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Home , Dipropanoylmorphine, Methyldesorphine

HI HAN AT USUN 20180110730A1AMI A HATA MAI A ME THE ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0110730 A1 CHANGOER et al. ( 43 ) Pub . Date: Apr . 26 , 2018

(54 ) CHEWING GUM COMPOSITION A61K 47 / 38 (2006 .01 ) COMPRISING CANNABINOIDS AND A61K 4736 ( 2006 .01 ) AGONISTS AND /OR ANTAGONISTS A61K 47 / 26 ( 2006 .01 ) A61K 47 / 12 (2006 .01 ) (71 ) Applicant: AXIM Biotechnologies, Inc ., New A61K 47/ 02 ( 2006 . 01 ) York , NY (US ) A61K 31/ 352 (2006 . 01) (52 ) U .S . CI. ( 72 ) Inventors : Lekhram CHANGOER , Ridderkerk CPC ...... A61K 9 /0058 (2013 . 01 ) ; A61K 31 /05 (NL ) ; George E . ANASTASSOV , New (2013 . 01 ) ; A61K 31/ 485 ( 2013 .01 ) ; A61K York , NY (US ) 4738 (2013 .01 ) ; A61K 31 / 352 ( 2013 .01 ) ; A61K 47 /26 ( 2013 .01 ) ; A61K 47 /12 (2013 .01 ) ; (21 ) Appl. No. : 15 /787 ,498 A61K 47/ 02 (2013 . 01 ); A61K 47/ 36 (2013 . 01 ) (22 ) Filed : Oct. 18 , 2017 ( 57 ) ABSTRACT Related U . S . Application Data A chewing gum composition comprising cannabinoids or derivatives thereof and at least one opioid and optionally an (60 ) Provisional application No . 62/ 410 , 469, filed on Oct. opioid antagonist is provided . The chewing gum composi 20 , 2016 . tion is formulated to provide controlled release of cannabi noids and opioid agonists and /or opioid antagonist during Publication Classification mastication . Methods to provide opioid addiction or depen (51 ) Int. Cl. dence treatment, opioid addiction or dependence with con A61K 9 / 68 ( 2006 .01 ) current cannabis addiction or dependence treatment, or A6IK 31/ 05 ( 2006 .01 ) treatment using the chewing gum composition according to A61K 31/ 485 ( 2006 .01 ) this invention are also provided . US 2018 /0110730 A1 Apr. 26 , 2018

CHEWING GUM COMPOSITION [0010 ] Opioid replacement therapy is not without adverse COMPRISING CANNABINOIDS AND OPIOID effect. used long term may lead to potentially AGONISTS AND /OR ANTAGONISTS deadly slowed breathing . The effect in methadone ends long before the methadone half life , thus more metha CROSS -REFERENCE TO RELATED done is needed , causing a built up of methadone . APPLICATIONS [0011 ] The cannabis plant has many naturally occurring 0001] This application claims priority to U . S . Provisional substances that are of great interest in the fields of science Application No. 62 /410 , 469, filed Oct . 20 , 2016 , the content and medicine. Isolated compounds from the cannabis plant of which is hereby incorporated by reference in its entirety . include 19 - ( THC ) , (CBD ), cannabichromene (CBC ), cannabigerol (CBG ), can BACKGROUND OF THE INVENTION nabidivarin (CBDV ) , among other compounds . While THC has psychoactive effects , CBD , CBC , CBG , and CBDV do Field of the Invention not. Isolated compounds from the cannabis plant are called cannabinoids . There are a total of one hundred and forty one [ 0002 ] Opioid addiction treatment and cannabis depen ( 141) cannabinoids that have been isolated from the canna dence treatment are developing areas with many proposed bis plant. Many researchers have confirmed the medicinal techniques and remedies. This invention involves a chewing value of cannabinoids . Cannabinoids have been investigated gum composition with controlled release of cannabinoids for possible treatment of seizures , nausea , vomiting, lack of and opioid agonists and / or antagonists for opioid and can appetite , pain , arthritis , inflammation , and other conditions. nabis addiction and / or dependence treatment. This chewing [0012 ] The IUPAC nomenclature of THC is (- ) -( 6aR , gum may also be used for treatment of chronic pain . 