JP2006506461A - Milnacipran pulsed release composition - Google Patents

Abstract

A once-daily oral milnacipran pulsed release formulation has been developed that releases the drug in spaced “pulses”. This dosage form consists of a first dosage unit, a second dosage unit, and optionally a third dosage unit, each dosage unit having a different drug release profile. This dosage form provides in vivo drug plasma levels characterized by a Cmax of less than about 3000 ng / mL, preferably less than 2000 ng / mL, and most preferably less than 1000 ng / mL. These levels help to avoid stimulation of cholinergic effects on the CNS. This composition, when administered to a patient, allows milnacipran to be delivered over a period of about 24 hours, thereby resulting in reduced incidence or reduced intensity of common milnacipran side effects.

Description

(Field of Invention)
The present invention generally relates to milnacipran pulsed release compositions.

  This application is filed on US Patent Application No. 60/421640 filed on October 25, 2002; US Patent Application No. 60/431626 filed on December 5, 2002; filed on December 5, 2002. U.S. Patent Application No. 60/431627; U.S. Patent Application No. 60/431906 filed on Dec. 9, 2002; U.S. Patent Application No. 60/431186 filed on Dec. 9, 2002; U.S. Patent Application No. 60/443618, filed Jan. 29, 2003; U.S. Patent Application No. 60/459061, filed Mar. 28, 2003; U.S. Patent Application filed Mar. 28, 2003 No. 60/458994; claims priority to US patent application No. 60 / 458,953 filed Mar. 28, 2003.

(Background of the Invention)
Efficacy and tolerability are important factors in selecting treatments for mental depression and other mental disorders, including Functional Somatic Disorders. The transition from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs) inhibits norepinephrine reuptake as well as a reduction in direct receptor interactions involved in adverse side effects of TCA It was also related to ability. The selectivity for one neurotransmitter serotonin may explain why SSRIs tend to be less effective than TCA, especially in more severe depression (Lopez-Ibor J. et al., 1996, Int. Clin. Psychopharm., 11: 41-46). Older TCAs are associated with significant behavioral toxicity, particularly psychomotor and cognitive impairment and sedation. Although SSRIs have little of these effects, gastrointestinal disorders such as nausea and dyspepsia are common for this drug (Hindmark I., 1997, Human Psychopharmacology, 12: 115-119). For example, for the widely prescribed SSRI sertraline (Zoloft®, Pfizer), the three most adverse events leading to treatment discontinuation were nausea, insomnia and diarrhea (Physician's Desk Reference, 57th Edition, 2003, Thomson Medical).

  Efforts to improve antidepressants are guided by cumulative evidence from neurochemical and clinical studies supporting the therapeutic potential to enhance monoamine function in depression. A number of antidepressants, including duloxetine, venlafaxine and milnacipran, serotonin and norepinephrine reuptake inhibitors (SNRIs) have been shown to interact with both serotonin (5-HT) and norepinephrine (NE) receptors. Based on the development. Milnacipran is more suitable to be referred to as norepinephrine and serotonin reuptake inhibitor (NSRI) because the ratio of norepinephrine (NE) / serotonin (5-HT) is 2: 1 (Moret et al. 1985, Neuropharmacology, 24: 1211-1219; Palmier et al., 1989, Eur. J. Clin. Pharmacol., 37: 235-238). Current clinical evidence indicates that this new drug may provide improved efficacy and / or faster onset of action compared to SSRI (Tran PV et al., 2003, J. Clin Psychopharmacol., 23: 78-86). Recent studies on NSRI milnacipran show that this compound is effective in reducing both pain associated with depression and pain not associated with depression (Briley M., 2003). Curr.Opin.Investig.Drugs, 4: 42-45: Cypress Bioscience Inc., Cypress Bioscience Inc. Available from .cypressbio.com).

  Unfortunately, these SNRI and NSRI compounds have shown many side effects in human clinical trials.

  For example, the safety and tolerability of duloxetine (Cymbalta (R), Eli Lilly and Company) is seven, including 1032 patients treated with duloxetine (40-120 mg / day) and 732 patients treated with placebo. Evaluated in a pooled analysis of a double blind study. Adverse events that occurred at a rate higher than 5% for duloxetine were nausea, dry mouth, fatigue, dizziness, constipation, somnolence, loss of appetite and sweating. Adverse events that discontinued treatment were nausea, dizziness, somnolence, dermatitis, insomnia, headache and fatigue. Nausea and dizziness were significantly more abolished in patients treated with duloxetine compared to placebo (Mallinckrodt C. et al., American Psychiatric Association 2002, Annual Meeting, New Research Abet. MJ et al., American Psychiatric Association 2002 Annual Meeting, New Research Abstracts, 33-34, May 18, 2002). Nausea was the only adverse event reported as the reason for discontinuation (Eli Lilly and Company, New Research Shows, Cyberreduces, Anxious Associates, Associates, Permission, Tess, Associates, Associates, Associates, Associates, Associates, Associates, Associates, Associates, Associates, Associates, Associates, Associates)

  For venlafaxine (Effexor®, Wyeth-Ayerst), which is included in the SNRI system, the main reported side effects are those that affect the gastrointestinal system. In a 4-8 week placebo-controlled clinical trial, the incidence of major gastrointestinal adverse events that occurred with treatment for Effexor® vs. placebo (n = 1033 vs. 609) was as follows: Nausea ( 37% vs 11%), constipation (15% vs 7%), anorexia (11% vs 2%), vomiting (6% vs 2%). In the same clinical trial, the incidence of major central nervous system adverse events that occurred with treatment was as follows: sleep (23% vs 9%), dry mouth (22% vs 11%), dizziness (19%) 7%), insomnia (18% vs. 10%), nervousness (13% vs. 6%), anxiety (6% vs. 3%), tremor (5% vs. 1%). Importantly, nausea, in addition to the most commonly reported side effect (see above), is the biggest reason why patients with venlafaxine discontinued treatment in the two-phase and three-phase depression trials : Almost 32% of patients who discontinued treatment were discontinued due to nausea (Physician's Desk Reference, 57th edition, 2003, Thomson Medical).

  Milnacipran (Ixel®, Pierre Fabre) exhibits many adverse reactions in human clinical trials and decreases with increasing doses (Puech A et al., 1997, Int. Clin. Psychopharm., 12). : 99-108). In a double-blind, randomized, multicenter clinical trial, the most frequent self-reported adverse events for 100 mg / day milnacipran (twice daily) were as follows: : Abdominal pain (13%), constipation (10%) and headache (9%). Interestingly, in the same study, when milnacipran was given at 200 mg / day (twice a day), the pain-related adverse effects decreased (headache decreased to 8%, abdominal pain decreased to 7%) Nausea and vomiting are more prominent side effects and have been reported by 7% of patients (Guelfi JD, 1998, Int. Clin. Psychopharm., 13: 121-128). Nausea was one adverse event reported more frequently by TCA imipramine recipients for milnacipran recipients in a double-blind comparative study of 219 elderly depressed patients. Milnacipran or imipramine 75-100 mg / day (twice daily) was administered to patients for 8 weeks (Tignol J. et al., 1998, Acta Psychiatrica Scandinavica, 95: 157-165). It was also found that when milnacipran was administered intravenously to 10 patients, 5 of them reported transient nausea. Nausea was mainly reported at the peak of milnacipran plasma levels (Caron J. et al., 1993, Eur. Neuropsychopharmacol., 3: 493-500). This study shows that nausea is directly related to milnacipran plasma concentration. In addition, the drug was administered intravenously in this study strongly suggests that nausea may be a central nervous-mediated side effect. Data from other studies indicate that milnacipran can also induce nausea mediated locally by gastrointestinal irritation (rapid onset of nausea was observed even before peak plasma levels were reached).

  The occurrence of self-reported milnacipran adverse events in placebo-controlled clinical trials is shown in Table 1 (adverse effects were noted when the frequency was higher than 2% in the milnacipran 100 mg / day group). As is apparent from the data shown in Table 1, the occurrence of several adverse events increases with dose, including nausea, vomiting, sweating, facial flushing, palpitation, tremor, anxiety, dysuria and insomnia.

  (Table 1. Self-reported milnacipran adverse events in placebo-controlled clinical trials)

初期うつ病試験の１つにおいて、副作用を減少させるために使用した１週間のミルナシプラン用量の段階的増加後でさえ、有害作用による治療中止の最も一般的に報告された理由は、吐き気および嘔吐であったことを認識することが重要である（Ｌｅｉｎｏｎｅｎ Ｅ．，１９９７，Ａｃｔａ Ｐｓｙｃｈｉａｔｒ．Ｓｃａｎｄ．，９６：４９７−５０４）。ミルナシプラン副作用を減少させ、患者の耐性を増加させるために実施した長い用量段階的増加期間（４週間）での最近の線維筋痛症臨床試験において、患者によって報告された最も一般的な用量相関副作用は、吐き気であった（Ｃｙｐｒｅｓｓ Ｂｉｏｓｃｉｅｎｃｅ Ｉｎｃ．，Ｃｙｐｒｅｓｓ Ｂｉｏｓｃｉｅｎｃｅ Ｉｎｃ．Ａｎｎｏｕｎｃｅｓ Ｆｉｎａｌ Ｒｅｓｕｌｔｓ ｏｆ Ｍｉｌｎａｃｉｐｒａｎ Ｐｈａｓｅ ＩＩ Ｃｌｉｎｉｃａｌ Ｔｒｉａｌ ｉｎ Ｆｉｂｒｏｍｙａｌｇｉａ，Ｍｅｄｉａ Ｒｅｌｅａｓｅ，Ｍａｒｃｈ ２１，２００３）。

In one of the early depression trials, even after a gradual increase in the weekly milnacipran dose used to reduce side effects, the most commonly reported reasons for discontinuing treatment due to adverse effects were nausea and It is important to recognize that it was vomiting (Leinonen E., 1997, Acta Psychiatr. Scand., 96: 497-504). The most common dose reported by patients in a recent fibromyalgia clinical trial with a long dose escalation period (4 weeks) conducted to reduce milnacipran side effects and increase patient tolerance The correlated side effect was nausea (Cypress Bioscience Inc., Cypress Bioscience Inc. Announces Final Results of Milaniplan Phase II Clinical TriaMileMilMig.

