mutated breast cancer, veliparib (ABT-888, developed by AbbVie) for advanced ovarian cancer, triple-negative breast cancer, non-small cell lung cancer (NSCLC) and metastatic melanoma, CEPHARO® for non-small cell lung cancer (NSCLC) 9722, such as E7016 for melanoma (developed by Eisai), BGB-290, iniparib, 3-aminobenzamide (3-AB, a prototype PARP inhibitor), PJ-34, Nu1085, INO-1001, CEP-8933 / CEP-9722, and nicotinamide.

[0117] As used herein, the term "skin" refers to skin or mucosal tissue, including the inner surface of body cavities having a mucosal lining. The term "skin" should be interpreted to include "mucosal tissue" and vice versa.

[0118] As used herein, the term "therapeutically effective amount" refers to an amount of an active agent that is non-toxic but sufficient to provide the desired therapeutic effect. An "effective" amount will vary from subject to subject depending on the age and general condition of the individual, the specific active agent or agents, and similar factors known to those skilled in the art.

[0119] As used herein, the term "transdermal" or "transdermal delivery" refers to administering an active agent to the body surface of a subject such that the agent passes through the body surface (e.g., through the skin) and enters the bloodstream of the subject. The term "transdermal" is intended to include transmucosal administration, i.e., administering a drug to the mucosal (e.g., sublingual, oral, vaginal, rectal, etc.) surface of a subject such that the agent passes through the mucosal tissue and enters the bloodstream of the subject.

[0120] II. Treatment

[0121] Olanzapine is an antipsychotic used to treat schizophrenia and bipolar disorder. It is generally classified as an atypical antipsychotic, a newer generation of antipsychotics. Olanzapine has also been studied as an antiemetic, at oral doses of 10 mg and 5 mg a day, generally in combination with one or more additional agents, for example to treat nausea and vomiting following administration of the chemotherapeutic agent cisplatin.

[0122] Described herein are methods of treating vomiting (emesis) and / or nausea by administering or indicating the administration of olanzapine.

[0123] A. Olanzapine in an amount greater than about 4 mg and less than about 8 mg

[0124] In one aspect, a method for reducing vomiting in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0125] In another aspect, a method for reducing the frequency of vomiting (emesis) in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0126] In another aspect, a method for reducing the intensity of vomiting (emesis) in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 4 mg and less than about 8 mg or instructing the subject to administer olanzapine in an amount greater than about 4 mg and less than about 8 mg.

[0127] In each of the foregoing aspects, the administering or indicated administering may be oral administration or transdermal administration.

[0128] In some embodiments, transdermal administration i) provides an olanzapine plasma concentration of at least about 7 µg / L 24 hours after administration, ii) provides an olanzapine plasma concentration of greater than about 11 µg / L 48 hours after administration, and iii) provides an olanzapine plasma concentration of greater than about 15 µg / L 60 hours after administration.

[0129] In some embodiments, transdermal administration provides an olanzapine plasma concentration of at least about 6 μg / L 24 hours after administration, and achieves an olanzapine steady-state plasma concentration of about 16-24 μg / L over a period of time beginning at 24 hours after administration and continuing for at least about 2 days.

[0130] In some embodiments, transdermal administration provides an olanzapine plasma concentration of at least about 8 μg / L 24 hours after administration, and achieves an olanzapine steady-state plasma concentration of about 18-22 μg / L over a period of time beginning at 24 hours after administration and continuing for at least about 2 days.

[0131] In some embodiments, the period of steady state plasma concentration achieved with transdermal administration lasts for at least about 3, 4, 5, or 6 days.

[0132] In each of the foregoing aspects and embodiments, the emesis may be associated with chemotherapy.

[0133] In each of the foregoing aspects and embodiments, sedation resulting from the administration is substantially unchanged relative to an oral dose of about 2 mg of olanzapine.

[0134] B. Olanzapine in an amount greater than about 2 mg and less than about 6 mg

[0135] In one aspect, a method of improving nausea in a subject in need thereof is provided. The method comprises administering olanzapine in an amount greater than about 2 mg and less than about 6 mg or instructing to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg. In some embodiments, nausea is improved by reducing the frequency of nausea and / or reducing the intensity of nausea.

[0136] In another aspect, a method of reducing the frequency of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0137] In another aspect, a method of reducing the intensity of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0138] In another aspect, a method for reducing the frequency of nausea in a subject in need thereof and for reducing the intensity of nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0139] In another aspect, a method of treating nausea in a subject in need thereof is provided. The method comprises administering olanzapine to the subject in an amount greater than about 2 mg and less than about 6 mg or instructing the subject to administer olanzapine in an amount greater than about 2 mg and less than about 6 mg.

[0140] In each of the foregoing aspects or embodiments, the administering or indicating administration may be oral administration or transdermal administration.

[0141] In some embodiments, transdermal administration provides an olanzapine plasma concentration of at least about 3 μg / L 24 hours after administration, and achieves an olanzapine steady-state plasma concentration of about 10-16 μg / L over a period of time beginning at 24 hours after administration and continuing for at least about 2 days.

[0142] In some embodiments, transdermal administration provides an olanzapine plasma concentration of at least about 4 μg / L 24 hours after administration, and achieves an olanzapine steady-state plasma concentration of at least about 11 μg / L over a period of at least about 2 days beginning at 24 hours after administration.

[0143] In some embodiments, transdermal administration provides an olanzapine plasma concentration of at least about 5 μg / L 24 hours after administration, and achieves an olanzapine steady-state plasma concentration of at least about 13 μg / L beginning at 24 hours after administration and continuing for a period of at least about 2 days.

[0144] In some embodiments, the period of steady state plasma concentration achieved with transdermal administration lasts for at least about 3, 4, 5, or 6 days.

[0145] In each of the foregoing aspects or embodiments, the nausea may be chronic nausea or acute nausea.

[0146] In each of the foregoing aspects or embodiments, the nausea may be associated with chemotherapy.

[0147] In each of the foregoing aspects or embodiments, sedation resulting from the administration is not substantially altered relative to an olanzapine dose of about 2 mg.

[0148] C. Olanzapine in an amount greater than about 2 mg and less than about 8 mg

[0149] In one aspect, a method of preventing chemotherapy-related nausea and vomiting in a subject in need thereof is provided. The method comprises administering olanzapine in an amount greater than about 2 mg and less than about 8 mg or instructing to administer olanzapine in an amount greater than about 2 mg and less than about 8 mg, wherein sedation resulting from the administration is substantially unchanged relative to an oral dose of about 2 mg of olanzapine.

[0150] In another aspect, a method of reducing chemotherapy-related nausea and vomiting in a subject in need thereof is provided. The method comprises administering olanzapine in an amount greater than about 2 mg and less than about 8 mg or instructing administration of olanzapine in an amount greater than about 2 mg and less than about 8 mg, wherein sedation resulting from the administration is not substantially altered relative to an oral dose of about 2 mg of olanzapine.

[0151] In each of the foregoing aspects, the administering or indicated administering may be oral administration or transdermal administration.

[0152] In each of the foregoing aspects and embodiments, the method reduces nausea intensity, vomiting frequency, or both.

[0153] In each of the foregoing aspects and embodiments, the administration prevents and / or reduces nausea and vomiting during the acute phase during the first 24 hours after chemotherapy and / or continuing the first 24 hours after chemotherapy.

[0154] In each of the foregoing aspects and embodiments, the method reduces nausea intensity, vomiting frequency, or both during a delay period of 24-120 hours following chemotherapy.

[0155] In each of the foregoing aspects and embodiments, the chemotherapy may be a highly emetogenic cancer chemotherapy.

[0156] In each of the foregoing aspects and embodiments, the chemotherapy can be an initially and repeatedly administered moderately emetogenic cancer chemotherapy.

[0157] D. Transdermal treatment methods

[0158] In one aspect, the method comprises administering olanzapine to a subject transdermally at a dose ranging from 2.0 mg to 6.0 mg per day or instructing to administer olanzapine to a subject transdermally at a dose ranging from 2.0 mg to 6.0 mg per day. The transdermal dose can be determined as an "apparent daily dose", which as used in this application refers to the difference between the drug load on the transdermal device before administration and the residual drug on the transdermal device obtained after administration, divided by the number of days the transdermal device is applied to the subject. In some embodiments, the apparent dose may be 3.0 to 5.1 mg, 3.1 to 5.0 mg, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0 mg per day.

