Transdermal delivery of dronabinol

Abstract

A transdermal drug delivery system comprising dronabinol is provided.SOLUTION: The dronabinol transdermal delivery system provides a drug plasma concentration at a predetermined rate for a predetermined period of time and provides a simplified treatment regimen by reducing the frequency of dosing for the treatment and / or prevention of, for example, chemotherapy-associated nausea and / or vomiting.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 910,255, filed October 3, 2019, which is incorporated herein by reference.

[0002] The present disclosure relates to the treatment of nausea and vomiting, such as that commonly experienced by patients undergoing chemotherapy. [Background technology]

[0003] Nausea and vomiting are common side effects of cancer chemotherapy. Medications such as dronabinol and 5-HT3 receptor antagonists have been recommended for the treatment of nausea and vomiting associated with cancer chemotherapy. Sometimes, more than one drug can be used to prevent nausea and vomiting (see Herrsted J., et al., 2016 Updated MASCC / ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy Support Care Cancer. 2017 January;25(1):277-288. Epub 2016 July 22).

[0004] Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (delta-9-THC), found in sesame oil. Dronabinol is approved for use in the treatment of emesis and is available as an oral capsule (MARINOL) and an oral liquid (SYNDROS). As stated in the package insert or drug labeling for dronabinol oral capsules, the drug is indicated for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded adequately to conventional antiemetic therapy. It is also indicated for the treatment of anorexia associated with weight loss in AIDS patients (see NDA Marinol Labeling, Labeling, Label Action Date June 21, 2006, accessed July 13, 2017 (hereinafter "Label").

[0005] Many disadvantages are associated with dronabinol oral capsules. The first challenge is the dosing regimen. For antiemetic efficacy, the following dosing regimen is recommended: an initial dose of 5 mg / m 2 1-3 hours before chemotherapy. 2 After chemotherapy, the drug is administered every 2-4 hours for a total of 4-6 times per day. Depending on the clinical response, if that dose is not sufficiently effective, the dose may be increased to 2.5 mg / m 2 increments of approximately 15 mg / m 2 This dosing regimen is inconvenient for patients already experiencing nausea and vomiting. A second challenge is that the pharmacological response is dose-related and subject to interpatient variability. A third challenge is the increased potential for disturbing psychiatric symptoms at maximum doses. A fourth challenge is that after oral administration, dronabinol undergoes first-pass hepatic metabolism and has high lipid solubility, resulting in 10%–20% of the administered dose reaching the systemic circulation. Another challenge is that the active ingredient, dronabinol, is unstable in capsules at room temperature; therefore, capsules are recommended to be packaged in a sealed container and stored in a refrigerator or at 8–15°C (see label). Dronabinol capsules are stable at room temperature for only 3 months. This is because synthetic delta-9-THC exhibits rapid oxidation and acid and basic degradation. Furthermore, synthetic delta-9-THC decomposes more rapidly in light and at elevated temperatures. Therefore, if dronabinol capsules are not stored refrigerated in their original containers, the concentration of delta-9-THC in the capsules may decrease and fall below therapeutically required levels.

[0006] Previous research has been conducted using naturally derived delta-9-THC from the marijuana plant Cannabis sativa L. However, extracting pure delta-9-THC from botanical sources such as Cannabis sativa L. is difficult. This occurs due to contamination of the extract with small amounts of other active cannabidiols (such as cannabinol, delta-8-THC, cannabidiol, and cannabichromene) present in the final product. Therefore, the amount of THC in the final extract depends on the extraction process, which is important due to the psychoactive properties of THC, among other considerations. Alternatively, synthetic forms of delta-9-THC are developed using more controlled procedures, as opposed to the extraction process of its naturally derived counterpart. For example, synthetically produced delta-9-THC essentially consists of uncontaminated delta-9-THC, uncontaminated by the presence of other active cannabidiols. Therefore, synthetic forms of delta-9-THC have a maximum flux through rat skin of 0.01 μg / cm compared to naturally extracted delta-9-THC. 2 This may provide improved transdermal permeability compared to previously published studies using naturally derived delta-9-THC, showing 400 mg / hr (U.S. Patent No. 6,503,532).

[0007] U.S. Patent No. 6,328,992 also relates to preparations for transdermal delivery of cannabinoids. However, this disclosure describes a combination of different cannabinoids and does not describe the use of pure synthetic delta-9-THC alone. Furthermore, the '992 patent inventors describe the use of a permeability enhancer that is not pharmaceutical grade and is not included in the US Food and Drug Administration Inactive Ingredient Listing (FDA IIG). Therefore, the '992 disclosure does not provide a composition with any pharmaceutical utility. Furthermore, the '992 patent describes the use of rat skin containing 50% ethanol as a receiving medium for transdermal permeability testing. However, ethanol can destroy the dermal structure and increase in vitro flux values, resulting in unsuitable results for transdermal patches for pharmaceutical use. For example, ethanol-treated rat skin is approximately 10 times more permeable than human cadaver skin.

[0008] US Patent No. 8,449,908 demonstrates the delivery of a cumulative dose of 10,000 ng of THC through human cadaver skin in 96 hours, with a flux of 60 ng / cm. 2 / hour. The patch area can be calculated using the following formula: In-Vitro Flux (ng / cm 2 / hr) = (Css (ng / mL) * CL (L / kg * hr) * BW (Kg)) / patch area (cm 2 ) Patch area (cm2)=(Css(ng / mL)*CL(L / kg*hr)*BW(kg)) / In-Vitro flux(ng / cm2 / hr) =(1.38*0.2*70*1000) / 60 =322cm 2

[0009] To deliver a therapeutic dose of 5 mg / day of delta-9-THC, the transdermal formulation must penetrate at least 325 cm of the patient's skin. 2 This is an impractical patch size for any transdermal drug delivery system (TDDS).

