[go: up one dir, main page]

WO2014168727A1 - Polythérapie à dose fixée pour la schizophrénie - Google Patents

Polythérapie à dose fixée pour la schizophrénie Download PDF

Info

Publication number
WO2014168727A1
WO2014168727A1 PCT/US2014/028283 US2014028283W WO2014168727A1 WO 2014168727 A1 WO2014168727 A1 WO 2014168727A1 US 2014028283 W US2014028283 W US 2014028283W WO 2014168727 A1 WO2014168727 A1 WO 2014168727A1
Authority
WO
WIPO (PCT)
Prior art keywords
risperidone
ldx
lisdexamfetamine
free base
olanzapine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/028283
Other languages
English (en)
Inventor
Peter Haynes Hutson
Bryan Larry DIRKS
Amir Shojaei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire LLC
Original Assignee
Shire LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shire LLC filed Critical Shire LLC
Publication of WO2014168727A1 publication Critical patent/WO2014168727A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to the field of pharmaceutical dosage forms and methods for treatment. More particularly, the present invention relates to a fixed dosage unit including lisdexamfetamine dimesylate and an atypical antipsychotic drug, and methods for treating schizophrenia comprising administering the fixed dosage unit.
  • Schizophrenia is a common disorder, affecting 1% of the world's population. Andreasen NC, Brain Res Rev. 2000;31(2-3): 106- 112. Approximately two-thirds of patients who develop schizophrenia require public assistance from governmental social security systems within a few years after onset. Ho et al., 1997;48(7):948-50. The majority of people who develop schizophrenia are unable to return to work or school and have relatively minimal social interactions. The cost to society is billions of dollars. Black DW, Andreasen NC, The American Psychiatric Association Textbook of Psychiatry, 1999, Washington DC, p. 425-478. In 2002, the overall societal costs relating to patients with schizophrenia in the United States was estimated to be $62.7 billion. Indirect costs were estimated to be $32.4 billion. Wu et al., J Clin Psychiatry, 2002;66(9): 1 122-. Decreased productivity and unemployment contributed to the largest component of the indirect costs (72%).
  • Schizophrenia is a chronic disorder that is associated with positive, negative, and cognitive symptoms that lead to significant social or occupational dysfunction.
  • Positive symptoms involve an exaggeration or distortion of normal function and include auditory hallucinations, delusions, or disorganized speech and thinking.
  • Negative symptoms involve a diminution or loss of normal functions and include features such as flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), and lack of motivation (avolition).
  • American Psychiatric Association 2000 Diagnostic and statistical manual of mental disorders, fourth edition, text revision, Washington DC, American Psychiatric Publishing, Inc. Negative symptoms contribute to unemployment and loss of productivity.
  • Increased dopamine activity in the mesolimbic pathway of the brain is found in schizophrenic patients. Although hyperactivity of dopamine transmission via D2-receptors in subcortical regions, including the mesolimbic pathway and nucleus accumbens, is believed to contribute to positive symptoms, deficits in dopamine transmission at Dl -receptors and glutamatergic transmission, particularly in the mesocortical pathway and prefrontal cortex may contribute to negative symptoms and cognitive impairments.
  • the first line of treatment for schizophrenia is to administer an antipsychotic medication, which is believed to work primarily by suppressing D2 mediated dopamine activity.
  • antipsychotic medications include atypical antipsychotics and the older typical antipsychotics. While antipsychotic medications are highly effective in reducing positive symptoms, they may have very limited impact upon negative symptoms.
  • Medications that have been investigated for the treatment of negative symptoms include: antidepressants, which may impact negative symptoms through serotonin and noradrenergic pathways; antiepileptic medications, which may enhance gamma-aminobutyric acid transmission; and agonists of the NMDA (N-methyl-D-aspartate) receptor, such as glycine and d-cycloserine, which may improve NMDA hypofunction, and nicotinic agonists.
  • Other drugs that are currently being investigated for the treatment of negative/cognitive symptoms include modulators of nicotinic receptors and inhibitors of glycine reuptake. Two recent studies demonstrated a benefit on cognition and negative symptoms with single low and moderate doses of amphetamine.
  • a major reason for the significant patient non-compliance with atypical antipsychotic treatment is the adverse effects that often accompany this treatment.
  • Side effects of atypical antipsychotic drugs include diabetes, hyperlipidemia and obesity.
  • Patients with schizophrenia are known to suffer from diabetes more often than the general population.