[0159] In another aspect, the method comprises administering olanzapine to a subject transdermally or instructing the subject to administer olanzapine transdermally, wherein the method achieves an AUC of olanzapine in the range of 1000 to 2500 μg / L / h. In some embodiments, the AUC of olanzapine is 1200 to 2200 μg / L / h, 1400 to 2200 μg / L / h, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, or 2200 μg / L / h.

[0160] In another aspect, the method comprises administering olanzapine transdermally to a subject or instructs a subject to administer olanzapine transdermally, wherein the method achieves a mean Cmax in the range of 5 to 20 μg / L. In some embodiments, the mean Cmax ranges from 5 to 15 μg / L, 8 to 15 μg / L, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 μg / L.

[0161] In another aspect, the method comprises administering olanzapine transdermally to a subject or instructing the subject to administer olanzapine transdermally, wherein the method achieves an AUC of olanzapine that is 20% to 80% of the AUC achieved by the standard of care treatment. In some embodiments, the AUC ranges from 25% to 70%, 25% to 60%, or 25% to 50%.

[0162] In some embodiments of each of the aforementioned aspects, the subject is less hungry and less sedated compared to a subject undergoing standard of care treatment.As used herein, standard of care treatment includes a daily oral dose of 5 or 10 mg olanzapine.

[0163] In some embodiments of each of the aforementioned aspects, the nausea and / or vomiting is induced by chemotherapy or a PARP inhibitor, wherein the chemotherapy or the PARP inhibitor may be administered before, after, or simultaneously with the administration of olanzapine.

[0164] In some embodiments, olanzapine is administered about 1 to about 24 hours prior to administration of the PARP inhibitor. In some embodiments, olanzapine and the PARP inhibitor are administered within a time window of 1 hour or less.

[0165] In each of the foregoing aspects of the method, olanzapine is administered in the form of a composition or transdermal device disclosed herein.

[0166] Example 5 describes a comparative bioavailability (BA) study in healthy female volunteers to characterize the systemic exposure profile of olanzapine administered for 7 days using two different sized transdermal devices as described herein, compared to the systemic exposure profile of olanzapine for a 7-day regimen of 10 mg / day of olanzapine once daily. The computer-modeled systemic exposure is illustrated by the AUC0-∞ of the transdermal devices used in the studies herein, which is less than the 10 mg oral dose of olanzapine. See Figure 8 .

[0167] Example 5 also describes hunger scores and sedation scores for each treatment group. Cumulative sums of intensity scores for diary responses to hunger questions were scored twice daily, based on an ordinal scale of 0-10 (maximum cumulative sum of intensity scores is 250, minimum is 0). The cumulative sum of hunger intensity scores was significantly lower with transdermal delivery than with oral administration (P<0.008), while hunger scores did not differ between cohorts 2 and 3 (P=0.19). These results appeared to be independent of dose, as the arithmetic values ​​of hunger scores were higher in the lower dose patch cohort. See Fig. 9 The cumulative sum of intensity scores for diary responses to the fatigue / sedation questions asked twice daily was scored on an ordinal scale of 0-10 (maximum cumulative sum of intensity scores was 250 and minimum was 0). The arithmetic value of the cumulative sum of sedation intensity was lower with transdermal delivery compared with oral administration (P = 0.09). Fig.10 .

[0168] III. Compositions comprising olanzapine

[0169] In the methods described herein, olanzapine may be administered in a formulation suitable for oral or transdermal administration.

[0170] A. Compositions for oral administration of olanzapine

[0171] The oral formulation comprises olanzapine and a pharmaceutically acceptable carrier. The oral formulation may be a tablet comprising 2 mg, 4 mg, 6 mg or 8 mg of olanzapine. The tablet may further comprise a pharmaceutically acceptable carrier comprising carnauba wax, crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate and microcrystalline cellulose.

[0172] In the methods described herein, olanzapine may also be administered in the form of a composition suitable for transdermal delivery. The transdermal composition comprises an adhesive matrix comprising olanzapine, oleic acid and one or more of a fatty acid, a fatty alcohol and a fatty ester.

[0173] In some embodiments, the transdermal composition does not include another acid (organic or inorganic, which is not a polymer or oligomer) having a pKa lower than the pKa of oleic acid. Such another acid includes acetic acid and trifluoroacetic acid.

[0174] In some embodiments, olanzapine and oleic acid form an association complex via proton transfer.

[0175] In some embodiments, the composition further comprises an emulsifier or a penetration enhancer.

[0176] In some embodiments, the emulsifier is a glyceride. In some embodiments, the glyceride is selected from monoolein, monotol, and triolein.

[0177] In some embodiments, the penetration enhancer is selected from dimethyl sulfoxide and n-dodecyl caprolactam (Azone).

[0178] In some embodiments, the molar amount of olanzapine corresponds to a therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 2-50 mg of olanzapine.

[0179] In some embodiments, the molar amount of olanzapine is selected to deliver 1-20 mg, such as 1-12 mg, of olanzapine within 24 hours when the composition is applied to the skin.

[0180] In some embodiments, the molar ratio of oleic acid to olanzapine is about 0.5: 1 to 5: 1, such as 1: 1 to 3: 1. In some embodiments, the molar ratio of oleic acid to olanzapine is about 1: 1 to 2.7: 1. In some embodiments, the molar ratio of oleic acid to olanzapine is about 1.2: 1 to 2.6: 1.

[0181] In some embodiments, the adhesive matrix comprises fatty alcohols and fatty esters.

[0182] In some embodiments, the fatty alcohol is myristyl alcohol.In some embodiments, the fatty ester is isopropyl palmitate.

[0183] In some embodiments, the adhesive matrix comprises polyvinylpyrrolidone.

[0184] In some embodiments, the polyvinyl pyrrolidone is selected from cross-linked polyvinyl pyrrolidone and copolymers of polyvinyl pyrrolidone. In some embodiments, the copolymer of polyvinyl pyrrolidone is a vinyl pyrrolidone-vinyl acetate copolymer.

[0185] In some embodiments, the adhesive matrix comprises silicon dioxide. In some embodiments, the adhesive matrix comprises ethyl cellulose. In some embodiments, the adhesive matrix further comprises a pressure sensitive adhesive. In some embodiments, the pressure sensitive adhesive is an acrylate copolymer.

[0186] In the methods described herein, olanzapine may also be administered transdermally in the form of a composition comprising: (i) at least about 40% by weight of a pressure-sensitive adhesive; (ii) about 3-15% by weight of a fatty acid ester; (iii) about 1-20% by weight, such as 5-20% by weight of olanzapine; and (iv) about 8-25% by weight of oleic acid; and wherein the amount of olanzapine is sufficient to deliver 1-20 mg, such as 1-12 mg of olanzapine within 24 hours when the composition is applied to the skin. In some embodiments, olanzapine may be administered in the form of a transdermal patch comprising the above composition.

[0187] In some embodiments, the pressure sensitive adhesive is an acrylate copolymer.

[0188] In some embodiments, the fatty acid ester is isopropyl palmitate.

[0189] In some embodiments, the molar ratio of oleic acid to olanzapine is about 1.2:1 to 2.7:1.

[0190] In some embodiments, the composition further comprises one or more of polyvinylpyrrolidone, ethylcellulose, and silicon dioxide.

[0191] In the methods described herein, olanzapine can also be administered transdermally in the form of a composition consisting essentially of: (i) at least about 40% by weight of a pressure-sensitive adhesive; (ii) optionally about 0.1-25% by weight, such as 3-10% by weight, of polyvinyl pyrrolidone, ethyl cellulose, or silicon dioxide; (iii) about 3-15% by weight of isopropyl palmitate; (iv) about 6-15% by weight of olanzapine; and (v) about 8-20% by weight of oleic acid; and wherein the amount of olanzapine is sufficient to deliver 1-20 mg, such as 1-12 mg of olanzapine within 24 hours when the composition is applied to the skin. In other words, olanzapine can be administered in the form of a transdermal patch. In some embodiments, olanzapine can be administered in the form of a transdermal patch comprising the above composition.

