JP2005533046A - Use of devazepide in combination with opioid analgesics to enhance the action of analgesics - Google Patents

Abstract

Described are methods of treating patients undergoing analgesic treatment, including therapeutically effective amounts of analgesics and analgesic-saving doses of devazepide alone, simultaneously or sequentially. In addition, the use of devazepide in the manufacture of a medicament that lowers the dose required to administer an opioid analgesic and super-enhance the action of the analgesic is also described.

Description

  The present invention relates to novel therapeutic methods and novel uses of drugs.

  Faris describes in Science 1984; 226: 1215-1217 that endogenous free cholecystokinin reduces morphine analgesics. Thus, Faris suggests that co-administration of morphine with a specific CCK antagonist allows a reduction in the required initial dose and frequency of administration of morphine.

  International Publication No. WO 99/18967 describes a pharmaceutical composition comprising an analgesic amount of an opioid and an opioid-enhancing amount of a CCK antagonist for the treatment of chronic and neuropathic pain. WO '967 describes the use of both CCK-A (CCK-1) antagonists and CCK-B (CCK-2) antagonists, but CCK-B (CCK-2) antagonists are generally preferred. It is described. In addition, International Publication No. '967, page 2, lines 6-8, states that CCK-A (CCK-1) antagonists may only be appropriate at considerably higher doses.

  One specific CCK-A (CCK-1) antagonist mentioned is 3s-(−) 1,3dihydro-3- (2-indolecarbonylamino) -1-methyl-5-phenyl-2H-1, It is devazepide which is 4-benzodiazepin-2-one.

  WO 99/18967 describes a pharmaceutical composition comprising a biphasic carrier comprising an organic phase of a CCK antagonist, opioid and glyceride derivative, such as Devazepide (R). The use of CCK antagonists is aimed at blocking the CCK receptor, thereby abolishing or preventing the development of opioid resistance in patients and enhancing the analgesic action of opioids.

  In general, patients receiving opioid treatment will receive a stable dose of opioid. Patients may also use doses of opioid therapy that relieve further “burst pain” depending on the symptoms.

  As described above, International Publication No. WO 99/18967 discloses the administration of devazepide in combination with opioid analgesics to enhance the analgesic action of the total dose of opioid. Indeed, the expected outcome is that analgesia occurs or the "pain level" experienced by the patient remains generally the same, but the dose of opioid administered to the patient is reduced or analgesic with the same dose of opioid Will either improve. However, the present inventors have now found that devazepide effectively has a “super-enhancing” effect when used in combination with opioids. Thus, in the present invention, the use of devazepide can improve analgesia, i.e. increase analgesia, or reduce the "pain level" experienced by the patient while simultaneously reducing or minimizing the total opioid dose. Can function to. Indeed, clinical trials have shown that opioid doses can be reduced by 95% in some cases and 75% in others. Thus, the combined administration of opioid and devazepide not only maintains the “pain level” experienced by the patient, but actually improves it. That is, it is not just opioid savings or opioid enhancement, but the opioid action is super-enhanced.

  Thus, according to the present invention, we provide a method of treating a patient undergoing analgesic treatment by administering a therapeutically effective amount of an agent effective for analgesia, wherein the dose of devazepide alone conserves the analgesic, Methods are provided that include simultaneous or sequential administration.

  A dose of devazepide that conserves analgesics would beneficially cause a reduction in the dose of analgesic administered to the patient. The reduction can vary, but can be, for example, a 25% to 95% (w / w) reduction of the analgesic dose required in the absence of devazepide, more preferably a 25% to 75% (w / w) reduction. There is sex.

  According to yet another aspect of the present invention, we provide a method for treating a patient characterized in that it can administer a 25% to 95% (w / w) reduced amount of an analgesic as described above. To do. In a preferred embodiment of the invention, a 25% to 75% (w / w) reduced amount of analgesic may be administered.

