Cannabis-based oral dissolvable film

Abstract

An oral dissolvable film for sustained transmucosal administration of at least one cannabinoid. The oral film comprises an effective amount of one or more cannabinoids in a dissolvable polymeric matrix. The oral film may include a full spectrum of the active ingredients present in cannabis plant material.

Description

[0001] CANNABIS-BASED ORAL DISSOLVABLE FILM

[0002] FIELD OF THE INVENTION

[0003] The present invention generally relates to pharmaceutical formulations of cannabinoids for use in the treatment of various disorders. More specifically, the invention relates to an oral dissolvable film (ODF) for sustained transmucosal delivery of cannabis-based compounds.

[0004] BACKGROUND

[0005] The study of cannabis for medical applications has been growing rapidly in recent years with new indications and territories of use added at high pace. Cannabis has been shown to provide relief and relaxation for a variety of symptoms and conditions, including chronic and acute pain, nausea and vomiting, appetite loss, neurological conditions, ADHD, epilepsy, sleeping disturbance, anxiety chronic inflammation and more. The wide range of potential therapeutic effects of cannabis is attributed to the extensive profile of cannabinoids, which act on cannabinoids receptors, also known as the human endocannabinoid system.

[0006] Over 120 different cannabinoids have been isolated from cannabis, of which tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most abundant and most widely studied. In addition to these main cannabinoids, there are many other cannabinoids (minor cannabinoids) that exist in smaller quantities. It was shown that for an effective treatment, the contribution of the minor cannabinoids is important. The contribution of the minor cannabinoids, as well as of other active phytochemicals, is known as the "entourage effect" which describes the synergic action of different components in the cannabis source.

[0007] Medical cannabis can be used as a whole-plant product by inhalation via smoking or via vaporization, by ingestion of edible products or by applying it topically on the skin.However, consuming cannabis by inhalation, especially by smoking, is unfavorable by many doctors, patients, and society in general as being associated with potentially harmful risks, while ingestion cannabis oil or other cannabis containing edible products is less effective because of cannabinoids degradation in the gastrointestinal tract. Moreover, it is hard to provide accurate and continuous dosing over an extended period of time by these methods.

[0008] With the expansion of legalization of medical cannabis to an increasing number of countries, there is a continuously growing demand for new and improved cannabis-based pharmaceutical products that overcome the aforementioned drawbacks. In particular there is a need for pharmaceutical products that provide controlled and continuous delivery of one or more cannabinoids over an extended period of time directly to the body's systemic circulation system in order to maintain continuous plasma levels, to lessen side-effects associated with high peak levels, to improve bioavailability and dosing accuracy and enhance efficacy.

[0009] There is also a need for sustained release cannabis-based pharmaceutical products that substantially comprise full spectrum of the cannabinoids and other beneficial compounds (e.g., terpenes and flavonoids) that are naturally present in cannabis to fully utilize the benefits of the plant and to exploit the synergetic "entourage effect".

[0010] The present invention provides for an oral dissolvable film that is adapted to adhere to oral mucosal tissue of a subject and to deliver one or more cannabinoids directly into the subject's blood stream over an extended period of time. Oral transmucosal delivery is based on the direct uptake of the drug by the highly vascularised oral mucosa, thereby bypassing the gastrointestinal tract.

[0011] SUMMARY OF THE INVENTION

[0012] One aspect of the present invention relates to an oral slow dissolving film configured for sustained transmucosal administration of at least one cannabinoid.Accordingly, there is provided a single-dose mucoadhesive oral dissolvable film (ODF) comprising an effective amount of one or more cannabinoids in a dissolvable polymeric matrix wherein the film is configured to be placed in an oral cavity of a subject and to be adhered to a mucosal tissue upon contact therewith and the polymeric matrix is selected for sustained release of said one or more cannabinoid. Preferably, the oral dissolvable film has a predetermined dissolution time in the range of 1 to 8 hours when placed in the oral cavity. The ODF may contain from 5 and up to 80 mg or more of cannabinoids. The one or more cannabinoids can be selected from the group consisting of A9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG) and any combination thereof. The In accordance with some embodiments, the polymeric matrix comprises (a) xanthan gum, (b) carboxymethyl cellulose (CMC) and (c) at least one other cellulose-based polymer and wherein the relative amounts of (a):(b):(c) is selected in accordance with the predetermined dissolution time. The oral dissolvable film may further comprise plasticizer polymers and permeation enhancer agents. The film may also comprise taste masking agents, flavoring agents, breath refresh agents and any combination thereof. In accordance with some embodiments, the oral dissolvable film is fabricated from a formulation comprising an organic phase and an aqueous phase wherein the two phases are mixed to form an emulsion. In accordance with some embodiments, the ODF comprises more than one layer. In accordance with such embodiments, the oral dissolvable film may comprise an active layer comprising the one or more cannabinoids and a backing layer that dissolves slower than said active layer. One or more of the layers may comprise a coloring agent to distinguish between the layers.