[0010] Therefore, there is a need for an improved drug delivery system for dronabinol that can overcome the above-mentioned drawbacks associated with oral administration and naturally-derived delta-9-THC. As provided herein, transdermal delivery of dronabinol with synthetic delta-9-THC can address the challenges associated with oral drug delivery. Summary of the Invention [Problem to be solved by the invention]

[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 pharmaceutical composition is provided that includes dronabinol in a dosage form for transdermal delivery.

[0013] In one embodiment, the pharmaceutical composition does not include an additional antiemetic drug.

[0014] In one embodiment, the dronabinol is in a form selected from the group consisting of co-crystal, amorphous, coated, crystalline, salt, isomer, solid solution, prodrug, analog, derivative, metabolite, solution, synthetic, ethanol solution, and naturally occurring delta-9-tetrahydrocannabinol.

[0015] In one embodiment, dronabinol is present in the composition at about 0.01% to 95% w / w or about 0.01% to 95% w / v.

[0016] In one embodiment, the dronabinol is selected from the group consisting of amorphous dronabinol, crystalline dronabinol, co-crystals of dronabinol, coated dronabinol, and ethanolic solutions of dronabinol, and ranges from 0.01% to 95% w / w or w / v of dronabinol.

[0017] In one embodiment, the dronabinol is in the form of a salt.

[0018] In one embodiment, the composition is formulated as a transdermal liquid formulation, a transdermal semisolid formulation, and / or a transdermal polymer matrix formulation.

[0019] In one embodiment, the composition includes an effective amount of a carrier or ingredient, either alone or in combination, selected from the group consisting of solvents, gelling agents, polymers, penetration enhancers, emollients, skin irritation reducers, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, surfactants, antioxidants, and oxidizing agents.

[0020] In one embodiment, the carrier or component ranges from about 0.01% to 95% w / w or w / v in the composition.

[0021] In one embodiment, the pharmaceutical composition is formulated as a transdermal patch.

[0022] In one embodiment, the transdermal patch is selected from the group consisting of a reservoir patch, a microreservoir patch, a matrix patch, a pressure-sensitive adhesive patch, and a sustained-release transdermal film.

[0023] In one embodiment, the pharmaceutical composition is formulated as a microneedle.

[0024] In one embodiment, the microneedles are formulated as a transdermal patch.

[0025] In one embodiment, a method for the treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy comprises selecting a patient in need of treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy, and topically applying, or instructing the patient to topically apply, a pharmaceutical composition described herein, wherein the topical application occurs at least once daily.

[0026] In one embodiment, the composition is a liquid and / or semi-solid formulation and topical application is performed 2-6 times daily, once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week.

[0027] In one embodiment, the composition is applied topically once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, or once every 10 days.

[0028] In one embodiment, topical application provides a constant delivery rate of the active ingredient of the transdermal patch over a period of time.

[0029] In one embodiment, the topical application provides a steady absorption rate of dronabinol over a period of time.

[0030] In one embodiment, the topical application achieves a constant serum level of dronabinol over a period of time.

[0031] In one embodiment, topical application achieves a reduced fluctuation in serum levels of dronabinol over a period of time compared to oral administration of dronabinol over a period of time.

[0032] In one embodiment, the topical application achieves plasma concentrations of dronabinol in the therapeutic range over a period of time.

[0033] In one embodiment, a method for the treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy and / or anorexia associated with weight loss in AIDS patients comprises selecting a patient in need of treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy and / or anorexia associated with weight loss in AIDS patients, and topically applying, or instructing the patient to topically apply, a pharmaceutical composition described herein, wherein applying achieves local delivery of dronabinol for the treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy and / or anorexia associated with weight loss in AIDS patients.

[0034] In one embodiment, the pharmaceutical composition is applied topically once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, or once every ten days.

[0035] In one embodiment, the pharmaceutical composition is applied topically 2-6 times daily, once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week.

[0036] In one embodiment, the pharmaceutical composition is a liquid or semi-solid formulation.

[0037] In one embodiment, the pharmaceutical composition is a transdermal delivery system.

[0038] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

[0039] Additional embodiments of the present methods, compositions, and the like will become apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and following description, each and every feature described herein, and each and every combination of two or more such features, is included within the scope of the present disclosure, provided that the features included in such combinations are not mutually inconsistent. Furthermore, any feature or combination of features may be specifically excluded from any embodiment of the present disclosure. Additional aspects and advantages of the present disclosure are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. [Brief explanation of the drawings]

[0040] [Figure 1] Graph showing plasma concentration of drug as a function of time (hours) when delivered via oral route (open circles) or transdermal route (filled circles). DETAILED DESCRIPTION OF THE INVENTION

[0041] In transdermal drug delivery, transdermal patch or transdermal composition is applied locally to the surface of skin.During the period of topical application of transdermal patch or transdermal composition, drug is continuously released and delivered through intact skin (through transcellular, intercellular and transappendicular pathways) to achieve systemic effect.Therefore, once applied, transdermal composition or transdermal patch can deliver drug to systemic circulation throughout the day or even for more than one day (can be up to one week or more) depending on the period of application.

[0042] Transdermal delivery can reduce the dosing frequency of dronabinol, which is currently administered orally four to six times daily. Through transdermal delivery, a dronabinol transdermal composition, formulation, or patch can be applied topically to the skin, thereby delivering the drug throughout the entire topical application period. Depending on the requirements, the topical application period can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. Therefore, transdermal delivery can eliminate the multiple-dose regimen of oral delivery by reducing the dosing frequency.

