THETWO TONTTITULUMLULUTTUUS 20170266128A1 MUHIMU ( 19) United States ( 12) Patent Application Publication ( 10 ) Pub. No. : US 2017 /0266128 A1 Aung - Din ( 43 ) Pub . Date: Sep . 21 , 2017

(54 ) TOPICAL REGIONAL NEURO - AFFECTIVE A61K 45 /06 ( 2006 .01 ) THERAPY IN MAMMALS WITH A61K 9 / 00 ( 2006 .01 ) CANNABINOIDS A61K 9 / 127 (2006 .01 ) ( 71 ) Applicant: Afgin Pharma, LLC , Sarasota , FL A61K 9/ 06 (2006 .01 ) (US ) ( 52) U . S . CI. ??? .. . . . A61K 31/ 05 (2013 .01 ); A61K 45 /06 (72 ) Inventor: Ronald Aung - Din , Sarasota , FL (US ) (2013 . 01 ) ; A61K 9/ 0017 (2013 . 01 ) ; A61K ( 73 ) Assignee : Afgin Pharma, LLC , Sarasota , FL 9 / 127 ( 2013 .01 ); A61K 31/ 352 ( 2013 . 01 ) ; (US ) A61K 36 / 185 (2013 .01 ); A61K 9 /0014 (21 ) Appl. No .: 15 /612 , 375 ( 2013. 01 ) ; A61K 9 / 06 (2013 .01 ) ( 22 ) Filed : Jun . 2 , 2017 (57 ) ABSTRACT Related U . S . Application Data Amethod of treating a disease state or condition in mammals (63 ) Continuation of application No . 15 /058 ,859 , filed on other than humans via topicalbrainstem afferent stimulation Mar. 2 , 2016 , now abandoned . therapy via the administration of a cannabinoid drug ( s ) to (60 ) Provisional application No . 62 /299 , 260 , filed on Feb . the back of the neck region and /or spine to provide regional 24 , 2016 , provisional application No . 62/ 126 , 757 , neuro - affective therapy is disclosed . In certain preferred filed on Mar. 2 , 2015 . embodiments , the cannabinoid drug ( s ) are not psychoactive Publication Classification or substantially not psychoactive . In certain embodiments , (51 ) Int. Ci. the cannabinoid drug ( s ) are incorporated into a pharmaceu A61K 31 /05 ( 2006 .01 ) tically acceptable topical carrier , e .g ., a cream or mousse . In A61K 31/ 352 ( 2006 . 01 ) certain preferred embodiments , the cannabinoid drug ( s ) A61K 36 / 185 ( 2006 . 01) comprises cannabidiol. US 2017 /0266128 A1 Sep . 21, 2017

TOPICAL REGIONAL NEURO - AFFECTIVE and comprises up to 40 % extracts of plant resin . At least 85 THERAPY IN MAMMALS WITH different cannabinoids isolated from cannabis exhibit varied CANNABINOIDS effects . 10006 ] There is no greater example of a “ double - edged FIELD OF THE INVENTION sword ” in medical therapeutics than medical marijuana . While benefits for treating symptoms of diverse neurologic [0001 ] The invention relates to topical regional neuro and psychiatric conditions have been known and practiced affective therapy (“ TRNA THERAPY ” ) with cannabinoids , by ancient civilizations for thousands of years , marijuana ' s such as cannabidiol (CBD ) on mammals other than humans . psychoactive effects have also led to abuse and labeling as This is accomplished via administration of effective amounts a “ gateway drug” for more addictive compounds. There is of these agents on the back of the neck region , and in certain no class of therapeutic compounds with more controversy embodiments also in proximity to the painful site or problem and stigma than cannabinoids, active components of the area . cannabis plant. However , while availability may still be of concern for humans, abuse is not a concern for other BACKGROUND OF THE INVENTION mammals . 10002 ] This application claims priority to U . S . Application f0007 ] The U .S . Government has indicated there is no No. 62 / 126 , 757 , filed on Mar. 2 , 2015 and U . S . Application medical benefit for marijuana and classified it Controlled No. 62 / 299 , 260 , filed on Feb . 24 , 2016 ; the disclosures of Substance Category 1 , as heroin . It is considered by federal which are hereby incorporated by reference herein . law , illegal to possess or use cannabis and its associated [0003 ] The approximate 21/ 2 pound human brain is com products . However, increasing number of states have chal prised of the most complex material known to man . The lenged this position and legalized cannabis within their neuron , the primary functional cell of the nervous system , territories with varying restrictions and conditions for use . operates on the basis of electrical impulses that result in the Even then , within individual states, such as in Colorado , release of neurochemical substances (neurotransmitters ) at marijuana laws vary greatly from county to county . specific receptors : dopamine , serotonin , acetylcholine , nor [0008 ] Although defined under U . S . federal law as having epinephrine , gamma -amino butyric acid GABA( ), and many no medical use , U . S . Pat. No . 6 ,630 ,507 is held by the others . There are estimated to be 80 - 100 billion ( 10 times the United States Department of Health and Human Services , world population ) neurons in the average human brain . covering use of cannabinoids for treating a wide range of These neurons, in turn , make 200 - 300 billion coded con diseases. It is directed to a method of treating diseases nections with other neurons to accomplish the complex tasks caused by oxidative stress comprising administering a thera of the human body. peutically effective amount of a cannabinoid ( e . g ., canna [0004 ] The brainstem serves as the vital pathway for relay bidiol) that has substantially no binding to the NMDA and processing of neural impulses flowing continuously receptor to a subject who has a disease caused by oxidative between the brain and the rest of the body . It is about the size stress . of the thumb and contains the most dense and complicated wiring systems in the human body . In addition to the axons SUMMARY OF THE INVENTION and dendrites (wires ) that carry nerve impulses , the brain stem also contains critical nuclei that function as electrical [0009 ] It is an object of the present invention to provide a generators and relays . Some of the nuclei are related to method of treatment in mammals with topical afferent neural cranial nerve function while others serve as generators and activation therapy via the regional administration of one or impulse centers for pain perception , the autonomic system more cannabinoids useful for the treatment of such diseases " fight or flight” response , wakefulness and alertness , as well or conditions that may be treated via such therapy . as cardio - respiratory and related autonomic functions. The [ 0010 ] It is an object of the present invention to provide a brainstem in mammals other than humans , while somewhat method for the treatment of lameness and gait issues ; elbow different than humans, is also responsible for these tasks. dysplasia ; hip dysplasia ; back and hind leg problems; arthri [0005 ] The endocannabinoid system ( ECS ) is involved in tis ; seizures ; encephalopathy , including lethargy , focus/ at regulating a variety of physiological processes including tentional problems, and cognitive issues: spasticity ; epi appetite , pain and pleasure sensation , immune system , lepsy ; cancer ; weakness ; pain ; numbness ; anxiety and other mood , and memory . Endocannabinoid receptors in the brain mood disorders ; hypertension ; tremors; peripheral neuropa interact with cannabinoids from different sources , including thy ; bowel and bladder control issues ; inactivity ; poor (endocannabinoids ( brain derived , e . g . , from foods ( Omega appetite ; tumors (e . g. , pituitary tumors ); Cushing 's disease ; 3s and Omega -6s ) ; phytocannabinoids ( plant derived , e . g . , aggressive behavior ; pruritis ; dermatitis ; vomiting ; lethargy ; from buds, tinctures, extracts , including tetrahydrocannabi dystonia ; personality change; as well as any other disease or nol ( THC ) , cannabidiol (CBD ) , cannabinol (CBN ) , etc . ) ; condition in a mammal other than humans that may be and synthetic cannabinoids (such as tetrahydrocannabinol treated with a cannabinoid . ( THC ) ) . Cannabinoids are a diverse class of chemical com [0011 ] The above objects and others are attained by virtue pounds that act on cannabinoid receptors on cells and of the present invention , which is directed in part to a influence neurotransmitter release in brain . These receptor method of treating a disease state or condition in mammals proteins include endocannabinoids produced naturally in via topical regional neuro - affective ( TRNA ) or regional humans and animals , phytocannabinoids in cannabis and neuro - affective ( RNA ) therapy via administration of a drug some other plants , and chemically manufactured synthetic at the back of the neck region , optionally also at the spine cannabinoids. Phytocannabinoid 49 - tetrahydrocannabinol region . The drug is one or more cannabinoids , administered ( THC ) is the primary psychoactive compound of cannabis . at the back of the neck region in proximity to and under or Cannabidiol (CBD ) is another major constituent of the plant, on the area of skin above the brain stem to provide regional US 2017 /0266128 A1 Sep . 21, 2017 neuro - affective therapy to mammals , and optionally also at [0018 ] In certain preferred embodiments, the mammal is a the spine region . In certain preferred embodiments , the canine . In other preferred embodiments, the mammal is a mammals are not human . feline . In other preferred embodiments, the mammal is a [0012 ] In other embodiments of the invention , the method horse or other equine. In other embodiments , the mammal is is directed in part to treating a disease state or condition in a goat , sheep , lamb , pig , wolf, cattle , etc . In yet other mammals other than humans via topical regional neuro embodiments , the mammal is a monkey or a hominoid ape . affective ( TRNA ) or regional neuro -affective (RNA ) therapy [0019 ] In certain preferred embodiments , the disease or via administration of a cannabinoid drug ( s) at the spine condition to be treated in the mammal includes lameness and region , to provide regional neuro - affective therapy to mam gait issues ; elbow dysplasia ; hip dysplasia ; back and hind mals , including humans but preferably other than humans. leg problems; arthritis ; seizures ; encephalopathy , including The administration may be along part or all of the spine , lethargy , focus /attentional problems, and cognitive issues : depending on the disease state or condition and /or the spasticity ; epilepsy ; cancer; weakness ; pain ; numbness ; location of the injured area on the mammal. anxiety and other mood disorders ; hypertension ; tremors ; [0013 ] In certain preferred embodiments , the cannabinoid peripheral neuropathy ; bowel and bladder control issues ; drug (s ) is derived from an endocannabinoid , a phytocan inactivity ; poor appetite ; tumors ( e . g . , pituitary tumors ) ; nabinoid , a synthetic cannabinoid , or mixtures of any of the Cushing 's disease; aggressive behavior; lethargy ; personal foregoing . In certain preferred embodiments , the cannabi ity change ; as well as any other disease or condition in a noid comprises cannabidiol. mammal other than humans that may be treated with a [ 0014 ] In certain preferred embodiments , the cannabinoid cannabinoid . drug mixture concentrate includes from about 0 to about 3 % [ 0020 ] In certain embodiments , the method further com tetrahydrocannabinol, from about 0 to about 1 % tetrahydro prises further comprises topically administering at the back cannabinolic acid , from about 20 to about 100 % canna of the neck region ( and optionally also at the spine region ) bidiol, from about 0 to about 1 % cannabidiolic acid , and together with , sequentially , or simultaneously but in separate from about 0 to about 1 % cannabinol, for a total active formulations, an additional drug ( s ) selected from the group cannabinoid level of from about 20 % to about 50 % . The consisting of: an anti - epileptic , an anxiolytic , a neuroleptic , remaining cannabinoids included in the mixture may be an anti -psychotic , an analgesic , an anti - inflammatory , an substantially therapeutically inactive . anti- Parkinson ' s disease / syndrome drug , a drug for the treat [0015 ] In certain preferred embodiments , the cannabinoid ment of dystonia , a drug for the treatment of spastic condi drug (s ) are incorporated into a pharmaceutically acceptable tions, a drug for the treatment of benign essential/ familial topical formulation . In certain preferred embodiments , the tremor, a drug for the treatment of tremor related to MS , a cannabinoid drug ( s ) in the topical pharmaceutical formula drug for the treatment of chronic encepahalopathies, a drug tion are at a concentration from about 0 .75 % to about 5 % , for the treatment of congenital CNS degeneration condi by weight. In certain embodiments , the unit dose of the tions/ cerebral palsy , a drug for the treatment of cerebellar cannabinoid drug ( s ) includes from about 1 mg to about 200 degeneration syndromes , a drug for the treatment of neuro mg cannabinoid drug ( s ) and the cannabinoid drug ( s ) com pathic and /or neurogenic pain , a drug for appetite suppres prise at least 80 % cannabidiol. In certain preferred embodi sion , a drug for neurodegenerative conditions , a drug for the ments, a unit dose of the topical pharmaceutical formulation treatment of multiple sclerosis , a drug for the treatment of comprises from about 3 mg to about 50 mg cannabidiol. insomnia , a drug for the treatment of fatigue , a drug for the [0016 ]. In certain preferred embodiments , the pharmaceu treatment of vertigo , nausea and / or dizziness , a drug for the tically acceptable topical formulation comprises a topical treatment of writer ' s cramp and restless leg syndrome, other aqueous -based carrier , with an optional penetration drugs which can beneficially be added to the treatment in enhancer. In certain preferred embodiments , the topical order to provide an additive or synergistic effect with respect aqueous- based carrier is a mousse , gel, or cream , and most to treating the patient' s disease state or condition ; and a preferably a mousse . combination of any of the foregoing . In certain embodi [ 0017 ] In certain preferred embodiments , the method fur ments, the additional drug ( s ) is a dopamine agonist selected ther comprises applying a sufficient amount of the topical from the group consisting of apomorphine , pramipexole , pharmaceutical formulation to the back of the neck region ropinirole , bromocriptine, cabergoline , pergolide , rotigotine , (and optionally also at the spine region ) of mammals other entacapone , tocapone, seligiline, dopamine , and mixtures of than humans such that the onset of a therapeutic effect any of the foregoing . In other embodiments , the disease state occurs in less than about 30 minutes , or in less than 15 or condition is Parkinson ' s disease and / or related syn minutes. The topical pharmaceutical formulation may be dromes /diseases . In other embodiments , the additional drug administered (applied to the back of the neck region ) on a ( S ) is selected from the group consisting of the drug is a once a day basis , a twice a day basis , or even three times per dopamine agonist , COMT inhibitors, MAO - B inhibitors , day. In other embodiments , particularly where the mammal and mixtures of any of the foregoing . In other embodiments , has been administered multiple doses of the topical phar the additional drug( s ) is an anti - epileptic drug selected from maceutical formulation and has realized a therapeutic benefit the group consisting of Valproic acid , Leviteracetem , Lam from the cannabinoid drug therapy , it is possible to reduce otrigene, Topiramate , Pregabalin , Gabapentin , Carbam the frequency of the dosing to less than once per day, e . g ., azepine, Oxcarbazepine , Phenobarbital and other barbitu once every two or three days, once a week , biweekly , or rates , Tiagabine , Retigabine , Lacosamide , Perampanel, and monthly . In certain instances , it is contemplated that the mixtures of any of the foregoing ; or the additional drug( s ) is administration of the topical pharmaceutical formulation an anxiolytic , a neuroleptic and /or an antipsychotic ; or the will no longer be necessary after an initial course of therapy, additional drug (s ) is an analgesic and /or an anti- inflamma as the mammal would no longer be suffering from the tory ; or the additional drug ( s ) is used in the treatment of underlying condition and may be in essence " cured ” . neuropathic and/ or neurogenic pain ; or the additional drug US 2017 /0266128 A1 Sep . 21, 2017