[0013] Another aspect of the invention is slow dissolving oral film that includes full spectrum of the active ingredients in cannabis plant material. The cannabis plant material may be cannabis inflorescence, cannabis trim comprising leaves trimmed from cannabis inflorescence and any combination thereof. Preferably, the cannabis plant material is cannabis inflorescences. The oral dissolving film may comprise a cannabis powder obtained from the cannabis plant material, an extract from cannabis plant material, adistillate from a cannabis plant material or a combination thereof. Preferably the cannabis powder is characterized by particle size in the range of 5 to 20 micrometers (pm). In accordance with some embodiments, cannabis extract may be prepared in-situ by mixing cannabis powder with organic solvents to form a mixture and using the filtrate of the mixture in the preparation the organic phase of the film's formulation.

[0014] A further aspect of the invention is a method of administering an effective amount of at least one cannabinoid to a subject in need thereof for the treatment of the subject's condition by applying the oral dissolvable film of the invention to an oral mucosal tissue of the subject.

[0015] Yet, a further aspect of the invention is a method for fabricating an oral dissolvable film for sustained transmucosal administration of at least one cannabinoid.

[0016] Other features and advantages of the invention will be apparent from the following detailed description.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The present invention will be understood and appreciated more fully from the following detailed description taken in conjunction with the drawings in which:

[0019] Fig. 1 is an overall block flow chart of a method of making an oral dissolvable film according to an embodiment of the present invention;

[0020] Fig. la is a flow chart of an in-situ extraction embodiment;

[0021] Fig. 2 graphically represents the results of an in vitro dissolution test; and.

[0022] Fig. 3 graphically represents results of pharmacokinetics study in hamsters showing mean THC plasma concentration after application of 0.77mg ODF.DETAILED DESCRIPTION OF THE INVENTION

[0023] It will be appreciated that the preferred methods, uses, materials, and examples that are described in the following, are illustrative only and are not intended to be limiting. Materials, uses and methods similar or equivalent to those described herein can be used in practice or testing of the invention.

[0024] The present invention involves the introduction of the cannabis plant potent ingredients to the mouth cavity to allow transmucosal permeation directly to the blood stream. This is achieved by adhering the orally dissolving film (ODF) of the invention to the mucosal tissue, followed by spontaneous release of the cannabinoid through the buccal tissue and to the bloodstream. The thin film may be applied to the oral cavity and may adhere to a mucosal surface, such as the inner cheek, gums or palate, where the film slowly disintegrates and releases the cannabinoid / s for absorption through the oral mucosa until full dissolution. The advantage is the prevention of the cannabinoids decomposition in the gastrointestinal tract (GI), in addition to the slow release of the cannabinoids over few hours (up to 8 hours and more). The polymeric platform can host several cannabinoids together with the rest of the cannabis plant ingredients (e.g. chlorophyl, phenols, terpenes, cellulose, etc). This allows efficiency enhancement because of the synergic action between the cannabinoids and between the cannabinoids and other cannabis plant ingredients (e.g., terpenes). The ODF of the invention can be loaded with an adjustable dosage according to patient needs.

[0025] In the context of the present application, the terms 'oral dissolvable film', 'oral dissolving film' and 'oral disintegrating film' (ODF) refer interchangeably to a thin device dimensioned to be placed in the mouth of a human subject, configured to be adhered to a mucosal tissue upon contact therewith and to dissolve and / or disintegrate in the buccal cavity over a preselected period of time. The device can assume any shape including film strips, discs, sheets, and the like. The ODFs are preferably bendable and flexible, capable of conforming to the irregular surface contour of the mucosa.The terms 'polymeric matrix', 'film matrix' and 'polymeric platform' refer to the polymer component / s that constitute the film structure and optionally contains pharmaceutically active components, e.g., cannabinoids, and / or other components.

