WO2018236957A1

WO2018236957A1 - Method and compositions for treating restless legs syndrome

Info

Publication number: WO2018236957A1
Application number: PCT/US2018/038430
Authority: WO
Inventors: Jeffrey FRIEDLAND; Linda KLUMPERS
Original assignee: Nexien Biopharma, Inc.
Priority date: 2017-06-20
Filing date: 2018-06-20
Publication date: 2018-12-27

Abstract

Methods and compositions for treating restless legs syndrome.

Description

METHOD AND COMPOSITIONS FOR TREATING RESTLESS LEGS SYNDROME

REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of U. S. Provisional Patent Application Serial No. 62/522,447 filed on June 20, 2017 and is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods and compositions for treating restless legs syndrome. The methods comprise the administration of a composition comprising a cannabinoid and/or a terpene to a patient in need of such treatment.

BACKGROUND OF THE INVENTION

Restless legs syndrome (RLS) is a term used to describe a neurological sensory disorder that also interferes with sleep and is thus also considered a sleep disorder. Restless legs syndrome is otherwise known as Willis-Ekbom Disease, and Wittmaack-Ekbom syndrome.

The clinical manifestations include the compelling, irresistible, or uncontrollable urge to move, restlessness, and abnormal, unpleasant, or uncomfortable sensations in the limbs or the skin of the feet, legs, arms, or elsewhere which include pain, aching, throbbing, pulling, itching, crawling, creeping, burning, jerking, fidgety, antsy, electrical, pins and needles, buzzing, and twitching. The movements may be persistent, repetitive, periodic, or intermittent with symptoms in remission for periods of time. Clinical manifestations appear mainly in the evening or nighttime, sometimes peaking between the hours of 12: 00 AM to 4:00 AM. They can also manifest during periods of relaxation, rest, inactivity, or by lying or sitting down for a period of time. RLS is believed to be related to dysfunction in the basal ganglia section of the brain that controls movement and that uses dopamine. This dysfunction is thought to be similar to the dopamine dysfunction of Parkinson's disease. There are also a number of factors or conditions that are linked to RLS which include iron deficiency, pregnancy, certain medications such as anticonvulsants, antidepressants, beta-blockers, antipsychotics, certain substances such as alcohol, caffeine, cigarettes, neuropathy, venous disorders, renal disease and failure, sleep disorders, genetic inheritance, fibromyalgia, vitamin and mineral deficiencies, amyloidosis, hyper or hypothyroidism, Lyme disease, arthritis, diabetes mellitus, Periodic Limb Movement Disorder (PLMD) and Parkinson's disease.

Sometimes RLS is described as primary restless legs syndrome or secondary restless legs syndrome. Primary RLS is restless legs syndrome beginning before the age of 40. It is sometimes associated with genetic inheritance. Secondary RLS is restless legs syndrome beginning after the age of 40, and is usually associated with the use of medications or other substances.

There is no known cure for RLS. Treatment options include treating the associated factors or conditions and physical measures, but most treatment options are futile resulting in progressively worsening clinical manifestations and which may eventually lead to insomnia. Lack of sleep due to RLS contributes to an impairment in life quality and an increase in depressive disorders, anxiety, and the occurrence of panic attacks. Patients with RLS sometimes use treatment options that include dopamine agonists, opiates, or anticonvulsants or a combination thereof, however most patients halt treatment due to the poor efficacy or harmful side effects.

There is a need for improved treatments of RLS. It is an obj ect of the present invention to provide methods and compositions that are effective in treating RLS. SUMMARY OF THE INVENTION

The present invention accomplishes the above objectives and others by providing a method of treating RLS comprising the administration of a composition comprising at least one cannabinoid, at least one terpene, or a combination of at least one cannabinoid and at least one terpene.

Embodiments of the present invention are specifically directed to the treatment of primary RLS and secondary RLS.

The administration may be topical, oral, nasal, inhalation or a combination thereof.

If the composition is administered topically, it may be applied to a patient's skin in the form of a patch, gel, cream, paste, lotion, ointment, salve, serum, spray, aerosol, mousse or foam.

If the composition is administered orally, it may be provided in a solid or liquid form that may be swallowed or held in the oral cavity. The solid oral form may be a tablet, capsule, powder, or sachet, and may be administered in the solid form or dispersed or mixed with a food such as applesauce or oatmeal, or water, for easier swallowing. The liquid oral form may be a solution, suspension or syrup that may be swallowed or applied to the oral cavity as a spray, mist, aerosol or drops.

If the composition is administered nasally, it may be in form of a spray, mist or powder that is applied to the nasal cavity.

If the composition is administered via inhalation, the composition may be delivered to a patient's respiratory system via a nebulizer, vaporization or a metered dose inhaler.

The at least one cannabinoid may be synthetic or naturally occurring, and is preferably selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannadidiolic acid (CBDA), the various isomers and enantiomers thereof, and combinations and mixtures of one or more of the foregoing.

The at least one terpene may be synthetic or naturally occurring, and is preferably selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole (aka eucalyptol), pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, and combinations and mixtures of one or more of the foregoing.

DETAILED DESCRIPTION OF THE INVENTION

Except where noted, all terms are intended to have their normal meaning in the art, and are used as they would have been used by a person of ordinary skill at the time of the disclosure. It should be understood that throughout this application the singular forms, such as "a," "an," and "the," are often used for convenience, however, these singular forms are intended to encompass the plural unless otherwise specified, or unless the context clearly calls for the singular alone. It should also be understood that all publications, patents, books, journal articles, and the like, which are referred to in this application, are incorporated by reference in their entirety and for all purposes to the extent not inconsistent with the present disclosure.

As used herein, the terms "treat," "treating" or "treatment" refers to providing relief of one or more of the symptoms associated with RLS or diminishing or lessening any one or more of the symptoms associated with RLS.

As used herein the term "immediate release" (also known as instant release (IR)) refers to a pharmaceutical formulation or component thereof which releases, or delivers, one or more pharmaceutical agents substantially immediately upon administration and will result in substantially complete dissolution within about one hour (or less), preferably less than 45 minutes and most preferably in about 30 minutes or less when tested in a United States

Pharmacopeia dissolution apparatus.

As used herein, the term "modified release" (MR) includes delayed release and controlled release, also known as sustained release, prolonged release or extended release.

As used herein the term "delayed release" (DR) relates to a pharmaceutical formulation or component that releases the active ingredients after a period of delay such as after one, two or three hours. One type of DR formulation is an enteric coated formulation that delays the release of the drug from the dosage form until the dosage form encounters an aqueous environment with a pH of 5 or greater.

As used herein the term "controlled release" (CR) refers to a pharmaceutical formulation or component thereof that releases, or delivers, one or more pharmaceutical agents over a prolonged period of time, in this case over a period of more than one hour.

As used herein, "transdermal" means delivery of a drug or biologically active substance by passage into and through the skin or mucosal tissue. Hence, the terms "transdermal" and "transmucosal" are used interchangeably unless specifically stated otherwise. Likewise, the terms "skin," "derma," "epidermis," "mucosa" and the like will also be used interchangeably unless specifically stated otherwise.

As used herein, the term "topical" refers to outer skin or derma of a patient. Hence, the phrase "topical application" refers to the application of a composition of the present invention and its various embodiments to the outer surface of a patient's skin or derma.

As used herein, the terms "occlude," "occluded," "occlusive" and the like refer to a transdermal formulation that is applied to the skin with the use of a supporting or otherwise associated structure. In other words, a topical formulation may be applied to the skin of a patient with the aid of a structure, such as a backing member, bandage or cover. A matrix patch is an example of an occluded device. Conversely, "unoccluded" and "non-occluded," which may be used interchangeably, refer to a transdermal formulation that is applied to the skin without the use of a support, backing member, cover or otherwise associated structure. In other words, the transdermal formulation is applied to the skin in a free form, which is sufficient to effect transdermal delivery of the drug or biologically active substance without the use of structures, such as a backing member, etc. A gel formulation is an example of a non-occluded composition; other non-occluded compositions include ointments, lotions, pastes, mousses, aerosols and creams.

Concentration, weight percent and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a percent range of 1 % to 20% should be interpreted to include not only the explicitly recited percent limits of 1 % and 20% but also to include individual percentages such as 1.25%, 2.49%, 3%, 4.75%, 8.34% and sub-ranges such as 1 % to 5%, 10% to 15%, 4.7% to 1 1.9% etc.

As used herein the term "cannabinoid" refers to any chemical known to activate cannabinoid receptors in cells. The cannabinoids may be synthetic or naturally occurring. Naturally occurring cannabinoids may be found in cannabis plants or produced endogenously in humans and other animals. If produced endogenously, the cannabinoids are sometimes referred to as endocannabinoids. Synthetic cannabinoids are chemicals with similar structures to plant cannabinoids or endocannabinoids. Naturally occurring cannabinoids may be extracted and purified from various plants such as the cannabis plant, using known methods such as those described in U. S. Patent Nos. 7,344,736; 8,895,078 and 9,034,395 which are incorporated herein by reference. Synthetic cannabinoids are commercially available and can be prepared by known methods such as those described in U.S. Patent Nos. 3,668,224; 3,560,528; 7,186,850; 7,524,881; 7,674,922; 8,324,408 and 8,530,670, which are incorporated herein by reference.

Examples of cannabinoids that may be used in the methods of treatment and compositions in accordance with the present invention include:

Cannabigerolic Acid (CBGA); Cannabigerolic Acid monomethylether (CBGAM); Cannabigerol (CBG); Cannabigerol monomethylether (CBGM); Cannabigerovarinic Acid (CBGVA); Cannabigerovarin (CBGV); Cannabichromenic Acid (CBCA); Cannabichromene (CBC); Cannabichromevarinic Acid (CBCVA); Cannabichromevarin (CBCV); Cannabidiolic Acid (CBDA); Cannabidiol (CBD); Cannabidiol monomethylether (CBDM); Cannabidiol-C₄ (CBD-C4); Cannabidivarinic Acid (CBDVA); Cannabidivarin (CBDV); Cannabidiorcol (CBD-Ci); Tetrahydrocannabinolic acid A (THCA-A); Tetrahydrocannabinolic acid B (THCA-B); Tetrahydrocannabinol (THC); Tetrahydrocannabinolic acid C4 (THCA-C4); Tetrahydrocannbinol C4 (THC-C4); Tetrahydrocannabivarinic acid (THCVA); Tetrahydrocannabivarin (THCV); Tetrahydrocannabiorcolic acid (THCA-Ci); Tetrahydrocannabiorcol (THC-Ci); A⁷-cis-iso-tetrahydrocannabivarin (A⁷-THCV); Δ⁸- tetrahydrocannabinolic acid (A⁸-THCA); A⁸-tetrahydrocannabinol (A⁸-THC); Cannabicyclolic acid (CBLA); Cannabicyclol (CBL); Cannabicyclovarin (CBLV); Cannabielsoic acid A (CBEA-A); Cannabielsoic acid B (CBEA-B); Cannabielsoin (CBE); Cannabinolic acid (CBNA); Cannabinol (CBN); Cannabinol methylether (CBNM); Cannabinol-C₄ (CBN-C4); Cannabivarin (CBV); Cannabino-C2 (CBN-C2); Cannabiorcol (CBN-Ci); Cannabinodiol (CBND); Cannabinodivarin (CBDV); Cannabitriol (CBT); 10-Ethoxy-9-hydroxy-A^6a- tetrahydrocannabinol; 8,9-Dihydroxy-A^6a(10a)-tetrahydrocannabinol (8,9-Di-OH-CBT-C₅); Cannabitriolvarin (CBTV); Ethoxy-cannabitriolvarin (CBTVE); Dehydrocannabifuran (DCBF); Cannbifuran (CBF); Cannabichromanon (CBCN); Cannabicitran (CBT); 10-Oxo- A^6a(10a)-tetrahydrocannabinol (OTHC); A⁹-cis-tetrahydrocannabinol (cis-THC); Cannabiripsol (CBR); 3,4,5, 6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-metha- no-2H- 1 -benzoxocin-5 -methanol (OH-iso-HHCV); and Trihydroxy-A⁹-tetrahydrocannabinol (triOH- THC).

Preferably the cannabinoid may be selected from the group consisting of:

tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannadidiolic acid (CBDA), cannabielsoin (CBE), cannabicyclol(CBL), cannabinodiol (CBND), and a mixture of the foregoing.

The most preferred cannabinoid is selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannadidiolic acid (CBDA), the various isomers and enantiomers thereof, and combinations and mixtures of one or more of the foregoing. The above-identified cannabinoids may also be present as pharmaceutically acceptable salts or as individual isomers, enantiomers or mixtures thereof.

As used herein, the term "terpene" means an organic compound containing an isoprene unit, i.e., (CsH8)_n of the general formula:

wherein n is a whole integer of 1 or greater.

Unless otherwise stated, the term "terpene" includes terpenoids which are known in the art to be a compound wherein the base isoprene unit, (CsH8)_n, has been modified to include a functional group.

The term terpene includes: Hemiterpenes which consist of a single isoprene unit, i. e., n =1, representative examples include isoprene, prenol and isovaleric acid; Monoterpenenes which consist of two isoprene units, i.e., n = 2, representative examples include geraniol, terpineol, limonene, myrcene, linalool and pinene; Sesquiterpenes which consist of three isoprene units, i.e., n =3, representative examples include humulene, famesenes and famesol; Diterpenes which consist of four isoprene units, i.e., n = 4, representative examples include cafestol, kahweol, cembrene, and taxadiene; Sesterterpenes which consist of five isoprene units, i.e., n= 5, representative example includes geranylfarnesol; Triterpenes which consist of six isoprene units, i.e., n =6, representative example includes squalene;

Sesquarterpenes which include seven isoprene units, i.e., n = 7, representative examples include ferrugicadiol and tetraprenylcurcumene; Tetraterpenes which contain eight isoprene units, i.e., n=8 representative examples include acyclic lycopene, money clic gamma-carotene, bicyclic alpha carotene and bicyclic beta carotene; and Polyterpenes which consist of long isoprene chains, i.e., n > 8.

