Treatment of chronic pain or gastrointestinal disorders using buprenorphine dimers

Abstract

This disclosure provides a method for treating a disease in a subject requiring treatment, such as chronic pain or IBS-D, the method of treating the disease by orally administering i) a therapeutically effective amount of buprenorphine dimer, or ii) a pharmaceutical composition comprising a therapeutically effective amount of buprenorphine dimer, wherein the buprenorphine dimer is represented by formula (I) or a pharmaceutically acceptable salt thereof. In particular, the administered buprenorphine dimer of formula (I) is in a neutral form. A method for producing a neutral form of buprenorphine dimer is also described.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 568,538, filed on 22 March 2024, and U.S. Provisional Application No. 63 / 512,783, filed on 10 July 2023, each of which is incorporated herein by reference in its entirety for all purposes.

[0002] Statement regarding the rights to inventions made based on research and development supported by the federal government. Not applicable

[0003] References to “sequence listings,” tables, or appendices to computer program listings submitted on compact discs. Not applicable [Background technology]

[0004] Buprenorphine Buprenorphine is a semi-synthetic μ-agonist / κ-antagonist mixed opioid receptor modulator used for the treatment of high-dose opioid dependence, the suppression of moderate acute pain in individuals without opioid tolerance at low doses, and the suppression of moderate chronic pain at low doses. Its structural formula is as follows: [ka]

[0005] Buprenorphine is currently available for pain treatment in intravenous, sublingual, and transdermal formulations. It is also used to treat opioid dependence. However, due to extensive presystemic extraction, buprenorphine has very low bioavailability when administered orally. Therefore, sublingual administration is necessary to obtain clinically effective systemic plasma concentrations. Even with sublingual administration, only about 30% of buprenorphine becomes available for systemic circulation.

[0006] chronic pain Chronic pain can be broadly divided into two categories: "nociceptive" pain (caused by inflammation or damaged tissue, which activates special pain sensors called nociceptors) and "neuropathic" pain (caused by damage or dysfunction of the nervous system). Neuropathic pain is further classified into "peripheral" pain, which originates in the peripheral nervous system, and "central" pain, which originates in the brain or spinal cord.

[0007] Peripheral neuropathic pain is a very common chronic condition in clinical practice. Many underlying causes are possible for peripheral neuropathic pain, including diabetes, alcoholism, vitamin deficiencies, trauma, toxic reactions to prescription drugs, infections, and malignancies.

[0008] Several mechanisms are involved in the onset and progression of neuropathic pain, and these differ significantly from the mechanisms that cause nociceptive pain. Nerve damage can result in several pathological changes, including impulse generation within the damaged nerve fiber, interactions between nerve fibers, dysfunction of normal nerve fiber inhibitory mechanisms, plasticity (degeneration and regeneration of damaged nerves), and changes in nerve fibers that lead to changes in conduction.

[0009] Pain associated with peripheral neuropathy can be severe and differs from most pain patients have experienced before, characterized by allodynia (painful reactions to stimuli that do not normally cause pain), hyperalgesia, and, in some cases, loss of sensation. The pain is often described as "burning, stabbing, tingling, or nauseating." It can be persistent or paroxysmal, and may or may not be accompanied by sensory disturbances. The type and severity of pain or loss of sensation depend on the underlying cause of the neuropathy. In chronic neuropathic pain, symptoms begin gradually and progress slowly. Some people may experience temporary relief followed by relapses. Others may reach a plateau where symptoms remain the same for months or even years. Many chronic neuropathys worsen over time. In the vast majority of neuropathic pain patients, the pain lasts a lifetime. Comorbidities such as depression, poor quality of life, employment problems, and family problems are extremely common.

[0010] Over 100 types of peripheral neuropathy have been identified, each with its own symptoms and prognosis. Generally, peripheral neuropathy is classified according to the type of nerve damage. Some types of neuropathy involve damage to only one nerve and are called mononeuropathy. However, more commonly, multiple nerves are affected, and these are called polyneuropathy.

[0011] Many different medications with various mechanisms of action are used to treat neuropathic pain, including the opioids oxycodone and tramadol (Ultram®). Neither has achieved complete success and is associated with serious adverse events. A common adverse event of opioid analgesics is sedation, which is related to the central nervous system effects of these drugs. In many patients, especially the elderly, treatment with opioid analgesics can lead to functional impairment and motor problems, which may increase the risk of hip fractures. All patients who chronically use opioid analgesics develop physical dependence and require close medical care if medication is discontinued for any reason.

[0012] Buprenorphine, an opioid μ-receptor agonist and a complete opioid delta- and kappa-receptor antagonist, has been extensively studied in patients with neuropathic pain. As an analgesic, buprenorphine is approximately 30 times more potent than morphine. Buprenorphine has been shown to possess not only analgesic effects but also significant anti-hyperalgesic properties. Hyperalgesia is a component of neuropathic pain. A major drawback of prescribing buprenorphine for this purpose is that, as an opioid μ-receptor agonist, it is highly addictive and unsuitable for safe long-term use.

[0013] Peripheral neuropathic pain is inherently localized, affecting one or more areas of the body, and the dose required to treat local symptoms with intravenous administration appears to make it impossible to use buprenorphine itself for this purpose. It is true that buprenorphine has been previously prescribed as a long-acting depot for subcutaneous injection in the treatment of opioid dependence (see U.S. Patents 8,921,387 and 8,975,270). However, buprenorphine depot formulations for the treatment of peripheral neuropathic pain appear to present an incompatible option between the need for a dose sufficient to treat local pain and concerns about drug access to the central nervous system and its serious consequences.

[0014] Therefore, there has long been a need for a treatment for peripheral neuropathic pain that has similar analgesic properties to buprenorphine but without the side effects expected to result from opioid use for this purpose.

[0015] As disclosed in U.S. Patent No. 9,321,780, the buprenorphine dimer is a homodimer containing two buprenorphine moieties conjugated to each other by O-alkylation via a phenol group. This dimer has been shown to retain the receptor affinity and pharmacological properties of the parent compound, buprenorphine. It maintains strong binding affinities for the mu (μ), delta (δ), and kappa (κ) receptors. The molecular weight of this dimer is approximately 961.32 daltons, which prevents it from being absorbed and entering the central nervous system. As described in U.S. Patent No. 9,549,924, the buprenorphine dimer can be used for the treatment of peripheral neuropathic pain, but patients need to receive the buprenorphine dimer by parenteral administration.

[0016] In view of the above, there is a need to develop an effective oral non-opioid agent for treating neuropathic pain that has no side effects expected to be associated with the use of opioids (such as buprenorphine). The present disclosure meets this need.

[0017] Diarrhea-predominant irritable bowel syndrome Diarrhea-predominant irritable bowel syndrome (IBS-D) is a very common gastrointestinal disorder that often involves diarrhea, as well as visceral and somatic hyperalgesia (enhanced pain due to colonic-rectal and somatic stimuli), discomfort, a feeling of fullness, and gas.

[0018] According to the International Foundation for Functional Gastrointestinal Disorders, it is estimated that IBS-D affects 25 million to 45 million Americans. It is the most common diagnosis by gastroenterologists and one of the most frequently treated diseases by primary care physicians.

[0019] Irritable bowel syndrome has a very significant impact on the quality of life and also results in high social costs. The symptoms of this disease tend to fluctuate but have a tendency to become chronic or subchronic. There is no evidence that the presence of IBS leads to a deterioration of the patient's average life expectancy, but it significantly reduces the health-related quality of life and work productivity. In more severe cases, patients experience abdominal pain and diarrhea several times a day, which may lead to serious impairments in interpersonal relationships and the workplace.

[0020] Serum C4 (7α-hydroxy-4-cholesten-3-one) is an inflammatory marker used to distinguish patients with IBS-D from those with inflammatory bowel disease (IBD) and bile acid diarrhea (BAD). Serum C4 levels generally do not increase in patients with IBS-D and are often less than 48 ng / ml in patients with IBS-D, because the symptoms are not due to inflammatory injury or bile acid malabsorption. Since the causes of abdominal pain and diarrhea in IBS-D are unknown, it is difficult to develop or discover treatment methods or pharmacological interventions based on the mechanism of action for IBS-D.

[0021] Treatment of IBS-D Most existing treatment methods control IBS-D by inducing constipation through full mu-agonist drugs. Bile acid binders, amitriptyline, probiotics, mast cell stabilizers, and 5-ASA have been used outside the indication in the treatment of IBS-D, despite the lack of convincing evidence regarding chronic effectiveness. The antidiarrheal loperamide, a synthetic opioid, has also been used, but due to its unblocked full mu-opioid agonist activity, it often causes severe constipation.

[0022] LX1033, a serotonin synthesis inhibitor in the gastrointestinal tract currently under development by Lexicon Pharmaceuticals, is one of the drugs under development for the treatment of IBS-D. However, its mechanism of action does not support pain relief. The neurokinin antagonist DNK-333 (Novartis) was withdrawn from IBS-D trials after Phase 2 due to lack of efficacy. Another neurokinin antagonist, ivodutant (Menarini), did not show efficacy compared to placebo in the overall population in Phase 2 trials, and an additional trial is underway with only women as subjects. Rifaximin (Salix Pharmaceuticals) showed moderate activity in IBS-D trials, but there are serious concerns about the development of antibiotic resistance and sustained efficacy.

[0023] Latronex (Alosetron, Prometheus Laboratories, Inc.) is the only medication approved in the United States for the treatment of IBS-D, with studies conducted exclusively on women. Its analgesic effect has not been demonstrated. Importantly, this drug comes with a black-bordered warning regarding serious side effects, particularly ischemic colitis.

[0024] To date, no medication has been approved in the United States as an unrestricted treatment for chronic IBS-D.

[0025] Eluxadoline (Forest Laboratories, Inc.) is a μ-opioid receptor agonist and δ-opioid receptor antagonist that achieved the primary endpoints of improved stool consistency and reduced abdominal pain in a Phase III trial. Its analgesic effect was at best moderate, and no clear effect was observed in reducing colonic hyperirritation leading to hyperalgesia. Furthermore, several cases of pancreatitis, a potentially life-threatening disease, were reported in the Phase II trial. Cases of pancreatitis were reported even after patients with a history of biliary tract disease were excluded from enrollment in the clinical trial. Generally, μ-agonists work by constricting the sphincter of Oddi, a muscular valve that regulates the flow of bile and pancreatic juice from the bile duct to the duodenum. Buprenorphine has partial μ-agonist and κ-antagonist effects and therefore does not cause increased tension or contraction of the sphincter of Oddi. We predict that buprenorphine dimers, which have the same receptor pharmacological activity as buprenorphine, will not exhibit a contractile effect on the sphincter of Oddi.

[0026] Therefore, there has long been a need for a chronic treatment for IBS-D that reduces intestinal motility, thereby lowering the incidence of diarrhea, has analgesic effects, does not cause pancreatitis, and has the potential to address not only the symptoms but also the underlying hypersensitivity and associated hyperalgesia associated with IBS-D. Summary of Disclosure

[0027] In one embodiment, the present disclosure provides a method for treating a disease in a human subject requiring treatment, the method comprising the subject with formula (I): [ka] The treatment involves orally administering a therapeutically effective dose of buprenorphine dimer or a pharmaceutically acceptable salt thereof, wherein the total daily dose of the therapeutically effective dose of buprenorphine dimer is at least about 100 mg / day on an unsalted and anhydrous basis, and the administration results in a plasma concentration of at least about 700 ng / mL in the subject.

[0028] In another embodiment, the present disclosure provides a method for treating chronic pain in a subject requiring treatment, wherein the method involves the subject receiving formula (I): [ka] This involves administering a therapeutically effective dose of a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the buprenorphine dimer is administered orally.

[0029] In some embodiments, the buprenorphine dimer is a neutral form represented by formula (I).

[0030] In another embodiment, the present disclosure provides a method for treating chronic pain in a subject requiring treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a neutral form of buprenorphine dimer represented by formula (I), wherein the pharmaceutical composition is administered orally.

[0031] In another embodiment, the present disclosure provides a method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, wherein the subject is given a therapeutically effective dose of formula (I): [ka] The method includes administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has undergone cholecystectomy. In some embodiments, the subject's blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) is 50 milligrams / deciliter (mg / dL) or less.

[0032] In some embodiments, the buprenorphine dimer is a neutral form represented by formula (I).

[0033] In another embodiment, the present disclosure provides a method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, the method comprising administering to the subject a therapeutically effective dose of a pharmaceutical composition comprising a neutral form of buprenorphine dimer represented by formula (I), wherein the subject's blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) is 50 milligrams / deciliter (mg / dL) or less.

[0034] In another embodiment, the present disclosure provides a method for producing the neutral form of buprenorphine dimer of formula (I). This method comprises the following steps: a) Formula: [ka] Buprenorphine or a salt thereof, represented by , a first inorganic base, water, and a first phase transfer agent are mixed in 1,2-dichloroethane to form formula (II): [ka] The process of forming the compound, and b) A step of mixing the compound of formula (II), buprenorphine or a salt thereof, a second inorganic base, water, and a second phase transfer agent in an aprotic solvent to obtain a neutral form of buprenorphine dimer of formula (I).

[0035] In another embodiment, the present disclosure provides a method for preparing a neutral form of buprenorphine dimer represented by formula (I), the method comprising the following steps: a) Formula: [ka] The buprenorphine HCl salt represented by , an aqueous solution of NaOH, and tetrabutylammonium hydroxide are mixed in 1,2-dichloroethane to obtain formula (II): [ka] The process of forming the compound; and b) A step of mixing the compound of formula (II), buprenorphine HCl salt, an aqueous solution of NaOH, and tetrabutylammonium hydroxide in toluene to obtain the neutral form of buprenorphine dimer of formula (I).

[0036] In yet another embodiment, this disclosure includes formula (II): [ka] The present invention provides a compound represented by or a salt thereof. [Brief explanation of the drawing]

[0037] [Figure 1] Figure 1 shows the experimental design for spinal nerve ligation-induced neuropathic pain in rats (Chung model) as described in Example 1.

[0038] [Figure 2] Figure 2 shows the results for mechanical allodynia on day 1 / 14 of the experiment in Example 1.

[0039] [Figure 3] Figure 3 shows the results for mechanical allodynia on day 2 / 22 of the experiment in Example 1.

[0040] [Figure 4] Figure 4 shows the results for mechanical allodynia on day 3 / 38 of the experiment in Example 1.

[0041] [Figure 5] Figures 5A and 5B show the anti-algesic hypersensitivity response in normal and sensitized mice after a single oral administration of buprenorphine dimer in Example 2. Figure 5A: Normal mouse, Figure 5B: Sensitized mouse.

[0042] [Figure 6]Figure 6 shows the anti-algesic effect of buprenorphine dimer and the disappearance of the anti-algesic effect by eluxadoline. Each of these was administered orally in Example 2.

[0043] [Figure 7] Figure 7 shows the anti-algesic effect of low-dose buprenorphine dimer in an IBS mouse model in Example 2.

[0044] [Figure 8A] Figures 8A and 8B show the Cmax and AUC0-t of the buprenorphine dimer in the Phase 1 clinical trial and single-dose escalation (SAD) study of Example 3. Figure 8A: Cmax of the buprenorphine dimer; and Figure 8B: AUC0-t of the buprenorphine dimer.

[0045] [Figure 8B] Figures 8A and 8B show the Cmax and AUC0-t of the buprenorphine dimer in the Phase 1 clinical trial and single-dose escalation (SAD) study of Example 3. Figure 8A: Cmax of the buprenorphine dimer; and Figure 8B: AUC0-t of the buprenorphine dimer.

[0046] [Figure 9A] Figures 9A-9B show the Cmax and AUC0-t of the buprenorphine dimer in the Phase 1 clinical trial, repeated dose escalation (SAD) study of Example 3. Figure 9A: Cmax of the buprenorphine dimer; Figure 9B: AUC0-24h of the buprenorphine dimer; Figure 9C: Plasma concentration of the buprenorphine dimer after daily oral administration for 7 days.

[0047] [Figure 9B] Figures 9A-9B show the Cmax and AUC0-t of the buprenorphine dimer in the Phase 1 clinical trial, repeated dose escalation (SAD) study of Example 3. Figure 9A: Cmax of the buprenorphine dimer; Figure 9B: AUC0-24h of the buprenorphine dimer; Figure 9C: Plasma concentration of the buprenorphine dimer after daily oral administration for 7 days.

[0048] [Figure 9C] Figures 9A-9B show the Cmax and AUC0-t of the buprenorphine dimer in the Phase 1 clinical trial, repeated dose escalation (SAD) study of Example 3. Figure 9A: Cmax of the buprenorphine dimer; Figure 9B: AUC0-24h of the buprenorphine dimer; Figure 9C: Plasma concentration of the buprenorphine dimer after daily oral administration for 7 days.

[0049] [Figure 10A] Figures 10A-10B show the spontaneous motility activity (LMA) of rats in Example 6 that were intravenously administered buprenorphine dimer (50 mg / kg), morphine (5 mg / kg), and erxadrine (50 mg / kg), respectively. Figure 10A: Distance traveled; Figure 10B: Time to move; and Figure 10C: Vertical standing.