  • Clozapine and olanzapine in particular, have been implicated in producing diabetes. Weight gain and alteration in triglycerides and cholesterol have been known to occur frequently with olanzapine and clozapine. The ensuing metabolic syndrome itself may cause insulin resistance and diabetes.
  • a fixed dosage unit according to the present invention addresses the well-recognized problem of poor patient compliance with atypical antipsychotic treatment for schizophrenic patients by reducing the incidence and/or degree of at least one adverse effect associated with atypical antipsychotic drug treatment.
  • a fixed dosage unit according to the present invention obligates a patient to take the two active agents, LDX and an atypical antipsychotic, together and thereby improve compliance with atypical antipsychotic drug treatment and avoid self- medication with LDX alone.
  • Adverse effects associated with atypical antipsychotic drug treatment, and reduced in incidence or degree by the fixed dosage unit of the present invention include, for example, weight gain, hyperprolactinemia, dyslipidemia or hyperlipidemia, sedation, somnolence, and hypotension. Further, the present invention reduces the incidence or degree of a reduction in bone mineral density associated with hyperprolactinemia; and the risk of fractures associated with the dizziness that is consequent to orthostatic hypotension caused by an atypical antipsychotic drug.
  • Examples of atypical antipsychotic drugs suitable for the fixed dosage units and methods according to the present invention include, but are not limited to: clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, aripiprazole, brexiprazole, and pharmaceutically acceptable salts thereof.
  • An aspect of the present invention provides a fixed dosage unit including: (a) lisdexamfetamine dismesylate; (b) an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable excipient or carrier.
  • the atypical antipsychotic drug is olanzapine and the fixed dosage unit is formulated for once daily administration.
  • This fixed dosage unit may include a fixed dose of LDX and a fixed dose of the olanzapine as follows: LDX 80mg and olanzapine 2.5mg; LDX 80mg and olanzapine 5mg; LDX 80mg and olanzapine 7.5mg, LDX 80mg and olanzapine lOmg, LDX 120mg and olanzapine 2.5mg, LDX 120mg and olanzapine 5mg, LDX 120mg and olanzapine 7.5mg, LDX 120mg and olanzapine lOmg, LDX 160mg and olanzapine 2.5mg, LDX 160mg and olanzapine 5mg, LDX 160mg and olanzapine 5mg,
  • the present invention further provides a method of reducing the incidence or degree of an adverse affect of olanzapine treatment in a patient suffering from schizophrenia, which comprises administering a fixed dosage unit including LDX and olanzapine, wherein the adverse effect is hyperprolactinemia, weight gain, hyperlipidemia, sedation, hyperglycemia, or hypotension; and the incidence or severity of the adverse effect is reduced relative to the adverse effect in a patient when the patient was administered olanzapine and not LDX.
  • a fixed dosage unit according to the present invention may include LDX and risperidone.
  • the risperidone may be formulated for (a) immediate release and (b) sustained or delayed release to mimic the bid dosing schedule of risperidone when it is administered alone.
  • Non-limiting examples of the fixed dose of LDX and the fixed dose of risperidone in the fixed unit dosage of the present invention include: LDX 80mg and risperidone 0.5mg; LDX 80mg and risperidone lmg; LDX 80mg and risperidone 2mg, LDX 80mg and risperidone 3mg, LDX 80mg and risperidone 4mg, LDX 80 and risperidone 5mg, LDX 80mg and risperidone 6mg, LDX 80mg and risperidone 7mg, LDX 80mg and risperidone 8mg, LDX 80mg and risperidone 9mg, LDX 80mg and risperidone lOmg, LDX 80mg and risperidone l lmg, LDX 80mg and risperi
  • a method for reducing the incidence or degree of an adverse affect of risperidone treatment in a patient suffering from schizophrenia which includes administering a fixed dosage unit containing LDX and risperidone, wherein the adverse effect is hyperprolactinemia, weight gain, hyperlipidemia, sedation, hyperglycemia, or hypotension; and the incidence or severity of the adverse effect is reduced relative to the adverse effect in a patient when the patient was administered risperidone and not LDX.
  • fixed dosage units of the present invention are administered in the morning.
  • the patient is treated for persistent negative symptoms of schizophrenia.
  • Figure 1 (A) and (B) are graphs showing the effect of LDX (1.5 mg/kg po) in combination with olanzapine (1.25 mg/kg ip) on medial prefrontal cortex dopamine (DA).