The term terpenes as used herein also includes terpene esters, terpenoids, terpenoid oxides, or their derivatives such as pharmaceutically acceptable salts and specific isomeric forms.

Representative examples of terpenes include:

Bisabolol, a monocyclic sesquiterpene alcohol and can be present in a racemic mixture, purified a or β forms or various ratios of the a or β forms; Cadinene, an isomeric hydrocarbon sesquiterpene and can be present in a racemic mixture, purified a or γ forms or various ratios of the a or γ forms; Cafestol, a diterpene molecule; Camphene, a bicyclic monoterpene; Camphor, a terpenoid; Carene, a bicyclic monoterpene; Carotene (and any of the isomeric forms of carotene and/or mixture thereof in any ratio); Carvacrol, a monoterpenoid phenol; Carvone, a monoterpenoid that can be also present in a racemic mixture, purified enantiomer forms S-(+) and R-(-) or various ratios of the enantiomer forms S-(+) and R-(-); Caryophyllene (a.k.a. β-Caryophyllene), a bicyclic sesquiterpene; Caryophyllene oxide; Cedrene, which can be present in a racemic mixture, purified a or β forms, or various ratios of the a or β forms; Cedrol, a sesquiterpene alcohol; Cembrene, a monocyclic diterpene; Citronellal, a monoterpenoid; Citronellol, an acyclic monoterpenoid which includes either or both of the (+) and (-) enantiomers as pure forms or mixtures in any ratio; Dehydrovomifoliol, a cyclic terpenoid oxide; Dihydroactinidiolide, a terpenoid oxide; Elemene (a.k.s β-Elemene), a cyclic sesquiterpene; EucalyptoU 1 ,8-Cineole, a cyclic ether and monoterpenoid; Euphol, a tetracyclic triterpene; Farnesene, six closely related sesquiterpenes having the following general structural formula:

as used herein the term "farnesene" includes one of more of the six closely related compounds; Famesol, a sesquiterpene alcohol; Fenchone, a monoterpene and a ketone; Geraniol, a monoterpenoid; Geranyl acetate, a monoterpene with a carboxylic acid; Geranylfarnesol an acyclic 25-carbon isoprenoid; Germacrenes a sesquiterpene having five isomers: Germacrene A; Germacrene B; Germacrene C; Germacrene D; Germacrene E; and combinations thereof; Guaia-l(lO), 11-diene, a bicyclic sesquiterpene; Guaiene, a bicyclic sesquiterpene; Gurjunene, a tricyclic sesquiterpene; Humulene, a monocyclic sesquiterpene; Ipsdienol, a terpene alcohol; Isomyrcenol, a monoterpenoid; Kahweol, a diterpene; Lavandulol, a monoterpene alcohol and may be present in a racemic mixture, in the R or S form or various ratios of the R and S forms; Limonene, a cyclic monoterpene; Linalool, a terpene alcohol; Linalyl acetate, an acetate ester of linalool; Longifolene, a tricyclic sesquiterpene and may be present in a racemic mixture, in (+) and/or (-) enantiomers, or various ratios of the (+) and (-) enantiomers; a-Longipinene, a bicyclic sesquiterpene; Lycopene, a tetraterpene; Myrcene, a monoterpene; y-Muurolene, a sesquiterpene; Nepetalactone, a bicyclic monoterpenoid; Nero, a monoterpene; Nerolidol, a sesquiterpene with C15H26O with cis and trans isomers; Neryl acetate, an acetate ester of nerol; Ocimene, a group of isomeric monoterpenes including a-Ocimene, β-cis-Ocimene, β-trans-Ocimene, in a single pure form and/or combination; p-Cymene, an aromatic monoterpene; Phellandrene, a cyclic monoterpene including the pure a form and the pure β form and combinations thereof; Phytol, a diterpene alcohol; a-Pinene, a bicyclic monoterpene; β-Pinene, a monoterpene; Pristimerin, a five-cyclic triterpene; Pulegone, a cyclic monoterpene; Retinol, a cyclic diterpenoid alcohol; Sabinene, a bicyclic monoterpene; Sabinene hydrate, a cyclic monoterpene alcohol and may present in the cis or trans form, or any ratio of the cis and trans form; Safranal, a monoterpene; a-Selinene, a bicyclic sesquiterpene; a-Sinensal, a sesquiterpenoid; fi-Sinensal, a sesquiterpenoid; Squalene, a triterpene; Taxadiene, a tricyclic diterpene; Terpineol, a cyclic monoterpene alcohol and isomers thereof; a-Terpinene, a cyclic monoterpene; y-Terpinene, a cyclic monoterpene; Terpinolene or A-Terpinene, a cyclic monoterpene; Thujone, a bicyclic monoterpene; Thymol, a monoterpene phenol; and combinations of the foregoing. The preferred terpenes are selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8- cineole (aka eucalyptol), pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof and combinations and mixtures of one or more of the foregoing.

Methods of Treatment The present invention includes methods for treating mammals, preferably humans, that exhibit RLS.

The methods of treating RLS comprise the step of:

(i) administering an effective amount of at least one cannabinoid to a patient in need of such treatment;

(ii) administering an effective amount of at least one terpene to a patient in need of such treatment; or

(iii) administering a combination of an effective amount of at least one cannabinoid and an effective amount of at least one terpene to a patient in need of such treatment.

As used herein the term "effective amount" means the amount of an active substance, i.e., cannabinoid and/or terpene that, when administered to a subj ect treats a symptom of RLS. The effective amount will vary depending on the chemical identity and formulation form of the active substance, the disease, symptom, or condition and its severity, and the age, weight, and other relevant characteristics of the patient to be treated. Determining the effective amount of a given active substance is within the ordinary skill of the art. For example, a beneficial effect for the treatment of RLS, includes but is not limited to, reducing the period of time a patient experiences restlessness, uncomfortable sensations in the limbs, pain, insomnia or a combination thereof. Other beneficial effects for the treatment of RLS may include slowing the progressive worsening of restlessness, uncomfortable sensations in the limbs, pain, and insomnia.

In certain embodiments, the methods of the present invention will reduce one or more symptoms such as restlessness, uncomfortable sensations in the limbs, pain, and insomnia 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% compared to a patient not receiving the cannabinoid, terpene or combination thereof. For example, if a patient diagnosed with RLS experiences 10 periods of restlessness during a single night sleep without the administration of the cannabinoid, terpene or combination thereof, a patient receiving the administration of the cannabinoid, terpene or combination thereof in accordance with the method of the present invention will experience 7 or fewer periods, 5 or fewer periods, 2 or fewer periods, or 0 periods in a single night sleep. Similarly if the patient diagnosed with RLS experiences a restlessness episode lasting 7-10 minutes without the administration of the cannabinoid, terpene or combination thereof, a patient receiving the administration of the cannabinoid, terpene or combination thereof in accordance with the method of the present invention will experience a restlessness episode lasting 5 minutes or less, 3 minutes or less, 1 minute or less, or 30 seconds or less.

In certain embodiments, the methods of the present invention will reduce the patient's International Restless Legs Syndrome Rating Scale Score by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% compared to a patient not receiving the cannabinoid, terpene or combination thereof. The International Restless Legs Syndrome Rating Scale Score was developed by the International Restless Legs Syndrome Study Group (IRLSSG) and is a questionnaire provided to patients meeting the IRLSSG criteria of having RLS. The answers to the questionnaire are scored and a total score of 31-40 points indicates a very severe case of RLS, 21-30 points indicates a severe case of RLS; 11-20 points indicates a moderate case of RLS, 1-10 indicates a mild case of RLS and a score of 0 indicates no RLS. The International Restless Legs Syndrome Rating Scale has been described in greater detail and validated by Horiguchi, J., et al, "Validation of the International Restless Legs Syndrome Study Group Rating Scale for Restless Legs Syndrome," Sleep Medicine, 2003; 4(2), pp.121-132. The administration of the effective amount of the at least one cannabinoid, the effective amount of the at least one terpene, or the effective amount of a combination of at least one cannabinoid and at least one terpene may occur about every 4 to about 6 hours, about every 6 to about 8 hours, about every 12 hours, or about every 24 hours. In certain embodiments the administration may occur once, twice, three or four times a day. In certain embodiments, the administration of an effective amount of the at least one cannabinoid, the effective amount of the at least one terpene, or the effective amount of a combination of at least one cannabinoid and at least one terpene may occur once per day, preferably after the evening meal, shortly before or at bedtime. As used herein shortly before bedtime means about one hour, about 45 minutes, about 30 minutes, about 15 minutes, or about 10 minutes before the patient attempts to sleep for the evening. At bedtime means within about 5 minutes before a patient attempts to sleep for the evening. The single administration after the evening meal or shortly before or at bedtime should provide therapeutic effective levels of the at least one cannabinoid, the least one terpene, or the combination of at least one cannabinoid and at least one terpene for a period of about 6 to about 12 hours, preferably about 7 to about 10 hours, and most preferably about 8 hours to allow the patient to obtain a restful night sleep without the experiencing the adverse symptoms of RLS.

In one embodiment, the administration of an effective amount of the at least one cannabinoid, the effective amount of the at least one terpene, or the effective amount of a combination of at least one cannabinoid and at least one terpene may occur once per day, preferably after the evening meal, shortly before or at bedtime. The administration comprises an oral administration, an intrapulmonary administration or a combination of oral and intrapulmonary administration. The oral administration may include the swallowing of a solid or liquid composition comprising an effective amount of the at least one cannabinoid, an effective amount of the at least one terpene, or an effective amount of a combination of at least one cannabinoid and at least one terpene or buccally, lingually or sublingually administering a solid or liquid composition comprising an effective amount of the at least one cannabinoid, an effective amount of the at least one terpene, or an effective amount of a combination of at least one cannabinoid and at least one terpene. The intrapulmonary administration may include the delivery of an effective amount of the at least one cannabinoid, an effective amount of the at least one terpene, or an effective amount of a combination of at least one cannabinoid and at least one terpene to a patient's respiratory system, i.e. lungs, via a nebulizer, vaporization or a metered dose inhaler. In certain embodiments, the administration comprises the oral administration of an effective amount of THC, CBD and/or CBDV and the intrapulmonary administration of an effective amount of THC, CBD and/or CBDV once per day, preferably after the evening meal, shortly before or at bedtime. The intrapulmonary administration in this combined oral-intrapulmonary once a day dosing regimen will allow for a quick onset of the therapeutic effects from the intrapulmonary administration and a prolonged therapeutic effect from the oral administration allowing a patient to obtain quality night sleep, i.e. about 6-8 hours of sleep without experiences of restlessness, pain or uncomfortable sensations in the limbs.

If a combination of the at least one cannabinoid and at least one terpene is administered, the at least one cannabinoid and at least one terpene may be administered concurrently, such as in the same dosage form, i.e., both the at least one cannabinoid and at least one terpene being present in the same tablet, capsule, liquid, suspension, aerosol, or topical patch, gel, cream lotion or serum. The combined administration of the at least one cannabinoid and at least one terpene may also occur sequentially wherein either the at least one cannabinoid or the at least one terpene is administered at a first time and the at least one terpene or at least one cannabinoid is administered at a second time, and the first and second times are different. The first and second times may be separated by a few seconds such as 30 seconds, a few minutes such as about 1 to 20 minutes preferably 1 to 10 minutes, and most preferably about 1 to about 5 minutes, or by an hour or more. In one embodiment, the combination of the at least one cannabinoid and at least one terpene occurs with both the cannabinoid and terpene in the same dosage form so the administration of the cannabinoids and/or terpenes are concurrent.

Although the effective amount of the at least one cannabinoid and the effective amount of the at least one terpene will vary depending upon the specific cannabinoid and terpene being administered, the route of administration, and the patient's individual characteristics such as age weight, sex, it is believed that the effective amount of the cannabinoid will range from about 0.01 mg to about 100 mg per administration, preferably about 0.05 mg to about 50 mg per administration, and most preferably about 0.1 mg to about 25 mg per administration. It is further believed that the foregoing dosing ranges are based on the total amount of cannabinoid being administered per dose. For example, if the at least one cannabinoid comprises a mixture of THC and CBD, the total amount of cannabinoid, i.e., THC and CBD being administered should be within the aforementioned ranges. Similarly, if the at least one cannabinoid comprises a mixture of CBD, CBN, CBDV and THC A, the total amount of cannabinoid, i.e., CBD, CBN, CBDV and THCA being administered should be within the aforementioned ranges.

In embodiments wherein the at least one cannabinoid being administered comprises THC, it is preferred that at least a second cannabinoid such as CBD be included in the administration to counteract the psychotropic or "high" effects of THC.

It is also believed that the effective amount of the terpene will range from about 0.01 mg to about 350 mg per administration, preferably about 0.05 mg to about 250 mg per administration, and most preferably about 0.1 mg to about 200 mg per administration. It is further believed that the foregoing dosing ranges are based on the total amount of terpene being administered per dose. For example, if the at least one terpene comprises a mixture of limonene and linalool, the total amount of terpene, i.e., limonene and linalool, being administered should be within the aforementioned ranges. Similarly, if the at least one cannabinoid comprises a mixture of limonene, caryophyllene, myrcene and terpinolene, the total amount of terpene, i.e., limonene, caryophyllene, myrcene and terpinolene, being administered should be within the aforementioned ranges.

The administration of the effective amount of the at least one cannabinoid, the effective amount of the at least one terpene, or the effective amount of a combination of the at least one cannabinoid and the at least one terpene, may be by any means commonly known in the art such as topical, nasal, oral, inhalation or a combination thereof. Embodiments of the invention will include combining the effective amount of the at least one cannabinoid, the effective amount of the at least one terpene, or the effective amount of the at least one cannabinoid and at least one terpene with a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition and administering the pharmaceutical composition to the patient.

In one embodiment, the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of one cannabinoid selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, and the various isomers and enantiomers thereof.