  Various opioids can be used in the method of the present invention. Thus, opioids can be selected from opioids that are effective analgesics, especially from opioids that need to be administered at considerably higher doses or in increasing doses. Examples include morphine, or salts thereof such as sulfate, chloride or hydrochloride, meperidine, pentazocine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprozine, dextromoramide, diphenoxylate, dipipanone, Other analgesics such as meptazinol, methadone, nalbuphine, phenadoxone, phenazosin, remifentanil, tramadol, or butorphanol, morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, buprenorphine, heroin (diacetylmorphine), hydrocodone (dihydrocodeinone) ), Hydromorphone (dihydromorphinone), levorphanol, methopone (methyldihydromorphinone), oxycodone (dihydrohydroxycodeinone) Oxymorphone (dihydro-hydroxymorphinone) like 1,4 hydroxymorphinan chick down opioid analgesic; or includes any salts of the above. Naloxone is also included within the definition of opioids. Particularly preferred analgesics that may be mentioned are hydromorphone, oxycodone, eg morphine such as morphine sulfate, and fentanyl. In a preferred embodiment of the invention, the analgesic is morphine or morphine sulfate. In another preferred embodiment, the opioid is fentanyl, or a salt thereof.

  According to yet another aspect of the present invention, we provide a method for treating patients in need of analgesia, wherein the dose of analgesic is minimized by simultaneous, simultaneous or sequential administration of a therapeutically effective amount of devazepide. A method comprising administration of a therapeutically effective amount of an analgesic while conserving.

  In a preferred embodiment of the invention, the analgesic will be an opioid analgesic.

  According to yet another aspect of the present invention, the inventors provide the use of devazepide in the manufacture of a medicament that reduces the dose of analgesic and superenhanes the analgesic action.

  We further provide the use of devazepide in the manufacture of a medicament for analgesic treatment, wherein the treatment simultaneously minimizes the analgesic dose by administering a therapeutically effective amount of devazepide alone, simultaneously or sequentially. Includes administration of therapeutically effective amounts of analgesics while controlling.

  In the methods of the present invention, devazepide and / or opioids can be administered using any method known per se. Thus, such methods include, but are not limited to, intravenous, intraarterial, oral, subarachnoid, intranasal, intrarectal, intramuscular / subcutaneous, inhalation and dermal patch administration. Where devazepide and / or opioid is administered intravenously, for example, it may be an intravenous bolus or continuous intravenous infusion. Where devazepide and / or opioid is administered subcutaneously, for example, it may be by subcutaneous injection. Preferably, the opioid and / or devazepide are administered intravenously or orally. Oral administration is particularly preferred. Preferentially, the opioid and devazepide are administered using the same method of administration. Thus, for example, if opioids are administered intravenously, devazepide is also administered intravenously. Similarly, if opioid is administered orally, devazepide is also administered orally. However, both opioids are administered orally and devazepide is administered intravenously, or vice versa, are within the scope of the present invention. In another preferred embodiment, the opioid can be administered by a transdermal patch. When a transdermal patch is used, the preferred opioid is fentanyl.

  According to yet another aspect of the present invention, we provide the use of devazepide in the manufacture of a pharmaceutical composition as described above.

  Thus, for example, in one embodiment of the invention, the composition can be made into a capsule formulation with a loading of, for example, 150 mg ± 5% by weight or 300 mg ± 5% by weight. In one preferred embodiment, the capsule formulation may contain 1.25 mg of devazepide, and 148.75 mg of filler or other excipients such as corn starch. In another preferred embodiment, the capsule formulation may contain 2.5 mg of devazepide and 297.5 mg of filler or other excipients such as corn starch.

  So such fillers are lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starch, directly compressible starch, microcrystalline cellulose, cellulose derivatives, sorbitol Sucrose, sucrose-based substances, icodextrin, calcium sulfate, dibasic calcium phosphate and dextrose. A preferred filler is starch such as corn starch.

  When the composition of the present invention contains a filler, the particle sizes of devazepide and the filler may be the same or different. However, in preferred embodiments, the particle size of devazepide and filler will be different. Preferentially, the particle size of devazepide and / or filler can be reduced, for example by milling.

  Therefore, in the method of the present invention, the daily dose of devazepide may vary depending on the patient's body weight, administration method and the like. In patients suffering from serious disabilities, such as cancer patients, the patient's weight is significantly reduced, so that the dose of devazepide may be low as a result. Thus, the daily dose of devazepide may be up to 0.7 mg / kg / day. Preferably, the daily dose of devazepide may be from 25 μg / kg / day to 0.7 mg / kg / day, more preferably from 50 μg / kg / day to 0.5 mg / kg / day. For oral administration, the daily dose of devazepide may preferably be from 0.07 mg / kg / day to 0.7 mg / kg / day. More preferably, the daily dose of devazepide for oral administration may be 0.07 mg / kg / day to 0.29 mg / kg / day. For intravenous administration, the daily dose of devazepide may preferably be from 50 μg / kg / day to 0.5 mg / kg / day.