[0050] [Figure 10B] Figures 10A-10B show the spontaneous motility activity (LMA) of rats in Example 6 that were intravenously administered buprenorphine dimer (50 mg / kg), morphine (5 mg / kg), and erxadrine (50 mg / kg), respectively. Figure 10A: Distance traveled; Figure 10B: Time to move; and Figure 10C: Vertical standing.

[0051] [Figure 10C] Figures 10A-10B show the spontaneous motility activity (LMA) of rats in Example 6 that were intravenously administered buprenorphine dimer (50 mg / kg), morphine (5 mg / kg), and erxadrine (50 mg / kg), respectively. Figure 10A: Distance traveled; Figure 10B: Time to move; and Figure 10C: Vertical standing.

[0052] [Figure 11] Figure 11 shows the stability of buprenorphine dimers incubated under neutral, acidic, and basic conditions, as in Example 7.

[0053] [Figure 12]Figure 12 shows a synthetic scheme for preparing the neutral form of buprenorphine dimer, as in Example 8.

[0054] [Figure 13] Figure 13 shows the composite responder rate at weeks 1–12 of treatment in patients with normal C4 levels at baseline in Example 10. Patients affected by per-protocol COVID-19 were excluded from the ITT analysis population, and loperamide overuse was treated as non-responders.

[0055] [Figure 14] Figure 14 shows the composite responder rate at weeks 1–12 of treatment in post-cholecystectomy patients with normal C4 levels at baseline in Example 10. Patients affected by the perprotocol COVID-19 were excluded from the ITT analysis population, and loperamide overuse was treated as non-responders.

[0056] [Figure 15] Figure 15 shows the therapeutic effects across multiple endpoints in protocol-compliant patients with normal C4 levels who were treated with buprenorphine dimer in Example 10.

[0057] [Figure 16] Figure 16 shows the therapeutic effects across multiple endpoints in a protocol-compliant post-cholecystectomy patient with normal C4 levels who was treated with buprenorphine dimer in Example 10.

[0058] [Figure 17] Figure 17 shows the therapeutic effects across multiple endpoints in protocol-compliant patients with all C4 levels who were treated with buprenorphine dimer in Example 10.

[0059] Detailed explanation of disclosure I. Overview This disclosure provides a method for treating chronic pain in a subject requiring treatment by orally administering: i) a therapeutically effective amount of buprenorphine dimer of formula (I) or a pharmaceutically acceptable salt thereof; or ii) a pharmaceutical composition comprising a therapeutically effective amount of buprenorphine dimer of formula (I). In particular, the administered buprenorphine dimer of formula (I) is in a neutral form.

[0060] This disclosure provides a method for treating IBS-D in subjects whose blood 7α-hydroxy-4-cholesten-3-one (C4) concentration is within the normal range (e.g., C4 concentration of 50 mg / dL or less) by administering: i) a therapeutically effective amount of buprenorphine dimer of formula (I) or a pharmaceutically acceptable salt thereof, or ii) a pharmaceutical composition comprising a therapeutically effective amount of buprenorphine dimer of formula (I). In particular, the administered buprenorphine dimer of formula (I) is in a neutral form.

[0061] Buprenorphine dimer, represented by formula (I) in therapeutically effective doses, provides both analgesic and anti-hyperalgesic effects while minimizing one or more undesirable side effects associated with opioid central nervous system action (e.g., sedation, drowsiness, euphoria, withdrawal symptoms, respiratory depression).

[0062] This disclosure also provides a method for producing a neutral form of buprenorphine dimer represented by formula (I). This method is suitable for the large-scale production of active pharmaceutical ingredients (APIs) for drug development.

[0063] II. Definition Unless otherwise specified, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this disclosure pertains. Furthermore, methods or materials similar to or equivalent to those described herein or materials may be used in the practice of this disclosure. For the purposes of this disclosure, the following terms are defined:

[0064] Unless otherwise specified, the base used in formula (I) in this specification is [ka] " refers to methyl.

[0065] Unless otherwise specified, the neutral form of the buprenorphine dimer is represented by formula (I), where both nitrogen atoms are not positively charged (e.g., protonated or quaternary ammonium cations). The neutral form of the buprenorphine dimer also refers to the free base form.

[0066] The words "comprise," "include," "have," and their derivatives are used interchangeably herein as comprehensive and unrestricted terms. For example, the use of "comprising," "including," or "having" means that the elements included, having, or being included are not the only elements included in the subject of the clause containing the verb.

[0067] A "base" refers to a functional group that deprotonates water to produce hydroxide ions. Bases useful in this invention include inorganic bases. Exemplary inorganic bases include alkali bicarbonates, alkali carbonates, tribasic alkali phosphates, dibasic alkali phosphates, alkali hydroxides, and alkali hydrides, as defined herein.

[0068] "First inorganic base" and "second inorganic base" refer to the bases defined above and described in the embodiments of the present invention. The base nomenclature is used solely to clarify the relevant steps of the process described herein and does not need to be in numerical order. Those skilled in the art will understand the meaning of these base nomenclature ("first inorganic base," "second inorganic base") from the context of the use of terms in the embodiments and claims herein.

[0069] "Alkali hydroxides" refer to a group of compounds consisting of an alkali metal cation and a hydroxide anion (OH-). Useful alkali hydroxides in this invention include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesium hydroxide (CsOH).

[0070] An "aprotic solvent" refers to a solvent that does not contain acidic hydrogen. Therefore, these are not hydrogen bond donors. Common characteristics of aprotic solvents are that they can accept hydrogen bonds, do not contain acidic hydrogen, and can dissolve salts. Examples of aprotic solvents, though not limited to these, include N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), ethyl acetate (ԅ), acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), propylene carbonate (PC), and hexamethylphosphoramide (HMPA).

[0071] A "phase transfer agent" or "phase transfer catalyst (PTC)" refers to a catalyst that facilitates the movement of reactants from one phase to another (where the reaction takes place). Phase transfer catalysts are a special form of heterogeneous catalyst. Ionic reactants are often soluble in the aqueous phase but insoluble in the organic phase when no phase transfer catalyst is present. The catalyst acts like a detergent to dissolve the salt in the organic phase. Using a PTC process can improve reaction rates, achieve higher conversion rates or yields, reduce by-products, eliminate the need for expensive or hazardous solvents to dissolve all reactants in one phase, eliminate the use of expensive raw materials, and / or minimize waste problems. PTCs are not limited to systems containing hydrophilic and hydrophobic reactants. PTCs can be used in liquid / solid and liquid / gas reactions. As the name suggests, one or more reactants are transported to a second phase containing both reactants. Phase transfer catalysts for anionic reactants are often quaternary ammonium salts.

[0072] "First phase transfer agent" and "second phase transfer agent" refer to the phase transfer agents defined above and described in the embodiments of the present invention. The naming convention for the phase transfer agents is used solely to clarify the relevant steps of the process described herein and does not necessarily have to be in numerical order. Those skilled in the art will understand the meaning of these naming conventions for phase transfer agents ("first phase transfer agent," "second phase transfer agent") in the context of the use of terms in the embodiments and claims herein.

[0073] "Quaternary ammonium salt" refers to a salt of a quaternary ammonium cation as defined herein. The quaternary ammonium cation is also called quat and is given by formula NR4. + This refers to a positively charged compound having an ammonium ion (NH4). + Unlike primary, secondary, or tertiary ammonium cations, quaternary ammonium cations are always charged regardless of the pH of the solution.

[0074] "Approximately" means a range of values ​​that includes a specified value and that a person skilled in the art would consider reasonably similar to the specified value. In some embodiments, the term "approximately" means within a standard deviation using measurements generally accepted in the art. In some embodiments, "approximately" means within ±10% of the specified value. In some embodiments, "approximately" means within ±5% of the specified value.

[0075] When a range of values ​​is disclosed and the notation "from n1 to n2" or "between n1 and n2" is used (where n1 and n2 are numbers), unless otherwise specified, this notation includes the numbers themselves and the range between them. This range may be an integer or a sequence of numbers between the two endpoints and including both endpoints. For example, the range "1 mg to 3 mg (milligrams)" includes all values ​​up to 1 mg, 3 mg, and any significant figures in between (e.g., 1.255 mg, 2.1 mg, 2.9999 mg, etc.).

[0076] "Salt" refers to an acid salt or base salt of the compounds of this disclosure. Specific examples of pharmaceutically acceptable acid addition salts include salts of mineral acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid) and salts of organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid). pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding appropriate pharmaceutically acceptable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0077] "Medically acceptable excipients" refers to substances that assist in the administration of an active agent to a subject and its absorption by the subject. Useful pharmaceutically acceptable excipients in this disclosure include, but are not limited to, binders, fillers, flow enhancers, disintegrants, surfactants, lubricants, coatings, sweeteners, flavorings, and colorants. Those skilled in the art will recognize that other pharmaceutically acceptable excipients may also be useful in this disclosure.

[0078] The term "tablet" refers to a solid pharmaceutical preparation, whether coated or not. The term "tablet" also refers to tablets having one, two, three, or more layers, and each of the aforementioned types of tablets may have one or more layers of coating or not. In some embodiments, the tablets of this disclosure may be prepared by roller compression or by other suitable methods known in the art. The term "tablet" also includes minitablets, melting tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets. A tablet comprises a buprenorphine dimer of formula (I) and one or more pharmaceutical excipients selected from one or more fillers, one or more binders, one or more flow enhancers, one or more disintegrants, one or more surfactants, one or more binders, and one or more lubricants. Optionally, a coating agent may also be included. For the purpose of calculating the weight percentage of the tablet preparation, the amount of the coating agent is not included in the calculation; that is, the weight percentages reported herein are for uncoated tablets.

[0079] "Administration" means providing a compound or its form to a subject therapeutically, such as by oral administration.

[0080] "Patient" or "subject" means an organism that is suffering from or susceptible to a disease or condition treatable by the administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, non-human primates (e.g., monkeys), goats, pigs, sheep, cows, deer, horses, bovines, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, and other non-mammalian animals. In some embodiments, the subject is human. In some embodiments, the subject is adult (e.g., at least 18 years of age). In some embodiments, the subject is under 18 years of age.

[0081] The "therapeutic dose" refers to the amount of compound or pharmaceutical composition useful for treating or improving a specific disease or condition, or for producing a detectable therapeutic or inhibitory effect. The exact amount varies depending on the therapeutic purpose and can be determined by clinicians, pharmacists, etc. (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1 3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0082] "To treat," "treating," and "treatment" refer to signs of success in treating or improving an injury, illness, or condition, including objective or subjective parameters such as reduction, remission, symptom reduction, or making the injury, illness, or condition more tolerable to the patient, slowing the rate of degeneration or debilitation, mitigating debilitation in the final stages of degeneration, and improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of health examinations, measurements (e.g., analysis of bodily fluids such as blood, plasma, or urine of the subject), imaging analysis, neuropsychiatric examinations, and / or psychiatric evaluations.

[0083] Unless otherwise specified, the content of buprenorphine dimer of formula (I) in a tablet formulation, for example, is calculated based on the normalized weight of unsalted, anhydrous buprenorphine dimer of formula (I). That is, the salt and / or water content in buprenorphine dimer of formula (I) is not included in the calculation.

[0084] III. Method In one embodiment, the present disclosure provides a method for treating a disease in a human subject requiring treatment, wherein the subject is given a therapeutically effective dose of formula (I): [ka] The treatment involves orally administering a therapeutically effective dose of buprenorphine dimer or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective dose of buprenorphine dimer is at least about 100 mg / day on an unsalted and anhydrous basis, and the administration results in a plasma concentration of at least about 700 ng / mL in the subject. In some embodiments, the administration results in a plasma concentration of about 700 ng / mL to about 2400 ng / mL in the subject. In some embodiments, the administration results in a plasma concentration of about 700 ng / mL to about 1600 ng / mL in the subject. In some embodiments, a plasma concentration of at least about 700 ng / mL in the subject is the steady-state plasma concentration.

[0085] In some embodiments, the buprenorphine dimer is a neutral form represented by formula (I).

[0086] In some embodiments, the therapeutically effective dose of buprenorphine dimer is a total daily dose of at least about 100 mg / day on an unsalted and anhydrous basis, such as 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, or 500 mg / day, or any amount in between. In some embodiments, the therapeutically effective dose of buprenorphine dimer is a total daily dose of at least about 200 mg / day on an unsalted and anhydrous basis.

[0087] In some embodiments, the buprenorphine dimer is administered once daily. For example, in some embodiments, the therapeutically effective dose of the buprenorphine dimer is a total daily dose of at least about 100 mg / day on an unsalted and anhydrous basis, administered once daily.

[0088] In some embodiments, the buprenorphine dimer is administered twice daily. For example, in some embodiments, the therapeutic effective dose of the buprenorphine dimer is a total daily dose of at least about 100 mg / day on an unsalted and anhydrous basis, administered as 50 mg twice daily. For example, in some embodiments, the therapeutic effective dose of the buprenorphine dimer is a total daily dose of at least about 200 mg / day on an unsalted and anhydrous basis, administered as 100 mg twice daily.

[0089] In some embodiments, the disease is chronic pain. In some embodiments, the chronic pain is nociceptive pain, neuropathic pain, or a combination thereof. In some embodiments, the chronic pain is peripheral chronic pain. In some embodiments, the chronic pain is peripheral neuropathic pain.

[0090] In some embodiments, the subject has sickle cell disease (SCD), cancer and / or chemotherapy, HIV, diabetes, herpes zoster, trauma, surgery, amputation, burns, or a combination thereof; and / or the subject has or has had coronavirus disease.

[0091] In some embodiments, chronic pain is one of the following 1) to 10): 1) Pain associated with sickle cell disease (SCD) in the subject; 2) Chemotherapy-induced neuropathic pain in subjects with cancer undergoing chemotherapy; 3) HIV-induced sensory neuropathy; 4) Diabetic neuropathic pain; 5) Postherpetic neuralgia in subjects who have or have had herpes zoster; 6) Post-traumatic chronic pain; 7) Postoperative pain; 8) Post-amputation pain; 9) Post-burn pain; and 10) Pain associated with long-term effects in subjects who had contracted coronavirus disease.

[0092] In some embodiments, a therapeutically effective dose of buprenorphine dimer reduces chronic pain as measured by one or more criteria selected from the following group: 1) A decrease in the mean monthly score on a 0-10 Likert scale over the past 1, 3, or 6 months compared to the mean monthly score before treatment; 2) A decrease in the mean monthly score of characteristic pain intensity and / or disability over the past 1 month, 3 months, or 6 months compared to the mean monthly score before treatment; and 3) Reduction in pain severity over the past 1 month, 3 months, or 6 months compared to the pain severity before treatment, with the reduced pain severity selected from the following groups: i) From Grade 4 (severe disability - severe limitation) to Grade 3 (severe disability - moderate limitation), Grade 2 (mild disability - high intensity), Grade 1 (mild disability - low intensity), and Grade 0 (no pain), up to one of these grades. ii) From Grade 3 up to one of Grade 2, Grade 1, and Grade 0, iii) From Grade 2 to Grade 1 or Grade 0, iv) From Grade 1 to Grade 0.

[0093] In some embodiments, a therapeutically effective dose of buprenorphine dimer produces an anti-algesic effect. In some embodiments, the subject's hyperalgesia is reduced or substantially eliminated during or after treatment. In some embodiments, the subject's hyperalgesia is eliminated during or after treatment.

[0094] In some embodiments, the disorder is diarrhea-predominant irritable bowel syndrome (IBS-D). In some embodiments, prior to treatment, the subject has a weekly mean score of 3 or higher for the most severe abdominal pain in the past 24 hours, based on a numerical rating scale of 1 to 10. In some embodiments, prior to treatment, the subject has a weekly mean score of 5 or higher for stool consistency, as assessed by the Bristol Stool Form Score (BSFS).

[0095] In some embodiments, the subject has undergone cholecystectomy.

[0096] In some embodiments, during treatment, the subject is administered loperamide. In some embodiments, during treatment, the subject is administered loperamide in a total dose not exceeding one of the following: 8 mg over 24 hours, 14 mg over 48 hours, and 22 mg over 7 days.

[0097] In some embodiments, the subject is not administered loperamide during treatment.

[0098] In some embodiments, a therapeutically effective dose of buprenorphine dimer alleviates one or more symptoms associated with IBS-D. In some embodiments, a therapeutically effective dose of buprenorphine dimer, 1) Reduce the weekly average score of worst abdominal pain in the past 24 hours by at least 30% compared to the weekly average score before treatment, and / or 2)i)Improve stool consistency, as measured by a reduction in the mean BSFS score to less than 6, or ii)Absence of bowel movements when the characteristics of 1) are met.

[0099] In some embodiments, the subject's blood C4 concentration is approximately 15 mg / dL to approximately 45 mg / dL.

[0100] In another embodiment, the present disclosure provides a method for treating chronic pain in a subject requiring treatment, wherein the subject receives a therapeutically effective dose of formula (I): [ka] The procedure involves administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the buprenorphine dimer is administered orally.

[0101] In another embodiment, the present disclosure provides a method for treating chronic pain in a subject requiring treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a neutral form of buprenorphine dimer represented by formula (I), the pharmaceutical composition being administered orally.