  • Figure 2 (A) and (B) are graphs showing the effect of LDX (1.5 mg/kg po) in combination with olanzapine (1.25 mg/kg ip) on nucleus accumbens DA.
  • Figure 3 (A) and (B) are graphs showing the effect of LDX (1.5 mg/kg po) in combination with olanzapine (1.25 mg/kg ip) on medial prefrontal cortex norepinephrine (NE).
  • Figure 4 (A) and (B) are graphs showing the effect of LDX (1.5 mg/kg po) in combination with olanzapine (1.25 mg/kg ip) on nucleus accumbens NE.
  • Figure 5 is a graph showing the effect of LDX (3, 10, 30 mg/kg po) on striatal dopamine D2 receptor occupancy by olanzapine (5mg/kg ip).
  • Figure 6 is a graph showing the effect of LDX (3, 10, 30 mg/kg po) in combination with olanzapine (5mg/kg ip) on plasma d-amphetamine concentration.
  • Atypical antipsychotic drugs are first line treatment for schizophrenia.
  • a major problem with atypical antipsychotic drug therapy is that the rate of patient non-compliance is high, due in main to the adverse effects associated with these drugs.
  • the present invention provides a fixed dosage unit for improving compliance with atypical antipsychotic drug therapy by combining an atypical antipsychotic drug with the amphetamine prodrug lisdexamfetamine dimesylate ("LDX"), which reduces the incidence or degree of adverse effects associated with atypical antipsychotic drugs, e.g., somnolence, weight gain, hyperprolactinemia, high triglycerides, hypercholesterolemia, hyperglycemia, and hypotension.
  • LDX amphetamine prodrug lisdexamfetamine dimesylate
  • LDX for maintenance (outpatient and inpatient) treatment of schizophrenia
  • the administration of LDX for maintenance (outpatient and inpatient) treatment of schizophrenia is counterintuitive to healthcare providers because amphetamines have been reported in the literature to precipitate psychosis, particularly in patients with schizophrenia.
  • the present invention is based in part on data showing that LDX, even in high doses, can be safely administered to patients with schizophrenia.
  • Amphetamines are known to be drugs of abuse. This risk is less with LDX. However, the possibility remains that a patient may choose to self-administer LDX and not a co-prescribed atypical antipsychotic drug. Such abuse may be harmful because the schizophrenia is not treated by the atypical antipsychotic drug, and any adverse effect of the LDX is unopposed by a counter effect of the atypical antipsychotic drug.
  • the present invention which provides a fixed dosage unit so that the LDX and atypical antipsychotic drug are necessarily administered together. Further, a fixed dosage unit of the present invention is formulated such the LDX component and the atypical antipsychotic component(s) are not easily distinguishable or separable. Accordingly, a patient attempting to inappropriately separate and self-administer the LDX without the atypical antipsychotic will find it very difficult, if not impossible, to do so.
  • a "patient” or “subject” according to the present invention is a mammal, preferably a human, who has been diagnosed with a disease or condition amenable to treatment by the dosage forms and methods of the present invention.
  • a particular disease or condition according to the present invention is schizophrenia.
  • the patient is treated for persistent negative symptoms of schizophrenia.
  • Lisdexamfetamine dimesylate (VYVANSE®, Shire) is an amphetamine prodrug having the structural formula:
  • LDX is approved by the FDA treatment for Attention Deficit Hyperactivity Disorder (ADHD).
  • ADHD Attention Deficit Hyperactivity Disorder
  • U.S. patents relating to LDX include Nos. 7,105,486; 7,223,735; 7,655,630; 7,659253; 7,659,254; 7,662,787; 7,662,788; 7,671,030; 7,671,031; 7,674,774; 7,678,770; 7,678,771 ; 7,687,466; 7,687,467; 7,700,561 ; 7,713,936; 7,718,619; and 7,723,305 (the contents of which are hereby incorporated by reference).
  • VYVANSE® for the treatment of ADHD are: a starting dose of 30mg once daily in the morning in patients 6 years old and above, to be increased in increments of 10 or 20mg at weekly intervals if needed, to a maximum dose of 70mg per day. It was thought that higher doses of lisdexamfetamine may be associated with greater potential for adverse neuropsychiatric and cardiovascular outcomes. However, in accordance with the present invention and the data provided below, LDX may be safely administered to schizophrenic patients in doses exceeding 70mg per day, e.g., 80mg/d, 120mg/d, and 160mg/d.
  • Atypical antipsychotic drugs are a class of medications that antagonize serotonin and dopamine receptors in the CNS.