[0026] A9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two of more than 120 identified cannabinoid compounds found in the plant genus Cannabis. The amount and composition of the cannabinoids vary from one strain of cannabis plant to another, within different parts of the plant, and may also depend on the growing conditions. The main source for cannabinoids are the upper (aerial) parts of the cannabis plant, in particular the budding heads (i.e., inflorescences) that are covered with trichomes rich in cannabinoids. There is a wide range of cannabis strains that have been selectively bred to produce different levels of THC and CBD and different THC to CBD ratios.

[0027] THC is potent and therapeutic and has psychoactive effects. It has proven effect in reducing chronic pains, treating PTSD, sleeping disorders and other medical conditions. CBD was found effective in treating inflammatory conditions and anxiety as well as treating epilepsy.

[0028] In the cannabis plant A9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are produced in their carboxylic acid form tetrahydrocannabinolic acid (THCA) and (CBDA), respectively and are decarboxylated by heating (e.g., smoking or baking), by light, or by natural degradation.

[0029]

[0030] THCA molecular structure THC molecular structure

[0031]

[0032] CBDA molecular structure CBD molecular structure

[0033] Upon storage, THC naturally degrades to cannabinol (CBN). Exposure to oxygen, light and elevated temperatures accelerates THC degradation.

[0034] The cannabis plant contains many more cannabinoids in lower amounts that show therapeutic effects. For example, cannabigerol (CBG) is another cannabinoid that has demonstrated an anti-inflammatory effect and has also been shown to reduce pain, to act as antibacterial agent, etc. The carboxylic acid form of CBG, plays an integral role in the cannabis plant’s biochemistry, being the parent molecule from which other cannabinoids are synthesized.

[0035] Conventional Cannabis treatment by smoking, vaporization or ingesting oil has many drawbacks:

[0036] • Many Cannabinoid treatments contain only one or two cannabinoids, and not the full cannabinoid spectrum of the plant, hence missing the “entourage effect” found essential for effective treatment.

[0037] • Dosing is not accurate.

[0038] • Absorption of oil is both via transmucosal (sublingual) route and GI route. The weight of each is use dependent.

[0039] • Patient inconvenience is reported, due to bitter taste and greasy mouthfeel.• Consuming cannabinoids by smoking is unfavorable by many Doctors, patients, and society in general.

[0040] • Cannabinoids shelflife is limited, especially for smokables.

[0041] • As a result of cannabis use, many patients have reported unpleasant feeling and a dry mouth phenomenon, also described as “cotton mouth”. Consuming marijuana can result in salivary glands producing less saliva than needed for a moist and healthy mouth. Saliva acts to neutralize acids and limit bacterial growth. Reduced saliva can lead to gum disease, increased risk of cavities and inflammation of mouth and lips.

[0042] In view of the disadvantages detailed above, a mucosal adhesive oral film for continuous release of at least one cannabinoid would be helpful. Accordingly, the invention provides a slow dissolving film loaded with a predetermined dosage of at least one cannabinoid and configured to adhere to mucosa tissue for allowing permeation of the cannabinoid across the mucosa, thereby bypassing gastrointestinal degradation and liver metabolism. This GI bypass allows incorporation of significantly lower amounts of cannabinoids while maintaining the same level of therapeutic efficacy. The predetermined dosage, in the range of 5-80 mg, is selected in accordance with the intended use. The ODF can be placed on along the inner cheek (buccal position), on upper gums or under the tongue (sublingual position). The slow dissolving films comprise slow dissolving or eroding polymeric matrix that dissolves and / or disintegrates upon exposure to aqueous media (e.g., saliva) and are designed for controlled or sustained release of the active agent contained therein. Moreover, regarding the dry mouth symptoms, the muco-adhesive agents of the ODF matrix (i.e. excipients) may provide relief of the “cotton mouth” feeling and promote saliva secretion.

[0043] US patent no. 11,000,473, the entire content of which is incorporated herein by reference, discloses dissolvable oral mucoadhesive films for managing various oral conditions such as halitosis and dry mouth. The films comprise three indigestible polymers and exhibit dissolving time of up to 8 hours or more until they fully dissolve in the mouth. The three indigestible polymers are xanthan gum, carboxymethyl cellulose(CMC) and another cellulose-based polymer. At least one of the cellulose based polymers had muco-adhesive properties, thus allowing the film to adhere to the mucus membrane.

[0044] The ODF of the present invention comprises polymeric matrix compositions similar to those disclosed in US patent no. 11,000,473. In addition to other advantages, the use of these compositions as the platform for oral transmucosal delivering of cannabinoids is especially advantageous because it alleviates or eliminates the symptoms associated with cannabis consumption such as bad mouth feel and reduced saliva. Additionally, the film may comprise a sweetener, a flavoring agent, a refreshing agent or a combination thereof.

