Transdermal delivery of dronabinol

Abstract

A transdermal drug delivery system containing dronabinol is provided, which provides drug plasma concentrations at a predetermined rate for a predetermined period of time, thereby simplifying treatment regimens by reducing dosing frequency, for example, for the treatment and / or prevention of chemotherapy-associated nausea and / or vomiting.

Description

[Technical Field]

[0001] Cross-reference with related applications This application claims the benefits of U.S. Provisional Application No. 62 / 910,255, filed on 3 October 2019, which is incorporated herein by reference.

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

[0003] Nausea and vomiting are common side effects of cancer chemotherapy. Drugs such as dronabinol and 5-HT3 receptor antagonists are recommended for the treatment of nausea and vomiting associated with cancer chemotherapy. Sometimes, one or more drugs 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. January 2017;25(1):277-288. Epub July 22, 2016).

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

[0005] Many drawbacks are associated with dronabinol oral capsules. The first challenge is the administration regimen. For antiemetic effects, the following administration regimen is recommended: initial dose of 5 mg / m² 1-3 hours before chemotherapy. 2 Administer orally. After chemotherapy, administer the drug every 2-4 hours for a total of 4-6 times per day. Depending on the clinical response, if the dose is not sufficiently effective, reduce the dose to 2.5 mg / m². 2 With this increment, it becomes approximately 15 mg / m². 2 The dose increases to [amount]. This dosing regimen is unsuitable for patients who have already experienced nausea and vomiting. The second challenge is that the pharmacological response is dose-dependent and variable among patients. The third challenge is that at the maximum dose, there is a higher likelihood of disrupting psychiatric symptoms. The fourth challenge is that after oral administration, dronabinol undergoes first-pass hepatic metabolism and has high lipid solubility, so 10% to 20% of the administered dose reaches systemic circulation. Another challenge is that the active ingredient, dronabinol, is unstable in capsules at room temperature; therefore, capsules should be packaged in a sealed container and stored in a refrigerator or at 8°C to 15°C (see label). Dronabinol capsules are stable for only 3 months at room temperature. This is because synthetic delta-9-THC exhibits rapid oxidation and acid- and basic degradation. Furthermore, synthetic delta-9-THC degrades more rapidly in light and at high temperatures. Therefore, if dronabinol capsules are not stored refrigerated in their original container, the concentration of delta-9-THC in the capsules may decrease and fall below the therapeutically necessary level.

[0006] Previous studies have used naturally derived delta-9-THC from the marijuana plant Cannabis sativa L. However, extracting pure delta-9-THC from plant sources such as sativa L is difficult. This is due to the contamination of the extract by 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, among other considerations, due to the psychoactive properties of THC. Alternatively, the synthetic form of delta-9-THC is developed through a more controlled procedure, in contrast to the extraction process of its naturally derived counterpart. For example, the synthetically produced delta-9-THC essentially consists of uncontaminated delta-9-THC, free from the presence of other active cannabidiols. Therefore, the synthetic form of delta-9-THC has a maximum flux of 0.01 μg / cm³ across rat skin compared to naturally extracted delta-9-THC. 2 Compared to previously published studies using naturally derived delta-9-THC, it can provide improved transdermal permeability (U.S. Patent No. 6503532).

[0007] U.S. Patent No. 6,328,992 is also related to preparations for the transdermal delivery of cannabinoids. However, the present disclosure describes different combinations of cannabinoids and does not describe the use of only pure synthetic delta-9-THC. Furthermore, the '992 patent inventors describe the use of a permeation enhancer that is not pharmaceutical grade and is not included in the U.S. Food and Drug Administration Inactive Ingredient Listing (FDA IIG). Thus, the disclosure of the '992 does not provide a composition having any pharmaceutical utility. Additionally, the '992 patent describes the use of rat skin containing 50% ethanol in the receptor medium for transdermal permeability testing. However, ethanol can disrupt the skin structure of the dermis and increase the in vitro flux value, resulting in inappropriate results for transdermal patches for pharmaceutical use. For example, the skin of ethanol-treated rats is approximately 10 times more permeable than the skin of human cadavers.

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

[0009] To deliver a therapeutic dose of 5 mg / day of delta-9-THC, the transdermal formulation would need to cover at least 325 cm 2 5 of the patient's skin surface area. This is a patch size that is not practical for any transdermal drug delivery system (TDDS).