  In particular, the dose ratio of devazepide to opioid may vary. Thus, the ratio of devazepide to opioid may be 2: 1 to 1: 200 (w / w), preferably 1: 2 to 1:40 (w / w).

  In the method of the present invention, the dose of the opioid analgesic may vary, particularly depending on the nature of the opioid analgesic, the patient's weight, the method of administration and the like. Thus, for example, the daily dose of opioids such as morphine may be 5 to 2,000 mg. A specific daily dose that may be mentioned is 10 to 240 mg. The daily dose of morphine may be 5 to 100 mg, or in some cases up to 500 mg.

  The devazepide used in the method of the present invention is the S-enantiomer, preferentially the S-enantiomer with a level of R-enantiomer that can be expressed as an impurity of 1.5 (w / w) or less.

  Hereinafter, the present invention will be described only for the purpose of illustrating.

Crossover Clinical Trial A multicenter, double-blind, placebo-controlled crossover trial was designed to investigate devazepide as an adjunct therapy for potent opioids in patients with moderate or severe neuropathic pain.

1.1 Basic principles of study design This study observes the effects on patients of two doses of devazepide (1.25 mg twice daily and 5 mg twice daily) administered as an adjunct to a potent opioid Carried out for. In previous studies, devazepide administered twice daily at levels up to 5 mg has been well tolerated. This study was designed to investigate in more detail the analgesic effect and safety and toxicity of devazepide when administered twice daily for 2 weeks compared to placebo.

1.2 Pretreatment Patients completed a pretreatment period of at least 2 weeks. During the pre-treatment period, patients continued to take regular doses of potent opioids and, if necessary, sudden pain analgesics. All uses of powerful opioids and analgesics were recorded. Patients completed their pain assessment using a pain questionnaire each night before going to bed. Adverse events and any changes in concomitant medications were also recorded.

1.3 Treatment After the 2 week pre-treatment period, each patient received blind treatment of devazepide 1.25 mg, devazepide 5 mg and placebo twice a day for 2 weeks, with a washout period between each treatment according to the following schedule: Placed.

  Every day during the treatment period, patients were evaluated for pain, general activity and sleep disturbances and recorded on a diary card. At the end of each treatment period, patients used a language scale to determine total pain relief, and both patient and clinical investigator assessments for that treatment were recorded. Throughout the study, all concomitant drug use (including the use of powerful opioids and sudden pain analgesics) and adverse events were recorded. Blood samples were collected at screening and at the end of each treatment for safety monitoring.

1.4 Results Forty-two of 62 patients undergoing screening tests completed the study according to the protocol. 18 women (44%) and 23 men (56%) participated, and their average age (range) was 48.6 (23.2 to 70.7) years. Patients were stabilized by administration of morphine (34 cases), oxycodone (2 cases), fentanyl (3 cases), methadone (1 case), hydromorphone (1 case) and diamorphine (1 case); And fentanyl. For the use of sudden analgesic preparations (in addition to the above) tramadol, diclofenac, dihydrocodeine, paracetamol, codeine, aspirin, ibuprofen, dextropropoxyphene, buprenorphine, pethidine, carbamazepine and hydromorphone (and for example Anadin ™ (aspirin) ), Anadin ™ extra (aspirin and paracetamol), co-codamol, co-daidramol, co-proxamol, and combination formulations containing the above, such as limedaine).

  Analysis of specific use of sudden pain analgesics, as opposed to normal opioid use, was not possible, but this meant that patients received a very wide range of analgesics (including opioids) in addition to normal opioids. Because it was. It was also difficult to define sudden pain analgesics in patients who were using the same opioid for both normal use and sudden pain analgesics (the latter being for controlling sudden pain). For this reason, all analgesics were included in determining the total dose during the treatment period, regardless of whether it was used as a regular stable medication or for sudden pain.

  The results are shown in Table II.

2.1 Clinical Evaluation Trials The study program included a double-blind, double-dummy, randomized crossover trial with a single dose of devazepide 1.25 mg, devazepide 5 mg or placebo. Patients who participated in this study had pain with neurogenic factors and were taking regular doses of strong opioids. After the study is completed, patients who benefit from participating in the study in the opinion of the study investigator will be given the opportunity to consent to continue receiving devazepide for a period of up to 6 months. It was.