[0045] The dissolving / disintegrating times (i.e., the residence time of the ODF in the mouth cavity) of the film and the release rate of the cannabis-based ingredients can be adjusted to meet specific requirements by changing the ratio between the main polymers that comprise the films and by increasing or decreasing the amounts of additives. For example, admixing polymers that are relatively more hydrophobic affects the release rate of the active ingredients. The hydrophobic polymers may be poly acrylic acid (PA)-based polymers such as Carbopol .

[0046] Typically, the ODF of the invention is fabricated by separately preparing an aqueous phase and an organic phase and combing the two to form emulsion that is further processed to form a film. The cannabis components are typically added to the organic phase. Fig. 1 schematically describes the method for fabricating ODFs of the invention.

[0047] As mentioned above, the cannabis plant contains, in addition to the main cannabinoids, many more minor cannabinoids in smaller quantities that contribute to the "entourage effect". Any or all of the cannabinoids found in the cannabis plant can be used in the present invention. Preferably, the ODF of the present invention comprises a full spectrum of the cannabinoids found in the cannabis plant, as well as other beneficial naturally occurring compounds. The full cannabinoid spectrum can be introduced into the film as a cannabis fine powder, a cannabis extract or both.Preferably the fine powder and / or the extract are made from the cannabis Inflorescences. It will be easily realized that the specific composition of the powder and / or of the cannabis extract (in terms of cannabinoids and / or other ingredients) may be selected in accordance with the intended use by selecting the specific cannabis strain from which the powder and / or the extract are prepared. For example, the powder and / or extract may be selected to be THC rich, CBD rich etc. It will be also realized that when the ODF comprises both powder and extract, the powder and extracts may be selected from different cannabis strains having different cannabinoid compositions.

[0048] Typically, cannabinoids as well as other cannabis components are extracted from the cannabis plant material by organic solvents. The most common solvent in use for cannabis extraction is ethanol.

[0049] In accordance with some embodiments of the invention, the cannabis extract can be added to the organic phase of the film formulation as a highly concentrated cannabis resin or as a cannabis distillate, i.e., the cannabis extract after the removal of the extracting solvent. According to these embodiments, the cannabis extract may be a commercially available extract. In accordance with other, "in-situ", embodiments, schematically described in Fig. 1A, the cannabis plant material (e.g., a cannabis powder) can be extracted into the organic solvents that are later used, after filtration, in the preparation of the organic phase of the film formulation.

[0050] Fine powders of cannabis that are suitable for use in the ODF of the invention are disclosed, for example, in US patent no 1,1364,505, the entire content of which is incorporated herein by reference. The powders, which are characterized by preselected particle size distribution (PSD), substantially maintain the composition of the cannabinoids and other beneficial components in natural cannabis, namely they substantially contain the full spectrum of the active ingredients in cannabis. Preselecting the PSD significantly influences pharmaceutical and biological properties, such as, for example, bioavailability and can be considered as cannabis powders with enhanced activity and / or bioavailability.In preferred embodiments, the ODF of the invention comprises a controlled release polymeric matrix loaded with a fine powder of cannabis inflorescences and / or an extract thereof, wherein the polymeric matrix comprises xanthan gum, CMC and another cellulose-based polymer and wherein the powder is preferably having an average particle size in the range of 5-20 micrometer.

[0051] The ODF of the invention is a thin flexible film that does not break upon folding. The film can be in any shape or form (such as square, rectangular, circular, oval, etc.) suitable to be placed in the oral cavity. Typically, the film has a thickness in the range of 0.2-2 mm, weight in the range of 100-400 mg and surface area in the range of 1-10 cm2.

[0052] In accordance with some embodiments, the ODF of the invention is fabricated by the solvent-casting method as outlined in Figure 1. However, other methods known in the art, such as for example, hot-melt extrusion ,can also be used without departing from the spirit of the invention. The solvent casting method can be used to form a film of known specific thickness by spreading a mixture containing the film ingredients in volatile solvents over a surface and evaporating the solvents to form a dry solid / semi-solid film thinner than the original wet film that can be cut to individual units.