  Data shown in Table 1 indicate that currently available immediate release formulations of milnacipran are administered once daily or twice daily due to the high incidence of treatment-induced side effects resulting in low patient tolerance It is not ideal for the treatment of health conditions requiring milnacipran doses of 100 mg / day or higher. Higher doses are required for the treatment of severe depression and other related diseases. As shown in one of the early antidepressant clinical trials, the 200 mg / day milnacipran dose was superior to the lower dose (Von Frenkell R et al., 1990, Int. Clin. Psychopharmacology 5: 49- 56). A daily 100-250 mg milnacipran regimen has recently been reported for the treatment of fibromyalgia (US Pat. No. 6,602,911). Reaching the upper end of the dose range using currently available formulations appears to be extremely difficult due to dose-related therapeutic side effects and the need for long-term titration to reach the required dose .

  In addition, the immediate release formulation of milnacipran is considered unsuitable for the once-daily dosing regimen for depression treatment because of the relatively short (about 8 hours) half-life of milnacipran (Ansseau) M. et al., 1994, Psychopharmacology 114: 131-137). The half-life of milnacipran is also the fact that twice-daily (relative to once-daily) administration of immediate release formulations in the fibromyalgia test resulted in statistically superior pain improvement over placebo treatment. It is considered to be involved (Cypress Bioscience Inc., Cypress Bioscience Inc. Announces Final Results of Milaniplan Phase II Clinical TriaMiaMiaMia, Mia 21M, 21M).

  Accordingly, the object of the present invention is to reduce the incidence and intensity of side effects, especially for higher dosages, and to titrate the drug slowly to obtain the frequency of administration and the therapeutic dose level required to treat these diseases. It is to provide milnacipran formulations that reduce or reduce sex.

  Accordingly, an object of the present invention is to provide a milnacipran formulation that exerts a therapeutic effect over about 24 hours when administered to a patient in need thereof, the release rate and dose of this formulation being immediate release Effective in alleviating at least one disease selected from the group consisting of the following, with reduced incidence and reduced intensity of common milnacipran side effects reported for the formulation: depression, Fibromyalgia syndrome, chronic fatigue syndrome, pain, attention deficit / hyperactivity disorder, and visceral pain syndrome (VPS) such as irritable bowel syndrome (IBS), non-cardiac chest pain (NCCP), functional dyspepsia, between Cystitis, instinct vulvar lesions, urethral neurosis, testicular pain, and affective disorders [depressive disorder (major depressive disorder, mood modulation, atypical depression) and anxiety disorder (systemic anxiety disorder) Phobias, obsessive-compulsive disorder, panic disorder, including the stress disorder) post-traumatic], premenstrual dysphoric disorder, the temporomandibular disorder, atypical facial pain, migraine, and tension headaches.

  A further object of the present invention is a formulation that provides a selective pharmacokinetic release profile that eliminates or reduces undesired side effects and the current need to slowly increase (titrate) the dose to reach the desired therapeutic dose. Is to provide.

  Yet another object of the present invention is to provide a formulation which provides a unit dose of 25-500 mg which gives flexibility in the morning or evening administration.

(Summary of the Invention)
A once-daily oral milnacipran pulsed release composition was developed. This pulsed composition, when administered orally, releases the drug in spaced “pulses”. This delivery profile minimizes internal mucosal surface exposure to drug substances, thus reducing the gastrointestinal side effects of milnacipran (eg, nausea and vomiting) while maintaining therapeutic milnacipran plasma levels To do. Furthermore, this pulsatile composition has been shown to be ideal for milnacipran, as twice-daily milnacipran administration has been shown to provide enhanced therapeutic response compared to once-daily administration. Suitable for delivery. This dosage form results in in vivo drug plasma levels characterized by a C _{max of} less than about 3000 ng / mL, preferably less than 2000 ng / mL, and most preferably less than 1000 ng / mL. These levels help to avoid stimulation of cholinergic effects in the CNS. This composition delivers milnacipran for about 24 hours, thereby causing nausea, vomiting, sleep disturbances, headache, tremors, anxiety, panic attacks, palpitation, urinary retention, orthostatic hypotension, sweating, chest pain, rash General, such as, weight gain, back pain, constipation, dizziness, increased sweating, mental agitation, flushing of face, tremor, fatigue, somnolence, dyspepsia, dysuria, nervousness, dry mouth, abdominal pain, irritability and insomnia Resulting in reduced incidence and reduced intensity of typical milnacipran side effects.

(Detailed description of the invention)
(Pulsed release milnacipran formulation)
This composition comprises an initial rapid release of a therapeutically effective dose of milnacipran followed by a so-called “delayed release” pulse (thus a second and optionally a third delayed dose of active agent is administered in this dose). Released from the form). By incorporating both an immediate release dosage unit and one or more delayed release dosage units of the active agent, this dosage form mimics multiple dosage profiles without repeated administration (ie, only a single dose per day) To do. For example, if the dosage form includes both an immediate release dosage unit and one delayed dosage unit, the dosage form provides a twice daily dosage profile. Alternatively, the dosage form provides a dosage profile of 3 times a day when the dosage form includes both an immediate release dosage unit and two delayed dosage units.

  This formulation provides a pulsed release dosage form for treating conditions responsive to administration of milnacipran. Here, the dosage form contains an immediate release dosage unit, a delayed dosage unit, and an optional second delayed dosage unit. The immediate release dosage unit contains a first dose of active agent that is released substantially immediately after oral administration of the dosage form to the patient. The delayed release dosage unit includes a second dose of the active agent and means for delaying the release of this second dose by about 3 to less than 14 hours after oral administration of the dosage form. The second delayed dosage unit comprises a third dose of active agent, if present, and means for delaying the release of the third dose from at least 5 hours to about 18 hours after oral administration of the dosage form.

  Each dosage form contains a therapeutically effective amount of the active agent. For dosage forms that mimic a twice daily dosage profile, about 30% to 70%, preferably 40% to 60% by weight of the total amount of active agent in this dosage form is released in the initial pulse, And about 70% to 30%, preferably 60% to 40% by weight of the corresponding total amount of active agent in this dosage form is released in the second pulse. For dosage forms that mimic a twice daily dosing profile, the second pulse is preferably released from about 3 hours to less than 14 hours, most preferably from about 5 hours to 12 hours after administration.

  For dosage forms that mimic a three times daily dosage profile, about 25% to 40% by weight of the total amount of active agent in the dosage form is released in the initial pulse, and the total amount of active agent in the dosage form About 25% to 40% by weight is released in each of the second and third pulses. For dosage forms that mimic a three times daily dosing profile, the release of the second pulse preferably occurs about 3 hours to 10 hours, most preferably about 4 hours to 9 hours after oral administration. The release of the third pulse occurs from about 2 hours to about 8 hours after the second pulse, and typically from about 5 hours to about 18 hours after oral administration.

  In one aspect, dosage forms that include closed capsules are used. The capsule contains a dosage unit containing at least two drugs. Each dosage unit can contain two or more compressed tablets or consist of multiple beads, granules or particles, each dosage unit providing a different drug release profile. The immediate release dosage unit releases the drug substantially immediately after oral administration and provides an initial dose. The delayed release dosage unit releases the drug about 3-14 hours after oral administration and provides a second dose. Finally, any second delayed release dosage unit releases the drug about 2 to 8 hours after the release of the second dose, and this is typically 5 to 18 hours after oral administration.

  Another dosage form includes a compressed tablet having an immediate release dosage unit containing the drug, a delayed release dosage unit, and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage form comprises a plurality of beads, granules or particles that release the drug substantially immediately after oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules that release the drug approximately 3 to 14 hours after oral administration and provide a second dose.

  An optional second delayed release dosage unit contains coated beads or granules that release the drug about 2 to 8 hours after the first delayed release dose, typically 5 to 8 hours after oral administration. The bead or granule in the delayed release dosage unit is coated with a bioerodible polymer material. This coating is applied until the appropriate time (ie, about 3 to less than 14 hours after oral administration for delayed release dosage units, and at least 5 hours to about 18 hours after oral administration for any second delayed release dosage unit). Prevent drug release. In this dosage form, the compounds can be mixed into tablets, stacked or formed into layered tablets.

  Another dosage form is a tablet having an immediate release dosage unit containing a drug, a delayed release dosage unit, and an optional second delayed release dosage unit, wherein the immediate release dosage unit is substantially immediately after oral administration. Including an outer layer that releases the drug. However, the placement of the remaining delayed release dosage unit depends on whether the dosage form is designed to mimic twice daily administration or to mimic three times daily administration .

