Patent Application
20190350876
The present disclosure relates to compositions (e.g., oral compositions such as an oral thin film) comprising cannabidiol (e.g., purified cannabidiol) and methods of making and using same.
Cannabidiol (“CBD”) is one of over 400 known compounds present in cannabis plants. Although its full range of pharmacological uses is not yet understood, CBD is known to act as a partial agonist of 5-HT1A receptor, as an antagonist of GPR55 receptor, and as an indirect antagonist of CB1 and CB2 receptors. CBD is highly hydrophobic, which presents challenges for formulating high purity compositions suitable for convenient administration to human and animal subjects. A need therefore exists for stable and convenient CBD dosage forms.
The present disclosure provides compositions (e.g., oral compositions such as an oral thin film) comprising cannabidiol (e.g., purified cannabidiol) and methods of making and using same.
In some embodiments, the present disclosure provides an oral delivery form comprising a cannabis extract, such as cannabidiol.
In some embodiments, the present disclosure provides a unit dosage form comprising a plant extract, wherein the plant extract comprises cannabidiol.
In some embodiments, the present disclosure provides an oral thin film comprising cannabidiol.
The present disclosure provides compositions comprising cannabidiol, optionally in the form of a cannabis extract, and methods of making and using same for treating a disease or disorder in a subject.
Cannabidiol (“CBD”) is a hydrophobic terpenoid produced by cannabis plants. The species of cannabis plants include Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Varieties contain different amounts of CBD, with hemp producing higher concentrations of CBD and lower concentrations of the psychoactive cannabinoid tetrahydrocannabinol (THC). In one embodiment, the CBD is extracted from hemp. CBD is a series of isomers represented by the following general structure
wherein a carbon-carbon double bond is present at one of the indicated
positions of the methy/methylenyl cyclohexenyl ring. The seven positional isomers are summarized below using IUPAC nomenclature corresponding to the general structure shown above.
In some embodiments, a composition of the present disclosure includes an active agent comprising, consisting essentially of, or consisting of CBD. In some embodiments, the active agent comprises one of the CBD isomers described above. In some embodiments, the active agent comprises a mixture of more than one of the CBD isomers described above, such as two of the isomers, three of the isomers, four of the isomers, five of the isomers, six of the isomers, or all seven of the isomers described above. In some embodiments, the active agent comprises, consists essentially of, or consists of a derivative of any one or more of the CBD isomers described above, such as an O-protected isomer, an ester, or an alkyl ether derivative.
In some embodiments, CBD (e.g., one or more CBD isomers or derivative(s) thereof) represents at least about 80% of all cannabis-related compounds in the composition. In some embodiments, CBD (e.g., one or more CBD isomers or derivative(s) thereof) represents at least about 90% of all cannabis-related compounds in the composition. In some embodiments, CBD represents at least about 95% of all cannabis-related compounds in the composition. In some embodiments, CBD represents at least about 96% of all cannabis-related compounds in the composition. In some embodiments, CBD represents at least about 97% of all cannabis-related compounds in the composition. In some embodiments, CBD represents at least about 98% of all cannabis-related compounds in the composition. In some embodiments, CBD represents at least about 99% of all cannabis-related compounds in the composition.
In some embodiments, an oral thin film composition of the present disclosure comprises one or more matrix polymers. As used herein, the term “matrix polymers” refers generally to high molecular weight (MW) polymers that can form high viscosity solutions in water or a volatile solvent, can dissolve or disperse an active agent, and can be cast as stable, self-standing films. In some embodiments, the matrix polymer comprises one or more of: a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, carboxymethyl cellulose (CMC), hydroxymethyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyethylene oxide) (PEO), polyvinyl alcohol) (PVA), and poly(acrylic acid). In some embodiments, dispersion of cannabidiol in the matrix polymer is accomplished by first dissolving the cannabidiol (e.g., a cannabis extract comprising cannabidiol) in a small amount of solvent (e.g., ethanol), and the cannabidiol solution is then mixed with the matrix polymer(s). In such embodiments, the matrix polymer(s) should be miscible with the cannabidiol solvent to avoid compromising integrity of the final oral thin film and to avoid unappealing mouth feel from, for example, precipitation of the matrix polymer. In some embodiments, the matrix polymer comprises, consists essentially of, or consists of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., Soluplus, BASF Cat. No. 410343-S), a pharmaceutical grade hydroxypropyl cellulose-based polymer (e.g., Klucel JXF, Ashland Cat. No. 420040), or a combination thereof. In some embodiments, the matrix polymer comprises, consists essentially of, or consists of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. In some embodiments, the matrix polymer comprises, consists essentially of, or consists of a pharmaceutical grade hydroxypropyl cellulose-based polymer.