2.2 Study design This follow-up study was a multicenter open label study of devazepide at doses of 1.25 mg, 2.5 mg and 5.0 mg twice daily.

2.3 Study Objectives The primary goal of this study was to compare assessments of pain and pain relief by language and visual analog scales (VAS) in patients with neuropathic pain.

2.4 Method After the completion of the preliminary randomization study, the patient took devazepide 1.25 mg twice a day for the initial week. After this initial one-week period, the dose of devazepide was reviewed and increased to 2.5 mg twice daily if necessary, and then to 5.0 mg twice daily as needed. Devazepide treatment continued for a period of up to 6 months.

  During the study, patients were required to maintain a normal dose of opioid at the dose prescribed by the investigator.

2.5 Trial Evaluation Patients were evaluated at week 1 and week 2 (dose escalation) and thereafter at routine monthly visits.

  Patients recorded pain and global analgesia relief using VAS and a descriptive pain questionnaire at weekly intervals during the initial 8 weeks and thereafter at monthly intervals. These questionnaires were returned to the investigator at the monthly visit.

  At each visit, the investigator assessed safety and patient pain relief, reviewed the dose, and decided whether to continue devazepide treatment.

2.6 Results Seventeen patients chose to stay on devazepide treatment by participating in a continuing study and took devazepide at a dose of 1.25 mg, 2.5 mg or 5.0 mg twice a day for up to 26 weeks .

  Ten of these patients appeared to have achieved long-term pain relief (5-26 weeks) with devazepide. Despite the requirement to maintain a stable normal dose opioid at the dose prescribed by the investigator, several patients have significantly reduced their daily opioid dose.

FIG. 1 shows the trend with dihydrocodeine, a weak opioid. The patient started with dihydrocodeine 120 mg / day.

Claims (86)