[0053] According to some embodiments, the ODF is formed as a mucoadhesive monolayer to be applied within the oral cavity where it adheres to the oral mucosa and facilitates cannabinoid / s permeation through the oral membrane to the underlying blood capillaries. Alternatively, the ODF may comprise two or more layers wherein one layer contains the cannabinoid / s and another layer is a protective (backing) layer that prevents or minimizes diffusion of cannabinoids from the cannabinoid containing layer into the oral cavity, thus directing delivery of the cannabinoids into the oral mucosa rather than into the GI tract. The backing layer also protects the cannabinoid containing layer from premature dissolution or disintegration due to excessive exposure to saliva and / or abrasion by the tongue. According to this embodiment, the cannabinoid containing layer is mucoadhesive and is placed against the mucosa while the backing (protective) layer is directed toward the oral cavity. Preferably, the backing layer comprises hydrophobicpolymers and dissolves slower than the active layer. A coloring agent may be added to one of the layers in order to distinguish between the layers and to facilitate correct placement of the film against the mucosa tissue. The protective layer may also contain flavoring agents and / or breath fresheners such as, for example, saccharin, menthol, etc. Various backing (protective) layers for ODFS are well known in the art. Examples of possible compositions of a backing layer are given in Table 1.

[0054] Table 1 : backing film compositions

[0055]

[0056] After fabrication, the ODFs may be packaged individually in sealed, vacuumed, air and moisture resistant packages, e.g., aluminum foil packages, in order to protect the cannabis active ingredients from exposure to environment and to extend the ODF's shelf life. The films of the invention are stable and durable for 6 months or more, well preserving the potency of the active ingredients

[0057] Following is a non-limiting summary of the new and advantageous features of the invention:

[0058] • A buccal ODF enhancing direct absorption to the blood stream while minimizing GI absorption and liver metabolism.• Controlled release over several hours

[0059] • The Cannabinoids may be in form of full-spectrum powder made directly from buds (Inflorescence) in addition to an extract of the same plant specie

[0060] • Accurate dose in a single-dose package

[0061] • Bitter taste is masked with mint flavor

[0062] • The combination of the cannabinoids with the dry mouth treatment

[0063] • The Cannabinoids in the formulation are stabilized over extended period of time

[0064] The following non-limiting examples further illustrate the present invention.

[0065] Materials: All materials used in the following examples were pharmaceutical grade and / or food grade materials. Ethanol (absolute): Fisher, Merck; Acetone: Merck;

[0066] Hydroxypropyl methylcellulose (HPMC) E5: Lotte; Carbopol® 97 IP: Lubrizol;

[0067] Carboxymethyl cellulose (CMC) type 12: Ashlend; Xanthan gum: Spectrum; PEG400: Merck; Propylene glycol: Merck; Menthol: Merck; Sucralose: JK Sweet; Xylitol: Xylisorb; Opalux® AS-R-7000 (white): Colorcon; Hydroxypropyl cellulose HPC-ELF: Ashland.

[0068] Cannabis powder was made from Cannabis inflorescence grown by BR-LEV, a medicalcannabis cultivating farm, micronized by FineCann technology and de-carboxylated by heating. Cannabis Extract was prepared by ethanol extraction, either in-situ or by a commercial facility. Cannabis distillate: was prepared by a Cannabis-distillation facility Method for determining cannabinoid content in a single-dose ODF:

[0069] Sample Preparation Procedure:

[0070] 1. Weigh a single dose film.

[0071] 2. Place it in a 5 mL Eppendorf tube.

[0072] 3. Add 2 stainless steel balls with a volume of 5 mL.

[0073] 4. Add 4 mL of ethanol (1:4 dilution, calculate concentration).

[0074] 5. Mix on a shaker at 2000 rpm for 30 minutes.

[0075] 6. Extract only the liquid phase (the gel is the polymeric residue of the sticker).7. Filter into a vial using a 0.22-micron filter.

[0076] 8. The sample is ready for analysis by HPLC.

[0077] HPLC methods for determination of cannabinoid content are known in the literature, for example: Fast Detection of 10 Cannabinoids by RP-HPLC-UV Method in Cannabis sativa L - PMC, Mandrioli et al., Molecules 2019, 24, 2113.

