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PCT/US2020/0393 12 (22) International Filing Da ( (51) International Patent Classification: A61K 31/55 (2006.01) (21) International Application Number: PCT/US2020/0393 12 (22) International Filing Date: 24 June 2020 (24.06.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/865,5 14 24 June 2019 (24.06.2019) US (71) Applicant: CAAMTECH LLC [US/US]; 58 E . Sunset Way, Suite 208, Issaquah, WA 98027 (US). (72) Inventor: CHADEAYNE, Andrew, R.; 13200 Squak Mt. Road S.E., Issaquah, WA 98027 (US). (74) Agent: LINDEMAN, Jeffrey, A.; J.A.lindeman & Co., PLLC, 3190 Fairview Park Drive, Suite 1070, Falls Church, VA 22042 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) (54) Title: IBOGAINE FORMULATIONS (57) Abstract: Disclosed herein are new compositions and methods comprising a combination of active ingredients that includes at least one ibogaine derivative. Several selected examples of non-naturally occurring ibogaine derivative formulations are also disclosed. The ibogaine derivatives are combined into formulations via human ingenuity to arrive at compositions and formulations that are not found in nature. These formulations have different physical properties from those found in nature and also provide different pharmacological properties. In many cases, the below disclosed combinations provide different clinical effects when administered to a subject. The disclosed compositions are useful in many contexts, including treating addictions, such as alcohol, nicotine, and opiate addictions. IBOGAINE FORMULATIONS Cross-Reference to Related Application This application claims priority to U.S. Application No. 62/865,514, filed June 24, 2019, which is incorporated herein by reference. Technical Field This disclosure relates to non-natural forms of natural medicines, in particular new formulations of ibogaine derivatives. Background Addiction affects millions of people worldwide. The abuse of legal and illegal drugs, tobacco, and alcohol take their toll on individuals, families, communities, and society. The addiction problem extends to dysfunctional behaviors involving gambling, food, sex, exercise, shopping, etc. According to the Addiction Center, in 2011 there were 20.6 million people in the United States over the age of 12 with an addiction (excluding tobacco). 1 Mental health conditions often accompany addiction. 2 This is often seen with substance abuse disorders and gambling addictions. Almost half of the substance abusers in the United States have mental disorders. 3 Psychology Today says addiction is "a condition in which a person engages in the use of a substance or in a behavior for which the rewarding effects provide a compelling incentive to repeatedly pursue the behavior despite detrimental consequences." Addictive substances and behaviors share the neurological feature of activating the reward and reinforcement pathways in the brain. These pathways often use the neurotransmitter dopamine. There are an estimated 38 million adult smokers in the United States.4 This is about 15.5% of the population. The World Health Organization (WHO) estimates there are 1.1 billion people worldwide who smoke.5 In addition, tobacco is considered the leading cause of death, illness, and impoverishment in the world. The WHO reports more than 7 million people worldwide die from tobacco-related illnesses each year. According to the National Institute on Drug Abuse, opioid overdoses account for more than 130 deaths every day in the United States.6 In 2017, over 47,000 Americans died of an opiate overdose. Using data from 2007-2013, the National Institute on Drug Abuse estimated that tobacco, illicit drugs, and alcohol combined to cost the United States over $740 billion annually. 7 These costs are related to lost work productivity, crime, and healthcare expenses. The costs continue to skyrocket. The estimated cost of America's drug epidemic alone in 2017 exceeded $1.0 trillion. 8 Historically, addiction was often thought of as a pleasure-seeking activity undertaken by people with a weak personal constitution and insufficient self-control. However, the current concept of addiction is changing based on scientific findings. It is now understood that a main driver of addictive behaviors is t o escape physical and/or emotional discomfort. 9 This is called self-medication. It is interesting t o note that the term addiction did not appear in the diagnostic manual of the American Psychiatric Association (Diagnostic and Statistical Manual of Mental Disorders, the DSM) until the recent 5t h edition update. Addiction experts now recognize that substance abuse disorders and non-substance abuse disorders have a lot in common. They have grouped them into the Syndrome Model of Addiction This model suggests there is one addiction which is associated with multiple expressions. The scientific basis of this model includes imaging data that shows the brain responds similarly t o different pleasurable experiences whether ingesting alcohol, shopping, sex, or gambling. In addition, studies have shown that some people are genetically predisposed t o addiction but not t o a specific type of addiction. Overall, it appears the object of a person's addiction (a substance or behavior) is less important than experts originally thought. Ibogaine (CAS 83-74-9) is a psychedelic tryptamine alkaloid first isolated in 1901 from the root bark of the Tabernanthe iboga shrub (also called iboga) of Central Africa 10 and the root bark of a shrub in the genus Tabernaemontana found in the Congo. 11 Since that time, ibogaine has been isolated from several plant species particularly those in the family Apocynaceae t o which T. iboga belongs. The crystalline structure of ibogaine was determined in I960. 12 It was first synthesized in 1966. 13 Ibogaine has two separate chiral centers and four stereoisomers but they are difficult t o resolve. 14 Plants containing ibogaine as well as extracts and preparations made from them include many other active and inactive molecules including several different ibogaine derivatives. Historically, iboga plants have been used for centuries in the religious rituals of people living the western part of Central Africa in countries such as the Republic of the Congo, Gabon, and Cameroon. 15 The ceremonial cocktails contained a mixture of the naturally-occurring molecules found in the plant. Harrison G. Pope of the Harvard Botanical Museum theorized in 1969 that humans learned about the effects of iboga by watching the behavior of animals. 16 First-hand accounts describe native animals like porcupines, boars, and gorillas digging up and eating iboga roots. After ingesting the roots they would enter " a wild frenzy." These indigenous people also use less potent versions of ibogaine cocktails t o treat fatigue, hunger, and thirst. In the 1930s, French pharmacists developed ibogaine as a drug which was sold as a stimulant under the trade name Lambarene. 17 Here, ibogaine was taken in its pure form without all the other active molecules and modulators of those molecules that are present in the plant. The drug was taken off the market in the 1960s when France declared ibogaine illegal. Howard Lotsof was the first person to realize the potential of ibogaine t o treat substance addictions. 18 He was a heroin addict when he tried ibogaine in 1962 with several of his friends who were also addicts. They were surprised to find it caused marked reductions in their cravings and withdrawal symptoms. All of them quit using heroin as a result. Lotsof went on t o become a scientist and dedicated his life to studying ibogaine for treating addiction. Ibogaine exhibits relatively low potency at target sites. Studies in rats suggest high doses may cause adverse effects. In minor treatment, high doses of 5.0 mg/kg body weight are used and up t o 30 mg/kg body weight for intense poly-substance addiction management. In 1988, Dzoljic et al. were the first to publish on the ability of ibogaine to relieve withdrawal from narcotics addiction. 19 Maisonneuve et al. elucidated the pharmacological interactions between ibogaine and morphine in 1991. After this, several other researchers showed ibogaine's ability to reduce or interrupt the self-administration of opiates in rats and mice and alter their behaviors. 21-25 Additional study results showed ibogaine was more effective in multiple administrations over time than from a single dose. 21,22 Recent review papers and meta-analyses have concluded that ibogaine is effective for treating substance addiction and warrants further investigation. 26-28 Several current studies have found ibogaine effective for treating opioid addiction. 29-32 There is also experimental evidence indicating that ibogaine and ibogaine derivatives help in relieving depressive symptoms.
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