( s ) is for multiple sclerosis ; or the additional drug ( s ) is for ( e . g , a mousse , cream , ointment or gel ) ; a transdermal insomnia ; or the additional drug ( s ) is for fatigue ; or the device ; or an implantable or injectable formulation . additional drug ( s ) is for vertigo , nausea and / or dizziness ; or [0030 ] The invention is further directed to the use of a the additional drug ( s ) is a tricyclic antidepressant ( TCA ) , a cannabinoid drug in the preparation of a medicament for tetracyclic antidepressant, or an atypical antipsychotic . providing regional neuro - affective therapy to a mammal [0021 ] In certain preferred embodiments , the drug is for other than a human , wherein the cannabinoid drug ( s ) is mulated in a pharmaceutically acceptable ( immediate administered at the back of the neck region and spine . release ) topical carrier. In certain preferred embodiments, Alternatively, the regional neuro - affective therapy can be the topical carrier is aqueous based , and may be a cream or described as administration of the cannabinoid drug ( s ) in gel or mousse . proximity to and at or on the back of the neck region , e . g ., [0022 ] In certain preferred embodiments , the method fur on the area of skin above the brain stem or in an area running ther comprises formulating the cannabinoid drug ( s) in a from around the pole to around or beyond the withers ( for pharmaceutically acceptable immediate release aqueous four- legged mammals ) , to provide regional neuro - affective based carrier. In other embodiments , the cannabinoid drug ( s ) therapy to the mammalian patient. is administered in a topical pharmaceutical formulation [0031 ] In certain preferred embodiments , the cannabinoid comprising liposomes . drug ( s ) is also administered to the mammal at or in prox [0023 ] In certain preferred embodiments where the can imity to an injured area on the mammal. For example , if the nabinoid drug ( s ) are administered in a topical pharmaceu four- legged mammal has an injury to its leg , the cannabinoid tical formulation , the method further comprises applying a drug ( s ) may also be administered to the leg or hip area . If the sufficient amount to the back of the neck region of the four- legged mammal has an injury to its hip , the cannabinoid mammal such that the onset of clinical effect occurs in less drug (s ) may also be administered directly to the hip region . than about 30 minutes, and in certain preferred embodiments 10032 ] In certain embodiments, the cannabinoid drug( s ) is in less than about 15 minutes . applied to the posterior cervical region of the mammal in 10024 ] In certain preferred embodiments , the therapeuti order to initiate the brainstem afferent stimulation therapy . cally effective amount of the cannabinoid drug( s ) is applied Most preferably , the topical formulation or topical therapeu as a unit dose comprising from about 0 . 25 mg to about 500 tic system is applied to the back of the neck region , mg. preferably near to or on the area of skin above the brain stem [0025 ] In certain preferred embodiments , the cannabinoid and / or along (part or all of) the spine . drug ( s ) is incorporated into a sustained release transdermal [0033 ] In other embodiments , the cannabinoid drug is delivery system which is capable of delivering from about administered via implantation or injection at the back of the 0 . 25 mg to about 5000 mg of the cannabinoid drug (s ) neck region and /or along the spine . In such embodiments , through the skin of a mammal other than humans over a 24 the therapy is accomplished via the availability of the hour period , the transdermal delivery system being capable drug (s ) at the free nerve endings under the epidermis . In of delivering the cannabinoid drug ( s ) in such amounts for a such embodiments , the drug may be incorporated into an time period from about 1 to about 7 days . implantation device or may be incorporated into a carrier [0026 ] In certain embodiments , the cannabinoid drug( s ) is such as a gel or matrix that will provide a prolonged administered via implantation or injection at the back of the release /effect of the cannabinoid drug (s ) at the site . The neck region , or is administered via injection in an immediate carrier may be a hydrophilic or hydrophobic material, a release pharmaceutically acceptable carrier for injection . In colloidal material, and may be in a state ranging from a certain embodiments , the cannabinoid drug ( s ) is adminis viscous liquid to a solid polymeric insert . tered via injection or implantation in a controlled release [0034 ] Certain embodiments of the invention are directed carrier to provide a prolonged effect of the cannabinoid to a method of treatment, comprising delivering a cannabi drug ( s ) . In certain embodiments , the cannabinoid drug ( s ) is noid drug ( s ) through regional neuro - affective therapy by administered to create a depot under the skin at the back of application as a cream /gel or a sustained release patch the neck region . applied at the back of the neck region and / or along the spine , [0027 ] Certain embodiments of the invention are directed or via administration under the skin at the back of the neck to a topical formulation , comprising a cannabinoid drug ( s ) region via an implantable or injectable drug formulation or in a pharmaceutically acceptable aqueous -based carrier , the device . cannabinoid drug ( s ) being incorporated into the carrier in at 0035 ] In certain embodiments , the method further pro least one unit dose comprising from about 0 . 25 mg to about vides for a therapeutically effective treatment through topi 80 mg cannabinoid drug ( s ) . Preferably , when applied in a cal regional neuro - affective (TRNA ) therapy by application unit dose to the back of the neck of a mammal other than of a drug ( s ) as a cream / gel or a sustained release patch humans the topical formulation provides an onset of clinical applied at the back of the neck region without the side effect occurs in less than about 30 minutes. effects and the other draw -backs of the current injection [0028 ] The invention is also directed to a topical formu method . lation , comprising a cannabinoid drug in a formulation [0036 ] In certain preferred embodiments , the cannabinoid suitable for administration at the back of the neck region in drug ( s ) is administered at the back of the neck region in an proximity to and under or on the area of skin above the brain immediate release topical formulation in a dose comprising stem of a mammal other than a human to provide regional from about 0 .25 mg to about 500 mg of the cannabinoid neuro - affective therapy to the patient. The topical formula drug (s ), and in certain embodiments more preferably from tion may be prepared as an immediate , controlled or sus about 1 to about 100 mg of the cannabinoid drug ( s ) . In tained release formulation . certain preferred embodiments , the cannabinoid drug ( s ) are 10029 ] The drug formulations useful in the present inven in a more potent form ( e . g ., crystallized CBD from a herbal tion may be in a form selected from a topical formulation source ) , and the dose is from about 10 mg to about 50 mg. US 2017 /0266128 A1 Sep . 21, 2017

In certain other embodiments , the ( e . g ., immediate release ) that there is nothing in the formulation ( e . g . , a sustained topical formulation includes from about 1 mgto about 30 mg release carrier ) that would delay or slow the availability of CBD when the CBD is provided as purified crystallized the drug at the site of application in contrast to , e . g ., a CBD from a herbal source. transdermal device or patch ). [0037 ] In certain preferred embodiments , the method of [0044 ] For purposes of the present invention , an “ implant treatment further comprises administering the cannabinoid able” formulation includes , for example , a solid , semisolid drug ( s ) to other areas of the spine and /or peripheral nerves or liquid drug formulation which can be administered at the in addition to administration on or at the back of the neck back of the neck region either via injection and / or via region , in order to provide an additive or synergistic effect surgical implantation . The solid may comprise micro and further modulate afferent neural input to the brain to spheres, microcapsules, pellets , discs, and the like. The affect efferent outflow for relief of symptoms. implantable formulations of the invention may provide a [0038 ] In certain preferred embodiments , the method of controlled or sustained release of the drug at the site of treatment further comprises topically administering at the administration . back of the neck together with , sequentially , or simultane [0045 ] For purposes of the present invention , a “ transder ously but in separate formulations, one or more additional mal therapeutic system ” is defined as a drug - containing active agents (“ drugs ” ) which may be chosen from the device ( including e . g ., patch , disc , etc . ) which releases one following : an anti - epileptic , an anxiolytic , a neuroleptic , an or more drugs at a predetermined rate over a defined period anti- psychotic , an analgesic , an anti - inflammatory , an anti of time to a defined site of application . Parkinson ' s disease /syndrome drug , a drug for the treatment [0046 ] For purposes of the present invention , “ transder of dystonia , a drug for the treatment of spastic conditions, a mal” delivery is the delivery by passage of a drug through drug for the treatment of benign essential / familial tremor, a the skin and into the bloodstream ( “ traditional ” transdermal drug for the treatment of tremor related to MS, a drug for the delivery ) and is termed “ transdermal systemic drug delivery treatment of chronic encepahalopathies , a drug for the ( TSD therapy ). treatment of congenital CNS degeneration conditions/ cere [0047 ] For purposes of the present invention , the term bral palsy, a drug for the treatment of cerebellar degenera “ topical neuro - affective therapy ” is synonomous with the tion syndromes , a drug for the treatment of neuropathic more accurately termed topical regional neuro - affective and / or neurogenic pain , a drug for appetite suppression , a therapy (or " TRNA therapy ” ) . This term describes important drug for neurodegenerative conditions , a drug for the treat aspects of this delivery method : topical , regional (near ment of multiple sclerosis , a drug for the treatment of brainstem and cervical spinal cord ) , and affecting the free insomnia , a drug for the treatment of fatigue , a drug for the nerve endings of the afferent nervous system , thereby not treatment of vertigo , nausea and / or dizziness, a drug for the requiring the presence of drug in the blood , as with systemic treatment of writer ' s cramp and restless leg syndrome, and therapies which includes the transdermal patch wherein the other drugs which can beneficially be added to the treatment skin is used to have drug enter into the bloodstream through in order to provide an additive or synergistic effect with a continuous application patch . In such situations, an iono respect to treating the patient ' s disease state or condition . tophoretic electric current generator may be required to [ 0039 For purposes of the present invention , the term “ back of the neck region ” is intended to encompass the area cause drug entry into blood against a concentration gradient. or region extending from behind ) one ear to the other ear of [ 0048 ] For purposes of the present invention “ therapeuti the mammal (other than a human patient ) and from the back cally effective ” or “ effective ” amount is meant to be a of the head (i . e . , above the neck ) to below the neck at the nontoxic but sufficient amount of a cannabinoid compound torso of the mammal. ( s ) to provide the desired therapeutic effect . [0040 ] With respect to four- legged mammals , the back of [0049 ] For purposes of the present invention , an “ effec the neck region refers to the area extending from the poll to tive ” amount of a permeation enhancer as used herein , for the withers and beyond , e . g . , along the spine. The poll is a example , means an amount that will provide the desired name of the part of an animal' s head , alternatively refer increase in skin permeability and , correspondingly , the encing a point immediately behind or right between the ears . desired depth of penetration , rate of administration , and The withers is the ridge between the shoulder blades of a amount of drug to be delivered . four- legged mammal. [0050 ] For purposes of the present invention , the term [0041 ] For purposes of the present invention , a “ topical “ delivers” when used with respect to the topical formulation formulation " includes , for example , ointments , creams, or transdermal therapeutic system means that the formula lotions , pastes , gels, etc . , which releases one or more drugs tion or system provides a mean relative release rate or flux ( e. g ., cannabinoid drug (s )s ) at a predetermined rate over a of the drug out of the formulation or system and through the defined period of time to a defined site of application . skin of the patient. [ 0042 ] For purposes of the present invention , an “ inject - [0051 ] “ Penetration enhancement” or “ permeation able” formulation includes , for example , an injectable solu enhancement " for purposes of the present invention relates tion , suspension , gel or the like and may be in immediate to an increase in the permeability of skin to a pharmaco release form or may provide a controlled or sustained release logically active agent , i. e ., so as to increase the rate at which of the drug at the site of administration . the drug permeates through the skin and enters the blood [0043 ] For purposes of the present invention , the term stream . The enhanced permeation effected through the use of “ immediate release ” means that the cannabinoid drug ( s ) is such enhancers can be observed by measuring the rate of administered at the site of application ( e . g ., the back of the diffusion of drug through animal (mammal ) skin using a neck ) and is available for immediate absorption at the site of diffusion cell apparatus. application . In other words , the term " immediate release ” is [0052 ] For purposes of the present invention , the drug may meant to convey in terms of a topical formulation the fact be in the form of the base , or may be provided as a US 2017 /0266128 A1 Sep . 21, 2017 pharmaceutically acceptable salt (inorganic or organic ) or responsible for anti- inflammatory effect such as pain relief . complex . Itmay be in an optically pure form or a mixture of One other main endocannabinoid is 2 - Arachidonoylglycerol stereoisomers . ( 2 - AG ) , active at both CB1 and CB2 cannabinoid receptors. Its mimetic phytocannabinoid is cannabidiol (CBD ) , while DETAILED DESCRIPTION that of Anandamide is THC , responsible for psycho - active [ 0053] The therapeutically active agents used in the for effects . 2 - AG and CBD are involved in regulation of appe mulations and methods of the invention comprise cannabi tite , immune system functions and pain management. noid drug ( s ). Cannabinoids are a diverse class of chemical [0056 ] Tetrahydrocannabinol ( THC ) has been the primary compounds that act on cannabinoid receptors on cells and focus of cannabis research since 1964 , when Raphael influence neurotransmitter release in brain . These receptor Mechoulam isolated and synthesized it . More recently , the proteins include endocannabinoids produced naturally in synergistic contributions of cannabidiol to cannabis phar humans and animals , phytocannabinoids in cannabis and macology and analgesia have been scientifically demon some other plants , and chemically manufactured synthetic strated . Other phytocannabinoids, including tetrahydrocan cannabinoids. Endo , phyto and / or synthetic cannabinoids nabivarin , cannabigerol and cannabichromene , exert cause neurotransmitter release which results in nerve trans additional effects of therapeutic interest . Innovative conven mission . Phytocannabinoid A9 - tetrahydrocannabinol tional plant breeding has yielded cannabis chemotypes ( THC ) , is primary psychoactive compound of cannabis . expressing high titres of each component for future study . Cannabidiol (CBD ) is another major constituent of the plant, [0057 ] Cannabidiol (CBD ) is considered the “ medical up to 40 % extracts of plant resin . Cannabidiol (CBD ) is one component” of cannabis and hemp . CBD is considered to of many active cannabinoids in cannabis . The cannabinoid have a wide scope of medical applications . It acts as may be derived from endocannabinoids ( derived , e . g . , from 5 -HT1A receptor agonist which may explain its antidepres foods (Omega - 3s and Omega -6s ) ; phytocannabinoids ( plant sant, anxiolytic , and neuroprotective effects . Cannabidiol derived ,e . g. , from buds, tinctures, extracts , including tetra modulates opioid receptors involved with pain perception . hydrocannabinol ( THC ) , cannabidiol (CBD ) , cannabinol CBD is not psychoactive and relieves convulsion , inflam (CBN ), etc .) ; and synthetic cannabinoids (such as tetrahy mation , anxiety , and nausea . It has also been found to play drocannabinol ( THC ) ) . At least 85 different cannabinoids a role in preventing short - term memory loss from THC . isolated from cannabis exhibit varied effects . In certain Antipsychotic effects of cannabidiol represent potential preferred embodiments , the cannabinoid drug ( s ) , or are not treatment of schizophrenia . Oral CBD formulation received psychoactive or are substantially not psychoactive (meaning orphan drug status in US as treatment for Dravet syndrome, that if included in the formulation , they are not in sufficient an intractable seizure disorder also known as Severe Myo amount that a unit dose of the formulation would cause the clonic Epilepsy of Infancy ( SMEI) . Nabiximols, trade name patient to have a psychoactive effect) . In certain preferred Sativex , is an aerosolized mist for oral administration con embodiments, as will be explained further below , the can taining 1 : 1 ratio of CBD and THC approved 2005 in Canada nabinoid drug is actually a mixture of two or more cannabi for multiple sclerosis associated pain . CBD has a greater noids ( e . g . , CBD and THC together in a CBD : THC ratio that affinity for CB2 than CB1 receptor. provides a therapeutic effect while substantially not psycho [0058 ] CBD acts as serotonin (5 -HT1A ) receptor agonist active or not psychoactive at all ) . which may explain its antidepressant, anxiolytic , and neu [0054 ] The endocannabinoid system ( “ ECS” ) consists of a roprotective effects . CBD modulates opioid receptors group of endogenous cannabinoid receptors located in mam involved with pain perception . CBD is not psychoactive and malian brain and throughout the central and peripheral relieves convulsion ( seizures ) , inflammation , anxiety , and nervous systems. These entail neuromodulatory lipids and nausea . It has been found to play a role in preventing their associated receptors . As the body ' s " endogenous, " short - term memory loss from THC . Antipsychotic effects of cannabinoid system , ECS is involved in a variety of physi cannabidiol represents potential treatment of schizophrenia . ological processes including neurological functions dealing CBD has a greater affinity for CB2 than CB1 receptors . with pain , mood , memory ; and , movement, and sensation . [0059 ] Strains of cannabis containing higher CBD con The body ' s immune function and cell homeostasis is also centrations did not produce short- term memory impairment maintained by ECS . It mediates the psychoactive effects of compared to those with similar concentrations of THC , but the cannabis (marijuana ) plant. Cannabinoids are a diverse lower CBD concentrations. Attenuation of memory effects class of compounds that include many of the unique com attributed to CBD 's function as CB1 antagonist. Transder pounds found in marijuana . mal CBD has been shown to be neuroprotective in animals . [ 0055 ] Cannabinoids produce physiological and behav Antioxidant properties of cannabidiol have been shown to ioral effects through interaction with specific membrane play a role in its neuroprotective and anti - ischemic effects . bound receptors . Two primary endocannabinoid receptors Animal experiments indicate CBD may help in treating have been identified in humans: CB1 and CB2. There is Parkinson ' s disease . mounting evidence that more endocannabinoid receptors [0060 ] It is known to those skilled in the art that studies exist . CB1 receptors are found predominantly in brain have suggested that many cannabinoid compounds work ( specifically in basal ganglia and limbic system , including together to produce a synergy of effects . This is known as the hippocampus ) and nervous system , as well as in peripheral ' entourage effect. " Thus , in certain preferred embodiments , organs and tissues. These are acted on by the endocannabi the formulations of the invention contain more than one noid binding molecule Anandamide. Of G protein - coupled cannabinoid compound , which provide an “ entourage effect . type receptors (GPCR ) in human brain , cannabinoid recep tors are the most plentiful. CB1 receptors responsible for [ 0061 ] CBD has anti -psychotic effects which may coun euphoric and anti - convulsive effects of cannabis . CB2 teract psychotomimetic effects of THC , euphoric and hallu receptors found only in peripheral nervous system appear cinogenic component of cannabis. Reports show CBD safe US 2017 /0266128 A1 Sep . 