[0102] In another embodiment, the present disclosure provides a method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, the method comprising formula (I): [ka] The procedure involves administering a therapeutically effective dose of a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the subject has a blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) of 50 milligrams / deciliter (mg / dL) or less.

[0103] In another embodiment, the present disclosure provides a method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a neutral form of buprenorphine dimer represented by formula (I), wherein the subject has a blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) of 50 milligrams / deciliter (mg / dL) or less.

[0104] III-1: Buprenorphine dimer of formula (I) The buprenorphine dimer of formula (I) may be in a pharmaceutically acceptable salt form or a neutral form.

[0105] In some embodiments, the buprenorphine dimer of formula (I) is in monosalt form, where one of the nitrogen atoms forms a pharmaceutically acceptable salt. In some embodiments, the buprenorphine dimer of formula (I) is in bissalt form, where both nitrogen atoms form a pharmaceutically acceptable salt. In some embodiments, the buprenorphine dimer of formula (I) is in formula (Ia): [ka] This is a form of bis salt represented by , where HX is a pharmaceutically acceptable acid adduct.

[0106] Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogenic acid, dihydrogenic acid, sulfuric acid, monohydrogenic acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. In some embodiments, the dimer of formula (I) is in the bisHCl salt form.

[0107] In some embodiments, the buprenorphine dimer of formula (I) is in a neutral form (for example, neither nitrogen atom in formula (I) is protonated, nor is it a quaternary ammonium cation).

[0108] In some embodiments, the buprenorphine dimer has the name (2S,2'S)-2,2'-((4R,4aS,4'R,4a'S,6R,6'R,7R,7aR,7'R,7a'R,12bS,12b'S)-(ethane-1,2-diylbis(oxy))bis(3-(cyclopropylmethyl)-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofl[3,2-e]isoquinoline-9,6-diyl))bis(3,3-dimethylbutan-2-ol).

[0109] III-2: Chronic pain Chronic pain can be nociceptive pain (caused by inflamed or damaged tissue that activates specific pain sensors called nociceptors), neuropathic pain (caused by damage or dysfunction of the nervous system), or a combination of nociceptive and neuropathic pain. In some embodiments, chronic pain is nociceptive pain, neuropathic pain, or a combination thereof. In some embodiments, chronic pain is nociceptive pain. In some embodiments, chronic pain is neuropathic pain. In some embodiments, chronic pain is a combination of nociceptive and neuropathic pain.

[0110] Chronic pain or neuropathic pain can be “peripheral,” meaning it originates in the peripheral nervous system. In some embodiments, chronic pain is peripheral chronic pain. In some embodiments, chronic pain is peripheral neuropathic pain (PNP).

[0111] Common types of peripheral neuropathic pain treatable with buprenorphine dimer of formula (I) or its pharmaceutical composition include: • Acute and chronic inflammatory demyelinating polyradiculoneuritis (CIDP) Alcoholic polyneuropathy, • Chemotherapy-induced polyneuropathy or chemotherapy-induced peripheral neuropathy (CIPN), ·Complex regional pain syndrome (CRPS), • Compressive neuropathy (e.g., carpal tunnel syndrome), • HIV sensory neuropathy (e.g., distal symmetrical polyneuropathy (DSP)), • Iatrogenic neuralgia (e.g., post-mastectomy pain or post-thoracotomy pain), • Idiopathic sensory neuropathy, • Nerve compression or infiltration due to tumor, Nutritional deficiency-related neurological disorders, ·Painful diabetic neuropathy, ·Phantom limb pain, • Postherpetic neuralgia (caused by shingles), and Radiation-induced nerve plexus damage.

[0112] Additional chronic pain treatable with buprenorphine dimer of formula (I) or its pharmaceutical composition includes: • Pain associated with sickle cell disease (SCD) • Visceral pain associated with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) accompanied by diarrhea or constipation. • Abdominal pain in subjects whose gastrointestinal (GI) inflammation has subsided but who continue to experience diarrhea with watery stools and abdominal pain. • Diabetic neuropathy pain, ·Post-traumatic chronic pain, ·Post-operative pain, • Post-amputation pain (e.g., phantom limb pain), • Post-burn pain, and • Pain associated with long-term effects in subjects who have contracted coronavirus disease.

[0113] In some embodiments, chronic pain includes acute and chronic inflammatory demyelinating polyradiculoneuritis (CIDP), alcoholic polyneuritis, chemotherapy-induced polyneuritis or chemotherapy-induced peripheral neuropathy (CIPN), complex regional pain syndrome, compressive neuropathy (e.g., carpal tunnel syndrome), HIV sensory neuropathy (e.g., distal symmetrical polyneuropathy (DSP)), iatrogenic neuralgia, idiopathic sensory neuropathy, nerve compression or infiltration by tumor, nutritional deficiency-related neuropathy, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, radiation-induced plexus injury, or a combination thereof.

[0114] In some embodiments, chronic pain is acute and chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, chronic pain is alcoholic polyneuropathy. In some embodiments, chronic pain is chemotherapy-induced polyneuropathy or chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, chronic pain is complex regional pain syndrome. In some embodiments, chronic pain is compressive neuropathy. In some embodiments, chronic pain is carpal tunnel syndrome. In some embodiments, chronic pain is HIV sensory neuropathy. In some embodiments, chronic pain is distal symmetrical polyneuropathy (DSP). In some embodiments, chronic pain is iatrogenic neuralgia. In some embodiments, chronic pain is iatrogenic neuralgia resulting from surgical trauma (e.g., post-mastectomy pain or post-thoracotomy pain). In some embodiments, chronic pain is idiopathic sensory neuropathy. In some embodiments, chronic pain is associated with nerve compression or infiltration by a tumor. In some embodiments, chronic pain is nutritional deficiency-related neuropathy. In some embodiments, chronic pain is diabetic neuropathy. In some embodiments, chronic pain is phantom limb pain. In some embodiments, chronic pain is postherpetic neuralgia. In some embodiments, chronic pain is radiation-induced plexus injury.

[0115] In some embodiments, chronic pain is associated with sickle cell disease (SCD) in the subject. In some embodiments, chronic pain is visceral pain associated with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) with diarrhea or constipation. In some embodiments, chronic pain is abdominal pain in a subject where gastrointestinal (GI) inflammation is in remission, but diarrhea with watery stools and abdominal pain persist. In some embodiments, chronic pain is diabetic neuropathic pain. In some embodiments, chronic pain is post-traumatic chronic pain. In some embodiments, chronic pain is post-surgical pain. In some embodiments, chronic pain is post-amputation pain (e.g., phantom limb pain). In some embodiments, chronic pain is post-burn pain. In some embodiments, chronic pain is associated with long-term effects in a subject who has contracted a coronavirus disease (e.g., COVID-19).

[0116] III-3: Subject The subject may be human. In some embodiments, the subject is human. In some embodiments, the human is an adult at least 18 years of age. In some embodiments, the human is under 18 years of age.

[0117] chronic pain The subject has one of the chronic pains described in Section III-2. In some embodiments, the subject has chronic pain according to one of the embodiments described in Section III-2.

[0118] In some embodiments, the subject had sickle cell disease (SCD), cancer or tumor, chemotherapy, radiotherapy, HIV, inflammatory bowel disease with diarrhea or constipation (IBD) or irritable bowel syndrome (IBS), diabetes, herpes zoster, trauma, surgery, amputation, burns, or a combination thereof, and / or the subject had or had had coronavirus disease.

[0119] In some embodiments, the subject has sickle cell disease (SCD). In some embodiments, the subject has cancer or a tumor. In some embodiments, the subject has cancer or a tumor that is receiving chemotherapy or radiotherapy. In some embodiments, the subject is receiving chemotherapy to treat cancer or a tumor. In some embodiments, the subject is receiving radiotherapy to treat cancer or a tumor. In some embodiments, the subject is infected with HIV. In some embodiments, the subject has IBD or IBS with diarrhea or constipation. In some embodiments, the subject is in remission for gastrointestinal (GI) inflammation but has persistent diarrhea with watery stools and abdominal pain. In some embodiments, the subject has diabetes. In some embodiments, the subject has or has had herpes zoster. In some embodiments, the subject has trauma (e.g., car accident, gunshot wound). In some embodiments, the subject has undergone surgery. In some embodiments, the subject has undergone amputation. In some embodiments, the subject has burns (e.g., from a car fire, house fire, or wildfire). In some embodiments, the subjects were currently suffering from or had previously suffered from a coronavirus disease (e.g., COVID-19).

[0120] digestive disorders The subjects have been diagnosed with IBS-D (diarrhea-predominant irritable bowel syndrome) and meet the Rome IV criteria based on their history of both IBS and IBS-D. In some embodiments, the subjects have undergone cholecystectomy. In some embodiments, the subjects have IBS-D and their blood 7α-hydroxy-4-cholesten-3-one (C4) levels are normal or slightly elevated. In some embodiments, the subjects have IBS-D and their blood C4 levels are 50 mg / dL or less. In some embodiments, the subjects have IBS-D and their blood C4 levels are approximately 15 mg / dL to approximately 45 mg / dL.

[0121] In some embodiments, prior to treatment with buprenorphine dimer, subjects experienced the most severe abdominal pain in the past 24 hours, with a weekly average score greater than 3 on a numerical rating scale of 1 to 10.

[0122] In some embodiments, prior to treatment with buprenorphine dimer, the subjects had a weekly mean score of stool hardness, as assessed by the Bristol Stool Firmness Score (BSFS), greater than 5. In some embodiments, prior to treatment with buprenorphine dimer, the subjects had a weekly mean score of stool hardness, as assessed by the Bristol Stool Firmness Score (BSFS), greater than 5.5. In some embodiments, prior to treatment with buprenorphine dimer, the subjects had a weekly mean score of stool hardness, as assessed by the Bristol Stool Firmness Score (BSFS), greater than 6.

[0123] In some embodiments, subjects have not received loperamide prior to treatment with buprenorphine dimer, or have discontinued loperamide at least 14 days prior to treatment with buprenorphine dimer.

[0124] In some embodiments, prior to treatment with buprenorphine dimer, the subjects have i) a fecal primary bile acid concentration exceeding approximately 4% by weight, and / or ii) a total fecal bile acid concentration exceeding approximately 1,000 μmol / 48 hours. In some embodiments, prior to treatment with buprenorphine dimer, the subjects have i) a fecal primary bile acid concentration exceeding approximately 4% by weight, and ii) a total fecal bile acid concentration exceeding approximately 1,000 μmol / 48 hours. In some embodiments, prior to treatment with buprenorphine dimer, the total fecal bile acid concentration of the subjects is less than approximately 2,337 μmol / 48 hours. In some embodiments, prior to treatment with buprenorphine dimer, the total fecal bile acid concentration of the subjects is between approximately 1,000 μmol / 48 hours and approximately 2,337 μmol / 48 hours. In some embodiments, prior to treatment with buprenorphine dimer, the subjects have i) a fecal primary bile acid content exceeding approximately 4% by weight, and ii) a total fecal bile acid content of approximately 1,000 μmol / 48 hours to approximately 2,337 μmol / 48 hours.

[0125] In some embodiments, the subject has undergone cholecystectomy.

[0126] In some embodiments, during treatment with buprenorphine dimer, the subject is administered loperamide. In some embodiments, during treatment with buprenorphine dimer, the subject is administered loperamide at a dose of approximately 2 mg every 6 hours. In some embodiments, during treatment with buprenorphine dimer, the subject is administered loperamide in a total dose not exceeding one of the following: 8 mg over 24 hours, 14 mg over 48 hours, and 22 mg over 7 days. In some embodiments, the subject is not administered loperamide during treatment with buprenorphine dimer.

[0127] In some embodiments, prior to administration of buprenorphine dimer, the subject meets all of the following comprehensive criteria: • Diagnosed with IBS-D (diarrhea-predominant irritable bowel syndrome), and meets Rome IV criteria based on a history of both IBS and IBS-D; • I kept an electronic diary (eDiary) every day for at least 6 days out of the 7 days in the week prior to treatment, and for at least 11 days out of the 14 days in the two weeks prior to treatment. • In the week prior to treatment, the weekly average of the worst abdominal pain score in the past 24 hours was greater than 3 on a numerical rating scale of 0 to 10; • In the week prior to treatment, the weekly average stool consistency, as assessed by the Bristol Stool Filtration Score (BSFS), was greater than 5; • Loperamide had not been used within 14 days prior to treatment; and • You have maintained a stable diet for the past 12 weeks and do not plan to change your lifestyle and / or diet during the treatment period.

[0128] In some embodiments, the subject does not meet any of the following exclusion criteria. • A history of clinically relevant pancreatic disease, such as pancreatitis, schizophrenia, or sphincter of Oddi (SO) dysfunction with pancreatic symptoms; • A history of biliary tract disease, including acute cholecystitis, within the past six months, or a history of biliary tract pain, including post-cholecystectomy pain; Patients who have undergone biliary sphincterotomy and have persistent postoperative liver function transaminase (LFT) abnormalities; • Patients scheduled for elective surgery within the next four months; • A history of serious or severe illness, such as cardiovascular, neurological, infectious, renal, hepatic, or respiratory diseases that could interfere with the patient's medical care, participation in the research, or the conduct of the research; • A history of intestinal obstruction, intestinal stenosis, toxic megacolon, GI (gastrointestinal tract) perforation, fecal embolism, gastric ligation, bariatric surgery, adhesions, ischemic colitis, or enterovascular disorders (e.g., aortic-iliac disease); • A history of lactose intolerance that cannot be controlled by a lactose-free diet, or other malabsorption syndromes (e.g., fructose malabsorption); • Difficulty swallowing or swallowing tablets; • A history of inflammatory bowel disease, celiac disease, Clostridium difficile colitis, or a history of unexplained gastrointestinal bleeding within three months prior to screening; • A history of major surgery on the stomach, liver, pancreas, or intestines (appendectomy, hemorrhoidectomy, or polypectomy are acceptable if performed at least 3 months prior to the screening; laparoscopic or open cholecystectomy without complications is acceptable if postoperative biliary pain and a history of surgery have not occurred more than 3 months prior to the screening); Patients over 40 years of age at high risk of colorectal cancer must have undergone a screening colonoscopy within 3 years prior to their trial screening visit. Patients over 50 years of age must have undergone a normal screening colonoscopy within 10 years prior to their trial screening visit. Patients with Lynch syndrome or familial polyposis will be excluded from the study.

[0129] Further inclusion and exclusion criteria for subjects who may benefit from treatment with the buprenorphine dimer of formula (I), such as subjects enrolled in a double-blind, placebo-controlled, phase 2 responsive adaptive randomized trial of the buprenorphine dimer in patients with diarrhea-predominant irritable bowel syndrome (IBS-D), are described in Example 9.

[0130] In some embodiments, the subject meets all of the inclusion criteria 1) to 4) described in Example 9. In some embodiments, the subject meets all of the inclusion criteria 1) to 4) described in Example 9, but the subject must not meet any of the exclusion criteria 1) to 11) described in Example 9.

[0131] III-4: Therapeutic effective dose / dosage The therapeutically effective dose may be a total daily dose of approximately 2000 mg or less of the salt-free, anhydrous base dimer of formula (I). In some embodiments, the therapeutically effective dose is a total daily dose of approximately 2000 mg or less, approximately 1600 mg or less, approximately 1200 mg or less, or approximately 800 mg or less of the salt-free, anhydrous base dimer of formula (I). In some embodiments, the therapeutically effective dose is a total daily dose of approximately 800 mg or less of the salt-free, anhydrous base dimer of formula (I). In some embodiments, the therapeutically effective dose is a total daily dose of approximately 400 mg or less of the salt-free, anhydrous base dimer of formula (I).

[0132] In some embodiments, the therapeutically effective dose is a total daily dose of approximately 50 mg to approximately 800 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 50 mg to approximately 400 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 50 mg to approximately 250 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 50 mg to approximately 150 mg of unsalted, anhydrous-based buprenorphine dimer.

[0133] In some embodiments, the therapeutically effective dose is a total daily dose of approximately 100 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 150 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 200 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 250 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 300 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 350 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 400 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 450 mg of unsalted, anhydrous-based buprenorphine dimer. In some embodiments, the therapeutically effective dose is a total daily dose of approximately 500 mg of unsalted, anhydrous-based buprenorphine dimer.

[0134] In general, the dimer of formula (I) can be administered orally. In some embodiments, the dimer of formula (I) is administered orally. In some embodiments, the neutral form of the dimer of formula (I) is administered orally. In some embodiments, the dimer of formula (I) in tablet formulations is administered orally. In some embodiments, the neutral form of the dimer of formula (I) in tablet formulations is administered orally.

[0135] In general, the dimer of formula (I) can be administered once or multiple times a day (for example, two, three, four, or more times). In some embodiments, the dimer of formula (I) is administered once, two, three, or four times a day. In some embodiments, the dimer of formula (I) is administered once a day. In some embodiments, the dimer of formula (I) is administered twice a day.

[0136] In some embodiments, the neutral form of the dimer of formula (I) is administered once, twice, three times, or four times daily. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily. In some embodiments, the neutral form of the dimer of formula (I) is administered twice daily.