[0192] In the methods described herein, olanzapine can also be administered transdermally in the form of a composition consisting essentially of: (i) about 56% by weight of a pressure-sensitive adhesive; (ii) about 10% by weight of ethylcellulose; (iii) about 10% by weight of isopropyl palmitate; (iv) about 8% by weight of olanzapine; (v) about 16% by weight of oleic acid; and (vi) about 0.5% by weight of butylated hydroxytoluene. In some embodiments, olanzapine can be administered in the form of a transdermal patch comprising the above composition.

[0193] In some embodiments, the amount of olanzapine in the transdermal patch or formulation is sufficient to deliver olanzapine whose AUC is 1% to 80%, 10% to 80%, 20% to 80%, 30% to 80%, or 40% to 80% of the exposure obtained by the standard of care treatment. The standard of care treatment can be 2.5 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, or 25 mg of the olanzapine compound via oral administration once daily or once every two days.

[0194] In some embodiments, the amount of olanzapine in the transdermal patch or formulation is sufficient to provide a plasma level of olanzapine that simulates an oral dose of 4 mg, 5 mg, 6 mg, 8 mg, or 10 mg per day. Figure 1 and the disclosure related to Example 1.

[0195] As described herein, can be for example, but not limited to by pouring composition solvent on backing layer or release liner, and sandwiched between the two to form patch.Many materials suitable for backing layer and release liner are known, and comprise polymer film, fabric and nonwoven material, for example, prevent external moisture from entering the continuous film of adhesive layer in activities such as showering or bathing.Backing and release liner should preferably be occluded, or substantially occluded.Such film includes but is not limited to polypropylene, polyvinyl chloride, cellulose acetate, ethyl cellulose, polyurethane, polyethylene and polyester.Optionally, backing can be a layered composite material, it comprises metal, for example but not limited to aluminum, for example polyethylene terephthalate-aluminum-polyethylene composite material, or for example polyester and ethylene-vinyl acetate copolymer heat seal layer (particularly as backing), or for example the polyester film (particularly as release liner) of fluoropolymer coating. Suitable backing layers include, but are not limited to, Scotchpak 1006, 1022, 1109, 9723, 9732, 9733 (3M Company); suitable release liners include, but are not limited to, Scotchpak 1006, 9709, 9741, 9742, 9744, and 9755 (3M Company). The thickness of the backing layer and the release liner is generally greater than 10 μm and less than 200 μm, typically about 20 μm to about 120 μm, for example, about 40 μm to about 100 μm.

[0196] Coating formulations for patches may contain volatile solvents that are removed from the patch matrix as it dries; such volatile solvents include: methanol, ethanol, propanol, 1-propanol, 2-propanol, ethyl acetate, acetone, methylene chloride, chloroform, toluene, and IPA.

[0197] Transdermal compositions, devices and / or systems described herein may be designed for long-term use and / or continuous administration of olanzapine. It will be appreciated that the total dose of olanzapine for each transdermal device will be determined by the size of the device and / or the olanzapine load in the adhesive matrix. In some embodiments, the application period of the transdermal device is about 1-10 days, 1-7 days, 1-5 days, 1-2 days, 1-3 days, 1-4 days, 3-10 days, 3-7 days, 3-5 days, 5-10 days and 5-7 days, including endpoint values. In some embodiments, olanzapine is released from the adhesive matrix in a continuous and / or sustained release manner during the application period.

[0198] The usage of the described percutaneous and topical systems described herein will have different dosages depending on the mode of administration, the specific illness to be treated and the desired effect. The dosage can be percutaneous application once a day, continuing 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days, or longer. Alternatively, several times a day can be used, continuing 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days, or longer. Alternatively, percutaneous application can be once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days.

[0199] In some embodiments, the transdermal or topical formulation provides a predetermined delivery rate of the active component of the transdermal patch within a predetermined time period. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks or 15 days. In some further embodiments, the predetermined rate is a constant rate.

[0200] In yet further embodiments, the transdermal or topical formulations described herein provide a steady absorption rate of the active ingredient of the transdermal patch to the patient over a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days. In some further embodiments, the predetermined rate is a constant rate.

[0201] In yet further embodiments, the transdermal or topical formulations described herein provide a predetermined serum level range of the active component of the transdermal patch in a patient within a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0202] In yet further embodiments, the transdermal or topical formulations described herein provide a therapeutic range of plasma concentrations of the active components of the transdermal patch in a patient over a predetermined period of time. In some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0203] In yet further embodiments, the percutaneous or topical formulations described herein achieve a reduced variability in the dosage of the active ingredient in a patient over a predetermined period of time. In some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0204] In some embodiments, the transdermal or topical formulations provided herein can be administered at a dosage regimen such as once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every 8 to about 13 days, once every two weeks, once every 15 to about 30 days.

[0205] In yet further embodiments, a pharmacokinetic assessment is performed on a blood sample of a subject treated with a transdermal delivery system as described herein. The transdermal formulations described herein are adjusted in response to the pharmacokinetic assessment. For example, the dosage can be adjusted so that a smaller patch, a larger patch, or multiple transdermal patches are administered to the subject, or a patch with a greater or lesser dose of the active ingredient can be administered. In some embodiments, formulations of various dosage strengths and patch sizes will be available to achieve the best therapeutic outcome based on the requirements of the subject.

[0206] Examples 2-5 disclose transdermal compositions that can be used in the methods disclosed herein.

[0207] Example 2 describes the preparation of olanzapine transdermal patches labeled OLA 1, OLA 2, OLA 3, OLA 4, OLA 5, OLA 6, and OLA 7.

[0208] In the permeation studies described in Example 3, using OLA 1 as an example, the flux increased rapidly, reaching 72% of the maximum value within the first 24 hours and reaching a maximum value at about 48 hours. After this, the transdermal flux gradually decreased at a steady rate, reaching about 61% of the maximum value at 168 hours. The average flux from 24 hours to 168 hours for 11 donors (50 replicates) was 4 ± 1.3 ug / hr / cm 2 .See Figure 7 .

[0209] Example 4 compares the cold flow properties of two compositions. The results show that the cold flow of the composition containing an additional polymer, such as ethylcellulose, is reduced.

[0210] Example 5 describes a comparative bioavailability (BA) study in healthy female volunteers to characterize the systemic exposure profiles of olanzapine administered for 7 days using two different sized transdermal devices as described herein, compared to the systemic exposure profiles of olanzapine administered once daily for 7 days at a 10 mg / day regimen. The computer modeled systemic exposures were illustrated by the AUC0-∞ of the transdermal devices used in the studies herein, which were doses less than the 10 mg oral dose of olanzapine. See Figure 8 .

[0211] Example 5 also describes hunger scores and sedation scores for each treatment group. Cumulative sums of intensity scores for diary responses to hunger questions were scored twice daily, based on an ordinal scale of 0-10 (maximum cumulative sum of intensity scores is 250, minimum is 0). The cumulative sum of hunger intensity scores was significantly lower with transdermal delivery than with oral administration (P<0.008), while hunger scores did not differ between cohorts 2 and 3 (P=0.19). These results appeared to be independent of dose, as the arithmetic values ​​of hunger scores were higher in the lower dose patch cohort. See Fig. 9 The cumulative sum of intensity scores for diary responses to the fatigue / sedation questions asked twice daily was scored on an ordinal scale of 0-10 (maximum cumulative sum of intensity scores was 250 and minimum was 0). The arithmetic value of the cumulative sum of sedation intensity scores was lower with transdermal delivery compared with oral administration (P = 0.09). Fig.10 .

[0212] B. Compositions for transdermal delivery of olanzapine

[0213] In some aspects, compositions are provided that include an adhesive matrix that includes olanzapine, oleic acid, and one or more of a fatty acid, a fatty alcohol, and a fatty ester.

[0214] In some embodiments, the adhesive matrix comprises a pressure sensitive adhesive.