21, 2017 and well - tolerated alternative treatment for schizophrenia . A ( cannabimimetics ) including the aminoalkylindoles, 1 ,5 double blind trial comparing purified cannabidiol to atypical diarylpyrazoles , qualenel7p , and arylsulfonamides , as well antipsychotic amisulpride in acute paranoid schizophrenia as eicosanoids related to the endocannabinoids. Cannab showed both treatments were associated with significant igerol (“ CBG ” ) is non -psychotomimetic but still impacts the decrease in psychotic symptoms after 2 weeks; but canna overall effects and affects of cannabis . CBG acts as a bidiol was associated with significantly fewer side effects. alpha2 - adrenergic receptor agonist , 5 -HT1A receptor Studies show cannabidiol affects limbic system , decreasing antagonist , CB1 receptor antagonist, and also binds to the symptoms of social anxiety and isolation . Cannabidiol has CB2 receptor . CBC is non - psychoactive , and exhibits anti demonstrated antidepressant- like effects in animalmodels of inflammatory and analgesic properties . Evidence suggests depression . that CBC may play a role in anti - inflammatory and anti- viral [ 0062 ] In certain preferred embodiments , the cannabinoid effects , may have antidepressant effects , may promote neu is not psychoactive, or only mildly psychoactive . Canna rogenesis , and may contribute to the overall analgesic effects bidiol (CBD ) is not psychoactive , and therefore in certain of cannabis . Delta - 9 - tetrahydrocannabinol (Dronabinol ; preferred embodiments , the active cannabinoid drug com commercially available in the U . S . under the tradename prises cannabidiol, or consists essentially of cannabidiol, or Marinol) is used as an appetite stimulant, anti - emetic , and consists of cannabidiol. In other preferred embodiments , analgesic . Nabilone (Cesamet , Canemes ) , a synthetic can cannabidiol comprises from about 5 % to about 99 . 9 % of the nabinoid and an analog of Marinol; Rimonabant total amount of cannabinoid drug (s ) included in the formu (SR141716 ) , a selective CB1 receptor inverse agonist once lations and treatments of the present invention . In other used as an anti -obesity drug under the tradename Acomplia , preferred embodiments , cannabidiol comprises about 20 % , and was also used for smoking cessation . about 30 % , about 40 % , about 50 % , about 60 % , about 70 % , [ 0064 ] In certain embodiments , the cannabinoid drug ( s ) is about 80 % , about 90 % or more, or greater than about 95 % industrial hemp or a non - psychoactive hemp product . of the total amount of cannabinoid drug ( s ) included in the [0065 ] In yet further embodiments , the cannabinoid drug formulations and treatments of the present invention . In ( s ) comprises a natural cannabinoid compound , a synthetic certain embodiments , the CBD is derived from crystalline cannabinoid compound , a semi- synthetic cannabinoid com powder, such that the powder is about 95 % pure CBD or pound, or mixtures thereof. Illustrative of such compounds greater . In other preferred embodiments , cannabidiol com are cannabinoids or cannabinoid analogues selected from the prises at least about 20 % of the total amount of cannabinoid group consisting of cannabinol, cannabidiol, delta 9 - tetra drug ( s ) included in the formulations and treatments of the hydrocannabinol, delta 8 - tetrahydrocannabinol, hydroxy present invention . In other embodiments , the cannabinoid tetrahydrocannabinol, 11 - hydroxy - 9 - tetrahydrocannabinol, drug comprises cannabinol (which is only mildly psycho levonantradol, delta 11 - tetrahydrocannabinol, tetrahydro active ) . In certain embodiments , the cannabinoid drug ( s ) cannabivarin , dronabinol, amandamide, nabilone , a natural contained in the formulationsof the invention is hemp CBD . or synthetic analogue thereof, a natural or synthetic mol In other embodiments , the cannabinoid drug ( s ) is cannabis ecule with a basic cannabinoid structure , and mixtures of based and comprises a THC - CBD ( and optionally other any of the foregoing . cannabinoid combinations derived from cannabis ) . As CBD [006 ] In certain embodiments , the cannabinoid drug ( s ) and THC have differentmechanisms of action , they may act included in the treatment and / or formulations of the present synergistically , e . g ., to control seizures . In such embodi invention comprise a ligand that binds to the CB , or the CB2 ments, the therapeutic effect may be via the " entourage receptor. effect ” . [ 0067 ] Cannabis terpenoids ( e . g . , limonene, myrcene , a - pinene , linalool, ß - caryophyllene , caryophyllene oxide , [ 0063 ] In other embodiments , the drug is a cannabinoid nerolidol and phytol) share a precursor with phytocannabi such as an endocannabinoids ( derived , e . g . , from foods noids , and are all 18quale and fragrance components com (Omega - 3s and Omega -6s ) ; a phytocannabinoid (plant deri mon to human diets that have been designated Generally ved , e . g ., from buds , tinctures , extracts , including tetrahy Recognized as Safe by the US Food and Drug Administra drocannabinol ( THC ) , cannabidiol (CBD ) , cannabinol (CBN ) , etc . ) ; and synthetic cannabinoids ( such as tetrahy tion and other regulatory agencies . Terpenoids are quite drocannabinol ( THC ) ) , mixtures thereof, and the like . Fur potent, and affect animal and even human 18qualene when ther representative cannabinoids useful in the present inven inhaled from ambient air at serum levels in the single digits tion include cannabigerol (CBG ), cannabichchromene ng. Ml - 1 . They display unique therapeutic effects that may ( CBC ), cannabicyclol (CBL ) , tetrahydrocannabivarin contribute meaningfully to the entourage effects of canna ( THCV ) , cannabidivarin (CBDV ) , cannabichromevarin bis - based medicinal extracts . Thus , in certain embodiments , (CBCV ) , cannabigerovarin (CBGV ) , delta - 8 -tetrahydrocan the formulations and treatments of the present invention nabinol, delta - 9 - tetrahydrocannabinol (Dronabinol ) , can include an active drug component which comprises both a nabigerol monomethyl ether (CBGM ) , nabilone , rimonabant phytocannabinoid ( s ) and a terpenoid ( s ) . Phytocannabinoid ( SR141716 , a selective cannabinoid (CB ) receptor inverse terpenoid interactions may produce synergy with respect to agonist) , JWH -018 , JWH - 073 , CP - 55940 , dimethylhep treatment of pain , inflammation , depression , anxiety , addic tylpyran , HU - 331 , SR 144528 ( a selective CB , receptor tion , epilepsy, cancer, fungal and bacterial infections (in agonist ) , levonantradol, AM - 2201, beta - caryophyllene , lipo cluding methicillin -resistant Staphylococcus aureus ). philic alkamides (alylamides ) which have affinity for the CB2 receptor, and chemical derivatives of any of the fore Administration at the Back of the Neck Region going . In certain embodiments , a synthetic cannabinoid is [0068 ] The cannabinoid drug formulations of the present used . Synthetic cannabinoids encompass a variety of distinct invention are preferably applied at the back of the neck chemical classes: the classical cannabinoids structurally region of the mammal other than a human patient. In its related to THC , including the nonclassical cannabinoids broadest sense , the term “ back of the neck region ” is US 2017 /0266128 A1 Sep . 21, 2017 intended to encompass the area or region extending from neum ), which are the peripheral end components of spinal (behind ) one ear to the other ear of the mammal and from the dorsal root ganglia . As skin and CNS are both derived from back of the head ( i. e ., above the neck ) to the withers or the same embryological tissue , neuro - ectoderm , receptors to beyond ( four- legged mammals ) , and below shoulder level neurotransmitters and other substances used in neural com (monkeys , huminoid apes, etc .) . The majority of mammals munication are similarly represented on both free nerve have seven cervical vertebrae , including humans , bats , endings and CNS . This makes sense as the skin needs to giraffes and whales . The exceptions are the manatee and the communicate directly with CNS with respect to external two - toed sloth , which have just six , and the three - toed sloth stimuli . In fact, these receptors are on the cell surface of skin with nine cervical vertebrae . Thus , the anatomy ofmammals free nerve endings , making them readily accessible to com are not very dissimilar to humans in this respect. The pounded drug applications to the skin for neural effect , administration of the cannabinoid drug ( s ) may be located “ topical neuro -affective therapy. ” The binding of the topi more directly at the back of the neck in the area in mammals cally administered cannabinoid drug ( s ) to these receptors above the cervical nerve roots, C1- C4 ( and optionally results in electrical action potential generation and propa including C5) such that administration of the cannabinoid gation to CNS , causing therapeutic effects to occur. As such , drug ( s ) are in the area at or above the skin where the afferent these same drug compounds do not need to enter the components of trigeminal nerve system , cervical sympa bloodstream to reach their sites of activity , as it is with thetic nerves, and vagus nerve are located . It is to be systemic delivery. Systemic side effects and drug activity at understood that application at the back of the neck region is sites other than intended are therefore not present . Further, not an exact art , and application of part or all of the dose in by working through established neural pathways than proximity to the back of the neck region ( e . g . , behind the through the blood stream , the therapeutic effects are rapid , ears or on the skin higher ( on the back of the head ) or lower generally with 15 - 30 minutes or less. Many of the current (below the shoulders or withers ) and /or along the spine than drugs used systemically for peripheral conditions such as directly above the C1 - C4 cervical nerve roots will still pain are thought to work by their effect on dorsal root provide a therapeutically effective dose in accordance with ganglia , modulating neural impulses to brain . With topical the invention ; however, such locations are not optimal and neuro - affective therapy the effects on dorsal root ganglia are may cause a lessening of the therapeutic effect or a delay in direct and immediate as free nerve endings are peripheral onset of therapeutic effect. All such treatments are consid extensions of the ganglia . ered to fall within the definition of “ back of the neck region ” [0072 ] An important aspect of the benefits of “ TRNA ” or for purposes of the present invention . “ RNA ” therapy in CNS drug delivery for brainstem related [0069 ] The administration of a cannabinoid drug ( s ) at the disorders lies in the anatomy of the region . The free nerve back of the neck for mammals is a novel way to deliver endings with receptors for the neuro -chemicals dopamine , cannabinoids. This is believed to be accomplished by acti serotonin , norepinephrine , and others are located just below vation of cutaneous afferent pathways through neuro - chemi the surface of the skin , easily assessable to drugs com cal receptors existing on free nerve - endings . The hypothesis pounded in an appropriate dermal penetration enhancing of this therapeutic modality is based on presence of numer medium and topically applied to the skin . ous (hundreds of thousands to millions ) of free nerve [0073 ] To understand the concept of " peripheral neural endings below the skin surface ( stratum corneum ) at upper afferent stimulation therapy ” as it applies to the brainstem posterior cervical region , the back of the neck or “ nuchal” and how topical drug delivery to the back of the neck works region . There exist at this location , direct connections requires a review of the neuro -anatomy and the neuro through cervical nerve roots , C1 -C4 , and occasionally , C5, physiology of the region . As indicated above , this area of the to afferent components of trigeminal nerve system , cervical nervous system is very complicated , compact and highly sympathetic nerves , and vagus nerve providing significant inter- active and inter- related . input to CNS . At no other location on the human body is [0074 ] The Trigeminal Nerve System is a component of such a magnitude of afferent neural input accessible through the brainstem which coordinates pain input from the face , skin nerve -endings than here .Modulated CNS efferent neu head , and the back of the neck . As such , it intimately ral outflow in response to afferent activation manifests as influences the production of other symptoms associated with improvement in clinical symptoms of MS and other condi syndromes attributed to dysfunction within the trigeminal tions of brain and spinal cord impairment. By using direct complex . These include the photophobia , phonophobia , nau nerve pathways , by -passing blood flow and avoiding restric sea , anxiety , allodynia , and other focal sensory symptoms tions of " blood - brain - barrier, " onset of therapeutic time is which may accompany a migraine attack . Similarly , epi greatly reduced and systemic side effects are avoided . sodes of trigeminal neuralgia (tic douloreux ) frequently [ 0070 ] The inventor has observed rapid therapeutic onset involve significant affective (emotional ) and visceral com of action , generally , less than 10 to 15 minutes administra ponents . Because of proximity and connections to other tion of cannabinoid drug ( s ) at the back of the neck , with structures in the brainstem , abnormalities of temperature maximal benefit noted well within 30 minutes . In certain regulation , thirst, alertness , and mood are common . Some of embodiments , a prolonged therapeutic effect has been noted , these symptomsmay be as equally disabling as the head and e . g . , about 4 to about 12 hours or more , depending on face pain . condition and severity of the condition being treated . [0075 ] In addition to receiving pain and sensory ( afferent) [ 0071 ] The peripheral nervous system (PNS ) communi input from the face , nasal and para - nasal sinuses , the teeth , cates with central nervous system (CNS , consisting of brain , scalp , the dura of the anterior and middle cranial fossa , the brainstem , and spinal cord ) through dorsal root ganglia trigeminal system receives similar input from the soft tissues which reside just outside the spine and act as neural relay of the posterior cervical region . The free nerve endings in the areas between PNS and CNS. Mammalian skin has free back of the neck are just below the surface of the skin , easily nerve endings just below the skin surface ( stratum cor accessible to topically delivered drugs formulated in an US 2017 /0266128 A1 Sep . 21, 2017 appropriate dermal penetration enhancing compounding nism of action appears to be the down - regulation of hyper medium . The free nerve endings, via the small un -myeli excitable , dysfunctional neuronal systems by increased nated and myelinated “ C - fibers ” (pain fibers ) carry pain inhibitory input to brainstem and associated connections impulses through afferent sensory nerves back to the through stimulation of the afferent system . Afferent stimu Trigeminal Nucleus Caudalis (TNC ) . TNC is the pain pro lation , by feed -back through TNC , causes reduction in cessing center extending from the pons through the entire efferent output from the brainstem , resulting in resolution of extent of the brainstem to the upper cervical spinal cord . clinical symptoms through down - regulation of hyper - active After synapsing at the thalamus , pain impulses from TNC neuronal structures . travel to the somatosensory cortex , where pain is perceived . [0081 ] In the same way the electrical stimulation of VNS [0076 ] As providing important afferent input to the brain , accomplishes its effect on the brainstem , topical drug the trigeminal system also receives afferent input from the therapy to the posterior cervical region , in close proximity to rest of the body . Afferent input is defined as any neural the brainstem and its afferent inputs , is theorized to provide impulses coming back to the brain from the body . As such effect for the conditions mentioned above . it provides information to the brain for processing and [0082 ] It is hypothesized that benefits of the present interpretation : pain , sensation , autonomic functions. Effer method of topical drug delivery of central nervous system ent output, on the other hand , consists of impulses originat (CNS ) active drugs lies in the fact that drug concentration ing in the central nervous system ( brain , brainstem , and gradients and blood flow factors are un - involved in the spinal cord ) flowing to the body for function : movement, therapeutic process. In contrast, the proposed delivery oper response , action . ates through direct nerve connections between skin periph [ 0077 In humans , the vagus nerve includes both efferent eral nerves at the back of the neck , region and brainstem and afferent fibers and is attached to the lower brainstem structures. Active drug compounded in an appropriate “ der (medulla oblongata ) via 8 - 10 radicles . Other mammals also mal penetration enhancing” medium topically applied to the have a vagus nerve which is somewhat similar. The afferent skin at the back of neck has effect on the free nerve endings fibers arise in the jugular and the nodose vagus ganglia . The of peripheral nerves located immediately below the skin somatic afferent fibers terminate in the nucleus of the surface . Receptors to dopamine , serotonin , norepinephrine , trigemino -spinal tract ( TNC ) . Both the jugular and the and other neuro - transmitters / neuro - chemicals involved with nodose ganglia are connected with the superior cervical neural transmission are located on these free nerve endings . sympathetic gangion through inter- communicating rami. Therefore , topically applied drug has near immediate thera The superior cervical sympathetic ganglion is located peutic effect as direct neural impulses are involved — the between the internal carotid artery and the jugular vein on concept of brainstem afferent stimulation through topical the ventral aspects of the transverse processes of the 2nd , 3rd regional neuro -affective (TRNA ) therapy . All prior art and and the 4th cervical vertebrae . It is the largest of the sym methods of drug delivery to the CNS have involved blood pathetic trunk ganglia . flow and therapeutic drug blood level requirements . The [0078 ] In humans, sympathetic roots arising from the inventive method does not require such , which are the ganglion join the 1st and the 2nd cervical nerves; frequently source of undesirable systemic and CNS side -effects . The the 3rd , and occasionally , the 4th . In addition to nerve fibers present drug delivery process operates on the principle of an which extend rostrally from the superior cervical sympa electrical capacitor whereas the prior relied on those fluid thetic ganglion , the sympathetic innervation of the head dynamics and reservoir principles . includes fibers which join the plexi on the common carotid [0083 ] The factors which determine the success of TRNA and the vertebrtal arteries. The one on the vertebral artery is therapy include : the drug being considered , the compound continuous with the plexus on the basilar artery. Rami ing substance (surfactant / dermal penetration enhancer ), the derived from the internal carotid plexus join the trigeminal disease process , and the location of application . The free nerve and the cavernous plexus in addition to the other nerve endings in the skin at the back of the neck area are structures such as the abducens and deep petrosal nerves . important components of the cervical nerves with rich From the cavernous plexus, located in the middle cranial connections to the trigeminal , vagal, and sympathetic sys fossa , sympathetic fibers join the oculomotor, trochlear, and tems communicating with brainstem structures and other the ophthalmic nerves . Fibers from the plexus also accom components of the central nervous system . These are the pany blood vessels into the hypophysis . The spheno - palatine areas pain and other symptoms related to neuro - chemical gangion , located in the pterygo -palatine fossa , receives release are processed and perceived . sypmpathetic fibers from the face with rami distributed to [0084 ] The skin at the upper part of the back of the neck , the mucous membranes of the nares , mouth , the pharynx , at the hairline in humans, is innervated by ( supplied by and some orbital structures. nerves ) the cervical nerve roots C 1 - 3 that are also part of the [0079 ] From the above, it is clear that cervical nerve Trigeminal Nerve system of the brainstem . These cervical function is intimately related to vagal afferents and afferents nerves ( the wires ) have their cell bodies ( their generators ) from the face , head , and the dura of cranial fossae associated within the Nucleus Caudalis (Spinal Nucleus) of the with migraine and other head and face pain syndromes. Trigeminal Nerve in the cervical spinal cord and the brain [0080 ] It has been long reported that vagal nerve stimu stem . Accordingly, they have direct neural connections with lation ( VNS) in the neck down - regulates abnormal dis brainstem processing areas . At the same time, the peripheral charges from epileptic foci and treats seizures . VNS is now nerve receptor sites for these nerves, the free nerve endings , approved as adjunct to medical therapy in certain forms of reside under the skin surface at the back of the neck . The intractable epilepsy . It is also of benefit in severe depression nerves in the soft tissues of the back of the neck , represent resistant to traditional drug therapy . Studies with VNS in ing the C1, C2 , and C3 segments of the cervical spinal cord migraine , anxiety , and fibromyalgia have been underway are unique in that they have intimate connections with and have shown preliminary promise in benefit . The mecha pathways directly affecting brainstem and autonomic system US 2017 /0266128 A1 Sep . 21, 2017 function . There are direct connections with the Trigeminal dients or systemic blood levels are necessary . Drug delivery Nerve system of the brainstem which provides for pain and is unaffected by cardiac output or cerebral blood flow other sensory input and interpretation from the head , face , factors . Of significance , persons afflicted with Parkinson ' s sinus cavities , the dural covering of the brain , and the back disease are typically elderly with concomitant cardiac and of the neck . There are also connections with the vagus nerve cerebral vascular disease . and the sympathetic nervous system through the sympathetic [0088 ] Thus, in certain embodiments , the methods and ganglia . It is through these connections, which are nowhere formulations of the invention deliver an amount of drug else in the body as inter -related or at such close proximity to ( e . g . , cannabinoid drug ( s ) in the TRNA therapy that would the surface of the human skin , that the potential for the provide sub - therapeutic plasma levels if administered orally , delivery of CNS acting drugs through the skin at the back of but which is therapeutically effective when administered via the neck region is realized . Finally , skin is embryologically TRNA therapy at the back of the neck region . derived from neuro - ectoderm which is also responsible for [0089 ] It is hypothesized by the inventor that a principal the formation of the brain and other aspects of the CNS . reason TRNA therapy is rapid in the onset of clinical effect Thus, the nerves in the human skin have a particularly direct ( e .g ., less than about 10 - 15 minutes ) for is that it operates relationship with these structures . This provides for the through an “ electro -chemical ” process. Active drug com efficacy noted with TRN /back of the neck therapy. At the pounded in an appropriate dermal penetration enhancing same time, systemic and other CNS side - effects are reduced medium acts at free nerve endings , changing the neurochem or avoided . Thus, drugs topically applied to the skin in this istry of receptors at the neural synapse : apomorphine (dop region have ready access to brainstem and other CNS amine and norepinephrine agonist ), increasing dopamine structures without the requirement of drug in the blood and norepinephrine levels and improving neural transmis stream reaching target sites. sion . After a point of receptor stimulation , neural ( electrical) [0085 ] In addition to the upper cervical nerves having impulses are generated back to neuronal cell bodies residing direct relation to the Trigeminal Nerve System , they also in the spinal cord and brainstem : “ afferent feed -back ” . The contribute to the Cervical Sympathetic Ganglia and the nervous system functions through neurons generating elec Vagal Nerve Systems through direct connections. These trical impulses and the release of neurochemicals / neuro latter two systems provide some of the most significant transmitters ( serotonin , norepinephrine , dopamine, and ace afferent feed - back to the brainstem and other portions of the tylcholine , being the major ones ) at neural receptor sites CNS from the rest of the body . This allows for additional called " synaptic clefts ” . Accordingly , the process in TRNA brainstem afferent stimulation potential through TRNA therapy may be considered analogous to an electrical capaci therapy at the back of the neck . Although skin at other areas tor discharging to perform a function , such as turning on a of the face and head have eventual neural feed -back to the light switch . Viewed from this perspective , the rapid onset of brainstem , the intimate connections to afferent feed - back clinical effect observed in TRNA therapy makes sense . systems are lacking. [0090 ] Alternatively , transdermal systemic patch delivery [0086 ] TRNA therapy at the back of the neck region operates on the principles of chemical gradients and fluid delivery differs from traditional therapy ( whether oral, injec dynamics . These processes have variability and inherent tion , nasal spray , inhalation , or rectal ) in that it has no idiosyncrasies , fluctuating heart function as a pump for reliance on the systemic or cerebral blood flow . Nor does it blood flow being one . Thus, despite the advantage of mea require therapeutic blood levels of drug . These latter factors surable drug levels, a more circuitous route with slower are responsible for systemic and CNS side - effects as drug is clinical effect is observed . This makes systemic transdermal delivered to areas not intended to be affected in the thera patch delivery inappropriate for acute therapy . peutic process. Transdermal systemic delivery by patch , although similarly applied to the skin as in TRNA therapy , Therapeutic Applications differs significantly in its reliance on a drug concentration [0091 ] Potential clinical applications of cannabinoids in gradient for absorption into the systemic capillary and mammals include but are not limited to the treatment of venous blood . TRNA therapy is unaffected by dermal ves lameness and gait issues ; elbow dysplasia ; hip dysplasia ; sels or systemic blood flow . It relies solely on the function back and hind leg problems; arthritis ; seizures; encepha of the free nerve endings of cutaneous nerves and their lopathy , including lethargy , focus /attentional problems, and connections at the point of application of compounded drug . cognitive issues : spasticity ; epilepsy ; cancer ; weakness; [0087 ] “ Traditional” transdermal drug delivery by patch pain ; numbness ; anxiety and other mood disorders ; hyper and TRNA are both “ transdermal” in that in both , drug tension ; tremors ; peripheral neuropathy ; bowel and bladder penetrates the skin ( epidermis ) for eventual clinical effect. control issues ; inactivity ; poor appetite ; tumors ( e . g . , pitu The difference lies in the fact that in “ traditional” transder itary tumors ); Cushing 's disease ; aggressive behavior; pru mal patch therapy, drug enters the systemic circulation ritis ; dermatitis ; vomiting ; lethargy ; dystonia ; personality through a concentration gradient and establishes a therapeu change ; as well as any other disease or condition in a tic drug blood level. Although measuring a blood level gives mammal other than humans that may be treated with a assurance drug is being taken or delivered systemically , cannabinoid . allowing for checking compliance , it is also the source of 10092 ] A representative cannabinoid drug mixture concen undesirable side - effects and drug interactions . Of necessity , trate may include with respect to total active cannabinoids , with systemic transdermal patch therapy, drug applied to the for example , from about 0 to about 3 % tetrahydrocannabi skin surface must be absorbed through the small vessels in nol, from about 0 to about 1 % tetrahydrocannabinolic acid , the dermis for eventual presence in the systemic venous from about 20 to about 50 % cannabidiol, from about 0 to blood for measurement of drug level. With TRNA therapy, about 1 % cannabidiolic acid , and from about 0 to about 1 % the cannabinoid drug ( s ) need only be available at the free cannabinol, for a total active cannabinoid level of from nerve endings under the epidermis . No concentration gra about 20 % to about 50 % . A particular cannabinoid concen US 2017 /0266128 A1 Sep . 21, 2017

trate useful in the formulations of the present invention may [0103 ] 10 . Appetite Suppressant drugs : Examples include , e . g . , about 0 . 84 % tetrahydrocannabinol, about include drugs such as Sibutramine . 0 . 23 % tetrahydrocannabinolic acid , about 26 .41 % canna [0104 ] 11. Neurodegenerative Diseases: Examples bidiol, about 0 % cannabidiolic acid , and about 0 .09 % can include drugs such as Aricept/ donepezil , Exelon / riv nabinol, for a total active cannabinoid level of about astigmine, Reminyl/ Razadyne / galantamine , and 27 .58 % , as detected using full spectrum cannabinoid pro Namenda/ memantine and their naturally occurring filing and analysis utilizing High Performance Liquid Chro counterparts , as well as NMDA antagonists . matography (HPLC /UV ) , and is commercially available [0105 ] 12 . Multiple Sclerosis (MS ) : Examples include from CannaVest . Such a cannabinoid drug mixture may drugs such as 4 -aminopyridine . provide the afore -mentioned entourage effect . [0106 ] 13. Insomnia : Examples include drugs such as zolpidem . Combination Therapy [0107 ] 14 . Fatigue : Examples include drugs such as [0093 ] In certain preferred embodiments of the invention , pemoline and Modafinil . the cannabinoid ( s ) is administered together with (e . g ., in the [0108 ] 15 . Vertigo , Nausea and / or Dizziness : Examples same formulation ) , or simultaneously (but separately ) or include drugs such as meclizine , dimenhydrinate , sequentially with an additional active agent( s ) (“ drug ( s ) ” ) prochlorperazine, scopolamine and diphenhydramine . suitable for treating the patient' s disease state or condition . [ 0109 ] 16 . Writer 's cramp and restless leg syndrome: Classes of drugs which would be suitable as an additional Examples include dopamine agonists such as apomor active agent( s ) include, but are not limited to : phine . [ 0094 ] 1 . Anti- Epileptic drugs: Examples include Val [0110 ] In certain embodiments , the additional drug ( s ) proic acid (Depacon® /Depakotke ), Leviteracetem includes a dopamine agonist such as apomorphine (Keppra® ), Lamotrigene (Lamictal® ), Topiramate ( To ( Apokyn® , APO - go® ), pramipexole (Mirapexin® ), ropini pamax® ) , Pregabalin (Lyrica® ) , Gabapentin (Neu role (Requip® ) , bromocriptine (Parlodel® ) , cabergoline rontin® ) , Carbamazepine ( Tegretol® ) , Oxcarbazepine ( Cabaser® , Dostinex® ) , pergolide (Permax® , Celance® ) ( Trileptal® ) , Phenobarbital and other barbiturates , rotigotine (Neupro® ) , mixtures of any of the foregoing , or Tiagabine (Gabatril® ), RetigabineTM ( Valeant Pharma other dopamine agonists known to those skilled in the art . ceuticals ) , Lacosamide® (Schwarz Biosciences) , and One skilled in the art will appreciate that dopamine agonists Perampanel® ( Eisai ) are in development as anti - epi other than apomorphinemay be used in the formulations and leptics and neuromodulators for other associated neu methods of the present invention , and all such agents are rological, pain , and psychiatric conditions . meant to be encompassed by the term " dopamine agonists ." For example , such drugs include , but are not limited to , [0095 ] 2 . Anxiolytic drugs: Benzodiazepines: Examples carbidopa (Sinemet® ) , dopamine agonists (Requip® , include lorazepam ( Ativan® ) , diazepam (Valium® ) , Rotigotine® , Mirapex® ) , COMT inhibitors ( Entacapone® , clonazepam (Klonopin® ) , chlordiazepoxide ( Lib Tocapone) , rasagiline (Azilect® ) (MAO inhibitors ) and rium® ), and alprazolam (Xanax® ). MAO - B inhibitors (Selegiline (Eldepryl® ) . [ 0096 ] 3 . Neuroleptics / Anti- Psychotic drugs : Examples [0111 ] In other embodiments , the additional drug ( s ) include chlorpromazine ( Thorazine® ), haloperidol includes an opioid such as morphine, codeine, dihydroco (Haldol® ), risperidone (Risperdal® ) , olanzapine (Zy deine , hydrocodone , hydromorphone , nicomorphine, oxyco prexa® ) and quetiapine (Seroquel® ). done , oxymorphone , fentanyl, alphamethylfentanyl, alfen [0097 ] 4 . Analgesics/ Anti- Inflammatory drugs : tanil, sufentanil , remifentanil, carfentanyl, ohmefentanyl, Examples include prednisone , solumedrol, and other thebaine , oripavine , diacetylmorphine (heroin ) , phenylpip steroids, naproxen , aspirin , acetaminophen , voltaren , eridines such as pethidine (meperidine ) and ketobemidone , ketoprofen , ibuprofen , other NSAID ' s . allylprodine , prodine , propoxyphene , dextropropoxyphene , [0098 ] 5 . Parkinson ' s Disease/ Similar or Related Syn dextromoramide, bezitramide , piritramide , methadone, dipi drome drugs: Examples include dopamine agonists panone , levomethadyl Acetate (LAAM ) , loperamide, diphe such as apomorphine . noxylate , dezocine , pentazocine , phenazocine , buprenor [0099 ] 6 . Dystonia (cervical and otherwise ), which phine , dihydroetorphine , etorphine , butorphanol, sometimes occur in conjunction with spasmodic torti nalbuphine , levorphanol, levomethorphan , lefetamine , collis and spastic conditions: Examples of drugs meptazinol, tilidine , tramadol, tapentadol, mixtures thereof, include dopamine agonists such as apomorphine . and the like . [0100 ] 7 . Benign essential/ familial tremor, tremor [0112 ] In yet other embodiments , the additional drug ( s ) is related to MS , chronic encepahalopathies such as from tarpentadol ( a centrally acting oral analgesic having two stroke or head injuries , congenital CNS degeneration mechanisms of action combining mu - opioid receptor ago conditions/ cerebral palsy , cerebellar degeneration syn nism and norepinephrine reuptake inhibition ). dromes , and spasicity conditions from the above : [0113 ] In yet other embodiments , the additional drug ( s ) is Examples of drugs include dopamine agonists such as a selective norepinephrine reuptake inhibitor, such as Ato apomorphine . moxetine (Strattera® ) , Mazindol (Mazanor® , Sanorex® ) , [0101 ] 8 . Neuropathic /Neurogenic pain drugs: Nisoxetine (LY - 94939 ) , Reboxetine ( Edronax® , Vestra® ) , Examples include carbamazepine , gabapentin , topira Viloxazine (Vivalan® ) , mixtures thereof, and the like . mate , zonisamide, phenytoin , desipramine , amitrip [0114 ] In yet other embodiments , the additional drug ( s ) is tyline , imipramine, doxepin , protriptyline, pentoxifyl a benzodiazepine , such as lorazepam ( Ativan® ) , diazepam line , and hydroxyzine. ( Valium® ) , clonazepam (Klonopin® ) , chlordiazepoxide [0102 ] 9 . Smoking Cessation drugs: Examples include (Librium® ) , alprazolam (Xanax® ) , temazepam ( Restoril® ), drugs such as varenicline . mixtures thereof, and the like . In other embodiments , the US 2017 /0266128 A1 Sep . 