10aR ) - 6 , 6 ,9 - trimethyl -3 - pentyl -6a , 7 , 8 , 10a -tetrahydro -6H benzo [ c ] chromen - 1 -ol . CBD ' s IUPAC nomenclature is Description of the Related Technology 2 - ( 1S , 65 ) - 3 -methyl - 6 - (prop - 1 - en - 2 - yl) cyclo - hex - 2 - enyl) 10003 ] are a group of analgesic agents commonly 5 -pentylbenzene - 1 , 3 -diol ) . CBC has the IUPAC nomencla used in clinical practice but are also commonly seen as ture of 2 -methyl - 2 - (4 -methylpent - 3 - enyl) -7pentyl - 5 -chrom addictive agents . Opioids bind to opioid receptors , which are enol. These are among the most prominent compounds in the found in the central and peripheral nervous system and the family of compounds extracted from the cannabis plant gastrointestinal tract. These receptors mediate both psycho referred to as cannabinoids. active and the somatic effects of opioids. [0013 ] Cannabinoidsmay be isolated by extraction or cold 10004 ) Opioids agonists include , , the pressing of cannabis plants . Plants in the cannabis genus baine , , , , oxymor include Cannabis sativa , Cannabis ruderalis , and Cannabis phone, , , methadone , , lev indica . These plants are the natural sources of cannabinoids. orphanol, , and . Cannabinoids are also available in synthetic forms. Methods [0005 ] Opioids cause and thus are used illicitly . to synthesize cannabinoids in lab settings were discovered In 2011 , an estimated of 4 million people in the United and are still currently practiced . Synthetic cannabinoids are States used opioids recreationally and were dependent on more targeted , in that the synthetic compound usually comes them . Opioid dependency may start with prescription use of isolated without other cannabinoids mixed in . opioid which turns into illicit drug use . 100141 Cannabinoids from industrial hemp are marketed [0006 ] Physical dependence is the physiological adapta in the United States, such as cannabidiol. Various products tion of the body to the presence of a substance , in this case containing cannabinoids have been marketed in recent years . an opioid . It is the development of withdrawal symptoms Cannabinoids may be consumed by ingestion , by inhalation , when the substance is discontinued . Withdrawal symptoms via transmucosal, or by transdermal delivery . of may include severe dysphoria , craving , irritability , [0015 ] Cannabis dependence is mainly due to 19 - THC sweating , nausea , tremor, vomiting, and myalgia . presence in cannabis . When a mammal consumes cannabis , [ 0007 ] The speed and severity of withdrawal symptoms A - THC gives the “ high ” feeling . Cannabis addiction in the occurrence depend on half - life of the opioid . and form of smoking cannabis also gives rise to lung cancer risk morphine withdrawal occur more quickly and are more similar to tobacco smoking . severe than methadone withdrawal. The acute withdrawal [0016 ] Opioid addiction treatment remains a challenge . phase is often followed by a protracted phase of depression This invention proposes a product to treat opioid addiction and insomnia that can last for months . standing alone or concurrent opioid and A9- THC addiction / [0008 ] Addiction is marked by a change in behavior dependence . caused by the biochemical changes in the brain after con tinued substance abuse. Substance use becomes the main ABBREVIATIONS CBC : cannabichromene CBD : priority of the addict , regardless of the harm they may cause cannabidiol CBDV : cannabidivarin CBG : to themselves or others . An addiction causes people to act cannabigerol 19- THC : delta - 9 - tetrahydrocannabinol irrationally when they don 't have the substance they are addicted to in their system . Addiction encompasses both mental and physical reliance on the substance . SUMMARY [ 0009 ] Opioid addiction therapy depends on a variety of [ 0017 ] The present invention relates to a chewing gum techniques. Among them is replacement therapy , wherein an composition comprising cannabinoids or derivatives thereof opioid is replaced with another less addictive opioid , which and at least one opioid agonist and / or antagonist . Cannabi curbs the craving feeling and reduces withdrawal symptoms, noids or derivatives thereof and opioid agonists and /or while maintains the subject ' s mental state such that the antagonists are under controlled release during mastication subject is still able to function normally . and consumption . This invention further relates to the use of US 2018 /0110730 A1 Apr. 26 , 2018 this chewing gum composition in treating opioid addiction opioid is an opioid antagonist selected from the group or dependence , concurrent cannabis and opioid addiction consisting ofNaloxone hydrochloride dehydrate and natrex and / or dependence , or pain . one hydrochloride. [0018 ] This invention provides a chewing composition [0036 ] This invention provides a chewing gum composi comprising, based on total weight of the composition : tion according to embodiments wherein the at least one 100191 0 . 