[0215] Pressure sensitive adhesives include, but are not limited to, one or more of the following: Duro-Tak® 87-2196, Duro-Tak® 387-2051, Duro-Tak® 87-2194, Duro-Tak® 87-235A, Duro-Tak® 387-2054, Duro-Tak® 87-900A, Duro-Tak® 87-9301, Duro-Tak® 387-2516, Duro-Tak® 387-2510, Duro-Tak® 280-2516, Duro-Tak® 87-4098, GELVA GMS® 788, GELVA GMS® 9073, Duro-Tak® 387-2353, Duro-Tak® 87-2074, Duro-Tak® 387-2287, Duro-Tak® 87-2852, Duro-Tak® 87-2054, GELVA® 737, Duro-Tak® 80-1196, Duro-Tak® 87-2070, Duro-Tak® 87-2979, Duro-Tak® 87-2888 and Duro-Tak® 87-2296. Exemplary silicone PSAs include, but are not limited to, one or more of the following: BIO-PSA® 7-4401, BIO-PSA® 7-4402, BIO-PSA® 7-4501, BIO-PSA® 7-4502, BIO-PSA® 7-4601, BIO-PSA® 7-4602 (Dow Corning®, Dow Chemicals, Midland, Michigan), SRS7-4502, SRS7-4501, SRS7-4602, SRS7-4602, amine-compatible silicone PSAs, rubber PSAs. Exemplary amine compatible silicone PSAs include, but are not limited to, one or more of the following: BIO-PSA® 7-4101, BIO-PSA® 7-4102, BIO-PSA® 7-4201, BIO-PSA® 7-4202, BIO-PSA® 7-4301, BIO-PSA® 7-4302. Exemplary rubber PSAs include, but are not limited to, one or more of the following: low molecular weight polyisobutylene, medium molecular weight polyisobutylene, high molecular weight polyisobutylene (including, for example, polyisobutylene 1100000 MW, 35000 MW, 800000 MW, 55000 MW, 2300 MW, or mixtures thereof), Duro-Tak® 87-6908, and polyisobutylene / polybutylene adhesives.

[0216] Adhesives that may therefore be particularly suitable for the drug-in-adhesive patches and formulations described herein include, but are not limited to, acrylate copolymers, such as high molecular weight or highly cross-linked adhesives, typically available as self-cross-linking acrylic adhesives. Examples of such adhesives include, but are not limited to, Duro-Tak® 387-2516, Duro-Tak® 387-2051, Duro-Tak® 87-2852, Duro-Tak® 87-2194, and Duro-Tak® 87-2852 self-crosslinking acrylic adhesives (available from National Starch and Chemical Company, 10 Finderne Ave, PO Box 6500, Bridgewater, NJ 08807-0500) and GELVA® 737, GELVA® 2655, and GELVA® 1753 self-crosslinking acrylic adhesives (Monsanto's Chemical Group, 730 Worcester Street, Springfield, Mass. 01151).

[0217] Duro-Tak® 387-2516 is an acrylic copolymer adhesive containing EHA, vinyl acetate and hydroxyethyl acrylate, and is commercially available from National Starch and Chemical Co, Bridgewater, NJ. Alternatively, the adhesive can be an acrylic adhesive having one or more hydroxyl functional groups and carboxyl functional groups. Still alternatively, the acrylic adhesive can be a "non-functional" adhesive that does not contain functional groups (e.g., lacking -OH groups, -COOH groups, or both). Preferably, the acrylic adhesive can be a pressure sensitive adhesive (PSA).

[0218] In some embodiments, the adhesive matrix comprises a fatty ester. In some embodiments, the adhesive matrix comprises a fatty alcohol and a fatty ester.

[0219] The fatty alcohol may include, but is not limited to, one or more saturated, monounsaturated or polyunsaturated fatty alcohols; it may include, but is not limited to, one or more of the following: butanol (C4), butyl alcohol (C4), tert-butyl alcohol (C4), tert-amyl alcohol (C5), 3-methyl-3-pentanol (C6), octanol (C8), nonanol (C9), decanol (C10), undecanol (C11), lauryl alcohol (C12), tridecanol (C13), myristyl alcohol (C14), pentadecanol (C15), hexadecanol (C16), palmitoleyl alcohol (cis-9-hexadecene-1-ol, C17), 1,2-dimethyl-1,3-pentanecarboxylic acid (C18), 1,2-dimethyl-1,3-pentanecarboxylic acid (C20), 1,2-dimethyl-1,3-pentanecarboxylic acid (C30), 1,2-dimethyl-1,3-pentanecarboxylic acid (C31), 1,2-dimethyl-1,3-pentanecarboxylic acid (C32), 1,2-dimethyl-1,3-pentanecarboxylic acid (C33), 1,2-dimethyl-1,3-pentanecarboxylic acid (C34), 1,2-dimethyl-1,3-pentanecarboxylic acid (C35), 1,2-dimethyl-1,3-pentanecarboxylic acid (C36), 1,2-dimethyl-1,3-pentanecarboxylic acid (C37), 1,2-dimethyl-1,3-pentanecarboxylic acid (C38), 1,2-dimethyl-1,3-pentanecarboxylic acid (C39), 1,2-dimethyl-1,3-pentanecarboxylic acid 16 H 32O), heptadecanol (1-n-heptadecanol, C 17 H 36 O), stearyl alcohol (C18:0), oleyl alcohol (C 18 H 36 O, C18:1), linolenic acid (C 18 H 34 O, cis, cis-9,12-octadecadien-1-ol), nonadecanol (C19), eicosanol (C 20 H 42 O), Octyldodecanol (C 20 H 42 O, 2-octyldodecan-1-ol), heneicosanol (C21), docosanol (C 22 H 46 O), docosenoyl alcohol (cis-13-docosenoyl-1-ol, C 22 H 44 O), wood wax alcohol (C24) and wax alcohol (C26). Saturated fatty alcohol penetration enhancers may include, but are not limited to, one or more of the following: lauryl alcohol (C12), isolauryl alcohol (C12, 10-methyl-1-undecanol), anteisolauryl alcohol (C12, 9-methyl-1-undecanol), myristyl alcohol (C14), isomyristyl alcohol (C14, 12-methyl-1-tridecanol), anteisomyristyl alcohol (C14, 11-methyl-1-tridecanol), cetyl alcohol (C16), isopalmityl alcohol (C16, 14-methyl-1-pentadecanol), anteisopalmityl alcohol (C16, 13-methyl-1-pentadecanol), stearyl alcohol (C18), isostearyl alcohol (C18, 16-methyl-1-heptadecanol) and anteisostearyl alcohol (C18, 15-methyl-1-pentadecanol). In some embodiments, the fatty alcohol is myristyl alcohol.

[0220] Fatty esters are products formed by reacting alcohol with fatty acids. Exemplary fatty esters include isopropyl palmitate, isopropyl myristate, 2-ethylhexyl palmitate, glyceryl oleate (mono-, di- or tri-oleate) and 2-ethylhexyl stearate. In some embodiments, the fatty ester is isopropyl palmitate.

[0221] Fatty acids that may be included in the composition include, but are not limited to, capric acid, lauric acid, palmitic acid, stearic acid, elaidic acid (C18:1), eicosapentaenoic acid (C20:1), erucic acid (C22:1), nervonic acid (C24:1), and ximenic acid (C26:1), hexadecatrienoic acid (16:3), linoleic acid (C18:2), alpha-linolenic acid (C18:3), gamma-linolenic acid (C18:3), octadecatrienoic acid (C18:3), octadecatrienoic acid (C18:4), mead acid (C20:3), eicosadienoic acid (C20:3), eicosatrienoic acid (C20:3), dihomo-gamma-linolenic acid (C20:3), arachidonic acid (C20:4), and docosadienoic acid (C22:2).

[0222] In some embodiments, the adhesive matrix further comprises an emulsifier or a penetration enhancer.