In another embodiment, the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of a combination of two cannabinoids, wherein the first cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers thereof and the second cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers wherein the first and second cannabinoid are not the same. The ratio of first to second cannabinoid in this embodiment may range from 1 : 5 to 5 : 1 , preferably 1 : 4 to 4 : 1 , and most preferably 1 : 3 to 3 : 1. In a further embodiment, the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of a combination of three cannabinoids, wherein the first cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers thereof; the second cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers, and the third cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers wherein the first, second and third cannabinoids are not the same. The ratio of first to second cannabinoid in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1, and the ratio of second cannabinoid to third cannabinoid in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1.

In one embodiment the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0.1 mg to 200 mg, of one terpene selected from the group consisting of limonene, pinene, linalool, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof.

In another embodiment, the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0.1 mg to 200 mg, of one terpene selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof. One of the more preferred terpenes is linalool and/or linalyl acetate, which may be administered in an amount of 1 mg to 300 mg, preferably 5 mg to 250 mg and most preferably about 10 mg to about 200 mg.

In a further embodiment, the method for treating one or more symptoms of RLS, comprises the administration of 0.01 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0. 1 mg to 200 mg, of a combination of two terpenes, wherein the first terpene is selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1 -8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof and the second terpene is selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof wherein the first and second terpene are not the same. The ratio of first to second terpene in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1. In one aspect of this embodiment, the combination two terpenes should comprise linalool and/or linalyl acetate, which may be administered in an amount of 1 mg to 300 mg, preferably 5 mg to 250 mg and most preferably about 10 mg to about 200 mg.

In a further embodiment, the method for treating RLS, comprises the administration of 0.01 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0.1 mg to 200 mg, of a combination of three terpenes, wherein the first terpene is selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, the second terpene is selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1 -8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, the third terpene is selected from selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, wherein the first, second and third terpenes are not the same. The ratio of first to second terpene in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1 and the ratio of second terpene to third terpene in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1. In one aspect of this embodiment, the combination three terpenes should comprise linalool and/or linalyl acetate, which may be administered in an amount of 1 mg to 300 mg, preferably 5 mg to 250 mg and most preferably about 10 mg to about 200 mg.

In one embodiment the method for treating one or more symptoms of RLS, comprises oral, buccal, lingual, sublingual and/or intrapulmonary administration preferably after the evening meal, shortly before or at bedtime of:

(i) 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of one cannabinoid selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers thereof, preferably THC, CBD or CBDV; and

(ii) 0 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0.1 mg to 200 mg, of one terpene selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, preferably linalool and/or linalyl acetate.

In another embodiment, the method for treating one or more symptoms of RLS, comprises oral, buccal, lingual, sublingual and/or intrapulmonary administration preferably after the evening meal, shortly before or at bedtime of:

(i) 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of a combination of two cannabinoids, wherein the first cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers thereof, preferably THC and the second cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers, preferably CBD and/or CBDV wherein the first and second cannabinoid are not the same; and

(ii) 0 mg to 350 mg, preferably 0.05 mg to 250 mg, and most preferably 0.1 mg to 200 mg, of one or more terpenes selected from the group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole, pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, preferably linalool and/or linalyl acetate;

wherein the ratio of first to second cannabinoid in this embodiment may range from

1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1.

In a further embodiment, the method for treating one or more symptoms of RLS, comprises oral, buccal, lingual, sublingual and/or intrapulmonary administration preferably after the evening meal, shortly before or at bedtime of:

(i) 0.01 mg to 100 mg, preferably 0.05 mg to 50 mg, and most preferably 0.1 mg to 25 mg, of a combination of three cannabinoids, wherein the first cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers thereof, preferably the first cannabinoid is THC; the second cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers, preferably the second cannabinoid is CBD or CBDV, and the third cannabinoid is selected from the group consisting of THC, CBD, CBN, CBG, CBC, THCV, THCA, CBDV, CBDA, the various isomers and enantiomers, preferably the third cannabinoid if CBD or CBDV wherein the first, second, and third cannabinoids are not the same; and

wherein the ratio of first to second cannabinoid in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1, and the ratio of second cannabinoid to third cannabinoid in this embodiment may range from 1 :5 to 5: 1, preferably 1 :4 to 4: 1, and most preferably 1 :3 to 3: 1.

In certain embodiments, the administration of the cannabinoid(s) and/terpene(s) should be provided in a single or twice daily dose or administration that will provide relief from the symptoms of RLS for about 4-24 hours, preferably for about 6-16 hours. In certain embodiments, the administration may be oral, buccal, lingual, sublingual and/or intrapulmonary which will provide relief from the symptoms of RLS for about 4-14 hours, preferably about 5-12 hours and most preferably for about 6-10 hours. The method of administration should result in therapeutic plasma levels of the cannabinoid(s) and/or terpene(s) within 1 hour or less, 45 minutes or less, 30 minutes or less, or 15 minutes or less after administration and maintain the therapeutic levels for at least 4 hours or more, at least 5 hours or more, at least 6 hours or more, at least 7 hours or more, at least 8 hours or more, at least 9 hours or more or at least 10 hours following administration. In certain embodiments the administration will occur once per day, preferably after the evening meal or shortly before or at bedtime. The administration will comprise an oral administration, an intrapulmonary administration or a combination of oral and intrapulmonary administration. The oral administration may include the swallowing of a solid or liquid composition as described in greater detail below or buccally, lingually or sublingually administering a solid or liquid composition as described in greater detail below. The intrapulmonary administration may include the delivery of composition as described in greater detail below to a patient's respiratory system, i.e. lungs, via a nebulizer, vaporization or a metered dose inhaler. In certain embodiments, the administration comprises the oral, buccal, lingual or sublingual administration of an effective amount of THC, CBD and/or CBDV and the intrapulmonary administration of an effective amount of THC, CBD and/or CBDV once per day, wherein both the oral, buccal, lingual or sublingual administration and the intrapulmonary administration are administered shortly before or at bedtime.

In certain embodiments, the methods of the present invention comprise the administration, preferably the oral, buccal, lingual, sublingual and/or intrapulmonary administration of tablet, capsule or liquid (i.e., solution or suspension) comprising a combination of THC and CBD and/or CBDV in a ratio of THC to CBD and/or CBDV of about 1 :5 to 5: 1, preferably 1 :4 to 4: 1 and most preferably 1 :3 to 3: 1. The oral, buccal, lingual, sublingual or intrapulmonary administration will occur once or twice, three or four times a day, preferably one or two times a day or as needed. Each administration will comprise: (i) about 0.25-50 mg of THC, preferably 0.5-20 mg of THC and most preferably 1-10 mg of THC and (ii) about 0.25-50 mg of CBD and/or CBDV, preferably 0.5-20 mg of CBD and/or CBDV and most preferably 1-10 mg of CBD and/or CBDV. The target oral, buccal, lingual, sublingual and/or intrapulmonary administration is to obtain a level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/niL, and a plasma level of CBD or metabolites and/or CBDV or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. The foregoing administrations and target pharmacokinetic plasma levels will be effective in the treatment of the symptoms of restless leg syndrome. The foregoing administrations are also expected to provide an improvement in sleep, and an overall improvement in the quality of a patient's life.

Examples of dosage forms that maybe used to administer the therapeutic amounts of the cannabinoids and/or terpenes are provided below in greater detail.

Examples of the dosage forms that may be used to administer the therapeutic amounts of the cannabinoids and/or terpenes include immediate release tablets, capsules, powders, solutions or suspension that can be orally, buccally, lingually or sublingually administered to a patient.

Another example of the dosage forms that may be used to administer the therapeutic amounts of the cannabinoids and/or terpenes include solid or liquid compositions that may be nebulized, vaporized or aerosolized for administration to a patient's lungs.

A further example of a dosage form that may be used to administer the therapeutic amounts of the cannabinoids and/or terpenes include transdermal patches that can be applied to a patient shortly after the evening meal or shortly before or at bedtime and removed when the patient awakes in the morning.

A still further example of a dosage form that may be used to administer the therapeutic amounts of the cannabinoids and/or terpenes include oral modified release dosage forms wherein the cannabinoid(s) and/or terpene(s) are combined with one or more release controlling excipients to deliver the cannabinoid(s) and/or terpene(s) in a manner to obtain the target therapeutic plasma levels. One example of an oral modified release dosage form is a capsule containing a plurality of particles wherein a first portion of the particles release a portion of the cannabinoid(s) and/or terpene(s) immediately or within a few minutes after swallowing the capsule and a second portion of the particles release the cannabinoid(s) and/or terpene(s) in a delayed release manner and/or in a controlled release manner after swallowing the capsule. The first portion of the particles can be in the form of a powder, granule, bead, pellet, or mini tablet. The second portion of the particles may also be a powder, granule, bead, pellet, or mini tablet, although granules, beads, pellets, or mini tablets are preferred because they may be more easily coated with a delayed (enteric coating) or a controlled release coating as described below. Another example of an oral modified release dosage form is a modified release tablet that contains: (a) an immediate release component that allows for the immediate release of a portion of the cannabinoid(s) and/or terpene(s), typically in the form of an immediate release layer or immediate release coating; and (b) a delayed or controlled release component that allows for the delayed and/or controlled release of cannabinoid(s) and/or terpene(s). The delayed or controlled release component may be in the form of: (i) a controlled release matrix that comprises a mixture of the cannabinoid(s) and/or terpene(s) with a controlled release excipient or (ii) a core comprising a mixture of the cannabinoid(s) and/or terpene(s) with one or more pharmaceutically acceptable excipients wherein the core is coated with a delayed or controlled release coating.

Compositions

The present invention includes pharmaceutical compositions that are useful for treating one or more symptoms of RLS. The pharmaceutical compositions in accordance with the present invention include:

(i) an effective amount of at least one cannabinoid and at least one

pharmaceutically acceptable carrier or excipient;

(ii) an effective amount of at least one terpene and at least one pharmaceutically acceptable carrier or excipient; or (iii) an effective amount of at least one cannabinoid, an effective amount of at least one terpene and at least one pharmaceutically acceptable carrier or excipient.

The pharmaceutically acceptable carrier(s) or excipient(s) are known in the art and their selection will depend upon the route of administration.

Topical Compositions

One embodiment of the invention is directed to topical compositions for the administration of the at least one cannabinoid, the at least one terpene, or the combination of at least one cannabinoid and at least one terpene. The topical compositions include occluded forms, such as matrix and reservoir patches, and unoccluded forms, such as gels, creams, lotions, ointments, and serums, as well as topical foams, and mousses.

Matrix patches in accordance with the present invention comprise at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene homogeneously blended in a solid or semisolid polymer carrier together with other additives (e.g., permeation enhancers, plasticizers, viscosity reducing agent, and the like). The general structure and fabrication of matrix patches are well known in the art. In a preferred embodiment, the matrix patch comprises an occlusive backing that is impermeable to the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene and defines the face or top surface of the patch and a solid or semisolid matrix layer comprised of a homogeneous blend of the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene and one or more skin permeation enhancers.

The polymeric carrier may be adhesive or nonadhesive. When it is a pressure sensitive adhesive the basal surface of the matrix layer may be used to affix the patch to the skin. When it is not, other means such as an underlying adhesive layer, a peripheral adhesive layer, an adhesive overlay, or straps may be used to affix the patch to the skin. Examples, without limitation, of specific polymers that may be used as the carrier are polyacrylates, polymethacrylates, natural and synthetic rubbers, silicone rubbers and elastomers, polyolefins, vinyl copolymers, urethanes, nylons, polyesters, polyethers, and the like.

The skin permeation enhancer(s) that are included in the matrix enhance the level of skin flux of cannabinoid and/or terpene. Examples of permeation enhancers that may be used in compositions of the present invention include, but are not limited to, fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid, glycerol tri-, di- and monoesters, triacetin, short chain alcohols, amine oxides and mixtures thereof. Particular examples of permeation enhancers include oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, ethanol, glycerol monooleate, methyl laurate, sorbitain monooleate, triacetin, aloe vera oil, benzothonium chloride, cetyl dimethylamine oxide, cetyl alcohol, cetyl lactate, cocamidopropyl betaine, cocoamine oxide diethanolamine, dimethyloctylamine oxide, 2-dodecoxyethyldimethylamine oxide, dimethyl-decylamine oxide, dimethylhexadecylamine oxide, dimethyl-tetradecylamine oxide, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate, glycolic acid, 3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide, lactic acid, lauramine oxide, lauryl betaine, lauryl lactate, lauryl laurate, isopropyl palmitate, macrogol 15 hydroxystearate (Solutol HS 15), menthol, menthyl lactate, myristyl alcohol, myristal lactate, octyldodecanol, octyl salicylate, oleamine oxide, oleic acid, oleyl betaine, oleyldi(2 -hydroxy ethyl) amine oxide, PEG 1000, pentadecalactone, propylene glycol, salicylic acid, stearyl alcohol, stearyl lactate, 3,6,9-trioxaheptadecyldiethylamine oxide, di(2- hydroxyethyl)-tetradecylamine oxide, triethanolamine triacetate and combinations thereof. Other permeation enhancers useful with the present invention may be found in U. S. Patent Application Publication No. 2007/0269379, which is incorporated in its entirety herein by reference. Preferred permeation enhancers include oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, glycerol monooleate, methyl laurate, sorbitain monooleate, triacetin, cetyl alcohol, cetyl lactate, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate, glycolic acid, lauramine oxide, lauryl betaine, lauryl lactate, lauryl laurate, isopropyl palmitate, myristyl alcohol, myristal lactate, octyl salicylate, oleamine oxide, oleic acid, oleyl betaine, salicylic acid, stearyl alcohol, stearyl lactate, triethanolamine triacetate and combinations thereof. The permeation enhancer will usually constitute 1 to 20 wt % of the matrix, more usually 5 to 15 wt % of the matrix.

The patches of the invention may be manufactured by conventional techniques used in transdermal drug delivery device art. For instance, the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene, carrier, and enhancer(s) may be mixed in the desired proportions to form a homogeneous mixture and cast or otherwise applied to a backing layer, by lamination to a release liner layer.