1 to 5 % by weight of at least one cannabinoid ; opioid comprises both opioid agonist and opioid antagonist . [0020 ] 0 .01 to 1 % by weight of at least one opioid ; [ 0037 ] This invention provides a chewing gum composi [ 0021] 20 to 95 % by weight of a gum base ; tion according to embodiments wherein the at least one [0022 ] 5 to 35 % by weight of at least one buffering agent opioid is provided in nanoencapsulated or microencapsu selected from the group consisting of acetates , glycinates , lated form . phosphates, carbonates, glycerophosphates, citrates, and [0038 ] This invention provides a chewing gum composi borates ; tion according to embodiments wherein the preservative is [0023 ] 1 to 10 % by weight of at least one flavoring agent citric acid . selected from the group consisting of peppermint, spearmint, [0039 ] The invention provides a chewing gum composi licorice , cinnamon , watermelon , vanilla , pineapple, apple , tion according to embodiments which may further comprise and cranberry ; at least one pharmaceutically acceptable excipient selected [0024 ] 1 to 65 % by weight of at least one sweetening agent from the group consisting of fillers , disintegrants , binders , selected from the group consisting of isomalt , sorbitol, and lubricants . stevia , maltitol , and xylitol; [0040 ] This invention provides a chewing gum composi 100251 at least one anti -oxidant selected from the group tion according to embodiments which may further comprise consisting of ascorbyl palminate and sodium ascorbate ; and silicon dioxide or magnesium stearate . [ 0026 ] at least one preservative . [0041 ] This invention provides a method to treat opioid [0027 ] This invention provides a chewing gum composi addiction in a mammal in need thereof, comprising admin tion according to embodiments wherein the at least one istering to themammal a chewing gum composition accord cannabinoid is cannabidiol , Aº- tetrahydrocannabinol, can ing to this invention . nabichromene , cannabigerol, cannabidivarin , derivatives [0042 ]. This invention provides a method to treat opioid thereof, or their acid metabolites . addiction or dependence in a mammal in need thereof, [0028 ] This invention provides a chewing gum composi comprising administering to the mammal a chewing gum tion according to embodiments wherein the at least one composition according to this invention , wherein the mam cannabinoid is provided in combination with at least one mal receives the chewing gum administration 1 to 6 times a suitable carrier selected from the group consisting of sugar day . alcohol, microcrystalline cellulose derivatives , dextran , aga [0043 ] This invention provides a method to treat opioid rose , agar, pectin , alginate , Xanthan , chitosan , and starch . addiction or dependence concurrent with cannabis addiction [0029 ] This invention provides a chewing gum composi or dependence in a mammal in need thereof, comprising tion according to embodiments wherein the at least one administering to the mammal a chewing gum composition cannabinoid is provided in microencapsulated form , nano according to this invention . encapsulated form , or in freeze dried form . [ 0044 ] This invention provides a method to treat opioid [ 0030 ] This invention provides a chewing gum composi addiction concurrent with cannabis dependence in a mam tion according to embodiments wherein the at least one mal in need thereof, comprising administering to the mam cannabinoid is provided in internal voids within a suitable mal a chewing gum composition according to this invention , solid carrier. [ 0031 ] This invention provides a chewing gum composi wherein the mammal receives the chewing gum administra tion according to embodiments wherein the at least one tion 1 to 6 times a day . cannabinoid is provided in a granule within the gum matrix . [0045 ]. This invention provides a method to treat pain in a [0032 ] This invention provides a chewing gum composi mammal in need thereof, comprising administering to the tion according to embodiments wherein the at least one mammal a chewing gum composition according to this cannabinoid is procured from natural sources , such as deriv invention . ing or extracting from cannabis plants , or synthetic . [0033 ] This