[0078] EXAMPLE 1

[0079] Oral dissolvable films comprising cannabis powder and cannabis distillate were prepared combining the components disclosed in table 2:

[0080] Table 2: ingredients of ODF

[0081]

[0082] *API- Active Pharmaceutical Ingredient

[0083] ** Cannabis distillate was obtained by solvent extraction of the same powder that is used in the formulation, followed by distillation.Film fabrication

[0084] ODFs were prepared by the method outlined in Fig. 1. The film formulation is an emulsion that is composed of an aqueous phase and an organic phase combined together. The two phases were prepared separately (steps 10 and 20), then the aqueous mixture was gradually poured into the organic mixture and a significant increase in viscosity was observed (step 30). The aqueous solution was prepared by dissolving the sweeteners and the mucoadhesive polymer HPMC E5 in water. The aqueous solution was then put to rest, allowing the trapped air bubbles to emerge from the solution. The organic mixture was prepared by adding the plasticizers, the mucoadhesive polymers (Carbopol, CMC, Xanthan gum) and the flavoring agent to the solvents Ethanol and Acetone under mixing with a high torque agitator. The cannabis was then added to the emulsion in two manners: fine powder of THC rich cannabis (particle size around 5-20 micrometers) and cannabis distillate obtained from the same inflorecense. Once mixing is complete the aqueous mixture was gradually poured into the organic mixture to form an emulsion of high viscosity. Next, a film was formed by the solvent casting technique (step 40). The viscous mixture was poured onto a non-stick liner (1022 by 3M) using a casting tool (Gardco Square Applicator) to form a thin wet layer of 25mil. A next layer of mixture was smeared over the first layer to form a total thickness of 50mil. This step repeated itself three times until a wet film of 90mil thickness was achieved. The film is casted in a multi-layer manner to avoid air bubbles so that the resulting film is smooth and homogeneous. The wet film was then set aside to dry spontaneously in an isolated well-ventilated space to allow the removal of solvents vapors (step 50). The drying process took about 18 hours at 30°C. At this stage, the solvents present in the film are evaporated (less than 500ppm are left as residues) and its thickness decreases from 2.29mm (90mil) to 0.45±0.04mm. At the end of the drying process, the dry film still contains around 10-20% water which did not evaporate and are held strongly by the hydrophilic polymers in the film. Once the film was dry enough to handle, it was die cut into individual ODF units (step 60). Die cutting (punching) was carried out manually using a stainless steel puncher. Each single ODF was then inserted manually into an aluminum easy peel pouchfollowed by hot sealing to protect it from environmental conditions and contaminations (step 60). A 600gr batch mixture yields about 300 ODFs. The ODFs are flexible, do not fracture under bending and have dark green color. Each ODF weighs 340 mg and contains 79 mg of THC as determined by the procedure described above. It will be realized that the ODFs contain other components that exist in the original Cannabis bud.

[0085] EXAMPLE 2

[0086] Oral dissolvable films were prepared combining the components disclosed in table 3. In this case, cannabis components were introduced into the organic phase both as a powder (2.96gr) and by in-situ extraction, namely by mixing cannabis powder in ethanol and in acetone and using the filtered solutions as the solvents for the organic phase of the film formulation, as described in Fig. la. Other steps of the preparation were similar to those described in Example 1. The cannabis powder was micronized powder of THC rich cannabis strain.

[0087] Table 3: ingredients of ODF

[0088]

[0089] ODFs of 240 mg each were prepared as described above in Example 1. The ODFs were packed in individual aluminum pouches made of two pieces of aluminum foils hot sealed to form a pouch. Each ODF contains about 9 mg of THC, as well as other components naturally occurring in the cannabis buds, including minor cannabinoids, Terpenes and Flavanols known to induce the ’’entourage effect” of a full-spectrum product.

[0090] EXAMPLE 3

[0091] Oral dissolvable films were prepared by the method described in Example 1 combining the components disclosed in table 4:

[0092] Table 4: ingredients of ODF

[0093]

[0094] Stability study

[0095] A Stability study was carried out for 6 months by putting ODF samples in stability chambers having three different temperature / humidity environment: 25°C, 60% RH (ambient); 30°C, 65% RH (intermediate); and 40°C, 75% RH (accelerated).

[0096] At specific time points, samples were taken from the stability chambers and analyzed by HPLC for 12 cannabinoids. The samples were also analyzed for general microbial count. The results for THC, for CBN (which is the main degradant of THC) and for general microbial count are summarized in Table 5. As can be seen, the ODF preserves the cannabinoids from both degradation and microbial burden. The microbial (micro) total count was tested as well.

[0097] Table 5: stability study

[0098]

[0099] EXAMPLE 4

[0100] Oral dissolvable films loaded with CBD as the active ingredient were prepared combining the components disclosed in table 6:

[0101] Table 6: ingredients of ODF

[0102]

[0103] Disk-shaped ODFs of 2.22±0.22 diameter were prepared according to the procedure described in Example 1. Each ODF was 280 mg in weight and contained 6.3 mg of CBD.Dissolution test

[0104] Dissolution tests were carried out by placing the ODF in 50g artificial saliva solution (USP phosphate buffer, pH 6.8) at 40°C. Samples were withdrawn for HPLC assay for CBD at 0.5 hr, 1 hr, 2 hr and 4 hr,

[0105] The results are summarized in Table 7 and are graphically presented in Fig.2.