[0223] Emulsifiers may include, but are not limited to, one or more of the following: glycerides (monoglycerides, diglycerides, triglycerides), polyoxyethylene stearate, triceteareth-4 phosphate, phosphate) and ethylene glycol palmitostearate and diethylene glycol palmitostearate, polyglyceryl-3 diisostearate, PEG-6 stearate and ethylene glycol palmitostearate and PEG-32 stearate, oleoyl polyoxyethylene-6 glycerides, lauroyl polyoxyethylene-6 glycerides, caprylocaproyl polyoxyethylene-8 glycerides, propylene glycol monocaprylate type I, propylene glycol monolaurate type II, propylene glycol monolaurate type I, propylene glycol monocaprylate type II, polyglyceryl-3 dioleate, PEG-6 stearate and PEG-32 stearate mixture, lecithin, cetyl alcohol, cholesterol, bentonite, magnesium aluminosilicate (veegum), magnesium hydroxide, dioctylsodium succinate sulfosuccinate), sodium lauryl sulfate, triethanolamine stearate, potassium laurate, polyoxyethylene fatty alcohol ether, glyceryl monostearate, polyoxyethylene-polyoxypropylene block copolymer (poloxamers), sorbitan monolaurate, lanolin alcohol and ethoxylated lanolin alcohol, sorbitan fatty acid esters, sucrose distearate, sodium alginate, alginic acid, hectorite and aluminum silicate.

[0224] In some embodiments, the emulsifier is a glyceride (the product of glycerol and fatty acids). In some embodiments, the glyceride is selected from monoolein, monotol, and triolein.

[0225] The penetration enhancer may include one or more of the following: ethanol, propanol, isopropanol, sulfoxides (e.g., decyl methyl sulfoxide or dimethyl sulfoxide), amides (e.g., dimethylformamide, azone, urea, dimethylacetamide), pyrrolidone derivatives (e.g., 1-methyl-4-carboxy-2-pyrrolidone, 1-methyl-2-pyrrolidone, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone), terpenes (e.g., menthol, limonene, terpineol, pinene, carvone), ethyl acetate, methyl acetate, octisalate, pentadecalactone, n-dodecyl caprolactam (azone) and acrylamide.

[0226] In some embodiments, the penetration enhancer is selected from dimethyl sulfoxide and n-dodecyl caprolactam (Azone).

[0227] In some embodiments, the molar amount of olanzapine corresponds to a therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 2-50 mg of olanzapine.

[0228] In some embodiments, another matric-forming polymer may be included in the composition. Exemplary polymers include cellulose and its derivatives (such as, but not limited to, hydroxymethylcellulose, Aquasolve™ hypermellose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose blends, cellulose acetate phthalate, propyl methyl cellulose phthalate. In some embodiments, the composition or adhesive matrix includes ethyl cellulose.

[0229] In some embodiments, the adhesive matrix may further comprise thickeners such as silica and polyvinyl pyrrolidone homopolymers and polyvinyl pyrrolidone copolymers such as, but not limited to, PVP, Kollidon 30 and poloxamers, cross-linked polyvinyl pyrrolidone and vinyl pyrrolidone-vinyl acetate copolymers.

[0230] Preservatives and stabilizers may be included in the composition, and the preservatives and stabilizers may be selected from, but are not limited to, one or more of the following: sodium metabisulfite, citric acid, ascorbic acid, vitamin E, BHA, butylated hydroxytoluene (BHT), butylated hydroxyanisole, alpha-tocopherol, ascorbyl palmitate, propionic acid, sodium bisulfate, propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, benzethonium chloride, chlorhexidine, phenethyl alcohol, chlorodimethylphenol, cresol, hexetidine, phenoxyethanol, chlorobutanol, ascorbic acid, benzoic acid, sorbic acid, potassium sorbate, potassium metabisulfite, sodium metabisulfite, phenol, potassium benzoate, dehydroacetic acid, cetylpyridinium chloride, parabens, benzyl alcohol, benzalkonium chloride, and decolorizing agents. In some embodiments, these agents are present in the range of 0.01% to about 30% weight / weight.

[0231] In some embodiments, a cross-linking agent, which may be selected from but not limited to, one or more of melamine formaldehyde (Aerotex® M3, Aerotex® 3730), may be present in a range of 0.01% to about 30% weight / weight.

[0232] In some embodiments, the adhesive matrix comprises at least about 40 wt %, such as about 55 wt %, 65 wt %, 61 wt %, and 56 wt % pressure sensitive adhesive.

[0233] In some embodiments, the adhesive matrix comprises about 3-15% by weight fatty ester, such as about 3%, 3.5%, 10.0%, and 10.5% by weight.

[0234] In some embodiments, the adhesive matrix comprises about 1-20% by weight, such as 5-20% by weight, such as about 6-15% by weight, about 7.4% by weight, 8% by weight, and 9% by weight of olanzapine.

[0235] In some embodiments, the adhesive matrix comprises about 8-25 wt %, such as about 8-20 wt %, about 10 wt %, 16 wt %, and 16.8 wt % and 9 wt % oleic acid.

[0236] In some embodiments, the amount of olanzapine is sufficient to deliver 1-20 mg, such as 1-12 mg olanzapine within 24 hours when the composition is applied to the skin.

[0237] In some embodiments, the amount of olanzapine is sufficient to deliver olanzapine whose AUC is 1% to 80%, 10% to 80%, 20% to 80%, 30% to 80%, or 40% to 80% of the exposure achieved by the standard of care treatment. The standard of care treatment includes 2.5 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, or 25 mg of the olanzapine compound via oral administration once daily or once every two days.

[0238] The method for preparing the composition generally involves mixing together the components (eg, binder, olanzapine, oleic acid and one of a fatty alcohol, fatty acid, fatty ester and optionally a stabilizer) and allowing the resulting mixture to dry.

[0239] IV. Transcutaneous devices

[0240] In certain aspects, the compositions disclosed herein are provided as transdermal devices (e.g., patches). Generally, transdermal patches include a backing layer and at least one drug matrix layer. In some embodiments, the transdermal patch further includes one or more release liners, a tie layer, a rate-controlling membrane, and / or various combinations thereof.

[0241] As described herein, can be for example, but not limited to by solvent casting on backing layer or release liner, and sandwiched between the two to form patch.In order to avoid brittleness and give adhesive matrix layer flexibility, one or more plasticizers can be added in the layer.Necessity and selection of plasticizer will depend on specific adhesive and preparation.Suitable plasticizer is well known in the art. For example, but not limited to, one or more optional plasticizers can be selected from, but not limited to, one or more of the following: glycols (specifically, but not limited to, for example, polyethylene glycol 400, polyethylene glycol 600, propylene glycol), higher alcohols (e.g., dodecanol), surfactants, sebacic acid esters (e.g., dibutyl sebacate, diethyl sebacate), citrates (e.g., tributyl citrate, triethyl citrate), phthalates (e.g., diethyl phthalate, dibutyl phthalate), glycerol or glycerides (e.g., triacetate, glycerol), sugar alcohols (e.g., sorbitol, sucrose), tartaric acid esters (e.g., diethyl tartrate), oils (e.g., silicone oil, mineral oil), triacetin, oleate, adipate, and diisopropyl adipate. For inclusion in adhesive patch formulations, particularly acrylic PSA patch formulations, preferred plasticizers include, but are not limited to, one or more of glycerol and glycerides. Additional plasticizers may be found in "Handbook of Plasticizers" by George Wypych, 2004, Chem Tec Publishing, which is hereby incorporated by reference in its entirety. In certain embodiments, the plasticizer is present in the range of 0.01% - 95% weight / weight.

[0242] The material that is used for backing layer and release liner that many are suitable for is known, and comprises polymer film, fabric and nonwoven material, for example, prevents external moisture from entering the continuous film of adhesive layer in the activity such as showering or taking a bath.Backing and release liner should preferably be occluded, or be occluded basically.Such film includes but not limited to polypropylene, polyvinyl chloride, cellulose acetate, ethyl cellulose, polyurethane, polyethylene and polyester.Optionally, backing can be a layered composite material, it comprises metal, for example but not limited to aluminium, for example polyethylene terephthalate-aluminum-polyethylene composite material, or for example polyester and ethylene-vinyl acetate copolymer heat seal layer (particularly as backing), or for example the polyester film (particularly as release liner) that fluoropolymer applies. Suitable backing layers include, but are not limited to, Scotchpak 1006, 1022, 1109, 9723, 9732, 9733 (3M Company); suitable release liners include, but are not limited to, Scotchpak 1006, 9709, 9741, 9742, 9744, and 9755 (3M Company). The thickness of the backing layer and the release liner is generally greater than 10 μm and less than 200 μm, typically about 20 μm to about 120 μm, for example, about 40 μm to about 100 μm.