Reservoir patches in accordance with the present invention may comprise a gelled liquid solution or suspension containing at least one cannabinoid, at least one terpene or a combination of at least one cannabinoid and at least one terpene and an enhancer within a carrier or be in the form of a fibrous body impregnated with the drug in the carrier. In addition to the reservoir, the device includes means for maintaining the reservoir in diffusional communication with the skin. Such means include a carrier which is also an adhesive, a separate basal adhesive layer underlying the reservoir, a peripheral ring of adhesive that is interconnected to the reservoir, an adhesive overlay for the reservoir, and straps. Preferably the means is either an adhesive carrier or a separate underlying adhesive layer.

In addition to the reservoir and affixation means, the patches may further include a backing that overlies the reservoir and protects the reservoir and/or prevents back-diffusion of the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene and enhancer from the reservoir, one or more structural layers to provide the device with appropriate mechanical properties, and/or a release liner layer that underlies the reservoir and which is removed prior to use and means for affixing the device to the skin.

The carrier or vehicle is permeable to the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene and the permeation enhancer. Preferably, the carrier is a fluid (e.g., liquid, gel, emulsion, suspension).

It may be aqueous or non-aqueous. Examples of fluid carriers that may be used are alcohols such as ethanol, alcohol-water mixtures, and low molecular weight polymers such as polyethylene glycol. Ethanol is preferred and also provides permeation enhancement. In the case of ethanol, the carrier normally constitutes 20% to 70% by volume of the reservoir, more usually 40% to 60%, and preferably approximately 50%. Alternatively, the carrier may be a solid or semisolid matrix such as a pressure-sensitive adhesive.

The reservoir patches may contain a permeation enhancer as discussed above. The reservoir may also contain amounts of other materials such as gelling agents and anti-irritants. Glycerin is a preferred anti-irritant and may be present at 5% to 50%, preferably 20% to 30% by volume. The use of glycerin as an anti-irritant is described in U. S. Pat. No. 4,855,294.

The reservoir patches may be manufactured by conventional techniques used in the transdermal drug delivery device art. For instance, at least one cannabinoid, at least one terpene or a combination of at least one cannabinoid and at least one terpene, a permeation enhancer and carrier may be mixed in the desired proportions to form a homogeneous mixture and cast or otherwise applied to a backing layer, followed by lamination to a release liner layer. If a separate basal adhesive layer is desired, it may be cast onto the release liner layer prior to such lamination.

The patches will be typically designed to be worn for 0.5 to 14 days, more preferably 1 to 7 days, and most preferably 1-3 days. The thickness of the matrix layer may be 0.01 to 1 mm, more preferably 0.025 to 0.25 mm. The thickness of the reservoir will usually be about 0.01 to 5 mm, more usually 0.03 to 2 mm. The area of the patch in diffusional contact with the skin may be between 1 and 150 cm², more preferably 5 and 100 cm², and most preferably 10 and 75 cm². The required dosing may be supplied by a single device or by a plurality of devices applied to the skin.

A further embodiment of the present invention is directed to topical gels, creams, lotions, ointments, serums, foams, and mousses of at least one cannabinoid, at least one terpene or combination of at least one cannabinoid and at least one terpene (collectively "unoccluded topical dosage forms").

In addition to the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene, the unoccluded topical dosage forms may contain a penetration enhancer as discussed above. Depending upon the specific topical dosage form, i.e., serum, cream or foam, the topical dosage form of the present invention may also include further additives such as solvents, film forming/polymeric agents, viscosity increasing agents, emulsifiers, antioxidants, preservatives, pH adjusting agents, propellants and combinations of the foregoing. The unoccluded topical dosage forms may be uniform compositions, emulsions, such as oil-in-water or water-in-oil emulsions, or liposomal compositions.

The unoccluded topical dosage forms of the present invention may include any suitable solvent. Preferably, the solvent may include water and/or one or more organic compounds, e.g., esters, alcohols, ketones, aldehydes, fatty acids, partially or fully esterified fatty acids, wherein the structures are cyclic, non-cyclic (e.g., alkyl), alicyclic (i.e., a bridged ring compound), or aromatic, as well as organic compounds having combinations of these functional groups. Specific examples of solvents that may be employed are water, methanol, ethanol, isopropyl alcohol, acetone, hexane, butyl alcohol, ethyl acetate, polyethylene glycol, propylene glycol, ethylene glycol, triethylene glycol, glycerin, 1,3-propane diol, 2-methyl-l ,3- propane diol, glycerol ricinoleate, mineral oil, peanut oil, corn oil, cottonseed oil, sesame oil or a combination thereof. The solvent may be employed in any suitable amount. Typically, the solvent can be present in the unoccluded topical composition in about 1.0 wt % to about 95.0 wt % based upon the total weight of the unoccluded topical dosage form, preferably about 3.0 wt % to about 85 wt % based upon the total weight of the unoccluded topical composition, and most preferably about 5.0 wt % to about 75 wt % of the total weight of the unoccluded topical composition.

The unoccluded topical dosage forms of the present invention also may optionally include a film-forming/polymeric agent. The film-forming/polymeric agent may enhance the adherence of the composition to the patient's skin and improve the composition's resistance to washing off or rubbing off. Film-forming/polymeric agents are preferably soluble or miscible with the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene, solvent and/or penetration enhancer. The unoccluded topical dosage forms of the present invention typically comprises from about 0.001 wt % to about 25 wt %, preferably about 0.005 wt % to about 15 wt %, and most preferably about 0.010 wt % to about 10 wt % based upon the total weight of the unoccluded topical composition of the film-forming/polymeric agents. Some examples of film-forming/polymeric agents that may be used in compositions of the present invention are polyalkenes, oleophilic copolymers of vinvylpyrrolidone, acrylic copolymers, polyethylene glycol derivative, polyolefins, polyurethanes and mixtures thereof.

Examples of polyalkenes that may be included in the topical dosage forms of the present invention are poly ethylenes having a molecular weight ranging from about 300 to about 3000 (available as PERFORMALENE® from New Phase Technologies, Piscataway, N.J.); polyisobutylenes (available as VISTANEX™ from Exxon Chemical Company, Houston, Tex.); polyisobutenes (available as PRESPERSE™ from Sumitomo Corp.); polydecenes (SILKFLO™ available from Amoco); and hydrogenated polyisobutenes (PANALANE® available from Lipo Chemicals, Inc., Paterson, N.J.).

Oleophilic copolymers of vinylpyrollidone suitable for use in the topical dosage forms of the present invention may be copolymers of polyvinylpyrrolidone (PVP) and long chain alpha olefins, including, but not limited to, PVP/eicosene copolymers (GANEX® V-220 and V-220F), and tricontanyl PVP copolymers (GANEX®) available from Ashland, formerly International Specialty Products, Wayne, N.J.

Examples of acrylic copolymers that may be used in the topical dosage forms of the present invention include acrylic copolymers having long (C8-C30) alkyl chains to enhance their oleophilicity, such as acrylate/octylacrylamide copolymers (available as DERMACRYL® from Akzo Nobel). An example of a polyethylene glycol derivative that may be used as a film forming agent in compositions of the present invention is a polyethylene glycol derivative of Beeswax (ESTOL® E04BW-3752, E06BW-3753 or E03BW-3751 formerly available from Unichema, Wilmington, Del. and currently available from Croda under the trade name CITHROL®). Examples of polyolefins that may be used as a film forming agent in compositions of the present invention are fatty acid ester/fatty acid anhydride grafted polyolefins wherein the esters and anhydrides are derived from C12-C22 fatty acid moieties, for example, C30-C38 olefin/isopropyl maleate/maleic anhydride copolymer (PERFORMA™ V 1608, available from New Phase Technologies, Piscataway, N.J.).

The film forming/polymeric agents may be water-insoluble, oleophilic, water-resistant, or water-soluble.

The unoccluded topical dosage forms of the present invention may also contain viscosity enhancing agents that thicken, gel, or harden the composition. An unoccluded topical dosage forms in accordance with the present invention, such as a topical gel, typically comprises from about 0.001 wt % to about 50 wt % of the viscosity enhancing agent, preferably about 0.005 wt % to about 40 wt % and most preferably about 0.01 wt % to about 25 wt % based upon the total weight of the unoccluded topical composition. Exemplary viscosity enhancing agents include organic materials such as natural or synthetic waxes, Ci₂- C6o alcohols, C12-C60 acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and inorganic/organic materials such as metal ester complexes containing zinc, calcium, aluminum or magnesium, fumed silicas, and organoclays. Additional viscosity enhancing agents include polyol polyesters, glyceryl esters, polyglyceryl esters and polysiloxanes that are a solid or semi-solid at ambient temperature.

Specific examples of viscosity enhancing agents that may be included in the unoccluded topical dosage forms of the present invention include C12-C60 alcohols, preferably C 16-C22 fatty alcohols, such as cetyl alcohol, stearyl alcohol, behenyl alcohol and mixtures thereof. Other suitable viscosity enhancing agents include C12-C60 acids, preferably C16-C22 fatty acids, such as palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, myristic acid, ricinoleic acid, eurcic acid, lauric acid, isostearic acid and mixtures thereof. Further suitable viscosity enhancing agents that may be used herein are alpha-hydroxy fatty acids, including 12- hydroxystearic acid, 12-hydroxylauric acid, 16-hydroxyhexadecanoic acid and mixtures thereof. Additional examples of suitable fatty acids are further described in Klofta et al, U. S. Pat. No. 7,449,613, Hofrichter, et al., U. S. Pat. No. 5,429,816 and Motley, U. S. Pat. No. 5,552, 136, disclosure of each is incorporated in its entirety herein by reference.

Waxes are also suitable for use as viscosity enhancing agents in unoccluded topical dosage forms of the present invention. Natural waxes may include, but are not limited to, camauba, ozokerite, beeswax, candelilla, paraffin, ceresin, esparto, ouricuri, rezowax and other known mined and mineral waxes. Synthetic waxes may include, but are not limited to, paraffin waxes and microcrystalline waxes. Additional viscosity enhancing agents that may be used include polyhydroxy fatty acid esters, polyhydroxy fatty acid amides and mixtures thereof. Preferred esters and amides will have three or more free hydroxy groups on the polyhydroxy moiety and are typically nonionic in character. Because of the possible skin sensitivity of those using articles to which the unoccluded topical dosage form is applied, these esters and amides should also be relatively mild and non-irritating to the skin. Suitable polyhydroxy fatty acid esters and polyhydroxy fatty acid amides are disclosed in Roe et al, U. S. Pat. No. 5,643,588, the disclosure of which is incorporated in its entirety herein by reference.

Still further viscosity enhancing agents that may be included in the unoccluded topical dosage forms of the present invention are gelling agents. Gelling agents are materials that can swell or expand when in contact with water. Examples of gelling agents that may be used in the present invention include swellable polymers, also known as osmopolymers or hydrogels as previously described. The swellable polymer can be non-cross-linked or lightly cross- linked. The cross-links can be covalent or ionic bonds with the polymer possessing the ability to swell in the presence of fluid, and when cross-linked it will not be dissolved in the fluid. The polymer can be of plant, animal or synthetic origin. Polymeric materials useful for the present purpose include polyhydroalkylcellulose having a molecular weight greater than 50,000, such as hydroxyl propylmethylcellulose (METHOCEL® K 100M available from Dow Chemical); poly(hydroxyalkylmethacrylate) having a molecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight of from 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinylalcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a polyether having a molecular weight of from 10,000 to 6,000,000; a water-swellable copolymer produced by a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, or isobutylene; a water-swellable polymer of N-vinyl lactams and the like.

Other gelling agents useful in the unoccluded topical dosage forms of the present invention include pectin having a molecular weight ranging from 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; CARBOPOL®, an acrylic acid polymer, a carboxyvinyl polymer, sometimes referred to as carboxypolymethylene, a polymer of acrylic acid cross-linked with a polyallyl ether of sucrose, as described in U.S. Pat. Nos. 2,798,053 and 2,909,462 and available as CARBOPOL® 934, 940 and 941, and its salt derivatives; polyacrylamides; water-swellable indene maleic anhydride polymers; GOOD-RITE® polyacrylic acid having a molecular weight of 80,000 to 200,000; POLYOX® polyethylene oxide polymers having a molecular weight of 100,000 to 7,000,000; starch graft copolymers; AQUA-KEEP® acrylate polymers with water absorbability of about 400 times its original weight; diesters of polyglucan; a mixture of cross- linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecular weight of 4,000 to 100,000. Representative polymers possessing gelling properties are described in U.S. Pat. Nos. 6,419,954, 4,915,949, 4,327,725, 4,207,893 and in Handbook of Common Polymers, by Scott and Roff, published by Cleveland Rubber Company, Cleveland, Ohio.

Examples of inorganic viscosity enhancing agents that may be included in the unoccluded topical dosage forms of the present invention include treated and untreated fumed silicas such as those available from Cabot Corp., Tuscola, 111. under the trade designations CAB-O-SIL M5 and MS-55. Exemplary surface-treated fumed silicas are also available from Cabot Corp., Tuscola, 111. under the trade designations TS-720 and TS-610.

Suitable clays such as hectorite and smectite may also be used as viscosity enhancing agents in unoccluded topical dosage forms of the present invention. Hydrogenated vegetable oils such as cocoa butter, shea butter and mixtures thereof may also be used as viscosity enhancing agents in unoccluded topical dosage forms of the present invention.

Suitable petroleum-based emollients may also be used as viscosity enhancing agents in unoccluded topical dosage forms of the present invention. Examples of suitable petroleum- based emollients that may be used include petrolatums, i.e., hydrocarbons or mixtures of hydrocarbons; particularly preferred are hydrocarbons having chain lengths of from Cio to Cioo. Petroleum-based emollients within this chain length range include mineral oil and petrolatum. Mineral oil usually refers to less viscous mixtures of hydrocarbons having from 10 to 30 carbon atoms, though the hydrocarbon molecular weight distribution may vary. Since the lower molecular weight hydrocarbons can cause irritation in some individuals, mineral oils having a small percentage of lower molecular weight hydrocarbons are preferred. Petrolatum usually refers to more viscous mixtures of hydrocarbons of higher molecular weight hydrocarbons. Petrolatum and mineral oil are preferred skin conditioning agents for compositions of the present invention due to their ability to protect the skin from harmful or irritating stimuli. Petrolatum is particularly preferred because of its good barrier properties.