  In dosage forms that mimic twice daily administration, the delayed release dosage unit comprises an inner core coated with a bioerodible polymer material. This coating is applied such that the release of the drug occurs from about 3 hours to less than 14 hours after oral administration. In this form, the outer layer completely surrounds the inner core.

  In dosage forms that mimic administration three times daily, the (first) delayed release dose comprises an inner layer that releases the drug about 3 to less than 14 hours after oral administration. This inner layer is surrounded by the outer layer. The second delayed release dosage unit comprises an inner core that releases the drug at least 5 hours to about 18 hours after oral administration. The tablet layer (starting from the outer surface) thus comprises an outer layer, an inner layer and an inner core. This inner core contains delayed release beads or delayed release granules. Further, the inner layer includes a drug that is coated with a bioerodible polymer material. Alternatively, in certain dosage forms that mimic administration three times daily, both the delayed release dosage form and the second delayed release dosage form are surrounded by an inner layer. This inner layer contains no active agent. The tablet layer (starting from the outer surface) thus comprises a mixture of outer layer, inner layer and delayed release dosage unit. The first delayed release pulse occurs when the inner layer is substantially eroded, thereby releasing a mixture of delayed release dosage units. The dose corresponding to the (first) delayed release dosage unit is released immediately after the inner layer prevents access to this dose for an appropriate time (eg, about 3-10 hours). However, the second delayed release dose is formulated to effectively delay release for at least 5 hours to about 18 hours after oral administration.

  For formulations that mimic twice daily administration, it is preferred that the delayed release dose is released from about 3 hours to less than 14 hours, most preferably from about 5 hours to 12 hours after oral administration. For dosage forms that mimic administration three times daily, it is preferred that the (first) delayed release dose be released less than about 3 to 10 hours, preferably 4 to 9 hours after oral administration. The third dose (ie, the second delayed release dose) is released at least 5 hours to about 18 hours after oral administration.

These drug dosage forms can be administered orally and used for the following treatments:
Depression, fibromyalgia syndrome, chronic fatigue syndrome, pain, attention deficit / hyperactivity disorder, and visceral pain syndrome (VPS) such as irritable bowel syndrome (IBS), non-cardiac chest pain (NCCP), functional digestion Poor, interstitial cystitis, instinct vulvar lesions, urethral neurosis, testicular pain, and affective disorders [depressive disorder (major depressive disorder, mood modulation, atypical depression) and anxiety disorder (systemic anxiety disorder, Phobia, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder)], premenstrual dysphoric disorder, temporal mandibular disorder, atypical facial pain, migraine, and tension headache.

  Unless otherwise indicated, the formulation and its method of use are not limited to a particular pharmaceutical carrier or a particular dosing regimen as may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

  Note that as used in the specification and appended claims, the singular forms “a”, “an”, and “the” encompass plural objects unless the context clearly dictates otherwise. Must. Thus, for example, reference to “an active agent” includes one active agent and a combination of various active agents, and reference to “a pharmaceutical carrier” includes a combination of one pharmaceutical carrier and two or more carriers Reference to “compressed tablets” includes one and more compressed tablets, and reference to “immediate release dosage forms” includes a single in addition to a military of two or more immediate release dosage forms. Immediate release dosage forms, and “coating” such as “delayed release coating” includes a single coating, two or more coatings, and the like.

  “Any” or “as required” means that the situation described thereafter may or may not occur, and thus this description is intended to be used when this situation occurs. Includes examples and examples that do not occur. For example, if “any second delayed release dosage unit” appears in the description of the dosage form, “any second delayed release dosage unit” means that a second delayed release dosage unit may or may not be present. Means. Accordingly, this description includes dosage units. It includes a dosage unit in which a second delayed release dosage unit is present and a dosage unit in which no second delayed release dosage unit is present. As used herein, “about” means approximately plus or minus 10%.

  The milnacipran composition provides a pulsed delivery dosage form for administering milnacipran and mimics the administration of milnacipran twice or three times daily. That is, the composition provides an immediate dose followed by one or more pulsed doses several hours after ingestion of the dosage form.

  If desired, only less than 10% of the first pulse release is released substantially immediately after ingestion of the dosage form. More than 90% of the first pulse becomes available after the formulation passes through the stomach and into the small intestine. The composition further provides a second drug dose, and optionally a third drug dose, several hours after ingestion of the dosage form. Since milnacipran is known to cause gastrointestinal tract disorders, delaying the first dose substantially reduces gastric mucosal exposure to the drug, and thus local effects of milnacipran (eg, nausea and vomiting) ).

  The predicted therapeutic benefits of these formulations are described in Cypress Bioscience, Inc. 41st Annual Meeting of American College of Neuropsychopharmacology by, San Juan, Puerto Rico (Gendreau R.M. et al., December 9, 2002, Poster presentation, Paster # 85 "Development of milnacipran, a dual reuptake inhibitor for treatment of 12-week randomized, double-blind, placebo-controlled, step-by-step, monotherapy trial evaluating milnacipran in patients diagnosed with fibromyalgia syndrome (FMS) as shown in "chronic pain associated with fibromyalgia") Depending on the result of Further corroborated.

  In FMS studies conducted by Cypress Bioscience, 25 mg / day, 50 mg / day, 100 mg / day, and finally 200 mg / day, or 1 week for all patients over 4 weeks until dose-limiting toxicity becomes apparent Administered in graded dose increments. In this study, the currently available immediate release (IR) milnacipran formulation was used as the only milnacipran dosage form. Patients who could reach 200 mg / day were then treated at that dose for an additional 8 weeks. It is important to emphasize that milnacipran once daily (QD-IR) patients were administered a total dose of immediate release milnacipran in the morning and placebo in the evening at any given dose level It is. Milnacipran twice daily (BID-IR) patients received the same total dose in divided doses administered in the morning and evening.

  The primary endpoint used by Cypress Bioscience was defined as the change in pain score from baseline to endpoint based on pain scores collected in the patient electronic diary. The endpoint was defined as the 12th week for evaluation with a single numerical value (eg, clinical measure) or diary-based results with an average of the scores at weeks 11 and 12. Milnacipran has been shown to effectively treat the pain associated with fibromyalgia syndrome and further improve the mood of depressed patients with FMS. When the 200 mg / day dose is reached, the improvement in pain score reported by study participants indicates that this dose, which is significantly higher than the dose commonly used for treating depression, is necessary for pain relief. . On a 1-7 scale of overall pain for all patients who reached the endpoint at the time of analysis (1 is a fairly high improvement, 4 is no change, 7 is a very low improvement), the mean value for milnacipran patients is Although it was 2.3, the average value of placebo patients was 4.3 (the difference between the milnacipran group and placebo is statistically significant at p = 0.0001). Importantly, in the milnacipran group, twice-daily administration was significantly more effective at reducing pain than once-daily administration. In addition to being more therapeutically effective, the twice-daily regimen also showed fewer dose-related adverse events resulting in a lower rate of dose intolerance than the once-daily regimen (QD- 19% of patients in the IR group failed to receive a gradual dose increase, compared with only 6% in the BID-IR group). It should be recognized that in the placebo group, no escalating dose failures were recorded.

These clinical differences between QD-IR and BID-IR are most likely due to the distinct differences in drug plasma levels (particularly _Cmax ) supported by these two regimens. The BID-IR dosing regime supports drug plasma levels characterized by lower C _max and lower drug plasma level fluctuations than QD-IR over 24 hours. When the daily dose is administered with QD-IR, the C _max is about 2-fold higher than the BID-IR dosing schedule. A higher C _max increases the severity of adverse side effects (which may also prevent objective pain level self-assessment by the patient), resulting in lower drug resistance and patient compliance. Thus, the superior milnacipran performance observed when the drug is administered BID-IR is believed to be due to more “sustained” drug plasma levels over 24 hours.

  According to clinical trial data obtained and presented by Cypress Bioscience, sleep quality is improved, even if slightly, when milnacipran is administered BID-IR. This indicates that formulations that provide more “sustained” drug plasma levels over 24 hours perform better than standard immediate release formulations and, importantly, produce less insomnia. It can be understood that this is further shown.

(Definition)
Delayed release dosage form: A delayed release dosage form is a dosage form that releases a drug at a predetermined time, not just after administration.

  Pulsed release dosage form: A pulsed dosage form is a dosage form that mimics a multiple dose profile without repeated administration, and is a conventional dosage form (eg, a solution or a conventional solid dosage form that releases drug immediately. ) As a dosage form that can reduce the frequency of administration by at least 2-fold compared to the drug present as. The pulsed release profile is characterized by rapid drug release followed by a period of no release (lag time).

(Milnacipran)
Milnacipran and its synthesis are disclosed in US Pat. No. 4,478,836. Milnacipran (Midalcipran, Midasiplan, F 2207) inhibits the uptake of norepinephrine (NE) and serotonin (5-HT) at a NE / 5-HT ratio of 2: 1 (Noret et al., 1985, Neuropharmacology. , 24: 1211-1219; Palmier et al., 1989, Eur. J. Clin. Pharmacol., 37: 235-238) does not affect dopamine uptake. Milnacipran has no affinity for alpha or beta adrenergic receptors, muscarinic receptors, histaminergic receptors, and dopaminergic receptors. This suggests that milnacipran is unlikely to produce anticholinergic, sedative and excitatory effects. Milnacipran does not affect many β-adrenergic receptors in rat cortex after chronic administration (Briley M et al., Int. Clin. Psychopharmac., 1996, 11: 10-14). Other information regarding the milnacipran can be found in the Merck Index, 12th edition, entry 6281.