  • schizophrenia is the most debilitating, and is often associated with high relapse rates and a chronic course.
  • Leo and Del Regno Prim Care Companion J Clin Psychiatry, 2000;2(6): 194-204.
  • Non-limiting examples of atypical antipsychotics according to the present invention include clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, aripiprazole, brexiprazole, and pharmaceutically acceptable salts thereof.
  • Clozapine was the first atypical antipsychotic marketed in the United States. Since its initial use in 1990, it has been prescribed for patients with schizophrenia unresponsive to conventional antipsychotics, patients with marked negative symptoms, patients with severe untoward effects on conventional antipsychotics, and patients with tardive dyskinesia. Dosing is generally begun at 12.5 mg/day, increased to 25 mg on day 2, then to 25 mg bid on day 3, then increased an initial 25 mg every 3 days thereafter. The recommended dose range is 300 to 900 mg/day. Sedation is the most common side effect. Another common adverse effect associated with clozapine use is increased salivation.
  • Risperidone was the second of the atypical antipsychotic drug marketed in the United States. Dosing is generally begun at 1 mg bid, increased to 2 mg bid on day 2 then to 3 mg bid on day 3. While clinical trials assessing the efficacy of risperidone have included doses up to 16 mg/day, the recommended daily dose for most individuals is between 4 and 8 mg/day. The most problematic side effects include sedation, weight gain, and sexual side effects due to alteration of CNS prolactin release. Sedation appears to be common early in the course of treatment and increases with higher doses. As with each of the atypical antipsychotics, weight gain can occur with risperidone use. Significant weight increases can adversely effect self-image and lead to noncompliance.
  • prolactin-lowering agents e.g., bromocriptine
  • Olanzapine is dosed between 5 and 20 mg daily. It may be dosed once-daily. Generally, patients are initiated at 5 mg/day and the dose is gradually increased up to a maximum of 20 mg/day. Common adverse effects associated with olanzapine use include postural hypotension, dizziness, constipation, and weight gain. Of these, weight gain has been the most significant; an average 26-lb weight gain by the end of 1 year of clinical trials has been reported. Weight gain can be a disincentive to comply with treatment and complicates comorbid medical conditions, such as obesity and heart disease.
  • Olanzapine use has also been linked to disturbances in glucose regulation, hyperglycemia, and diabetic ketoacidosis and increases in triglyceride levels. Leo and Del Regno, Prim Care Companion J Clin Psychiatry, 2000;2(6):194- 204.
  • Quetiapine is usually begun at 25 mg bid or tid and increased by 25 to 50 mg bid every 1 to 2 days until a daily dose of 300 mg is achieved by the end of 1 week.
  • the most frequent adverse effects associated with quetiapine use include sedation, fatigue, dizziness, and orthostatic hypotension. Similar to other atypical agents, weight gain with quetiapine use can be quite troublesome to patients and can interfere with medication compliance. Leo and Del Regno, Prim Care Companion J Clin Psychiatry, 2000;2(6): 194-204.
  • Ziprasidone is administered at an initial dose of 20mg bid. The daily dosage may be adjusted up to 80mg bid. Adverse effects of ziprasidone include orthostatic hypotension, hyperprolactinemia, somnolence, and weight gain. As with several other atypical antipsychotic drugs, ziprasidone has a propensity to prolong the QT/QTc interval, which can lead to torsade de pointes or sudden death. See GEODON (ziprasidone HC1) Package Insert.
  • Amisulpride is administered in doses between 50mg/d and 800mg/d. For patients with predominant negative symptoms, oral doses between 50mg/d and 300mg/day are recommended. Doses above 400mg should be administered bid. Adverse effects of amisulpride include QT prolongation and ventricular arrhythmias, somnolence, hyperprolactinemia, hypotension, and weight gain. See Amisulpride Package Insert.
  • Asenapine is available as a sublingual tablet.
  • the starting dose is 5mg twice daily, and the recommended maintenance dose is lOmg twice daily.
  • Adverse effects of asenapine include somnolence, weight gain, and orthostatic hypotension. See Asenapine Package Insert.
  • Paliperidone is available as an extended release tablet for oral administration or as a suspension for intramuscular injection.
  • the initial p.o. dose in adults is 6 mg/d, and the recommended dose is 3-12 mg/d.
  • the initial dose in adolescents weighing less than 51 kg is 3 mg/d and the recommended dose is 3-6 mg/d.