The unoccluded topical dosage forms of the present invention may also contain humectants. Unoccluded topical dosage forms in accordance with the present invention typically comprises from about 0.001 wt % to about 30 wt % of a humectant, preferably about 0.005 wt % to about 20 wt %, and most preferably about 0.01 wt % to about 10 wt % based upon the total weight of the unoccluded topical composition. Examples of compounds that may be used as humectants in compositions of the present invention are esters of polyhydroxy alcohols. This type of ester may include glyceryl esters including glycerides and derivatized glycerides, polyglyceryl esters, and glycolic esters. Glyceryl esters are derived from glycerin, its derivatives and one or more carboxylic acid moieties. Non-limiting examples include various Ci-C3omono-, di- or tri-esters of glycerin and derivatives thereof, such as mono-, di-, tri-glycerides, acetoglycerides, and ethoxylated glycerides. Exemplary glyceryl esters include glyceryl behenate, glyceryl oleate, glyceryl stearate, glyceryl palmitate, glyceryl distearate, glyceryl dipalmitate and the like. Polyglyceryl esters having C12-C22 acid moieties are also suitable for use herein. Non-limiting examples include polyglyceryl-4 isostearate, polyglyceryl-3 oleate, diglyceryl monooleate, tetraglyceryl monooleate and the like. Glycolic esters are derived from C2-C6 glycols, including ethylene glycol, propylene glycol, butylene glycol, hexylene glycol and derivatives thereof, and one or more carboxylic acid moieties having C1-C30 chains. Specific examples of glycolic esters include polyethylene glycols (PEGs), such as PEG-2, PEG-3, PEG-30 and PEG-50, and polypropylene glycols (PPGs), such as PPG-9, PPG-12, PPG-15, PPG-17, PPG-20, PPG-26, PPG-30 and PPG-34.

The unoccluded topical dosage forms of the present invention may also contain emulsifiers or dispersing agents such as anionic, cationic, and nonionic surfactants. Unoccluded topical dosage forms in accordance with the present invention typically comprises from about 0.001 wt % to about 15 wt % of an emulsifier or dispersing agent, preferably about 0.005 wt % to about 10 wt %, and most preferably about 0.01 wt % to about 5 wt % based upon the total weight of the unoccluded topical composition. Nonionic surfactants are preferred because of their low level of irritation to skin. Typical nonionic surfactants are monoglycerides such as glyceryl monostearate and the like; sorbitan aliphatic esters such as sorbitan monolaurate and the like; sucrose aliphatic esters; polyoxyethylene aliphatic esters such as polyoxyethylene stearate; and polyoxyethylene higher alcohol ethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene fatty ethers and the like.

The unoccluded topical dosage forms of the present invention may also contain an antioxidant to minimize or prevent the oxidation process and enhance the shelf life of the composition. Unoccluded topical dosage forms in accordance with the present invention typically comprises from about 0.001 wt % to about 25 wt % of an anti-oxidant, preferably about 0.005 wt % to about 15 wt %, and most preferably about 0.01 wt % to about 10 wt % based upon the total weight of the unoccluded topical composition. Antioxidants useful herein should preferably be mild and non-irritating. Antioxidants from natural sources are preferred, such as Vitamin E and its derivatives, including tocopherol, tocopherol acetate, mixed tocopherols (available as COVI-OX T-50 or T-70 from Henkel Corp, Ambler, Pa.), and the like or butylated hydroxytoluene, butylated hydroxyanisole, sodium pyrosulfite, acetone sodium bisulfate and the like. Some of these antioxidants are also useful as skin antioxidants, which minimizes the wrinkles and dullness of the skin and provides a more youthful looking and firmer textured skin.

The unoccluded topical dosage forms of the present invention may also contain a preservative to prevent bacterial growth and odors thereof, particularly in compositions having a relatively high water content. Unoccluded topical dosage forms in accordance with the present invention typically comprise from about 0.001 wt % to about 10 wt % of a preservative, preferably about 0.005 wt % to about 5 wt %, and most preferably about 0.01 wt % to about 2.5 wt % based upon the total weight of the unoccluded topical composition. Suitable preservatives include propyl paraben, methyl paraben, benzyl alcohol, benzalkonium chloride, tribasic calcium phosphate, phenoxyethanol, or acids such as citric, tartaric, maleic, lactic, malic, benzoic, salicylic, and the like.

The unoccluded topical dosage forms of the present invention may include an acid or base to adjust the pH of the composition to the desired or optimal range. Examples of compounds typically used to adjust the pH of topical compositions include oleic acid, hydrochloric acid, citric acid, lactic acid, tartaric acid, glacial acetic acid, sodium hydroxide or the like. Depending upon the form in which the unoccluded topical dosage form is applied, i.e., gel, serum or cream, and the location, the desired final pH value of the composition may vary, however, it is generally preferred that the composition range from a pH of about 5.0 to about 8.5, preferably about 6 to about 8.0, and most preferably about 6.5 to about 7.5.

In order to increase the stability of the unoccluded topical dosage forms of the present invention, it may be necessary to add a chelating agent. Suitable chelating agents may include ethylenediaminetetraacetic acid (EDTA) and its derivatives, thioglycolic acid, thiolactic acid, thioglycerol, and the like.

A fragrance may also be added to unoccluded topical dosage forms of the present invention if desired.

If the unoccluded topical dosage form of the present invention is an aerosol, foam, or mousse, the composition will require a propellant for dispensing the composition from the container. The propellant may be any type of propellant commonly used in the cosmetic/pharmaceutical industry such as nitrogen, carbon dioxide, dimethyl ether, hydrocarbons, i.e., methane, ethane, propane, butanes and pentanes, halogenated hydrocarbons, i.e., CH₂C1F, CCIF2CHCIF, CF3CHCIF, CHF2CCIF2, CHCIFCHF2, CF3CH2CI, CCIF2CH3, CHF2CHF2, CF3CH2F (HFC 134a), CHF₂CH₃ (HFC 152a), CF3CHFCF3 (HFC 227), CF3CF3 and CF3CF2CF3. Some of the more commonly used hydrocarbon propellants are A-46 (15.2% propane/84.8% isobutene); and NP-46 (25.9% propane/74. 1% n-butane), NIP-46 (21.9% propane/31.3% isobutene/46.8% n-butane). The amount of propellant will depend on the type of container for the composition of the present invention, the amount of the composition in the container, the amount of composition to be dispensed per actuation and the form in which the composition will be dispensed, i.e., mist or foam. The optimization of the propellant and container are within the ability of the skilled artisan and examples can be found in Wai-Chiu So et al, U. S. Pat. No. 6,946, 120 and Remington, Science and Practice of Pharmacy, 21 ^st ed. , pp. 1000- 1017 which are incorporated in their entireties herein by reference. The propellant is generally not included in the calculation of the weight percentages of the composition prepared in accordance with the present invention because it is merely part of the dispensing device and typically does not remain part of the composition once the composition is dispensed and applied to the patient's skin.

The aerosols, foams and mousses of the present invention will include a solvent, preferably water and/or a lower alcohol, i.e., Ci-C₆ alcohols such as methanol, ethanol, isopropanol or mixtures thereof. The aerosols, foams, or mousses may also comprise a co- solvent selected from one or more of the group consisting of aromatic and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, polyethylene glycol 400, hexylene glycol and dipropylene glycol or glycerol. When the co-solvent is present, it may be present in amounts of approximately 10% by weight or less, preferably approximately 5% by weight or less based upon the total weight of the composition.

The emulsions of the present invention are either water-in-oil (W/O) emulsions or oil- in-water (O/W) emulsions, and may include, but are not limited to, cetyl alcohol, glyceryl monostearate, lanolin, polyalkylsiloxanes, and stearic acid. Water-soluble ointment bases suitable for use in the present invention may be prepared from polyethylene glycols of varying molecular weight. Emulsion formulations are generally formed from a dispersed phase (e.g., a pharmacologically active agent), a dispersion medium and an emulsifying agent. If desired, emulsion stabilizers can be included in the formulation as well. Emulsifying agents suitable for use in such formulations include, but are not limited to, TWEEN 60^®, Span 80^®, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

W/O emulsions may be prepared by taking a mixture of the active agent(s) with oil phase ingredients, bacteriostats/preservatives and buffer salts which are dissolved or suspended therein and to which water has been added to form a water-in-oil emulsion. O/W emulsions are semisolid emulsions, micro-emulsions, or foam emulsion systems containing the active agent(s). Usually such a system has a "creamy white" appearance. Typically, the internal oil phase is in the range in percentage composition of about 10% to about 40% oil by weight and the external phase may contain 80% or more water. The oleaginous phase may contain, but is not limited to, long-chain alcohols (cetyl, stearyl), long-chain esters (myristates, palmitates, stearates), long-chain acids (palmitic, stearic), vegetable and animal oils and assorted waxes. These can be made with anionic, cationic, nonionic, or amphoteric surfactants, or with combinations especially of the nonionic surfactants.

Oral Compositions

One embodiment of the invention is directed to oral compositions for the administration of at least one cannabinoid, at least one terpene or the combination of at least one cannabinoid and at least one terpene. The oral compositions include both solid and liquid dosage forms. Solid dosage forms include but are not limited to tablets, capsules, pellets, granules, powders. The liquid dosage forms include syrups, solutions, and suspensions. The oral compositions may be swallowed or applied to the oral cavity, i.e., sublingually, lingually or buccally. The oral compositions may be formulated to be immediate release, delayed release, controlled release, or a combination thereof.

In embodiments of the present invention where the oral composition is a solid dosage form, the at least one cannabinoid, at least one terpene or the combination of at least one cannabinoid and at least one terpene may be combined with pharmaceutically acceptable excipients such as fillers, diluents, binders, stabilizing agents, lubricants, disintegrants or mixtures thereof. These pharmaceutically acceptable excipients are well known in the art and are described in Remington, the Science and Practice of Pharmacy, 21^st Ed. (2006), pp. 1058- 1092, published by Lippincott Williams & Wilkins; United States Pharmacopeia 27 (2004), pp. 2809-2812; and Handbook of Pharmaceutical Excipients, 5^th Ed. (2006), published by the Pharmaceutical Press, both incorporated by reference. The solid oral dosage forms are made by methods commonly known in the art such as direct compression, wet or dry granulation, and extrusion spheronization. In one embodiment, the solid oral dosage form is a soft gel capsule wherein the at least one cannabinoid, at least one terpene or the combination of at least one cannabinoid and at least one terpene are dissolved or suspended in a suitable solvent, such as mineral or vegetable oil and mixed with other conventional excipients to prepare the soft gel capsule.

Examples of acceptable fillers, sometimes referred to as diluents, include water, sugars such as lactose, dextrose, sucrose, maltose, or microcrystalline cellulose, clays, and mixtures thereof.

Binders that are useful in the present invention include pharmaceutically acceptable substances with cohesive properties. Some examples include celluloses such as hydroxypropyl methycellulose, hydroxypropyl cellulose and carboxymethycellulose sodium, polyvinylpyrrolidone, sugars, starches, and mixtures thereof.

Examples of stabilizing agents that are useful in the present invention include organic acids and alkaline metal salts of organic acids, such as succinic acid, fumaric acid, citric acid, sodium citrate, and mixtures thereof.

Examples of lubricants, glidants and/or antiadherents that may be used in the present invention include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycols, silicon dioxide, and mixtures thereof.

Examples of disintegrating agents that can be used in the present invention include corn starch, croscarmelose sodium, crospovidone (polyplasdone XL-10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), or any combination of the foregoing.

The liquid dosage forms include syrups, solutions or suspensions. The syrups, solutions or suspensions of the present invention typically contain pharmaceutically acceptable excipients such as a liquid carrier, i.e., water and/or alcohol, solvent, flavoring agents, stabilizing agents, coloring agents, viscosity increasing agents or mixtures thereof. The pharmaceutically acceptable excipients employed in the syrups, solutions or suspensions of the present invention are described in Remington, the Science and Practice of Pharmacy, 21^st Ed. (2006), pp. 745-775, published by Lippincott Williams & Wilkins; United States Pharmacopeia 27 (2004), pp. 2809-2812; and Handbook of Pharmaceutical Excipients, 5^th Ed. (2006), published by the Pharmaceutical Press, incorporated by reference and further described below. The liquid dosage forms may be swallowed or applied to the buccal, lingual or sublingual regions of a patient's oral cavity. Examples of controlled release oral solutions that are useful in the present invention can be found in U. S. Patent Nos. 5,980,882; 8,062,667 and International Patent Application WO 2008/064163 which are incorporated herein by reference.

Examples of solvents have been previously described.

Flavoring agents that may be used in the present invention include peppermint, spearmint, wintergreen, cinnamon, coconut, coffee, chocolate, vanilla, menthol, licorice, anise, apricot, caramel, pineapple, strawberry, raspberry, grape, cherry, mixed berry, tropical fruits, mint, and mixtures thereof.

Coloring agents that may be employed in the present invention include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and mixtures thereof.

Viscosity increasing agents have been described previously, and a few representative examples that may be included in the liquid dosage forms include methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, acacia, agar, alginate, carrageenan, gum tragacanth, collagen, carboxypolymethylene, glyceryl monostearate, monostearate, polyvinylpyrrolidone, polyacrylamide, and mixtures thereof.

The solid oral dosage form may be in the form of a powder, granule, pellet, mini-tablet, tablet, or capsule and comprise the cannabinoid(s) and/or terpene(s) and at least one additional pharmaceutically acceptable excipient. The powder, granule, or pellets may be packaged into individual dosing units that provide a therapeutic amount of the cannabinoid(s) and/or terpene(s) and allow the user to sprinkle the powder, granules, or pellets onto or into food for administration. The powder, granules, or pellets may also be further processed into mini- tablets, tablets or capsules. Preferably, the oral solid dosage form is a modified release formulation such as delayed release, e.g., enteric, or controlled release mini -tablets, tablets, pellets, or granules. The oral solid dosage forms may be formulated for once-, twice- or thrice- daily administration.