In some embodiments, an oral thin film composition of the present disclosure comprises one or more plasticizers. Any suitable plasticizer may be used, such as propylene glycol. When present, a plasticizer may represent about 0.5 wt. % to about 20 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting), such as about 0.5 wt. %, about 1 wt. %, about 1.5 wt. %, about 2 wt. %, about 2.5 wt. %, about 3 wt. %, about 3.5 wt. %, about 4 wt. %, about 4.5 wt. %, about 5 wt. %, about 5.5 wt. %, about 6 wt. %, about 6.5 wt. %, about 7 wt. %, about 7.5 wt. %, about 8 wt. %, about 8.5 wt. %, about 9 wt. %, about 9.5 wt. %, about 10 wt. %, about 10.5 wt. %, about 11 wt. %, about 11.5 wt. %, about 12 wt. %, about 12.5 wt. %, about 13 wt. %, about 13.5 wt. %, about 14 wt. %, about 14.5 wt. %, about 15 wt. %, about 15.5 wt. %, about 16 wt. %, about 16.5 wt. %, about 17 wt. %, about 17.5 wt. %, about 18 wt. %, about 18.5 wt. %, about 19 wt. %, about 19.5 wt. %, or about 20 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting).
In some embodiments, a solvent is used to prepare a solution of the matrix polymer, the active agent, and one or more excipients for casting into thin film form. In some embodiments, the solvent comprises ethanol. In some embodiments, the solvent comprises water.
In some embodiments, an oral thin film of the present disclosure comprises one or more excipients. In some embodiments, the one or more excipients comprise a preservative, a flavoring, a sweetener, a colorant, a salivating agent, a penetration enhancer, or a combination thereof.
In some embodiments, the excipient comprises a preservative. In some embodiments, the preservative comprises, consists essentially of, or consists of butylated hydroxytoluene (BHT) (e.g., Spectrum Chemical Cat. No. B1196, New Brunswick, N.J.). In some embodiments, the preservative is present in an amount of about 0.01 wt. % to about 0.5 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting), such as about 0.01 wt. %, about 0.05 wt. %, about 0.1 wt. %, about 0.15 wt. %, about 0.2 wt. %, about 0.25 wt. %, about 0.3 wt. %, about 0.35 wt. %, about 0.4 wt. %, about 0.45 wt. %, or about 0.5 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no added preservative or no added preservative.
In some embodiments, the excipient comprises a flavorant. In some embodiments, the flavorant comprises, consists essentially of, or consists of peppermint oil (e.g., Mother Murphy's Cat. No. 2318186, Greensboro N.C.). In some embodiments, the flavorant is present in an amount of about 0.2 wt. % to about 2 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting), such as about 0.2 wt. %, about 0.4 wt. %, about 0.6 wt. %, about 0.8 wt. %, about 1 wt. %, about 1.2 wt, %, about 1.4 wt. %, about 1.6 wt. %, about 1.8 wt, %, or about 2 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no added flavorant or no added flavorant.
In some embodiments, the excipient comprises a sweetener. In some embodiments, the sweetener comprises, consists essentially of, or consists of xylitol (e.g., Spectrum Chemical Cat. No. X1017, New Brunswick, N.J.). In some embodiments, the sweetener is present in an amount of about 0.2 wt. % to about 2 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting), such as about 0.2 wt. %, about 0.4 wt. %, about 0.6 wt. %, about 0.8 wt. %, about 1 wt. %, about 1.2 wt. %, about 1.4 wt. %, about 1.6 wt. %, about 1.8 wt. %, or about 2 wt. % of the total weight of the oral thin film composition (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no added sweetener or no added sweetener.