[0137] In some embodiments, the dimer of formula (I) is administered at least about 30 minutes before breakfast. In some embodiments, the dimer of formula (I) is administered once daily at least about 30 minutes before breakfast.

[0138] In some embodiments, the neutral form of the dimer of formula (I) is administered at least about 30 minutes before breakfast. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily at least about 30 minutes before breakfast.

[0139] The dimer of formula (I) may be present in one or more oral dosage forms of dose strength, where the dimer of formula (I) is present in an amount of about 5 mg to about 800 mg on a salt-free and anhydrous basis. In some embodiments, the oral dosage form is a tablet formulation of one or more dose strengths. In some embodiments of the tablet formulation, the dimer of formula (I) is present in an amount of about 5 mg, 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg on a salt-free and anhydrous basis in each tablet. In some embodiments of the tablet formulation, the dimer of formula (I) is present in an amount of about 25 mg, 50 mg, or 100 mg on a salt-free and anhydrous basis in each tablet. In some embodiments of the tablet formulation, the dimer of formula (I) is present in an amount of about 25 mg on a salt-free and anhydrous basis in each tablet. In some embodiments of the tablet formulation, the dimer of formula (I) is present in an amount of approximately 50 mg in each tablet on a salt-free and anhydrous basis. In some embodiments of the tablet formulation, the dimer of formula (I) is present in an amount of approximately 100 mg in each tablet on a salt-free and anhydrous basis.

[0140] The neutral form of the dimer of formula (I) may be present in one or more oral dosage forms of dose strength, where the neutral form of the dimer of formula (I) is present in an amount of approximately 5 mg to approximately 800 mg on an anhydrous basis. In some embodiments, the oral dosage form is a tablet formulation of one or more dose strengths. In some embodiments of the tablet formulation, the neutral form of the dimer of formula (I) is present in an amount of approximately 5 mg, 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg on an anhydrous basis in each tablet. In some embodiments of the tablet formulation, the neutral form of the dimer of formula (I) is present in an amount of approximately 25 mg on an anhydrous basis in each tablet. In some embodiments of the tablet formulation, the dimer of formula (I) in its neutral form is present in an amount of approximately 50 mg per tablet on an anhydrous basis. In some embodiments of the tablet formulation, the dimer of formula (I) in its neutral form is present in an amount of approximately 100 mg per tablet on an anhydrous basis.

[0141] Tablets containing the buprenorphine dimer of formula (I) may be immediate-release tablets or sustained-release tablets. In some embodiments, tablets containing the buprenorphine dimer of formula (I) are immediate-release tablets.

[0142] Tablets containing the neutral form of buprenorphine dimer of formula (I) may be immediate-release tablets or sustained-release tablets. In some embodiments, tablets containing the neutral form of buprenorphine dimer of formula (I) are immediate-release tablets.

[0143] In some embodiments, the dimer of formula (I) provides a total daily dose of dimers of about 2000 mg or less, about 1600 mg or less, about 1200 mg or less, or about 800 mg or less on a salt-free and anhydrous basis, administered once daily. In some embodiments, the dimer of formula (I) provides a total daily dose of dimers of about 800 mg or less on a salt-free and anhydrous basis, administered once daily. In some embodiments, the dimer of formula (I) provides a total daily dose of dimers of about 400 mg or less on a salt-free and anhydrous basis, administered once daily.

[0144] In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of dimers of approximately 2000 mg or less, approximately 1600 mg or less, approximately 1200 mg or less, or approximately 800 mg on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of dimers of approximately 800 mg or less on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of dimers of approximately 400 mg or less on an anhydrous basis.

[0145] In some embodiments, the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 800 mg of the dimer on a salt-free and anhydrous basis. In some embodiments, the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 400 mg of the dimer on a salt-free and anhydrous basis. In some embodiments, the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 250 mg of the dimer on a salt-free and anhydrous basis. In some embodiments, the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 150 mg of the dimer on a salt-free and anhydrous basis. In some embodiments, the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 100 mg of the dimer on a salt-free and anhydrous basis.

[0146] In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 800 mg of the dimer on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 400 mg of the dimer on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 250 mg of the dimer on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 50 mg to approximately 150 mg of the dimer on an anhydrous basis. In some embodiments, the neutral form of the dimer of formula (I) is administered once daily to provide a total daily dose of approximately 100 mg of the dimer on an anhydrous basis.

[0147] In general, subjects can be treated with the dimer of formula (I) for at least 12 weeks or for an extended period. In some embodiments, subjects are treated with the dimer of formula (I) for at least 12 weeks. In some embodiments, subjects are treated with the dimer of formula (I) for at least 6 months. In some embodiments, subjects are treated with the dimer of formula (I) for at least 1 year. In some embodiments, subjects are treated with the dimer of formula (I) for an extended period.

[0148] In some embodiments, subjects are treated with a dimer of formula (I) in its neutral form for at least 12 weeks. In some embodiments, subjects are treated with a dimer of formula (I) in its neutral form for at least 6 months. In some embodiments, subjects are treated with a dimer of formula (I) in its neutral form for at least 1 year. In some embodiments, subjects are treated with a dimer of formula (I) in its neutral form for an extended period.

[0149] III-5: Effectiveness A therapeutically effective dose of buprenorphine dimer of formula (I) can alleviate any of the chronic pains described in Section III-2. In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) alleviates the chronic pain described according to any one of the embodiments described in Section III-2.

[0150] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain as measured by one or more criteria selected from the group consisting of: 1) A decrease in the mean monthly score on a 0-10 Likert scale over the past 1, 3, or 6 months compared to the mean monthly score before treatment; 2) A decrease in the mean monthly score of characteristic pain intensity and / or disability over the past 1, 3, or 6 months compared to the mean monthly score before treatment; and 3) A reduction in pain severity over the past 1 month, 3 months, or 6 months compared to the pain severity before treatment, wherein the reduced pain severity is selected from the following groups: i) From Grade 4 (severe disability - severe limitation) to Grade 3 (severe disability - moderate limitation), Grade 2 (mild disability - high intensity), Grade 1 (mild disability - low intensity), and Grade 0 (no pain), up to one of these grades. ii) From Grade 3 up to one of Grade 2, Grade 1, and Grade 0; iii) From Grade 2 to Grade 1 or Grade 0; and iv) From Grade 1 to Grade 0.

[0151] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain as measured by a decrease in the mean monthly score on a 0-10 Likert scale over the past 1, 3, or 6 months compared to the mean monthly score before treatment.

[0152] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain, as measured by a decrease in the mean monthly score of characteristic pain intensity and / or disability over the past 1, 3, or 6 months compared to the mean monthly score before treatment.

[0153] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain as measured by a reduction in pain severity over the past 1, 3, or 6 months compared to the pain severity before treatment, where the reduced pain severity is selected from the following group: i) From Grade 4 (severe disability - severe limitation) to Grade 3 (severe disability - moderate limitation), Grade 2 (mild disability - high intensity), Grade 1 (mild disability - low intensity), and Grade 0 (no pain), up to one of these grades. ii) From Grade 3 up to one of Grade 2, Grade 1, and Grade 0; iii) From Grade 2 to Grade 1 or Grade 0; and iv) From Grade 1 to Grade 0.

[0154] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain as measured by meeting two of the criteria 1), 2), and 3) described herein. In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) reduces chronic pain as measured by meeting all of the criteria 1), 2), and 3) described herein.

[0155] In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) relieves chronic pain for at least 12 weeks without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) relieves chronic pain for at least 6 months without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) relieves chronic pain for at least 1 year without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) relieves chronic pain in long-term treatment without significantly adjusting the total daily dose.

[0156] A therapeutically effective dose of buprenorphine dimer of formula (I) provides both analgesic and anti-hyperalgesic effects while simultaneously minimizing one or more undesirable side effects associated with opioid central action (e.g., sedation, drowsiness, euphoria, withdrawal symptoms, and respiratory depression).

[0157] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) provides an anti-algesic effect. In some embodiments, the subject's hyperalgesia is reduced or substantially eliminated during or after treatment. In some embodiments, hyperalgesia is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% during or after treatment. In some embodiments, the subject does not exhibit hyperalgesia during or after treatment.

[0158] In some embodiments, the buprenorphine dimer of formula (I) or its metabolites are absent from the subject's central nervous system during or after treatment. In some embodiments, the buprenorphine dimer of formula (I) or its metabolites are absent from the subject's brain during or after treatment. In some embodiments, the buprenorphine dimer of formula (I) or its metabolites are absent from the subject's pupils during or after treatment.

[0159] In some embodiments, during or after treatment, the subject experiences a minimal number of symptoms selected from the group consisting of sedation, drowsiness, euphoria, withdrawal symptoms, and respiratory depression, each of which is related to the central effects of opioids. In some embodiments, during or after treatment, the subject experiences none of the following: sedation, drowsiness, euphoria, withdrawal symptoms, and respiratory depression, each of which is related to the central effects of opioids.

[0160] As described in Examples 9 and 10, the effects of buprenorphine dimers in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) can be evaluated by a double-blind, placebo-controlled, phase 2 responsive adaptive randomized trial.

[0161] A therapeutically effective dose of buprenorphine dimer of formula (I) can alleviate one or more symptoms associated with IBS-D (e.g., reduced abdominal pain, improved stool consistency). In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) alleviates one or more symptoms associated with IBS-D. In some embodiments, a therapeutically effective dose of buprenorphine dimer 1) reduces the weekly mean score of worst abdominal pain in the past 24 hours by at least 30% compared to the weekly mean score before treatment, and / or 2) i) the mean BSFS score decreases to less than 6 (e.g., score 1, 2, 3, 4, or 5), or ii) provided that the feature in 1) is met, stool consistency, as measured by the absence of a bowel movement, improves (i.e., the weekly mean score of worst abdominal pain in the past 24 hours decreases by at least 30% compared to the weekly mean score before treatment). In some embodiments, a therapeutically effective dose of buprenorphine dimer 1) reduces the weekly mean score of worst abdominal pain in the past 24 hours by at least 30% compared to the weekly mean score before treatment, and / or 2) i) the mean BSFS score decreases to less than 5 (e.g., score 1, 2, 3, or 4), or ii) the condition in 1) is met, improves stool consistency as measured by the absence of a bowel movement (i.e., the weekly mean score of worst abdominal pain in the past 24 hours decreases by at least 30% compared to the weekly mean score before treatment).

[0162] In some embodiments, a therapeutically effective dose of buprenorphine dimer of formula (I) satisfies either a secondary efficacy endpoint or an exploratory endpoint, as described in the Phase 2 trial of Example 9.

[0163] In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) alleviates one or more symptoms associated with IBS-D for at least 12 weeks without substantial adjustment of the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) alleviates one or more symptoms associated with IBS-D for at least 6 months without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) alleviates one or more symptoms associated with IBS-D for at least 1 year without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective dose of the dimer of formula (I) alleviates one or more symptoms associated with IBS-D in long-term treatment without substantially adjusting the total daily dose.

[0164] III-6: Oral dosage form An oral dosage form containing the dimer of formula (I) may be any oral dosage form containing one or more pharmaceutically acceptable carriers and / or excipients. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for patient administration.

[0165] To prepare oral dosage forms containing the dimer of formula (I), pharmaceutically acceptable carriers may be either solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Details of formulation and administration techniques are well described in the scientific literature and patent documents; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington's”).

[0166] In powder form, the carrier is a finely ground solid, which is mixed with a finely ground active ingredient. In tablet form, the active ingredient is mixed in the appropriate proportion with a carrier having the required binding properties and compressed into the desired shape and size.

[0167] Powders, capsules, and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, cocoa butter, and the like. The term “formulation” is intended to include the formulation of the active compound together with an encapsulating material as a carrier, with or without other excipients, to provide a capsule in which the active ingredient is encapsulated by the carrier and thus bound to the active ingredient. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0168] Suitable solid excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, tragacanth, low-melting-point wax, cocoa butter, carbohydrates, sugars (including, but not limited to, lactose, sucrose, mannitol, and sorbitol), starches derived from corn, wheat, rice, potato, or other plants, cellulose (e.g., methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose), and gums such as gum arabic and gum tragacanth, as well as proteins (including, but not limited to, gelatin and collagen). Disintegrants or solubilizers (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid, or salts thereof, e.g., sodium alginate) may be added as needed.

[0169] The core of the sugar-coated tablet is coated with a suitable coating, such as a concentrated sugar solution, a lacquer solution, or a suitable organic solvent or solvent mixture, which may contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide. Dyes or pigments may be added to the coating of the tablet or sugar-coated tablet for product identification or to characterize the amount of the active compound (i.e., dosage). Pharmaceutical formulations in these dosage forms can also be administered orally using, for example, gelatin push-fit capsules and soft-seal capsules made of gelatin coated with glycerol or sorbitol. Push-fit capsules may contain the dimer of formula (I) mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the dimer of formula (I) may be dissolved or suspended in a suitable liquid, with or without a stabilizer, such as fatty oil, liquid paraffin, or liquid polyethylene glycol.

[0170] To prepare the suppositories, first, a low-melting-point wax such as a mixture of fatty acid glycerides or cocoa butter is melted, and the dimer of formula (I) is uniformly dispersed in it by stirring or other means. Next, the molten homogeneous mixture is poured into a mold of an appropriate size and cooled to solidify.

[0171] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions.

[0172] An aqueous solution suitable for oral use can be prepared by dissolving the dimer of formula (I) in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral administration can be prepared by dispersing a finely powdered active ingredient in water containing a viscous substance [e.g., natural or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth rubber, acacia rubber] and a dispersant or wetting agent [e.g., natural phospholipids (e.g., lecithin), condensates of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensates of ethylene oxides and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensates of ethylene oxides and partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate)]. The aqueous suspension may contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more colorants, one or more flavoring agents, and one or more sweeteners (e.g., sucrose, aspartame, or saccharin). The formulation can be adjusted for osmotic pressure.

[0173] This also includes solid dosage forms intended to be converted into liquid formulations for oral administration immediately before use. Such liquid formulations include solutions, suspensions, and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0174] Oil suspensions can be formulated by suspending the dimer of formula (I) in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil), a mineral oil such as liquid paraffin, or a mixture thereof. The oil suspension may contain a thickener (e.g., beeswax, hard paraffin, or cetyl alcohol). Sweeteners (e.g., glycerol, sorbitol, or sucrose) can be added to provide an oral formulation with a pleasant mouthfeel. These formulations can be preserved by adding antioxidants such as ascorbic acid. For an example of an oily vehicle for injection, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Pharmaceutical formulations containing the dimer of formula (I) can also take the form of an oil-in-water emulsion. The oil phase can be the aforementioned vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifiers include natural rubber (e.g., acacia rubber and tragacanth rubber), natural phospholipids such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensates of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Emulsions may also contain sweeteners and flavorings, as with syrup and elixir formulations. Such formulations may also contain lubricants, preservatives, or colorants.

[0175] IV. Method for producing buprenorphine dimers In a third embodiment, the present disclosure provides a method for producing a buprenorphine dimer represented by formula (I) in a neutral form. This method includes the following steps: a) Formula: [ka] Buprenorphine or a salt thereof, represented by , a first inorganic base, water, and a first phase transfer agent are mixed in 1,2-dichloroethane to form formula (II): [ka] The process of forming the compound; and b) A step of mixing the compound of formula (II), buprenorphine or a salt thereof, a second inorganic base, water, and a second phase transfer agent in an aprotic solvent to obtain a buprenorphine dimer represented by formula (I) in a neutral form.

[0176] In some embodiments, buprenorphine in steps a) and b) is buprenorphine HCl salt, respectively.

[0177] In some embodiments, the first and second inorganic bases are each an alkali hydroxide. In some embodiments, the first and second inorganic bases are each independently selected from the group consisting of LiOH, NaOH, KOH, and CsOH. In some embodiments, the first and second inorganic bases are each NaOH. In some embodiments, the first and second inorganic bases are each an aqueous solution of NaOH with water. In some embodiments, the aqueous solution of NaOH is a 25% aqueous solution of NaOH.

[0178] In some embodiments, the first and / or second phase transfer agent is independently a quaternary ammonium salt. In some embodiments, the first and second phase transfer agents are each independently a quaternary ammonium salt. In some embodiments, the first and second phase transfer agents are each independently a tetrabutylammonium salt. In some embodiments, the first and / or second phase transfer agent is independently tetrabutylammonium hydroxide or tetrabutylammonium iodide. In some embodiments, the first and second phase transfer agents are each tetrabutylammonium hydroxide (TBAOH).

[0179] In general, the first phase transfer agent in step a) may be in any amount suitable for the reaction. In some embodiments, the first phase transfer agent in step a) is present in an amount of about 50% by weight or less, about 40% by weight or less, less than about 30% by weight, about 20% by weight, or about 10% by weight, based on buprenorphine or a salt thereof. In some embodiments, the first phase transfer agent in step a) (e.g., tetrabutylammonium hydroxide) is present in an amount of about 10% by weight or less, based on buprenorphine or a salt thereof. In some embodiments, the tetrabutylammonium hydroxide in step a) is present in an amount of about 10% by weight or less, based on buprenorphine or a salt thereof. In some embodiments, the tetrabutylammonium hydroxide in step a) is present in an amount of about 2% by weight to about 10% by weight, based on buprenorphine or a salt thereof. In some embodiments, the tetrabutylammonium hydroxide in step a) is present in an amount of about 3% by weight to about 8% by weight, based on buprenorphine or a salt thereof. In some embodiments, tetrabutylammonium hydroxide in step a) is present in an amount of about 5% by weight, based on buprenorphine or a salt thereof.