invention provides a chewing gum composi DETAILED DESCRIPTION OF CERTAIN tion according to embodiments wherein the at least one INVENTIVE EMBODIMENTS opioid is an opioid agonist selected from the group consist [0046 ] Embodiments of this application relate to a chew ing of morphine, codeine , , hydrocodone , hydro ing gum composition comprising cannabinoids and opioid morphone, oxycodone , , buprenorphine , fen agonists and / or antagonists , wherein cannabinoids and opi tanyl, methadone , pethidine , , tramadol, and oid agonists and / or antagonists are incorporated into the dextropropoxyphene . chewing gum for controlled release . The chewing gum [ 0034 ] This invention provides a chewing gum composi composition may be consumed by a human for cessation of tion according to embodiments wherein the at least one opioid and / or cannabis dependence and / or addiction . opioid is an opioid prodrug selected from the group con [0047 ] In embodiments , the chewing composition may sisting of 6 -monoacetyl morphine , , dipro comprise 0 . 1 - 5 % by weight of at least one cannabinoid or panoylmorphine , , methyldesorphine , acetyl derivatives thereof based on total weight of the composition . propionyl morphine, dibenzoyl morphine, and diacetyl In a 2 g chewing gum piece , cannabinoids or derivatives . thereof may comprise 2 - 100 mg. Cannabinoids in the chew [ 0035 ] This invention provides a chewing gum composi ing gum composition according to embodiments may be tion according to embodiments wherein the at least one synthetic or procured from natural source . US 2018 /0110730 A1 Apr. 26 , 2018

[ 0048 ] Cannabinoids may also be in oily form , as cannabis or buprenorphine. Buprenorphine, in particular , is both an oil , hemp oil , or hashish oil . In these embodiments , can opioid agonist and antagonist , and thus its effect in opioid nabinoids may be provided in a carrier to prevent absorption addiction in treatment is both as a replacement opioid and an into the gum matrix . It is contemplated that cannabinoids antagonist of opioids. Synthetic opioids may also be used , provided in oily form may be used in the embodiments such as fentanyl , methadone , pethidine, levorphanol , trama described herein . dol, or dextropropoxyphene . Prodrugs of the above opioids ( 0049 ) Cannabinoids may be provided in a solid material may also be used , such as 6 - monoacetyl morphine , nico carrier composed of an edible solid , such as a sugar alcohol, morphine (morphine dinicotinate ) , dipropanoylmorphine and cannabinoids, to prevent binding with the gum base . (morphine dipropionate ) , desomorphine (di - hydro - desoxy Cannabinoids may be embedded into the sugar alcohol. morphine ), methyldesorphine , acetylpropionyl morphine , Other solids suitable for embedding cannabinoids are con dibenzoyl morphine , or diacetyl dihydromorphine . templated , such that cannabinoids are provided within inter [0057 ] Opioid antagonists such as hydrochlo nal voids of solid materials . Alternatively , cannabinoids or ride dehydrate (C19H21N04 ) and hydrochloride derivatives thereof may be provided in a granule embedded (C20H23N04 ) may also be included in the chewing gum into the gum matrix . Cannabinoids provided in these man composition according to embodiments in addition to opioid ners may improve cannabinoid release during mastication of agonists . Where opioid antagonists are included , opioid the chewing gum according to embodiments . antagonists may be at 3 : 1 to 5 : 1 , more specifically 4 : 1 ratio [0050 ] Cannabinoids may also be provided in microen by weight for opioid agonist :opioid antagonist. capsulated or nanoencapsulated form or in freeze dried form . [ 0058 ] Certain opioids may reduce craving sensation Microencapsulated or nanoencapsulated and freeze dried while minimizing adverse effects on users. In opioid addic cannabinoids may improve the chewing gum ' s taste , tion treatments , withdrawal symptoms may be the main improve stability , prevent binding with the gum matrix , obstacle to recovery . When opioid agonists are provided , control cannabinoid release during mastication , and further they may bind to opioid receptors , reducing the adverse improve bioavailability of the cannabinoids once entering effect of opioid withdrawal. Moreover , opioids consumed by the