  As used herein, “milnacipran” refers to both individual enantiomers of milnacipran (dextrorotatory and levorotatory enantiomers) and their pharmaceutically acceptable unless otherwise specified. Milnacipran enantiomers, mixtures of milnacipran enantiomers and their pharmaceutically acceptable salts, and active metabolites of milnacipran and their pharmaceutically acceptable salts Active derivatives. It is understood that in some cases, the dosage of enantiomers, derivatives and metabolites needs to be adjusted based on the relative activity of the racemic mixture of milnacipran.

  As used herein, “pharmaceutically acceptable salt” means a derivative of a disclosed compound in which the parent compound has been modified by the production of its acid or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acidic salts of basic residues such as amines: alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the common non-toxic salts or quaternary ammonium salts of the parent compound made, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and organic acids such as acetic acid, propion Acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamonic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy A salt derived from benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, succinic acid and isethionic acid.

  Pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared in water or an organic solvent, or a mixture of the two (generally preferred are non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile) or the free acid of these compounds or The base form can be generated by reacting with a theoretical amount of a suitable base or acid. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. Found at 704.

  As used herein, the term “pharmaceutically acceptable” refers to excessive toxicity, irritation, allergic reactions or other problems, within reasonable medical judgment, commensurate with a moderate benefit / risk ratio. Or means a compound, substance, composition and / or dosage form suitable for use in contact with human and animal tissue without complications.

  As used herein, the term “stereoisomer” refers to compounds made up of the same atoms joined by the same bonds but having different spatial structures that are not interchangeable. The three-dimensional structure is called a configuration. The term “enantiomer” as used herein refers to two stereoisomers whose molecules are non-superimposable mirror images of each other. As used herein, the term “optical isomer” is synonymous with the term “enantiomer”. The terms “racemate”, “racemic mixture” or “racemic modification” refer to a mixture of equal amounts of enantiomers. The term “chiral center” means a carbon atom to which four different groups are attached. As used herein, the term “enantiomeric enrichment” means an increase in the amount of one enantiomer as compared to the other. Enantiomeric enrichment is readily determined by those skilled in the art using standard methods and procedures, such as gas or high performance liquid chromatography on chiral columns. J. et al. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc. The selection of the appropriate chiral column, eluent and conditions necessary to perform the separation of enantiomeric pairs using standard methods well known in the art, such as Is within the range. Examples of resolution are recrystallization of diastereomeric salts / derivatives or preparative chiral chromatography.

(Combination with other active compounds)
Milnacipran has other active compounds such as analgesics, anti-inflammatory drugs, antipyretic drugs, antidepressants, anticonvulsants, antihistamines, antimigraine drugs, antimuscarinic drugs, anxiolytics, sedatives, Hypnotic, antipsychotic, bronchodilator, asthma, cardiovascular, corticosteroid, dopamine, electrolyte, gastrointestinal, muscle relaxant, nutrition, vitamin, parasympathomimetic, stimulant, appetite Suppressors and anti-sleep seizures can be administered supplementarily.

  Specific examples of compounds that can be administered adjunctively with milnacipran include but are not limited to the following compounds: aceclofenac, acetaminophen, admexetine, almotriptan, alprazolam, amantadine, amsinonide, aminocyclopropane , Amitriptyline, amorodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azadazine, beclomethasone, benactidine, beoxaprofen, vermoprofen, betamethasone, bicifazine, bromocriptine, budesonide, buprenorphine, bupretorphine, bupretorphin Caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordi Zepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazen, chlorazepate, clothiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cycloheptazine, demexidedexone, demexidedeson Ninabinol, dextroamphetamine sulfate, dextromolamide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimethacrine, divalprox, dizatriptan, drasetron, donepezil Doxepin, daloxetine Ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, phenamate, phenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, flovatriptan, gantapentine, gabapentine, gabapentine , Granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindol, ipsapirone, ketaserin, ketoprofen, ketorolac, resopitron, levodopa, lipase, lofepramine, lafepramine, Loxapine, maprotiline, gusset Ndole, mefenamic acid, melatonin, melitracene, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, metcarbamol, methyldopa, methylphenidate, methyl salicylate, methysergide, metoclopramide, mianserin, miferine Priston, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (anti-sleep attack), morindon, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, nalattriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondan Cetron, opipramol, orphenadrine, oxafurozan, oxaprazine, oxazepa , Oxytryptane, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pyrindole , Piroxicam, Pizotifen, Pizotirin, Pramipexole, Prednisolone, Prednisone, Pregabalin, Propanolol, Propizepine, Propoxyphene, Protriptyline, Quazepam, Quinupramine, Levoxitine, Reserpine, Risperidone, Ritansigmine, Rizatoximine, Rozatributine , Salsalate, sertraline, sibutramine, sildenafil, sul Asalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenodine, thiazide, thioridazine, thiothixene, thioprid, thiacipyrone, tizanidine, tophenacin, tolmetine, troxatone, topiramate, tramadol, trazodone, triazolam, triflupramide, triflupramide, triflupramide Setron, valdecoxib, palproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone, and isomers, salts and combinations thereof.

  Auxiliary administration means simultaneous administration of the compounds in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of the compounds.

(Prescription)
Using a pharmaceutically acceptable “carrier” of a material that is considered safe and effective and that can be administered to an individual without causing undesirable biological side effects or undesirable interactions, Prepare. A “carrier” is any ingredient other than the active ingredient present in a pharmaceutical formulation. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers and coating compositions.

  “Carrier” also includes all components of the coating composition that may contain plasticizers, pigments, colorants, stabilizers and glidants. Delayed release dosage formulations can be prepared as described in the literature as follows: “Pharmaceutical dosage form tablets”, edited by Liberman et al. (New York, Marcel Dekker, Inc., 1989), “Remington-Thescien "practice of pharmacy", 20th edition, Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage form and i ll, i et al. Tablets and capsules Provides information on carriers, materials, devices and methods for the manufacture of tablets, capsules and granules in delayed and / or pulsed release dosage forms).

  Examples of suitable coating materials include cellulose polymers such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers And methacrylic resins (commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany)), zein, shellac and polysaccharides. Other polymers that may be used include biodegradable polymers such as polyhydroxy acid-like poly (lactic acid-glycolic acid) and other approved hydrolyzable or enzymatically degradable polymers.

  In addition, the coating material may also contain conventional carriers such as plasticizers, pigments, colorants, gridants, stabilizers, pore formers and surfactants.

  Optional pharmaceutically acceptable excipients present in tablets, beads, granules or particles containing drugs include diluents, binders, lubricants, disintegrants, colorants, stabilizers and surfactants. But not limited to. Diluents, also referred to as “fillers,” are generally necessary to increase the bulk of solid dosage forms to provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, for example, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dried starch, hydrolyzed starch, pregelatinized starch , Silicon dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar, but are not limited thereto.

  The binder is used to impart stickiness to the solid dosage formulation, thereby ensuring that the tablet or beads or granules are maintained intact after the dosage form is formed. Suitable binder materials include starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, wax, natural rubber and synthetic rubber (eg gum arabic, tragacanth gum) ), Sodium alginate, cellulose (including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose), and bee gum, and synthetic polymers (eg, copolymers of acrylic acid and methacrylic acid, methacrylic acid copolymer, methyl methacrylate copolymer, aminoalkyl methacrylate) Copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone), but are not limited thereto.

  Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc and mineral oil.

  Disintegrants are used after administration to promote the disintegration or “degradation” of the dosage form and include starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clay, Cellulose, arginine, rubber or a cross-linked polymer such as, but not limited to, cross-linked PVP (Polyplastdone XL from GAF Chemical Corp.) is generally included.

  Stabilizers are used to inhibit or delay drug degradation reactions, including oxidative reactions.

  As the surfactant, an anionic, cationic, amphoteric, or nonionic surfactant can be used. Suitable anionic surfactants include, but are not limited to, surfactants containing carboxylic acid, sulfonic acid and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium long chain alkyl sulfonates and alkyl aryl sulfonates (eg, sodium dodecylbenzene sulfonate); dialkyl sodium sulfosuccinate (eg, sodium dodecyl benzene sulfonate); Dialkyl sodium sulfosuccinate (eg, sodium bis- (2-ethylthioxy) -sulfosuccinate); and alkyl sulfates (eg, sodium lauryl sulfate), but are not limited thereto. Cationic surfactants include, but are not limited to, quaternary ammonium compounds (eg, benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene and coconut amine). Examples of nonionic surfactants include ethylene glycol monostearate, polyethylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acrylate, sucrose acrylate, PEG-150 laurate, PEG-400 mono Laurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octyl phenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and poly Examples include oxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristamphoacetate, lauryl betaine and lauryl sulfobetaine.

  If desired, the tablets, beads, granules or particles may also contain minor amounts of nontoxic auxiliary materials such as wetting or emulsifying agents, dyes, pH buffering agents and preservatives.

  The amount of active agent released at each dose is a therapeutically effective amount. For milnacipran, the total amount in the dosage form ranges from about 25 to 500 mg.