[0043] Furthermore, with transdermal drug delivery, the drug is delivered slowly and continuously throughout the duration of topical application, eliminating the peaks and troughs in drug plasma concentrations associated with multiple daily doses. Thus, transdermal delivery of dronabinol allows patients to experience the therapeutic effects of the drug over an extended period without dramatic changes in drug plasma concentrations.

[0044] With transdermal delivery, drugs are delivered through the skin into the systemic circulation, avoiding first-pass hepatic metabolism, so less drug is needed to achieve the desired therapeutic activity, resulting in reduced adverse or toxic effects. Dronabinol is highly lipid-soluble and undergoes first-pass hepatic metabolism after oral administration, resulting in 10% to 20% of the administered dose reaching the systemic circulation. Therefore, compared with oral administration, transdermal delivery allows for a lower dose of dronabinol to achieve the desired therapeutic effect while also overcoming the psychiatric disturbances associated with higher doses.

[0045] Additionally, the transdermal delta-9-THC delivery described herein provides nearly 10-fold greater in vitro permeability through human cadaver skin compared to conventional systems using the FDA IIG database of ingredients listed in approved drug products.

[0046] For example, according to the FDA label for Marinol (dronabinol capsules), when given twice daily in the fasted state to healthy volunteers (n=34; 20-25 years old), the following pharmacokinetic (PK) parameters were found (see label): [Table 1]

[0047] Furthermore, PK parameters indicate that the maximum plasma concentration for oral delivery of 5 mg / day dronabinol capsules is 1.32 ng / mL, and for oral delivery of 20 mg / day, it is 7.88 ng / mL. Oral delivery PK values ​​indicate peaks and valleys in plasma concentration over time. In contrast to oral delivery, transdermal drug delivery delivers drug molecules at a defined rate and maintains a consistent average plasma concentration over time (Figure 1).

[0048] The mean plasma concentration is calculated in the following way: 5mg / day mean plasma concentration = AUC (0-t) / t=2.88 / 12=0.24ng / mL 20mg / day=15.2 / 12=1.27ng / mL

[0049] Therefore, the transdermal drug delivery system (TDDS) is calculated to deliver delta-9-THC at an average plasma concentration of 0.24 to 1.27 ng / mL.

[0050] The oral route is often not the most convenient for preventing nausea and vomiting. Patients may already experience nausea and vomiting, and if they vomit shortly after drug administration, there is uncertainty as to whether the dose was absorbed or vomited. Transdermal dronabinol, on the other hand, is delivered through the skin, which completely eliminates this type of uncertainty.

[0051] Furthermore, there are a variety of additional side effects, such as central nervous system (CNS) side effects, associated with oral administration of dronabinol capsules. Because side effects are dose-related, patients receiving oral doses require close monitoring so that the dose can be adjusted and reduced as needed.

[0052] Alternatively, the TDDS systems provided herein provide constant drug delivery at a predetermined, defined input rate. Thus, the provided TDDS systems provide a constant average plasma concentration with a constant input rate and do not exhibit the PK peaks and valleys of plasma concentration associated with orally delivered delta-9-THC. Therefore, the currently provided TDDS systems are also less likely to cause CNS side effects compared to their orally delivered counterparts. For example, adverse effects of delta-9-THC are less likely to occur at a dose of 7 mg / m of delta-9-THC. 2 It is not induced by

[0053] Furthermore, oral doses must be delivered four to six times daily instead of once daily to avoid adverse effects. Furthermore, oral doses undergo first-pass metabolism, resulting in only 10-20% of the oral dose being available in plasma, making them an inefficient delivery method and a significant loss of active pharmaceutical ingredient. Furthermore, to achieve therapeutic benefit from any drug molecule, the drug must have continuous delivery to achieve a steady-state plasma concentration or a plasma concentration within a therapeutic window (between the minimum and maximum therapeutically effective concentrations). Therefore, the delta-9-THC TDDS system provided herein addresses a long-felt and unmet need in the field of cannabidiol-based pharmaceuticals.

[0054] Transdermal delivery is also easy, non-invasive, and convenient. Administration of a transdermal patch or transdermal composition does not require medical supervision, as patients can self-apply the transdermal patch or transdermal composition topically.

[0055] For dronabinol, interpatient variability in pharmacological response is expected to be less with transdermal delivery because the drug plasma concentration can be controlled by controlling the rate of drug delivery from the transdermal composition or transdermal patch. Dronabinol's alpha half-life is approximately 4 hours, and oral administration results in rapid metabolism in the body. In contrast, transdermal delivery can deliver smaller amounts of dronabinol for longer periods than oral administration. Transdermal formulations of dronabinol also offer greater abuse deterrence than immediate-release dosage forms.

[0056] Furthermore, in case of any adverse effects, side effects or urgent transdermal delivery, one has the freedom to terminate the treatment at any time by removing the transdermal patch or transdermal composition from the skin.

[0057] For the reasons mentioned above, transdermal delivery can provide a more patient-friendly, simplified and convenient treatment regimen than traditional delivery systems to prevent nausea and vomiting associated with cancer chemotherapy.Transdermal delivery can reduce the frequency of dronabinol administration.As needed, the administration frequency can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days or once a week.

[0058] To prevent nausea and vomiting associated with cancer chemotherapy, patients are prescribed a variety of different drugs, some of which are administered multiple times a day.By formulating antiemetic drug(s) in transdermal patch or transdermal composition, it provides a significantly simplified administration regimen for patients who are already weakened and fatigued by chemotherapy.Depending on the need, the administration frequency of transdermal patch or transdermal composition containing drug can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.This will greatly aid patient compliance.

[0059] Dronabinol is an unstable drug. The stability of dronabinol can be improved by preparations such as cocrystals of dronabinol, coatings of dronabinol, crystalline dronabinol, amorphous forms, and / or inactive materials.