In some embodiments, the excipient comprises a colorant. In some embodiments, the colorant comprises, consists essentially of, or consists of chlorophyll (e.g., Swanson Health Products Cat. No. DES001, Fargo, N. Dak.). In some embodiments, the colorant is present in an amount of about 0.1 wt. % to about 1 wt. % (e.g., total weight before casting), such as about 0.1 wt. %, about 0.2 wt. %, about 0.3 wt. %, about 0.4 wt. %, about 0.5 wt. %, about 0.6 wt. %, about 0.7 wt. %, about 0.8 wt. %, about 0.9 wt. %, or about 1 wt. % (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no added colorant or no added colorant.
In some embodiments, the excipient comprises a salivating agent. In some embodiments, the salivating agent comprises, consists essentially of, or consists of citric acid (e.g., Avantor Performance Materials, Inc. Cat. No. 0616-12, Center Valley, Pa.). In some embodiments, the salivating agent is present in an amount of about 0.1 wt. % to about 1 wt. % (e.g., total weight before casting), such as about 0.1 wt. %, about 0.2 wt. %, about 0.3 wt. %, about 0.4 wt. %, about 0.5 wt. %, about 0.6 wt. %, about 0.7 wt. %, about 0.8 wt. %, about 0.9 wt. %, or about 1 wt. % (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no added salivating agent or no added salivating agent.
In some embodiments, the excipient comprises a penetration enhancer. In some embodiments, the penetration enhancer comprises, consists essentially of, or consists of glyceryl monooleate, Tween 80, oleyl alcohol, or a combination thereof. In some embodiments, the penetration enhancer comprises, consists essentially of, or consists of glyceryl monooleate (e.g., Spectrum Chemicals Cat. No. G1017, New Brunswick, N.J.). In some embodiments, the penetration enhancer comprises, consists essentially of, or consists of Tween 80 (e.g., MP Biomedicals Cat, No. 103170, Santa Ana, Calif.). In some embodiments, the penetration enhancer comprises, consists essentially of, or consists of oleyl alcohol (e.g., Super Refined™ Novol NF, Croda International Plc, East Yorkshire, England). In some embodiments, the one or more penetration enhancers is/are present in a total amount of about 1 wt. % to about 15 wt. % (e.g., total weight before casting), such as about 1 wt. %, about 2 wt. %, about 3 wt. %, about 4 wt. %, about 5 wt. %, about 6 wt. %, about 7 wt. %, about 8 wt. %, about 9 wt. %, about 10 wt. %, about 11 wt. %, about 12 wt. %, about 13 wt. %, about 14 wt. %, or about 15 wt. % (e.g., total weight before casting). In some embodiments, the penetration enhancers comprises an combination of two or more penetration enhancers, wherein each penetration enhancer is individually present in an amount of about 1 wt. % to about 15 wt. % (e.g., total weight before casting), such as about 1 wt. %, about 2 wt. %, about 3 wt. %, about 4 wt. %, about 5 wt. %, about 6 wt. %, about 7 wt. %, about 8 wt. %, about 9 wt. %, about 10 wt. %, about 11 wt. %, about 12 wt. %, about 13 wt. %, about 14 wt. %, or about 15 wt. % (e.g., total weight before casting). In some embodiments, the oral thin film comprises substantially no penetration enhancer, or no penetration enhancer.
In some embodiments, an oral thin film consistent with the present disclosure comprises a matrix polymer, about 2 wt. % cannabidiol, about 0.5 wt. % to about 20 wt. % total plasticizer, about 0.2 wt. % to about 2 wt. % flavorant, about 0.1 wt. % to about 1 wt. % salivating agent, about 1 wt. % to about 15 wt. % penetration enhancer, if present, about 0.1 wt. % to about 1 wt. % colorant, about 0.01 wt. % to about 0.5 wt. % preservative, wherein the amounts refer to the weight of each component present in the composition before casting into thin film form.