gastrointestinal tract. injection , such as heroin injection , may pose additional risks 10051 ] In embodiments , cannabinoids provided in encap to users . By providing replacement opioids in a controlled sulated form may be particles of size 20 - 40 nm , which may release chewing gum , replacement opioidsmay curb craving improve bioavailability profiles of cannabinoids and prevent sensation while reducing adverse withdrawal symptoms and degradation in gastric fluid . Encapsulation may result in preventing adverse effects caused by injection . On the other liposomal particles containing cannabinoids and derivatives hand , adding an opioid antagonist may counteract the effects thereof. of the agonists , for example the addictive opioid such as [0052 ] In these embodiments , cannabinoidsmay be 19 - tet heroin , and thus eventually reduce opioid addiction . rahydrocannabinol ( THC ) , cannabichromene (CBC ) , can nabigerol (CBG ) , cannabidivarin (CBDV ) , cannabidiol [0059 ] Cannabinoids , on the other hand , may also curb (CBD ) , other cannabinoids , derivatives thereof, their acid craving sensation . Finally , by providing replacement opioids metabolites , or a combination of cannabinoids and / or their such as opioid agonists and / or antagonists and cannabinoids acid metabolites and /or derivatives thereof. Cannabinoids in a chewing gum form , users may avoid adverse effects described herein may be natural or synthetic cannabinoids . caused by injection and /or smoking . [0053 ] Other suitable carriers which may be combined [0060 ] In embodiments , opioids provided may be micro with cannabinoids before inclusion into the gum matrix may encapsulated or nanoencapsulated . Encapsulation may include certain celluloses, such as microcrystalline cellulose improve the chewing gum ' s taste as a whole . Encapsulation derivatives , dextran , agarose , agar , pectin , alginate , Xanthan , may aid with dissolution in the subject ' s oral cavity and chitosan , or starch . The combination of cannabinoids and transmucosal delivery mechanism . Encapsulation may also suitable carriers may result in cannabinoid being present enable controlled release of opioids during chewing of the within internal voids of these carriers . chewing gum composition . Encapsulation may improve [0054 ] Providing cannabinoids by combining with a suit opioids' bioavailability profile upon mastication of the able carrier or by providing cannabinoids in a capsule within chewing gum composition . the gum matrix may enable controlled release of cannabi [0061 ] Methods to encapsulate opioids may be methods noids during chewing of the chewing gum composition . commonly used in the art , such as precision particle encap Providing cannabinoids in microencapsulated , nanoencap sulation . A method to encapsulate active ingredients in sulated , or freeze dried form may also enable controlled described in Berkland , C . , M . King , et al. ( 2002 ) . “ Precise release of cannabinoids during chewing of the chewing gum control of PLG microsphere size provides enhanced control composition . of drug release rate . ” J Control Release 82 ( 1 ) : 137 - 147 . This [0055 ] In embodiments , the chewing gum composition reference is hereby included in its entirety . may further comprise at least one opioid to act as opioid [ 0062 ] Gum base provided for the chewing gun composi agonist and /or antagonist. Opioids may be present in the tion according to these embodiments may be non -disinte chewing gum composition at 0 .01 - 1 % by weight based on grating . Gum base such as Gum powder PG 11 TA , Gum the total weight composition . In a 2 g chewing gum piece , powder PG 11 TA New , Gum powder PG 5 TA , Gum powder opioid may comprise 0 .2 - 20 mg. PG 5 TA New , and Gum powder PG N12 TA may be used . [ 0056 ] Opioids in the chewing gum composition accord Gum base may comprise 20 - 95 % by weight of the compo ing to embodiments may be opioid agonists . Opioid agonists sition . may be derived from plant, such as morphine , codeine, or [0063 ] In embodiments , at least one buffering agent may thebaine . Semi- synthetic opioids may be used , such as be included in this chewing gum composition . Suitable hydrocodone , hydromorphone , oxycodone , oxymorphone , buffering agents may include acetates, glycinates , phos US 