One such embodiment of the present invention is directed to modified release mini- tablets, pellets or granules containing the cannabinoid(s) and/or terpene(s). The cannabinoid(s) and/or terpene(s) may be incorporated into the mini -tablets, pellets, or granules of the present invention in various manners. For example, the cannabinoid(s) and/or terpene(s) may be blended together with conventional excipients, such as a polymeric binder, and formed into mini-tablets, pellets, or granules. In another embodiment, the dosage form employs a population of the cannabinoid(s) and/or terpene(s) -containing mini -tablets, pellets, or granules. Each population of mini-tablets, pellets or granules may also include conventional excipients such as fillers, diluents, binders, stabilizing agents, lubricants, disintegrants or mixtures thereof previously described. In another embodiment, the mini-tablets, pellets or granules of the present invention employ an inert core surrounded by a layer of the cannabinoid(s) and/or terpene(s) and conventional excipients.

The inert core is typically a starch, sugar or microcrystalline cellulose sphere, having a diameter ranging from about 12-45 mesh, and more preferably from about 35-45 mesh. The inert core may be coated by dissolving or dispersing the cannabinoid(s) and/or terpene(s) in water and then spraying the solution or dispersion onto the inert core using a Wurster insert. Optionally, additional ingredients are also added prior to coating the inert core in order to assist in binding. For example, a product which includes hydroxypropyl methylcellulose, etc. with or without colorant (e.g., Opadry®, commercially available from Colorcon, Inc.) may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the inert core.

The resultant cannabinoid(s) and/or terpene(s) cores may then be optionally overcoated with a barrier agent, to separate the core from any modified release coating.

The cores or layers of the mini-tablets, granules or pellets may also employ a polymeric binder which may be present from 5 to 10 wt % (based on the combined weight of the binder and the cannabinoid(s) and/or terpene(s). Examples of polymeric binders include ethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropylcellulose. The binder is applied using conventional solvents which are removed during processing. In some embodiments of the present invention, the binder is a water soluble polymer, preferably with a molecular weight of less than 100,000, preferably less than 50,000. In some embodiments, the water soluble polymer exhibits a viscosity at room temperature when a 2% water solution is formed with the polymer of less than 25 cps, preferably less than 15 cps, and most preferably less than 10 cps.

The mini-tablets, granules, pellets, or cores of the present invention may also include one or more modified release layers, such as an enteric coating or controlled release coating or combination thereof. In an embodiment, the dosage form may employ separate populations of immediate release mini-tablets, granules, or pellets, delayed release mini-tablets, granules or pellets, and/or controlled release mini-tablets, granules, or pellets, or a combination thereof, to achieve a desired release profile.

The mini-tablets, granules, or pellets may be provided with an enteric coating that is a polymeric enteric coating material. The enteric coatings are "pH dependent," meaning that the enteric coating prevents release of the dosage form in the low pH conditions of the stomach but permits release in the higher pH conditions of the small intestine. The enteric coating may be present from 4 to 10%, preferably from 5 to 8%, by weight based on the combined weight of the mini-tablet, granule, or pellet component and the total weight of the coating. The enteric coating polymer may be selected from the group consisting of shellac, methacrylic acid copolymers, (Eudragit S or L) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate and polyvinyl acetate phthalate. The thickness of the coating is selected to provide the desired release rate depending on the thickness of the coating and the particular coating.

A commercially available copolymer is Eudragit® S I 00 which is based on methacrylic acid and methyl methacrylate and has a weight average molecular weight of about 150,000. Other auxiliary coating aids such as a minor amount (1 -15 wt % based on the pellet component and the total weight of the final coating) of a plasticizer such as acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol (molecular weight of from 200 to 1,000, preferably 300-600), propylene glycol and mixtures thereof in combination with an antisticking agent which may be a silicate such as talc. The antisticking agent may be added in an amount which is equivalent to 0.3 to 1.0: 1.0 by weight of the methacrylic acid copolymer. These components may be added to the methacrylic acid copolymer in combination with appropriate solvents.

The mini-tablet, granules, or pellets may also be provided with a controlled or sustained release coating. A non-limiting list of suitable controlled-release materials which may be included in a controlled-release coating according to the invention include hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac, and oils such as hydrogenated castor oil, hydrogenated vegetable oil. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled-release material which is capable of imparting controlled-release of the cannabinoid(s) and/or terpene(s) may be used in accordance with the present invention. Preferred controlled-release polymers include alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, especially hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Certain preferred embodiments utilize mixtures of any of the foregoing controlled-release materials in the coatings of the invention.

The modified release coating may be applied to the mini-tablet, granules, or pellets using methods and techniques known in the art. Typically a suspension, emulsion, or solution of the polymeric coating is prepared as is known in the art. The amount of fluidized polymeric coating required in the coating process may be readily calculated depending upon the amount of polymeric coating desired in the dried mini-tablet, granules or pellets. The fluid polymeric coating may be applied to the mini-tablet, granule or pellet by a number of coating techniques known in the art. Examples of suitable coating devices include fluid bed coaters, pan coaters, etc.

In a preferred embodiment, the mini-tablets, granules or pellets may be overcoated with an aqueous dispersion of the modified release material. The aqueous dispersion of the modified release material preferably further includes an effective amount of plasticizer, e.g. , tri-ethyl citrate.

The plasticized aqueous dispersion of modified release material may be applied onto the mini-tablets, granules or pellets by spraying, using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized-bed system is used, in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the aqueous dispersion of modified- release material to obtain a predetermined modified-release of the therapeutically active agent when said coated mini-tablet, granule or pellet is exposed to aqueous solutions, e.g., gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with the modified-release material, a further overcoat of a film-former, such as Opadry®, is optionally applied to the mini-tablets, granules, or pellets. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the particles.

The powder, granules, mini-tablets or pellets may be filled into hard or soft gelatin capsules or packaged into individual dosing unites, e.g. , sachets. The powders, granules, mini- tablets, or pellets may also be compressed into tablets using a binder and/or hardening agent commonly employed in tableting such as microcrystalline cellulose sold under the Trademark "AVICEL" or a co-crystallized powder of highly modified dextrins (3% by weight) and sucrose sold under the Trademark "DI-PAC" in such a way that the specific dissolution rate of the individual pre-compression particles is maintained. The powders, granules, mini-tablets, or pellets in the capsules or individual dosing units may be sprinkled onto food such as applesauce or dispersed into water for easier administration to patients that have difficulty swallowing a large capsule or tablet.

Another embodiment of the present invention is directed to modified release tablets containing a therapeutically effective amount of the cannabinoid(s) and/or terpene(s). Suitable tablets in accordance with the present invention include enteric tablets, osmotic tablets, and matrix tablets.

The enteric tablets according to the present invention employ a core element that is preferably a compressed tablet that comprises the cannabinoid(s) and/or terpene(s) and conventional excipients such as fillers, diluents, binders, stabilizing agents, lubricants, disintegrants or mixtures thereof as previously described. The core element is surrounded by an enteric coating. The core element is preferably manufactured by first passing all of the dry ingredients through a screen (e.g., 300 mesh USSS) and thereafter tumble blending the dry ingredients for 5 to 120 minutes to form a compressible powder blend. The compressible powder blend is preferably pressed into tablets using an automatic tableting machine provided with a suitable die.

In another embodiment, the core element employs separate layers of the cannabinoid(s) and/or terpene(s). Each layer may be manufactured by preparing separate powder blends, as described above, and then pressing the separate blends together into a bilayer or trilayer tablet. Each of the layers may be formulated to release the cannabinoid(s) and/or terpene(s) in a different manner.

The enteric coating may be any of the polymeric enteric coating materials mentioned above. The enteric coating may comprise from 1 to 10%, preferably 1 to 6%, and most preferably from 2 to 4% by weight based on the combined weight of the tableted core and the coating. Other auxiliary coating aids such as a minor amount (1-15 wt % based on the active core component and the total weight of the final coating) of a plasticizer such as acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, poly ethylenegly col (molecular weight of from 200 to 1,000, preferably 300-600), propylene glycol and mixtures thereof in combination with an antisticking agent which may be a silicate such as talc. The antisticking agent may be added in an amount which is equivalent to 0.3 to 1.0: 1.0 by weight of the enteric coating polymer. These components may be added to the enteric coating polymer in combination with appropriate solvents. A further embodiment of the present invention is directed to osmotic tablets that may contain a homogenous core or a multilayer core such as a bilayer core comprising a drug layer and a delivery or push layer, wherein the core is surrounded by a semipermeable wall and optionally having at least one passageway disposed therein. In certain embodiments, the homogeneous core comprises the cannabinoid(s) and/or terpene(s), a hydrogel, and optionally additional pharmaceutically acceptable excipients. A hydrogel as used herein is a natural or synthetic compound that absorbs water when exposed to an aqueous environment and expands to at least twice its unhydrated volume. Examples of hydrogels are provided below. The homogeneous core is prepared by mixing and or granulating the core ingredients to obtain a uniform blend and compressing the uniform blend into a tablet core. In another embodiment, the bilayer core comprises a drug layer with the cannabinoid(s) and/or terpene(s) and a displacement or push layer that does not contain the cannabinoid(s) and/or terpene(s). In certain embodiments the drug layer(s) may also comprise at least one polymeric hydrogel. The polymeric hydrogel employed in the drug layer may have an average molecular weight of between about 500 and about 6,000,000. Examples of polymeric hydrogels employed in the drug layer include but are not limited to a maltodextrin polymer comprising the formula (C6Hi205)n.H20, wherein n is 3 to 7,500, and the maltodextrin polymer comprises a 500 to 1,250,000 number-average molecular weight; a poly(alkylene oxide) represented by, e.g., a poly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to 750,000 weight-average molecular weight, and more specifically represented by a poly(ethylene oxide) of at least one of 100,000, 200,000, 300,000 or 400,000 weight-average molecular weights; an alkali carboxyalkylcellulose, wherein the alkali is sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000 weight-average molecular weight; and a copolymer of ethylene-acrylic acid, including methacrylic and ethacrylic acid of 10,000 to 500,000 number- average molecular weight. Additional examples of hydrogels include natural and synthetic gums.

In certain embodiments of the present invention, the delivery or push layer comprises a hydrogel or gelling polymer. Examples of hydrogels for use in the delivery or push layer include but are not limited to a member selected from the group consisting of a polyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxide possesses a 1,000,000 to 10,000,000 weight-average molecular weight. The polyalkylene oxide may be a member selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene oxide having a 1,000,000 average molecular weight, polyethylene oxide comprising a 5,000,000 average molecular weight, polyethylene oxide comprising a 7,000,000 average molecular weight, cross-linked polymethylene oxide possessing a 1,000,000 average molecular weight, and polypropylene oxide of 1,200,000 average molecular weight. The carboxyalkylcellulose comprises a member selected from the group consisting of alkali carboxyalkylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium carboxyethylcellulose, lithium carboxymethylcellulose, sodium carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcellulose and carboxymethylhydroxypropylcellulose. The hydrogels used for the displacement layer should exhibit an osmotic pressure gradient across the semipermeable wall. The hydrogels imbibe fluid into dosage form, thereby swelling and expanding, whereby they push the cannabinoid(s) and/or terpene(s) from the osmotic dosage form, preferably through a preformed passage way, i.e. laser drilled hole in the semipermeable wall or a weakened area of the semipermeable wall that cracks or ruptures as the osmotic pressure within the semipermeable wall increases.

The push layer may also include one or more osmotically effective compounds, also known as osmagents and as osmotically effective solutes. They imbibe an environmental fluid, for example, from the gastrointestinal tract, into dosage form and contribute to the delivery kinetics of the displacement layer. Examples of osmotically active compounds include members selected from the group consisting of osmotic salts and osmotic carbohydrates. Examples of specific osmagents include, but are not limited to, sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, sodium sulfate, potassium phosphate, glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulose represented by a member selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose. Depending upon the type and molecular weight, the hydroxypropylalkylcellulose may also be a hydrogel.

The push layer may also optionally comprise an antioxidant to inhibit the oxidation of ingredients. Some examples of antioxidants include, but are not limited to, members selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabi sulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, and propylgallate.

In certain embodiments, the semipermeable wall comprises a member selected from the group consisting of a cellulose ester polymer, a cellulose ether polymer and a cellulose ester- ether polymer. Representative wall polymers comprise members selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkenylates, and mono-, di- and tricellulose alkinylates. The poly(cellulose) used for the present invention comprises a number-average molecular weight of 20,000 to 7,500,000. Additional semipermeable polymers for the purpose of this invention comprise acetaldehyde dimethycellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate, propylcarbamate, cellulose acetate diethylaminoacetate, semipermeable polyamide, semipermeable polyurethane, semipermeable sulfonated polystyrene, semipermeable cross-linked polymer formed by the coprecipitation of a polyanion and a poly cation as disclosed in U. S. Pat. Nos. 3, 173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876, semipermeable polymers as disclosed by Loeb and Souriraj an in U. S. Pat. No. 3, 133, 132, semipermeable crosslinked polystyrenes; semipermeable cross-linked poly(sodium styrene sulfonate), semipermeable crosslinked poly(vinylbenzyltrimethyl ammonium chloride), and semipermeable polymers possessing a fluid permeability of 2.5 x l 0^~8 to 2.5 x l O^"2 (cm²/hr atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the semipermeable wall. Other polymers useful in the present invention and known in the art are described in U. S. Pat. Nos. 3,845,770; 3,916,899 and 4, 160,020; and in Handbook of Common Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, the semipermeable wall is preferably nontoxic, inert, and it maintains its physical and chemical integrity during the dispensing life of the drug. In certain embodiments, the dosage form comprises a binder as described above.