  • the initial dose in adolescents weighing at least 51 kg is 3 mg/d and the recommended dose is 3-12 mg/d.
  • Adverse effects of paliperidone include somnolence, weight gain, orthostatic hypotension, dyslipidemia, and hyperprolactinemia. See INVEGA (paliperidone) Package Insert.
  • Iloperidone is administered at an initial dose of 1 mg twice daily (2mg/day) for 1 week, and increased to a recommended dose range of 6-12 mg twice daily (12-24mg/day). The maximum dose recommended dose is 12 mg twice daily (24mg/day).
  • Adverse effects of iloperidone include dyslipidemia, weight gain, orthostatic hypotension, fatigue, and somnolence. See FANAPT (paliperidone) Package Insert.
  • Zotepine is administered in an initial adult dose of 25mg tid (25mg bid in the elderly), which may be increased to a maximum dosage of lOOmg tid. Adverse effects of zotepine include hypotension, hyperprolactinemia, somnolence, and weight gain.
  • Aripiprazole is administered to adults once daily in an initial dose of 10-15mg/d, which may be increased to a maximum recommended dose of 30mg/d.
  • Adolescents receive an initial dose of 2 mg/d and a recommended daily dose of 10 mg/d, which may be increased to a maximum dose of 30 mg/d.
  • Adverse effects of aripiprazole include somnolence, dyslipidemia, weight gain, and orthostatic hypotension. See ABILIFY package insert.
  • Brexiprazole is currently in development for the treatment of schizophrenia.
  • brexiprazole will be administered as a tablet at 1 to 4 mg/day.
  • Cariprazine is currently under development for treatment of schizophrenia in adults. Phase 3 trials are dosed once daily in a range of 1.5 mg/d to 4.5 mg/d. Adverse effects of Cariprazine include somnolence, dyslipidemia, weight gain, and orthostatic hypotension.
  • Lurasidone is administered to adults once daily in an initial dose of 40mg/d, which may be increased to a maximum recommended dose of 160mg/d.
  • Adverse effects of lurasidone include somnolence, dyslipidemia, weight gain, and orthostatic hypotension. See LATUDA package insert.
  • a "fixed dosage unit" according to the present invention is a dosage form (solid or liquid) including LDX and an atypical antipsychotic medication in which the two active agents cannot be distinguished from each other on gross inspection and/or are not easily separated from each other by means readily available to a patient (e.g., physical separation based on color weight, or size).
  • a fixed dosage unit according to the present invention may be a capsule or compressed tablet comprised of an LDX bead population and an atypical antipsychotic drug bead population wherein the populations are mixed together and are not distinguishable based on gross inspection of size, weight, or color.
  • Another non-limiting example of a fixed dosage unit according to the present invention is a solution including LDX and an atypical antipsychotic drug.
  • Specific fixed dosage units according to the present invention may include, for example, the following dosage amounts of LDX and an antitypical antipsychotic drug.
  • Amount of LDX (mg) Amount of Atypical Antipsychotic Drug (mg)
  • the present invention encompasses lisdexamfetamine free base and atypical antipsychotic drug fixed dosage units.
  • the amount of lisdexamfetamine free base may be about 23mg (corresponding to about 29% of LDX 80mg), about 35mg (corresponding to about 29%» of LDX 120mg), and about 46 mg (corresponding to about 29% of LDX 160mg).
  • a fixed dosage unit according to the present invention also encompasses pharmaceutically acceptable salts of lisdexamfetamine (not limited to the dismesylate salt).
  • pharmaceutically acceptable salts include a hydrochloride, a sulfate, an oxalate, a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, an acetate, a carbonate, a hydroxide, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, an ammonium salt, or a mixture thereof.
  • Pharmaceutically acceptable salts are discussed in the "Handbook of Pharmaceutical Salts. Properties, selection and use", P.
  • the amount of a pharmaceutically acceptable salt of lisdexamfetamine in a fixed dosage unit of the present invention may be determined based upon the lisdexamfetamine free base amount for each LDX fixed dosage unit disclosed herein.
  • a fixed dosage unit according to the present invention may include a tablet, a capsule (hard or soft shell), a caplet, a pill, a lozenge, a syrup, a solution, a powder, granules, an elixir, a suspension, a sublingual tablet, a wafer or a patch.
  • a fixed dosage unit according to the present invention may be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA (incorporated by reference).
  • a fixed dosage unit according to the present invention is preferably formulated such that the LDX component and the atypical antipsychotic drug component(s) are not easily distinguishable and not easily separable.