[0010] Therefore, an improved drug delivery system for dronabinol is needed that can overcome the aforementioned drawbacks associated with oral administration and naturally derived delta-9-THC. As provided herein, transdermal delivery of dronabinol containing synthetic delta-9-THC can address the challenges associated with oral drug delivery. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] The embodiments and models described and illustrated below are intended to be illustrative and illustrative, and are not intended to limit the scope.

[0012] In one embodiment, a pharmaceutical composition containing dronabinol in a transdermal delivery dosage form is provided.

[0013] In one embodiment, the pharmaceutical composition does not contain additional antiemetics.

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

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

[0016] In one embodiment, dronabinol is selected from the group consisting of amorphous dronabinol, crystalline dronabinol, cocrystals of dronabinol, coated dronabinol, and ethanol solutions of dronabinol, and is in the range of 0.01% to 95% w / w or w / v of dronabinol.

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

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

[0019] In one embodiment, an effective amount of a carrier or component is included in the composition, either alone or in any combination thereof. In one embodiment, the carrier or component is selected from the group consisting of a solvent, a gelling agent, a polymer, a penetration enhancer, a skin softener, a skin irritation reducer, a buffer, a pH stabilizer, a solubilizer, a suspending agent, a dispersing agent, a stabilizer, a plasticizer, a surfactant, an antioxidant, and an oxidizing agent.

[0020] In one embodiment, the carrier or component is in the range of about 0.01% - 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 controlled-release transdermal film.

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

[0024] In one embodiment, the microneedle is 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 who requires treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy, and topically applying or instructing to topically apply the pharmaceutical composition described herein, wherein the topical application is performed at least once a day.

[0026] In one embodiment, the composition is a liquid formulation and / or a semi-solid formulation, and topical application is performed 2 to 6 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once a week.

[0027] In one embodiment, the composition is applied topically once every two days, once every three days, once every four days, once every five days, once every six days, once every week, or once every ten 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, topical application provides a stable absorption rate of dronabinol over a period of time.

[0030] In one embodiment, topical application can achieve a certain serum level of dronabinol over a period of time.

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

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

[0033] In one embodiment, a method for treating and / or preventing and / or controlling 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 applying or instructing to apply a pharmaceutical composition described herein topically, thereby achieving topical delivery of dronabinol for 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 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, or once every ten days.

[0035] In one embodiment, the pharmaceutical composition is applied topically 2 to 6 times a day, 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.

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

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

[0038] In addition to the exemplary embodiments and models described above, further embodiments and models will become apparent by referring to the drawings and considering the following description.

[0039] Additional embodiments of the method and composition will become apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and the following description, each and all features described herein, as well as each and all combinations of two or more such features, are included within the scope of the 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 disclosure. Additional aspects and advantages of the disclosure are described in the following description and claims, particularly in conjunction with the appended examples and drawings. [Brief explanation of the drawing]

[0040] [Figure 1] This graph shows the plasma concentration of a drug in relation to time (hours) when delivered via oral route (white circles) or transdermal route (black circles). [Modes for carrying out the invention]

[0041] In transdermal drug delivery, a transdermal patch or transdermal composition is applied topically to the skin surface. During the period of topical application of the transdermal patch or transdermal composition, the drug is continuously released and delivered through intact skin (via transcellular, intercellular, and transadnexal pathways) to achieve a systemic effect. Therefore, once applied, the transdermal composition or transdermal patch can deliver the drug into the systemic circulation throughout the day or beyond (potentially for up to a week or more), depending on the duration of its application.

[0042] Transdermal delivery can reduce the frequency of administration of dronabinol, which is currently administered orally 4 to 6 times a day. Through transdermal delivery, a transdermal composition, preparation, or patch of dronabinol can be applied topically to the skin, thereby delivering the drug throughout the entire period of topical application. Depending on the requirements, the duration of topical application may be once daily, 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 break away from the multi-dose regimen of oral delivery by reducing the frequency of administration.

[0043] Furthermore, with transdermal drug delivery, the drug is delivered slowly and continuously throughout the period of topical application, so there are no peaks and troughs in drug plasma concentration associated with multiple daily doses. Therefore, with transdermal delivery of dronabinol, patients can experience the therapeutic effects of the drug over a long period without dramatic changes in drug plasma concentration.

[0044] In transdermal delivery, drugs are delivered to the systemic circulation via the skin, bypassing first-pass hepatic metabolism. Therefore, less drug is required to achieve the desired therapeutic activity, resulting in reduced adverse effects or side effects. Dronabinol is highly lipid-soluble and undergoes first-pass hepatic metabolism after oral administration, with 10% to 20% of the dose reaching the systemic circulation. Therefore, compared to oral administration, transdermal delivery allows lower doses of dronabinol to produce the desired therapeutic effect while also overcoming the mental disturbances associated with high doses.