21, 2017 drug is a neuroleptic or psychotropic such as chlorpromazine din® ), Maprotiline (Ludiomil® ), Mianserin ( Tolvon® ) , ( Thorazine® ) , haloperidol ( Haldol® ), risperidone (Risper mixtures thereof, and the like . dal® ) , olanzapine (Zyprexa® ) and quetiapine (Seroque® ) . [0125 ] In yet other embodiments , the additional drug ( s ) is [0115 ] In other embodiments , the additional drug (s ) is an an atypical antipsychotic , such as Ziprasidone (Geodon® , agent that treats depression and /or anxiety , for example , Zeldox® ) , Nefazodone ( Serzone® ) , and the like . selective serotonin reuptake inhibitors (SSRIs ) such as flu [0126 ] In yet other embodiments , the additional drug ( s ) is oxetine (Prozac ) , sertraline (Zoloft® ), venlafaxine ( Ef an anti - convulsant or anti - epileptic drug such as arylsulfo fexor® ) , citalopram (Celexa® ), parocetine (Paxil ) , mixtures nimide analogues such as Acetazolimide (Diamox ) ® , tricy thereof, and the like ( such as trazodone (Desyrel ) ) , and /or clic iminostilbene derivatives such as carbamazepine ( Te serotonin - norepinephrine reuptake inhibitors ( SNRI) , such greto® ) , benzodiazepines such as clonazepam (Klonopin® ) , as Desvenlafaxine ( Pristiq® ) , Duloxetine (Cymbalta® ) , clorazepate dipotassium ( Tranxene® ), lorazepam (Ativan® ) Milnacipran ( Ixel® , Savella® ), Venlafaxine (Effexor® ) , and diazepam ( Valium® ), carboxylic acid derivatives such mixtures thereof, and the like . as valproic acid (Depakene ) and divalproex sodium (De [0116 ] In yet other embodiments, the additional drug ( s ) is pakote® ) , succinimide derivatives such as ethosuximide a norepinephrine -dopamine reuptake inhibitor (NDRI ) , such (Zarontin® ) , carbamate esters of 2 - phenyl- 1 , 3 - propanediol as Amineptine (Survector® ) , an aminoketone antidepressant such as felbamate ( Felbatol® ) , hydantoins such as pheny such as Bupropion ( Wellbutrin® , Zyban® ) , Dexmethyl toin ( Dilantin® ), phenytoin sodium (Dilantin® ) and fosphe phenidate (Focalin ), Methylphenidate (Ritalin® , Con nytoin sodium (Cerebyx® ) , structural analogues of GABA certa® ) , Nomifensine (Merital® ), a phenylpiperazine anti such as gabapentin (Neurontin® ) and pregabalin (Lyrica® ) , depressant such as nefazodone (Serzone® ) , a piperazino phenyltriazines such as lamotrigine (Lamictal® ), pyrroli azepine antidepressant such as mirtazapine (Remeron® ) , dine derivatives such as levitiracetam (Keppra® ) , tricyclic mixtures thereof, and the like . iminostilbene derivatives such as 33qualene33pine ( Trilep [0117 ] In yet other embodiments , the additional drug (s ) tal) , barbiturates such as Phenobarbital, desoxybarbiturates may be an NMDA receptor antagonist . Phencyclidine , ket such as primidone (Mysoline® ), nipecotic acid derivatives amine , and dextromethorphan , are used as recreational such as tiagabine hydrochloride (Gabitril® ) , sulfamated drugs. At subanesthetic doses , however , these drugs have monosaccharides such as topiramate ( Topamax® ) , oxazoli mild stimulant effects , and these agents have shown promise dinedione derivatives such as trimethadione ( Tridione® ) , for the treatment of conditions that involve excitotoxicity, and methanesulfonamides such as zonisamide ( Zonigran® ) . including traumatic brain injury , stroke, and neurodegenera Additional drugs such as Retigabine® ( Valeant Pharmaceu tive diseases such as Alzheimer' s , Parkinson ' s , and Hun ticals ) , Lacosamide? (Schwarz Biosciences ) , and Peram tington ' s . panel® ( Eisai ) are in development as anti - epileptics and [0118 ] Additionally , the additional drug (s ) may be an neuromodulators for other associated neurological , pain , and agent that treats neuropathic /neurogenic pain (pain that psychiatric conditions , and thus are further examples of arises from nerve dysfunction and not as a result of injury , potentially useful drugs in the present invention . e . g ., trigeminal neuralgia ) , such as carbamazepine, gabapen [0127 ] In yet other embodiments , the additional drug ( s ) is tin , topiramate , zonisamide , phenytoin , desipramine , ami an analgesic /anti - inflammatory agent such as acetamino triptyline, imipramine , doxepin , protriptyline , pentoxifyl phen ; prednisone , solumedrol, and other steroids; naproxen , line , and hydroxyzine . aspirin , voltaren , ketoprofen , ibuprofen , nabumetone , and [ 01191. In other embodiments , the additional drug ( s ) treats other NSAID ' s . The NSAID may be COX - 1 , COX - 2 or insomnia , such as zolpidem ( Ambien® ) . mixed COX - 1 / COX - 2 inhibitors. Examples of COX - 2 [ 0120 ] In other embodiments , the additional drug( s ) treats inhibitors include oxicam , meloxicam , and the more selec fatigue. Such drugs include central nervous system stimu tive celecoxib , rofecoxib , valdecoxib , parecoxib and etori lants such as pemoline (Cylert® ) and Modafinil ( Provigil® ) . coxib . Further examples of corticosteroids include methyl [0121 ] In yet other embodiments , the additional drug ( s ) prednisolone, prednisolone , dexamethasone , and adreno treats vertigo , nausea and /or dizziness , such as meclizine (Antivert® ) , dimenhydrinate (32qualene32 ) , prochlorpera corticotrophic hormone (ACTH ) , corticotropin . zine ( 32qualene32® ) , scopolamine ( Transderm® ) and [0128 ] Additionally , the additional drug ( s) may be an diphenhydramine (Benadryl® ) . agent that treats neuropathic / neurogenic pain (pain that [0122 ] In yet other embodiments , the drug is a serotonin arises from nerve dysfunction and not as a result of injury , norepinephrine reuptake inhibitor ( SNRI) , such as Desven e .g ., trigeminal neuralgia ) , such as carbamazepine, gabapen lafaxine (Pristiq® ), Duloxetine (Cymbalta® ) , Milnacipran tin , topiramate , zonisamide , phenytoin , desipramine , ami ( Ixel® , Savella® ) , Venlafaxine (Effexor® ) , mixtures triptyline , imipramine, doxepin , protriptyline , pentoxifyl thereof, and the likene. line , and hydroxyzine , mixtures thereof, and the like. [0123 ] In yet other embodiments , the additional drug ( s ) is [0129 ] In other embodiments , the additional drug (s ) is a tricyclic antidepressant ( TCA ), such as Amitriptyline 4 -aminopyridine ( 4 - AP ; also known as Fampridine® ) or a ( Elavil® ) , Butriptyline (Evadene® , Evadyn®e ), Clomip pharmaceutically acceptable derivative thereof. This drug ramine ( Anafranil® ), Desipramine (Norpramin® , Pertof has been shown to have the ability to improve the commu rane ) , Dosulepin ( Prothiade ), Doxepin ( Adapin , Sinequan ) , nication between damaged nerves, which may result in Imipramine ( Tofranil® ) , Lofepramine (Feprapax® , Gama increased neurological function in the treatment of condi nil® , Lomont® ), Nortriptyline ( Aventyl® , Nortrilen® , tions such as multiple sclerosis (MS ). An example of another Pamelor® ), Protriptyline (Vivacti®1 ) , Trimipramine ( Sur such drug is 3 ,4 diaminopyridine . montil® ), mixtures thereof, and the like. [0130 ] In other embodiments , the additional drug (s ) is [0124 ] In yet other embodiments , the additional drug ( s ) is useful for the treatment of Dementia / Alzheimer ' s disease , a tetracyclic antidepressant, such as Amoxapine (Asen such as Aricept® /donepezil , Exelon® / rivastigmine, Remi US 2017 /0266128 A1 Sep . 21, 2017 nyl® /Razadyne® / galantamine , and Namenda®/ memantine , be necessary after an initial course of therapy , as the their naturally occurring counterparts, and mixtures thereof. mammal would no longer be suffering from the underlying condition and may be in essence " cured ” or no longer in Formulations need of chronic treatment. [ 0131] All currently approved therapies for the conditions [0135 ] In certain preferred embodiments , a unit dose of the described above reach the central nervous system through topical cannabinoid drug ( s ) formulation provides a cannabi the systemic circulation . Cerebral blood flow to brainstem noid ( e . g . , CBD ) unit dose from about 0 . 1 mg to about 500 structures is through the posterior circulation , via the ver mg, or from about 0 .25 mg to about 80 mg , or from about tebral and basilar arteries and their branches . In view of the 1 mg to about 100 mg. In certain embodiments , the unit dose undesirable side - effects associated with this form of drug of cannabinoid ( e . g . , CBD ) is from about 3 mg to about 50 delivery to the brain , it makes sense that targeted regional mg or from about 7 . 5 mg to about 30 mg. This may be delivery to the brainstem is sought. Topical delivery of administered in a topical mousse cream , ointment , gel or the currently used drugs compounded in an appropriate " dermal like . penetration enhancer” and applied in cream / gel form or as a [0136 ] A unit dose of the topical formulation ( s) of can sustained -release patch at the posterior cervical region ( back nabinoid drug ( s ) used in accordance with the present inven of the neck ) at the hairline is such a method . Lipoderm® is tion preferably includes at least 80 % cannabidiol, in certain an example of an effective commercially available com preferred embodiments at least 90 % cannabidiol, and in pounding medium . However, one skilled in the art will certain further preferred embodiments at least 95 % canna recognize that topical carriers meeting the specific chemical bidiol. In certain preferred embodiments , the amount of requirements of an individual drug can be formulated for psychoactive cannabinoid drug ( s ) present in the topical maximum efficiency in topical delivery . formulations of the present invention is less than 20 % , more [0132 ] In certain preferred embodiments , the cannabinoid preferably less than 10 % or less than 5 % of the total active drug ( s ) is formulated in a vehicle that allows for the drug to cannabinoids in the topical formulation . be immediately absorbable and available for the free nerve endings of the trigeminal nervous system which reside under [ 0137 ] For example , the topical formulation may be the skin surface in the form of a mousse , cream , gel or administered as a unit dose in an amount from about 0 .5 g ointment. On the other hand , it is contemplated in certain to about 1 g at a cannabinoid (e . g ., CBD ) concentration from embodiments of the invention that the topical or implantable about 0 . 1 % to about 5 % ( or more ) . cannabinoid drug ( s ) formulation can be administered in the [0138 ] It has been found that with respect to mammals form that provides a prolonged release at the back of the other than humans, and dogs in particular, a topical mousse neck region , for example , in the form of a transdermal patch . formulation containing the cannabinoid drug ( s ) is particu In further embodiments , the cannabinoid drug( s ) is applied larly beneficialbecause of the ease of application and greater ( i ) in a topical form that provides a therapeutically effective likelihood of the application remaining at the site while the dose of the cannabinoid drug ( s ) immediately absorbable at cannabinoid drug ( s ) is being absorbed . the site ( e . g . , back of the neck region and/ or along the spine ) , [0139 ] The formulations of the present invention are pre and ( ii ) a further therapeutically effective dose (s ) in a pared such that the drug ( s ) may be delivered acutely as prolonged or sustained release formulation ( e . g . , a transder single dose applications as mousse /cream / gel/ ointment or as mal patch or contained in liposomes ) that releases the a sustained release topical patch , depending on the condition cannabinoid drug ( s ) over time such that the cannabinoid treated and associated symptom complex in the individual drug ( s ) is absorbed in therapeutically effective amounts over patient. The critical point, again , is in the location of the a span of multiple dosage time intervals ( e . g ., 1 - 7 days ) . application : at the back of neck at the hair- line for access to 10133 ] In certain embodiments , the topical cannabinoid posterior cervical afferents with free nerve endings under the formulation of the present invention is administered at the surface of the skin . Through feedback connections with back of the neck region and / or spine on the mammal and a vagal and trigeminal afferent systems, this results in ultimate therapeutic effect is preferably provided within about 45 effect on brainstem structures . minutes , preferably within about 30 minutes , or 25 minutes , [0140 ] By virtue of the method of treatment described or 20 minutes , or 15 minutes, or 10 minutes after the herein , the disease state / condition to be treated may be administration . In certain preferred embodiments , a thera treated much faster and more effectively than such prior art peutic effect is noticed within about 10 to about 15 minutes after the administration (e . g ., application of the topical modes of administration . formulation to the back of the neck region ) . [0141 ] In certain embodiments of the present invention , [ 0134 ] In certain embodiments , the topical cannabinoid the method of treating a human patient comprises applying formulation is administered on an “ as needed ” basis . In other a topical formulation which comprises a drug suitable for embodiments , the topical cannabinoid formulation is admin topical administration , which is useful for the treatment of a istered on a once a day basis , or on a twice a day basis , or disease state or condition treatable via the topical brainstem on a three times a day basis , or on a four times a day basis . afferent stimulation (de -afferentation ) drug therapy In other embodiments , particularly where the mammal has described herein . been administered multiple doses of the topical pharmaceu [0142 ] The methods of the present invention may also , if tical formulation and has realized a therapeutic benefit from desired , involve pre - treatment of the skin with an enhancer the cannabinoid drug therapy, it is possible to reduce the to increase the permeability of the skin to the applied drug . frequency of the dosing to less than once per day, e. g ., once The methods of the present invention may include pre every two or three days , once a week , biweekly , or monthly. treatment or " prepping ” of the skin area with a substance In certain instances, it is contemplated that the administra that opens up the skin pores . Additionally , themethods of the tion of the topical pharmaceutical formulation will no longer present invention may include, if desired , pre- treatment or US 2017 /0266128 A1 Sep . 21, 2017 13

“ prepping ” of the skin with an alcohol swab or the like to rid cream , ointment, gel or the like . For example , the topical the area of dirt, make- up , oil, and the like, prior to applica formulation may be administered as a unit dose in an amount tion of the drug . from about 0 . 5 g to about 1 g at a cannabinoid ( e . g . , CBD ) [ 0143] In certain embodiments , the topical formulation of concentration from about 0 . 1 % to about 5 % ( or more ) . When the present invention comprises a drug in an amount which the CBD is provided as purified crystallized CBD ( e . g . , is therapeutically effective when administered topically at about 95 % pure ) from a herbal source , the amount of CBD the at the back of neck at the hair -line for access to posterior ( cannabinoid drugs in total ) may be reduced . cervical afferents with free nerve endings under the surface [0148 ] In certain embodiments , the topical formulations of the skin , but which provides a plasma concentration comprising a cannabinoid drug ( s ) with or without additional which is subtherapeutic if orally administered . drugs (collectively referred to herein as “ drug ( s) ” ) in an [ 0144 ]. The topical formulations of the present invention ointment, gel, cream or the like , will typically contain on the ( e . g . , mousse , ointment , gel, cream , or the like ) , must be order of about 0 . 001 to about 80 % by weight, preferably suitable for topical administration of a drug , i. e ., must 0 .01 wt. % to 50 wt. % drug ( s ) or from about 0 . 5 % to about contain pharmaceutically acceptable excipients compatible 5 % drug ( s ) ; and about 0 wt. % to about 50 . 0 wt. % , with application to the skin tissue, and may optionally preferably from about 1 wt. % to about 30 wt. % of a contain a sufficient amount of an enhancer composition as permeation enhancer composition , with the remainder of the described hereinafter. composition comprising a carrier or vehicle . In certain [0145 ] In certain embodiments , in addition to the drug preferred embodiments , the drug comprises CBD and is ( e. g ., cannabinoid drug (s )) , the topical formulations and /or included in a cream or gel or ointment in a concentration of, transdermal therapeutic systems of the present invention e . g ., 1 mg drug /ml of carrier ( e . g . , Lipoderm ) . However, it may include at least one adjuvant such as a penetration is to be understood that one skilled in the art can increase the enhancer, anti - oxidant, stabilizer, carrier , or vehicle. Addi amount of carrier or change the carrier and maintain or tionally or alternatively , the present invention may include improve efficacy of the topical formulation for TRNA the application of electric current ( iontophoresis ) for therapy . enhancing permeation of the cannabinoid drug (s ) . 10149 ) Suitable ( optional) permeation enhancers may also [0146 ] Suitable penetration enhancers useful in the for be included in the formulations. Such enhancers include , but mulations of the present invention include but are not are not limited to , dimethylsulfoxide (DMSO ), N , N - dim limited to isostearic acid , octanoic acid , oleic acid , oley1 ethylacetamide ( DMA ), decylmethylsulfoxide (C10 MSO ) , alcohol, lauryl alcohol, ethyl oleate , isopropyl myristate , polyethylene glycolmonolaurate (PEGML ) , propylene gly butyl stearate , methyl laurate , diisopropyl adipate , glyceryl col (PG ) , PGML , glycerol monolaurate (GML ) , lecithin , the monolaurate , tetrahydrofurfuryl alcohol polyethylene glycol 1 -substituted azacycloheptan - 2 -ones , particularly 1 - n - dode ether , polyethylene glycol, propylene glycol, 2 -( 2 -ethoxy cylcyclazacycloheptan -2 -one (available under the trademark ethoxy ) ethanol, diethylene glycol monomethyl ether, dieth Azone® from Whitby Research Incorporated , Richmond , ylene glycolmonoethyl ether, alkylaryl ethers of polyethyl Va. ) , alcohols , and the like. The permeation enhancer may ene oxide , polyethylene oxide monomethyl ethers, also be a vegetable oil as described in U . S . Pat. No . polyethylene oxide dimethyl ethers , dimethyl sulfoxide , 5 , 229 , 130 to Sharma. Such oils include , for example , saf glycerol, ethyl acetate , acetoacetic ester, N -alkylpyrroli flower oil, cotton seed oil and corn oil. done , and terpenes. [0150 ] Additional optional enhancers for use in conjunc 10147 ] In certain embodiments , the topical formulations tion with the present invention are lipophilic compounds comprising a drug in an ointment, gel, cream or the like , will having the formula [RCOO ]n R ', wherein n is 1 or 2 and R typically contain on the order of about 0 . 