[0060] In one embodiment, a transdermal drug delivery composition in the form of a transdermal patch or delivery system containing dronabinol is contemplated. Transdermal delivery can provide drug plasma concentrations at a predetermined rate for a predetermined period of time, simplifying treatment regimens by reducing dosing frequency. Preferably, the dronabinol is selected from the group including, but not limited to, co-crystals of dronabinol, amorphous forms of dronabinol, coated dronabinol, and crystalline forms of dronabinol.

[0061] As used herein, "dronabinol" refers to all forms of dronabinol, either alone or in combination, including, but not limited to, the following forms: delta-9-tetrahydrocannabinol, or synthetic delta-9-tetrahydrocannabinol free base, or salts, or isomers, or amorphous forms, or crystals, or co-crystals, or solid solutions, or prodrugs, or analogs, or derivatives, or metabolites, or coated forms, or natural extracts, or solutions of dronabinol. For example, dronabinol free form, or salts, or isomers, or amorphous forms, or crystal forms, or co-crystals, or solid solutions, or prodrugs, or analogs, or derivatives, or metabolites, or coated forms, or delta-9-tetrahydrocannabinol, or natural extracts of synthetic delta-9-tetrahydrocannabinol, or ethanol solutions of dronabinol. Dronabinol can also be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or base salt, or a solvate (hydrate thereof). Suitable acid addition salts are formed from acids which form non-toxic salts. Chemical name: (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-1-3-penty-1-6H-dibenzo[b,d]pyran-1-ol Empirical formula: C 21 H 30 O2 Molecular weight: 314.47 Structure: Formula (I) [ka]

[0062] Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a naturally occurring compound found in Cannabis sativa L.

[0063] In embodiments of the present disclosure, preferred forms of dronabinol are selected from the group including, but not limited to, dronabinol co-crystals, dronabinol amorphous forms, coated dronabinol, dronabinol crystalline forms, etc. Dronabinol co-crystals, coated dronabinol, and dronabinol crystalline forms may be prepared.

[0064] Amorphous forms of drugs have no defined structure and have higher solubility compared to crystalline forms. A variety of techniques and methods are used to produce amorphous forms of drugs.

[0065] As stated in the Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, "A co-crystal is a crystalline material composed of two or more different molecules, typically a drug and a co-crystal former ('co-former'), in the same crystal lattice" (USDepartment of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry Draft Guidance, Pharmaceutical Quality / CMC Revision 1, August 2016, see https: / / www.fda.gov / downloads / Drugs / Guidances / UCM516813.pdf, accessed July 12, 2017). Various methods are available for preparing co-crystals. Each drug has a different chemical structure and physicochemical properties, making it difficult to predict the success rate of a co-crystallization reaction. Tests under a variety of experimental conditions have been conducted to determine approaches for forming drug cocrystals (see Nate Schultheiss, Ann Newman Pharmaceutical Cocrystals and their Physicochemical Properties. Cryst Growth Des. 2009 Jan. 3;9(6):2950-2967).

[0066] Drug coatings can be achieved using polymers or other excipients. Various techniques are used to coat drugs. Drug stability can also be enhanced by encapsulation.

[0067] As used herein, the term "pharmaceutically acceptable salts" includes acid addition salts or addition salts of the free base. Within its scope, the term "pharmaceutically acceptable salts" of dronabinol includes all possible isomers and mixtures thereof, as well as any pharmaceutically acceptable metabolites, bioprecursors and / or prodrugs, e.g., compounds having a structural formula different from one of the compounds of the present disclosure but which, upon administration to a subject, such as a mammal, particularly a human, are converted in vivo, directly or indirectly, to a compound of the present disclosure.

[0068] In one embodiment, dronabinol is incorporated into the transdermal system in the form of a pharmaceutically acceptable salt form, either as a single salt, a combination of salts, or a combination of the base form with one or more salt forms. Examples of various forms of dronabinol include, but are not limited to, the free base, salts, racemic forms, isomers, amorphous forms, crystalline forms, cocrystals, solid solutions, prodrugs, analogs, derivatives, metabolites, solutions, hydrates, etc. The therapeutic agent may be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or a base salt, or a solvate thereof (hydrate thereof). Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include, but are not limited to, acetate, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, sodium phosphate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts. Suitable base salts are formed from bases which form non-toxic salts, examples of which include, but are not limited to, sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts.

[0069] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkeys and humans), and most preferably a human. In some embodiments, the subject is a non-human animal such as a farm animal (e.g., horse, pig, or cow) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.

[0070] As used herein, the term "agent" refers to any molecule, compound, methodology and / or substance for use in the prevention, treatment, management and / or diagnosis of a disease or condition.

[0071] As used herein, the term "effective amount" refers to the amount of a therapy that is sufficient to result in prevention of the onset, recurrence, or development of a disease or condition and one or more symptoms thereof, reduce the severity, shorten the duration of a disease or condition, ameliorate one or more symptoms of a disease or condition, prevent the progression of a disease or condition, cause regression of a disease or condition, and / or enhance or improve the therapeutic effect(s) of another therapy.

[0072] As used herein, the phrase "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government, or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopoeias, for use in animals, and more particularly in humans.

[0073] As used herein, the term "therapeutic agent" refers to any molecule, compound, and / or substance used to treat and / or manage a disease or disorder.

[0074] As used herein, the term "therapy(s)" may refer to any method(s), composition(s), and / or agent(s) that can be used to prevent, treat, and / or manage a disease or condition, or one or more symptoms thereof. In certain embodiments, the term "therapy(s)" refers to small molecule therapy.