[0045] Furthermore, the transdermal delta-9-THC delivery described herein offers nearly 10 times higher 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), the following pharmacokinetic (PK) parameters were observed when administered twice daily to healthy volunteers (n=34; 20-25 years old) in a fasted state (see label). [Table 1]

[0047] Furthermore, according to PK parameters, the maximum plasma concentration for oral delivery of 5 mg / day via dronabinol capsules is 1.32 ng / mL, and the maximum plasma concentration for oral delivery of 20 mg / day is 7.88 ng / mL. Oral delivery PK values ​​show the peaks and troughs of plasma concentration over time. In contrast to oral delivery, transdermal drug delivery delivers drug molecules at a predetermined rate and maintains a constant mean plasma concentration over time (Figure 1).

[0048] The mean plasma concentration is calculated using the following method: Average plasma concentration of 5 mg / day = 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 0.24–1.27 ng / mL.

[0050] To prevent nausea and vomiting, the oral route is often the least convenient. If the patient has already experienced nausea and vomiting and vomits immediately after drug administration, it remains uncertain whether the dose was absorbed or vomited. Transdermal dronabinol, on the other hand, is delivered via the skin, which completely eliminates this type of uncertainty.

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

[0052] Alternatively, the TDDS system provided herein provides constant drug delivery at a predetermined defined input rate. Therefore, the provided TDDS system yields a constant mean plasma concentration at a constant input rate and does not exhibit the peaks and troughs in the PK of plasma concentration associated with orally delivered delta-9-THC. Consequently, the currently provided TDDS system is also less likely to cause CNS side effects compared to orally delivered equivalents. For example, the adverse effects of delta-9-THC are less pronounced at a dose of delta-9-THC of 7 mg / m². 2 Therefore, it is not triggered.

[0053] Furthermore, oral doses need to be delivered 4-6 times a day instead of once a day to avoid adverse effects. Additionally, oral doses undergo first-pass metabolism, with only 10-20% of the oral dose becoming available in plasma, resulting in an inefficient delivery method and significant loss of active pharmaceutical ingredients. Moreover, to achieve therapeutic effects from any drug molecule, the drug must undergo continuous delivery to achieve steady-state plasma concentrations or plasma concentrations within the therapeutic window (between minimum and maximum therapeutically effective concentrations). Therefore, the TDDS system for delta-9-THC provided herein addresses a long-held and unmet need in the field of cannabidiol-based pharmaceuticals.

[0054] Furthermore, transdermal delivery is easy, non-invasive, and convenient. Administration of transdermal patches or compositions does not require medical supervision, as patients can apply the patches or compositions themselves.

[0055] Regarding dronabinol, inter-patient variability in pharmacological responses is expected to be lower with transdermal delivery, as drug plasma concentrations can be controlled by controlling the rate of drug delivery from transdermal compositions or patches. The alpha half-life of dronabinol is approximately 4 hours, and with oral administration, it is rapidly metabolized in the body. In contrast, transdermal delivery allows for the delivery of smaller amounts of dronabinol over a longer period than oral administration. Transdermal formulations of dronabinol also offer greater abuse deterrence than immediate-release formulations.

[0056] Furthermore, in the event of any adverse effects, side effects, or urgent transdermal delivery, the treatment is terminated at any time by removing the transdermal patch or transdermal composition from the skin.

[0057] For the reasons stated above, transdermal delivery can provide a more patient-friendly, simplified, and convenient treatment regimen than conventional delivery systems to prevent nausea and vomiting associated with cancer chemotherapy. Transdermal delivery can reduce the frequency of dronabinol administration. Depending on the needs, the frequency may be once daily, 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 various different medications, some of which are administered multiple times a day. Formulating antiemetic drugs(s) as transdermal patches or compositions provides a considerably simplified dosing regimen for patients who are already weakened and fatigued by chemotherapy. Depending on the circumstances, the frequency of administration of the drug-containing transdermal patch or composition may be once daily, 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 would be a great help to 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, crystals of dronabinol, amorphous forms, and / or inert substances.

[0060] In one embodiment, a transdermal drug delivery composition is envisioned, in the form of a transdermal patch or delivery system containing dronabinol. Transdermal delivery can deliver drug plasma concentrations at a predetermined rate for a predetermined period of time in a simplified treatment regimen by reducing the frequency of administration. Preferably, dronabinol is selected from the group including, but is not limited to, cocrystals of dronabinol, amorphous forms of dronabinol, coated dronabinol, and crystalline forms of dronabinol.