[0106] Table ?:

[0107]

[0108] The results demonstrate the slow sustained release character of the film. It is reasonably expected that in the real situation inside the mouth cavity, quicker dissolution of the ODF due to shear forces and enzymes, will lead in some degree to a faster release profile of the cannabis-based ingredients to the mucosal tissue. In other words, although maintaining the slow release character, the release of the active ingredients in the oral cavity is expected to be to some extent faster than in the in vitro dissolution test.

[0109] EXAMPLE 5

[0110] A dual layer ODF comprising an active layer and a backing layer of the compositions presented in Tables 8 and 9, respectively, was prepared. The dual layer film is designed for unidirectional trans-buccal administration of THC. The active layer comprising the THC (as well as other cannabis-based active ingredient / s) is adapted to be placed in contact with the buccal tissue while the backing layer faces the oral cavity and serves as abarrier that minimizes leaking of THC into the oral cavity and consequently into the GI tract.

[0111] The backing layer was prepared, similarly to the method described in Fig. 1, by mixing an aqueous solution and an organic solution (each prepared separately) to form emulsion from which a film was formed by solvent casting. The aqueous phase was prepared by mixing Opalux with water (mixing ~400 rpm) and gradually adding the HPMC E5 until completely dissolved. The solution was covered and was set aside. The alcohol phase was prepared in a mixer (2.5" blade) by mixing ethanol, acetone and PEG400 and gradually adding Carbopol until well-dispersed. The aqueous solution was then gradually poured into the alcohol phase and the mixture was mixed at high speed (~800 rpm) for about 1.5 h until significant increase in viscosity was observed. The obtained emulsion was poured onto a non-stick liner and was air dried for 2-3 hr at a temperature of 30C. After 2 hr, the active layer, prepared as described above in Example 1, was cast onto the backing film.

[0112] Table 8: Active layer formulation

[0113]

[0114]

[0115] The cannabis powder used in this formulation is micronized decarboxylated powder made from cannabis buds, containing about 12 - 15% THC.

[0116] Table 9: Backing layer formulation

[0117]

[0118] It will be noted that since the active layer containing the cannabis components is green, the color added to the backing layer is white so as to achieve a clear distinction between the two faces of the ODF. The green (active layer) side is to be adhered to the buccal tissue while the white side is facing the oral cavity.

[0119] The dissolution rates of the two different layers (as well as the release and permeation of THC and other cannabinoids) can be measured in Franz cell equipment, using a membrane that mimics the oral mucosal tissue and using artificial saliva as the reservoir fluid. Two sets of measurements can be performed. One with the active face of ODF incontact with the membrane for measuring the dissolution rate of the active layer and the other set without the membrane for the backing layer

[0120] EXAMPLE 6

[0121] Animal pharmacokinetics (PK) study

[0122] A pharmacokinetics study for testing the unidirectional dual-layer film of the invention was conducted with Syrian hamsters chosen as a suitable model for buccal administration.

[0123] Individual single-dose ODFs were made from a dual layer film having the composition of Example 5. The single-dose ODF having

[0124] Six male Syrian hamsters of average lOOgr weight were divided to 2 groups:

[0125] Three hamsters received one round ODF each with the following characteristics: diameter of 1.1 cm, weight of about 145 mg and thickness of about 750 microns. Each ODF contained about 0.77 mg THC (equivalent to about 80 mg in human of ~70 Kg). For comparison, three hamsters received 0.77 mg THC in the form of commercial Cannabis oil droplets. Blood samples were withdrawn from all hamsters at 30, 120 and 480 minutes after administration and THC blood levels were measured. The results are graphically represented as concentration-time curves in Fig. 4. As can be seen, the THC plasma concentration profile following ODF administration clearly demonstrates the slow sustained release character of the film while in the oil drops case, the THC level increases much faster reaching a peak at about 100 minutes. It is noted that the constant slow increase of the THC level after the ODF application indicated that THC was continuously being absorbed, or in other words that THC was continuously being released from the ODF over the whole observation time.