  The pharmaceutical dosage form provides pulsed delivery of milnacipran. “Pulsed” is the release of multiple drug doses at time intervals. In general, upon oral ingestion of this dosage form, the release of the first dose is substantially immediate, that is, the first drug releases a “pulse” that occurs within about 1 hour of oral ingestion. . This first pulse is followed by a first period (delay time) during which very little drug is released from the dosage form or not at all, after which the second dose is then released. Similarly, a second interval may be designed between the second drug release pulse and the third drug release pulse that substantially does not release the drug. The duration of the interval during which the drug is almost not released will vary depending on the dosage form design (eg, twice daily dosage profile, three times daily dosage profile, etc.). For dosage forms that provide a twice daily dosing profile, the near-release interval of the drug has a period of approximately 3 to 14 hours between the first and second doses. For a dosage form that provides a three times daily profile, the interval of almost no drug release has a duration of approximately 2-8 hours between each of the three doses.

  In one embodiment, the pulsed release profile is achieved by a dosage form that is a closed capsule and preferably a sealed capsule to accommodate at least two drug-containing “dosage units”, Each dosage unit provides a different drug release profile. Control of the delayed release dosage unit is achieved by the incorporation of the active agent into a controlled release polymer or controlled polymer matrix that coats the dosage unit. Each dosage unit may contain a compressed tablet or molded tablet, and each tablet in the capsule provides a different drug release profile. For a dosage form that mimics a twice daily dosage profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, while the second tablet is after ingestion of the dosage form. Release drug in approximately 3-14 hours. For a dosage form that mimics a three times daily dosage profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, and the second tablet approximately 3 after ingestion of the dosage form. The drug is released in less than 10 hours and the third tablet releases the drug at least 5 hours to approximately 18 hours after ingestion of the dosage form. This dosage form may contain more than two tablets. This dosage form generally does not include more than two tablets, but dosage forms containing more than two tablets may be utilized.

  Alternatively, each dosage unit within the capsule can comprise a plurality of drug-containing beads, granules, or particles. As is known in the art, a drug-containing “bead” refers to a bead produced using a drug and one or more excipients or polymers. Drug-containing beads apply the drug to an inert support (eg, an inert sugar bead coated with a drug) or generate a “core” that includes both the drug and one or more excipients Can be manufactured. As is also known, drug-containing “granules” and “particles” include drug particles, which may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. In general, the granules contain drug particles and require further processing. In general, the particles are smaller than the granules and are not further processed. Beads, granules and particles can be formulated to provide immediate release, but beads and particles are generally used to provide delayed release.

  For dosage forms that mimic a twice daily dosing profile, the first group of beads, granules or particles release drug substantially immediately after ingestion of the dosage form, while the second group of beads or granules are preferred. Releases the drug approximately 3 to less than 14 hours after ingestion of this dosage form. For a dosage form that mimics a three times daily dosage profile, the first group of beads, granules or particles will substantially release the drug immediately after ingestion of the dosage form, and the second group of beads or granules preferably The drug is released approximately 3 hours to 10 hours after ingestion of the dosage form, and the third group of beads, granules or particles releases the drug at least 5 hours to approximately 18 hours after ingestion of the dosage form. The above tablets, beads, granules or particles of different drug release profiles (eg immediate release profile and delayed release profile) are mixed and contained in a capsule, tablet or matrix, pulsed with the desired release profile A dosage form may be provided.

  In another embodiment, the individual dosage units are compressed into a single tablet and may be present in the composite but separate segments (eg, layers) or as a simple mixture. For example, drug-containing beads, granules or particles having different drug release profiles (eg, immediate release profile and delayed release profile) can be compressed together into a single tablet using conventional tableting methods.

  In a further alternative embodiment, a dosage form is provided comprising an inert drug-containing core and at least one drug-containing layer surrounding the inner core. The outer layer of this dosage form contains an initial immediate release dosage of the drug. For a dosage form that mimics twice daily dosing, the dosage form is preferably about 3 to 14 hours after ingestion of the outer layer that releases the drug substantially immediately after oral administration and the dosage unit. It has an inner core with a polymer coating that releases this active factor in less than. For dosage forms that mimic dosing three times daily, the dosage form releases the drug substantially immediately after oral administration, an outer layer that releases the drug, preferably at least 5-18 hours after oral administration. It has an inner core and an intervening layer between the inner and outer nuclei and an outer layer that releases the drug preferably after approximately 3-10 hours after ingestion of the dosage form. The inner core of a dosage form that mimics dosing three times daily can be formulated as compressed delayed release beads or granules.

  Alternatively, for a dosage form that mimics dosing three times a day, the dosage form has an outer layer and an inner layer without drug. This outer layer releases the drug substantially immediately after oral administration and completely surrounds this inner layer. This inner layer surrounds both the second and third doses and preferably prevents the release of these doses for approximately 3-10 hours after oral administration. Once released, this second dose will be available immediately, but this third dose will result in the release of the third dose approximately 2-8 hours thereafter, after ingestion of this dosage form. Formulated as delayed release beads or granules to effectively produce a third dose release in at least 5 hours to approximately 18 hours. The second and third doses are mixed with immediate release and delayed release beads, granules or particles, and the mixture is compressed to form nuclei containing the second and third doses, followed by It can be formulated by polymer coating to achieve the desired 3 times daily dosing profile.

  In yet another embodiment, the dosage form comprises a coated karyotypic delivery system, the outer layer comprising an immediate release dosage unit, nucleus, such that the active agent therein is released immediately after oral administration. Composed of an intermediate layer and a core surrounding it, the nucleus being such that the second dose is provided by immediate release beads or granules and the third dose is provided by delayed release beads or granules, Consists of immediate release beads or granules and delayed release beads or granules. A number of methods are available to produce tablets, beads, granules, or particles containing drugs that provide a variety of drug release profiles, as evaluated by those skilled in the art and described in the appropriate textbooks and literature. Is available. Such methods may include, but are not limited to: coating a drug or drug-containing composition with a suitable coating material (incorporation of a polymeric material is typical but not necessary); Increasing the size of the drug particles; placing the drug in a matrix; and forming a complex of the drug with an appropriate complexing agent.

  Delayed release of dosage units in any of the above embodiments can be produced, for example, by coating a drug or drug-containing composition with a selected coating material. This drug-containing composition is, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or for incorporation into either a tablet or capsule. It can be a plurality of drug-containing beads, particles or granules. Preferred coating materials are composed of bioerodible polymers, slowly hydrolyzable polymers, slowly water soluble polymers, and / or enzymatically degradable polymers, and conventional “enteric” polymers It can be. Enteric polymers, as understood by those skilled in the art, are soluble in the high pH environment of the lower gastrointestinal tract or are slowly eroded while the dosage form passes through the gastrointestinal tract, but are enzymatically degradable. The polymer is degraded by bacterial enzymes present in the lower gastrointestinal tract (especially the colon). Suitable coating materials that provide delayed release include cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, Cellulose acetate, cellulose acetate phthalate, cellulose acetate trimyrate and sodium carboxymethylcellulose); acrylic acid polymers and copolymers (preferably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate and others Methacrylic resins (commercially available under the trade name Eudragit. RTM. (Rohm Pharma; Westerstadt, Germany) (Eudragit. RTM. L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit. RTM L-100 (soluble at pH 6.0 and above), Eudragit.RTM.S (soluble at pH 7.0 and above, highly esterifying) and Eudragits.RTM.NE, RL and RS ( Vinyl polymers and copolymers (polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymers, and ethylene). Len-vinyl acetate copolymers); enzymatically degradable polymers (including but not limited to azopolymers, pectin, chitosan, amylose and guar gum), and shellacs, and combinations of different coating materials can also be used. The multilayer coating used can also be applied.

  Preferred coating weights for a particular coating material can be readily determined by one skilled in the art by evaluating each release profile for tablets, beads and granules prepared with various amounts of various coating materials. It is the combination of materials, methods, and application forms that produces the desired release characteristics that can be determined from clinical trials alone.

  The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, gridants, and the like. Plasticizers are usually present to reduce the brittleness of the coating and are generally present at about 10% to 50% by weight relative to the dry weight of the polymer. Examples of typical plasticizers are polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethylacetyl citrate, castor oil and acetyl However, it is not limited to these. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. The glidants are recommended to reduce the sticking effect during film formation and drying and are generally present at about 25% to 100% by weight of the polymer weight in the coating solution. One effective gridant is talc. Other glidants such as magnesium stearate and glycerol monostearate may also be used. Pigments such as titanium dioxide can also be used. A small amount of antifoaming agent, such as silicone (eg, simethicone) may also be added to the coating composition.

  Delayed release dosage form units are based on delayed release polymer coating using conventional techniques (eg, coating pan, airless spraying, fluidized bed coating equipment (with or without Wurslar insert), etc.). Can be coated. For detailed information on the materials, devices and processes for preparing tablets and delayed release dosages, reference may be made to pharmaceutical dosage forms: Tables, edited by Lieberman et al. (New York: Marcel Dekker, Inc., 1989). ) And Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6 Addendum, Ed. (Media, PA: Williams & Wilkins, 1995).

  Alternatively, delayed release tablets can be formulated by dispersing the drug in a matrix of a suitable material such as a hydrophilic polymer or fatty compound. The hydrophilic polymer may be composed of a polymer or a copolymer of cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, and vinyl or a polymer that can be enzymatically degraded, or a copolymer as described above. These hydrophilic polymers are particularly useful for providing delayed release matrices. Fatty compounds for use as the matrix material include, but are not limited to, waxes (eg, carnauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material, the mixture can be compressed into tablets.