[0061] As used herein, “dronabinol” means, but is not limited to, all forms of dronabinol, either alone or in combination thereof; for example, delta-9-tetrahydrocannabinol, or the free base or salt of synthetic delta-9-tetrahydrocannabinol, or isomers or amorphous forms, or crystalline or cocrystals, or solid solutions, or prodrugs or analogs, or derivatives or metabolites, or coated forms, or natural extracts, or solutions of dronabinol. For example, the free form of dronabinol, or its salts, or its isomers, or its amorphous forms, or its crystalline forms, or its cocrystals, or its solid solutions, or its prodrugs, or its analogs, or its derivatives, or metabolites, or its coated forms, or natural extracts of delta-9-tetrahydrocannabinol, or synthetic delta-9-tetrahydrocannabinol, or solutions of dronabinol in ethanol. Dronabinol may be in the form of pharmaceutically acceptable salts, e.g., acid addition salts or basic salts, or its solvates (its hydrates). A suitable acid addition salt is formed from an acid that forms a non-toxic salt. Chemical name: (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-1-3-penti-1-6H-dibenzo[b,d]pyran-1-ol Experimental formula: C 21 H 30 O2 Molecular weight: 314.47 Structure: Formula (I) [ka]

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

[0063] In embodiments of this disclosure, preferred forms of dronabinol are selected from the group including, but are not limited to, dronabinol cocrystals, dronabinol amorphous forms, coated dronabinol, and dronabinol crystalline forms. Cocrystals, coated dronabinol, and crystalline forms of dronabinol can be prepared.

[0064] The amorphous form of a drug does not have a distinct structure. The amorphous form of a drug has higher solubility compared to its crystalline form. Amorphous forms of drugs are manufactured using various techniques and methods.

[0065] As stated in the regulatory classification of the industry guidance on pharmaceutical co-crystals, "a co-crystal is a crystalline material composed of two or more different molecules in the same crystal lattice, typically a drug and a co-crystal-forming agent ("co-forming agent")" (see USD Department 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, https: / / www.fda.gov / downloads / Drugs / Guidances / UCM516813.pdf, accessed July 12, 2017). Various methods are available for the preparation of co-crystals. Each drug has a different chemical structure and physicochemical properties, making it difficult to predict the success rate of co-crystallization reactions. Tests under various experimental conditions are being conducted to determine approaches for forming drug cocrystals (see Nate Schultheiss, Ann Newman, Pharmaceutical Cocrystals and their Physicochemical Properties, Cryst Growth Des., January 3, 2009; 9(6):2950-2967).

[0066] Drug coating can be performed using polymers or other excipients. Various techniques are used for drug coating. Drug stability can also be enhanced by encapsulation.

[0067] As used herein, the term “pharmaceutically acceptable salt” includes acid addition salts or addition salts of a free base. Within that scope, the term “pharmaceutically acceptable salt” of dronabinol includes all possible isomers and mixtures thereof, as well as any pharmaceutically acceptable metabolites, bioprecursors and / or prodrugs, for example, compounds that are different from one of the compounds of this disclosure but have a structural formula that, when administered to a mammalian subject, such as a human, is directly or indirectly converted to one of the compounds of this disclosure in vivo.

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

[0069] As used herein, the terms “subject” and “patient” are used synonymously. As used herein, the term “patient” refers to mammals, most preferably humans, including animals, non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, etc.) and primates (e.g., monkeys and humans). In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, pig, or cattle) or a pet (e.g., a 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 used for the prevention, treatment, management and / or diagnosis of a disease or condition.

[0071] As used herein, “effective dose” means a quantity of a treatment that is sufficient to prevent the onset, recurrence, or onset of a disease or condition and one or more of its symptoms; to reduce its severity; to shorten the duration of a disease or condition; to improve one or more of the symptoms of a disease or condition; to prevent the progression of a disease or condition; to cause regression of a disease or condition; and / or to enhance or improve the therapeutic effect(s) of another treatment.

[0072] As used herein, the phrase “pharmaceutically acceptable” means that it has been approved by a federal or state regulatory authority for use in animals, more specifically in humans, or that it is listed in the United States Pharmacopeia, the European Pharmacopeia, or any other generally accepted pharmacopoeia.