In some embodiments, an oral thin film consistent with the present disclosure comprises about 5 wt. % to about 7 wt. % cannabidiol, about 20 wt. % to about 22 wt. % matrix polymer, about 0.5 wt. % to about 1 wt. % sweetener, about 8 wt. % to about 12 wt. % plasticizer, about 2 wt. % to about 4 wt. % penetration enhancer, about 0.5 wt. % to about 1 wt. % flavorant, about 0.2 wt. % to about 0.4 wt. % colorant, about 0.2 wt. % to about 0.4 wt. % salivating agent, about 0.05 wt. % to about 0.1 wt. % preservative, wherein the amounts refer to the weight of each component present in the composition after being cast into thin film form (e.g., into a 1 mm-thick thin film).
In some embodiments, an oral thin film consistent with the present disclosure comprises about 6.0 wt. % cannabidiol, about 21.6 wt. % matrix polymer, about 0.7 wt. % sweetener, about 10.8 wt. % plasticizer, about 3.6 wt. % penetration enhancer, about 0.7 wt. % flavorant, about 0.4 wt. % colorant, about 0.4 wt. % salivating agent, and about 0.07 wt. % preservative, wherein the amounts refer to the weight of each component present in the composition after being cast into thin film form (e.g., into a 1 mm-thick thin film).
In some embodiments, an oral thin film consistent with the present disclosure comprises about 6.0 wt. % cannabidiol, about 21.6 wt. % Soluplus matrix polymer, about 0.7 wt. % xylitol, about 10.8 wt. % Tween 80, about 3.6 wt. % propylene glycol, about 0.7 wt. % peppermint oil, about 0.4 wt. % chlorophyll, about 0.4 wt. % citric acid, and about 0.07 wt. % BHT, wherein the amounts refer to the weight of each component present in the composition after being cast into thin film form (e.g., into a 1 mm-thick thin film).
A composition for use in accordance with the disclosure can be formulated as one or more dosage units. The terms “dose unit” and “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent (e.g., CBD) suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
In some embodiments, compositions of the present disclosure are in the form of orally deliverable dosage forms or units. More specifically, embodiments of the present disclosure include compositions in the form of oral thin films. Such oral thin films provide stable storage of the CBD active agent over time, and convenience in administering an accurate specified dose of the CBD upon administration of a single oral thin film.
In discussing the amount of CBD in a composition of the present disclosure, this may be split over several dosage forms. There is a limit as to the size for oral administration due to practical limits on the size of a single oral thin film that is convenient and tolerable to a subject. An adult subject may be able to tolerate a relatively larger sized oral thin film compared to a child. In addition, CBD is a highly hydrophobic molecule and thus there is a practical limit on the amount of CBD that may be included in an oral thin film of given dimensions. For example and without limitation, if a subject is to be administered 300 mg of CBD per day, the subject may be administered more than one CBD oral thin film dosage form each day, such as three 100-mg CBD oral thin films, or ten 30-mg CBD oral thin films.
In another embodiment, compositions of the present disclosure comprise one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipient” herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition, and that does not produce unacceptable toxicity or interaction with other components in the composition. By way of example only, a pharmaceutical composition according to the present disclosure may comprise one or more of: antioxidants, surfactants, preservatives, flavoring agents, co-solvents, viscosity aids, suspension aids, and lipophilic phases.
Oral thin films may be cast using any suitable method known in the art. Generally, a viscous solution is prepared comprising cannabidiol (e.g., a cannabis extract) as described herein, and the viscous solution is fed through a casting machine. The extruded film is then dried or heated to evaporate excess solvent, leaving a stable sheet. The sheet may then be divided into dosage units or other sized portions for further processing.
In some embodiments, the viscous solution is degassed (e.g., using a vacuum pump) before casting.
