CA3046638A1 - Formulations for efficient delivery of cannabinoids - Google Patents

Abstract

Lozenges comprising ethyl cellulose and cannabinoids for rapid and efficient delivery of medical cannabinoids are provided. The lozenge is suitable for administration of the cannabinoid(s) through the oral mucosa to the bloodstream. Embodiments of the lozenge are disclosed that comprise additives which alleviate other issues related to administration of cannabinoids. Additives disclosed include xanthan gum to alleviate dry mouth syndrome, essential oils for flavoring and anti-bacterial activities, zinc for breath improvement, permeation enhancers and alkali metal bicarbonates for reducing acidity in the mouth. Methods for manufacture of the lozenges and its use in treatment of disease conditions are provided.

Description

FORMULATIONS FOR EFFICIENT DELIVERY OF CANNABINOIDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application Serial No.
62/420,981 filed November 11, 2016 and titled "FORMULATIONS FOR EFFICIENT
DELIVERY OF CANNABINOIDS," the contents of which are incorporated herein in their entirety by reference.
TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to medical cannabis lozenges, and more particularly, to lozenges that rapidly deliver cannabidiol ("CBD"), A9-tetrahydrocannabinol ("THC") or combinations through the oral mucosa into the bloodstream.
BACKGROUND OF THE INVENTION

[0003] Cannabis products have been consumed in various forms for thousands of years. The first descriptions of the medical uses date from Chinese herbal texts in the first century A.D.
Cannabis products were taken orally in an herbal tea concoction and were used for their pain-relieving and sleep-inducing properties.

[0004] Cannabinoids are the chemical compounds secreted by cannabis (Cannabis indica and Cannabis sativa) flowers that provide relief to an array of symptoms including pain, nausea, and inflammation. These work their medicinal effect by imitating compounds human bodies naturally produce, endocannabinoids, which activate to maintain internal stability and health.
Besides the psychoactive A9-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN).

[0005] As states increasingly legalize cannabis for medical use, there is a need to develop cannabis products for the efficient and effective treatment of many medical conditions.
Medical marijuana refers to the use of cannabis and its constituent cannabinoids, such as cannabidiol ("CBD"), as medical therapy to treat disease or alleviate symptoms. Cannabis has been used to reduce nausea and vomiting in chemotherapy and people with AIDS, and to treat pain and muscle spasticity.

[0006] When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain (CB-1) and body (CB-2). Different cannabinoids have different effects depending on which receptors they bind to. For example, A9-tetrahydrocannabinol (THC) binds to receptors in the brain whereas CBN (cannabinol) has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable.

[0007] The endogenous cannabinoid system performs a multitude of roles. A
large number of endogenous cannabinoid neurotransmitters or endocannabinoids have been identified, and the CB-1 and CB-2 cannabinoid receptors have been characterized. The complex functions of this system have created multiple new targets for pharmacotherapies focused on separating the behavioral psychoactive effects of cannabinoid agonists from their therapeutic effects.
These efforts have been largely unsuccessful.

[0008] Another strategy centers on changing the pharmacokinetics of drug delivery to maximize therapeutic effect and minimize cognitive and subjective drug effects.
Development of oral, rectal, and transdermal medications of synthetic A9-tetrahydrocannabinol (THC) are examples of this type of approach. The potential therapeutic benefits of administering unique combinations of cannabinoids by the oromucosal route.
(Reviewed in Huestis MA, Chem Biodivers. 2007 Aug; 4(8): 1770-1804.)

[0009] Besides the psychoactive A9-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). Pharmacologically, the principal psychoactive constituent of cannabis is THC, an aromatic terpenoid, representing one of hundreds of known compounds in the plant, including many other cannabinoids, such as cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV) and cannabigerol (CBG).
In general, THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in the periaqueductal gray. Other effects include relaxation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked anti-emetic properties, and may also reduce aggression in certain subjects. THC helps alleviate symptoms suffered both by AIDS patients, and by cancer patients undergoing chemotherapy, by increasing appetite and decreasing nausea. It has also been shown to assist some glaucoma patients by reducing pressure within the eye, and is used in the form of cannabis by a number of multiple sclerosis patients, who use it to alleviate neuropathic pain and spasticity.

[0010] Cannabidiol ("CBD") is one of at least 85 cannabinoids found in cannabis. It is a major constituent of the plant, second to THC, and represents up to 40% in its extracts.
Cannabidiol (CBD) is a natural, non-psychoactive constituent of Cannabis sativa, but possesses pharmacological activity, which is explored for therapeutic applications.
Cannabidiol (CBD) is known to modify the effects of A9-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. Compared with THC, CBD
is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder, schizophrenia, nausea, convulsion and inflammation, as well as inhibiting cancer cell growth.

[0011] Compositions containing THC and/or CBD suitable for use in palliative cancer therapy were disclosed in US Patent App. Pub. No. 20040138293 (Werner et al.).
A
pharmaceutical composition comprising A9-tetrahydrocannabinol for treating or preventing symptoms associated with multiple sclerosis (MS) was disclosed in US Patent App. Pub. No.
20080181942 (Zajicek).

[0012] Medical cannabis is administered by a variety of routes, including vaporizing or smoking dried bud and leaf portions, eating leaf or extracts, and taking capsules. Synthetic cannabinoids are available as prescription drugs in some countries. Medical cannabis can also be made into an edible form such as lozenges, candies, baked goods. Many cannabis-based products contain harmful preservatives (e.g., BHT, BHA) and stabilizers, artificial flavorings, colors, as well as toxic byproducts (e.g., Benzene, Hexane, heavy metals, etc.) from extraction methods, and/or trigger side effects and fail to provide effective relief for the subject medical condition.