[0243] Coating formulations for patches may contain volatile solvents that are removed from the patch matrix as it dries; such volatile solvents include: methanol, ethanol, propanol, 1-propanol, 2-propanol, ethyl acetate, acetone, methylene chloride, chloroform, toluene, and IPA.

[0244] In some embodiments, a transdermal device for systemic delivery of olanzapine comprises a drug (matrix) comprising an acrylate polymer binder, a fatty ester, oleic acid, and olanzapine, and wherein the transdermal device, when applied to the skin, (i) delivers an amount of olanzapine effective to relieve nausea, vomiting, or both within a first period of about 4-8 hours, and (ii) delivers an amount of olanzapine effective to relieve nausea, vomiting, or both for a sustained period of at least about 1-7 days.

[0245] In some embodiments, the transdermal device has a pH of at least about 4 µg / cm2 over a sustained period of time when applied to (human cadaver) skin in vitro. 2 Average flux of hr.

[0246] In some embodiments, the sustained period is about 2-7 days or 2-5 days.

[0247] In some embodiments, the amount of olanzapine delivered during the first period and the sustained period is at least about 3 mg per day.

[0248] In some embodiments, the amount of olanzapine delivered during the first period and the sustained period is about 3-6 mg per day.

[0249] In some embodiments, the drug matrix comprises about 1-20% by weight, such as 5-20% by weight olanzapine.

[0250] In some embodiments, a transdermal device for delivering olanzapine comprises: a drug matrix comprising an acrylate polymer binder, a fatty ester, oleic acid, and olanzapine, and wherein the transdermal device has a flux profile when applied to the skin in vitro, wherein (i) a maximum flux rate is achieved within about 36-54 hours, (ii) about 65-80% of the maximum flux rate is achieved within about 18-36 hours, and (iii) at least about 3 µg / cm2 is achieved within a period of about 1-7 days. 2 Average flux rate in hr.

[0251] In some embodiments, the average flux rate is for a period of about 1-3 days or 1-5 days.

[0252] In some embodiments, wherein the flux profile provides an amount of olanzapine effective to relieve nausea, vomiting, or both during the time period.

[0253] The usage of percutaneous and topical systems described herein will have different dosages depending on the mode of administration, the specific illness to be treated, and the desired effect. The dosage can be percutaneous administration once a day, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days, or longer. Alternatively, several times a day can be used, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days, or longer. Alternatively, percutaneous administration can be once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days.

[0254] In some embodiments, the transdermal or topical formulation provides a predetermined delivery rate of the active component of the transdermal patch within a predetermined time period. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks or 15 days. In some further embodiments, the predetermined rate is a constant rate.

[0255] In yet further embodiments, the transdermal or topical formulations described herein provide a steady absorption rate of the active ingredient of the transdermal patch to the patient over a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days. In some further embodiments, the predetermined rate is a constant rate.

[0256] In yet further embodiments, the transdermal or topical formulations described herein provide a predetermined serum level range of the active component of the transdermal patch in a patient within a predetermined time. In some embodiments, the predetermined time period is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0257] In yet further embodiments, the transdermal or topical formulations described herein provide a therapeutic range of plasma concentrations of the active components of the transdermal patch in a patient over a predetermined period of time. In some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0258] In yet further embodiments, the transdermal or topical formulations described herein achieve a reduced variability in the dosage of the active ingredient in a patient over a predetermined period of time. In some embodiments, the predetermined period of time is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.

[0259] In some embodiments, the transdermal or topical formulations provided herein can be administered at a dosage regimen such as once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every 8 to about 13 days, once every two weeks, once every 15 to about 30 days.

[0260] In yet further embodiments, a pharmacokinetic assessment is performed on a blood sample of a subject treated with a transdermal delivery system as described herein. The transdermal formulations described herein are adjusted in response to the pharmacokinetic assessment. For example, the dosage can be adjusted so that a smaller patch, a larger patch, or multiple transdermal patches are administered to the subject, or a patch with a greater or lesser dose of the active ingredient can be administered. In some embodiments, formulations of various dosage strengths and patch sizes will be available to achieve the best therapeutic outcome based on the requirements of the subject.

[0261] Example 1 describes the preparation of olanzapine transdermal patches labeled OLA 1, OLA 2, OLA 3, OLA 4, OLA 5, OLA 6, and OLA 7.

[0262] In the permeation studies described in Example 2, using OLA 1 as an example, the flux increased rapidly, reaching 72% of the maximum value within the first 24 hours and reaching a maximum value at about 48 hours. After this, the transdermal flux gradually decreased at a steady rate, reaching about 61% of the maximum value at 168 hours. The average flux from 24 hours to 168 hours for 11 donors (50 replicates) was 4 ± 1.3 ug / hr / cm 2 .See Figure 7 .

[0263] Example 3 compares the cold flow properties of two compositions. The results show that the cold flow of the composition containing an additional polymer such as ethylcellulose is reduced.

[0264] V. Antiemetic effect of olanzapine

[0265] Olanzapine has been tested for the prevention of nausea and vomiting at a dose of 10 mg a day, and some studies have used 5 mg a day, but without pharmacodynamic evaluation. No studies have evaluated the minimum effective dose for nausea and vomiting. One side effect of olanzapine is fatigue / sedation, which is problematic in certain types of cancer treatment, and olanzapine causes sedation.

[0266] Transdermal drug delivery can be compared to continuous intravenous infusion, because the drug is absorbed directly into the blood at a steady rate throughout the application of the patch. One advantage of transdermal patch delivery is the avoidance of high blood levels (maximum) and low blood levels (minimum). In the case of most drugs, the maximum concentration (Cmax) is related to the toxicity of the drug, while the minimum concentration (Cmin) is generally below the desired therapeutic blood level. In general, the target of the patch is a blood level that provides the same area under the time-concentration curve (AUC0-∞) over the dosing interval. AUC0-∞ is a measure of total drug exposure.

[0267] Therefore, the blood drug level target for simulating oral administration requires the determination of the maximum and minimum blood drug level ranges at the first dose and at steady state. This target modeling can be estimated in silico based on the in vitro flux of the drug in a cadaveric skin test system (Franz Cell) using a traditional pharmacokinetic model.

[0268] The following Figure 1Computer modeling showing oral olanzapine at 7-day dosing intervals reaching steady state at doses of 10 mg, 5 mg, and 2.5 mg per day, respectively, from published data (Polasek T et al., Br J Clin Pharmacol (2018) 84 462-476). The black lines at each dosing level represent the planned patch blood drug level targets to simulate each specific oral dose. Despite the ability to model these data, in vivo studies in humans are needed to validate the data used in the model.

[0269] Example 1 describes a Phase 1 study of the antiemetic effects of four doses of oral olanzapine. The primary objectives of the study were to evaluate the antiemetic effects of four different doses of olanzapine or placebo given for 8 consecutive days after an 8-day apomorphine challenge and to determine the target blood levels required for the proposed optimal dose.

[0270] The study showed that the optimal dose determined for nausea and vomiting was 6 mg per day, while the minimum effective dose for nausea was 4 mg per day based on statistical integration of planned nausea scores and the incidence of retching and vomiting.

[0271] Figure 2 Olanzapine Cmax and Cmin plasma levels are provided by dose group. The range of target plasma levels at steady state (Cmin to Cmax) for the transdermal patch was 11-16 mcg / L for the 4 mg dose and 17-24 mcg / L for the 6 mg dose, while the range of day 1 plasma levels (which are effective for CINV) was 4-6 mcg / L for the 4 mg dose and 6-9 mcg / L for the 6 mg dose. Targets were selected by calculating the midpoint of the day 1 and steady state plasma level ranges. To achieve the optimal dose equivalent of 6 mg per day, the target steady state plasma level was 20 mcg / L and the day 1 level was 8 mcg / L. For the minimum dose equivalent of 4 mg per day, the target steady state plasma level was 13 mcg / L and the day 1 level was 5 mcg / L.