  Use of devazepide in the manufacture of a medicament that lowers the dose required to administer an opioid analgesic and superenhance the action of the analgesic.   Use of devazepide in the manufacture of a medicament for analgesic treatment, wherein the treatment administers a therapeutically effective amount of an analgesic while minimizing the dose of the analgesic by simultaneous or sequential administration of a therapeutically effective amount of devazepide Including use.   Use according to claim 1 or 2, characterized in that the dose of analgesic required by the patient is reduced by 25% to 95% by the weight of analgesic required in the absence of devazepide.   Use according to claim 3, characterized in that the dose of analgesic required by the patient is reduced by 25% to 75% by the weight of analgesic required in the absence of devazepide.   3. Use according to claim 1 or 2, characterized in that the opioid is selected from opioids that need to be administered at considerably higher doses or in increasing doses.   Use according to claim 1 or 2, characterized in that the analgesic is an opioid.   The analgesic is morphine or a salt of morphine such as sulfate, chloride or hydrochloride, meperidine, pentazocine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprozin, dextromoramide, diphenoxylate, dipipanone , Meptazinol, methadone, nalbuphine, phenadoxone, phenazosin, remifentanil, tramadol and other analgesics, or butorphanol, morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, buprenorphine, heroin (diacetylmorphine), hydrocodone (dihydrocodeine) Non), hydromorphone (dihydromorphinone), levorphanol, methopone (methyldihydromorphinone), oxycodone (dihydrohydroxycode) Non-), 1,4-hydroxymorphinan opioid analgesics such as oxymorphone (dihydrohydroxymorphinone); or any one of the above-mentioned salts, Use of.   Use according to claim 6, characterized in that the opioid is naloxone.   Use according to claim 7, characterized in that the analgesic is selected from the group consisting of hydromorphone, oxycodone, morphine and fentanyl or a salt thereof.   Use according to claim 9, characterized in that the opioid is fentanyl or a salt thereof.   Use according to claim 9, characterized in that the analgesic is morphine or morphine sulfate.   7. Use according to claim 6, characterized in that the ratio of devazepide to opioid is 2: 1 to 1: 400 (w / w).   Use according to claim 12, characterized in that the ratio of devazepide to opioid is 2: 1 to 1: 200 (w / w).   14. Use according to claim 13, characterized in that the ratio of devazepide to opioid is from 1: 2 to 1:40 (w / w).   Devazepide and / or opioid may be administered using a method selected from intravenous, intraarterial, oral, intrathecal, intranasal, rectal, intramuscular / subcutaneous, inhalation, and transdermal patches. Use according to claim 1 or 2.   16. Use according to claim 15, characterized in that devazepide and / or opioid is administered intravenously.   Use according to claim 16, characterized in that intravenous administration is by intravenous bolus administration or continuous intravenous infusion.   Use according to claim 15, characterized in that devazepide and / or opioid is administered subcutaneously.   Use according to claim 18, characterized in that the subcutaneous administration is performed as a subcutaneous injection.   Use according to claim 15, characterized in that the opioid and / or devazepide are administered intravenously or orally.   21. Use according to claim 20, characterized in that the opioid and / or devazepide are administered orally.   Use according to claim 15, characterized in that the opioid and devazepide are administered using the same method of administration.   Use according to claim 22, characterized in that the opioid is administered orally and the devazepide is administered orally.   Use according to claim 15, characterized in that the opioid is administered by a transdermal patch.   Use according to claim 24, characterized in that the opioid is fentanyl or a salt thereof.   Use according to claim 1, characterized in that the daily dose of devazepide is up to 0.7 mg / kg / day.   27. Use according to claim 26, characterized in that the daily dose of devazepide is 25 μg / kg / day to 0.7 mg / kg / day.   28. Use according to claim 27, characterized in that the daily dose of devazepide is from 50 [mu] g / kg / day to 0.5 mg / kg / day.   27. Use according to claim 26, characterized in that the dose of devazepide is an oral dose.   30. Use according to claim 29, characterized in that devazepide is administered orally and the daily dose of devazepide is 0.07 mg / kg / day to 0.29 mg / kg / day.   27. Use according to claim 26, characterized in that devazepide is administered intravenously at a dose of 50 [mu] g / kg / day to 0.5 mg / kg / day.   Use according to claim 6, characterized in that the daily dose of opioid is 5 to 2,000 mg.   Use according to claim 32, characterized in that the daily dose of opioid is 10 to 240 mg.   34. Use according to claim 33, characterized in that the daily dose of opioid is 5 to 100 mg.   Use according to claim 1 or 2, characterized in that devazepide is provided as a composition incorporating fillers or other excipients.   36. Use according to claim 35, characterized in that the composition is filled into capsules.   Use according to claim 36, characterized in that the capsule is a gelatin capsule.   Use according to claim 36, characterized in that the capsule has a filling of 150 mg ± 5% by weight or 300 mg ± 5% by weight.   Use according to claim 36, characterized in that the capsule formulation contains 1.25 mg devazepide or 2.5 mg devazepide.   40. Use according to claim 39, characterized in that 1.25 mg or 2.5 mg of devazepide is delivered at least twice a day.   Use according to claim 1 or 2, characterized in that the devazepide used in the method of the invention is substantially the S-enantiomer.   Use according to claim 41, characterized in that the level of R-enantiomer that may be present as an impurity is not more than 1.5% (w / w).   