[0013] International Patent App. Pub. No. W02015/200864 (Crowley et al.) discloses cannabinoid troche or lozenge including polyethylene glycol for buccal or sublingual administration. US Patent App. Pub. No. 20160158298 discloses a hard candy formulation containing high amounts of CBD and controlled amounts of THC. US Patent App.
Pub. No.
20160106705 discloses preparation of a botanical drug substance containing cannabinoids and flavonoids or terpenes. US Patent App. Pub. No. 20150209322 discloses preparation of a preparation of a chewing gum containing cannabinoids provided within internal voids of a solid cellulose carrier. However, water-soluble matrices reduce the time for retention of the cannabis lozenge in the mouth thereby reducing the efficiency of oromucosal delivery.

[0014] There is a need for more efficient, sustained and safer delivery of cannabis extracts for various medical methods that are useful to treat pain and various medical conditions, by altering the pharmacokinetics of drug delivery in order to maximize therapeutic effects and minimize cognitive and subjective drug effects.
SUMMARY OF THE INVENTION

[0015] The invention provides lozenges comprising cannabinoids embedded in a matrix such as ethyl cellulose. The extract contains at least 1, 2, 3, 4, 5, 6, 7 or more cannabinoids. The cannabinoids are selected from tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD) or cannabichromene (CBC). In some aspects the cannabinoids are THCa and CBDa and may include at least two other cannabinoids selected from CBNa, CBCa, THC, CBN and CBC. In a preferred embodiment the cannabinoids are THC, CBN, CBC and CBD. In another preferred embodiment the cannabinoids are THCa, CBDa, CBNa and CBCa. In yet another preferred embodiment the cannabinoids are THCa, CBDa, THC, CBN, and CBC. In another embodiment the cannabinoids comprise or tetrahydrocannabivarin (THCV).

[0016] In some embodiments, the cannabis lozenges are formulated using ethyl cellulose as the matrix and essential oils (such as peppermint oil) plus sucralose (or other sweeteners such as Stevia ).

[0017] In some embodiments, the cannabis lozenges last 0.5 to 1.5 hours in the mouth.
Pharmaceutical efficacy is noticed within 30 minutes compared to oral intake which requires 2 hours or more.

[0018] In some embodiments, the cannabis lozenges comprise xanthan gum to alleviate dry mouth problem caused by cannabis.

[0019] In some embodiments, the cannabis lozenges are further supplemented with constituents such as zinc for fresh breath, bicarbonate for acidity control of the mouth, and essential oils for anti-bacterial activity.

[0020] In some embodiments permeation enhancers such as MSM are incorporated in the lozenges for even more efficient absorption through the oral mucosa into blood stream.

[0021] The present invention includes a variety of other useful aspects, which are detailed herein. These aspects of the invention can be achieved by using the articles of manufacture and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the invention. In addition, a variety of other aspects and embodiments of the present invention are described herein.

[0022] The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following detailed description, as well as from the claims.
DETAILED DESCRIPTION OF THE INVENTION

[0023] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where such term is used.
Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way.
Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.

[0025] The invention provides lozenges comprising cannabinoids embedded in a matrix such as ethyl cellulose. The extract contains at least 1, 2, 3, 4, 5, 6, 7 or more cannabinoids. The cannabinoids are selected from the at least 85 cannabinoids found in cannabis.
In preferred embodiments, the cannabinoids are selected from tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and tetrahydrocannabivarin (THCV).

[0026] Components of the cannabis plant Cannabis sativa are substantially known and are also employed in therapy. Thus, for example, A9-tetrahydrocannabinol (A9-THC) corresponds to formula (a), and cannabidiol (CBD) corresponds to formula (b).
(a) OH
kW;