001 to about 80 % is C1 -C16 alkyl optionally substituted with 1 or 2 hydroxyl by weight, preferably 0 .01 wt. % to 50 wt. % drug ( i . e . , groups , and R ' is hydrogen or C1 -C16 alkyl optionally cannabinoid drug (s ) plus optional additional drugs as substituted with 1 or 2 hydroxyl groups. Within this group , described herein ), and about 0 wt. % to about 50 .0 wt. % , a first subset of compounds are represented by the formula preferably from about 1 wt. % to about 30 wt. % of a [ CH3 ( CH 2 ) m COO ] n R ' in which m is an integer in the permeation enhancer composition , with the remainder of the range of 8 to 16 , n is 1 or 2 , and R ' is a lower alkyl (C1 - C3 ) composition comprising a carrier or vehicle . In certain residue that is either unsubstituted or substituted with one or preferred embodiments , the drug is included in a cream or two hydroxyl groups . Preferred enhancers within this group gel or ointment in a concentration of , e . g . , 1 mg drug /ml of include an ester which is a lower alkyl ( C1- C3 ) laurate ( i. e . , carrier ( e . g ., Lipoderm ) . However, it is to be understood that m is 10 and n is 1 ) such as “ PGML” . It will be appreciated one skilled in the art can increase the amount of carrier or by those skilled in the art that the commercially available change the carrier and maintain or improve efficacy of the material sold as “ PGML " is typically although not neces topical formulation for TRNA therapy. In certain preferred sarily a mixture of propylene glycol monolaurate itself, embodiments , the drug is applied as a unit dose at the back propylene glycol dilaurate , and either propylene glycol, of the neck region in immediate release form ( e . g . , cream , methyl laurate , or both . Thus, the terms “ PGML " or " pro ointment or gel) for acute treatment with a cannabinoid drug pylene glycol monolaurate” as used herein are intended to as would be beneficial to a human patient . In such instances , encompass both the pure compound as well as the mixture it is preferred that the concentration of cannabinoid drug ( s ) that is typically obtained commercially . Also within this included in the unit dose is from about 1 mg to about 100 group is a second subset of compounds, namely , esters of mg, based on cannabidiol, or an therapeutically equivalent fatty alcohols represented by the formula CH3 (CH2 ) m - 0 amount of another cannabinoid drug ( s ) as described herein . CO CHR1R2 , in which R1 and R2 are independently In certain preferred embodiments , a unit dose of cannabinoid hydrogen , hydroxyl, or lower alkyl (C1 - C3 ), and m is as ( e . g ., CBD ) is from about 5 mg to about 50 mg or from about above . Particularly preferred enhancers within this group are 7 . 5 mg to about 30 mg. This may be administered in a topical lauryl lactate and myristyl lactate . In addition , a third subset US 2017 /0266128 A1 Sep . 21, 2017 14 of compounds within this group are analogous fatty acids , vegetable oils , hydrous lanolin and its derivative, squalene , i. e . , acids having the structural formula CH3 (CH2 ) m 41qualene; higher fatty acids such as palmitic acid , stearic COOH where m is as above . A particularly preferred acid is acid , etc . and the like. lauric acid . [0157 ] In certain embodiments , the topical formulation [0151 ] Other optional enhancer compositions are wherein may further include emulsifiers and dispersing agents which a lipophilic compound as just described , particularly PGML include , for example , anionic , cationic and nonionic surfac is combined with a hydrophilic compound , such as a C2 - C6 tants . Nonionic surfactants are preferred because of their low alkanediol. One preferred hydrophilic enhancer within this levels of irritation to skin . Typical of nonionic surfactants group is 1 , 3 -butanediol . Such enhancer compositions are are fatty acid monoglycerides such as glyceryl monostear described in detail in PCT Publication No . WO 95 /05137 , ate , etc .; sorbitan fatty acid esters such as sorbitan mono published Feb . 23 , 1995 , herein incorporated by reference . laurate , etc . ; sucrose fatty acid esters ; polyoxyethylene fatty Another hydrophilic enhancer thatmay be included in these acid esters such as polyoxyethylene stearate , etc . , and poly compositions is an ether selected from the group consisting oxyethylene higher alcohol ethers such as polyoxyethylene of diethylene glycol monoethyl ether ( Transcutol) and dieth cetyl ether, polyoxyethylene oleyl ether , etc . ylene glycol monomethyl ether . Such enhancer composi [0158 ] In certain preferred embodiments , the topical tions are described in detail in U . S . Pat. Nos . 5 ,053 ,227 and TRNA formulation is aqueous- based . 5 , 059 ,426 to Chiang et al. , the disclosures of which are [0159 ] In certain embodiments of the present invention , the topical formulation may include a gelling agent such as herein incorporated by reference . methylcellulose , ethylcellulose , hydroxyethylcellulose , [ 0152 ] Other optional enhancer compositions may include hydroxypropyl- cellulose , hydroxypropylmethylcellulose , mixture or combinations of any of the aforementioned carboxymethylcellulose , carbomer, and the like. Examples enhancers , and the like . of pharmaceutical compositions which rely upon an aqueous [0153 ] One preferred topical formulation comprises the gel composition as a vehicle for the application of a drug are cannabinoid drug ( s ) in oil, together with a suitable amount U . S . Pat. Nos . 4 ,883 ,660 ; 4 , 767 ,619 ; 4 ,511 , 563 ; 4 , 861 , 760 ; of a penetration enhancer , dimethyl sulfoxide and a base . For and 5 ,318 , 780 , the disclosures of which are herein incorpo example , such a formulation may include the CBD oil , and rated by reference . about 3 mldimethyl sulfoxide in 30 g of base . The CBD can 10160 ] The topical formulation may further include one or be incorporated at a concentration of, e .g . , from about 0 . 5 % more preservatives, stabilizers, or anti -oxidants . to about 5 % of the topical formulation in a preferred [ 0161 ] Examples of preservatives that may be used in a embodiment, and most preferably from about 1 . 5 % to about formulation according to the present invention include, but 3 % in a certain embodiment . The dose of such a formulation are not limited to , bacteriostatic compounds and other pre would be , e . g . , from about 0 . 5 g to about 1 g applied servatives suitable for topical administration including vari topically on the back of the neck of the human patient. ous alcohols , sorbic acid and salts and derivatives thereof, [0154 ] U . S . Patent Publication No . 20080112895 , hereby ethylenediamine, monothioglycerol, and thimerosal. incorporated by reference , describes a room temperature 10162 ] Examples of stabilizers that may be present in a stable aqueous cannabinoid formulation comprising an formulation according to the present invention include pH effective amount of a cannabinoid in a semi- aqueous solu buffers suitable for topical administration , complexing tion buffered to a pH of about 5 - 1 , the solution comprising agents , chelating agents and the like . water and an effective amount of an organic cosolvent to [0163 ] Examples of anti- oxidants that may be used in a maintain the physical stability of the formulation , which formulation according to the present invention include may be incorporated into a pharmaceutically acceptable ascorbic acid and its derivatives, e . g . , ascorbyl palmitate , as carrier. well as butylated hydroxyanisole, butylated hydroxytoluene , sodium bisulfite , sodium metabisulfite , and others . [0155 ] In certain embodiments the topical formulation [0164 ] Other adjuvants that may be included in the drug may include at least one water- insoluble , pharmacologically formulation include carriers , tackifiers , pigments , dyes , and approved , alkyl cellulose or hydroxyalkyl cellulose , and the other additives that do not adversely affect the mechanical or like . Alkyl cellulose or hydroxyalkyl cellulose polymers for adhesive properties of the formulation . use in this invention include ethyl cellulose , propyl cellu [0165 ] “ Carriers ” or “ vehicles ” as used herein refer to lose , butyl cellulose , cellulose acetate , hydroxypropyl cel carrier materials suitable for transdermal drug administra lulose , hydroxybutyl cellulose , and ethylhydroxyethyl cel tion , and include any such materials known in the art , e . g . , lulose , alone or in combination . In addition , a plasticizer or any liquid , gel, emulsion , solvent, liquid diluent, solubilizer, a cross linking agent may be used to modify the polymer ' s or the like , which is nontoxic and which does not interact characteristics. For example , esters such as dibutyl or diethyl with other components of the composition in a deleterious phthalate , amides such as diethyldiphenyl urea , vegetable manner. The term " carrier" or " vehicle” as used herein may oils , fatty acids and alcohols such as acid oleic and myristyl also refer to stabilizers , crystallization inhibitors, dispersing may be used in combination with the cellulose derivative . agents or other types of additives useful for facilitating [0156 ] In certain embodiments , the topical formulation transdermal drug delivery . It will be appreciated that com may further include hydrocarbons such as liquid paraffin , pounds classified as “ vehicles ” or “ carriers ” may sometimes qualene , solid paraffin , microcrystalline wax , etc . , higher act as permeation enhancers , and vice versa , and , accord aliphatic alcohols such as cetyl alcohol, hexadecyl, alcohol, ingly, these two classes of chemical compounds or compo stearyl alcohol, oleyl alcohol, etc . , esters of higher fatty sitions may sometimes overlap . acids with higher alcohols such as beeswax, etc . , esters of [0166 ] Carrier materials suitable for use in the instant higher fatty acids with lower alcohols such as isopropyl compositions include those well -known for use in the cos myristate , isopropyl palmitate , etc . , vegetable oils, modified metic and medical arts as bases for ointments , lotions, US 2017 /0266128 A1 Sep . 21, 2017 15 salves, aerosols , suppositories and the like . Suitable carriers formulated as a transdermal delivery system ( also referred to include, for example, water, liquid alcohols , liquid glycols , herein as a transdermal therapeutic system ) such as a trans liquid polyalkylene glycols , liquid esters , liquid amides , dermal patch , a transdermal plaster, a transdermal disc , liquid protein hydrolysates , liquid alkylated protein hydro iontophoretic transdermal device, or the like. Such formu lysates , liquid lanolin and lanolin derivatives , and like lations are recognized by those skilled in the art as providing materials commonly employed in cosmetic and medicinal a release of drug and absorption into the skin of the patient compositions . Other suitable carriers herein include for in a sustained manner over an extended period of time ( e . g . , example alcohols , including both monohydric and polyhy 1 - 7 days ) . In such embodiments of the present invention , the dric alcohols , e .g ., ethanol, isopropanol, glycerol, sorbitol, transdermal delivery system comprises, e . g . , a cannabinoid 2 -methoxyethanol , diethyleneglycol, ethylene glycol, hex drug ( s ) contained in a reservoir or a matrix , and an adhesive yleneglycol, mannitol, and propylene glycol, ethers such as which allows the transdermal patch to adhere to the skin , diethyl or dipropyl ether; polyethylene glycols and methoxy allowing the passage of the active agent from the transder polyoxyethylenes (carbowaxes having molecular weight mal patch through the skin of the patient . In preferred ranging from 200 to 20 ,000 ) ; polyoxyethylene glycerols , embodiments , the transdermal patch is applied topically at polyoxyethylene sorbitols , stearoyl diacetin , and the like . In the back of the neck so as to achieve topical regional certain preferred embodiments , the carrier is an aqueous neuro -affective therapy (“ TRNA THERAPY " ) as described based cannabidiol cream is produced using Lipoderm® as herein . In embodiments in which the drug is contained in a the carrier. Lipoderm® /LIP is a whitish cream with no smell , transdermal patch , it is contemplated that the drug will be commercially marketed compounding agent ( from PCCA , absorbed more slowly and the transdermal patch will pro Pharmaceutical Compounding Centers of America ) having vide a sustained release and prolonged therapeutic effect, as the following ingredients : Ethoxydiglycol, Water ( Aqua ) , compared , e . g . , to a cream or ointment intended to provide Glycerin , C12 - 15Alkyl Benzoate , Glyceryl Stearate , Dime an immediate release of the drug and rapid onset of the thicone, Cetearyl Alcohol, Cetearyl Glucoside, Polyacryl TRNA therapy. In such embodiments , the dose of cannabi amide , Cetyl Alcohol, Magnesium Aluminum Silicate , Xan noid drug ( s ) may be that which is sufficient to provide a than Gum , Aloe Vera ( Aloe Barbadensis ) , Tocopheryl therapeutically effective dose to the back of the neck ( e . g . , Acetate ( Vitamin E Acetate ) , Prunus Amygadalus Amara non - systemic dose ) over the course of e . g ., from about 1 , 2 , (Bitter Almond ) Kernel Oil , Vitis Vinifera (Grape ) Seed 3 , 4 , 5 , 6 or 7 days . In certain embodiments , the dose of Extract, Triticum Vulgare (Wheat ) Germ Oil , Retinyl Palmi cannabinoid drug ( s ) contained in the transdermal delivery tate ( Vitamin A Palmitate ), Ascorbyl Palmitate (Vitamin C system is from about 0 .5 mg to about 1000 mg. In certain Palmitate ) , Pro -Lipo Multi - emulsion Liposomic System , preferred embodiments , the dose of the cannabinoid drug is Tetrasodium EDTA , Phenoxyethanol, and Sodium from about 1 mg to about 100 mg. In certain preferred Hydroxymethylglycinate . embodiments in which the cannabinoid drug is cannabidiol, [ 0167 ] In certain embodiments of the invention , part or all the dosage is from about 8 mg to about 80 mg, and in certain of the dose of cannabinoid drug ( s ) may be encapsulated preferred embodiments , about 40 mg. As there are only a within liposomes . For example , U . S . Patent Publication No . finite number of receptors on the skin , once these receptors 2015 /0302148 , hereby incorporated by reference , describes are bound , the rest of the active drug is contained in the ( e . g . , fast- acting liposomal and micelle formulations of cannabi topical ) preparation is superfluous . Therefore , there is no noids which are prepared by ( a ) dissolving one or more possibility of " over - dosing , ” only of extra drug of poten cannabinoids or cannabinoid analogues in ethanol to obtain tially irritating the skin surface . Accordingly , in preferred an ethanol cannabinoid solution ; ( b ) adding a phospholipid embodiments , the methods and formulations of the present to the ethanol cannabinoid solution to obtain an ethanol invention provide reduced side effects as compared to a phospholipid cannabinoid solution ; ( c ) injecting the ethanol systemic administration of the same drug . phospholipid cannabinoid solution into distilled water to [0169 ] In certain embodiments , the transdermal delivery obtain a liposomal cannabinoid suspension ; and ( d ) remov devices, as well as other transdermal delivery systems in ing the ethanol from the liposomal cannabinoid suspension , accordance with the invention can be made in the form of an thereby producing a stable liposomal suspension of one or article such as a tape , a patch , a sheet, a dressing or any other more cannabinoids or cannabinoid analogue . In certain form known to those skilled in the art . Generally the device embodiments , the method further comprises the step of will be in the form of a patch of a size suitable to deliver a adding sodium alginate to the liposomal suspension of one unit dose of serotonin agonist through the skin . The drug or more cannabinoids or cannabinoid analogues to obtain an may be introduced into a transdermal therapeutic system in alginate liposomal cannabinoid suspension that has a final different forms ( solid , in solution , in dispersion ) ; it may also alginate concentration of 2 % w / v , followed by the addition be microencapsulated . of calcium chloride to the alginate liposomal cannabinoid [0170 ] In certain embodiments the present invention pro suspension to obtain a calcium alginate - encapsulated lipo vides a transdermal therapeutic system comprising a can somal cannabinoid suspension . This suspension is then nabinoid drug ( s ) in an amount that would provide sub cold -pressed and air -dried to remove the water so as to therapeutic plasma levels if administered orally , but is obtain a dry cannabinoid powder. The dry cannabinoid therapeutically effective when administered via transdermal powder can be re - suspended in citrate buffer to obtain an delivery at the back of the neck . aqueous cannabinoid solution . The amount of cannabinoid [0171 ] A transdermal delivery system for use in accor or cannabinoid analogue in the aqueous cannabinoid solu dance with the present invention can also be constructed tion is greater than 40 % . with an enhancer composition and other ingredients [0168 ] In certain preferred embodiments of the present described hereinabove with respect to the topical formula invention where it is desired that the drug is administered tion . Preferably , the transdermal delivery system is formu chronically , the formulations of the present invention may be lated for the prolonged delivery of the cannabinoid drug (s ). US 2017 /0266128 A1 Sep . 21, 2017 16