2018 /0110730 A1 Apr. 26 , 2018 phates, carbonates, glycerophosphates , citrates, borates , [ 0072 ] The chewing gum composition according to and /or mixtures thereof. Buffering agents may be present at embodiments may be used in treatment of cannabis depen 5 - 35 % by weight. dence , in particular A -tetrahydrocannabinol dependence , [ 0064 ] In embodiments , the chewing gum composition concurrent with opioid addiction . Cannabis dependence , in may have other ingredients to improve organoleptic prop particular 19 - THC dependence, concurrent with opioid erties . The chewing gum composition according to embodi addiction may be treated or alleviated by consumption of ments may include at least one flavoring agent and at least chewing gums according to embodiments. A mammal, such one sweetening agent. as a human being , may chew the chewing gum composition [0065 ] Ingredients such as certain flavoring agents may be according to embodiments 1 - 6 times a day to aid opioid included . Flavoring agents may include peppermint, spear and /or A? - THC craving sensation while curbing this craving . mint, licorice , cinnamon , watermelon , vanilla , pineapple , [0073 ]. The chewing gum composition according to apple , cranberry , and /or other suitable flavoring agents . embodiments may be used in treatment of pain and / or Certain food colorants may be included to improve the chronic pain . A mammal , such as a human being , may chew aesthetic appearance of the chewing gum composition . Fla the chewing gum composition according to embodiments as voring agents may be present in this chewing composition at need for treatment of pain . A mammal, such as a human 1 - 10 % by weight. being ,may chew the chewing gum composition according to [0066 ] Sweetening agents may be present at 1 -65 % of by embodiments 1 - 6 times a day to treat and / or alleviate pain . weight of the composition according to embodiments . Sweetening agents used in chewing gums according to EXAMPLES embodiments may be isomalt, sorbitol , stevia , maltitol, xylitol, or other suitable sweetening agents , and /or combi Example 1 nations thereof. [ 0074 ] Chewing Gum Composition Preparation [ 0067 ] In embodiments , the chewing gum composition may comprise ingredients for preservation such as citric [0075 ] Chewing gum compositions having 10 mg of CBD acid . Additional ingredient to assist with powder flow and and 1 mg of buprenorphine are prepared by cold pressing . prevent the gum base from sticking to manufacturing sur Percentages are given in weight percentage . faces may be included . Such ingredient may be silicon dioxide or magnesium stearate . Other ingredients for pres TABLE 1 ervation and manufacturing management may also be used . Phase Raw material Percentage ( % ) [0068 ] Additional pharmaceutically acceptable excipients A1 Isomalt 28 . 89 used in the chewing gum composition according to embodi A2 CBD (microencapsulated ) 0 . 50 ments may be fillers , disintegrants , binders , or lubricants . A3 Cellulose 0 . 50 Anti -oxidants such as ascorbyl palminate and sodium ascor A4 Buprenorphine (microencapsulated ) 0 . 04 bate may also be included . The chewing gum composition A5 Naltrexone hydrochloride (microencapsulated ) 0 . 01 B1 Gum base 24 . 50 according to embodiments may comprise at least one phar B2 Sorbitol 10 . 00 maceutically acceptable excipient and /or at least one anti B3 Maltitol 10 . 00 oxidant. B4 Citric acid 0 . 50 B5 Magnesium stearate 2 . 00 [ 0069] The chewing gum composition according to Silicon dioxide 0 . 40 embodiments may be made by a compressing process or by va Xylitol 13 . 60 a hot process . In the compressing process , ingredients are mmmB8 Stevia 1 . 