0 el

[0027] The composition of the invention comprises both the compounds produced by a synthetic route and the compounds obtained from plant extracts. The compound tetrahydrocannabinol (THC) can be produced for example by a synthetic route.
The compounds THC and CBD which are used according to the invention are preferably extracted from the plant Cannabis sativa. Operations are always carried out with exclusion of oxygen.
The cannabis compounds are moreover extracted from the plant in a manner known per se, for example using low molecular alcohols such as methanol, ethanol, butanol or propanol;
acetic esters such as the methyl ester or ethyl ester; ketones, for example acetone; ethers such as methyl ether or ethyl ether; or with low-boiling aliphatic or aromatic or chlorinated hydrocarbons. For example, the cleaned, dried and cut plants (inflorescences, leaves, stalks etc.) are normally treated at the reflux temperature with about three to ten times the amount by weight of the stated solvent or a mixture of such solvents, preferably for at least about one hour, after which the residue is filtered off. The liquid still present in the residue is carefully expelled and added to the filtrate. The solvent is subsequently removed, preferably under vacuum, for example under a pressure of about 80 mbar and at a temperature of about 40-60 C. The resulting extract, which usually results from this process as a honey-like resin, is then heated at a temperature of about 110 C. to about 135 C., preferably at about 120 C., preferably in an autoclave, for about 40 minutes. At this temperature, the compounds which are present as carboxylic acids in the extract are decarboxylated, and the compounds THC
and CBD are formed in virtually quantitative yield. The cold product is subsequently taken up preferably in petroleum ether and subjected to a chromatography on silica gel with a suitable mobile phase, for example with a petroleum ether/ethyl acetate mixture. The resulting cannabinoid fraction, which can be detected with the aid of thin-layer chromatography, is subsequently subjected to a chromatographic separation on a hydrophobic silica gel, for example on octadecyl-silylated silica gel, preferably using for the chromatography a mobile phase mixture consisting of methanol/water and acetic acid or ethanol/water and acetic acid. This purification results in purified CBD as a first fraction and purified THC as second fraction. The purity of the resulting compounds or active ingredients is determined with the aid of HPLC, and usually a purity of at least 90% by weight based on the total weight of the components present in this fraction is obtained.
However, a possible alternative procedure is also to extract the cannabis compounds from the cleaned, dried and cut plant parts in a manner known per se using about three to ten times the amount by weight of an organic solvent which is insoluble in water, that is to say forms a two-phase system with water. Operations are carried out in each case with exclusion of oxygen here too.
Suitable solvents are, for example, water-insoluble acetic esters, preferably the methyl or ethyl esters of acetic acid; water-insoluble ethers such as, for example, diethyl ether or ethyl propyl ether; or aliphatic or aromatic or chlorinated hydrocarbons. The organic solvent which contains the extracted cannabis compounds is then filtered and subsequently extracted at least twice with a 2% strength aqueous sodium hydroxide solution, which preferably contains about 20% by weight ethanol. During this, the cannabis compounds which contain a carboxyl group in particular pass into the aqueous/alcoholic phase. The combined aqueous/ethanolic phases are then mixed with a 5% strength sulfuric acid solution so that an acid value (pH) of about 2-4 is produced, after which very low-boiling lipophilic solvent, for example a low-boiling aliphatic or aromatic or chlorinated hydrocarbon, an acetic ester such as, for example, the methyl or ethyl ester of acetic acid or an ether or a mixture of such compounds is used for at least two extractions. The solvent is then removed in vacuo at low temperature. The residue is subsequently subjected to a chromatographic separation of a hydrophobic silica gel, for example on octadecylsilylated silica gel, preferably using for the chromatography a mobile phase mixture consisting of methanol/water and acetic acid or ethanol/water and acetic acid. A UV detector is used for detection at 280 nm. The active ingredient-containing fractions with the natural substances CBD acid and THC acid are obtained.
Identification and determination of the purity of the fractions takes place with the aid of HPLC.
The extractant (solvent) present in the fractions is then removed in vacuo. The active ingredients or the natural starting substances (i.e. CBD acid and THC acid) are preferably taken up in a lipophilic solvent or a suspension carrier. The active ingredients or active ingredient solutions are subsequently heated at about 110 C. to about 135 C., preferably at about 120 C., preferably in an autoclave, for about 40 minutes with exclusion of oxygen. At this temperature, the compounds which are present in the extract as carboxylic acids are decarboxylated and the compounds THC and CBD are formed in virtually quantitative yield.
The components can be identified using methods known per se, for example using thin-layer chromatography (TLC). High pressure liquid chromatography (HPLC) is advantageously used to determine the purity and content.

[0028] Examples of suitable lipophilic solvents or suspension carriers are medium- and/or short-chain triglycerides, medium-chain partial glycerides, polyethoxylated fatty alcohols, polyethoxylated fatty acids, polyoxyethylated fatty acid triglycerides or partial glycerides, esters of fatty acids with low molecular weight alcohols, partial esters of sorbitan with fatty acids, polyethoxylated partial esters of sorbitan with fatty acids, partial esters of sugars or oligomeric sugars with fatty acids, polyethylene glycols, and mixtures of said compounds.
Also suitable are mixtures of said compounds with fats, oils and/or waxes or glycols or suspensions in mixtures of lecithins and/or oils and/or waxes.

[0029] The extraction process described above usually results in extracts or extract fractions which in each case contain the components tetrahydrocannabinol (THC) or cannabidiol (CBD) or THCV in an amount of at least 80-90% by weight, calculated from the total weight of the cannabinoids present in the extract. The remaining proportions by weight consist of other compounds present in the cannabis plant.

[0030] Methods for making trans-(¨)-A9-tetrahydrocannabinol and trans-(+)-A9-tetrahydrocannabinol are disclosed in US patent No. 8383842.

[0031] Temperature control is necessary in the processing of cannabis extracts. As a result, the embodiments of the present invention recognize and use temperatures necessary to optimize cannabinoid, terpene and flavonoid content and ratios. Temperatures in the range of approximately 109 F. to 212 F. (at normal atmospheric pressure; temperatures change with negative pressures which allow for extraction and processing using different methods), maintain certain percentages of all cannabinoids and retain natural terpene and flavonoid content in the extracts thereby resulting in more medicinal value being retained instead of isolating one active.

[0032] Depending on the embodiment, Cannabis, C. sativa, C. indica, C.
ruderalis and hybrids in the raw material yield different ratios of CBD to THC. Percentages range from 24000:1 CBD:THC (i.e., 240 mg CBD to 0.01 mg THC) to 1:24000 CBD:THC (i.e., 0.01 mg CBD to 240 mg THC). In another embodiment, percentages range 200,000:1 CBD:THC
and 1:200,000 CBD:THC.

[0033] The procedure for producing the mixture of the invention is preferably such that the two solutions containing the active ingredient are mixed together in the appropriate ratio so that a ratio of the active ingredients THC :CBD in the range from 75:25 to 80:20, preferably 3:1 to 1:2, and in particular about 2:1, is obtained.

[0034] The total content of tetrahydrocannabinol (THC) and cannabidiol (CBD) in the pharmacologically active solution or suspension is moreover preferably in the range from 1%
by weight to 25% by weight, preferably in the range from 1% by weight to 6% %
by weight and in particular in the range from 1.5% by weight to 6% by weight, based on the weight of all the ingredients of the solution or of the suspension. On production of lozenges of the present invention, the ratio of the active ingredients THC:CBD remains as stated above, but the concentration thereof based on the total weight of the tablet or coated tablet may be higher.