The targeted skin flux for delivery of the cannabinoid said polar lipid material are present in a weight ratio of drug ( s ) can be achieved by adjusting vehicle composition solventmaterial : lipid material of from about 60 :40 to about and vehicle loading , as well as by adjusting the surface area 99 : 1 . through which the compositions are administered to skin . [0177 ] In certain embodiments , the dosage form also [0172 ] In certain preferred embodiments , the transdermal comprises a transdermal plaster comprising : ( 1 ) a film layer delivery system ( e . g ., patch ) is formulated to deliver from which comprises a polyester film of 0 . 5 to 4 . 9 microns about 1 mg to about 800 mg of the cannabinoid drug ( s ) per thickness, 8 to 85 g /mm strength , respectively in the two each 24 hours through the skin of the patient, based on directions intersecting substantially at right angles, 30 to cannabidiol (CBD ) , or a therapeutically equivalent amount 150 % elongation , in the two directions intersecting substan of a suitable alternative cannabinoid ( s ) as described herein . tially at right angles and an elongation ratio of A to B of 1 .0 In embodiments in which the transdermal delivery system is to 5 . 0 , wherein A and B represent data in two directions intended to be applied to the skin at the back of the neck for intersecting at right angles , and A is greater than B , and multiple days , the transdermal delivery system ( e . g ., patch ) wherein said polyester film comprises 0 .01 to 1 . 0 % by is formulated to provide a flux rate over the useful life of the weight, based on the total weight of said polyester film , of system such that a similar amount ( e . g ., mean dose ) is solid fine particles in which ( a ) the average particle size is delivered on a daily basis until the system is removed and 0 . 001 to 3 . 0 microns , and ( b ) the average particle size is replaced with a fresh system . substantially not more than 1 . 5 times the thickness of said [0173 ] The transdermal delivery system used in the pres polyester film ; and ( 2 ) an adhesive layer ( a ) which is ent invention may be prepared , for example , in accordance composed of an adhesive containing said serotonin agonist with U . S . Pat. Nos . 5 ,069 , 909 ; 4 , 806 , 341 ; 5 ,026 , 556 ; 4 , 588, and further wherein said adhesive layer ( a ) is laminated on 580 ; 5 ,016 ,652 ; 3 ,598 , 122 ; 4 , 144 ,317 ; 4 , 201, 211 ; 4 ,262 , said film layer over the surface in a 2 to 60 microns 003 ; and 4 ,379 ,454 ; all ofwhich are incorporated herein by thickness . reference . [0178 ] In certain embodiments , the dosage form can be a [0174 ] Additionally , the transdermal delivery system used transdermal disc comprising : ( a ) a backing layer which is in the present invention may be in accordance with U . S . Pat. substantially impervious to the cannabinoid drug ( s) ; and ( b ) No. 6 ,689 , 379 , hereby incorporated by reference , which a polymer matrix disc layer which is adhered to said backing system is a matrix or reservoir system which comprises at layer and which has microdispersed therein said serotonin least one pharmaceutical active agent and a pressure -sensi - agonist, said polymer being bioacceptable and permitting tive adhesive comprising a polyacrylate polymer, wherein said serotonin agonist to be transmitted for transdermal said polyacrylate polymer has a polyacrylate backbone absorption , the cannabinoid drug ( s ) being stable in said containing monomer units selected from the group consist polymer matrix . ing of acrylic acid , methacrylic acid and ester derivatives of [0179 ] In certain embodiments , the topical formulation or acrylic or methacrylic acid , and said monomer units com transdermal therapeutic system may further comprise prise at least 50 % ( w / w ) relative to a mean polymer mass of another active ingredient in combination with the first drug said polyacrylate polymer , a total amount of monomers ( e . g ., as previously described herein ). selected from the group consisting of non - esterified acrylic [0180 ] The present invention is contemplated to encom acid and non - esterified methacrylic acid is 0 . 5 to 10 . 0 % pass all transdermal formulations, e . g . , the technologies ( w / w ) relative to the mean polymer mass of said polyacry described above , with the inclusion of the cannabinoid late polymer, and the carboxyl groups of said non - esterified drug ( s) , such that the administration of a drug useful for acrylic and methacrylic acid monomers are present stoichio treatment of disease state or condition in humans via topical metrically at 5 to 100 % in the form of alkali salts or brainstem afferent stimulation ( de - afferentation ) therapy via alkaline - earth salts , said salts being reaction products of a topical administration . Therefore, modifications of the neutralization reaction of an alcoholic solution of an alkaline invention via , e . g ., the choice and / or amount of drug are hydroxide or an alkaline -earth hydroxide with said acrylate considered to be obvious variations of this disclosure and polymer ( s ) , or of a neutralization reaction of an alkali within the scope of the appended claims. alcoholate or an alkaline - earth alcoholate with said acrylate [0181 ] The present invention also contemplates the polymer( s ) . administration of the cannabinoid drug (s ) directly below the [ 0175 ] In certain embodiments , the dosage form can be a skin to affect direct brainstem afferent stimulation to the free transdermal patch comprising a laminated composite for nerve endings under the epidermis . Such administration may administering the drug ( e . g . , cannabinoid drug ( s ) ) to an be effected as an injection ( e . g . , subcutaneous injection ) or individual transdermally comprising : ( a ) a polymer backing implantation of the drug in immediate release or sustained layer that is substantially impermeable to the cannabinoid release form . It will be appreciated by those skilled in the art drug ( s ) ; and ( b ) a reservoir layer comprising a water - base that providing the drug in sustained release form and admin acrylate pressure - sensitive adhesive , 1 to 12 % by weight istering it in a suitable form below the skin may provide serotonin agonist and 2 to 25 % by weight of a permeation benefits , including less frequent administration ( e. g ., in enhancer comprising propylene glycolmonolaurate in com chronic therapy ) . bination with capric acid or oleic acid , wherein the skin [0182 ] In certain embodiments of the invention , the can contact area of the composite is 10 to 100 cm2. nabinoid drug ( s ) can be formulated for controlled or sus [ 0176 ] The dosage form can be a transdermal patch com tained delivery at the back of the neck via incorporation into prising ( a ) a polar solvent material selected from the group a biocompatible and implantable polymer which can be in consisting of C3 - C4 diols , C3 - C6 triols , and mixtures the form of microparticles or an implantable insert , or a thereof; and ( b ) a polar lipid material selected from the liquid that forms a gel or colloid or a semi- solid after group consisting of fatty alcohol esters, fatty acid esters , and injection ( thereby encapsulating the drug and allowing it to mixtures thereof; wherein said polar solvent material and be released in a prolonged and controlled manner at the US 2017 /0266128 A1 Sep . 21, 2017 17 desired site ) . For chronic conditions ( e . g ., Parkinson ' s ) or must be sterile and it must be stable under the conditions of desired prolonged effect, it is contemplated that a drug depot manufacture and storage . The carrier for injectable formu or reservoir may be created under the skin at the back of the lations is typically water but can also include ethanol, a neck , which then provides a sustained release of the drug in polyol ( for example , glycerol, propylene glycol and liquid proximity to the desired nerve endings and which may be polyethylene glycol) , mixtures thereof, and vegetable oil. replenished or replaced at the end of the dosing interval. It [0186 ] Injectable formulations used in the present inven is contemplated that such administrations of the drug may tion can also be formulated as injectable prolonged release provide a prolonged therapeutic effect for at least about 3 formulations in which the active compound is combined days, preferably at least about 7 days, or longer. Such with one or more natural or synthetic biodegradable or formulations may be administered in certain embodiments biodispersible polymers such as carbohydrates , including as, for example , a subcutaneous depot. starches, gums and etherified or esterified cellulosic deriva [0183 ] Implants are placed subcutaneously by making an tives, polyethers , polyesters, polyvinyl alcohols , gelatins, or incision in the skin and forcing the implants between the alginates . Such dosage formulations can be prepared for skin and the muscle . At the end of their use, if not dissolved , example in the form of microsphere suspensions, gels , or these implants are surgically removed . U . S . Pat . No. 4 ,244 , shaped polymer matrix implants that are well- known in the 949 , hereby incorporated by reference , describes an implant art for their function as “ depot- type ” drug delivery systems which has an outer matrix of an inert plastic such as that provide prolonged release of the biologically active polytetrafluoroethylene resin . Examples of this type of components . Such compositions can be prepared using implantable therapeutic system are Progestasert IUD and art -recognized formulation techniques and designed for any Ocusert system . It is contemplated that such systems can be of a wide variety of drug release profiles . appropriately modified by one skilled in the art for use in f0187 ] One example of a useful formulation which may be conjunction with the present invention . A commercially used in the methods of the present invention for providing a available product , Norplant® , which is an implant having a prolonged duration of action is described in U . S . Pat. No . core containing levonorgestrel as the active substance , and 7 ,332 , 503 (Wikstrom , et al . ), hereby incorporated by refer where the core it surrounded by a membrane of a silicone ence. Therein , apomorphine derivatives and the physiologi elastomer of poly (dimethylsiloxane ) (PDMS ) . Another cally acceptable salts thereof as well as formulations thereof preparation of this kind is Jadelle? , in which the core is a are described which provide a prolonged duration of action . poly (dimethylsiloxane ) based matrix with levonorgestrel The apomorphine pro - drugs can be suspended ( as a neat oil dispersed therein . The membrane is an elastomer made from or as crystals , or dissolved in a suitable and pharmaceuti PDMS and silica filler , which , besides giving necessary cally acceptable solvent ( e . g . water, ethanol, DMSO , i - PrOH strength properties to the membrane, also retards the per or benzylbenzoate ) ) in a pharmaceutically acceptable depot meation of the active agent through the membrane . U . S . Pat. oil (e . g . viscoleo , sesame oil or olive oil ) and injected No. 3 , 854 , 480 , hereby incorporated by reference , describes subcutaneously or intramuscularly with a syringe or a " pen a drug delivery device , e . g . an implant, for releasing a drug injector ” . Alternatively , these drugs may, in a suitable com at a controlled rate for a prolonged period of time. The position and with a suitable vehicle ( penetration enhancer ) , device has a core of a matrix in which the drug is dispersed . be applied to a patch for transdermal administration . The The core is surrounded by a membrane that is insoluble in composition could include also a local anesthetic ( e . g . body fluids. The core matrix as well as the membrane are lidocaine ) to avoid injection pain , in particular at intramus permeable to the drug by diffusion . The materials of the core cular injections . In one embodiment, the composition is in and the membrane are chosen so that the drug diffuses the form of a patch or an ointment for transdermal admin through the membrane at a lesser rate than through the core istration . The patch or ointment preferably also comprises matrix . Thus , the membrane controls the release rate of the stabilizers , solubilizers and permeation activators to facili drug . As a suitable polymer for the core matrix is mentioned tate the passage of the active principle through the skin . In poly (dimethylsiloxane ) (PDMS ) , and as suitable polymers another preferred embodiment, the composition is in the for the membrane are mentioned polyethylene and a copo form of a depot preparation for subcutaneous or intramus lymer of ethylene and vinyl acetate (EVA ) . It is contem cular administration comprising the cannabinoid drug ( s ) plated that the above systemsmay be adapted by one skilled dissolved or suspended in an oil . In certain embodiments , in in the art to deliver the cannabinoid drug (s ) in accordance addition to the apomorphine derivative, the formulation with the present invention . further contains a local anesthetic . The formulations [0184 ) One device which may be adapted by one skilled in described in the ' 503 patent can be modified as understood the art for use in the present invention is described in U . S . by one skilled in the art to contain other active drugs as Pat . No . 5, 968 ,542 ( Tipton ) , hereby incorporated by refer described herein for use at the back of the neck region . ence , which describes a high viscosity liquid controlled [0188 ] An injectable depot formulation is a dosage form , delivery system as a medical or surgical device is provided which is generally intended to have a therapeutic activity for that includes : ( i ) a non -polymeric , non -water soluble liquid 2 to 4 weeks after administration ( e . g . in sesame oil ) . In carrier material (HVLCM ) of viscosity of at least 5 , 000 Cp order to maintain effective drug plasma levels the dosage at 37° C . that does not crystallize neat under ambient or form should release the drug at a more or less constant rate physiological conditions ; and , optionally , ( ii ) a substance to during the desired dosing interval. The difference between be delivered . such prior art depots and depots used in the present invention [ 0185 ] The pharmaceutical compositions suitable for is that the in accordance with the present invention , the drug injectable use in accordance with this invention include is not needed to be absorbed into the systemic circulation . sterile aqueous solutions or dispersions and sterile powders [0189 ] A suitable form of depot preparation is the subcu or lyopholysates for the extemporaneous preparation of taneous or intramuscular administration of an oil solution sterile injectable solutions or dispersions . The dosage forms and /or oil suspension of a lipophilic drug . This gives a slow US 2017 /0266128 A1 Sep . 21, 2017 transport over the oil- biofluid interface and a slow dissolu tially intact throughout the release period . The delivery tion in the biophase . Thus , when the drug is dissolved in a device is a two - phase system that is manufactured using polar solvent ( e . g . oils ) , which is non -miscible with the standard techniques such as blending , mixing or the equiva aqueous biological fluids, the drug has to be transported over lent thereof, following selection of the biologically active the oil /water interface . When the oil/ water partition coeffi material to be delivered and an appropriate polymer for cient is high , the transport will be slow . For very lipophilic formation of the matrix . The general method of solvent drugs , the release from the oil phase may last for up to casting as disclosed by Siegel and Langer , “ Controlled several weeks. The use of depot preparations such as those release of polypeptides and other macromolecules ” , Phar described herein may be used to deliver the drugs described maceutical Research 1 , 2 - 10 ( 1984 ) , is modified so that drug herein at the back of the neck region . is dispersed within the devices to create channels and pores [0190 ] The maximum volume of an oil solution/ suspen to the surface for release of the drug at the desired rate . sion to be injected intramuscularly or subcutaneously is 2 -4 Where appropriate , a coating impermeable to the drug is Ml. This is feasible for the preparations of the cannabinoid placed over a portion of the drug containing polymer matrix drug formulations of the present invention . For example , the to further regulate the rate of release . One skilled in the art cannabinoid drug (s ) may be dissolved or dispersed in 1 M1 can adapt that drug delivery system for delivering the drugs of an oil ( sesame oil , Viscoleo or another approved oil ) and contemplated herein at the back of the neck region . the mixture gently heated (max 50° C . ) shaken in a test tube [0193 ] Yet another formulation which may used to deliver shaker and ultrasonicated for a short time (minutes ) until the the drug as set forth in the present invention at the back of mixture becomes a homogeneous solution or suspension . If the neck region is described in U . S . Pat . No . 7 , 314 ,636 necessary, the cannabinoid drug ( s ) may first be dissolved in (Caseres et al. ) , hereby incorporated by reference , which 50 -300 ul DMSO , water, t - BuOH , PEG , benzylbenzoate , or describes injectable implants comprising glycolic acid and another suitable and approved solvent or mixtures thereof , bio - compatible /bio - absorbable polymeric particles contain before adding the oil to a total volume of 1 Ml. ing a polymer of lactic acid . The particles are small enough [0191 ] Another example of a polymeric drug delivery to be injected through a needle but large enough to avoid system which may be adapted for use in the present inven engulfment by macrophages. The injectables of this inven tion by one skilled in the art is described in U . S . Pat. No. tion may be in a pre - activated solid form or an activated 5 ,601 , 835 ( Sabel, et al. ) , hereby incorporated by reference , form ( e . g . , injectable suspension or emulsion ) . which describes a polymeric drug delivery system for deliv ery of any substance to the central nervous system . The [0194 ] It is further contemplated that the system described delivery system is preferably implanted in the central ner in U .S . Pat . No . 6 ,586 ,006 (Roser , et al. ), hereby incorpo vous system for delivery of the drug directly to the central rated by reference , can be adapted by one skilled in the art nervous system . These implantable devices can be used , for for use in the present invention for delivery of drugs at the example , to achieve continuous delivery of dopamine , which back of the neck region . Therein are described delivery cannot pass the blood brain barrier, directly into the brain for systems suitable for delivery of bioactive materials to sub an extended time period . The implantable devices display cutaneous and intradermal, intramuscular, intravenous tis controlled , " zero -order ” release kinetics, a life time of a sue , the delivery system being sized and shaped for pen minimum of several weeks or months even when the devices etrating the epidermis . The delivery systems comprise a contain water soluble , low molecular weight compounds , vitreous vehicle loaded with the guest substance and capable biocompatibility, and relative non - invasiveness . The poly of releasing the guest substance in situ at various controlled meric devices are said to be applicable in the treatment of a rates . Subdermal implantable therapeutic systems have also variety of central nervous system disorders including Par been formulated for slow release of certain pharmaceutical kinson ' s disease , Alzheimer' s dementia , Huntington ' s dis agents for extended periods of time such as months or years . ease , epilepsy , trauma , stroke, depression and other types of A well -known example is Norplant® for delivery of steroid neurological and psychiatric illnesses, and one skilled in the hormones . art can adapt that drug delivery system for delivering the f01951 In membrane permeation - type controlled drug drugs contemplated herein at the back of the neck region . delivery, the drug is encapsulated within a compartment that [0192 ] Yet another example of a system that may be is enclosed by a rate - limiting polymeric membrane. The adapted for use in the present invention is described in U . S . drug reservoir may contain either drug particles or a disper Pat. No . 5 , 601, 835 ( Sabel, et al. ), hereby incorporated by sion ( or solution ) of solid drug in a liquid or a matrix type reference , wherein an active compound is encapsulated dispersing medium . The polymeric membrane may be fab within a polymer to form a polymeric device , the device ricated from a homogeneous or a heterogeneous nonporous formed of a biocompatible polymer that is plastically polymeric material or a microporous or semipermeable deformable selected from the group consisting of ethylene membrane . The encapsulation of the drug reservoir inside vinyl acetate , polyurethanes , polystyrenes , polyamide, poly the polymeric membrane may be accomplished by molding, acrylamide, and combinations thereof having a non - porous encapsulation , microencapsulation , or other techniques. The polymer coating thereon with one or more openings , with implants release drugs by dissolution of the drug in the inner limited water sorptivity and slight permeability to the pas core and slow diffusion across the outer matrix . The drug sage of small , aqueous -soluble molecules, wherein said release from this type of implantable therapeutic system compound is linearly released ( e . g ., zero order release ) from should be relatively constant and is largely dependent on the said polymeric device over a sustained period of time of at dissolution rate of the drug in the polymeric membrane or least 65 days at a predetermined level and rate when the diffusion rate across or a microporous or semipermeable implanted in a patient at a specific site within the central membrane . The inner core may substantially dissolve over nervous system where the compound is released directly into time; however, in devices currently in use , the outer matrix the central nervous system and the device remains essen does not dissolve . US 2017 /0266128 A1 Sep . 21, 2017 19