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

[0074] As used herein, the term “treatment” may refer to any method, composition, and / or agent 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 “treatment” may refer to a small molecule therapy.

[0075] As used herein, the terms “derivative” or “derivativeization” include chemical modifications of the compounds of this disclosure, or pharmaceutically acceptable salts thereof or mixtures thereof. That is, a “derivative” may be a functional equivalent of a compound of this disclosure that can induce improved pharmacological activity in a given subject.

[0076] As used herein, the terms “composition” and “formulation” are used synonymously.

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

[0078] Transdermal composition 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 preparation comprises dronabinol in a form selected from the group including cocrystalline, amorphous, crystalline, coated, and aqueous salts thereof, which may be anhydrous and / or aqueous alone or in combination thereof. More preferably, the transdermal preparation may comprise dronabinol alone or in combination thereof in one of the following forms: amorphous or cocrystalline or crystalline or coated, or an ethanol solution thereof.

[0080] One embodiment of the present disclosure may be a transdermal drug delivery system that includes, but is not limited to, transdermal formulations, transdermal patches, topical formulations, microneedles, iontophoresis, or quantitative transdermal sprays.

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

[0082] Transdermal patches may preferably include all transdermal drug delivery systems described in the Art, but are not limited to reservoir patches, matrix patches, two-layer matrix patches, multilayer matrix patches, microreservoir patches, adhesive systems, transdermal tapes, etc.

[0083] In certain embodiments of the present disclosure, a 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 dronabinol to pass from the transdermal patch through the patient's skin. The transdermal delivery system may be occlusive, semi-occlusive, or non-occlusive, and may 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. In some embodiments, the predetermined period is approximately 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 patch described herein provides a stable absorption rate of the active ingredient of the transdermal patch by the patient over a predetermined period of time. In some embodiments, the predetermined period 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 patch described herein provides a patient with a constant serum level of the active ingredient of the transdermal patch over a predetermined period of time. In some embodiments, the predetermined period is approximately 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 patch described herein provides a plasma concentration of the active ingredient of the transdermal patch within the patient's therapeutic area over a predetermined period of time. In some embodiments, the predetermined period is approximately 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 a reduction in the variation of the dose of the active ingredient in a patient over a predetermined period of time. In some embodiments, the predetermined period is approximately 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 this art include, but are not limited to, ointments, creams, emulsions, microemulsions, nanoemulsions, pastes, perfumes, gels, lotions, mousses, and other semi-solids; liquids such as solutions, suspensions, microsuspensions, nanosuspensions, dispersions, and nanodispersions; and sprays, aerosols, and magmas. Topical formulations containing dronabinol can be applied topically to the skin surface for transdermal delivery of dronabinol.

[0090] Transdermal and / or topical formulations of some embodiments of the present disclosure may contain, alone or in combination, effective amounts of carriers or components, without being limited to carriers or components such as solvents, gelling agents, polymers, biodegradable polymers, penetration enhancers, emollients, skin irritation reducing agents, buffers, pH stabilizers, solubilizers, suspending agents, dispersants, 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, mixture of carriers, or combination of carriers described above.

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

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

[0094] Example 2 Transdermal and / or topical preparations include, but are not limited to, gelling agents and / or thickeners and / or suspending agents, either alone or in combination; natural polymers such as (agar, alginic acid and derivatives, cassia tora, collagen, gelatin, gellan gum, guar gum, pectin, potassium, or sodium carrageenan, tragacanth, xantham, gum copal, chitosan, resins, etc.), polysaccharides and their derivatives, semi-synthetic polymers and their derivatives such as cellulose and its derivatives (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), synthetic polymers and their derivatives such as carboxyvinyl polymers or carbomers (Carbopol 940, Carbopol 934, Carbopol 971p NF), polyethylene and its copolymers such as (silicates, bentonite), clay, and (PVP, Kollidon) (but are not limited to these); 30. Polyisobutylene swellable polymers such as silicon dioxide (e.g., poloxamer), polyvinyl alcohol, acrylic polymers (eudragit), acrylic acid esters, polyacrylate copolymers, polyacrylamide, polyvinylpyrrolidone homopolymers and polyvinylpyrrolidone copolymers, isobutylene (e.g., bio-psa 4302, bio-psa 4202), ethyl acetate vinyl copolymers, natural rubber, synthetic rubber, pressure-sensitive adhesives, such as silicone polymers, acrylic pressure-sensitive adhesives such as (e.g., DURO-TAK 87-2156, DURO-TAK 387-2287), polyisobutylene (e.g., low molecular weight polyisobutylene, medium molecular weight polyisobutylene, polyisobutylene 35000mw), acrylic copolymers, rubber-based adhesives, hot-melt adhesives, styrene-butadiene copolymers, bentonite, all water and / or organic solvents, etc. In one embodiment, the agent mentioned is in the range of 0.1%, 70%, w / w, or w / v.