[0075] As used herein, the term "derivative" or "derivatization" includes chemical modifications of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or mixtures thereof. That is, a "derivative" may be a functional equivalent of a compound of the present disclosure that is capable of inducing improved pharmacological functional activity in a given subject.

[0076] As used herein, the terms "composition" and "formulation" are used interchangeably.

[0077] As used herein, the term "topical delivery" means delivery of a drug through the skin into the systemic circulation.

[0078] Transdermal Compositions According to certain embodiments, the transdermal compositions described herein are for the prevention and / or treatment of nausea and / or vomiting associated with cancer chemotherapy.

[0079] According to certain embodiments described herein, the pharmaceutical composition or transdermal formulation comprises dronabinol in a form selected from the group including co-crystals, amorphous forms, crystalline forms, coated forms thereof, solutions thereof, and salts thereof, which may be anhydrous and / or hydrous, alone or in combination thereof. More preferably, the transdermal formulation may comprise dronabinol selected from the following forms: amorphous or co-crystal or crystalline or coated form, or an ethanolic solution thereof, either alone or in combination thereof.

[0080] One embodiment of the present disclosure can be a transdermal drug delivery system, which can include, but is not limited to, a transdermal formulation, a transdermal patch, a topical formulation, microneedles, iontophoresis, or a metered dose transdermal spray.

[0081] Transdermal formulations include liquids, such as, but not limited to, solutions, suspensions, dispersions, and emulsions. Transdermal formulations include semi-solids, such as, but not limited to, gels, ointments, emulsions, creams, suspensions, pastes, lotions, and balms. Liquid and / or gel formulations incorporated into transdermal patches are preferred. Transdermal formulations containing a polymer matrix can be, but are not limited to, an adhesive matrix or a non-adhesive matrix.

[0082] Without being limited thereto, the transdermal patch may preferably include any transdermal drug delivery system described in the art, including but not limited to, reservoir patches, matrix patches, bilayer matrix patches, multilayer matrix patches, microreservoir patches, adhesive systems, transdermally applicable tapes, etc.

[0083] In certain embodiments of the present disclosure, the transdermal patch comprises dronabinol contained in a reservoir or matrix and an adhesive that allows the transdermal patch to adhere to the skin and allows the dronabinol to pass from the transdermal patch through the patient's skin. Transdermal delivery systems can be occlusive, semi-occlusive, or non-occlusive, and can be adhesive or non-adhesive.

[0084] In some embodiments, the transdermal patch provides a constant delivery rate of the active ingredient of the transdermal patch over a predetermined period of time, which in some embodiments is about 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0085] In yet another embodiment, the transdermal patches described herein provide a steady rate of absorption of the active ingredient of the transdermal patch by the patient over a predetermined period of time, which in some embodiments is 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0086] In further embodiments, the transdermal patches described herein provide a patient with a constant serum level of the active ingredient of the transdermal patch over a predetermined period of time, which in some embodiments is about 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0087] In further embodiments, the transdermal patches described herein provide a plasma concentration of the active ingredient of the transdermal patch in the therapeutic range in a patient over a predetermined period of time, which in some embodiments is about 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0088] In further embodiments, the transdermal patches described herein allow for reduced fluctuations in the dosage of the active ingredient in a patient over a predetermined period of time, which in some embodiments is about 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8-13 days, 2 weeks, or 15 days.

[0089] Topical formulations described in the art include, for example, but are not limited to, semisolids such as ointments, creams, emulsions, microemulsions, nanoemulsions, pastes, balms, gels, lotions, mousses, etc.; liquids such as solutions, suspensions, microsuspensions, nanosuspensions, dispersions, nanodispersions, etc.; sprays, aerosols, magmas, etc. Topical formulations containing dronabinol can be applied topically to the skin surface for transdermal delivery of dronabinol.

[0090] The transdermal and / or topical formulations of some embodiments of the present disclosure may comprise effective amounts of carriers or ingredients, either alone or in combination, including but not limited to, carriers or ingredients such as solvents, gelling agents, polymers, biodegradable polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers, tackifiers, surfactants, volatile chemicals, antioxidants, oxidizing agents, chelating agents, complexing agents, diluents, excipients, materials for preparing patches, materials for preparing matrix patches or reservoir patches.

[0091] Dronabinol may be dissolved, suspended, dispersed, or homogeneously mixed in the single carrier, mixtures of carriers, and combinations of carriers described above.

[0092] The desired optimal transdermal and / or topical formulation of dronabinol may include, but is not limited to, the following carriers, either alone or in combination, as described in Examples 1-11:

[0093] Example Example 1 Transdermal and / or topical formulations may contain solvents, alone or in combination, including but not limited to C1-C20 alcohols such as, but not limited to, methanol, ethanol, isopropyl alcohol, butanol, propanol, etc.; polyhydric alcohols such as, but not limited to, propylene glycol, polyethylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, glycerin, etc.; glycols, derivatives of glycols such as, but not limited to, N-methyl 2-pyrrolidone, 2-pyrrolidone, etc.; pyrrolidones; sulfoxides such as, but not limited to, dimethyl sulfoxide, decyl methyl sulfoxide, etc.; dimethyl isosorbide that can be used to prepare matrix patches such as, but not limited to, ethanol, propanol, ethyl acetate, acetone, methanol, dichloromethane, chloroform, toluene, IPA; mineral oil, vegetable oil, water; polar solvents, semi-polar solvents, non-polar solvents; volatile chemicals; acids such as, but not limited to, acetic acid, lactic acid, levulinic acid, fatty acids, bases, and others. The solvents mentioned are in one embodiment in the range of 0.01% to 95% w / w (or w / v).