[0035] In the therapeutic use of the composition of the invention on average 5 mg of THC, in a dosage range of 2.5-20 mg of THC, are administered each day as therapeutic dose (this is equivalent to 3.75-120 mg of the composition of the invention, calculated from the dry weight of THC and CBD). In some indications, on average 10 mg of THC, in a dosage range of 5-30 mg THC, are administered each day as therapeutic dose.

[0036] The invention provides cannabinoid dosage forms for release of a cannabinoid in the mouth. Delivery to a mucosal surface within the oral cavity may be used within the context of systemic drug administration, in which case the beneficial agent is actually delivered transmucosally, e.g., through the buccal mucosa of the gums. In one embodiment, the dosage form is a cannabinoid lozenge that comprises a sustained release wet matrix of a biocompatible, water-insoluble hydrophilic polymer, e.g., ethylcellulose, a cannabinoid selected from THC, THCV, CBD and any other cannabinoids found in cannabis. In this embodiment, the dosage form is composed of a wet matrix formulated so as to have a surface that is sufficiently tacky to enable the dosage form to adhere to the teeth or a mucosal surface within the mouth. This may be accomplished by using a relatively low molecular weight biocompatible polymer, as discussed infra, and/or by incorporating one or more adhesive polymers that are conventionally used in buccal drug delivery systems, e.g., polyisobutylene, polyisoprene, acrylic acid polymers and copolymers (e.g., those known as "carbomers,"
polyalkylene oxides (e.g., polyethylene glycol and copolymers thereof), polyvinyl lactams (e.g., polyvinyl pyrrolidone), and cellulosic materials (e.g., hydroxypropylmethyl cellulose).
Preferably, the dosage form is made adhesive by using a lower molecular weight hydrophilic polymer rather than by incorporation of additional polymers not contained within the wet matrix. When the dosage forms of the invention serve as transmucosal delivery systems, various carriers and additives may be incorporated as is well known in the art of transmucosal (e.g., buccal) drug delivery. Typical additives include permeation enhancers such as methylsulfonylmethane (MSM), polyethylene glycol esters, long-chain fatty acid esters of diols and triols (e.g., glycerol monolaurate, propylene glycol monolaurate), lower alkanols, and the like.

[0037] The fraction of each component in the dosage form is not particularly important, although, typically, in a lozenge, the hydrophilic polymer and the cannabinoid each represents approximately 25-49.5 wt. % of the lozenge, and optional additives, e.g., added beneficial agents, sweeteners, and excipients typically represent about 1-50 wt. %, preferably about 1-45 wt. %, of the lozenge.

[0038] The hydrophilic polymer is both water-insoluble and biocompatible as those terms are defined herein. That is, the polymer component of the dosage form has: an octanol-water partition coefficient P of less than 1.0, preferably less than 0.5; solubility in water of less than wt. %, preferably less than 3 wt. %, most preferably less than 1 wt. % at 0 C.; and does not give rise to undesirable biological effects or interact in an adverse manner with any of the other components of the dosage form.

[0039] When the dosage form is a lozenge, varying the molecular weight or viscosity of the polymer can impart certain properties to the dosage form. More specifically, a lower molecular weight polymer (e.g., ethylcellulose having a solution viscosity of about 6 to 15 cP) can give rise to a pliable, sticky lozenge, while a higher molecular weight polymer can provide a soft, rubbery, and non-tacky lozenge. Molecular weight also impacts on release rate and time to disintegration in the mouth, i.e., on the rate at which flavoring agent and/or other components in the dosage form are released and on the time the dosage form remains intact, respectively. With lozenges, use of a higher molecular weight polymer, as compared to a lower molecular weight polymer, tends to give rise to a product that exhibits more rapid release kinetics and more rapid breakdown, given an equivalent amount of other components present.

[0040] The particle size of the polymer is also relevant to the properties of the dosage forms made therewith. Generally, the polymers useful in conjunction with the invention have a particle size in the range of about 1 micron to about 250 microns. Micronized polymers, e.g., micronized ethylcellulose, are preferred for formation of strong polymer matrix systems, while matrices manufactured with polymers having a larger particle size tend to break apart faster. Micronized polymers generally have a particle size of less than 75 microns, with a mean of about 20 microns, and a typical size range in the range of about 1 micron to about 50 microns.

[0041] An exemplary cellulosic polymer is ethylcellulose. The ethylcellulose should have a solution viscosity in the range of approximately 1 to 120 cP, with a preferred solution viscosity in the range of approximately 3 to 100 cP, and a most preferred solution viscosity in the range of approximately 6 to 49 cP. The ethoxyl content is typically in the range of about 45.0% to 52.0%, preferably in the range of about 48.0-49.5%. Suitable ethylcellulose polymers that are available commercially include, without limitation, those that may be obtained from the Dow Chemical Company (Midland, Mich.) as ETHOCEL
ethylcellulose, e.g., ETHOCEL Standard 4 Premium (solution viscosity range approximately 3 to 5.5 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 7 Premium (solution viscosity range approximately 6 to 8 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 10 Premium (solution viscosity range approximately 9 to 11 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 14 Premium (solution viscosity range approximately 12.6 to 15.4 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 20 Premium (solution viscosity range approximately 18 to 22 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 45 Premium (solution viscosity range approximately 41 to 49 cP, ethoxyl content 48.0-49.5%), ETHOCEL Standard 100 Premium (solution viscosity range approximately 90 to 110 cP, ethoxyl content 48.0-49.5%), ETHOCEL Medium 50 (solution viscosity range approximately 43 to 55 cP, ethoxyl content 45.0-47.0%), ETHOCELO Medium 70 (solution viscosity range approximately 63 to 85 cP, ethoxyl content 45.0-47.0%), ETHOCELO
Medium 100 (solution viscosity range approximately 90 to 110 cP, ethoxyl content 45.0-47.0%), and ETHOCELO HE 10 (solution viscosity range approximately 9 to 11 cP, ethoxyl content 49.5-52.0%), with all solution viscosities determined using an Ubbelohde viscometer and a solvent mixture of 80% toluene and 20% alcohol.