05 B9 Vanilla 4 .00 mixed and compressed into the gum base using a compress B10 Spearmint /peppermint 4 .00 machine . In the hot process , ingredients are mixed and B11 Colorants FD & C blue 0 .01 heated before the gum base is poured in . The gum mixture is then molded and left to cure . Total 100 .00 [0070 ] The gum mixture may then be cut into appropriate size for consumption , such as 2 grams for each piece . The [0076 ] Step 1 : Make a blend of A2 , A3 , A4 , and A5 into gum pieces may be coated with a polyol coating such as A1 to form Phase 1 . sorbitol, maltitol, isomalt , or starch . The coating layer may prevent moisture from penetrating into the gum matrix . The [0077 ] Step 2 : Mix B1- B11 in a separate vessel to form gum pieces may be wrapped in separate pieces of wrapping Phase 2 . materials and packaged into a pack or box , or packaged into [0078 ] Step 3 : Use a double layer chewing gum machine a blister package . to compress Phase 1 and Phase 2 together. [0071 ] The chewing gum composition according to [0079 ] Chewing gum composition may be cut into 2 gram embodiments may be used for opioid dependence and /or pieces as appropriate . Chewing gum compositions with a addiction treatment. Opioid dependence and/ or addiction mass at about 2 grams and containing 10 mg of CBD and 1 may be treated or alleviated by consumption of chewing mg of buprenorphine were prepared . gums according to embodiments . Cannabinoids and opioid agonists and / antagonists in these chewing gums may be Example 2 released in a controlled manner and absorbed by a subject via transmucosal delivery mechanism . A mammal, such as a [0080 ] Chewing Gum Composition Preparation human being , may chew the chewing gum composition [0081 ] Chewing gum compositions having 10 mg of according to embodiments 1 - 6 times a day to aid with opioid Aº - THC and 1 mg of buprenorphine are prepared . Percent craving sensation whiling curbing this craving . ages are given in weight percentage . US 2018 /0110730 A1 Apr. 26 , 2018

TABLE 2 2 grams and containing 10 mg of CBD , 0 . 8 mg of thebaine ( semi- synthetic ), and 0 . 2 mg of Naloxone hydrochloride Phase Raw material Percentage ( % ) were prepared . A1 Gum base 75 .00 10094 ) Variations and modifications will occur to those of A2 Xylitol 14 .00 skill in the art after reviewing this disclosure. The disclosed A3 Glycerine 4 .50 features may be implemented , in any combination and B1 Sacharrine 0 . 40 B2 Water 1 . 50 sub -combination ( including multiple dependent combina B3 Buprenorphine (microencapsulated ) 0 . 05 tions and sub - combinations ) , with one or more other fea B4 Citric acid 0 . 50 tures described herein . The various features described or O Peppermint aroma oil 1 .50 illustrated above, including any components thereof, may be Vanilla /cranberry flavor 1 .50 combined or integrated in other systems. Moreover , certain A9 - THC (microencapsulated ) 0 . 50 features may be omitted or not implements . Cellulose 0 . 50 [0095 ] Examples of changes, substitutions, and alterations Total 100. 00 are ascertainable by one skilled in the art and could be made without departing from the scope of the information dis closed herein . All references cited are hereby incorporated [ 0082 ] Step 1 : Heat the gum base (Al ) to 90° C ., then add by reference herein in their entireties and made part of this A2- A5 to form Phase 1 . application . [0083 ] Step 2 : Dissolve B1 and B4 in B2 to form Phase 2 . What is claimed is : 10084 ) Step 3 : Heat the peppermint oil (C1 ) to 60 - 70° C ., 1 . A chewing gum composition comprising , based on total then add C2 and B3 to form Phase 3 . weight of the composition : [0085 ] Step 4 : Add Phase 2 to Phase 1 , stir vigorously and 0 .1 to 5 % by weight of at least one cannabinoid ; add Phase 3 , stir for 7 minutes . 0 . 01 to 1 % by weight of at least one opioid ; [0086 ] Step 5 : Pour the gum mixture out and prepare 20 to 95 % by weight of a gum base ; chewing gum tablets by molding as need . 5 to 35 % by weightof at least one buffering agent selected [0087 ] Chewing gum composition may be cut into 2 gram from the group consisting of acetates, glycinates , phos pieces as appropriate . Chewing gums with a mass at about phates, carbonates, glycerophosphates, citrates, and 2 grams and containing 10 mg of Aº - THC and 1 mg of borates ; buprenorphine were prepared . 1 to 10 % by weight of at least one flavoring agent selected from the group consisting of peppermint, spearmint , Example 3 licorice , cinnamon , watermelon , vanilla , pineapple , apple , and cranberry ; [0088 ] Chewing Gum Composition Preparation to 65 % by weight of at least one sweetening agent [ 0089 ] Chewing gums having 10 mg of CBD , 0 . 8 mg of selected from the group consisting of isomalt , sorbitol, thebaine, and 0 . 