[0095] Example 3 The transdermal and / or topical formulations of this disclosure may, either alone or in combination, contain penetration enhancers known to those skilled in the art, but are not limited to: sulfoxides and similar chemicals such as (dimethyl sulfoxide, dimethylacetamide, dimethylformamide, decimethyl sulfoxide, dimethyl isosorbide, etc.), azons such as (N-methyl-2-pyrrolidone, 2-pyrrolidone, etc.), pyrrolidones, esters such as (propylene glycol monolaurate, butyl ethanolate, ethyl ethanolate, isopropyl myristate, isopropyl palmitate, methyl ethanolate, decyl oleate, glycerol monooleate, glycerol monolaurate, lauryl laurate, etc.), fatty acid esters, and (not limited to) Fatty acids such as pric acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid, stearic acid, palmitic acid, etc.; alcohols, fatty alcohols, and glycols, fatty alcohols, and glycols, fatty alcohols, and glycols, fatty alcohols, and glycols, and ether alcohols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and glycols, and ether alcohols, and glycols, and glycols, and glycols, and ether alcohols, and glycols, and glycols, and ether alcohols, and glycols, and glycols, and ether alcohols, and glycols, and ether alcohols, and glycols, and ether alcohols, and glycols, and ether alcohols, and glycols, and ether alcohols, fatty alcohols, and ether alcohols, and ether alcohols, and ether alcohols, and ether alcohols, and ether alcohols, and glycols, and fatty alcohol ethers, and ether alcohols, fatty alcohol ethers, and ether alcohols, and ether alcohols, and ether alcohols, and glycols, and fatty alcohol ethers, and ether alcohols, and glycol The agent mentioned is in the range of 0.01% to 95% w / w (or w / v) in one embodiment.

[0096] Example 4 Transdermal and / or topical formulations may contain, alone or in combination with, plasticizers including, but not limited to, glycerol and its esters, phosphate esters, glycol derivatives, sugar alcohols, sebacate esters, citrate esters, tartaric acid esters, adipates, phthalates, triacetins, oleates, and all plasticizers available for use in transdermal drug delivery systems as mentioned in the book "Handbook of Plasticizers" (George Wypych, 2004, Chem Tec Publishing). The agents mentioned are in the range of 0.01% to 95% w / w (or w / v) in one embodiment.

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

[0098] Example 6 Transdermal and / or topical formulations may, alone or in combination, contain solubilizers, surfactants, emulsifiers, and dispersants, not limited to: anionic, cationic, nonionic, and amphoteric surfactants, including but not limited to sorbitan oleate, SPAN 80, SPAN 20, etc. under the trade name SPAN; and polysorbates, not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, etc., propylene glycol monocaprylate type I, propylene glycol Examples include chlorocaprylate type II, propylene glycol dicaprylate, medium-chain triglycerides, propylene glycol monolaurate type II, linoleyl 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, and cyclodextrins. In one embodiment, the concentrations of the mentioned agents range from 0.01% to 95% w / w (or w / v).

[0099] Example 7 The stability and / or solubility of dronabinol in a formulation can be enhanced using various technologies and components, including but not limited to coating, encapsulation, microencapsulation, nanoencapsulation, lyophilization, chelating agents, and complexing agents.

[0100] Example 8 The transdermal and / or topical formulations include, either alone or in combination, auxiliary pH buffers and pH stabilizers, as well as similar compounds known to those skilled in the art to maintain the appropriate pH of the formulation preferably in the range of 4.0 to 8.0; acids such as (carboxylic acids, inorganic acids, sulfonic acids, vinyl carboxylic acids, fatty acids, etc.), and bases such as (sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, etc.), not limited to phosphate buffers, acetate buffers, citrate buffers, etc. In one embodiment, the concentration of the above agents is in the range of 0.01% to 30% w / w or w / v.