  The immediate release dosage unit of this dosage form, i.e. the tablet, the plurality of drug-containing beads, granules or particles, or the outer layer of the coated core dosage form comprises a therapeutically effective amount of the active substance comprising conventional pharmaceutical excipients. Containing. Immediate release dosage units may or may not be coated, and delayed release dosage units or encapsulated immediate release drugs containing granules, particles or beads and delayed release drugs containing granules or beads May or may not be mixed with a plurality of units (as a mixture of). Preferred methods for preparing immediate release tablets (eg, as incorporated in capsules) include drug-containing blends (eg, direct blending, wet-granulation or dry-granulation processes). by compressing the blend of granules prepared using process). Immediate release tablets can also be molded starting with a moist material containing a suitable water-soluble lubricant, rather than compression. However, the preferred tablets herein are manufactured using compression rather than molding. A preferred method for forming an extended release drug-containing blend is to use drug particles as one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants and colorants. It is a method of directly mixing with. As an alternative to the direct blending step, the drug-containing blend can be prepared by a wet granulation process or a dry granulation process. Beads containing the active ingredient can also be prepared, typically starting from a dispersion, by any one of a number of conventional techniques. For example, typical methods for preparing drug-containing beads include active ingredients that are mixed with conventional pharmaceutical excipients (eg, microcrystalline cellulose, starch, polyvinylpyrrolidone, methylcellulose, talc, metal stearate, dioxide Blending with silicon and the like). This mixture is used to coat bead nuclei (eg, sugar spheres having a size of about 20-60 mesh (ie, so-called “non-pareil”)).

  An alternative procedure for preparing drug beads is to make the drug one or more pharmaceutically acceptable excipients (eg, microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrant, etc. ), Extruding the blend, spheronizing the extrudate, drying, and optionally coating to form immediate release beads.

  Any pharmaceutically acceptable excipient is present in the drug-containing tablet, bead, granule or particle, including diluents, binders, lubricants, disintegrants, pigments, stabilizers, surfactants Examples include, but are not limited to, agents. Diluents are also referred to as “fillers” and are typically required to increase the bulk of solid dosage forms to provide particle size for tablet compression or bead and granule formation. Suitable diluents include, for example, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dried starch, hydrolyzed starch, pregelatinized starch , Silicon dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. The binder is used to impart tackiness to the solid dosage formulation, thereby ensuring that the tablet or beads or granules remain intact after the dosage form is formed. Suitable binder materials include starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, wax, natural and synthetic rubbers (eg gum arabic, gum tragacanth), Sodium alginate, cellulose and bee gum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone Lubricants are used to facilitate tablet manufacture Examples of suitable lubricants include, for example, magnesium stearate, stear Examples include, but are not limited to, calcium acid, stearic acid, glycerol behenate, and polyethylene glycol, talc and mineral oil Disintegrants are used to facilitate the disintegration or “degradation” of the dosage form after administration. In general, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, arginine, gum or cross-linked polymers such as cross-linked PVP (GAF Chemical Corp. Stabilizers are used, for example, to inhibit or retard drug degradation reactions due to oxidation reactions.Surfactants are anionic, Suitable anionic surfactants include, but are not limited to, surfactants containing carboxylic acid, sulfonic acid and sulfate ions. Examples of agents are sodium, potassium, ammonium (eg, sodium dodecylbenzene sulfonate) of long chain alkyl sulfonates and alkylaryl sulfonates; dialkyl sodium sulfosuccinate (eg, sodium dodecylbenzene sulfonate); dialkyl sulfos Succinate sodium (eg, bis- (2-ethylthioxyl) sulfosuccinate sodium); and alkyl sulfates (eg, sodium lauryl sulfate). Non-limiting examples include nium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene (15) and coconut amine. Examples of nonionic surfactants are ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acrylate, sucrose acrylate, PEG-150 laurate, PEG-400 monolaur Rate, polyoxyethylene (8) monolaurate, polysorbate, polyoxyethylene (9) octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene (3) tridecyl ether, polypropylene glycol (18) butyl ether, Poloxamer 401, stearoyl Monoisopropanolamide, and polyoxyethylene (5) hydrogenated tallow amide, but are not limited thereto. Examples of amphoteric surfactants are sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristamphoacetate, lauryl betaine and lauryl sulfobetaine. If desired, the tablets, beads, or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents and preservatives.

  The amount of active agent released at each dose is a therapeutically effective amount. For milnacipran, the total amount in the dosage form is in the range of about 25-500 mg. Typically, the total amount in the dosage form of the active agent is evenly distributed between each pulse contained in the dosage form. For dosage forms that mimic a twice daily profile, the active agent in the immediate release form is generally about 30% to 70%, preferably 40%, of the total active agent in one dosage form. Active agents in delayed release form are also generally about 70% to 30% by weight of the total active agent in a dosage form, preferably from 60% to 60% by weight, 60 wt% to 40 wt% is shown. Similarly, for a dosage form that mimics a dosage profile of 3 times daily, each of the active agent in the immediate release unit and the two delayed release units is about 20% by weight to the total active agent in one dosage form. 50% by weight, preferably 25% to 40% by weight.

  All publications mentioned in this specification are incorporated by reference in their entirety.

(Kit containing pulsed release formulation)
To provide a way to conveniently start dose titration with smaller doses (e.g. starting at 25 mg and gradually increasing to 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg in 3-16 weeks) A kit is provided that packages a once-per-day pulsed release dosage form. In this kit, the packaging material can be a box, bottle, blister package, tray or card. The kit instructs the patient to take a specific dose at a specific time (eg, first dose on day 1, second higher dose on day 2, until the maintenance dose is reached) A larger third dose, etc.) including package inserts.

(Production method)
Many methods are available to prepare drug-containing tablets, beads, granules or particles that provide a variety of drug release profiles, as understood by those skilled in the art and described in the relevant books and literature. . Such methods include, but are not limited to, the following: a drug or drug-containing composition is coated with a suitable coating material, typically but not necessarily, incorporating a polymeric material, and a drug particle size , Put the drug in the matrix, and form a complex of the drug with a suitable complexing agent.

  Pulsed release dosage units can be coated with a delayed release polymer coating using conventional techniques such as conventional coated pans, airless spraying, fluidized bed coating equipment (with or without Wurster inserts), etc. . For detailed information regarding materials, equipment and processes for preparing tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Edited by Tables, Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutic. See Dosage Forms and Drug Delivery Systems, 6th Addendum, (Media, PA: Williams & Wilkins, 1995).

(Administration of milnacipran formulation)
The formulation can be administered to any patient in need thereof. The preferred patient is a human, but any mammal can be treated including domestic animals such as dogs, cats and horses.

  The amount of active ingredient administered is selected based on the amount that provides the desired dose to the patient in need of treatment such as alleviating symptoms or treating the disease.

  Milnacipran has been used as an antidepressant in approximately 400,000 patients and is known to be non-toxic in humans. Pharmacokinetic studies have shown that oral doses of milnacipran are rapidly absorbed and widely dispersed in the body within 1-2 hours. Maximum plasma levels are reached quickly and the half-life in humans is about 8 hours. Metabolism in the liver results in the formation of ten chemically identified metabolites, which are only about 10% of the parent drug concentration. In humans, 90% of the parent drug is excreted via the kidneys unchanged. This pharmacokinetic profile has several pharmacokinetic benefits on milnacipran, such as low interindividual changes in plasma levels, low drug interaction potential, and limited impact on the liver cytochrome P-450 system . These pharmacokinetic properties distinguish milnacipran from most other antidepressants and contribute to the superior safety profile of milnacipran (Puzozo C et al., 1996, Int. Clin. Psychopharmacol. 11: 15-27; Caccia S., 1998, Clin. Pharmacokinet., 34: 281-302; Puozzo C. et al., 1998, Eur. J. Drug Metab. Pharmacokinet., 23: 280-286).

  Milnacipran can be administered for the following treatments: depression, fibromyalgia syndrome, chronic fatigue syndrome, pain, attention deficit / hyperactivity disorder, and visceral pain syndrome (VPS) such as irritable bowel syndrome (IBS), non-cardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, instinct vulvar lesions, urethral neurosis, testicular pain, and affective disorders [depressive disorder (major depressive disorder, mood modulation Atypical depression) and anxiety disorders (systemic anxiety disorder, phobia, obsessive compulsive disorder, panic disorder, posttraumatic stress disorder)], premenstrual dysphoric disorder, temporal mandibular disorder, non Regular facial pain, migraine, and tension headache.

  Adverse reactions to oral administration of milnacipran typically include at least one of the following: nausea, vomiting, headache, dyspepsia, abdominal pain, insomnia, tremor, anxiety, panic attacks, palpitation, urinary retention, orthostaticity Low blood pressure, sweating, chest pain, rash, weight gain, back pain, constipation, dizziness, increased sweating, mental agitation, flushing of the face, tremor, fatigue, somnolence, dysuria, nervousness, dry mouth and irritation.