2 mg of Naloxone hydrochloride are pre stevia , maltitol, and xylitol; pared . Percentages are given in weight percentage . at least one anti -oxidant selected from the group consist ing of ascorbyl palminate and sodium ascorbate ; and TABLE 3 at least one preservative . Phase Raw material Percentage ( % ) 2 . The chewing gum composition of claim 1 , wherein the at least one cannabinoid is cannabidiol, Aº - tetrahydrocan A1 Isomalt 28 . 89 A2 CBD (microencapsulated ) 0 . 50 nabinol, cannabichromene, cannabigerol, cannabidivarin , A3 Cellulose 0 . 50 derivatives thereof, or their acid metabolites . A4 Thebaine (microencapsulated ) 0 .04 3 . The chewing gum composition of claim 1 , wherein the A5 Naloxone hydrochloride (microencapsulated ) 0 .01 at least one cannabinoid is provided in combination with at B1 Gum base 24 .50 B2 Sorbitol 10 .00 least one suitable carrier selected from the group consisting B3 Maltitol 10 . 00 of sugar alcohol, microcrystalline cellulose derivatives , dex B4 Citric acid 0 . 50 tran , agarose , agar, pectin , alginate , Xanthan , chitosan , and B5 Magnesium stearate 2 . 00 starch . B6 Silicon dioxide 0 . 40 B7 Xylitol 13 . 60 4 . The chewing gum composition of claim 1 , wherein the B8 Stevia 1 . 05 at least one cannabinoid is provided in microencapsulated B9 Licorice 4 . 00 form , nanoencapsulated form , or in freeze dried form . B10 Spearmint 4 . 00 5 . The chewing gum composition of claim 1 , wherein the B11 Colorants FD & C blue 0 . 01 at least one cannabinoid is provided in internal voids within Total 100 .00 a suitable solid carrier . 6 . The chewing gum composition of claim 1 , wherein the at least one cannabinoid is provided in a granule within the [0090 ] Step 1: Make a blend of A2 , A3, A4 , and A5 into gum matrix . A1 to form Phase 1 . 7 . The chewing gum composition of claim 1 , wherein the [ 0091 ] Step 2 : Mix B1- B11 in a separate vessel to form at least one cannabinoid is procured from natural sources or Phase 2 . synthetic . [0092 ] Step 3 : Use a double layer chewing gum machine 8 . The chewing gum composition of claim 1 , wherein the to compress Phase 1 and Phase 2 together . at least one opioid is an opioid agonist selected from the 10093] Chewing gum composition may be cut into 2 gram group consisting of morphine , codeine , thebaine , hydroco pieces as appropriate. Chewing gums with a mass at about done , hydromorphone, oxycodone, oxymorphone, buprenor US 2018 /0110730 A1 Apr . 26 , 2018 phine, fentanyl, methadone, pethidine , levorphanol, trama 14 . The chewing gum composition of claim 1 , further dol, and dextropropoxyphene. comprising at least one pharmaceutically acceptable excipi 9 . The chewing gum composition of claim 1 , wherein the ent selected from the group consisting of fillers , disinte at least one opioid is an opioid prodrug selected from the grants, binders , and lubricants. group consisting of 6 -monoacetyl morphine , nicomorphine , 15 . The chewing gum composition of claim 14 , further comprising silicon dioxide or magnesium stearate . dipropanoylmorphine, desomorphine, methyldesorphine , 16 . A method to treat opioid addiction or dependence in , dibenzoylmorphine , and diacetyl a mammal in need thereof, comprising administering to the dihydromorphine. mammal the chewing gum composition of claim 1 . 10 . The chewing gum composition of claim 1 ,wherein the 17 . The method of claim 16 , wherein the mammal at least one opioid is an opioid antagonist selected from the receives the chewing gum administration 1 to 6 times a day . group consisting of Naloxone hydrochloride dehydrate and 18 . A method to treat opioid addiction or dependence natrexone hydrochloride . concurrent with cannabis addiction or dependence in a 11. The chewing gum composition of claim 1 , wherein the mammal in need thereof, comprising administering to the at least one opioid comprises both opioid agonist and opioid mammal the chewing gum composition of claim 1 . antagonist . 19 . The method of claim 18 , wherein the mammal 12 . The chewing gum composition of claim 1 , wherein the receives the chewing gum administration 1 to 6 times a day . at least one opioid is provided in nanoencapsulated or 20 . A method to treat pain in a mammal in need thereof, microencapsulated form . comprising administering to the mammal the chewing gum 13 . The chewing gum composition of claim 1, wherein the composition of claim 1 . preservative is citric acid . * * * * *