[0272] Figure 3 The severity of nausea following apomorphine challenge is shown. Nausea scores were measured every 15 minutes for 6 hours, with 1 = no nausea and 10 = severe nausea. The development of nausea following apomorphine challenge was observed within 15 minutes, with maximum intensity at 15-45 minutes. In almost all subjects, nausea was absent after 120 minutes following apomorphine challenge (except at the 8 mg dose level). The maximum intensity of nausea did not differ between the 4 mg, 6 mg, and 8 mg doses, however, the intensity of nausea observed at the 8 mg dose over the 120-minute interval was not different from the placebo control.

[0273] Figure 4 Nausea scores after apomorphine challenge are shown. Nausea severity scores during the period 0-120 minutes after apomorphine challenge, where 1 = no nausea and 10 = severe nausea. The 4 mg and 6 mg olanzapine steady-state doses were significantly different from placebo (p<0.05) but were not significantly different from each other. The 2 mg and 8 mg olanzapine doses were not significantly different from placebo.

[0274] Figure 5 Shown are sedation scores after 1 day of oral olanzapine by dose. Sedation severity scores on day 1 of olanzapine treatment, where 1 = no sedation and 10 = severe sedation. All olanzapine doses were significantly different (higher degree of sedation) compared with placebo. The incidence of sedation on day 1 was significantly higher for all doses of olanzapine compared with placebo. These data suggest that sedation observed on the first day of dosing with olanzapine is not dose-dependent and occurs with similar intensity at all doses tested. This is the first report of a lack of dose relationship for sedation with olanzapine for the doses tested. Sedation appeared to differ from placebo only on the first day of dosing and was not of significant intensity after day 1.

[0275] Figure 6 Modeled plasma targets for the olanzapine patch are shown to simulate a 6 mg daily dose with an error bar of 4 mg. A revised model was generated based on the in vivo plasma concentrations of 6 mg daily observed from this study. In addition, the lower level of acceptable plasma levels associated with the variability in flux is represented by the lower error bar. The estimated patch size for this delivery is 65 cm 2 .

[0276] VI. Example

[0277] The following examples are illustrative in nature and are not intended to be limiting in any way.

[0278] Example 1

[0279] Antiemetic effect of different oral doses of olanzapine

[0280] The study was an exploratory phase 1 design to determine the minimum effective dose of olanzapine represented by plasma concentrations. Twenty-four healthy female volunteers were enrolled. Four active treatment groups and one placebo-treated cohort of subjects were evaluated. The oral dose assignments in each cohort were: (1) olanzapine 2.0 mg per day (n=5) or placebo (n=1), (2) olanzapine 4.0 mg per day (n=5) or placebo (n=1), (3) olanzapine 6.0 mg per day (n=5) or placebo (n=1), and (4) olanzapine 8.0 mg per day (n=5) or placebo (n=1).

[0281] Subjects were given study medication once daily for 8 days. During this period, subjects kept a study diary of their side effects. Subject diaries were used to collect any adverse events daily, including an assessment of the presence and / or intensity of sedation on a numerical scale, with 1 = no sedation and 10 = excessive sedation.

[0282] On day 8, subjects were given apomorphine at a dose of 0.05 mg / kg and assessed over a 6-hour period. During this time period, subjects were asked to record episodes of nausea using a digital scale every 15 minutes during the assessment period. Nausea intensity was recorded using a rating scale of 1-10, where 1=no nausea and 10=severe nausea. Vomiting intensity was also recorded, where 1=no vomiting and 10=severe vomiting. Episodes of retching or vomiting were collected, and the absolute number of retching or vomiting during the collection period was measured, and the time of specific events after the administration of apomorphine was recorded.

[0283] Blood samples for olanzapine measurements were obtained prior to study drug administration on Day 1, prior to the last dose of olanzapine on Day 8, just prior to apomorphine challenge, and just prior to transfer from the CRU after 6 hours of observation. To help understand the change in blood levels from the first to the last dose of olanzapine, published data were used to predict Cmax and Cmin (trough) on Day 1 (Polasek T et al., Br J Clin Pharmacol (2018) 84 462-476).

[0284] The frequency of sedation was categorized as the percentage of subjects who experienced sedation during the 8-day olanzapine dosing interval. The intensity of sedation was categorized using the area under the curve (AUC) of the intensity measure during the 8-day dosing period. The frequency of nausea was categorized as the percentage of subjects who did not experience nausea. Nausea intensity was calculated using the AUC of the intensity measure during the 6-hour observation period after apomorphine. The frequency of vomiting was categorized as the percentage of subjects who did not experience vomiting. The intensity of vomiting was categorized using the AUC of the intensity measure during the 6-hour observation period. The frequency of retching was categorized as the percentage of subjects who did not experience retching. The intensity of retching was categorized using the AUC of the intensity measure during the 6-hour observation period. The minimum effective dose was determined using a predetermined method. Steady-state trough and pre-apomorphine plasma olanzapine concentrations were integrated by dose group. The data were arranged to provide target plasma drug levels for each equivalent oral dose.

[0285] The following table lists the incidence of nausea, retching, vomiting, and sedation by dose level.

[0286] 0 mg 2 mg 4 mg 6 mg 8 mg Nausea score ranged from 1 to 120 minutes. 6.9 Medium 6**Medium 3.4 #Minor 3.7 #Minor 5** Mild Retching 50% 40% 0% 0% 20% Vomit 50% 40% 20% 0% 20%

[0287] **: compared to 0 mg p = NS

[0288] #: lower compared to 0 mg p < 0.05

[0289] The optimal dose for nausea and vomiting was determined to be 6 mg per day, while the minimum effective dose for nausea was 4 mg per day, based on a planned statistical integration of nausea scores and the incidence of retching and vomiting.

[0290] Figure 2 Displays blood levels of olanzapine following oral dosing. Figure 2 Target steady-state plasma levels (20 mcg / L and 13 mcg / L for 6 mg / day and 4 mg / day, respectively) and day 1 levels (8 mcg / L and 5 mcg / L for 6 mg / day and 4 mg / day, respectively) can be determined. Figure 3-5 The severity of nausea after apomorphine challenge, the nausea score after apomorphine challenge, and the sedation score after 1 day of oral olanzapine dosing are shown, respectively.

[0291] Figure 6 Modeled blood drug targets for the olanzapine patch are shown to simulate an oral dose of 6 mg / day, with error bars for the 4 mg dose.

[0292] Example 2

[0293] Preparation of olanzapine transdermal patch

[0294] Compositions for transdermal delivery are prepared by mixing the ingredients in the following table in a solvent such as ethyl acetate.

[0295] Element OLA 1 OLA 2 OLA 3 OLA 4 OLA 5 OLA 6 OLA 7 Olanzapine 9.0% 7.4% 8.0% 8.0% 8.0% 8.0% 8.0% Oleic acid 10.0% 16.8% 16.0% 16.0% 16.0% 16.0% 16.0% DMSO 16.0% - - - - - Isopropyl Palmitate 3.5% 10.5% 10.0% 10.0% 10.0% 10.0% 10.0% Myristyl alcohol 3.0% - - - - - GMO (Croda) 3.5% - - - - - Kollidon CL-M (BASF) - - 5.0% - - - Kollidon VA 64 (BASF) - - - 5.0% - - Aerosil 200 Pharma (SiO2) - - - - 5.0% - Aqualon EC-N50 Pharma (Ethylcellulose) - - - - - 5.0% 10.0% Butylated Hydroxytoluene (BHT) - 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% Duro-Tak 87-9301 55.0% 64.7% 60.5% 60.5% 60.5% 60.5% 55.50%

[0296] Composition OLA 1 is used as an example to provide the following steps for preparing a transdermal patch. The above ingredients are blended by stirring for 18 hours, and then the matrix is ​​evenly spread on a release liner (such as 3M 9744) sheet of 8x14 inches using a commercial desktop coating machine to a thickness of 0.5 mm. The sheet is then placed in an oven at 100 degrees Fahrenheit for one hour to evaporate the ethyl acetate adhesive solvent. The opaque backing film (such as 3M 9730 NR film) with low oxygen permeability to inhibit photodegradation and oxidative degradation is then carefully applied by hand to avoid forming bubbles and voids. A circular mold (1.5 inches in diameter) is used to cut the patch (7 square centimeters) for subsequent research. The average weight of the sample (n=52) of the patch is 213 mg. Since the average weight of the sample of the backing film and the release liner is 124 mg, the calculated adhesive matrix weight is 89 mg. Therefore, after drying, the drug adhesive matrix had a surface density of 13 mg / cm2 and contained 9% or 1.2 mg / cm2 of olanzapine.