In certain embodiments, the dosage form comprises a lubricant, which may be used during the manufacture of the dosage form to prevent sticking to die wall or punch faces. Examples of lubricants include, but are not limited to, magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate.

An additional embodiment of the present invention is direct to a controlled-release matrix tablet. The matrix tablet should comprise a therapeutically effective amount of the cannabinoid(s) and/or terpene(s), a matrix forming agent. The matrix forming agent can be a hydrophobic material such as a wax, a hydrophilic material such as a hydrogel, or a combination of the two. The matrix forming agent will control the release of the cannabinoid(s) and/or terpene(s) by diffusion from the matrix, erosion of the matrix, or a combination of diffusion and erosion. The amount of diffusion and erosion will depend upon the materials selected for the formation of the matrix.

Examples of hydrogels that may be used for the matrix forming agent include those previously described, and preferably hydroxypropyl methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, acrylic polymers and copolymers, sodium alginate, polyethylene oxides or mixtures thereof.

Examples of hydrophobic materials that can be used for the matrix forming agent include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, free wax acids such as stearic acid, esters of wax acids, propylene glycol monostearate, glycerol monostearate, camauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax, and mixtures thereof. Other possible rate controlling excipients useful in the present invention include saturated hydrocarbons having from 25 to 31 carbon atoms, saturated alcohols having from 25 to 31 carbon atoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms, esters obtained from said alcohols and monocarboxylic acids which are described in U. S. Pat. No. 6,923,984, incorporated herein by reference.

A combination of hydrophobic and hydrophilic materials may also be used in preparing a controlled release matrix of the present invention.

The controlled release matrix in accordance with the present invention may further comprise conventional excipients that improve processing or modify the release characteristics. Examples of these conventional excipients include fillers, glidants and lubricants described previously.

Some embodiments of the controlled release matrix tablets may include a multilayer tablet wherein at least one layer is a controlled release matrix comprising the cannabinoid(s) and/or terpene(s) and the matrix forming agent. Alternatively, the multilayer tablet may comprise at least one controlled release layer comprising the cannabinoid(s) and/or terpene(s) and the matrix forming agent and at least one immediate release layer that comprises an immediate release dose of the cannabinoid(s) and/or terpene(s).

Delayed release oral dosage forms in accordance with the present invention, and described above (i.e., pellets or tablets), should exhibit an in vitro dissolution profile when measured in 0. IN HC1 in a USP XXII Type II apparatus at 37° C and 100 rpm that substantially corresponds to the following:

a) from 0 to 30%, preferably from 0 to 25%, and most preferably from 0 to 20% of the total cannabinoid(s) and/or terpene(s) is released after 2 hours.

Delayed release oral dosage forms in accordance with the present invention, and described above (i.e., pellets or tablets), should also exhibit an in vitro dissolution profile when measured in an aqueous medium with a pH of 6.0 or greater, preferably 6.8 in a USP XXII Type II apparatus at 37° C. and 100 rpm that substantially corresponds to the following: a) from 50 to 100%, preferably from 75 to 100%, and most preferably from 90 to 100% of the total cannabinoid(s) and/or terpene(s) is released after 2 hours.

Controlled release oral dosage forms in accordance with the present invention, and described above (i.e., pellets or tablets), for a single night time dosing preferably exhibit an in vitro dissolution profile when measured in 0.1N HC1 in a USP XXII Type II apparatus at 37° C. and 100 rpm which substantially corresponds to the following: a) from 0 to 45% and preferably from 10 to 40% of the total cannabinoid(s) and/or terpene(s) is released after 2 hours;

b) from 35 to 75% and preferably from 45 to 70% of the total cannabinoid(s) and/or terpene(s) is released after 6 hours;

d) not less than 95% and preferably not less than 99% of the total the cannabinoid(s) and/or terpene(s) is released after 10 hours.

In certain embodiments, the composition of the present invention comprises a tablet, soft gelatin capsule or hard gelatin capsule for oral administration once or two times a day, preferably shortly before or at bedtime or as needed throughout the day, wherein the tablet or capsule comprises CBD and/or CBDV and optionally THC along with a pharmaceutically acceptable carrier. Examples of methods for preparing the capsules and pharmaceutically acceptable excipients that may be used in the capsule can be found in U. S. Patent Nos. 6,703,418 and 8,741,341, which are incorporated herein by reference. The THC may be in the form of dronabinol, also known as delta-9-tetrahydrocannabinol and A9-THC. The ratio of THC, if present, to CBD and/or CBDV in the tablet or capsule is about 1 : 1 to 1 :5, preferably 1 : 1 to 1 :4 and most preferably 1 : 1 to 1 : 3. In certain embodiments of the present invention, the amount of THC in the tablet or capsule will be equal to the amount of CBD and/or CBDV or the amount of CBD and/or CBDV will exceed the amount of THC. For example, the weight ratio of THC to CBD and/or CBDV in the tablet or capsule may include but are not limited to the values provided in Example 1 herein.

In certain embodiments, the tablets or capsules are substantially free (i.e., less than 1 wt% of the total cannabinoid content, less than 0.5 wt% of the total cannabinoid content, less than 0.1 wt% of the total cannabinoid content) or free of any cannabinoid other than THC, CBD and/or CBDV and are substantially free or free of any terpene. Each tablet or capsule will further comprise: (i) about 0.25-50 mg of THC, preferably 0.5-20 mg of THC and most preferably 1-10 mg of THC and (ii) about 0.25-50 mg of CBD and/or CBDV, preferably 0.5-20 mg of CBD and/or CBDV and most preferably 1-10 mg of CBD and/or CBDV. The target of the oral administration is to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL, and a plasma level of CBD or metabolites and/or CBDV or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. In alternative embodiments, the tablet or capsule will be free of THC and will comprise CBD and/or CBDV in the above amounts as the only cannabinoid. The oral administration of the tablet or capsule may begin at a lower dose and increased over 3 to 14 days until the desired dosing level is obtained with a once or twice a day administration that will provide the target effect.

In certain embodiments, the composition of the present invention comprises a syrup, solution or suspension for oral administration once or two times a day wherein the syrup, solution or suspension comprises a combination of THC and CBD and/or CBDV along with a pharmaceutically acceptable liquid carrier. Examples of methods for preparing the syrup, solution or suspension and pharmaceutically acceptable excipients that may be used in the solution or suspension can be found in U. S. Patent Nos. 8,222,292 and 9,345,771, which are incorporated herein by reference. The ratio of THC, if present to CBD and/or CBDV in the syrup, solution or suspension is about 1 :5 to about 5: 1, preferably a ratio of about 1 :4 to about 4 : 1 and most preferably a ratio of about 1 : 3 to about 3 : 1. For example, the weight ratio of THC to CBD in the syrup, solution or suspension may include but are not limited to the values provided in Example 2 herein.

In certain embodiments, the syrup, solution or suspension are substantially free (i.e. less than 1 wt% of the total cannabinoid content, less than 0.5 wt% of the total cannabinoid content, less than 0.1 wt% of the total cannabinoid content) or free of any cannabinoid other than THC, CBD and CBDV and are substantially free or free of any terpene.

Each dose of the syrup, solution or suspension will further comprise: (i) about 0.1-50 mg/mL of THC, preferably 0.5-25 mg/mL of THC and most preferably 1-20 mg/mL of THC and (ii) about 5-100 mg/mL of CBD and/or CBDV, preferably 7.5-80 mg/mL of CBD and/or CBDV and most preferably 10-50 mg/mL of CBD and/or CBDV. The target of the oral administration of the syrup, solution or suspension is to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites and/or CBDV or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. In alternative embodiments, the syrup, solution or suspension will be free of THC and will comprise CBD and/or CBDV in the above amounts as the only cannabinoid. The oral administration of the solution or suspension may begin at a lower dose and increased over 3 to 14 days until the desired dosing level is obtained with a once or twice a day administration that will provide the target effect.

Nasal Compositions

One embodiment of the invention is directed to nasal compositions for the administration of the at least one cannabinoid, the at least one terpene, or the combination of at least one cannabinoid and at least one terpene. The nasal compositions may be in the form of a liquid, preferably a solution of suspension that can be sprayed onto or applied to the nasal passages via drops or swabs. In addition to the at least one cannabinoid, the at least one terpene, or the combination of at least one cannabinoid and at least one terpene, the nasal compositions may contain inert diluents and/or solvents commonly used in the art. Water is the preferred solvent, however, combinations of water with other physiologically acceptable solvents are also contemplated. Other solvents, solubilizing agents and emulsifiers suitable for use in place of, or in addition to, water include but are not limited to saturated aliphatic mono- and polyvalent alcohols which contain 2-6 carbon atoms (including, but not limited to, ethanol, 1,2- propylene glycol, sorbitol, and glycerine), polyglycols such as polyethylene glycols, and surfactants/emulsifiers like the fatty acid esters of sorbitan, and mixtures thereof. Oils, in particular, cottonseed, peanut, or corn oils, may also be added to the compositions. The combination of the additional solvents in the aqueous solution should preferably not exceed about 15% (w/v) of the total composition.

The nasal compositions of the present invention may further comprise one or more preservatives and/or one or more stabilizers. Preservatives that are suitable for use in the compositions of the invention include, but are not limited to, edetic acid and their alkali salts such as disodium EDTA and calcium EDTA, benzyl alcohol, methylparaben, propylparaben, butylparaben, chlorobutanol, phenylethyl alcohol, benzalkonium chloride, thimerosal, propylene glycol, sorbic acid, and benzoic acid derivatives. The preservatives should be used at a concentration of from about 0.001 % to about 0.5% (w/v) in the final composition. The combination of benzalkonium chloride, used at a concentration of from about 0.001 % to about 0.5%, preferably from about 0.005% to about 0.1% (w/v), and edetic acid (as a disodium salt), used at a concentration of from about 0.005% to about 0.1 % (w/v), are the preferred preservative/stabilizer combination used in the liquid compositions of the present invention.

It is desirable that the nasal compositions of the present invention that are to be administered have a pH of about 4.5 to about 7.4, and preferably have a pH of about 5.5 to 7. 1, for physiological reasons. Accordingly, in additional embodiments of the present invention, the compositions of the invention may further comprise one or more buffering agents that are used to adjust and/or maintain the compositions in the desired pH range. Examples of pH or buffering agents that are suitable for use in the compositions of the invention include, but are not limited to, citric acid, sodium citrate, sodium phosphate (dibasic, heptahydrate form), and boric acid or equivalent conventional buffers, and combinations thereof. The appropriate amounts of buffers and buffering agents, or combinations thereof, that are to be used in the compositions of the invention are described in the United States Pharmacopoeia, Remington: The Science and Practice of Pharmacy, and the like, the disclosures of which are incorporated herein by reference in their entireties.

The nasal compositions of the invention may also further comprise one or more taste- masking agents, one or more flavoring agents, one or more sweetening agents, and/or a combination of such agents.

In an embodiment of the invention, the nasal compositions may further comprise one or more water-soluble viscosity-increasing agents. Such agents are preferably used at the concentration of about 0.01 % to about 5.0% (w/v), in order to typically produce a viscosity of the final solution between about 2 and about 300 centipoise. Viscosity-increasing agents that are suitable for use in accordance with the present invention include, but are not limited to, polyvinylpyrrolidones, cellulose derivatives including, but not limited to, hydroxyethyl cellulose, carboxymethyl cellulose or its salts, hypromellose, carrageenan, guar gum, alginates, carbomers, polyethylene glycols, polyvinyl alcohol, and xanthan gum.

Inhalation Compositions

One embodiment of the invention is directed to inhalation compositions for the administration of the at least one cannabinoid, the at least one terpene, or combination of at least one cannabinoid and at least one terpene to the respiratory system of the patient. The composition may be in the form of a powder, aerosol or vapor, which is inhaled by the patient to deliver the at least one cannabinoid, the at least one terpene or the combination of at least one cannabinoid and at least one terpene to the respiratory system of the patient, preferably the lungs. The powders, solutions and suspensions that comprise the at least one cannabinoid, the at least one terpene, or combination of the at least one cannabinoid and the at least one terpene for delivery to the respiratory system of the patient may be prepared by any means commonly employed in the art, and employ excipients as described above for preparation of the solid and liquid oral dosage forms. The inhalation compositions may be delivered to a patient's respiratory system, using apparatuses commonly known in the art such as those described in U.S. Patent Nos. 5,349,945; 5,394,868; 5,674,472; 5,766,573; 5,860,419; 6,641,800; 6,521,212; 9,339,507 and U.S. Patent Publication Nos. 2004/0265238; 2005/0042172; 2005/0061314; 2005/0079136; and 2007/0020193 which are incorporated herein by reference.

In certain embodiments, the composition of the present invention comprises a solution or suspension for intrapulmonary administration of a combination of THC and CBD and/or CBDV. Examples of methods for preparing the solution or suspension can be found in Patent Publication Nos. 2005/0042172; 2005/0061314; 2005/0079136; and 2007/0020193 which are incorporated herein by reference. The ratio of THC, if present to CBD and/or CBDV in the solution or suspension is about 1 :5 to about 5: 1, preferably a ratio of about 1 :4 to about 4: 1 and most preferably a ratio of about 1 :3 to about 3: 1.

In certain embodiments, the solution or suspension are substantially free (i.e. less than 1 wt% of the total cannabinoid content, less than 0.5 wt% of the total cannabinoid content, less than 0.1 wt% of the total cannabinoid content) or free of any cannabinoid other than THC, CBD and CBDV and are substantially free or free of any terpene.

The solution or suspension for intrapulmonary administration will formulated to administer about 0.1-15 mg of THC, preferably 0.5-10 mg of THC and most preferably 0.75- 7.5 mg of THC and (ii) about 0.1-15 mg of THC, preferably 0.5-10 mg of THC and most preferably 0.75-7.5 mg of CBD and/or CBDV. The target of the intrapulmonary administration is to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites and/or CBDV or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. The target plasma levels should be obtained within 30 minutes or less, preferably within 20 minutes or less and most preferably within 15 minutes or less of completion of the intrapulmonary administration.