  The emetic reflex is triggered by stimulation of both chemoreceptors in the upper gastrointestinal tract and mechanical receptors in the gastrointestinal tract activated by both contraction and dilation of the intestinal tract and physical damage. A coordinated center in the central nervous system controls the emetic response. Its center resides in the small cell ciliary body in the outer medullary region of the brain. Afferent nerves to the vomiting center arise from the abdominal visceral and vagus nerves, vestibular-maze receptors, cerebral cortex and chemoreceptor trigger points (CTZ). CTZ is present in close proximity to the last cortex and contains chemoreceptors that sample both blood and cerebrospinal fluid. There is a direct bond between the emetic center and the CTZ. CTZ is exposed to emetic stimuli of endogenous origin and stimuli of exogenous origin such as drugs. The efferent branches of cranial nerves V, VII and IX, as well as the vagus and sympathetic trunks, produce a complex coordinate set of reverse peristalsis that is characteristic of muscle contraction, cardiovascular response, and vomiting. The last field is rich in dopamine receptors as well as 5-hydroxytryptamine (5HT) receptors.

When administered orally, the formulation provides an immediate dose followed by one or more pulsed doses several hours after ingestion of the dosage form. The pharmaceutical composition of milnacipran is less than 3000 ng / ml, preferably less than 2000 ng / ml, and preferably less than 1000 ng, occurring within about 0.05 to about 3 hours (first T _max ) after oral administration. In vivo drug plasma levels characterized by a first initial peak plasma concentration (C _max ) of less than / ml. The second in vivo plasma concentration peak occurs within about 3 hours to about 14 hours after oral administration (second T _max ), 3000 ng / ml or less, preferably 2000 ng / ml or less, most preferably 1000 ng / ml. Characterized by the following C _max . A third optional in vivo plasma concentration peak occurs within about 5 hours to about 18 hours after oral administration (third T _max ), 3000 ng / ml or less, preferably 2000 ng / ml or less, most preferably 1000 ng. Characterized by a C _{max of} / ml or less.

When an enteric coating is added to the above formulation, the oral dosage form formulation will release less than about 10% of the first “pulse” milnacipran dose and will first pass through the stomach, then Enters the intestine where it releases the rest of the first “pulse”. This release profile is characterized by a lag time of 0.05-4 hours during which less than about 10% of the first “pulse” is released, after which the first “pulse” is completely released. . The enteric coating minimizes direct milnacipran interaction with the gastric mucosa, thereby further reducing the incidence of common milnacipran side effects and reducing their strength. The enteric coated formulation exhibits in vivo plasma C _max levels similar to the uncoated formulation, but the T _max for the first pulse is increased by 0.05-4 hours. The T _max for the second and third (optional) pulses can be kept equal for the uncoated formulation by adjusting the formulation components to meet the desired release profile.

  This dosage form has numerous advantages when compared to immediate release delivery systems (eg, minimizing peak-to-bottom fluctuations, avoiding undesirable side effects and / or reducing their strength / severity, frequency of administration) And improved patient adaptability).

  This formulation is designed to be administered once a day to patients in need thereof, thereby causing nausea, vomiting, headache, shivering, anxiety, panic attacks, palpitation, urinary retention, orthostatic hypotension, sweating , Chest pain, rash, weight gain, back pain, constipation, dizziness, increased sweating, mental agitation, flushing of the face, tremor, fatigue, somnolence, dyspepsia, dysuria, nervousness, dry mouth, abdominal pain, irritability and insomnia Milnacipran is delivered over about 24 hours, with a decrease in the occurrence and intensity of one or more of the common milnacipran side effects such as

  The invention will be better understood with reference to the following non-limiting examples.

Example 1 Production of Immediate Release Part of Pulsed Release Milnacipran Formulation
Ingredients, manufacturing method and tablet parameters (lot number 1) for the immediate release portion of the pulsed release milnacipran pharmaceutical composition.

この処方物を、湿式粒状化工程のために水溶性媒体を用いて調製した。即時放出錠剤を製造するため、重量を測った塩酸ミルナシプラン、微結晶性セルロース、および事前ゼラチン化デンプンを混合した。精製水を、混合しながらゆっくりと加えた。湿った全体を、１２番メッシュスクリーンに通した。得られた湿った顆粒を、トレイドライヤー上で５０℃にて乾燥させ、次いで、３０番メッシュスクリーンを通した。最後に、乾燥した顆粒をステアリン酸マグネシウムと混合することによって潤滑し、次いで、この混合物を、１６ステーションシングル回転圧縮機上で圧縮した。

This formulation was prepared using an aqueous medium for the wet granulation process. To produce an immediate release tablet, weighed milnacipran hydrochloride, microcrystalline cellulose, and pregelatinized starch were mixed. Purified water was added slowly with mixing. The whole wet was passed through a # 12 mesh screen. The resulting wet granules were dried at 50 ° C. on a tray dryer and then passed through a 30 mesh screen. Finally, the dried granules were lubricated by mixing with magnesium stearate and then the mixture was compressed on a 16 station single rotary compressor.

（実施例２：パルス型放出ミルナシプラン処方物の代替的即時放出部分の製造）
パルス型放出ミルナシプラン薬学的組成物の代替的即時放出部分についての、成分、製造法および錠剤パラメータ（ロット番号２）。

Example 2: Production of an alternative immediate release portion of a pulsed release milnacipran formulation
Ingredients, manufacturing method and tablet parameters (lot number 2) for an alternative immediate release portion of a pulsed release milnacipran pharmaceutical composition.

この処方物を、上述のように製造した。

This formulation was prepared as described above.

（実施例３：パルス型放出ミルナシプラン処方物の腸溶性被膜部分の製造）
パルス型放出ミルナシプラン薬学的組成物の腸溶性被膜部分についての、成分、製造法およびインビトロ溶解データ。

Example 3: Production of enteric coating portion of pulsed release milnacipran formulation
Ingredients, manufacturing methods and in vitro dissolution data for the enteric coated portion of the pulsed release milnacipran pharmaceutical composition.

  Lot number 1 (immediate release tablet) was used in the manufacture of enteric coated dosage forms. The manufacturing process consists of spraying a water-soluble enteric coating suspension onto an immediate release tablet fluidized in GPCG-1 (Glatt Air Technologies, Inc.). For Lot No. 3, a 20% film weight gain was achieved. Process parameters were adjusted to achieve good quality coatings. The components of the water-soluble enteric coating suspension are shown below.

ロット番号３腸溶性被膜錠剤のインビトロ溶解データを、以下に示す。インビトロ薬物放出研究を、ＵＳＰ溶解装置ＩＩ（ｐａｄｄｌｅｓ）を５０ｒｐｍで用いて行った。実験を、溶解媒体（３７．０±０．５℃）中で、最初の２時間は０．１Ｎ塩酸中で、続いて１．５時間をｐＨ６．８のリン酸緩衝液中で行った（叙法性物質についてはＵＳＰ ２６＜７２４＞方法Ｂを参照）。０．１Ｎ塩酸中での２時間後、そしてｐＨ６．８緩衝液中で１５分、３０分、４５分および９０分後、サンプルアリコートを採取し、ＨＰＬＣ法を用いて分析した。

The in vitro dissolution data for Lot No. 3 enteric coated tablets are shown below. In vitro drug release studies were performed using a USP dissolution apparatus II (paddles) at 50 rpm. Experiments were performed in dissolution medium (37.0 ± 0.5 ° C.) for the first 2 hours in 0.1 N hydrochloric acid followed by 1.5 hours in phosphate buffer at pH 6.8 ( (See USP 26 <724> Method B for narrative material). Sample aliquots were taken after 2 hours in 0.1 N hydrochloric acid and after 15, 30, 45 and 90 minutes in pH 6.8 buffer and analyzed using HPLC methods.

ＮＳ−１％未満しか検出されなかった
ＮＡ−適用不可能
（実施例４：パルス型放出ミルナシプラン処方物の遅延放出部分の製造）
パルス型放出ミルナシプラン薬学的組成物の即時放出部分についての、成分、製造法およびインビトロ溶解データ。

NS-less than 1% detected NA-not applicable (Example 4: Production of delayed release portion of pulsed release milnacipran formulation)
Ingredients, manufacturing methods and in vitro dissolution data for the immediate release portion of the pulsed release milnacipran pharmaceutical composition.

  Lot number 2 (immediate release tablet) was used in the manufacture of delayed release dosage forms. The manufacturing process consists of spraying the water-soluble coating suspension onto an immediate release tablet fluidized in GPCG-1 (Glatt Air Technologies, Inc.). For Lot No. 4, an acquisition of 30% coating weight was achieved. Process parameters were adjusted to achieve good quality coatings. After completion of the coating process, the tablets were further dried in GPCG-1 at 40 ° C. for 30 minutes and then “cured” in an oven dryer at 30 ° C. for 60 hours. The “curing” time can be shortened by increasing the drying temperature (eg, only 6 hours of drying is required at 50 ° C.). The components of the water-soluble enteric coating suspension are shown below.