  • the fixed dosage unit is formulated as a homogeneous composition, wherein the active ingredients are dispersed substantially evenly throughout the mixture.
  • the homogenous composition may be prepared by mixing the active agents of the invention (or a pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).
  • pharmaceutical carriers such as a starch, sugar, diluent, granulating agent,
  • Non-limiting examples of binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth).
  • Non-limiting examples of disintegrating agents include starch, methyl cellulose, agar, and bentonite.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and may contain the active agents in solid, semi-solid, or liquid form.
  • Gelatin capsules may be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • a capsule of the present invention may comprise beads or granules.
  • the beads or granules may contain different active agent formulations (e.g., an LDX bead and an immediate release atypical antipsychotic drug bead; an LDX bead, an immediate release atypical antipsychotic drug bead, and a controlled release antipsychotic drug bead).
  • the populations of the beads or granules should be of uniform or near-uniform size, shape, weight, and color to prevent or make it very difficult for a patient to separate the LDX component from the antitypical antipsychotic component(s).
  • one component of the fixed dosage unit may be formulated for immediate release of the atypical antipsychotic drug and another component may be formulated for sustained or delayed release of the atypical antipsychotic drug.
  • the sustained or delayed release atypical antipsychotic drug component of the invention may be a slow release component; wherein the component includes an atypical antipsychotic drug of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).
  • one atypical antipsychotic component may be formulated for sustained release and one atypical antipsychotic drug component may be formulated for delayed release.
  • sustained release means release that is maintained for a prolonged period of time, i.e., longer than immediate release.
  • delayed release means a release that does not begin immediately.
  • one component of the fixed dosage unit may be formulated for immediate release of the atypical antipsychotic drug, another component may be formulated for sustained or delayed release of the atypical antipsychotic drug, and a third component may be formulated for a different sustained or delayed release such that the atypical antipsychotic drug release approximates the release pattern when the drug is give alone.
  • atypical antipsychotic drug requiring tid dosing when administered alone
  • quetiapine one component of the fixed dosage unit may be formulated for immediate release of the atypical antipsychotic drug
  • another component may be formulated for sustained or delayed release of the atypical antipsychotic drug
  • a third component may be formulated for a different sustained or delayed release such that the atypical antipsychotic drug release approximates the release pattern when the drug is give alone.
  • atypical antipsychotic drug component of the fixed dosage unit of the present invention may be provided in a similar or comparable type of release formulation.
  • a fixed dosage unit may be a capsule including LDX beads and extended release paliperidone beads.
  • Biodegradable and non-biodegradable slow release carriers are well known in the art.
  • Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound(s) therein.
  • a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.
  • a fixed dosage unit of the invention may be a suspension or liquid.
  • the fixed dosage unit may be in a liquid form such as an aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin.
  • the liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums.
  • the aim of this study was to determine the effects of LDX (1.5 mg/kg po) and olanzapine (1.25 mg/kg ip) on extracellular levels of the monoamine neurotransmitters dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in the prefrontal cortex and DA and 5-HT in the nucleus accumbens using the in vivo technique of dual-probe microdialysis in the freely-moving rat.
  • the neurochemical data will be measured in conjunction with locomotor activity, in the same animals, through use of the Culex Bambino. Behavioural activation was measured using the Raturn® system.
  • Dual-probe dialysis was performed in which each rat had a probe implanted into i) the prefrontal cortex (coordinates: AP +3.2 mm, ML, +2.5 mm relative to bregma; DV -4.0 mm, 2 mm membrane tip) and ii) the nucleus accumbens (AP +2.2 mm, ML, +1.5 mm relative to bregma; DV -8 mm, 2 mm membrane tip).
  • the rats were placed in the Culex Bambino 'bins' with their microdialysis probes connected to swivels and a counter-balanced arm that allowed unrestricted movement.
  • Rats were allowed a recovery period of at least 16 h with food and water available ad libitum. During this time the probes were continuously perfused with an artificial cerebrospinal fluid (aCSF; Harvard Apparatus, UK) at a flow rate of 1.2 ⁇ /min.
  • aCSF cerebrospinal fluid
  • Dialysate samples were collected at 20 min intervals into Eppendorf vials (300 ⁇ ) containing 5 ⁇ 0.1 M perchloric acid to prevent oxidation contained within a refrigerated fraction collector.