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

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

[0103] Example 11 Materials for making the transdermal delivery system of this disclosure, including but not limited to patch forms known to those skilled in the art, such as reservoir patches, matrix patches, drugs in adhesives, and transdermal films, may include, but not limited to, polymers, copolymers, derivatives, backing films, release films, release liners, etc., either alone or in combination thereof. Pressure-sensitive adhesives (but not limited to, silicone polymers, rubber-based adhesives, acrylic polymers, acrylic copolymers, polyisobutylene, acrylate-isooctyl acrylate copolymer, hot-melt adhesives, polybutylene, etc.), backing films (but not limited to, ethylene vinyl acetate copolymer, vinyl acetate resin, polyurethane, polyvinyl chloride, metal foil, polyester, aluminized film, polyethylene, etc.), release films (but not limited to, microporous polyethylene films, microporous polypropylene films, speed-controlled ethylene vinyl acetate copolymer films, etc.), release liners (but not limited to, silicone-treated polyester films, fluoropolymer-coated polyester films, polyester films, silicone-treated polyethylene terephthalate films, etc.), tapes, etc.

[0104] The transdermal and / or topical formulations and / or transdermal delivery systems of this disclosure are capable of delivering at least a therapeutically effective dose of dronabinol. The therapeutically effective dose of dronabinol refers to the therapeutic concentration of dronabinol in human plasma required to treat and / or prevent chemotherapy-related nausea and / or vomiting. Furthermore, the exact therapeutically effective dose of dronabinol in the transdermal or topical formulation or transdermal delivery system may be determined by those skilled in the art based on factors such as the patient's condition, but is not limited to these. The transdermal or topical formulation or transdermal delivery system may be available in different dosing intensities and patch sizes to achieve optimal therapeutic outcomes based on patient requirements.

[0105] In another embodiment, the transdermal and / or topical formulations and / or transdermal delivery systems of this disclosure can deliver at least a therapeutically effective dose of dronabinol. The therapeutically effective dose of dronabinol refers to the therapeutic concentration of dronabinol in human plasma required for treatment, as described on the Marinol label, “Anorexia Associated with Weight Loss in Patients with AIDS” (see label). Furthermore, the exact therapeutically effective dose of dronabinol in the transdermal or topical formulation or transdermal delivery system may be determined by those skilled in the art based on factors such as the patient’s condition, but is not limited to these. The transdermal or topical formulation or transdermal delivery system may be available in different dose strengths and patch sizes to achieve optimal therapeutic outcomes based on patient requirements.

[0106] Dronabinol transdermal formulations or transdermal patches are preferred, but not limited to, and can be applied to the skin surface in any of the following administration regimens: 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, once every eight to approximately 13 days, once every two weeks, or once every 15 days.

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

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

[0109] The prepared transdermal formulations were then subjected to flux measurement tests 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 the test. The transdermal flux was then measured using a standard Franz diffusion cell consisting of a cylindrical donor compartment with a capacity of 13 mL and a separate cylindrical receptor compartment with a water jacket. Human cadaver skin was fixed between the two compartments with the dermal side 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 the receptor fluid is always in contact with the skin. The receptor compartment was emptied at 24-hour intervals for the delta-9-THC assay and replaced with fresh receptor solution. To maintain the sedimentation state within the receptor compartment, it was important to keep the delta-9-THC concentration below 10% of its solubility. The experimental conditions are shown in Table 3. [Table 3]

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

[0111] Example 13 Additional synthetic delta-9-THC formulations for transdermal delivery (formulation numbers 010-018) were prepared by mixing the components 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 passing through the skin of human corpses was measured for a minimum of 96 hours (4 days). The results of the flux measurement experiment are shown in Table 6. [Table 6]

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

[0115] Synthetic delta-9-THC formulations (019-027) for transdermal delivery were 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.

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

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

[0118] Synthetic delta-9-THC formulations for transdermal delivery (formulation numbers 028-034) were 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.

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

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

[0121] To prepare a transdermal patch containing synthetic delta-9-THC, all components in Table 11, excluding 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 spread evenly to a thickness of 0.5 mm on an 8x14 inch (20.3x35.6 cm) release liner sheet (e.g., 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 oxygen permeability (e.g., 3M 9730 NR film) was then carefully applied to the sheet by hand to avoid the formation of bubbles and voids. A circular die (1.5 inch (3.8 cm) in diameter) was used to create a patch (7 cm) for subsequent testing. 2 ) was cut off.