[0196 ] Other implantable therapeutic systems involve extending along the length of the needle from a first end of matrix diffusion - type controlled drug delivery. The drug the needle to a second end of the needle . The second end is reservoir is formed by the homogeneous dispersion of drug substantially aligned to a plane parallel to a body surface of particles throughout a lipophilic or hydrophilic polymer a biological body when the device is placed on the body matrix . The dispersion of drug particles in the polymer surface . The device also includes an actuator which pumps matrix may be accomplished by blending the drug with a the formulation through the bore of the needle between a viscous liquid polymer or a semisolid polymer at room target area of the body and the reservoir . temperature , followed by cross - linking of the polymer , or by [0201 ] In yet other embodiments of the invention , the mixing the drug particles with a melted polymer at an cannabinoid drug ( s ) is infused into the patient at the back of elevated temperature . It can also be fabricated by dissolving the neck using technology known to be useful for infusing the drug particles and /or the polymer in an organic solvent other drugs , such as an insulin pump . One such system , U . S . followed by mixing and evaporation of the solvent in a mold Pat. No . 7 ,354 ,420 (Steil , et al. ) , hereby incorporated by at an elevated temperature or under vacuum . The rate of drug reference , describes a closed loop infusion system controls release from this type of delivery device is not constant. the rate that fluid is infused into the body of a user. The Examples of this type of implantable therapeutic system are closed loop infusion system includes a sensor system , a the contraceptive vaginal ring and Compudose implant. controller, and a delivery system . The sensor system PCT /GB 90 / 00497 describes slow release glassy systems for includes a sensor formonitoring a condition of the user. The formation of implantable devices. The described implants sensor produces a sensor signal, which is representative of are bioabsorbable and need not be surgically removed . One the condition of the user. The sensor signal is used to skilled in the art can adapt these drug delivery systems for generate a controller input. The controller uses the controller delivering the drugs contemplated herein at the back of the input to generate commands to operate the delivery system . neck region . The delivery system infuses a liquid into the user at a rate [ 01971 In microreservoir dissolution - controlled drug dictated by the commands from the controller. Preferably, delivery , the drug reservoir , which is a suspension of drug the sensor system monitors the glucose concentration in the particles in an aqueous solution of a water -miscible polymer , body of the user, and the liquid infused by the delivery forms a homogeneous dispersion of a multitude of discrete , system into the body of the user includes insulin . unleachable , microscopic drug reservoirs in a polymer [0202 ] The present invention is contemplated to encom matrix . The microdispersion may be generated by using a pass all implantable or injectable formulations, e .g ., the high - energy -dispersing technique. Release of the drug from technologies described above , with the inclusion of a drug ( s ) this type of drug delivery device follows either an interfacial ( e . g ., cannabinoid drug ( s ) ( s ) ) , such that the administration of partition or a matrix diffusion -controlled process . An a drug useful for treatment of disease state or condition in example of this type of drug delivery device is the Syncro humans via topical brainstem afferent stimulation (de -affer Mate - C Implant. entation ) therapy . Therefore , modifications of the invention [0198 ] Yet another formulation which may be adapted by via , e . g ., the choice and / or amount of drug are considered to one skilled in the art for use in the present invention is be obvious variations of this disclosure and within the scope described in U . S . Pat. No. 6 , 576 , 263 ( Truong , et al. ), hereby of the appended claims. incorporated by reference, which describes a preformed object for delivering an active agent for a subject, the DETAILED DESCRIPTION OF PREFERRED preformed object including cross - linked protein , and meth EMBODIMENTS ods of making and using . [0203 ] The present invention will now be more fully [0199 ] Yet another formulation which may be adapted by described with reference to the accompanying examples . It one skilled in the art for use in the present invention is described in U . S . Pat. No. 6 ,287 ,588 ( Shih , et al. ) , hereby should be understood , however, that the following descrip incorporated by reference , which describes a composition tion is illustrative only and should not be taken in any way and method for releasing a bio - active agent or a drug within as a restriction on the generality of the invention specified a biological environment in a controlled manner. The com above . position is a dual phase polymeric agent -delivery composi tion comprising a continuous biocompatible gel phase, a Example 1 discontinuous particulate phase comprising defined microparticles and an agent to be delivered . A microparticle Topical Formulation containing a bio -active agent is releasably entrained within [0204 ] An aqueous based cannabidiol cream is produced a biocompatible polymeric gel matrix . The bio - active agent using Lipoderm® as the carrier . Lipoderm® /LIP is a com release may be contained in the microparticle phase alone or mercially marketed compounding agent ( from PCCA, Phar in both the microparticles and the gelmatrix . The release of maceutical Compounding Centers of America ) having the the agent is prolonged over a period of time, and the delivery following ingredients: Ethoxydiglycol, Water (Aqua ), Glyc may be modulated and/ or controlled . In addition , a second erin , C12- 15Alkyl Benzoate , Glyceryl Stearate , Dimethicone , agent may be loaded in some of themicroparticles and /or the Cetearyl Alcohol, Cetearyl Glucoside , Polyacrylamide , gel matrix . Cetyl Alcohol , Magnesium Aluminum Silicate , Xanthan [0200 ] Yet another formulation which may be adapted by Gum , Aloe Vera (Aloe Barbadensis ) , Tocopheryl Acetate one skilled in the art for use in the present invention is ( Vitamin E Acetate ), Prunus Amygadalus Amara (Bitter described in U . S . Pat. No . 7 , 364 , 568 ( Angel , et al. ) , hereby Almond ) Kernel Oil , Vitis Vinifera (Grape ) Seed Extract, incorporated by reference, which describes a transdermal Triticum Vulgare (Wheat ) Germ Oil, Retinyl Palmitate (Vi transport device includes a reservoir for holding a formula tamin A Palmitate ) , Ascorbyl Palmitate ( Vitamin C Palmi tion of an active principle , and a needle with a bore tate ), Pro - Lipo Multi -emulsion Liposomic System , Tetraso US 2017 /0266128 A1 Sep . 21, 2017 20 dium EDTA , Phenoxyethanol, and Sodium neck of the human patient once a day, twice a day, three Hydroxymethylglycinate . The concentration is 4 mg of CBD times a day , or four times a day depending on the condition in 1 ml of Lipoderm . Lipoderm is a whitish cream with no to be treated and its severity . smell . The cannabinoid drug ( s ) are incorporated into the Lipoderm cream in the form of a CBD oil product as Example 4 _ CBD Crystalline Powder described herein . [0207 ] A 60 g topical formulation of CBD is prepared utilizing CBD crystalline powder ( 95 % + pure CBD ). The Example 2 CBD is incorporated into the topical formulation of Example [0205 ] A 60 g topical formulation of CBD is prepared by 2 having a CBD concentration between 0 .75 % to about 10 % incorporating 2 . 2 g CBD (CBD - RSHO - Clear 43 . 5 % ) , 20 g CBD . Pluronic 20 % , 40 g Carbomer hydroalcoholic gel and 1 ml Example 5 ethyl alcohol to obtain a CBD topical formulation having a 1 . 6 % concentration of CBD . [0208 ] In Example 5 , a total of 7 dogs suffering from a variety of diseases / conditions were treated with a 30 mg topical cannabidiol (CBD ) formulation administered on the Example 3 — Oil- Based CBD back of the neck and spine on each of these dogs . Table 1 [0206 ] A 30 g topical formulation of CBD is prepared by reports the subject demographics and condition /disease state incorporating CBD oil, Dimethyl sulfoxide 3 ml and enough of each dog , as well as the subject response to treatment . base for total quantity of 30 grams. The CBD is incorporated Three of the dogs suffered from chronic back and hind leg in a concentration sufficient to yield an end product having problems of several months duration with weakness of legs , a CBD concentration of 0 . 75 % , 1 % , 1 . 5 % , 2 % and 3 % . The bowel & bladder control issues . Two of the dogs suffered topical formulation is in the form of a cream . The oil- based from acute back problems with pain , inactivity & poor CBD includes CBD oil commercially available from Can appetite . One dog suffered from a pituitary tumor, Cush na Vest. A unit dose of the topical CBD cream is from about ing ' s , lethargy, inactivity and poor appetite . One dog suf 0 . 5 to about 1 g , with respect to formulations having a CBD fered from a head injury and chronic encephalopathy, which concentration from 1 . 5 % - 3 % . After initial application , the manifested as a personality change, agitation , aggressive topical CBD formulation can be applied to the back of the behavior.

1 . “ RUBY " : After several doses of topical CBD to the back 14 y /o dachshund -retriever mix of neck , became alert , active , started to eat and with pituitary brain tumor and drink . Subsequently , able to take medication for Cushing 's with days of lethargy , Cushing ' s and now doing well after a year . CBD inactivity, poor appetite . no longer required . 2 . " COCOA ” : 2 weeks after injury, on Dec. 17 , 2015 , 5 y / o miniature dachshund , had received first treatment of topical CBD to back back injury Nov . 28 , 2015 , crying of neck and lower back . Showed improvement with every move and acted as if within few minutes: more alert, active , and paralyzed . Had problems looking up walking around wagging tail. Was able to lift and unable to sleep . Taken to vet as head and kiss owner for first time. Continued emergency and told was slipped with 2x /day CBD for additional 5 days and disc ; given Tramadol and told to normalized . Owner states now even more be crated to prevent further injury . energetic than before . Continued in pain with poor appetite and constipation . 3 . “ RASCAL " : Observations by vet and owners : 7 y / o pug with several months 10 - 15 minutes after topical CBD to back of progressive episodic weakness of neck and lower back , walking improved and left hips and legs , with left leg kicking leg no longer kicking out, showed better control out and causing balance problems of hips. 2 days later, was lifting leg to urinate , and waddling gait . Squats like a which it had not done in some time. 5 days after female to urinate and with bowel initial treatment , began to show some urgency. No longer jumps up . recurrence of prior problems and started on daily CBD therapy . 4 . “ ROBIN ” : After treatment with CBD to back of neck and 7 y / o male litter mate of “ Rascal” lower back , was standing with toes spread out but with worse symptoms: entire normally, walked without hind legs giving way. hind section giving out Now also lifting his leg to urinate . Chronic intermittently and using front legs daily CBD therapy started 5 days later after to get up . Leaks urine with several day period of continued benefit after occasional bowel incontinence and one treatment. squats . Stands with toes curled under pads . 5 . “ DORA ” : Several minutes after application of topical 12 y / o female pug with 2 years of CBD to neck and back , becamemore active and lower back problems with hip and was walking with improved control of hips and hind legs weakness and bowel legs. Will be using 3x /day . control problems. Over past 6 months, worsening symptomswith giveaway of legs , altered gait. Several courses of steroids with minimal temporary benefit. US 2017 /0266128 A1 Sep . 21, 2017

- continued 6 . “ SISSY ” . Several minutes after application of topical 6 y / o female chihuahua at age 1 CBD to neck , dog mellowed , uninterested in had head injury and developed other dogs coming near her , and quietly rested ; personality change with agitation , which lasted several hours . aggressive behavior, jealous of other dogs coming near whoever is holding her. 7 . “ RILEY " : Sometime after topical CBD to the lower back , 11 y/ o male German Shepard mix began moving around , ate and drank ; became with acute onset pain , immobility , more active. Within 12 hours , was back to and lethargy . normal and did not require additional doses.

CONCLUSION lipo multi -emulsion liposomic system , tetrasodium EDTA , [ 0209 ] The examples provided above are not meant to be phenoxyethanol, and sodium hydroxymethylglycinate . exclusive . Many other variations of the present invention 15 . The method of claim 8 , wherein cannabidiol is CBD would be obvious to those skilled in the art , and are oil. contemplated to be within the scope of the appended claims. 16 . The method of claim 8 wherein cannabidiol is a [0210 ] The hypotheses of the inventor provided through purified crystalline CBD . out the specification are for possible explanation purposes 17 . The method of claim 4 , wherein the topical pharma only , and are not meant to be limiting in any way . ceutical formulation comprises liposomes . 1. A method of treating a disease state or condition in a mammal other than a human with a cannabinoid drug ( s ) 18 . The method of claim 4 , wherein the unit dose com comprising administering a cannabinoid drug ( s ) in a thera prises from about 3 mg to about 100 mg cannabidiol. peutically effective amount to treat the disease state or 19 . The method of claim 1, further comprising formulat condition topically on the area of skin on one or more skin ing the cannabinoid drug ( s ) in a pharmaceutically acceptable regions in an area extending from behind ) one ear to the topical aqueous - based carrier, and applying a sufficient other ear of the mammal and from the back of the head to amount to the back of the neck region of the mammal such below the neck to provide regional neuro - affective therapy. that the onset of a therapeutic effect occurs in less than about 2 . (canceled ) 30 minutes . 3 . ( canceled ) 20 . The method of claim 7 , wherein the cannabinoid drug 4 . The method of claim 1 , wherein the cannabinoid mixture concentrate includes from about 0 to about 3 % drug ( s ) is administered in a topical pharmaceutical formu tetrahydrocannabinol, from about 0 to about 1 % tetrahydro lation in a unit dose containing a therapeutically effective cannabinolic acid , from about 20 to about 50 % cannabidiol, amount of the cannabinoid drug ( s ) which penetrates the skin from about to about 1 % cannabidiolic acid , and from about to act at free nerve endings under the skin . 0 to about 1 % cannabinol, for a total active cannabinoid 5 . The method of claim 4 , wherein the cannabinoid level from about 20 % to about 50 % . drug ( s ) is administered in a topical mousse formulation . 21. The method of claim 20 , wherein the cannabinoid 6 . The method of claim 1 , wherein the mammal is a drug ( s ) in the topical pharmaceutical formulation are at a canine . concentration from about 0 .75 % to about 5 % , by weight. 7 . The method of claim 1 , wherein the cannabinoid drug ( s ) comprise a mixture of pharmaceutically acceptable 22 . The method of claim 4 , wherein the unit dose of the cannabinoids, such that the mixture provides substantially cannabinoid drug ( s ) includes from about 1 mg to about 200 no psychoactive effect or no psychoactive effect. mg cannabinoid drug ( s ) and the cannabinoid drug ( s ) com 8 . The method of claim 1 , wherein the cannabinoid prise at least 80 % cannabidiol. drug ( s ) comprises at least about 80 % cannabidiol. 23. The method of claim 1 , wherein the disease state or condition is selected from the group consisting of lameness 9 . ( canceled ) and gait issues ; elbow dysplasia ; hip dysplasia ; back and 10 . The method of claim 5 , wherein the cannabinoid hind leg problems, arthritis ; seizures; encephalopathy leth drug ( s ) in the pharmaceutical formulation comprises at least argy ; focus/ attentional problems; cognitive issues : spastic about 80 % cannabidiol. ity ; epilepsy ; cancer ; weakness; pain ; numbness ; anxiety and 11 . ( canceled ) other mood disorders; hypertension ; tremors ; peripheral 12 . ( canceled ) neuropathy ; bowel and bladder control issues; inactivity ; 13 . ( canceled ) poor appetite; tumors; Cushing ' s disease ; aggressive behav 14 . The method of claim 10 , wherein the pharmaceuti ior ; pruritis ; dermatitis ; vomiting ; lethargy ; dystonia ; and cally acceptable carrier comprises ethoxydiglycol, water personality change . ( aqua ) , glycerin , C12 - 15 alkyl benzoate , glyceryl stearate , dimethicone , cetearyl alcohol, cetearyl glucoside, polyacry 24 . The method of claim 4 , wherein the cannabinoid lamide , cetyl alcohol, magnesium aluminum silicate , xan drug ( s) is further administered onto an area of skin along the than gum , aloe vera ( aloe barbadensis ), tocopheryl acetate spine of the mammal. ( vitamin E acetate ), prunus amygadalus amara ( bitter 25 . The method of claim 1 , wherein the disease state or almond ) kernel oil, vitis vinifera ( grape ) seed extract, triti condition is selected from the group consisting of lameness cum vulgare (wheat ) germ oil, retinyl palmitate ( vitamin A and gait issues; elbow dysplasia ; hip dysplasia ; back and palmitate ), ascorbyl palmitate (vitamin C palmitate ), pro hind leg problems; lethargy ; cancer ; weakness ; pain ; numb US 2017 /0266128 A1 Sep . 21, 2017 ness ; anxiety and other mood disorders ; bowel and bladder control issues ; inactivity ; poor appetite ; lethargy ; dystonia ; and personality change. * * * * *