[0126] Based on vast experience and clinical trials, therapeutic doses are in a wide range from 5 mg (usually for starters) and up to 20 mg in long-time users, for one treatment. It is also known that patients may administer THC more than once a day. Karschner et al. (Clinical Chemistry 2011; 57(1); 66-75) studied THC plasma concentration profiles following oraladministration of oromucosal Sativex® and of THC oil and show that doses in the 5-20 mg / L range give maximum plasma concentration, Cmax, of 5-15 pg / L (equivalent to 5-15 ng / mL). Grotenhermen (Clin Pharmacokinet 2003; 42 (4): 327-360) compares Cmax values of a 20 mg THC dose by oral digesting (cookie) and by smoking and the time course of the subjective “high” score, on a scale 1-10, given by the participants indicating that the "high" score value is in correlation with Cmax rather than with current blood level. It is therefore suggested that avoiding high peaks and maintaining THC blood levels substantially constant at 3-4 pg / L can provide the therapeutic effect while reducing the psychotropic effects.

[0127] It will be realized that in accordance with preset invention, the permeation rate of the cannabinoids into the mucosal tissue as well as the dissolution time of the active layer in the oral cavity, can be adjusted ('tailored') to required values by selecting a suitable composition of the polymeric matrix (components and their percentage)For example, the permeation rate can be controlled by varying the percentage of Propylene glycol in the active layer's composition and by adding surfactants and the dissolution time can be decreased or increased to meet requirements by decreasing / increasing the percentage of Carbopol. IT will also be realized that the composition and thickness of the backing layer affect the dissolution rate of the active layer in the oral cavity. Thus, it is also possible to modify the dissolution time of the active layer by varying the properties of the backing layer.

[0128] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined only by the claims which follow.

Claims

CLAIMS1. An oral dissolvable film comprising an effective amount of one or more cannabinoids in a dissolvable polymeric matrix, said oral dissolvable film is configured to be placed in an oral cavity of a subject and to be adhered to a mucosal tissue upon contact therewith and said polymeric matrix is selected for sustained release of said one or more cannabinoid.

2. The oral dissolvable film according to claim 1 having a predetermined dissolution time in the range of 1 to 8 hours when placed in the oral cavity.

3. The oral dissolvable film according to claim 1, wherein said one or more cannabinoids are selected from the group consisting of A9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG) and any combination thereof.

4. The oral dissolvable film according to claim 1 containing 5-80 mg of said one or more cannabinoids.

5. The oral dissolvable film according to claim 1, wherein said oral dissolving film comprises a full spectrum of active ingredients present in cannabis plant material.

6. The oral dissolvable film according to claim 1, wherein said oral dissolving film comprises a cannabis powder obtained from a cannabis plant material, an extract from a cannabis plant material, a distillate from a cannabis plant material or any combination thereof.

7. The oral dissolvable film according to claim 1, wherein the film is fabricated from a formulation comprising an organic phase and an aqueous phase.

8. The oral dissolvable film according to claim 6 wherein said cannabis extract is made in-situ by mixing cannabis powder with organic solvents to form a mixture and using filtrate of said mixture in the preparation of said organic phase.

9. The oral dissolvable film according to claim 6, wherein said cannabis powder is characterized by particle size in the range of 5 to 20 micrometers (pm).

10. The oral dissolvable film according to claim 6, wherein said cannabis plant material is selected from the group consisting of cannabis Inflorescence, cannabis trim comprising leaves trimmed from cannabis Inflorescence and any combination thereof.

11. The oral dissolvable film according to claim 2, wherein said polymeric matrix comprises (a) xanthan gum, (b) carboxymethyl cellulose (CMC) and (c) at least one other cellulose-based polymer and wherein the relative amounts of (a):(b):(c) is selected in accordance with said predetermined dissolution time.

12. The oral dissolvable film according to claim 11 further comprising at least one plasticizer polymer.13 The oral dissolvable film according to claim 11 further comprising a taste masking agent, a flavoring agent, a breath refresh agent or any combination thereof.

14. The oral dissolvable film according to claim 1, wherein the oral dissolving film comprises more than one layer.

15. The oral dissolvable film according to claim 14, wherein the oral dissolving film comprises an active layer comprising said one or more cannabinoids and a backing layer that dissolves slower than said active layer.

16. The oral dissolvable film according to claim 15 wherein one of said more than one layer comprises a coloring agent to distinguish between the layers.

17. A method of administering an effective amount of at least one cannabinoid to a subject in need thereof for the treatment of the subject's condition, the method comprising applying the oral dissolvable film of any one of the preceding claims to an oral mucosal tissue of said subject.

18. The use of an oral dissolvable film according to any one of claims 1 - 16 for the administration of an effective amount of at least one cannabinoid to a subject in need thereof.

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