[0180] In general, the second phase transfer agent in step b) can be present in any amount suitable for the reaction. In some embodiments, the second phase transfer agent in step b) is present in less than a stoichiometric amount (e.g., less than 1 equivalent) relative to the compound of formula (II). In some embodiments, the second phase transfer agent in step b) (e.g., tetrabutylammonium hydroxide) is present in an amount of about 0.5 equivalents or less relative to the compound of formula (II). In some embodiments, the tetrabutylammonium hydroxide in step b) is present in an amount of about 0.5 equivalents or less relative to the compound of formula (II). In some embodiments, the tetrabutylammonium hydroxide in step b) is present in an amount of about 0.2 to about 0.5 equivalents relative to the compound of formula (II). In some embodiments, the tetrabutylammonium hydroxide in step b) is present in an amount of about 0.3 equivalents relative to the compound of formula (II).

[0181] In general, buprenorphine or its salt in step b) can be present in any amount suitable for the reaction. In some embodiments, buprenorphine or its salt is present in less than a stoichiometric amount (e.g., less than 1 equivalent) relative to the compound of formula (II). In some embodiments, buprenorphine or its salt in step b) is present in an amount of about 0.8 equivalents to about 1.0 equivalent relative to the compound of formula (II). In some embodiments, buprenorphine or its salt in step b) is present in an amount of about 0.9 equivalents relative to the compound of formula (II). In some embodiments, buprenorphine or its salt in step b) is present in an amount of about 0.8 equivalents relative to the compound of formula (II).

[0182] In general, in step b), the aprotic solvent can be any aprotic solvent suitable for the reaction. In some embodiments, the aprotic solvent in step b) is toluene.

[0183] In general, steps a) and b) can be carried out at any suitable temperature. In some embodiments, steps a) and b) are carried out at high temperatures (e.g., above room temperature). In some embodiments, step a) is carried out at a temperature of about 40°C to about 80°C. In some embodiments, step a) is carried out at a temperature of about 50°C to about 70°C. In some embodiments, step a) is carried out at a temperature of about 60°C. In some embodiments, step b) is carried out at a temperature of about 60°C to about 110°C. In some embodiments, step b) is carried out at a temperature of about 70°C to about 100°C. In some embodiments, step b) is carried out at a temperature of about 85°C.

[0184] In general, the compound of formula (II) obtained in step a) can be used in step b) with or without purification. In some embodiments, the compound of formula (II) obtained in step a) is used directly in step b). In some embodiments, the compound of formula (II) obtained in step a) is used directly in step b) without purification.

[0185] In general, the neutral form of buprenorphine dimer of formula (I) can be further purified by standard purification methods (e.g., chromatography, extraction, recrystallization, etc.). In some embodiments, the neutral form of buprenorphine dimer of formula (I) is further purified by grinding in an organic solvent. In some embodiments, the neutral form of buprenorphine dimer of formula (I) is further purified by grinding in acetone.

[0186] In a fourth aspect, the disclosure provides a method for producing a neutral form of buprenorphine dimer represented by formula (I), the method comprising the following steps: a) Formula: [ka] The buprenorphine HCl salt represented by , an aqueous solution of NaOH, and tetrabutylammonium hydroxide are mixed in 1,2-dichloroethane to obtain formula (II): [ka] The process of forming the compound; and b) A step of mixing the compound of formula (II), buprenorphine HCl salt, an aqueous solution of NaOH, and tetrabutylammonium hydroxide in toluene to obtain the neutral form of buprenorphine dimer of formula (I).

[0187] The reaction conditions for steps a) and b) are described above in the third embodiment, respectively.

[0188] In some embodiments, the NaOH aqueous solution in each of steps a) and b) is a 25% NaOH aqueous solution. In some embodiments, tetrabutylammonium hydroxide in step a) is present in an amount of about 5% by weight based on buprenorphine HCl salt. In some embodiments, tetrabutylammonium hydroxide in step b) is present in an amount of about 0.3 equivalents relative to the compound of formula (II). In some embodiments, buprenorphine or its salt in step b) is present in an amount of about 0.8 equivalents relative to the compound of formula (II). In some embodiments, step a) is carried out at a temperature of about 60°C. In some embodiments, step b) is carried out at a temperature of about 85°C. In some embodiments, the compound of formula (II) obtained in step a) is used directly in step b) without purification. In some embodiments, the buprenorphine dimer of formula (I) in its neutral form is further purified by grinding in acetone.

[0189] In some embodiments, the compound of formula (II) is obtained from step a) in a yield of at least 95%. In some embodiments, the compound of formula (II) is obtained from step a) in a quantitative yield.

[0190] In some embodiments, the neutral form of buprenorphine dimer of formula (I) is obtained in two steps (i.e., steps a) and b)) in at least 80% yield. In some embodiments, the neutral form of buprenorphine dimer of formula (I) is obtained in two steps (i.e., steps a) and b)) in at least 80% yield and with at least 95% purity.

[0191] In some embodiments, after purification (e.g., grinding in acetone), the buprenorphine dimer of formula (I) in its neutral form is isolated with a purity of at least 99%.

[0192] V. Compound In one embodiment, this disclosure relates to formula (I): [ka] This provides a neutral form of buprenorphine dimer represented by [formula].

[0193] In another embodiment, this disclosure includes formula (II): [ka] The present invention provides a compound represented by [formula], or a salt thereof.

[0194] In some embodiments, the compound of formula (II) is in a neutral form. VI. Enumerated Embodiments 1. A method for treating a disease in a human subject requiring treatment, wherein the therapeutically effective dose for the subject is given by formula (I): [ka] This includes orally administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein The therapeutically effective dose of buprenorphine dimer is at least about 100 mg / day in total daily dose on an unsalted and anhydrous basis, and A method by which the aforementioned administration achieves a plasma concentration of at least approximately 700 ng / mL in the subject. 2. The method according to Embodiment 1, wherein the buprenorphine dimer is in a neutral form represented by formula (I). 3. The method according to Embodiment 1 or 2, wherein the therapeutically effective amount of buprenorphine dimer is at least about 200 mg / day in total daily dose on a salt-free and anhydrous basis. 4. The method according to any one of Embodiments 1 to 3, wherein the buprenorphine dimer is administered once daily. 5. The method according to any one of Embodiments 1 to 3, wherein the buprenorphine dimer is administered twice daily. 6. The method according to any one of Embodiments 1 to 5, wherein the disease is chronic pain. 7. The method according to any one of Embodiments 1 to 5, wherein the disease is diarrhea-predominant irritable bowel syndrome (IBS-D). 8. A method for treating chronic pain in a subject requiring treatment, wherein the subject receives a therapeutically effective dose of formula (I): [ka] A method comprising administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the buprenorphine dimer is administered orally. 9. The method according to Embodiment 8, wherein the buprenorphine dimer is in a neutral form and is represented by formula (I). 10. A method for treating chronic pain in a subject requiring treatment, wherein the subject is given formula (I): [ka] A method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a neutral form of buprenorphine dimer represented by , wherein the pharmaceutical composition is administered orally. 11. The method according to any one of embodiments 8 to 10, wherein the chronic pain is nociceptive pain, neuropathic pain, or a combination thereof. 12. The method according to any one of embodiments 8 to 11, wherein the chronic pain is peripheral chronic pain. 13. The method according to any one of embodiments 8 to 12, wherein the chronic pain is peripheral neuropathic pain. 14. A method according to any one of Embodiments 8 to 13, wherein the subject has sickle cell disease (SCD), cancer and / or is undergoing chemotherapy, HIV, diabetes, herpes zoster, trauma, surgery, amputation, burn, or a combination thereof, and / or the subject has or has had coronavirus disease. 15. A method according to any one of embodiments 8 to 14, wherein the chronic pain is any one of the following 1) to 10): 1) Related to sickle cell disease (SCD) in the subject; 2) Chemotherapy-induced neuropathic pain in subjects with cancer undergoing chemotherapy; 3) HIV-induced sensory neuropathy; 4) Diabetic neuropathic pain; 5) Postherpetic neuralgia in a subject who has or had herpes zoster; 6) Chronic pain after trauma; 7) Postoperative pain; 8) Pain after amputation; 9) Pain after burns; and 10) Related to long-term effects in a subject who had coronavirus disease. 16. The method according to any one of embodiments 8 to 15, wherein the therapeutically effective amount is the total daily dose of buprenorphine dimer on a salt-free and anhydrous basis of about 50 mg to about 800 mg, about 50 mg to about 700 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, or about 50 mg to about 250 mg. [[ID=十五]]17. The method according to embodiment 16, wherein the therapeutically effective amount is the total daily dose of buprenorphine dimer on a salt-free and anhydrous basis of about 100 mg. 18. The method according to embodiment 16, wherein the therapeutically effective amount is the total daily dose of buprenorphine dimer on a salt-free and anhydrous basis of about 200 mg. 19. The method according to any one of embodiments 8 to 18, wherein the buprenorphine dimer is administered once, twice, three times, or four times a day. 20. The method according to embodiment 19, wherein the buprenorphine dimer is administered once a day. 21. The method according to embodiment 19, wherein the buprenorphine dimer is administered twice a day. 22. The method according to any one of embodiments 10 to 21, wherein the pharmaceutical composition comprising the buprenorphine dimer is a tablet. 23. The method according to embodiment 22, wherein the tablet comprising the buprenorphine dimer is an immediate-release tablet. 24. The method according to any one of embodiments 8 to 23, wherein the therapeutically effective amount of buprenorphine dimer reduces chronic pain measured by one or more criteria selected from the following group: 1) Decrease in the monthly average score on a 0-10 Likert scale over the past 1 month, 3 months, or 6 months compared to the monthly average score before treatment; 2) A decrease in the mean monthly score of characteristic pain intensity and / or disability over the past 1, 3, or 6 months compared to the mean monthly score before treatment; and 3) Reduced pain severity is selected from the following groups, representing a reduction in pain severity over the past 1 month, 3 months, or 6 months compared to pre-treatment pain severity: i) From Grade 4 (severe disability - severe limitation) to Grade 3 (severe disability - moderate limitation), Grade 2 (mild disability - high intensity), Grade 1 (mild disability - low intensity), and Grade 0 (no pain)—up to one of these grades: ii) From Grade 3 up to one of Grade 2, Grade 1, and Grade 0; iii) From Grade 2 to Grade 1 or Grade 0; and iv) From Grade 1 to Grade 0. 25. The method according to any one of embodiments 8 to 24, wherein the therapeutically effective amount of buprenorphine dimer provides an anti-hyperalgesic effect. 26. The method according to any one of Embodiments 8 to 25, wherein the hyperalgesia of the subject is reduced or substantially eliminated during or after the treatment. 27. The method according to Embodiment 26, wherein the hyperalgesia of the subject disappears during or after the treatment. 28. The method according to any one of embodiments 8 to 27, wherein the subject is a human. 29. The method according to Embodiment 28, wherein the person is an adult aged at least 18 years or older. 30. A method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, wherein the subject is given formula (I): [ka] A method comprising administering a therapeutically effective amount of a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) in the subject is 50 milligrams / deciliter (mg / dL) or less. 31. The method according to Embodiment 30, wherein the buprenorphine dimer is in a neutral form represented by formula (I). 32. A method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, comprising administering to the subject a pharmaceutical composition containing a therapeutically effective amount of a neutral form of buprenorphine dimer represented by formula (I), wherein the subject's blood 7α-hydroxy-4-cholesten-3-one (C4) concentration is 50 milligrams / deciliter (mg / dL) or less. 33. A method according to any one of embodiments 30 to 32, wherein the buprenorphine dimer is named (2S,2'S)-2,2'-((4R,4aS,4'R,4a'S,6R,6'R,7R,7aR,7'R,7a'R,12bS,12b'S)-(ethane-1,2-diylbis(oxy))bis(3-(cyclopropylmethyl)-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofl[3,2-e]isoquinoline-9,6-diyl))bis(3,3-dimethylbutan-2-ol). 34. The method according to any one of embodiments 30 to 32, wherein the blood C4 concentration of the subject is approximately 15 mg / dL to approximately 45 mg / dL. 35. The method according to any one of embodiments 30 to 34, wherein, prior to the treatment, the subject has the worst abdominal pain in the past 24 hours, with a weekly average score of 3 or more on a numerical rating scale of 1 to 10. 36. The method according to any one of embodiments 30 to 35, wherein, prior to the treatment, the subject has a stool consistency of greater than 5, as assessed by the Bristol Stool Stool Filtration Score (BSFS) on a weekly mean basis. 37. The method according to any one of embodiments 30 to 36, wherein the subject has undergone cholecystectomy. 38. The method according to any one of embodiments 30 to 37, wherein the subject is administered loperamide during the treatment. 39. The method according to any one of embodiments 30 to 38, wherein during the treatment, the subject is administered loperamide in a total dose of no more than one of the following: 8 mg over 24 hours, 14 mg over 48 hours, and 22 mg over 7 days. 40. The method according to any one of embodiments 30 to 37, wherein the subject is not administered loperamide during the treatment. 41. The method according to any one of Embodiments 30 to 40, wherein the therapeutically effective dose is a total daily dose of approximately 50 mg to approximately 250 mg of buprenorphine dimer on a salt-free and anhydrous basis. 42. The method according to Embodiment 41, wherein the therapeutically effective dose is a total daily dose of approximately 100 mg of buprenorphine dimer on a salt-free and anhydrous basis. 43. The method according to any one of embodiments 30 to 42, wherein the buprenorphine dimer is administered orally. 44. The method according to any one of Embodiments 30 to 43, wherein the buprenorphine dimer is administered once, twice, three times, or four times daily. 45. The method according to Embodiment 44, wherein the buprenorphine dimer is administered once daily. 46. ​​The method according to embodiment 45, wherein the buprenorphine dimer is administered at least about 30 minutes before breakfast. 47. The method according to any one of embodiments 32 to 46, wherein the pharmaceutical composition comprising the buprenorphine dimer is a tablet. 48. The method according to Embodiment 47, wherein the tablet containing the buprenorphine dimer is an immediate-release tablet. 49. The method according to any one of embodiments 30 to 48, wherein the subject is treated for at least 12 weeks. 50. The method according to any one of embodiments 30 to 49, wherein the therapeutically effective amount of buprenorphine dimer alleviates one or more symptoms associated with IBS-D. 51. The method according to Embodiment 50, wherein the therapeutically effective amount of buprenorphine dimer is 1) Reduce the weekly average score of worst abdominal pain in the past 24 hours by at least 30% compared to the weekly average score before treatment, and / or 2) i) A method for improving the measured stool hardness by a decrease in the average value of the BSFS score to less than 6, or ii) the disappearance of defecation when the characteristics of 1) are satisfied. 52. The method according to any one of embodiments 30 to 51, wherein the subject is a human. 53. The method according to embodiment 52, wherein the human is an adult of at least 18 years old. 54. Formula (I):

Chemical formula

Chemical formula

Chemical formula

[0195] VII. Examples Example 1: Study of spinal nerve ligation-induced neuropathic pain in rats (Chung model) Buprenorphine dimer HCl was dissolved in dimethyl sulfoxide (DMSO) / Solutol HS-15 / phosphate-buffered saline (PBS) (5 / 5 / 90) and administered subcutaneously, intraperitoneally, or intravenously at doses of 5 mL / kg or 10 mL / kg.

[0196] A group of 30 male Sprague Dolly (SD) rats weighing 180–220 g upon arrival were housed under constant temperature and humidity conditions and a 12-hour light-dark cycle. After acclimatization of the rat population, the baseline withdrawal response to mechanical allodynia (von Frey filaments) was tested using the method described below. The rats were anesthetized with pentobarbital (50 mg / kg, intraperitoneal administration). The left paravertebral muscle was separated from the spinous processes (L4–S2). The L6–S1 facet joint was clamped. The transverse process of L6 was removed to locate the L5 and L6 spinal nerves. The left L5 and L6 spinal nerves were isolated and securely ligated with 6.0 silk sutures.

[0197] Rats were tested for pre-administration mechanical allodynia using a manual von Frey test (Chaplan up / down method using a von Frey filament on the plantar surface of the left hind limb) on postoperative days 13, 21, or 37. Rats were randomly assigned to either the vehicle group or the treatment group based on their mechanical allodynia score.

[0198] Mechanical allodynia was performed on days 14, 22, or 38, 1 and 3 hours after administration of the vehicle or test substance, as shown in Figure 1. Rats were free to eat and drink until the test. Rats were placed in an inverted plastic cage on a wire rack and allowed to acclimate for 20-30 minutes. Allodynia was evaluated using the Chaplin "up / down" method with von Frye hairs. The force filaments had intensities of 3.61 (0.4g), 3.84 (0.6g), 4.08 (1.0g), 4.31 (2.0g), 4.56 (4.0g), 4.74 (6.0g), 4.93 (8.0g), and 5.18 (15.0g).