In some embodiments, the present disclosure provides an oral delivery form comprising a cannabis extract. In some embodiments, the cannabis extract comprises cannabidiol. In some embodiments, the cannabis extract comprises at least about 95% cannabidiol. In some embodiments, the cannabis extract comprises at least about 98% cannabidiol. In some embodiments, the cannabis extract comprises at least about 99% cannabidiol. In some embodiments, the oral delivery form is an oral thin film. In some embodiments, the oral thin film is in a unit dose form comprising about 30 mg of the cannabidiol. In some embodiments, the oral thin film is in a unit dose form comprising about 100 mg of the cannabidiol. In some embodiments, the unit dose form comprises a width of about 2.5 cm and/or a length of about 2.5 cm. In some embodiments, the cannabis extract is present in an amount of about 3 wt. % to about 12 wt. %, based on a total weight of the oral delivery form before casting into unit dose form. In some embodiments, the oral thin film further comprises hydroxypropylcellulose. In some embodiments, propylene glycol is present in an amount of about 5 wt. %, based on a total weight of the oral delivery form before casting into unit dose form. In some embodiments, the oral thin film further comprises a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, propylene glycol is present in an amount of about 5 wt. % to about 15 wt. %, based on a total weight of the oral delivery form before casting into unit dose form. In some embodiments, the cannabidiol comprises Δ1-cannabidiol. In some embodiments, the cannabidiol comprises Δ2-cannabidiol. In some embodiments, the cannabidiol comprises Δ3-cannabidiol. In some embodiments, the cannabidiol comprises Δ3,7-cannabidiol. In some embodiments, the cannabidiol comprises Δ4-cannabidiol. In some embodiments, the cannabidiol comprises Δ5-cannabidiol. In some embodiments, the cannabidiol comprises Δ6-cannabidiol. In some embodiments, the oral delivery form further comprises an excipient. In some embodiments, the excipient comprises a preservative. In some embodiments, the preservative comprises butylated hydroxytoluene. In some embodiments, the excipient comprises a flavoring agent. In some embodiments, the flavoring agent comprises peppermint oil. In some embodiments, the the excipient comprises a coloring agent. In some embodiments, the coloring agent comprises chlorophyll. In some embodiments, the excipient comprises citric acid.
In some embodiments, the present disclosure provides an oral thin film comprising cannabidiol. In some embodiments, the cannabidiol represents at least about 95% of all pharmaceutically active agents present in the oral thin film. In some embodiments, the cannabidiol represents at least about 98% of all pharmaceutically active agents present in the oral thin film. In some embodiments, the cannabidiol represents at least about 99% of all pharmaceutically active agents present in the oral thin film. In some embodiments, the oral thin film is in a unit dose form comprising about 30 mg of the cannabidiol. In some embodiments, the oral thin film is in a unit dose form comprising about 100 mg of the cannabidiol. In some embodiments, the unit dose form comprises a width of about 2.5 cm and/or a length of about 2.5 cm. In some embodiments, the cannabidiol is present in an amount of about 3 wt. % to about 12 w %, based on a total weight of the oral thin film before casting into unit dose form. In some embodiments, the oral thin film further comprises hydroxypropylcellulose. In some embodiments, propylene glycol is present in an amount of about 5 wt. %, based on a total weight of the oral thin film before casting into unit dose form. In some embodiments, the oral thin film further comprises a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, propylene glycol is present in an amount of about 5 wt. % to about 15 wt. %, based on a total weight of the oral thin film before casting into unit dose form. In some embodiments, the cannabidiol comprises Δ1-cannabidiol. In some embodiments, the cannabidiol comprises Δ2-cannabidiol. In some embodiments, the cannabidiol comprises Δ3-cannabidiol. In some embodiments, the cannabidiol comprises Δ3,7-cannabidiol. In some embodiments, the cannabidiol comprises Δ4-cannabidiol. In some embodiments, the cannabidiol comprises Δ5-cannabidiol. In some embodiments, the cannabidiol comprises Δ6-cannabidiol. In some embodiments, the oral thin film further comprises an excipient. In some embodiments, the excipient comprises a preservative. In some embodiments, the preservative comprises butylated hydroxytoluene. In some embodiments, the excipient comprises a flavoring agent. In some embodiments, the flavoring agent comprises peppermint oil. In some embodiments, the excipient comprises a coloring agent. In some embodiments, the coloring agent comprises chlorophyll. In some embodiments, the excipient comprises citric acid.