[0042] Cannabis oils are unpleasant in taste and the lozenges according to the invention mask the unpleasant taste by incorporating flavoring agents. Flavoring agents may be combined, if desired, to produce a particular flavor mix. Ideal flavoring agents in this regard are pharmaceutically acceptable essential oils and chemical constituents of essential oils that can impart a desired flavor. Essential oils, as known in the art, are naturally occurring compounds or compositions that accumulate in the oil cells, glandular trichomes, and oil or resin ducts of aromatic plants. Essential oils also exhibit anti-bacterial activity.
Essential oils that can be incorporated into the present flavored dosage forms as suitable flavoring agents include, without limitation, citrus oils such as lemon oil, lime oil, neroli oil, and orange oil, mint oils such as peppermint oil and spearmint oil, and other oils such as anise oil, wintergreen oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eriodictyon fluidextract, eucalyptus oil, fennel oil, glycyrrhiza extract, lemongrass oil, and nutmeg oil. The citrus and mint oils are generally preferred.

[0043] As is widely appreciated in the art, essential oils contain a number of constituents, many of which can by themselves serve as additives. Of these, the most well-known essential oil constituents that are widely used as flavoring agents are hydrocarbons, particularly terpenes and sesquiterpenes. "Terpenes" generally refer to hydrocarbons of the formula C101-116, and, as the term is used herein, also encompass terpene analogs of the formula CnH2n-4, as well as terpenes and terpene analogs substituted with one or more nonhydrogen substituents and/or containing a heteroatom such as N, 0, or S. Analogously, "sesquiterpenes" generally refer to hydrocarbons of the formula C15H24, but for the purpose of the present invention also encompass sesquiterpene analogs of the formula CnH2n_6 as well as substituted and/or heteroatom-containing derivatives thereof.

[0044] In order to enhance the taste of the dosage form, at least one sweetener is preferably incorporated into the formulation. The sweetener may be a sugar, e.g., sucrose, fructose, or dextrose, or, more preferably, a non-sugar sweetening agent to reduce both caloric intake and the likelihood of dental caries. Sweeteners falling within the latter group include well known artificial sweetening agents, such as Stevia (a sugar substitute extracted from the leaves of the plant species Stevia rebaudiana), stevioside, steviol, aspartame, saccharin, saccharin salts (e.g., sodium saccharin, calcium saccharin), sucralose, acesulfame-K
(potassium acetosulfam), sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin. In lozenges of the invention, the sweetener is generally incorporated within the wet matrix, i.e., physically entrapped therein.

[0045] The dosage form optionally contains a colorant and/or other conventional additives as well. With respect to colorants, some essential oils are already colored. For example, peppermint oil imparts a yellow color, while cinnamon oil imparts a brown color. Without an added colorant, and in the absence of a colored flavoring agent, the lozenges of the present invention will tend to be off-white or slightly darker, and may have some degree of translucence. Accordingly, a colorant must be added if a colored dosage form is desired.
Suitable colorants include natural colorants, i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, and quercetin. Synthetic colorants may also be used, and will typically be an FD&C or D&C dye, e.g., an approved dye selected from the so-called "coal-tar" dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a "lake" thereof, i.e., an aluminum or calcium salt thereof.
Particularly preferred colorants are food colorants in the "GRAS" (Generally Regarded as Safe) category.

[0046] Other optional additives include, for example: adhesion modifiers (including adhesion-increasing agents and adhesion-reducing agents) such as ingestible solvents (e.g., ethyl acetate and ethanol increase tack when admixed with ethylcellulose), mineral oil and vegetable oils (which tend to decrease tack when admixed with ethylcellulose), and additional polymers and polymer compositions, including polymers typically used to form hydrogels, e.g., ethylene vinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, cellulose acetate, cellulose diacetate, and other cellulose esters, which may increase or decrease tack depending on the particular polymer or polymer composition; pH-adjusting agents (e.g., acids, bases, buffer systems); preservatives (e.g., antioxidants, antimicrobial agents, etc.);
fillers (e.g., maltodextrin, microcrystalline cellulose, lactose, mannitol, etc.); and enhancers to increase permeation of cannabinoid(s) into the tissues of the oral cavity and/or through the oral mucosa and into the bloodstream, to achieve enhanced systemic levels of the cannabinoid(s). Methyl sulfonyl methane ("MSM") represents a preferred enhancer.

[0047] Other beneficial agents that may be incorporated in the cannabis lozenges include include, but are not limited to: sources of Zn2 , i.e., ionizable zinc compounds. Ionizable zinc compounds are useful for reducing the duration and/or symptoms of common colds, managing upper respiratory allergy, as nutritional agents, and in treating halitosis, i.e., for reducing or eliminating bad breath. The ionizable zinc compound may be an inorganic or organic complex; examples of suitable complexes include zinc gluconate, acetate, chloride, propionate, butyrate, n-butyrate, B-hydroxybutyrate, benzoate, formate, and sulfate, although zinc acetate and gluconate are generally preferred for reasons of stability.
Generally, the amount of ionic zinc (i.e., Zn2 ) in a dosage form of the invention is in the range of about 1 mg to about 50 mg, typically in the range of about 5 mg to about 40 mg, preferably in the range of about 15 mg to about 35 mg (these ranges correspond to about 12.8 mg to about 640 mg, typically about 64 mg to about 512, preferably about 192 mg to about 448 mg zinc gluconate, insofar as ionic zinc represents approximately 12.8 wt. % of zinc gluconate).