[0199] The mechanical allodynia test began with a monofilament handle labeled 4.31 (2.0 g), and the nylon filament under the wire mesh was applied perpendicularly to the appropriate plantar surface of the left hind limb. This procedure was repeated 3 to 5 times consecutively, covering a broad area of ​​the same rat's plantar surface, until a response was observed. A rapid withdrawal of the foot or flinching of the foot was considered a positive response, after which a weaker monofilament was selected and the same method was applied. Static limb movement (excluding walking) was considered a negative response, after which a stronger monofilament was applied in the same manner.

[0200] Mechanical allodynia (Study 1 / Day 14): On day 14 after SNL, buprenorphine dimer HCl of formula (I), morphine, and a vehicle were administered intraperitoneally or subcutaneously to a group of 10 SD rats. Mechanical allodynia was evaluated 1 and 3 hours after administration. One-way analysis of variance (ANOVA) followed by Dunnett's test was applied to compare the vehicle control group with the test compound administration group. The results are shown in Figure 2. * P<0.05, treatment versus vehicle control.

[0201] Mechanical allodynia (Study 2 / Day 22): On day 22 after SNL, buprenorphine dimer HCl of formula (I), morphine, buprenorphine, and a vehicle were administered subcutaneously, intraperitoneally, or intravenously to groups of 3-5 SD rats. Mechanical allodynia was evaluated 1 and 3 hours after administration. One-way analysis of variance (ANOVA) followed by Dunnett's test was applied to compare the vehicle control group with the test compound administration group. The results are shown in Figure 3. * P<0.05, treatment versus vehicle control.

[0202] Mechanical allodynia (Study 3 / Day 38): On day 38 after SNL, buprenorphine dimer HCl of formula (I), buprenorphine, gabapentin, and a vehicle were administered orally or subcutaneously to groups of 2-5 SD rats. Mechanical allodynia was evaluated 1 and 3 hours after administration. One-way analysis of variance (ANOVA) followed by Dunnett's test was applied to compare the vehicle control group with the test compound administration group. The results are shown in Figure 4. * P<0.05, treatment versus vehicle control.

[0203] Subcutaneous administration of buprenorphine dimers at 100 mg / kg and 200 mg / kg (488 mg and 976 mg HED in a 60 kg human, respectively) resulted in a statistically significant reduction in hyperalgesia after 3 hours. This effect was equivalent to that of orally administered gabapentin at 100 mg / kg.

[0204] In conclusion, Chung et al.'s findings suggest that the minimum threshold plasma concentration required to elucidate the antinociceptive effect is approximately 729 ng / mL for the buprenorphine dimer.

[0205] Example 2: Anti-algesic effect of buprenorphine dimer in a mouse model Before examining the anti-hyperalgesic effects of buprenorphine dimers in the mouse model described herein, it was important to confirm that this model was sufficiently sensitive to distinguish between hyperalgesic pain (sensitized state) and mechanically non-hyperalgesic pain (unsensitized state). The first part of this study involved a single oral administration of buprenorphine dimer and control saline under fixed colorectal balloon pressure (30 mmHg).

[0206] As shown in Figure 5A, a slight difference was observed between the vehicle group and the dimer-administered group in normal mice exhibiting mechanical pain. In the sensitized group (Figure 5B), a large statistically significant difference was observed between the vehicle control group and the dimer-treated group, and a clear anti-algesic hypersensitivity response was confirmed after a single dose.

[0207] In the second experiment (Figure 6), the effects of orally administered buprenorphine dimer (50 mg / kg) and oral eluxadoline (50 mg / kg) were compared after daily administration for 5 days, with increasing inflation pressure. A significant difference was observed between the visceral motility response of buprenorphine dimer and eluxadoline, confirming the anti-algesic effect of buprenorphine dimer. With buprenorphine dimer, the curve shifted downward (p=0.001, two-way ANOVA), indicating a potent anti-algesic effect. Elxadoline did not show an anti-algesic effect, and its effect was no different from that of placebo.

[0208] Next, as shown in Figure 7, the anti-algesic effect of oral administration of low doses of buprenorphine dimer was investigated. The results confirmed that buprenorphine dimer reduced visceral pain induced by colorectal balloon dilation at all doses examined, i.e., 1–15 mg / kg. The human equivalent doses examined in this study included doses in the 5–50 mg range, which are expected to be effective in alleviating increased gastrointestinal motility.

[0209] Example 3: Phase 1 clinical trial in healthy subjects The buprenorphine dimer (neutral form) of formula (I) was absorbed after oral administration in healthy volunteers. All doses examined were safe and well-tolerated.

[0210] In a single-dose escalation (SAD) study, the safety, pharmacodynamics, and pharmacokinetics of oral buprenorphine dimer were evaluated at six dose levels. These doses were 5, 15, 50, 150, 400, and 800 mg, administered after overnight fasting. Plasma concentrations of buprenorphine dimer were measured up to 72 hours. maxThe median was 8 hours (range 4 - 12 hours) at all dose levels. The half-life was consistent across all doses and was 21 - 27 hours. As shown in Figures 8A and 8B, the pharmacokinetics of oral buprenorphine dimer after single-dose administration were dose-dependent and non-linear. Table 1 shows a summary of the plasma concentrations (ng / mL) of buprenorphine dimer at selected doses and time points.

Table 1

[0211] In the multiple ascending dose (MAD) study, the safety, pharmacodynamics, and pharmacokinetics of oral buprenorphine dimer were evaluated at six dose levels. These doses were 5, 15, 50, 100, 150, and 400 mg and were administered daily for 7 days after an overnight fast. On days 1 and 7, serial blood samples were collected to measure the plasma concentration of buprenorphine dimer. Additionally, samples were collected on days 4 - 6 to measure trough concentrations. T max The median was approximately 6 hours (range 1 - 8 hours) at all dose levels, and the mean half-life on day 7 based on plasma concentrations over 96 hours was 36 - 43 hours. Statistical analysis showed that buprenorphine dimer reached steady state by day 5 at all doses, and the steady-state plasma exposure (C max and AUC 0-24h ) was generally shown to be approximately 2.5 times the level on day 1 (accumulation factor 2.6). As shown in Figures 9A and 9B, the steady-state pharmacokinetics of oral buprenorphine dimer after daily dosing were also dose-dependent and non-linear. Table 2 shows a summary of the plasma concentrations (ng / mL) of buprenorphine dimer at selected doses and time points.

Table 2

[0212] Surprisingly and unexpectedly, in humans, the neutral form (i.e., free base) of buprenorphine dimer of formula (I) is rapidly absorbed, reaching blood concentrations of 2000–3000 ng / ml. See Tables 1 and 2. Based on mean plasma concentrations (MAD), by day 7, with a daily dose of 100 mg, the mean plasma concentration of buprenorphine dimer of formula (I) reached a steady-state level exceeding 700 ng / mL. See Figure 9C.

[0213] Example 4: Dosage appropriateness in the treatment of peripheral chronic pain in subjects with sickle cell disease. Results from clinical pharmacokinetic studies in healthy volunteers indicate that at least a 100 mg dose (e.g., 100 mg once or twice daily) is required to achieve a threshold plasma concentration of 700 ng / mL that elicits any antinociceptive effect in patients. The data also suggest significant concentration variability, with the mean concentration falling below 700 ng / mL approximately 18 hours after administration. Furthermore, renal clearance in sickle cell disease patients is generally reported to be higher than in healthy volunteers (contact with Dr. K. Gupta). Data from healthy volunteer studies suggest that renal clearance is not the primary excretion route for buprenorphine dimers. To minimize variability between healthy volunteers and patients and maintain drug exposure above 700 ng / mL, a study administering 200 mg of buprenorphine dimer twice daily, 30 minutes before meals, would be considered in a phase 2 chronic efficacy trial in sickle cell disease patients.

[0214] Example 5: Whole-body autoradiography test Approximately 100 mg / kg 14 After oral administration of 13C-labeled buprenorphine dimer to healthy male rats, a limited distribution of drug-derived radioactivity was observed. The limit of quantification (LOQ) was approximately 1,174 nanogram equivalents per gram of tissue. 14It was identified as 14C-labeled buprenorphine dimer. A total of 45 tissues were quantified. The majority of strongly positive tissues were from the gastrointestinal tract and related organ systems. The few positive tissues disappeared from the body relatively quickly. Only two tissues, the spleen and the adrenal gland, remained positive (slightly above LOQ) 168 hours after administration.

[0215] In healthy male rats, the distribution of C in most tissues is max The earliest time point analyzed, at 2 hours, was observed, with 11 out of 45 tissues showing positive results. Table 3 shows the results across various tissues. 14 The observed concentrations (ng-equivalent / g) of 1C-labeled buprenorphine dimers are shown. [Table 3]

[0216] The 11 tissues, in order from highest to lowest concentration, contained the following: cecal contents, small intestine contents, stomach contents, large intestine contents, esophageal contents, liver, adrenal gland, spleen, urine, blood, and bone marrow. The individual tissues that tested positive are listed below.

[0217] Cecal contents: C 2 hours after administration max The concentration was 4,474,873 ng-equivalents / g. The concentration steadily decreased until 48 hours after administration, and fell below the LOQ after 168 hours.

[0218] Small intestinal contents: C 2 hours after administration max The concentration was 1,232,817 ng-equivalents / g. The concentration steadily decreased up to 48 hours after administration, and was undetectable after 168 hours.

[0219] Gastric contents: C 2 hours after administration max The concentration was 1,226,432 ng-equivalents / g. The concentration steadily decreased until 48 hours after administration, and fell below the LOQ after 168 hours.

[0220] Colon contents: C 8 hours after administration maxThe concentration was 1,655,177 ng-equivalents / g. The concentration steadily decreased until 48 hours after administration, and fell below the LOQ at 168 hours after administration.

[0221] Esophageal contents: C 2 hours after administration max The concentration was 12,943 ng-equivalents / g. The concentration steadily decreased up to 24 hours after administration, and fell below the LOQ at 48 and 168 hours after administration.

[0222] Liver: C 8 hours after administration max The concentration was 5,388 ng-equivalents / g. The concentration steadily decreased until 48 hours after administration, and fell below the LOQ after 168 hours.

[0223] Adrenal gland: C 8 hours after administration max The concentration was 4,737 ng-equivalents / g. The concentration remained stable until 48 hours after administration, and a decrease was observed after 168 hours.

[0224] Example 6: Absence of buprenorphine dimers in the brain and spinal cord, pupillary constriction, and absence of signs and symptoms of opioid central action. A. Rat brain and spinal cord Table 3 of Example 5 shows: 14 This shows the radioactivity in body fluids and tissues after a single oral administration of 14C-labeled buprenorphine dimer. The radioactive dimer was not detected in the cerebellum, cerebrum, or spinal cord.

[0225] B. Human pupil measurement results Pupillary constriction was evaluated in both the single-dose escalation (SAD) and repeated-dose escalation (MAD) studies of the Phase I clinical trial (described in Example 4).

[0226] SAD trial: No subjects reported pinpoint pupil size (<2mm) before or after administration. Only one subject had a pupil diameter of less than 4mm (3.9mm at baseline), and this patient's pupil diameter did not change after administration.

[0227] Statistically significant changes in pupil diameter from baseline were observed in the 5 mg, 150 mg, and 400 mg groups. However, these post-baseline changes are considered clinically insignificant and may reflect test-specific variability.

[0228] MAD trial: At baseline before administration, the mean (SD) pupil diameters in the buprenorphine dimer group and the placebo group were 6.393 (0.829) and 6.082 (0.663) mm, respectively. On day 7, approximately 6 hours after administration, the mean (SD) pupil diameters in the buprenorphine dimer group and the placebo group were 6.278 (0.764) and 6.271 (0.574) mm, respectively.

[0229] In subjects receiving buprenorphine dimer, no dose-response trend was observed in the change of pupil diameter from baseline at the time of administration. Throughout the study period, no subjects in either the administration group or the placebo group experienced pupil diameters of 4 mm or less. Overall, no clinically significant changes in pupil diameter from baseline were observed in any subject in the buprenorphine dimer groups, and there was no evidence of pinpoint pupils (defined as pupil diameter of 2.0 mm or less) after administration.

[0230] C. Disappearance of signs and symptoms of opioid central nervous system effects in humans. A double-blind, placebo-controlled phase 2 trial of buprenorphine dimers showed no clinical features suggestive of central nervous system effects from the dimers.

[0231] D. Spontaneous motility activity (LMA) and pupil diameter in rats The potential adverse effects on spontaneous motor activity (LMA) and pupil diameter of intravenous (IV) administration of 50 mg / kg of buprenorphine dimer HCl were evaluated compared to those of 5 mg / kg of morphine and 50 mg / kg of erxadrine.

[0232] A group of 4-6 Sprague Dolly (SD) rats weighing 200±20g was used. Buprenorphine dimer HCl and elxadrine were dissolved in DMSO / Solutol® HS15 / PBS (5 / 5 / 90, v / v / v) and administered intravenously (IV) at a dose of 50 mg / kg, while morphine was injected at a dose of 5 mg / kg.

[0233] Immediately after injection of the test compound, rats were individually placed in LMA chambers (Columbus Instruments, USA) in a quiet room at 25°C. The number of individual movements (distance traveled, travel time, vertical stand-up) was totaled every 10 minutes for 60 minutes after administration, measured by blocking an infrared grid. The mean ± SEM values ​​were then calculated for each treatment group. Furthermore, pupillary constriction was observed immediately before and after the LMS test. One-way ANOVA followed by Dunnett's test was applied to compare the vehicle group and the treatment group. A p-value of < 0.05 indicated a statistically significant difference.

[0234] As shown in Figure 10A, the total distance traveled by each individual (DTcm) was summed up every 10 minutes for 60 minutes after administration, measured by blocking the infrared grid. * P<0.05, treatment versus vehicle control.

[0235] As shown in Figure 10B, the total migration time (ST) of individuals was measured every 10 minutes for 60 minutes after administration by blocking the infrared grid. sec ) was totaled. * P<0.05, treatment versus vehicle control.

[0236] As shown in Figure 10C, the total vertical rise (VC) of individuals was summed up every 10 minutes for 60 minutes after administration, measured by blocking the infrared grid. * P<0.05, treatment versus vehicle control.

[0237] Buprenorphine dimer HCl showed comparable activity to the vehicle control group in terms of horizontal movement frequency (distance and time) and vertical movement frequency (vertical rise) during a 60-minute recording period (Figures 10A-10C). In contrast, morphine and erxadrine significantly reduced both vertical and horizontal movement by over 90%, exhibiting a strong sedative effect. Consistent with this inhibitory effect, this dose level of erxadrine was associated with a 40% mortality rate within 3 hours post-administration. However, administration of buprenorphine dimer HCl, morphine, and erxadrine did not affect pupil diameter. Buprenorphine dimer HCl at 50 mg / kg showed no effect on spontaneous movement activity and did not induce miosis.

[0238] Example 7: Stability of the buprenorphine dimer of formula (I) The stability of the buprenorphine dimer of formula (I) (1 mg / mL) was evaluated by incubation at room temperature and 60°C for 30 minutes under conditions of water (neutral), 1N HCl (acidic), and 5% NaHCO3 (basic). As shown in Figure 11, the buprenorphine dimer was relatively stable, but there was a loss of approximately 20% under the acidic conditions of 60°C. The substance formed during incubation under the acidic conditions of 60°C was the dimer product due to the disappearance of methanol. Buprenorphine was not detected.

[0239] In conclusion, the buprenorphine dimer of formula (I) does not hydrolyze to release buprenorphine or other individual thebaine-derived molecules under neutral, acidic, and basic conditions, at room temperature or high temperatures. The only decomposition observed was the disappearance of methanol after incubation under acidic conditions at 60°C. The results of these tests indicate that it is impossible to recover buprenorphine or individual thebaine-derived molecules under various chemical or thermal conditions.

[0240] Example 8: Method for producing a neutral form of buprenorphine dimer Process a) [ka] Buprenorphine hydrochloride (130 g), tetrabutylammonium hydroxide (TBAOH) (6.0 g, 5%), 25% NaOH aqueous solution (1150 mL), and 1,2-dichloroethane (1380 mL) were added to the reaction vessel. The resulting mixture was heated to 60°C and held for 4 hours to confirm the completion of the reaction. After the reaction was complete, the reaction mixture was cooled to room temperature and the phases were separated. The aqueous phase was back-extracted with methyl tert-butyl ether (MTBE) (1.5 L). The organic phases were combined and concentrated to dryness. The crude product (3) was used in the next step without purification.