A method of treating a patient undergoing analgesic treatment, comprising a therapeutically effective amount of an analgesic and a dose that conserves analgesic alone, simultaneously or sequentially.   A method of treating a patient in need of analgesia, comprising administering a therapeutically effective amount of an analgesic while minimizing the dose of the analgesic by administration of a therapeutically effective amount of devazepide alone, simultaneously or sequentially.   45. The method of claim 43 or 44, wherein the method comprises administration of a therapeutically effective amount of an analgesic and a super-enhancing amount of devazepide.   45. A method according to claim 43 or 44, characterized in that the dose of analgesic required for the patient is reduced by 25% to 95% by the weight of analgesic required in the absence of devazepide.   49. The method of claim 46, wherein the analgesic dose required for the patient is reduced by 25% to 75% by weight of the required analgesic in the absence of devazepide.   45. A method according to 43 or 44, wherein the opioid is selected from opioids that require administration at considerably higher doses or in increasing doses.   45. A method according to claim 43 or 44, characterized in that the analgesic is an opioid.   The analgesic is morphine or a salt thereof such as sulfate, chloride or hydrochloride, meperidine, pentazocine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprozin, dextromoramide, diphenoxylate, dipipanone, meptazinol , Methadone, nalbuphine, phenadoxone, phenazosin, remifentanil, tramadol and other analgesics, or butorphanol, morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, buprenorphine, heroin (diacetylmorphine), hydrocodone (dihydrocodeinone) , Hydromorphone (dihydromorphinone), levorphanol, methopone (methyldihydromorphinone), oxycodone (dihydrohydroxycodeinone) Oxymorphone (dihydro-hydroxymorphinone) like 1,4 hydroxymorphinan chick down opioid analgesics; or characterized in that it is selected from the group consisting of a salt of any of the above, the method according to claim 43 or 44.   50. The method of claim 49, wherein the opioid is naloxone.   51. The method of claim 50, wherein the analgesic is selected from the group consisting of hydromorphone, oxycodone, morphine, and fentanyl or a salt thereof.   53. The method of claim 52, wherein the opioid is fentanyl, or a salt thereof.   54. A method according to claim 53, characterized in that the analgesic is morphine or morphine sulfate.   50. The method of claim 49, wherein the ratio of devazepide to opioid is 2: 1 to 1: 400 (w / w).   56. The method of claim 55, wherein the ratio of devazepide to opioid is 2: 1 to 1: 200 (w / w).   57. The method of claim 56, wherein the ratio of devazepide to opioid is 1: 2 to 1:40 (w / w).   Devazepide and / or opioid may be administered using a method selected from intravenous, intraarterial, oral, intrathecal, intranasal, rectal, intramuscular / subcutaneous, inhalation, and transdermal patches. 45. A method according to claim 43 or 44.   59. The method according to claim 58, characterized in that devazepide and / or opioid is administered intravenously.   60. The method of claim 59, wherein intravenous administration is by intravenous bolus administration or continuous intravenous infusion.   59. Method according to claim 58, characterized in that devazepide and / or opioid is administered subcutaneously.   62. The method of claim 61, wherein the subcutaneous administration is performed as a subcutaneous injection.   59. The method according to claim 58, characterized in that the opioid and / or devazepide are administered intravenously or orally.   64. Method according to claim 63, characterized in that the opioid and / or devazepide are administered orally.   59. The method of claim 58, wherein the opioid and devazepide are administered using the same method of administration.   60. The method of claim 59, wherein the opioid is administered orally and devazepide is administered orally.   59. The method of claim 58, wherein the opioid is administered by a transdermal patch.   68. The method of claim 67, wherein the opioid is fentanyl, or a salt thereof.   44. The method of claim 43, wherein the daily dose of devazepide is up to 0.7 mg / kg / day.   70. The method of claim 69, wherein the daily dose of devazepide is from 25 [mu] g / kg / day to 0.7 mg / kg / day.   71. The method of claim 70, wherein the daily dose of devazepide is 50 [mu] g / kg / day to 0.5 mg / kg / day.   70. The method of claim 69, wherein the dose of devazepide is an oral dose.   73. The method of claim 72, wherein devazepide is administered orally and the daily dose of devazepide is 0.07 mg / kg / day to 0.29 mg / kg / day.   70. The method of claim 69, wherein devazepide is administered intravenously at a dose of 50 [mu] g / kg / day to 0.5 mg / kg / day.   The method according to claim 49, characterized in that the dose of opioid is 5 to 2,000 mg per day.   76. The method of claim 75, wherein the opioid dose is 10 to 240 mg per day.   77. Method according to claim 76, characterized in that the dose of opioid is 5 to 100 mg per day.   45. A method according to claim 43 or 44, characterized in that devazepide is provided as a composition incorporating a filler or other excipient.   79. A method according to claim 78, wherein the composition is filled into capsules.   80. The method of claim 79, wherein the capsule is a gelatin capsule.   80. Method according to claim 79, characterized in that the capsules have a filling of 150 mg ± 5% by weight or 300 mg ± 5% by weight.   80. The method of claim 79, wherein the capsule formulation comprises 1.25 mg devazepide or 2.5 mg devazepide.   83. The method of claim 82, wherein 1.25 mg or 2.5 mg devazepide is delivered at least twice daily.   45. A method according to claim 43 or 44, characterized in that the devazepide used in the method of the invention is substantially the S-enantiomer.   85. The method of claim 84, wherein the level of R-enantiomer that may be present as an impurity is 1.5% (w / w) or less. A method or use substantially as described with reference to the accompanying examples.

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