  • LDX 1.5 mg/kg po
  • Dialysate samples were assayed by HPLC with electrochemical detection over the remainder of the week. Monoamines were only measured in brain regions where their concentration is above the limit of detection. Locomotor activity data was recorded by automated means and collated into 20 min time bins to correlate with the neurochemical data.
  • LDX was dissolved in a suitable vehicle (eg deionised water) and administered orally, via gavage, using a suitable dose volume (eg 2 ml/kg po).
  • a suitable dose volume eg 2 ml/kg po.
  • Olanzapine was purchased from Sigma Aldrich (UK) and was administered via the ip route using a suitable vehicle (eg 0.9% saline) and dose volume (eg 2-5 ml/kg ip).
  • Drug doses were expressed as the free base or salt, using the relevant factors.
  • results were expressed as means ⁇ S.E.M.
  • Statistical analysis of post-treatment responses was typically by one-way analysis of covariance (ANCOVA) on log transformed data for each time point with group as a factor and baseline as a covariate.
  • locomotor activity was reported as total time spent active during each 20 min interval.
  • baseline defined as the back-transformed mean of the four pre-drug activity scores.
  • Analysis was typically by ANCOVA with group as a factor and sqrt(baseline) as a covariate. A P value of ⁇ 0.05 was considered statistically significant.
  • Olanzapine Dose-Response & Concomitant Olanzapine + Lisdexamfetamine Dose-Response - Dopamine-2 Receptor Occupancy Study in Male Sprague-Dawley Rats
  • Drug naive male SD rats were dosed with vehicle, quality control or test compound via a specified dose and route of administration. After a specific length of time has passed, the animals were intravenously dosed with D2 tracer [Raclopride 3 ⁇ g/kg, IV + 15-minutes], and euthanized by cervical dislocation. Trunk blood was collected in EDTA coated eppendorf tubes and stored on wet ice until study completion. The whole brain was rapidly removed, and lightly rinsed with sterile water. Striatum and cerebellum brain tissues were dissected, weighed, stored in 1.5 ml eppendorf tubes, and placed on dry ice until tissue extraction. Using a drug naive rat, six cortical brain tissues samples were collected for use in generating blank and standard curve samples.
  • Tissue samples were kept on wet ice during sample preparation for LCMS analysis. Acetonitrile containing 0.1% formic acid was added to each sample at a volume of four times the weight of the tissue sample (ex. Add 600 ⁇ acetonitrile to a 150 mg brain tissue).
  • Tracer or test compound eluted from the column was identified by its characteristic retention time and mass to charge (m/z) ratio, and quantified by comparison to a standard curve prepared in brain or plasma matrixes. Tracer levels and test compound exposure (olanzapine, d-amphetamine and LDX) in brain tissue and plasma are represented in units of ng/g of tissue or ng/ml of plasma.
  • Occupancy was summarized by treatment group mean % occupancy ⁇ standard error of the mean. All dose-occupancy curves were plotted using the software program Graph Pad Prism, version 5.0. Absolute ED50 and/or ED80 were estimated from the dose-occupancy curves.
  • Figure 5 shows that increasing doses of LDX (3, 10, 30 mg/kg po) did not affect the ability of olanzapine (5mg/kg ip) to occupy -80% D2 receptor occupancy in the rat striatum (a clinically relevant level of D2 occupancy), even though plasma d amphetamine concentrations increased markedly and dose dependently (Figure 6). These results suggest that LDX does not interfere with the beneficial affect of olanzapine on the positive symptoms of schizophrenia.
  • L-lysine-d-amphetamine as adjunctive therapy in adult subjects.
  • the subjects were diagnosed with clinically stable schizophrenia, predominant negative type, as measured by the SANS total score of all non-global item ratings of, e.g., affective flattening, inappropriate affect, alogia, avolition-apathy, and anhedonia-asociality.
  • the study was designed to follow test subjects for a four week initial screening period to determine stability and response while receiving a base antipsychotic medication. After the initial screening period, stable patients meeting the study criteria were administered LDX in a range of doses as adjunctive therapy for a period of ten weeks. The ten week period was divided into an optimization period and a maintenance period. The LDX dosing was titrated for each patient during the optimization period of seven weeks. This was followed by a maintenance period of three weeks. This was followed by a double-blind randomized withdrawal phase of four weeks, with a one week final washout period.