A prepared polymer solution of (i) 31 wt. % fungal polysaccharide (Pullulan USP-NF, Hayashibara Co. LTD) in water, (ii) 30 wt. % polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus, BASF Cat. No. 410343-S) in water, (iii) 17 wt. % pharmaceutical grade hydroxypropyl cellulose-based polymer (Klucel JXF, Ashland Cat. No. 420040) in water, (iv) 23 wt,% pharmaceutical grade hydroxypropylmethyl cellulose-based polymer (Benecel E15 PH, Ashland Cat. No. 794037) in water, or (v) 25 wt. % hypromellose acetate succinate AS-LG (Shin-Etsu Cat. No. AQOAT AS LG) in 1:1 ethanol/water was mixed with an amount of anhydrous ethanol sufficient to disperse the cannabis extract (BioSynthesis Pharma Group Ltd., Sandwich, England: Cat. No, CBD1001, >99.0% CBD, referred to herein as “CBD1001”), a plasticizer, and a salivating agent.
The mixture (optionally degassed) was fed through a motorized film applicator equipped with a square blade applicator having a desired slot size (e.g., 1.27 mm or 50 mil, 2 mm, or 3 mm) onto a glass bed lined with a polyester liner.
The glass bed, polyester liner, and wet film were dried in a forced air oven at 40° C. for about 24 hours. The dried thin film was then peeled from the liner using a narrow-tipped steel spatula.
Compositions of several stable oral thin films produced by this general method are described in more detail in Tables 1-39.
Two 1×1 cm2 square pieces of Formulation 21 of Example 1 were cut, weighed and dissolved in MeOH (at ˜2 mg/mL). The films dissolved quickly (<3.0 minutes) and completely in the MeOH. A 0.221 mg/mL working solution (WS) of each was prepared by dilution into 50:50 MeoH:H2O, followed by further dilution to a 5 μg/mL test solution. Duplicate 100 μL injections of the nominal 5 μg/mL test solutions were performed. HPLC was conducted on a guard-protected Waters XBridge C18 (5 μm; 4.6×250 mm) analytical column eluted with 35:65 0.1% TFA (pH 6 with 5% ACN):ACN at a 1.5 mL/min flow rate. Eluant was monitored for absorbance at 230 nm. Preparations were compared to freshly prepared 5 μg/mL TA-001-2015 calibrator. Results are shown in Table 41.
A PermeGear flow-through diffusion cell system with membrane supports (In-Line, Hellertown, Pa.) was assembled using purified water (NANOpure® DIamond™ Life Science (UV/UF) ultrapure water, Barnstead International, Dubuque, Iowa) with 10% ethanol filtered through a 0.2 μm nylon membrane filter was used as the receiver fluid.
Tissue harvested from Yucatan miniature pigs (Sinclair Bio Resources, Auxvasse, Mo.) was transported on wet ice and stored at −20° C. until used. Immediately before use, the top layers of the tissue were removed with a dermatome. A second cutting with the dermatome was used for the permeation studies.
Briefly, a 4.84 cm2 section of tissue was arranged in the diffusion cell such that the permeation area of the tissue was 0.95 cm2. Diffusion cells were kept at 32° C. with a circulating water bath. Flow rate was set at about 0.5 rpm. Each cell was charged with a 0.9525 cm2 circular disc of the test thin film of Test Formulas 1-14 and 19-21 of Example 1 by first applying 10 μL of nanopure water to the tissue. After applying the thin film to the wet tissue, an additional 50 μL of nanopure water was applied on top of the thin film to simulate exposure to saliva. The samples were then applied to the equilibrated permeation cells and sealed with a stopper. For some studies, a polypropylene surgical mesh (PPKM603, Textile Development Associates Inc. Brookfield, Conn.) overlay was used to ensure the thin film had secure contact to the tissue sample.
Samples were collected at 1 hour, 2 hours, 3, hours, 4, hours, 5, hours, 6, hours, 10, hours, 14 hours, and 18 hours for initial studies; additional samples were collected at 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, and 24 hours for some studies. All samples were stored at 4° C. until analyzed by HPLC.