[0241] Step b) [ka] Toluene (1.2 L) was added to the container of crude intermediate (3) to make a homogeneous solution, which was then packed into a 5 L three-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, and condenser. Buprenorphine HCl (0.8 equivalents per 183.2 g, step a), TBAOH (72 g, 0.3 equivalents), and 25% NaOH aqueous solution (1.2 L) were added to the reactor. The resulting mixture was heated to 85°C and held for at least 16 hours. After completion, the reaction mixture was cooled to room temperature and the phases were separated. The aqueous phase was then back-extracted with methyl tert-butyl ether (MTBE) (0.6 L). The combined organic phases were washed twice with brine (0.5 L), then dried over Na2SO4 and filtered. The wet cake was washed with additional MTBE (0.5 L). The filtrate was collected and concentrated to approximately 782 g (approximately 3 volumes), then IPA (1.1 L, 5 volumes) was added and it was further concentrated to approximately 787 g (approximately 3 volumes), then IPA (1.1 L) was added and it was further concentrated to approximately 987 g (3-4 volumes). The slurry was transferred to a flask and then IPA (1.1 L) was added. Next, the resulting mixture was heated under reflux and held for 2 hours. The mixture was cooled to 25°C and filtered. The moist cake was washed twice with additional IPA (0.5 L), and then dried under vacuum at 50°C to obtain 290 g of white solid (yield: 83%, purity: 98.9%).

[0242] Purification by grinding: The purity of the crude dimer can be improved by grinding with 10 volumes of acetone. Crude dimer (24 g, HPLC purity: 99.04%) was added to acetone (0.24 L, 10 volumes). The resulting mixture was heated under reflux and held for 3 hours, then cooled to room temperature. The solid was filtered and washed twice with acetone (50 mL, 2 volumes). Finally, the solid was dried under vacuum at 50°C to obtain 20 g of white solid (83%, HPLC purity: 99.48%).

[0243] Another batch of the neutral form of buprenorphine dimer was prepared according to the process described above. Starting with buprenorphine HCl (275 g), the neutral form of buprenorphine dimer was isolated as a white solid (300 g, yield: 80%, HPLC purity: 99.5%).

[0244] Example 9: Double-blind, placebo-controlled Phase 2 trial - Protocol summary Study Name: Double-blind, placebo-controlled, phase 2 responsive, adaptive randomized trial of buprenorphine dimers in patients with diarrhea-predominant irritable bowel syndrome (IBS-D)

[0245] the purpose:

[0246] Main purpose To evaluate the efficacy of buprenorphine dimers in IBS-D patients, and to evaluate the safety and tolerability of buprenorphine dimers in IBS-D patients.

[0247] Secondary purpose : Evaluate changes in quality of life (QoL) during the treatment period.

[0248] method:

[0249] This study was a randomized, double-blind, placebo-controlled, 12-week parallel proof-of-concept trial using a responsive, adaptive randomized approach, comprising two treatment groups (50 mg and 100 mg buprenorphine dimers) and one placebo group. After a two-week screening period, eligible patients entered a baseline symptom assessment period, which lasted up to three weeks. During the baseline symptom assessment period, patients were instructed to keep an electronic diary (eDiary) containing daily data on IBS symptoms, bowel function, and loperamide rescue use (not permitted during the baseline period).

[0250] Patients who met all enrollment criteria were randomly assigned to receive either two different doses of buprenorphine dimer tablets or placebo for 12 weeks. The study drug was to be taken once daily (QD), approximately 30 minutes before breakfast. Patients visited the clinic for follow-up on days 14, 28, 56, 84, and 2 weeks after completion of administration (day 98). Patients who discontinued the study before completion were instructed to return to the study clinic as soon as possible after discontinuing the study drug to complete the early discontinuation procedure.

[0251] Patients kept a daily electronic diary throughout the 12-week double-blind treatment period, recording data on IBS symptoms, bowel function, and loperamide rescue use. The data entered into the electronic diary was never provided to the principal investigator or the staff of the clinical trial site during the study period. However, the principal investigator received daily notifications regarding patient diary adherence, infrequent bowel movements recorded in the diary (four consecutive days without bowel movements confirmed by complete diary entries), and overuse of loperamide rescue for uncontrolled diarrhea. Patients were permitted to take 2 mg of loperamide every six hours as needed, but were instructed not to exceed a total of 8 mg (4 tablets) within 24 hours, 14 mg (7 tablets) within 48 hours, or 22 mg (11 tablets) over seven days. Use exceeding these amounts was considered an overdose and resulted in follow-up by the principal investigator. The principal investigator was instructed to contact the patient as soon as possible and request an evaluation and / or unscheduled visit if they received notification of loperamide overuse or a decrease in bowel movement frequency.

[0252] Two interim analyses using a Bayesian hierarchical model based on binary complex reactions were planned to evaluate the following items: 1. Dose-response and patient allocation to the active treatment group using response-based adaptive randomization. 2. Early discontinuation of registration if sufficient efficacy or futility is found.

[0253] The interim analysis was conducted by a third-party biostatistician, and a firewall was in place to prevent the interim results from being provided to the sponsor or the principal investigator of the clinical trial site.

[0254] Patient numbers (after planning and analysis): This study was planned to randomly assign 320 patients with IBS-D. Randomization was stratified by whether or not there was a history of cholecystectomy / agallbladder aplasia. A total of 1,691 patients were screened, and 320 were randomly assigned to one of three treatment groups (65 in the buprenorphine dimer 50 mg group, 127 in the buprenorphine dimer 100 mg group, and 128 in the placebo group).

[0255] Diagnostic and main inclusion and exclusion criteria:

[0256] Inclusion Criteria Patients aged 18 to 75 years were diagnosed with IBS-D based on the Rome IV diagnostic criteria. To be eligible for randomization to the double-blind treatment phase, patients had to meet all four of the following conditions. 1. Participants must have completed daily electronic journaling for at least 6 out of 7 days in the week prior to randomization, and for at least 11 out of 14 days in the two weeks prior to randomization. 2. The weekly average of the worst abdominal pain score in the past 24 hours during the week prior to randomization is greater than 3 on a numerical rating scale of 0 to 10. 3. The weekly average stool consistency, as assessed by the Bristol Stool Filtration Score (BSFS), must be greater than 5 during the week prior to randomization. 4. Loperamide was not used during the 14 days prior to randomization.

[0257] Exclusion criteria Subjects who meet any of the following criteria during screening are ineligible to participate in this study. 1. A history of clinically relevant pancreatic disease, including pancreatitis, schizophrenia, or sphincter of Oddi (SO) dysfunction with pancreatic symptoms. 2. A history of biliary tract disease, including acute cholecystitis, within the past 2.6 months, or a history of biliary tract pain, including post-cholecystectomy pain. 3. Patients who have undergone biliary sphincterotomy and have persistent abnormal liver function transaminase (LFT) levels postoperatively. 4. Elective surgery is scheduled within the next four months. 5. Serious and / or severe medical conditions, such as cardiovascular disease, neurological disease, infection, kidney disease, liver disease, or respiratory disease, that could interfere with the patient's medical care, participation in or conduct of this study. 6. A history of intestinal obstruction, intestinal stenosis, toxic megacolon, GI (gastrointestinal tract) perforation, fecal embolism, gastric ligation, bariatric surgery, adhesions, ischemic colitis, or enterovascular disorders (e.g., aortic-iliac disease). 7. A history of lactose intolerance (which cannot be controlled even with a lactose-free diet) or other malabsorption syndromes (e.g., fructose malabsorption). 8. Difficulty swallowing or swallowing tablets. 9. A history of inflammatory bowel disease, celiac disease, Clostridium difficile colitis, or unexplained gastrointestinal bleeding within 3 months prior to screening. 10. History of major surgery on the stomach, liver, pancreas, or intestines (appendectomy, hemorrhoidectomy, or polypectomy are acceptable if performed at least 3 months prior to the clinical trial screening. Postoperative biliary pain and surgery not performed at least 3 months prior to the screening are acceptable, however, laparoscopic or open cholecystectomy without complications are acceptable). 11. Patients at high risk of colorectal cancer who are over 40 years of age must have undergone a screening colonoscopy within 3 years prior to their clinical trial screening visit, or if they are over 50 years of age, they must have undergone a normal screening colonoscopy within 10 years prior to their clinical trial screening visit. Patients with Lynch syndrome or familial polyposis will be excluded from this study.

[0258] Study drug, dosage, and administration method: Formula (I) (dibuprenorphine ethyl ether) tablets, prepared as 25 mg or 100 mg immediate-release tablets, were administered orally once daily at a dose of 50 mg or 100 mg for a total of 12 weeks.

[0259] Control drug, dosage, and administration method: Buprenorphine dimer tablets were administered orally once daily for a total of 12 weeks.

[0260] Treatment duration: The study treatment was administered once daily for 12 weeks. Each patient was enrolled in the study for approximately 19 weeks, and if all 320 patients were randomized, it was estimated that enrollment would take approximately 16-20 months. Therefore, the clinical portion of the study was expected to last up to approximately 25 months.

[0261] Test evaluation:

[0262] The effectiveness evaluation based on electronic diary data included the following items: daily recording of worst abdominal pain score; abdominal discomfort score; abdominal distension score; BSFS; bowel movement frequency, urgency, and incontinence; IBS-D general symptom score; weekly recording of IBS abdominal symptom relief (IBS-AR); monthly recording of IBS-QoL and IBS inflammatory bowel syndrome severity scoring system (IBS-SSS); and completion of the patient's overall impression change assessment (PGIC) at week 12.

[0263] Safety assessments include monitoring of adverse events, clinical laboratory evaluation, 12-lead electrocardiogram (ECG), vital sign measurement, physical examination findings (including neurological examination), concomitant medications, and pregnancy testing in women of childbearing potential.

[0264] Patients who experienced characteristic, clinically significant, but uncharacteristic, changes in the location, severity, and / or nature of typical IBS abdominal pain, or right upper abdominal pain and / or epigastric pain with colic (with or without associated nausea, vomiting, loss of appetite, or radiating pain to the back), or who experienced an exacerbation of abdominal pain that accelerated withdrawal from the study, should have had blood drawn immediately to measure plasma concentrations of lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and direct bilirubin, alkaline phosphatase (ALK-P), and buprenorphine dimer. Patients who experienced severe constipation, a potentially persistent abuse-related adverse event (AE), or a serious adverse event (SAE) should have had blood drawn as soon as possible to measure buprenorphine dimer plasma concentration.

[0265] To measure the plasma concentrations of buprenorphine dimers and their metabolites, blood samples were taken once per patient between 4 and 6 hours post-administration on day 14 of treatment.

[0266] Evaluation criteria:

[0267] Primary efficacy endpointsThe primary endpoint was the study composite responder status determined during the 12-week treatment period. A study composite responder was defined as a patient who met the daily composite response criteria on at least 50% of the days on which electronic diary entries were made between day 1 and day 84. To be eligible as a responder, patients needed to have completed electronic diary entries for at least 60 days between day 1 and day 84. Patients with fewer than 60 days of electronic diary entries were considered non-responders.

[0268] In order to obtain a daily response, the patient needed to meet both of the following criteria on a specific day: • Pain response: Worst abdominal pain score in the past 24 hours has improved by 30% or more compared to the average for the week prior to randomization. • Stool consistency response: The average BSFS score (daily average) for all bowel movements reported on a given day is less than 6, or there is no bowel movement even if the worst abdominal pain improves by 30% or more.

[0269] Secondary efficacy endpoints The following secondary efficacy endpoints were analyzed: composite endpoint, modified composite, pain, stool consistency, IBS general symptom assessment, IBS-AR, and further analysis of other IBS symptoms (bloating, discomfort, frequent urination, and incontinence).

[0270] Exploratory evaluation items Quality of life (QOL) assessment, PGIC, and urinary urgency were analyzed as exploratory outcome measures.

[0271] Safety variables Safety variables include adverse events (including SAEs and AEs of special interest), vital signs, body weight, electrocardiogram, physical examination, hematology, and serological chemistry.

[0272] Statistical Methods: In the final analysis, conducted approximately 12 weeks after the last patient was randomized, a one-sided p-value was calculated for a two-sample proportion test comparing all patients in the optimal active drug group with placebo. An active drug was considered superior to placebo if the corresponding one-sided p-value was 0.030 or less. This threshold was chosen to keep the overall one-sided type 1 error (using multiple interim analyses and multiple doses) to approximately 0.05.

[0273] The analysis of secondary efficacy endpoints was as follows: Therapeutic effects were evaluated for each active drug and placebo using a paired, one-sided Cochrane-Mantel-Haenszel (CMH) test, stratified by a history of cholecystectomy / gallbladder aplasia. Treatment efficacy was evaluated for all patients using a paired, one-sided CMH test, stratified by a history of cholecystectomy / gallbladder aplasia, comparing the active drug and placebo in a pooled sample. • Pain responders during weeks 1-12: Defined as patients who met the daily pain response criteria for at least 50% of the days they kept an electronic diary during this period. To be considered a responder, patients needed to keep an electronic diary for at least 60 days over a 12-week period. • Stool consistency responders during weeks 1-12: Defined as patients who met the daily stool consistency response criteria for at least 50% of the days they kept an electronic diary during this period. To be considered a responder, patients needed to keep an electronic diary for at least 60 days over a 12-week period. • IBS General Symptom Score: Change from baseline over the period from week 1 to week 12. Responders were defined as having an IBS General Symptom Score of 0 (none) or 1 (mild), or an improvement of 2.0 or more in their daily IBS Symptom Score compared to the mean of the week prior to randomization. Responders were required to keep an electronic diary for at least 60 days over the 12-week period. • IBS Abdominal Symptom Relief (IBS-AR): Responder rate during weeks 1-12. This was defined as patients who responded "yes" to appropriate relief of IBS symptoms every week for at least 50% of the weeks during that period. As a secondary evaluation item, a modified composite responder evaluation item was analyzed, and in this evaluation item, the daily responder was defined as follows: o Pain response: Worst abdominal pain score in the past 24 hours has improved by 30% or more compared to the average for the week prior to randomization. o Stool consistency response: No bowel movement if the BSFS for all bowel movements reported on a given day is less than 6, or if the worst abdominal pain has improved by 30% or more. Other IBS symptoms: o Discomfort: Change from baseline in the daily abdominal discomfort score o Bloating: Change from baseline in the daily bloating score o Bowel movement frequency: Change from baseline in the average number of bowel movements per day o Incontinence: Change from baseline in the average number of fecal incontinence episodes per day and the number of incontinence-free days.

[0274] The exploratory evaluation criteria are as follows: • IBS-Quality of Life (IBS-QOL) Responders: Defined as patients whose IBS-QOL total score, assessed at the relevant visit, showed an improvement of at least 14 points compared to their baseline IBS-QOL total score. • IBS Severity Scoring System (IBS-SSS) Responder: Defined as a patient whose IBS-SSS total score, assessed at the relevant visit, decreased by 50 points or more compared to their baseline IBS-SSS total score. • Patient Global Impression Change Score (PGIC): At week 12, patients were asked to complete the PGIC assessment to evaluate their IBS-D symptoms compared to baseline. • Constipation as defined by diary entries: Based on electronic diary entries, this was defined as an average BSFS score of less than 2 for any given test week. • Other exploratory IBS symptoms: The following diary evaluation items were measured daily using an electronic diary. o Urinary urgency (number of episodes of urinary urgency) o Number of days without urinary urgency.

[0275] The composite endpoints of abdominal pain and stool consistency at 12 weeks were analyzed within the following subgroup variable categories: • Baseline C4 level (normal or elevated) • Baseline CRP level (normal or elevated) • Use of PPI (Yes, No)

[0276] Safety variables were summarized using descriptive statistics. Summaries of treatment-related adverse events (TEAEs), adverse events leading to discontinuation, and SAEs, as well as particularly noteworthy adverse events (AESIs), including severe constipation, new-onset abdominal pain (regardless of nausea, vomiting, loss of appetite, or presence of back radiation), and potentially abuse-related adverse events, were evaluated. Responses to questions in the QoL assessment tools were not considered adverse events. However, for sensitivity analysis, certain responses were assumed to be "potential QoL adverse events" and summarized separately.

[0277] Plasma concentration data was listed.

[0278] Example 10: Double-blind, placebo-controlled Phase 2 trial - Results patient placement A total of 1,691 patients underwent eligibility assessment, and 320 were randomly assigned to one of three treatment groups. The percentage of patients who completed active treatment was 78.5% in the buprenorphine dimer 50 mg group and 83.5% in the buprenorphine dimer 100 mg group. The most common reasons for discontinuing active treatment were adverse events, patient dropout from follow-up, and patient withdrawal from treatment.

[0279] Demographic characteristics and baseline characteristicsThe average age of all patients was 43.6 years (range: 19 to 75 years). The majority of patients reported being Caucasian (256 people [80.0%]) and non-Hispanic or non-Latino (290 people [90.6%]). The youngest group was the 100 mg buprenorphine dimer group, with an average age of 42.3 years. The oldest group was the 50 mg buprenorphine dimer group, with an average age of 44.8 years. Overall, 70.3% of patients were female. The average body mass index (BMI) was 33.1 kg / m2 (range: 17 to 65). The group with the lowest BMI was the 50 mg buprenorphine dimer group, with an average BMI of 32.1, and the group with the highest BMI was the 100 mg buprenorphine dimer group, with an average BMI of 34.2.

[0280] Eighty-five patients with a history of cholecystectomy were enrolled in this study, representing 27% of the total randomized patients.

[0281] Baseline CRP levels were within the normal range in 229 patients and elevated in 87 patients. Baseline C4 levels were within the normal range in 254 patients and elevated in 58 patients. 63 patients used proton pump inhibitors, while 257 did not. Baseline CRP and C4 levels were unavailable for some patients.