[0297] Example 3

[0298] In vitro transdermal flux measurements

[0299] The general procedure for flux measurement of transdermal patches is as follows. The release liner is peeled off from the patch and the adhesive surface is applied to a piece of human cadaver skin. The skin is stored as a sheet frozen on dry ice, thawed under room temperature water, and visually inspected for defects before applying the patch. Transdermal flux is measured in a standard Franz diffusion cell, which consists of a cylindrical donor chamber and a separate water-jacketed cylindrical receptor chamber. The skin is sandwiched between the two chambers, with the subcutaneous side facing the receptor chamber. The receptor chamber is filled with receptor medium, maintained at a constant temperature, and is constantly stirred to collect olanzapine as it diffuses through the skin and into the receptor chamber. The receptor chamber is emptied at intervals of 24 hours for the determination of olanzapine and replaced with a fresh receptor solution. The concentration of olanzapine in the receptor chamber never exceeds 10% of its solubility, so that the tank conditions are maintained. The following table lists the flux determination conditions.

[0300] In vitro flux assay conditions Receiving medium PBS, 0.01% sodium azide, pH 6.5 Receiving medium volume 13 mL The volume of the sample 13 mL Sampling interval 24 hours Franz cell surface area for diffusion <![CDATA[1.76 cm 2 ]]>

[0301] Flux was measured for a period of 7 days (or 168 hours), except for 2 experiments which lasted only 6 days. Figure 7 is the in vitro flux graph of composition OLA 1. Compositions OLA 2-6 were also tested in the flux assay by following the above procedure. The table below lists the average flux rate for each formulation.

[0302] OLA1 OLA2 OLA3 OLA4 OLA5 OLA6 Flux 24 hours (n=3) 2.4（57%） 1.3（25%） 2.0（38%） 1.9（46%） 2.1（62%） 3.0（50%） Flux 24-144 hours (n=3) 4.4（7%） 3.8（9%） 4.1（14%） 3.9（11%） 3.5（20%） 4.2（6%）

[0303] (%) refers to relative standard deviation.

[0304] Example 4

[0305] Cold flow studies

[0306] The patch was cut with a 7 cm square die and subjected to compression using a 1 kg weight as follows: (1) the release liner was removed from the patch and the patch was carefully applied to the fluoropolymer side of a new 3.5 x 3.5 square release liner, (2) another 3.5 x 3.5 square release liner was placed on top of the patch with the fluoropolymer side facing down so that the patch was now sandwiched between the two release liners, (3) a 1 kg weight was carefully applied to the patch to avoid any lateral movement and left in place for 3 days, (4) at the end of the 3 days, the weight was carefully removed and the percent increase in surface area was measured. The results are as follows.

[0307] OLA1 OLA2 OLA3 OLA4 OLA5 OLA6 Cold flow (% relative standard deviation) 20.41（44%） 13.09（11%） 14.08（19%） 8.62（20%） 4.25（15%） 2.63（21%）

[0308] Example 5

[0309] Comparative bioavailability of olanzapine transdermal patch and oral olanzapine

[0310] A comparative bioavailability study was conducted to determine the optimal formulation for clinical studies and to evaluate the bioavailability of the transdermal patch described herein compared to oral olanzapine at the primary published dose of 10 mg / day in chemotherapy-induced nausea and vomiting.

[0311] The study was an open-label study with 3 allocated cohorts of approximately 12 subjects each. Subjects were allocated 1:1:1 to OLA 1-1 x 35 cm 2 Patches (set 2), or OLA 1-2 x 35 cm 2 Patches (Group 3) or 10 mg oral Zyprexa® (Group 1) for seven consecutive days. Treatment for each of the OLA 1 cohorts was given as (multiple) patches applied to the deltoid area of ​​the body. Treatment with 10 mg oral Zyprexa® was given daily with 240 ml of water at the same time each morning. A total of approximately 36 healthy volunteers aged 18 to 55 years (inclusive) participated in the study. A diary was issued to each subject to conduct daily self-evaluations of sedation and hunger levels based on a numerical scale twice a day with a 0-10 ordinal score. Daily self-evaluations of sedation and hunger levels continued until the morning of Day 13.

[0312] Subjects in the assigned group will either have the OLA 1 patch placed on them on Day 1 and remain on until Day 8, or will be given 10 mg oral Zyprexa ® QD with 240 mL of water for 7 days (without giving on Day 8). Water will be restricted for 1 hour after dosing.

[0313] Blood samples for pharmacokinetic (PK) analysis were obtained at the following times: pre-dose (within 30 minutes prior to dosing) and 1, 2, 4, 8, 12, 24, 28, 48, 52, 72, 76, 96, 100, 120, 124, 144, 148, and 168 hours (+ / - 15 minutes); then at 192, 216, 240, 264, and 288 hours (+ / - 2 hours) after the initial dose. For the patch group, blood samples were obtained at the same time each morning, 4 hours after the morning trough sample. For the oral Zyprexa ® group, PK samples (trough) were obtained 4 hours after dosing.

[0314] Figure 8 The median plasma levels of olanzapine for each group are shown in FIG. 5 as a function of time in hours.

[0315] The following table summarizes the pharmacokinetic information for the three cohorts. The total dose for Groups 2 and 3 is the apparent dose absorbed during the 7-day study. The apparent dose is obtained after mass balance studies / calculations. In the mass balance study, a post-study test for residual olanzapine remaining in the patch dosage form after removal was analyzed using a validated method. The difference between the drug load (47.25 mg / patch) and the residual is the apparent dose in the table below.

[0316] Total dose in 7 days (mcg) AUC (mcg / L / h) Average Cmax over 7 days (mcg / L) Average daily dose over 7 days (mcg) % bioavailability expressed as AUC compared to 10 mg oral Group 1 70000 5287 41.6 10000 100% Group 2 22770 1496 9.3 3252 28.3% Group 3 34850 2117 13.2 4980 40.0%

[0317] Fig. 9 and Fig.10 The mean cumulative sums of intensity ratings for hunger and sedation during the study period by group are presented separately.

[0318] Equivalence

[0319] Although some exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims introduced thereafter be interpreted as including all such modifications, permutations, additions and sub-combinations within their true spirit and scope.

[0320] All patents, patent applications, patent publications, and other publications mentioned herein are hereby incorporated by reference in their entirety. Where a patent, application, or publication contains explicit definitions, those definitions should be understood to apply to the patent, application, or publication in which they appear, and not to this application, unless otherwise indicated.

Claims

1. A transdermal preparation for preventing or treating nausea or vomiting, comprising: (i) at least 40% by weight of a pressure-sensitive adhesive; (ii) 3-15 wt% fatty acid esters; and (iii) 1-9% by weight of olanzapine; in, The fatty acid ester is isopropyl palmitate; The transdermal formulation optionally further comprises a fatty alcohol.

2. The transdermal preparation according to claim 1, wherein The pressure sensitive adhesive is an acrylate copolymer.

3. The transdermal preparation of claim 1, further comprising polyvinyl pyrrolidone, ethyl cellulose, silicon dioxide or a combination thereof.

4. The transdermal preparation according to claim 1, wherein The fatty alcohol is myristyl alcohol.

5. The transdermal preparation according to claim 1, wherein The transdermal formulations may also contain an emulsifier or a penetration enhancer.

6. The transdermal preparation according to claim 5, wherein The emulsifier is a glyceride.

7. The transdermal preparation according to claim 6, wherein The glyceride is selected from the group consisting of monoolein, monotolglyceride and triolein.

8. The transdermal preparation according to claim 5, wherein The penetration enhancer is selected from dimethyl sulfoxide and azone.

9. The transdermal preparation according to claim 1, wherein The olanzapine is formulated for transdermal administration in an amount of 2 mg to 8 mg.

10. The transdermal preparation according to claim 1, wherein After the transdermal formulation is applied to the skin, a concentration of at least 3 μg / cm 2 The average flux rate of olanzapine was / hr.

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