[0094] Example 2 The transdermal and / or topical formulations may contain gelling and / or thickening and / or suspending agents, alone or in combination, including but not limited to natural polymers such as, but not limited to, agar, alginic acid and derivatives, cassia, collagen, gelatin, gellan gum, guar gum, pectin, potassium or sodium carrageenan, tragacanth, xanthan, gum copal, chitosan, resins, etc.; polysaccharides and derivatives thereof; semi-synthetic polymers and derivatives thereof such as, but not limited to, cellulose and its derivatives (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxylpropylcellulose, hydroxylpropylmethylcellulose, etc.); carboxyvinyl polymers or carbomers (Carbopol 940, Carbopol 934, Carbopol 971p); NF), synthetic polymers and derivatives thereof such as polyethylene and its copolymers, clays such as but not limited to (silicates, bentonite), silicon dioxide, polyvinyl alcohol, eudragit, acrylic esters, polyacrylate copolymers, polyacrylamides, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers such as but not limited to (PVP, Kollidon 30, poloxamer), isobutylene, ethyl vinyl acetate copolymers, natural rubber, synthetic rubber, pressure sensitive adhesives such as silicone polymers such as but not limited to (bio-psa 4302, bio-psa 4202, etc.), but not limited to (DURO-TAK 87-2156, DURO-TAK 387-2287, etc.), polyisobutylenes such as, but not limited to, (Polyisobutylene low molecular weight, Polyisobutylene medium molecular weight, Polyisobutylene 35000mw, etc.), acrylic copolymers, rubber-based adhesives, hot melt adhesives, styrene-butadiene copolymers, bentonite, water and / or organic solvent swellable polymers in general, etc. In one embodiment, the mentioned agents are in the range of 0.1% to 70% w / w or w / v.

[0095] Example 3 The transdermal and / or topical formulations of the present disclosure may contain penetration enhancers known to those skilled in the art, either alone or in combination, including but not limited to sulfoxides such as (dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, decimethyl sulfoxide, dimethyl isosorbide, etc.) and similar chemicals, azones such as (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), pyrrolidones, esters such as (propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monooleate, glycerol monolaurate, lauryl laurate, etc.), fatty acid esters, carboxylates, carboxymethyl ester ... Fatty acids such as caprylic acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc., alcohols such as but not limited to (oleyl alcohol, naphthalene, dodecanol, propylene glycol, glycerol, etc.), fatty alcohols and glycols, ether alcohols such as but not limited to (diethylene glycol monoethyl ether), urea such as essential oils, triglycerides, surfactant type enhancers such as but not limited to (brij, sodium lauryl sulfate, tween, polysorbates), terpenes, terpenoids, and all transdermal penetration or permeation enhancers mentioned in the book "Percutaneous Penetration Enhancers" (Eric W. Smith, Howard I. Maibach, 2005. Nov, CRC press). The mentioned agents are in one embodiment in the range of 0.01% to 95% w / w (or w / v).

[0096] Example 4 The transdermal and / or topical formulations may contain, alone or in combination, plasticizers, including, but not limited to, glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacates, citrates, tartrates, adipates, phthalates, triacetin, oleates, and all plasticizers that can be used in transdermal drug delivery systems, as mentioned in the book "Handbook of Plasticizers" (George Wypych, 2004, Chem Tec Publishing). The mentioned agents, in one embodiment, range from 0.01% to 95% w / w (or w / v).

[0097] Example 5 The transdermal and / or topical formulations may contain, either alone or in combination, emollients, moisturizers, and / or skin irritation reducers, including but not limited to petrolatum, lanolin, mineral oil, dimethicone, zinc oxide, glycerin, propylene glycol, etc. The mentioned agents, in one embodiment, range from 0.01% to 95% w / w (or w / v).

[0098] Example 6 The transdermal and / or topical formulations may contain, alone or in combination, agents such as, but not limited to, solubilizers, surfactants, emulsifiers, dispersants; surfactants, including anionic, cationic, nonionic, and amphoteric surfactants, such as, but not limited to, sorbitan oleate under the tradename SPAN, Span 80, Span 20, and polysorbates, such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol monocaprylate type I, propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol monocaprylate type III ... Examples of suitable additives include capryloyl caprylate type II, propylene glycol dicaprylate, medium chain triglycerides, propylene glycol monolaurate type II, linoleoyl polyoxyl-6 glyceride, oleoyl-polyoxyl-1-6-glyceride, lauroyl polyoxyl-6-glyceride, polyglyceryl 1-3-dioleate, diethylene glycol monoethyl ether, propylene glycol monolaurate type I, polyglyceryl-3-dioleate, caprylocaproyl polyoxyl-8 glyceride, cyclodextrins, etc. The mentioned agents, in one embodiment, are in the range of 0.01% to 95% w / w (or w / v).

[0099] Example 7 Different techniques and ingredients such as, but not limited to, coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, chelating agents, complexing agents, etc. may be used to enhance the stability and / or solubility of dronabinol in the formulation.

[0100] Example 8 The transdermal and / or topical formulations may contain, either alone or in combination, auxiliary pH buffers and stabilizers and similar compounds known to those skilled in the art to maintain a suitable pH of the formulation, preferably in the range of 4.0 to 8.0; phosphate buffer, acetate buffer, citrate buffer, etc.; acids, including but not limited to carboxylic acids, inorganic acids, sulfonic acids, vinyl carboxylic acids, fatty acids, etc.; bases, including but not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, etc. The above agents, in one embodiment, range from 0.01% to 30% w / w or w / v.

[0101] Example 9 The transdermal and / or topical formulations may contain antioxidants, oxidizing agents, stabilizers, discoloring agents, preservatives, and similar compounds or chemicals, such as, but not limited to, sodium metabisulfite, citric acid, ascorbic acid, BHA, and BHT, to provide a stable formulation. The mentioned agents, in one embodiment, range from 0.01% to 50% w / w (or w / v).