Following the diffusion experiment, the test film was removed from each tissue sample. Tissue was washed with nanopure water, dried and tape-stripped twice with book tape to remove any surface drug. The diffusional area was excised, chopped and placed into a pre-weighed vial. After recording the tissue weight, 10 mL of acetonitrile was added and the vials sealed. After shaking overnight at room temperature, the liquid portions were analyzed by HPLC.
Quantification of cannabidiol was performed by high performance liquid chromatography (HPLC) using a Waters 2695 Alliance Separations Module and column heater with a Waters 2487 Dual Wavelength Absorbance Detector. The solvent system consisted of 20% 0.1% TFA pH=3.0 and 80% acetonitrile and was run through a Waters XBridge™ 5 μm, 4.6 mm i.d.×250 mm column at a flow rate of 1.5 mL/min. Samples were injected in duplicate at 100 μL each. The limit of quantification was 0.5 μg/mL of cannabidiol. Samples were assayed the day of collection or within 48 hours after collection. When peaks from the original cannabis extract interfered with test analytes, the isocratic elution was changed to 35% 0.1% TFA buffer:65% acetonitrile and the run time was extended to 30 minutes from 6 minutes.
Results are shown in Table 42 below.
2TA = trace amounts, below LOQ
3NA = due to limited volume of samples and assay interference, weren't able to reanalyze samples
TA-001 oral films were prepared as described above and stored at 38° C., 75% relative humidity for up to 28 days. The temperature was selected so that the films would not undergo significant melting during the studies, since it was observed that higher temperatures can result in unsuitable softening of the films. On days 0, 3, 7, 14, 21 and 28, six TA-001 oral films (2.5×2.5 cm; ˜17,244% drug load based on Day 0 analysis of films) were examined for color, clarity, thickness and mass prior to being dissolved in methanol (nominal 7.5 mg total film weight/mL). These methanolic stock solutions were weighed then immediately used to prepare diluted solutions (8 μL QS to 2 mL with 50:50 H2O:methanol; ˜5.17 μg TA-001/mL) for analysis by HPLC-UV. Samples were injected (100 μL duplicates) onto a guard-protected (5μ; 4.6×10 mm) Waters X-Bridge C18 (5μ; 4.6×250 mm at 35° C.) analytical column and eluted at 10.1 min with a gradient mixture of mobile phase A (0.1% trifluoroacetic acid, pH 3, containing 5% acetonitrile) and B (100% acetonitrile) delivered at 1.5 mL/min, and monitored for absorbance at 230 nm. Gradient conditions were 35% mobile phase A:65% mobile phase B for 12 min, followed by a linear ramp to 100% mobile phase B for 30 min, constant at 100% mobile phase B for 10 min, returning linearly to 35% mobile phase A:65% mobile phase B over 5 min with a final equilibration at 35:65 mobile phase A:mobile phase B of 5 min (62 min total run time). Peak areas from duplicate injections were averaged and divided by the gravimetrically determined concentration of TA-001 in the injection solutions to determine the response ratio (RR) for analyte in each oral film. Stability of TA-001 in the oral films under the specified storage conditions was calculated by the change in RRs as compared to the initial Day 0 RRs. Results from the 28 day accelerated stability studies are shown below in Tables 43 and 44. Based on the results at 28 days, there was no apparent degradation of the active ingredient in the TA-001 oral films throughout the study.
For the disintegration studies, placebo films were placed into ˜21 mL of isotonic phosphate buffer, pH 6.8 to determine how long the films would take to dissolve. On Day 0, it took 12.7±6.0 min (n=3) for the films to fully disintegrate in vitro. At Day 7, it took 13-14 min for the films to disintegrate. At Day 14, it took 10-11 min for the films to disintegrate.
From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
The present application is a § 371 U.S. National Stage Application of International Application No. PCT/US2017/062001 filed on Nov. 16, 2017, which claims priority to U.S. Provisional Application No. 62/423,258 filed on Nov. 17, 2016, the entirety of each of which is incorporated herein by reference and relied upon.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2017/062001 | 11/16/2017 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62423258 | Nov 2016 | US |