The following embodiments are provided by way of example only and are by no means intended to be limiting.

Example 1

The following capsules comprising THC (dronabinol), CBD and sesame oil may be prepared as described in U.S. Patent No. 6,703,418.

0/15.0 2.0/15.0 3.0/15.0 4.0/15.0 5.0/15.0

CAPSULE

F G H I J

THC(mg) THC(mg) THC(mg) THC(mg) THC(mg)

/ / / / /

CBD(mg) CBD(mg) CBD(mg) CBD(mg) CBD(mg)

6.0/2.0 7.0/2.0 8.0/2.0 9.0/2.0 10.0/2.0

6.0/3.0 7.0/3.0 8.0/3.0 9.0/3.0 10.0/3.0

6.0/4.0 7.0/4.0 8.0/4.0 9.0/4.0 10.0/4.0

6.0/5.0 7.0/5.0 8.0/5.0 9.0/5.0 10.0/5.0

6.0/6.0 7.0/6.0 8.0/6.0 9.0/6.0 10.0/6.0

6.0/7.0 7.0/7.0 8.0/7.0 9.0/7.0 10.0/7.0

6.0/8.0 7.0/8.0 8.0/8.0 9.0/8.0 10.0/8.0

6.0/9.0 7.0/9.0 8.0/9.0 9.0/9.0 10.0/9.0

6.0/10.0 7.0/10.0 8.0/10.0 9.0/10.0 10.0/10.0

6.0/11.0 7.0/11.0 8.0/11.0 9.0/11.0 10.0/11.0

6.0/12.0 7.0/12.0 8.0/12.0 9.0/12.0 10.0/12.0

6.0/13.0 7.0/13.0 8.0/13.0 9.0/13.0 10.0/13.0

6.0/14.0 7.0/14.0 8.0/14.0 9.0/14.0 10.0/14.0

6.0/15.0 7.0/15.0 8.0/15.0 9.0/15.0 10.0/15.0

CAPSULE

K L M N o

THC(mg) THC(mg) THC(mg) THC(mg) THC(mg)

/ / / / /

CBD(mg) CBD(mg) CBD(mg) CBD(mg) CBD(mg)

11.0/2.0 12.0/2.0 13.0/2.0 14.0/2.0 15.0/2.0

11.0/3.0 12.0/3.0 13.0/3.0 14.0/3.0 15.0/3.0

11.0/4.0 12.0/4.0 13.0/4.0 14.0/4.0 15.0/4.0

11.0/5.0 12.0/5.0 13.0/5.0 14.0/5.0 15.0/5.0

11.0/6.0 12.0/6.0 13.0/6.0 14.0/6.0 15.0/6.0 6 11.0/7.0 12.0/7.0 13.0/7.0 14.0/7.0 15.0/7.0

7 11.0/8.0 12.0/8.0 13.0/8.0 14.0/8.0 15.0/8.0

8 11.0/9.0 12.0/9.0 13.0/9.0 14.0/9.0 15.0/9.0

9 11.0/10.0 12.0/10.0 13.0/10.0 14.0/10.0 15.0/10.0

10 11.0/11.0 12.0/11.0 13.0/11.0 14.0/11.0 15.0/11.0

11 11.0/12.0 12.0/12.0 13.0/12.0 14.0/12.0 15.0/12.0

12 11.0/13.0 12.0/13.0 13.0/13.0 14.0/13.0 15.0/13.0

13 11.0/14.0 12.0/14.0 13.0/14.0 14.0/14.0 15.0/14.0

14 11.0/15.0 12.0/15.0 13.0/15.0 14.0/15.0 15.0/15.0

The capsule formulations as described in A1-A14 to 01-014 may be administered to patients diagnosed with RSL and in particular to patients with an International RLS Rating Scale Score of 31-40 (very severe case), 21-30 (severe cases) and 11-20 (moderate case) to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. Preferably, the capsules are administered once in the evening just prior to bedtime.

The patients are asked to complete the International Restless Leg Rating Scale questionnaire daily prior to and 10, 20 and 30 days after the initial dose. There should be at least a 10%, 25%, 50% or more reduction from the baseline of the International Restless Leg Rating Scale Score during the treatment period.

Example 2

The following solutions comprising THC (dronabinol), CBD and liquid carriers such as water, ethanol, polyethylene glycol, propylene glycol and combinations thereof may be prepared as described in U. S. Patent No. 8,222,292:

THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL)

/ / / / /

CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL)

0/2.0 2.0/2.0 3.0/2.0 4.0/2.0 5.0/2.0

0/3.0 2.0/3.0 3.0/3.0 4.0/3.0 5.0/3.0

0/4.0 2.0/4.0 3.0/4.0 4.0/4.0 5.0/4.0

0/5.0 2.0/5.0 3.0/5.0 4.0/5.0 5.0/5.0

0/6.0 2.0/6.0 3.0/6.0 4.0/6.0 5.0/6.0

0/7.0 2.0/7.0 3.0/7.0 4.0/7.0 5.0/7.0

0/8.0 2.0/8.0 3.0/8.0 4.0/8.0 5.0/8.0

0/9.0 2.0/9.0 3.0/9.0 4.0/9.0 5.0/9.0

0/10.0 2.0/10.0 3.0/10.0 4.0/10.0 5.0/10.0

0/11.0 2.0/11.0 3.0/11.0 4.0/11.0 5.0/11.0

0/12.0 2.0/12.0 3.0/12.0 4.0/12.0 5.0/12.0

0/13.0 2.0/13.0 3.0/13.0 4.0/13.0 5.0/13.0

0/14.0 2.0/14.0 3.0/14.0 4.0/14.0 5.0/14.0

0/15.0 2.0/15.0 3.0/15.0 4.0/15.0 5.0/15.0

SOLUTION

F G H I J

THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL)

/ / / / /

CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL)

6.0/2.0 7.0/2.0 8.0/2.0 9.0/2.0 10.0/2.0

6.0/3.0 7.0/3.0 8.0/3.0 9.0/3.0 10.0/3.0

6.0/4.0 7.0/4.0 8.0/4.0 9.0/4.0 10.0/4.0

6.0/5.0 7.0/5.0 8.0/5.0 9.0/5.0 10.0/5.0

6.0/6.0 7.0/6.0 8.0/6.0 9.0/6.0 10.0/6.0

6.0/7.0 7.0/7.0 8.0/7.0 9.0/7.0 10.0/7.0

6.0/8.0 7.0/8.0 8.0/8.0 9.0/8.0 10.0/8.0

6.0/9.0 7.0/9.0 8.0/9.0 9.0/9.0 10.0/9.0

6.0/10.0 7.0/10.0 8.0/10.0 9.0/10.0 10.0/10.0 10 6.0/11.0 7.0/11.0 8.0/11.0 9.0/11.0 10.0/11.0

11 6.0/12.0 7.0/12.0 8.0/12.0 9.0/12.0 10.0/12.0

12 6.0/13.0 7.0/13.0 8.0/13.0 9.0/13.0 10.0/13.0

13 6.0/14.0 7.0/14.0 8.0/14.0 9.0/14.0 10.0/14.0

14 6.0/15.0 7.0/15.0 8.0/15.0 9.0/15.0 10.0/15.0

SOLUTION

K L M N o

THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL) THC(mg/mL)

/ / / / /

CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL) CBD(mg/mL)

1 11.0/2.0 12.0/2.0 13.0/2.0 14.0/2.0 15.0/2.0

2 11.0/3.0 12.0/3.0 13.0/3.0 14.0/3.0 15.0/3.0

3 11.0/4.0 12.0/4.0 13.0/4.0 14.0/4.0 15.0/4.0

4 11.0/5.0 12.0/5.0 13.0/5.0 14.0/5.0 15.0/5.0

5 11.0/6.0 12.0/6.0 13.0/6.0 14.0/6.0 15.0/6.0

6 11.0/7.0 12.0/7.0 13.0/7.0 14.0/7.0 15.0/7.0

7 11.0/8.0 12.0/8.0 13.0/8.0 14.0/8.0 15.0/8.0

8 11.0/9.0 12.0/9.0 13.0/9.0 14.0/9.0 15.0/9.0

9 11.0/10.0 12.0/10.0 13.0/10.0 14.0/10.0 15.0/10.0

10 11.0/11.0 12.0/11.0 13.0/11.0 14.0/11.0 15.0/11.0

11 11.0/12.0 12.0/12.0 13.0/12.0 14.0/12.0 15.0/12.0

12 11.0/13.0 12.0/13.0 13.0/13.0 14.0/13.0 15.0/13.0

13 11.0/14.0 12.0/14.0 13.0/14.0 14.0/14.0 15.0/14.0

14 11.0/15.0 12.0/15.0 13.0/15.0 14.0/15.0 15.0/15.0

The solution formulations as described in A1-A14 to 01-014 may be administered to patients diagnosed with RSL and in particular to patients with an International RLS Rating Scale Score of 31-40 (very severe case), 21-30 (severe cases) and 11-20 (moderate case) to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL. Preferably, the solutions are administered once in the evening just prior to bedtime.

The patients are asked to complete the International Restless Leg Rating Scale questionnaire daily prior to and 10, 20 and 30 days after the initial dose. There should be at least a 10%, 25%, 50% or more reduction from the baseline of the Intemational Restless Leg Rating Scale Score during the treatment period. Example 3

Liquid dosage forms for intrapulmonary administration comprising THC (dronabinol) and CBD may be prepared as described in U. S. Patent Publication Nos. 2005/0061314 wherein the amount of THC ranges from 100 μg/actuation to 1000 μg/actuation and the amount of CBD from 100 μg/actuation to 1000 μg/actuation.

These intrapulmonary administrations are preferably administered in the evening just prior to bedtime so a total of about 0.5 mg to 5 mg of THC and 0.5 mg to 5 mg of CBD is dosed to patients diagnosed with RSL and in particular to patients with an Intemational RLS Rating Scale Score of 31-40 (very severe case), 21 -30 (severe cases) and 11-20 (moderate case) to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL.

The patients are asked to complete the International Restless Leg Rating Scale questionnaire daily prior to and 10, 20 and 30 days after the initial dose. There should be at least a 10%, 25%, 50% or more reduction from the baseline of the Intemational Restless Leg Rating Scale Score during the treatment period. Example 4

A vaporization composition for intrapulmonary administration of THC (dronabinol) and CBD may be prepared as described in U. S. Patent Publication Nos. 2005/0042172.

These intrapulmonary vapor administrations are preferably administered in the evening just prior to bedtime so a total of about 0.5 mg to 5 mg of THC and 0.5 mg to 5 mg of CBD is dosed to patients diagnosed with RSL and in particular to patients with an International RLS Rating Scale Score of 31 -40 (very severe case), 21-30 (severe cases) and 1 1-20 (moderate case) to obtain a plasma level of THC or metabolites ranging from 0.25 ng/mL to 25 ng/mL, preferably 0.5 ng/mL to 17.5 ng/mL and most preferably 1 ng/mL to 12.5 ng/mL and a plasma level of CBD or metabolites greater than 0.25 ng/mL, preferably greater than 0.5 ng/mL and most preferably greater than 1 ng/mL.

Example 5

An oral compositions as described in Examples 1 or 2 may be combined with the intrapulmonary administrations described in Examples 3 and 4 for treating patients with RLS as described in Examples 1 -4.

Example 6

The dosage forms and administrations described in Examples 1-4 may further comprise the co-administration of about 50 mg to about 120 mg of linalool and/or linalyl acetate administered orally and/or about 1 mg to about 50 mg of linalool and/or linalyl acetate administered intrapulmonary.

Example 7 The CBD employed in the dosage forms and administrations described in Examples 1- 4 may be replaced in part or in whole by CBDV. Specifically, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the CDB may be replaced with CBDV.

While certain preferred and alternative embodiments of the present invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.

All documents, patents and other literature referred to herein are incorporated by reference in their entireties.

It is envisioned that any feature or element that is positively identified in this description may also be specifically excluded as a feature or element of an embodiment of the present invention as defined in the claims.

The invention described herein may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the claims.

Claims

CLAIMS:

1. A method for treating one or more symptoms of restless legs syndrome comprising the step of:

2. The method of claim 1 wherein the at least one cannabinoid is selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV) cannadidiolic acid (CBD A), the various isomers and enantiomers therefore, and combinations and mixtures of one or more of the foregoing.

3. The method of claim 1 wherein the at least one terpene is selected from the

group consisting of limonene, pinene, linalool, linalyl acetate, caryophyllene, caryophyllene oxide, nerolidol, phytol, myrcene, 1-8-cineole (aka eucalyptol), pulegone, teroineol, terpinolene, the various isomers and enantiomers thereof, and combinations and mixtures of one or more of the foregoing.

4. The method of claim 1 wherein the symptom to be treated is selected from the

group consisting of restlessness, uncomfortable sensations in the limbs, pain, insomnia or a combination thereof.

5. The method of claim 1 wherein the administration will reduce the patient's International Restless Legs Syndrome Rating Scale Score.

6. The method of claim 1 wherein the at least one cannabinoid comprises a first and a second cannabinoid, wherein the first and second cannabinoid are different cannabinoids.

7. The method of claim 1 wherein the at least one cannabinoid comprises a first, a second and a third cannabinoid, wherein the first, second and third cannabinoids are different cannabinoids.

8. The method of claim 1 wherein the at least one terpene comprises more than one terpene.

9. The method of claim 1 wherein the administration is oral, buccal, lingual, sublingual, intrapulmonary or a combination thereof.

10. The method of claim 9 wherein the administration is a single administration per day occurring after the evening meal or shortly before or at bedtime.

1 1. The method of claim 10 when the administration comprises oral, buccal, lingual or sublingual administration of a composition comprising 0.25 mg to 50 mg of THC and 0.25 mg to 50 mg of CBD or CBDV.

12. The method of claim 10 when the administration comprises intrapulmonary administration of a composition comprising 0.25 mg to 50 mg of THC and 0.25 mg to 50 mg of CBD or CBDV.