[0102] Example 10 Transdermal and / or topical preparations containing dronabinol formulated in ointment and / or cream bases, gels, lotions, and other topical preparations.

[0103] Example 11 Materials for making the transdermal delivery system of the present disclosure, in patch forms known to those skilled in the art, such as, but not limited to, reservoir patches, matrix patches, drug in adhesive, transdermal films, etc., may include, either alone or in combination, polymers, copolymers, derivatives, backing films, release membranes, release liners, etc., pressure-sensitive adhesives (including, but not limited to, silicone polymers, rubber-based adhesives, acrylic polymers, acrylic copolymers, polyisobutylene, acrylic acid-isooctyl acrylate copolymers, hot melt adhesives, polybutylene, etc.), backing films (including, but not limited to, ethylene vinyl acetate copolymers, vinyl acetate resins, polyurethanes, polyvinyl chloride, metal foils, polyesters, aluminized films, polyethylene, etc.), release membranes (including, but not limited to, microporous polyethylene membranes, microporous polypropylene membranes, rate-controlling ethylene vinyl acetate copolymer membranes), release liners (including, but not limited to, siliconized polyester membranes, fluoropolymer-coated polyester membranes, polyester membranes, siliconized polyethylene terephthalate membranes, etc.), tapes, etc.

[0104] The transdermal and / or topical formulations and / or transdermal delivery systems of the present disclosure can deliver at least a therapeutically effective dose of dronabinol. A therapeutically effective dose of dronabinol refers to the therapeutic concentration of dronabinol in human plasma required to treat and / or prevent chemotherapy-associated nausea and / or vomiting. Furthermore, the precise therapeutically effective amount of dronabinol in a transdermal or topical formulation or transdermal delivery system can be determined by one skilled in the art based on factors such as, but not limited to, the patient's condition. The transdermal or topical formulations or transdermal delivery systems may be available in different dosage strengths and patch sizes to achieve optimal therapeutic results based on the patient's requirements.

[0105] In another embodiment, the transdermal and / or topical formulations and / or transdermal delivery systems of the present disclosure are capable of delivering at least a therapeutically effective dose of dronabinol. A therapeutically effective dronabinol dose refers to the therapeutic concentration of dronabinol in human plasma required for treatment, as described in the Marinol label "Anorexia Associated with Weight Loss in AIDS Patients" (see label). Furthermore, the precise therapeutically effective amount of dronabinol in a transdermal or topical formulation or transdermal delivery system can be determined by one of skill in the art based on factors such as, but not limited to, the patient's condition. The transdermal or topical formulations or transdermal delivery systems may be available in different dosage strengths and patch sizes to achieve optimal therapeutic results based on the patient's requirements.

[0106] The transdermal formulation or transdermal patch of dronabinol can be applied to the skin surface preferably in one of the following dosing regimens, including, but not limited to, once daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 to about 13 days, once every 2 weeks, or once every 15 days.

[0107] Example 12 Synthetic delta-9-THC formulations for transdermal delivery (Formulation Nos. 001, 002, 006, 007, 008, and 009) were prepared by mixing the ingredients as shown in Table 2. [Table 2]

[0108] All of the ingredients in Table 2, except for THC, were mixed together with stirring for 18 hours. The THC in ethanol was then added to the excipient mixture to prepare the final transdermal formulation.

[0109] The prepared transdermal formulations were then subjected to flux measurement testing as follows. Human cadaver skin stored at -80°C was thawed at room temperature in phosphate-buffered saline (PBS) and visually inspected for defects before use in testing. Transdermal flux was then measured using a standard Franz diffusion cell, consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment with a volume of 13 mL. The human cadaver skin was clamped between the two compartments, with the dermis facing the receptor compartment. The donor compartment was filled with the transdermal THC formulation prepared as described above. The receptor compartment was filled with receptor medium, maintained at a constant temperature, and constantly stirred to collect THC as it diffused through the skin into the receptor compartment. It is important to ensure that receptor fluid is constantly in contact with the skin. The receptor compartment was emptied and replaced with fresh receptor solution at 24-hour intervals for assay of delta-9-THC. It is important to maintain the delta-9-THC concentration in the receptor compartment below 10% of its solubility to maintain a submerged state in the receptor compartment. The experimental conditions are shown in Table 3. [Table 3]

[0110] The flux of THC through human cadaver skin was measured for a minimum of 96 hours (4 days). The flux results are shown in Table 4. [Table 4]

[0111] Example 13 Additional synthetic delta-9-THC formulations for transdermal delivery (Formulation Nos. 010-018) were prepared by mixing the ingredients as shown in Table 5. [Table 5]

[0112] A synthetic delta-9-THC formulation (010-018) for transdermal delivery was prepared using the same procedure as described in Example 12. Flux measurements were also performed as described in Example 12. The experimental conditions were the same as those provided in Table 3 of Example 12.

[0113] The flux of THC through human cadaver skin was measured for a minimum of 96 hours (4 days). The results of the flux measurement experiments are shown in Table 6. [Table 6]

[0114] Example 14 Additional synthetic delta-9-THC formulations for transdermal delivery (Formulation Nos. 019-027) were prepared by mixing the ingredients as shown in Table 7. [Table 7]

[0115] Synthetic delta-9-THC formulations (019-027) for transdermal delivery were prepared using the same procedure described in Example 12. Flux measurements were also performed as described in Example 12. The experimental conditions were the same as those provided in Table 3 of Example 12.