[0048] Cannabis often causes dry mouth. A dosage form of the subject invention may also be formulated so as to include a beneficial agent to alleviate the problem, such as xanthan gum, polycarbophil, polyethylene oxide, hydroxypropylmethylcellulose (HPMC), pectin, guar gum, and the like, that may further treat or prevent an underlying condition such as xerostomia, Sjogren's syndrome, Eaton-Lambert syndrome, diabetes, and the like. For instance, a suitable saliva substitute, such as methyl cellulose, carboxymethyl cellulose, xylitol, pilocarpine, and the like, may be added as a beneficial agent to a dosage form of the subject invention to both produce a lubricated condition in the mouth as well as to treat or reduce the underlying symptoms of xerostomia when delivered to the mouth.

[0049] The addition of alkali metal bicarbonates to toothpaste for medicinal, general cleansing, or esthetic purpose is known in the art. In optional embodiments, bicarbonates are included for acidity control of the mouth (lower cavities), clean mouth feel effect and sweetening of any initial acid taste.

[0050] The dosage forms of the invention are useful for the delivery of a cannabinoid to the mucosal surface within the oral cavity. In one embodiment, the dosage form is a cannabinoid lozenge that comprises a sustained release wet matrix of a biocompatible, water-insoluble hydrophilic polymer, e.g., ethylcellulose, a cannabinoid selected from THC, THCV, CBD
and any other cannabinoids found in cannabis, flavoring agents selected from essential oils, constituents of essential oils, and mixtures thereof, wherein, in an aqueous environment, the matrix gradually releases the cannabinoid therein over a time period of at least 15 minutes, generally over a time period of 30 to 90 minutes, while the lozenge is capable of providing sustained release over a time period of one, two, three, or even four or more hours. The lozenges of the invention do not dissolve within the mouth, but rather remain intact until removed by the user and/or until a substantial fraction of the cannabinoid has been released.
In the latter case, release of a substantial fraction of the cannabinoid results in degradation of the wet matrix into small fragments.

[0051] The length of time that the lozenge can remain in the mouth and provide sustained release is controlled in part by the appropriate selection of hydrophilic polymer and cannabinoid, and in part by the relative amounts of the hydrophilic polymer and the cannabinoid. In general, the weight ratio of the hydrophilic polymer to the cannabinoid should be in the range of approximately 1:5 to 2:1, preferably in the range of approximately 1:2 to 1.5:1, and optimally in the range of approximately 1:1.5 to 1.2:1. A
higher ratio of cannabinoid to polymer may provide a matrix that may be too sticky for some of the present purposes, while a lower ratio may result in a composition that is not sufficiently cohesive to provide the desired matrix, depending on the polymer and on other components of the composition. Accordingly, the aforementioned ratios are not intended to be limiting, however, and ratios outside of the recited ranges may be desirable to provide a different type of composition, e.g., compositions having a particularly soft consistency or a tendency to degrade more quickly.

[0052] Any of the optional additives may be in the form of a salt, ester, amide, prodrug, active metabolite, isomer, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite, isomer, or analog is pharmaceutically acceptable and retains at least some degree of the desired activity. Salts, esters, amides, prodrugs, metabolites, analogs, and other derivatives of the beneficial agents herein may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described inter alia in Smith MB, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (Wiley, 2013). Other agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature. In addition, chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers.

[0053] The lozenges are prepared by admixture of the hydrophilic polymer and the flavoring agent and any additional components, including sweeteners, colorants, other additives discussed herein, and additional beneficial agents. Admixture can generally be carried out at room temperature and ambient humidity, unless a particular beneficial agent or other component of the lozenge requires a protected environment, a lower temperature, or lower humidity. Using the appropriate weight ratio of the hydrophilic polymer to the flavoring agent as discussed supra, admixture of the components results in a pliable wet matrix that can be formed into a roll or sheet. After allowing the composition to set, typically over a 24-hour period, the lozenges are then created by cutting of the roll or die cutting of the sheet. In a preferred embodiment, the mixture of the components is compressed to form lozenges. For example, the mixture can be compressed in a two-part lozenge-shaped mold, wherein after the mixture is added to a recess within the lower half of the mold, the upper half is aligned therewith and pressure is applied to compress the mixture. Compressed lozenges can be made so as to remain intact within the mouth for extended time periods, on the order of five hours or more. It will be appreciated, however, that the present process can be tailored to provide compressed lozenges that degrade more quickly, for example by varying the proportion of flavoring agent(s) and/or excipients.

[0054] If a somewhat tacky lozenge is desired, e.g., a dosage form that adheres to the buccal mucosa for delivery of a beneficial agent, the same procedures are followed except that a lower molecular weight hydrophilic polymer is used to impart adhesive strength to the lozenge by virtue of the tacky surface provided. Alternatively, or in addition, one or more adhesive polymers can be incorporated into the lozenge formulation to provide the desired degree of adhesion, as described elsewhere herein.

[0055] The dosage forms of the invention may be prepared in any number of shapes and sizes, and the invention is not limited in this regard. Different shapes and sizes may be desirable for different applications. Typical dimensions, however, are on the order of 0.4" x 0.5" x 2" for lozenges, while lozenge weight is generally in the range of about 0.4 to 0.8 g.