このサンプルを、最終投薬形態が経口で投与された場合（すなわち、胃において酸性ｐＨで約２時間に次いで、腸において中性ｐＨで数時間）（Ｍｕｌｔｉｐａｒｔｉｃｕｌａｔｅ Ｏｒａｌ Ｄｒｕｇ Ｄｅｌｉｖｅｒｙ，１９９４，Ｇｈｅｂｒｅ−Ｓｅｌｌａｓｓｉｅ Ｉ．，編集，Ｍａｒｃｅｌ Ｄｅｋｋｅｒ，Ｉｎｃ．；ＷｉｌｄｉｎｇＩ．Ｒ．，２００１，Ａｄｖ．ＤｒｕｇＤｅｌｉｖ．Ｒｅｖ．，４６：１０３−１２４）に曝されるインビボの条件を模倣する、インビトロ溶解試験に供した。インビトロ薬物放出研究を、ＵＳＰ溶解装置ＩＩ（ｐａｄｄｌｅｓ）を５０ｒｐｍで用いて行った。実験を、溶解媒体（３７．０±０．５℃）中で、最初の２時間は０．１Ｎ塩酸中で、続いて０．５時間をｐＨ６．０のリン酸緩衝液中で、４時間をｐＨ６．５のリン酸緩衝液中で、そして最後に、４時間をｐＨ７．２のリン酸緩衝液中で行った。サンプルを採取し、ＵＶ法を用いて分析した（別の実験において、ＵＶ法は、ＨＰＬＣ法と実質的に同じ結果を与えることが示された）。

This sample was administered when the final dosage form was administered orally (i.e., about 2 hours at acidic pH in the stomach followed by several hours at neutral pH in the intestine) (Multiparticulate Oral Drug Delivery, 1994, Ghebre-SELLASSIE I.). , Edited by Marcel Dekker, Inc .; Wilding IR, 2001, Adv. Drug Deliv. Rev., 46: 103-124) and subjected to in vitro dissolution tests. In vitro drug release studies were performed using a USP dissolution apparatus II (paddles) at 50 rpm. Experiments were performed in dissolution medium (37.0 ± 0.5 ° C.) for the first 2 hours in 0.1N hydrochloric acid, followed by 0.5 hours in pH 6.0 phosphate buffer for 4 hours. Was carried out in phosphate buffer at pH 6.5 and finally 4 hours in phosphate buffer at pH 7.2. A sample was taken and analyzed using the UV method (in another experiment, the UV method was shown to give substantially the same results as the HPLC method).

（実施例５：パルス型放出ミルナシプラン処方物の製造）
ミルナシプランのパルス型送達のための最終形態を、実施例１または実施例２の即時放出部分と実施例４の遅延放出部分とを所望の割合で合わせることにより、製造した。異なった大きさのカプセルを、必要な日用量に依存して製造し得た。

Example 5 Production of Pulsed Release Milnacipran Formulation
The final form for pulsed delivery of milnacipran was prepared by combining the immediate release portion of Example 1 or Example 2 with the delayed release portion of Example 4 in the desired proportions. Different sized capsules could be manufactured depending on the daily dose required.

Example 6: Production of an alternative pulsed release milnacipran formulation
The final form for pulsed delivery of milnacipran was made by combining the enteric coating portion of Example 3 and the delayed release portion of Example 4 in the desired proportions. Different sized capsules could be manufactured depending on the daily dose required.

Claims (24)

  Provides pulsatile release of milnacipran that exerts a therapeutic effect over approximately 24 hours with reduced incidence and reduced intensity of one or more immediate release milnacipran side effects when administered to patients in need , Milnacipran formulation.   The milnacipran formulation according to claim 1, wherein the side effect is nausea.   The side effects include vomiting, headache, tremor, anxiety, panic attacks, palpitation, urinary retention, orthostatic hypotension, sweating, chest pain, rash, weight gain, back pain, constipation, dizziness, increased sweating, mental agitation, facial flushing. The milnacipran formulation of claim 1 selected from the group consisting of: tremor, fatigue, somnolence, dyspepsia, dysuria, nervousness, dry mouth, abdominal pain, irritation and insomnia. The milnacipran formulation according to claim 1, wherein:
(A) an immediate release dosage unit containing a first dose of active agent, wherein the first dose of active agent is released substantially immediately after administration to the patient in an oral dosage form, after oral administration An immediate release dosage unit that reaches the peak of the first plasma level in about 0.05 to less than 3 hours;
(B) a delayed release dosage unit containing a second dose of the active agent, and a delayed release of the second dose that reaches a second plasma level peak in about 3 to less than 14 hours after administration in an oral dosage form. And, optionally, (c) a second delayed release dosage unit containing a third dose of the active agent, and a third in less than about 5-18 hours after administration in the oral dosage form Means for delayed release of the third dose to reach a peak in plasma levels;
A milnacipran formulation containing   The milnacipran formulation according to claim 4, wherein an enteric coating is added to the formulation and the release profile is further characterized by a lag time of 0.05 hours to 4 hours, A milnacipran formulation in which at least about 10% of the first “pulse” milnacipran dose is released during the lag time, followed by complete release of the first “pulse”. The milnacipran formulation of claim 1 that provides milnacipran plasma levels characterized by a C _max of less than about 3000 ng / ml. The milnacipran formulation of claim 6, wherein the milnacipran plasma level is characterized by a C _max of less than about 2000 ng / ml. The milnacipran formulation of claim 6, wherein the milnacipran plasma level is characterized by a C _max of less than about 1000 ng / ml.   Analgesic, anti-inflammatory, antipyretic, antidepressant, anticonvulsant, antihistamine, antimigraine, antimuscarinic, anxiolytic, sedative, hypnotic, antipsychotic, bronchodilator, asthma Select from the group consisting of therapeutic drugs, cardiovascular drugs, corticosteroids, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants and anti-sleep seizures The milnacipran formulation according to claim 1, further comprising at least one other active compound.   The following: aceclofenac, acetaminophen, admexetine, almotriptan, alprazolam, amantadine, amsinonide, aminocyclopropane, amitriptyline, amorodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethadone, bexamethazine Vermoprofen, betamethasone, biscifazine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, buttriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, cholopromazine, citalopramine, citalopramine Clonitazen, chlorazepate, clothiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cycloheptadine, dexiteptylline, desipramine, desomorphin, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromolamide, dextro Propoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimethacrine, divalprox, dizatriptan, dolasetron, donepezil, dothiepine, doxepin, dargotetine, estrotamine, estrotamine, estrophem , Phenamates Fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, flovatriptan, gabapentin, galantamine, gepirone, ginkgo, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone Hydroxyzine, ibuprofen, imipramine, indiprone, indomethacin, indoprofen, iprindol, ipsapirone, ketaserine, ketoprofen, ketorolac, resopitron, levodopa, lipase, lofepramine, lorazepam, roxapine, maprotiline, matindole, mefenmelate, melatomeline , Meperidine, meprobamate, mesalamine, me Tapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methyl salicylate, methysergide, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil, morindon, morphine Morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxafuran, oxaprazine, oxazepam, oxytriptan, oxycodone, oxymorphone, Pancrelipase, parecoxib, paroxetine, pemoline, pentazo , Pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirindole, piroxicam, pizotifen, pizotirin, pramipexole, prednisolone, prednisone, pregabalin, propilol, propilol Propoxyphene, Protriptyline, Quazepam, Quinupramine, Levoxitine, Reserpine, Risperidone, Ritanserin, Rivastigmine, Rizatriptan, Rofecoxib, Ropinirole, Rotigotine, Salsalate, Sertraline, Sibutramine, Sildenafil, Sulfasalazine, Sulindac Temazepam, tetrabenodine, thiazide, thioridazine, thiothixene, Aprid, thiacipyrone, tizanidine, tofenacin, tolmethine, troxaton, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, palproic acid, venlafaxine, viloxazine, vitamin E, dimerzidone 10. A milnacipran formulation according to claim 9, comprising a compound selected from the group consisting of, zolmitriptan, zolpidem, zopiclone, and isomers, salts and combinations thereof.   The milnacipran formulation according to claim 1, wherein the milnacipran is in the form of a therapeutic equivalent dose of the dextrorotatory or levorotatory enantiomer of milnacipran or a pharmaceutically acceptable salt thereof.   The milnacipran formulation according to claim 1, wherein the milnacipran is in the form of a therapeutic equivalent dose of a mixture of milnacipran enantiomers or pharmaceutically acceptable salts thereof.   The milnacipran formulation according to claim 1, wherein the milnacipran is in the form of a therapeutic equivalent dose of an active metabolite of milnacipran or a pharmaceutically acceptable salt thereof.   The milnacipran formulation according to claim 1, wherein the milnacipran is in the form of a therapeutic equivalent dose of parahydroxy-milnacipran (F2782) or a pharmaceutically acceptable salt thereof.   The milnacipran formulation of claim 1 comprising an enteric coating.   The milnacipran formulation according to claim 1, wherein the administrable milnacipran unit dose is 25-500 mg.   The milnacipran formulation according to claim 1, wherein the administrable milnacipran unit dose is 200-500 mg.   The milnacipran formulation according to claim 9, containing 25-500 mg milnacipran and 100-600 mg modafinil.   The milnacipran formulation of claim 1 containing a mixture of beads or particles that release drug at different times.   A kit comprising the milnacipran formulation according to any one of claims 1-19.   21. The kit of claim 20, comprising various dosage units that allow a gradual increase in dosage.   21. The kit of claim 20, comprising instructions for taking the formulation once a day before going to bed.   A method for producing a milnacipran formulation comprising the step of providing a formulation according to any one of the preceding claims.   A method for delivering a therapeutic dose of milnacipran as a starting dose to a patient in need thereof, with reduced incidence or reduced intensity of common milnacipran side effects, said method comprising: A method comprising administering a milnacipran formulation according to any one of claims 1 to 19 or a kit according to claims 20 to 22 to a patient in need thereof.