[0116] The flux of THC through human cadaver skin was measured for a minimum of 72 hours (3 days). The results of the flux measurement experiments are shown in Table 8. [Table 8]

[0117] Example 15 Additional synthetic delta-9-THC formulations for transdermal delivery (Formulation Nos. 028-034) were prepared by mixing the ingredients as shown in Table 9. [Table 9]

[0118] Synthetic delta-9-THC formulations for transdermal delivery (Formulation Nos. 028-034) were prepared by the same procedure described in Example 12. Flux measurements were also performed as described in Example 12. The experimental conditions were the same as those provided in Table 3 of Example 12.

[0119] The flux of THC through human cadaver skin was measured for a minimum of 120 hours (5 days). The results of the flux measurement experiments are shown in Table 10. [Table 10]

[0120] Example 16 Additional synthetic delta-9-THC formulations for transdermal delivery patches (Formulation Nos. 035-038) were prepared by mixing the ingredients as shown in Table 11. [Table 11]

[0121] To prepare a transdermal patch containing synthetic delta-9-THC, all ingredients in Table 11, except for THC, were mixed together with stirring for 18 hours. THC was then added 30 minutes before spreading the formulation. The formulation was spread using a commercially available benchtop spreader. Specifically, the formulation matrix was evenly spread to a thickness of 0.5 mm onto an 8x14 inch (20.3x35.6 cm) release liner sheet (such as 3M 9744). The sheet was then placed in a 100°F (37.8°C) oven for 1 hour to evaporate the ethyl acetate and ethanol adhesive solvents. To inhibit degradation by light and oxidation, an opaque backing film with low permeability to oxygen (such as 3M 9730 NR film) was then carefully applied by hand to the sheet to avoid the formation of bubbles and voids. A circular die (1.5 inch (3.8 cm) diameter) was used to cut patches (7 cm) for subsequent testing. 2 ) was cut off.

[0122] The general procedure for measuring the flux of the transdermal formulations in the above examples was as follows: Human cadaver skin stored at -80°C was thawed in PBS at room temperature and visually inspected for defects before use. Transdermal flux was measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment and a separate water-jacketed cylindrical receptor compartment with a volume of 13 mL. The human cadaver skin was clamped between the two compartments with the dermis side facing the receptor compartment. The general procedure for measuring the flux of the transdermal adhesive patch was as follows: The release liner was peeled from the patch and the adhesive side was applied to human cadaver skin (Example 16, Table 11 only). The transdermal patch was adhered to the skin with the side of the patch in contact with the donor compartment. The receptor compartment was filled with receptor medium, maintained at a constant temperature, and constantly stirred to collect THC as it diffused from the attached patch through the skin into the receptor compartment. It was ensured that the receptor fluid was in constant contact with the skin. The receptor compartment was emptied and replaced with fresh receptor solution at 24-hour intervals for delta-9-THC assay. To maintain a submerged state in the receptor compartment, the delta-9-THC concentration in the receptor compartment was maintained below 10% of its solubility. The experimental conditions were the same as those provided in Table 3 of Example 12.

Claims

1. A pharmaceutical composition in the form of a transdermal matrix patch comprising dronabinol, wherein the dronabinol is present in a concentration of about 1% to about 15% w / w; The pharmaceutical composition further comprises: a solvent comprising about 0.5% to about 17% w / w propylene glycol; a penetration enhancer comprising about 2% to about 30% w / w oleic acid; about 50% to about 90% w / w silicone pressure sensitive adhesive Including, The transdermal matrix patch provides a mean flux of dronabinol of about 0.10 μg / cm for at least 6 days. ２ / hour ~ approx. 0.6μg / cm ２ A pharmaceutical composition provided at 100 mg / h.

2. 10. The pharmaceutical composition of claim 1, which does not contain an additional antiemetic drug.

3. 10. The pharmaceutical composition of claim 1, wherein the dronabinol is in a form selected from the group consisting of co-crystal, amorphous, coated, crystalline, salt, isomer, solid solution, prodrug, analog, derivative, metabolite, solution, synthetic, ethanol solution, and naturally occurring delta-9-tetrahydrocannabinol.

4. 10. The pharmaceutical composition of claim 1, wherein the dronabinol is selected from the group consisting of amorphous dronabinol, synthetic delta-9-tetrahydrocannabinol, and an ethanolic solution of dronabinol in the range of 0.01% to 95% w / w or w / v.

5. 10. The pharmaceutical composition of claim 1, further comprising an effective amount of a carrier or ingredient selected from the group consisting of gelling agents, polymers, emollients, skin irritation reducers, tackifiers, diluents, bulking agents, solubilizers, dispersants, stabilizers, plasticizers, antioxidants, chelating agents, and combinations thereof.

6. 1. A method for the treatment of nausea and / or vomiting associated with cancer chemotherapy, comprising: Selecting patients in need of treatment for nausea and / or vomiting associated with cancer chemotherapy; and 10. Topical application or instructions for topical application of the pharmaceutical composition of claim 1. A method comprising:

7. 7. The method of claim 6, wherein the transdermal matrix patch can be topically applied at a dosage regimen selected from the group consisting of once every 3 days, once a week, once every about 8 to about 13 days, and once every two weeks.

8. 7. The method of claim 6, wherein the transdermal matrix patch is topically applied for a period selected from 3 days, 4 days, 5 days, 6 days, or up to 10 days.

9. 7. The method of claim 6, wherein the topical applying provides a constant rate of delivery of the active ingredient of the transdermal patch over a period of time.

10. 7. The method of claim 6, wherein the topical application achieves a constant serum level of dronabinol over a period of time.

11. 7. The method of claim 6, wherein the topical application achieves reduced fluctuations in serum levels of dronabinol over a period of time compared to oral administration of dronabinol over a period of time.

12. 7. The method of claim 6, wherein the topical application achieves a plasma concentration of dronabinol in the therapeutic range over a period of time.

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