[0056] In a typical embodiment, lozenges were manufactured with 10, 25, 50 or 100 mg of CBD or THC using ethyl cellulose as the matrix and peppermint oil plus sucralose and other excipients. Lozenge weight was typically 0.45 to 0.5 g.

[0057] 11-0H-THC and THC-COOH are primary metabolites of THC in rabbits and rhesus monkeys. (Burstein S, et al. Science. 1972; 176:422-423.). After orally ingested THC
dosing, higher THC-COOH concentrations are observed compared those of THC
almost immediately after dosing, in contrast to what is found after smoking.
(Nadulski T, et al.. J.
Anal. Toxicol. 2005; 29:782-789). Concentrations of 11-0H-THC also were higher than those of THC. Metabolism of THC to 11-0H-THC, THC-COOH and other analytes also contributes to the reduction of THC in blood. Ratios of [11-0H-THCMTHC1 of >1 and >1.5 within and after 2 h after consumption, respectively, are the result of orally ingested THC. Orally ingested THC accumulated in the liver, lung, heart, and spleen.

[0058] Lozenges were clinically tested for pharmaceutical efficacy. Preferred lozenges typically lasted 0.5 to 1.5 hours in the mouth. Pharmaceutical efficacy was noticed within 30 minutes and was due to absorption through the oral mucosa into blood stream.
In contrast, oral intake requires longer time periods, typically 2 hours or more, to make its way from the intestinal tract to the blood stream. While lozenges enabled immediate and prolonged period of efficacy lasting hours, edibles used currently require longer periods to take effect.

[0059] Level of clinical efficacy reported was proportional to dosage.
Efficacy was noticed, even at the lower dosage of 10 mg. Another advantage of lozenge is the ability of the user to self-regulate medication either by using higher (or lower) doses or by adjusting the length of time lozenges is retained in the mouth, or both.

[0060] In contrast, a recent lozenge is marketed by Trokie. (See US Pat. App.
Ser. No.
14/754,160 to Crowley et al.). The lozenge made by Trokie is formulated with PEG
(Polyethylene glycol). In clinical testing the Trokie lozenge lasted 4 minutes in tester's mouth. Delivery of the cannabinoids was based on intestinal absorption/metabolism and did not occur for 2 hours.

[0061] The embodiments of the present invention are useful for the treatment and prevention of a wide range of disorders, including, for example, cancer, multiple sclerosis (MS), inflammatory bowel disease (IBS), Crohn's disease (CD), irritable bowel syndrome (IBS), ulcerative colitis (UC), nausea, vomiting, anorexia, cachexia, all forms of pain (i.e. acute, chronic, neuropathic, etc.), gastrointestinal tract distress (i.e. heartburn, indigestion, stomachache, etc.), migraine headaches, postmenstrual syndrome (PMS), neurodegenerative diseases like Lou Gehrig's disease, Huntington's disease, Alzheimer's dementia, Parkinson's disease and Parkinsonian-type symptoms, spinal-cord injuries; HIV/AIDS, agitation, insomnia, depression, muscle spasms, spasticity from multiple sclerosis, glaucoma, Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), Post-Traumatic Stess Disorder (PTSD), and anxiety disorders.

[0062] The actives used in the embodiments of the present invention affect the human physiology in positive ways including the improvement of the immune system, prevention or

63 treatment of certain cancers, and reduction of inflammation. Those skilled in the art will recognize that the lozenges of the present invention may be used to treat any and all medical conditions that respond favorably.
EXAMPLES
[0063] Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
Example 1: Preparation of Flavored Lozenges

[0064] Lozenges were prepared by mixing 10, 25, 50 or 100 mg of CBD and/or THC, 0.4 g ETHOCEL Standard 100 Premium (The Dow Chemical Company, Midland, Mich.), 0.38 g peppermint oil, and 0.16 g sucralose at room temperature and ambient humidity.
Admixture of the components resulted in a soft, wet composition that was allowed to set for 24 hours in the form of a sheet, and lozenges were then cut therefrom. The lozenges were soft, pliable, and tacky, and typically weighed 0.45 to 0.5 g.
Example 2: Pharmacokinetics of Lozenges

[0065] Two subjects tested the currently available cannabis lozenges formulated around a PEG matrix. Both subjects reported that these lozenges did not last longer than 4 minutes in the mouth. Without being bound by theory, it is postulated that this short tenure of the PEG-based lozenges in the mouth is caused by the high water-solubility of PEG.

[0066] These subjects also felt the effects of the cannabinoids after about 2 hours. This is consistent with a mostly oral ingestion of the cannabinoids and intestinal or hepatic absorption instead of a mucosal delivery.

[0067] In contrast, lozenges formulated according to the instant invention with ethyl cellulose and like matrices, typically lasted 0.5 to 1, 1.5, 2, 3 and 4 hours or more while pharmaceutical efficacy was noticed within 30 minutes.

[0068] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0069] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claim.

Claims (29)

What is claimed is:

1. A lozenge for rapid delivery of cannabinoids through the oral mucosa, the lozenge comprising:
a water-soluble polymer; and cannabis extracts comprising one or more of CBD, THC, and other cannabinoids.

2. The lozenge of claim 1, wherein the water-soluble polymer is ethyl cellulose.

3. The lozenge of claim 1, wherein the cannabinoids are selected from tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and tetrahydrocannabivarin (THCV).