[0122] The general procedure for measuring the flux of transdermal preparations 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 with a capacity of 13 mL and a separate cylindrical receptor compartment with a water jacket. The human cadaver skin was fixed between the two compartments with the dermal side facing the receptor compartment. The general procedure for measuring the flux of transdermal adhesive patches was as follows: The release liner was peeled off the patch and the adhesive side was applied to the skin of a human cadaver (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 continuously stirred to collect THC as it diffused from the THC-adhered patch through the skin into the receptor compartment. The receptor solution was ensured to be in constant contact with the skin. The receptor compartment was emptied at 24-hour intervals for the delta-9-THC assay and replaced with fresh receptor solution. To maintain the sedimentation state of the receptor compartment, the delta-9-THC concentration in the receptor compartment was kept below 10% of its solubility. The experimental conditions were the same as those provided in Table 3 of Example 12.

Claims

1. below: about 0.1 to about 25% by weight of synthetic delta-9-tetrahydrocannabinol (delta-9-THC); from about 1 to about 99% by weight of at least one solubilizing agent comprising propylene glycol; from about 1 to about 40% by weight of at least one penetration enhancer comprising oleic acid; from about 1 to about 30% by weight of at least one polymer selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone homopolymer, polyvinylpyrrolidone copolymer, and combinations thereof; from about 0.1 to about 10% by weight of at least one suspending agent comprising silicon dioxide; about 20 to about 90% by weight of at least one pressure sensitive adhesive, including a silicone pressure sensitive adhesive A pharmaceutical composition comprising: The pharmaceutical composition is in a transdermal drug delivery system (TDDS) comprising an impermeable backing layer and a release membrane, optionally covered with a removable protective layer, and further wherein the pharmaceutical composition provides a constant delivery rate of the active ingredient over a period of 72 hours, 96 hours, 120 hours, 144 hours, or 7 days.

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

3. 3. The pharmaceutical composition of claim 1, wherein the synthetic delta-9-THC is in a form selected from the group consisting of co-crystal, amorphous, coated, crystalline, salt, isomer, solid solution, solution, synthetic, and ethanol solution.

4. 2. The pharmaceutical composition of claim 1, wherein the synthetic delta-9-THC is selected from the group consisting of amorphous synthetic delta-9-THC, crystalline synthetic delta-9-THC, a co-crystal of synthetic delta-9-THC, coated synthetic delta-9-THC, and an ethanol solution of synthetic delta-9-THC.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the synthetic delta-9-THC is in the form of a salt.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is formulated as a transdermal liquid formulation, a transdermal semisolid formulation and / or a transdermal polymer matrix formulation.

7. 10. The pharmaceutical composition of claim 1, further comprising an effective amount of a carrier or ingredient selected from the group consisting of solvents, gelling agents, emollients, skin irritation reducers, buffers, pH stabilizers, dispersants, stabilizers, plasticizers, surfactants, antioxidants, and oxidizing agents, either alone or in combination.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is formulated as a transdermal patch.

9. 9. The pharmaceutical composition of claim 8, wherein 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.

10. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated as microneedles.

11. The pharmaceutical composition of claim 10, wherein the microneedles are formulated as a transdermal patch.

12. Use of the pharmaceutical composition according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment and / or prevention and / or control of nausea and / or vomiting associated with cancer chemotherapy.

13. 13. The use according to claim 12, wherein the composition is a liquid and / or semi-solid formulation and the topical application is performed 2 to 6 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once a week.

14. 13. The use of claim 12, wherein the composition is topically applied 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.

15. The use according to any one of claims 12 to 14, wherein the topical applying provides a constant rate of delivery of the active ingredient of the transdermal patch over a period of time.

16. 16. The use of any one of claims 12 to 15, wherein the topical application provides a steady absorption rate of synthetic delta-9-THC over a period of time.

17. 16. The use of any one of claims 12 to 15, wherein the topical applying achieves a constant serum level of synthetic delta-9-THC over a period of time.

18. 18. The use of any one of claims 12 to 17, wherein the topical applying achieves reduced fluctuations in serum levels of synthetic delta-9-THC over a period of time compared to oral administration of synthetic delta-9-THC over a period of time.

19. 19. The use of any one of claims 12 to 18, wherein the topical application achieves a plasma concentration of synthetic delta-9-THC in the therapeutic range over a period of time.

20. Use of the pharmaceutical composition according to any one of claims 1 to 11 for the manufacture of a medicament 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.

21. 21. The use of claim 20, wherein the pharmaceutical composition is topically applied 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, or once every ten days.

22. 21. The use of claim 20, wherein the pharmaceutical composition is topically applied 2 to 6 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week.

23. The use according to any one of claims 20 to 22, wherein the pharmaceutical composition is a liquid or semi-solid formulation.

24. The use according to any one of claims 20 to 22, wherein the pharmaceutical composition is a transdermal delivery system.

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