[0282] Results of the primary efficacy endpoint : Regarding the primary endpoint (composite response), in the intention-to-treat (ITT) analysis population (n=320), the responder rates for the buprenorphine dimer 50 mg group, 100 mg group, and placebo group were 16.9%, 28.3%, and 21.9%, respectively (100 mg vs. placebo, p=0.117).

[0283] To account for the potential trial effects of COVID-19, the statistical analysis plan (SAP) included two analysis populations defined as "COVID-19 affected" patients and "COVID-19 perprotocol affected" patients (SAP sections 4.3.4 and 4.3.5). "COVID-19 affected" patients were defined as patients in whom a COVID-19 adverse event was recorded (n=11). "COVID-19 perprotocol affected" patients were defined as patients evaluated as having COVID-19 or who experienced a COVID-19-related protocol deviation (n=20). The composite responder ratios in the ITT analysis population excluding COVID-19 perprotocol affected patients (n=300) were 18.3%, 29.5%, and 20.3% for the buprenorphine dimer 50 mg group, 100 mg group, and placebo group, respectively (100 mg vs. placebo, p=0.051).

[0284] Primary endpoints for predefined patient subgroups Overuse of loperamide (rescue drug): Overuse of loperamide, a rescue drug, was significantly more common in patients in the placebo group. Therefore, these patients (n=37) were considered treatment failures and a post-hoc analysis was conducted (see the explanation of the protocol-compliant analysis population below).

[0285] Protocol-compliant analysis population: Post-hoc analyses were performed on the primary endpoint, primary secondary endpoint, and exploratory endpoint to determine the outcomes of "protocol-compliant" patients, i.e., the group from the ITT analysis population that excluded perprotocol COVID-19 patients and considered loperamide overuse as treatment failure (referred to as the "protocol-compliant" analysis population in this study report, n=300). In this protocol-compliant analysis population, the composite response rates for the buprenorphine dimer 50 mg group, 100 mg group, and placebo group were 16.7%, 27.0%, and 14.4%, respectively (100 mg vs. placebo, p=0.008).

[0286] Patients with elevated C4 levels vs. patients with normal C4 levels: The response rate in patients with elevated C4 levels was lower than in patients with normal C4 levels. Therefore, a post-hoc analysis of the primary and other endpoints was performed in the protocol-compliant analysis population (n=240) with normal C4 levels at baseline to determine the optimal patient population for future studies. The composite response rates in the protocol-compliant analysis population with normal C4 levels were 19.6%, 31.6%, and 15.4% in the buprenorphine dimer 50 mg group, 100 mg group, and placebo group, respectively (100 mg vs. placebo, p=0.005) (Figure 13). None of the patients in the protocol-compliant analysis population with elevated C4 levels were composite responders in any of the three groups.

[0287] Post-cholecystectomy patients: In the protocol-compliant analysis population, a similar post-hoc analysis was performed only in patients without a gallbladder (post-cholecystectomy patients, n=85). The composite responder rates in protocol-compliant post-cholecystectomy patients were 13.3%, 28.6%, and 11.4% in the buprenorphine dimer 50 mg group, 100 mg group, and placebo group, respectively (100 mg vs. placebo, p=0.036).

[0288] Figure 14 shows the composite responder rate at weeks 1–12 of treatment in post-cholecystectomy patients with normal C4 levels at baseline. Patients affected by the COVID-19 perprotocol were excluded from the ITT analysis population, and loperamide overuse was treated as non-responders.

[0289] Results of secondary efficacy endpoints : In the ITT analysis population, the IBS-AR response rate in the 100 mg buprenorphine dimer group was statistically significantly better than that of the placebo group. The response rates in the 50 mg and 100 mg buprenorphine dimer groups did not show significant differences compared to the placebo group in terms of modified composite response, pain response, overall IBS-D symptom assessment, and stool consistency.

[0290] In the protocol-adherent analysis group (post-hoc analysis), the response rate in the buprenorphine dimer 100 mg group was statistically significantly better than the placebo group in terms of stool consistency and IBS-AR (p=0.022 and 0.007, respectively).

[0291] Results of exploratory evaluation items : In the ITT analysis population, the IBS-QOL response rate in the 100 mg buprenorphine dimer group was statistically significantly better than that of the placebo group. The response rates in the 50 mg and 100 mg buprenorphine dimer groups did not show significant differences compared to the placebo group in other exploratory endpoints.

[0292] In the protocol-adherent analysis group (post-hoc analysis), the response rate in the buprenorphine dimer 100 mg group was statistically significantly better than the placebo group in terms of IBS-QOL and IBS-SSS (p-values ​​for placebo were 0.020 and 0.044, respectively). The response rate for patients who reported a "significant improvement" in their PGIC score at week 12 was significantly higher in the 100 mg group than in the placebo group (p=0.038).

[0293] Figure 15 shows the therapeutic effects across multiple endpoints in protocol-compliant patients with normal C4 levels treated with buprenorphine dimers. Buprenorphine dimers (which are a partial μ-agonist and a complete κ-antagonist) effectively reduced the clinical distress of all IBS-D patients, with or without gallbladder, where these abdominal pains are not due to intestinal inflammation, or diarrhea is caused by malabsorption of bile acids. Improvements in patients' overall impression of change during and at the end of the study, adequate relief of IBS, symptom severity, and quality of life scores indicate that patients felt and benefited from relief after treatment, and this relief was not limited to improvement in abdominal pain and diarrhea.

[0294] Figure 16 shows the therapeutic effects across multiple endpoints in post-cholecystectomy patients with normal C4 levels and adherence to the protocol, treated with buprenorphine dimers. The therapeutic effect of buprenorphine dimers is stronger in IBS-D patients without a gallbladder than in patients with a gallbladder.

[0295] Figure 17 shows that patients are more likely to achieve therapeutic effects from buprenorphine dimers when they adhere to the treatment protocol.

[0296] safety results : Eighteen patients dropped out of the clinical trial due to adverse events (4 in the 50 mg group, 7 in the 100 mg group, and 7 in the placebo group). A total of four patients (1 in the 50 mg group, 2 in the 100 mg group, and 2 in the placebo group) experienced serious TEAEs. None of these serious TEAEs were found to be related to the investigational drug. No deaths were reported.

[0297] In 12 patients, a total of 14 adverse events requiring special attention (AESIs) were reported (3 in the 50 mg group, 5 in the 100 mg group, and 6 in the placebo group) (3 in the 50 mg group [4.6%], 4 in the 100 mg group [3.2%], and 5 in the placebo group [3.9%]). Abdominal pain (including epigastric pain) was the most frequently reported AESI, occurring in 0 patients in the 50 mg group, 4 patients (3.2%) in the 100 mg group, and 1 patient (0.8%) in the placebo group. None of the AESIs were serious.

[0298] conclusion : Buprenorphine dimer 100 mg administered once daily for 12 weeks was shown to be effective in IBS-D patients who adhered to the protocol and had normal C4 levels at screening. This included patients without a gallbladder (post-cholecystectomy). Buprenorphine dimer was safe and well-tolerated, including in post-cholecystectomy patients. No clinical findings suggestive of central nervous system effects were observed.

[0299] Although the above invention has been described in detail by examples and embodiments for the sake of ease of understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference to the same extent as if each reference were incorporated by reference individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A method for treating a disease in a human subject requiring treatment, wherein the effective therapeutic dose for the subject is given by formula (I): 【Chemistry 1】 This includes orally administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein The therapeutically effective dose of buprenorphine dimer is at least about 100 mg / day in total daily dose on an unsalted and anhydrous basis, and A method by which the aforementioned administration achieves a plasma concentration of at least approximately 700 ng / mL in the subject.

2. The method according to claim 1, wherein the buprenorphine dimer is in a neutral form represented by formula (I).

3. The method according to claim 1 or 2, wherein the therapeutically effective amount of buprenorphine dimer is at least about 200 mg / day in total daily dose on a salt-free and anhydrous basis.

4. The method according to any one of claims 1 to 3, wherein the buprenorphine dimer is administered once daily.

5. The method according to any one of claims 1 to 3, wherein the buprenorphine dimer is administered twice a day.

6. The method according to any one of claims 1 to 5, wherein the disease is chronic pain.

7. The method according to any one of claims 1 to 5, wherein the disease is diarrhea-predominant irritable bowel syndrome (IBS-D).

8. A method for treating chronic pain in a subject requiring treatment, wherein the subject receives a therapeutically effective dose according to formula (I): 【Chemistry 2】 A method comprising administering a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the buprenorphine dimer is administered orally.

9. A method for treating chronic pain in a subject requiring treatment, wherein the subject is given formula (I): 【Transformation 3】 A method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a neutral form of buprenorphine dimer represented by , wherein the pharmaceutical composition is administered orally.

10. The method according to claim 8 or 9, wherein the chronic pain is nociceptive pain, neuropathic pain, or a combination thereof.

11. The method according to any one of claims 8 to 10, wherein the chronic pain is peripheral chronic pain.

12. The method according to any one of claims 8 to 11, wherein the chronic pain is peripheral neuropathic pain.

13. A method according to any one of claims 8 to 12, wherein the subject has sickle cell disease (SCD), cancer and / or is undergoing chemotherapy, HIV, diabetes, herpes zoster, trauma, surgery, amputation, burns, or a combination thereof, and / or the subject has or has had coronavirus disease.

14. A method according to any one of claims 8 to 13, wherein the chronic pain is any one of the following 1) to 10): 1) Related to sickle cell disease (SCD) in the subject; 2) Chemotherapy-induced neuropathic pain in subjects with cancer undergoing chemotherapy; 3) HIV sensory neuropathy; 4) Diabetic neuropathic pain; 5) Postherpetic neuralgia in subjects who have or have had herpes zoster; 6) Post-traumatic chronic pain; 7) Postoperative pain; 8) Post-amputation pain; 9) Post-burn pain; and 10) Related to long-term effects in subjects who had contracted coronavirus disease.

15. A method according to any one of claims 8 to 14, wherein the therapeutically effective dose is a total daily dose of salt-free, anhydrous-based buprenorphine dimers of about 50 mg to about 800 mg, about 50 mg to about 700 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, or about 50 mg to about 250 mg.

16. The method according to claim 15, wherein the therapeutically effective dose is a total daily dose of approximately 100 mg of salt-free, anhydrous-based buprenorphine dimer.

17. The method according to claim 15, wherein the therapeutically effective dose is a total daily dose of approximately 200 mg of salt-free, anhydrous-based buprenorphine dimer.

18. The method according to any one of claims 8 to 17, wherein the buprenorphine dimer is administered once, twice, three times, or four times a day.

19. The method according to claim 18, wherein the buprenorphine dimer is administered once daily.

20. The method according to claim 18, wherein the buprenorphine dimer is administered twice a day.

21. The method according to any one of claims 9 to 20, wherein the pharmaceutical composition comprising the buprenorphine dimer is a tablet.

22. The method according to claim 21, wherein the tablet containing the buprenorphine dimer is an immediate-release tablet.

23. The method according to any one of claims 8 to 22, wherein the therapeutically effective amount of buprenorphine dimer reduces chronic pain as measured by one or more criteria selected from the group consisting of: 1) A decrease in the mean monthly score on a 0-10 Likert scale over the past 1, 3, or 6 months compared to the mean monthly score before treatment; 2) A decrease in the average monthly score of characteristic pain intensity and / or disability over the past 1 month, 3 months, or 6 months compared to the average monthly score before treatment; and 3) Reduced pain severity is selected from the following groups, representing a reduction in pain severity over the past 1 month, 3 months, or 6 months compared to the pain severity before treatment: i) From Grade 4 (severe disability - severe limitation) to Grade 3 (severe disability - moderate limitation), Grade 2 (mild disability - high intensity), Grade 1 (mild disability - low intensity), and Grade 0 (no pain); ii) From Grade 3 up to one of Grade 2, Grade 1, and Grade 0; iii) From Grade 2 to Grade 1 or Grade 0; and iv) From Grade 1 to Grade 0.

24. The method according to any one of claims 8 to 23, wherein the therapeutically effective amount of buprenorphine dimer provides an anti-hyperalgesic effect.

25. The method according to any one of claims 8 to 24, wherein the hyperalgesia of the subject is reduced or substantially eliminated during or after the treatment.

26. The method according to claim 25, wherein the hyperalgesia of the subject disappears during or after the aforementioned treatment.

27. A method for treating diarrhea-predominant irritable bowel syndrome (IBS-D) in a subject requiring treatment, wherein the subject is given formula (I): 【Chemistry 4】 A method comprising administering a therapeutically effective amount of a buprenorphine dimer represented by or a pharmaceutically acceptable salt thereof, wherein the blood concentration of 7α-hydroxy-4-cholesten-3-one (C4) in the subject is 50 milligrams / deciliter (mg / dL) or less.

28. The method according to claim 27, (a) The blood C4 concentration of the subject is approximately 15 mg / dL to approximately 45 mg / dL; and / or (b) Prior to the treatment, the subject had the most severe abdominal pain in the past 24 hours, with a weekly average score of 3 or higher on a numerical rating scale of 1 to 10; and / or (c) Prior to the treatment, the subject had a weekly average score of 5 or higher for stool consistency as assessed by the Bristol Stool Stool Filtration Score (BSFS); and / or (d) A method wherein the subject undergoes cholecystectomy.

29. The method according to claim 27 or 28, wherein the subject is administered loperamide during the treatment.

30. The method according to any one of claims 27 to 29, wherein during the treatment, the subject is administered loperamide in a total dose of no more than one of the following: 8 mg over 24 hours, 14 mg over 48 hours, and 22 mg over 7 days.

31. The method according to any one of claims 29 or 28, wherein the subject is not administered loperamide during the treatment.

32. A method according to any one of claims 29 to 30, wherein the therapeutically effective amount of buprenorphine dimer is 1) Reduce the average weekly score of worst abdominal pain in the past 24 hours by at least 30% compared to the average weekly score before treatment, and / or 2) i) a reduction in the mean BSFS score to less than 6, or ii) improvement of stool hardness as measured by the absence of bowel movements when the characteristics of 1) are met,

33. The method according to any one of claims 8 to 32, wherein the subject is a human.

34. The method according to claim 33, wherein the person is an adult at least 18 years of age.

35. Equation (I): 【Transformation 5】 A method for producing a neutral form of buprenorphine dimer represented by, a) Formula: 【Transformation 6】 Buprenorphine or a salt thereof, represented by , a first inorganic base, water, and a first phase transfer agent are mixed in 1,2-dichloroethane to form formula (II): 【Transformation 7】 The process of forming the compound, and b) A method comprising the step of mixing a compound of formula (II), buprenorphine or a salt thereof, a second inorganic base, water, and a second phase transfer agent in an aprotic solvent to obtain a neutral form of buprenorphine dimer of formula (I).

36. The method according to claim 35, wherein the buprenorphine in steps a) and b) is a buprenorphine HCl salt, respectively.

37. The method according to claim 35 or 36, wherein the first and second inorganic bases are alkali hydroxides independently selected from the group consisting of LiOH, NaOH, KOH, and CsOH, respectively.

38. The method according to claim 37, wherein the first and second inorganic bases are each NaOH.

39. The method according to any one of claims 35 to 38, wherein the first and second phase transfer agents are each independently a quaternary ammonium salt.

40. The method according to claim 39, wherein the first and second phase transfer agents are each tetrabutylammonium hydroxide.

41. The method according to claim 40, wherein in step a), tetrabutylammonium hydroxide is present in an amount of about 5% by weight based on buprenorphine or a salt thereof, and / or in step b), tetrabutylammonium hydroxide is present in an amount of about 0.3 equivalents relative to the compound of formula (II).

42. The method according to any one of claims 35 to 41, wherein in step b), buprenorphine or a salt thereof is present in an amount of about 0.8 equivalents relative to the compound of formula (II).

43. The method according to any one of claims 35 to 42, wherein in step b), the aprotic solvent is toluene.

44. The method according to any one of claims 35 to 43, wherein step a) is performed at a temperature of about 50°C to about 70°C, and / or step b) is performed at a temperature of about 70°C to about 100°C.

45. The method according to claim 44, wherein step a) is performed at a temperature of approximately 60°C and / or step b) is performed at a temperature of approximately 85°C.

46. The method according to any one of claims 35 to 45, wherein the compound of formula (II) obtained in step a) is used directly in step b) without purification.

47. The method according to any one of claims 35 to 46, wherein a neutral form of buprenorphine dimer of formula (I) is further purified by grinding in acetone.

48. Equation (I): 【Transformation 8】 A method for producing a neutral form of buprenorphine dimer represented by, a) Formula: 【Chemistry 9】 The HCl salt of buprenorphine represented by , an aqueous NaOH solution, and tetrabutylammonium hydroxide are mixed in 1,2-dichloroethane to obtain formula (II): 【Chemistry 10】 The process of forming the compound: and b) A method comprising the step of mixing the compound of formula (II), the HCl salt of buprenorphine, an aqueous solution of NaOH, and tetrabutylammonium hydroxide in toluene to obtain a neutral form of buprenorphine dimer of formula (I).

49. Formula (II): 【Chemistry 11】 A compound represented by, or a salt thereof.

50. The compound according to claim 49 in a neutral form.

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