4. The lozenge of claim 1, further comprising an essential oil, a constituent of an essential oil, or a mixture thereof.

5. The lozenge of claim 4, wherein the essential oil is selected from the group consisting of:
a citrus oil, lemon oil, lime oil, neroli oil, orange oil, a mint oil, peppermint oil, spearmint oil, wintergreen oil, anise oil, ginger oil, mango oil, tangerine oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, eriodictyon fluid extract, glycyrrhiza extract, and combinations thereof.

6. The lozenge of claim 4, wherein the essential oil comprises a terpene, a sesquiterpene, or combinations thereof.

7. The lozenge of claim 1, further comprising an effective amount of a sweetener selected from a sugar, a non-sugar sweetening agent, and a mixture thereof.

8. The lozenge of claim 1, wherein the non-sugar sweetening agent is selected from stevia extract powder, stevioside, steviol, aspartame, saccharin, saccharin salts, sucralose, potassium acetosulfam, sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin.

9. The lozenge of claim 1, further comprising a dry mouth alleviating agent selected from the group consisting of xanthan gum, pectin, hydroxypropyl methylcellulose (HPMC), a poly(ethylene oxide) polymer, guar gum, and locust bean gum.

10. The lozenge of claim 1, further comprising a breath improving agent selected from a source of Zn2+, zinc gluconate and zinc acetate.

11. The lozenge of claim 1, further comprising at least one additive selected from the group consisting of: release rate accelerants, release rate retardants, adhesion-increasing agents, adhesion-reducing agents, flavor stabilizers, flavor diluents, pH-adjusting agents, preservatives, other lubricants, and fillers.

12. The lozenge of claim 11, wherein the pH-adjusting agent is an alkali metal bicarbonate.

13. The lozenge of claim 1, further comprising a permeation enhancer.

14. The lozenge of claim 1, wherein the permeation enhancer is methyl sulfonyl methane (MSM).

15. The lozenge of claim 1, wherein the cannabis extracts comprise one or more of the following: decarboxylated .DELTA.9-tetrahydrocannabinol, natural tetrahydrocannabinolic acid , cannabidiols, tetrahydrocannabivarin (THCV) and .DELTA.8-tetrahydrocannabinol.

16. A method for making a lozenge according to claim 1, the method comprising:
(i) preparing an admixture of 10, 25, 50 or 100 mg of one or more desired cannabinoids, ethyl cellulose, and optionally, an essential oil and a sweetening agent; and (ii) setting the admixture at room temperature and ambient humidity until a soft, pliable, and tacky lozenge material is formed.

17. The method of claim 16, wherein the essential oil is selected from the group consisting of:
a citrus oil, lemon oil, lime oil, neroli oil, orange oil, a mint oil, peppermint oil, spearmint oil, anise oil, wintergreen oil, ginger oil, mango oil, tangerine oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, eriodictyon fluid extract, glycyrrhiza extract, and combinations thereof.

18. The method of claim 16, wherein the sweetening agent is selected from;
sugar, anon-sugar sweetening agent is selected from stevia extract powder, stevioside, steviol, aspartame, saccharin, saccharin salts, sucralose, potassium acetosulfam, sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin, and admixtures thereof.

19. The method of claim 16, further comprising: adding to the admixture a dry mouth alleviating agent selected from the group consisting of xanthan gum, pectin, hydroxypropyl methylcellulose (HPMC), a poly(ethylene oxide) polymer, guar gum, and locust bean gum.

20. The method of claim 16, further comprising: adding to the admixture a breath improving agent selected from a source of Zn2+, zinc gluconate and zinc acetate.

21. The method of claim 16, further comprising: adding to the admixture at least one additive selected from the group consisting of: release rate accelerants, release rate retardants, adhesion-increasing agents, adhesion-reducing agents, flavor stabilizers, flavor diluents, pH-adjusting agents, preservatives, other lubricants, and fillers.

22. The method of claim 21, wherein the pH-adjusting agent is an alkali metal bicarbonate.

23. The method of claim 16, further comprising: adding to the admixture a permeation enhancer.

24. The method of claim 23, wherein the permeation enhancer is methyl sulfonyl methane (MSM).

25. A method for treating, preventing, or alleviating a disease or condition responsive to the administration of a cannabinoid in a subject, the method comprising:
administering a lozenge according to any of claims 1-15 for a time between 15minutes to 4 hours to a subject;
wherein the lozenge comprises one or more cannabinoid products at an amount and ratio sufficient to treat, prevent or alleviate the condition.

26. The method of claim 25 wherein the disease or condition is selected from:
cancer, multiple sclerosis (MS), inflammatory bowel disease (IBS), Crohn's disease (CD), irritable bowel syndrome (IBS), ulcerative colitis (UC), nausea, vomiting, anorexia, cachexia, acute pain, chronic pain, neuropathic pain, gastrointestinal tract distress, migraine headaches, postmenstrual syndrome (PMS), neurodegenerative diseases like Lou Gehrig's disease, Huntington's disease, Alzheimer's dementia, Parkinson's disease and Parkinsonian-type symptoms, spinal-cord injuries; HIV/AIDS, agitation, insomnia, depression, muscle spasms, spasticity from multiple sclerosis, glaucoma, Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), Post-Traumatic Stess Disorder (PTSD), and anxiety disorders.

27. The method of claim 25, wherein the cannabinoids are selected from tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and tetrahydrocannabivarin (THCV).

28. A method for therapeutic administration of cannabinoids to a subject, the method comprising:
administering to the subject a lozenge according to claim 1, wherein the lozenge is resident in the oral cavity between about 0.5 to about 1.5 hours.

29. The method of claim 28, wherein the pharmaceutical effects of the cannabinoids were experienced by the subject within 30 minutes.