  • the atypical antipsychotic agents tested were aripiprazole, olanzapine, quetiapine and risperidone/paliperidone. The later are named in that way because paliperidone is the active metabolite of risperidone. Study Inclusion Criteria Included:
  • Subject has a reliable informant/caregiver that would be able to supervise the subject and provide information to the investigator/site staff at visits or via telephone.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders Fourth Edition
  • Subject has a total score of >55 on the SANS of the sum of the items: 1 to 6, 8 to 12, 14 to 16, and 18 to 21 on at least four visits (e.g., all screening visits and at baseline).
  • Subject has at least moderate scores (>3) on two or more SANS Global item ratings of affective flattening, alogia, avolition-apathy, or anhedonia-asociality
  • Subject has a baseline score of ⁇ 20 on the PANSS positive subscale at all screening visits and at baseline.
  • Subject is maintained on antipsychotic monotherapy (only long-acting risperidone injection, or oral risperidone, paliperidone, quetiapine, or olanzapine is permitted) for at least 12 weeks with no dose change >10% of
  • Subject has been clinically stable and is in the non-acute phase of illness with no history of harm to others, other psychiatric crises, emergency room visits, hospitalization, or increased level of care for psychiatric reasons for 12 weeks prior to screening, at all screening visits and at baseline.
  • Subject has clinically notable positive symptoms defined by a score of 20 on the PANSS positive scale or a score of >4 on the PANSS Positive scale items of PI (delusions), P3 (hallucinatory behavior), or P6 (suspiciousness/persecution) at all screening visits and at baseline.
  • PI delusions
  • P3 hallucinatory behavior
  • P6 suspiciousness/persecution
  • Subject has a score >9 on the CDSS at all screening visits and at baseline.
  • Subject has a SAS Akinesia Score (items 1-7) >2 at all screening visits and at baseline.
  • Subject has a history of psychiatric crises, emergency room visits, hospitalization, or increased level of care for psychiatric reasons within 12 weeks of screening.
  • Subject has a history of dose change in psychotropic medication or medication for any movement disorder >10% within 12 weeks of screening
  • Subject is considered to be treatment refractory by the Investigator and has a history of lack of response of positive symptoms to at least two atypical antipsychotic medications given at adequate dose and duration.
  • Subject is currently considered at risk for suicide, is demonstrating suicide ideation with suicide intent, or has previously made a suicide attempt within 3 years.
  • Subject is currently considered at risk for harm to others, has previously harmed others, has a prior history of, or is currently demonstrating thoughts of harm to others.
  • the medication groups were comparable by age. With the exception of the quetiapine group, there were more males present across all antipsychotic groups. With the exception of olanzapine, there were more non-white patients present across all antipsychotic groups. Across the olanzapine and risperidone (potent D2 blockers) medication groups, more subjects received an LDX dose > 60mg. In contrast, for the aripiprazole (partial Dl agonist) and quetiapine groups, greater proportions received LDX at a dose ⁇ 50mg.
  • Systolic BP mean -2.9 (7.1) 3.8 (4.7) 4.7 (8.9) 2.6 (8.6)
  • Diastolic BP mean 0.1 (4.1) 1.9 (5.0) 3.6 (7.7) 2.4 (8.1)
  • CRP C-reactive protein
  • Subjects who met the above-noted criteria e.g., who had a total SANS score of >55 on the sum of the items: 1 to 6, 8 to 12, 14 to 16, and 18 to 21 on at least four visits at the end of the four week initial screening period were then administered LDX.
  • LDX LDX
  • psychiatric testing scores were recorded for all subjects. Raters were experienced clinicians trained on the SANS, Positive and Negative Syndrome Scale (PANSS), and CGI. The SANS and PANSS were completed by raters who were blinded to the protocol. Ratings were not changed after the visit in which they were made.
  • the Scale for the Assessment of Negative Symptoms is a 20-minute clinician administered scale which assesses five symptom complexes to rate the negative symptoms of subjects (see, e.g., Andreasen NC, 1984, Scale for the Assessment of Negative Symptoms (SANS), Iowa City, University of Iowa, incorporated by reference herein in its entirety).
  • the primary efficacy measure of the study will be the change in the modified SANS- 18 score.
  • SANS- 18 is a SANS score modified for the purposes of the present study to remove the SANS domains related to attention, in order to confirm that the attention promoting properties of LDX do not represent a significant contribution to the beneficial effects of the treatment.
  • SANS-18 includes SANS items: 1 to 6, 8 to 12, 14 to 16, and 18 to 21, thus excluding items 7, 13, 17 and 22-25.
  • SANS-25 is the full SANS scale as published by Andreasen, supra.
  • the PANSS test evaluates the presence, absence, and severity of 30 symptoms of schizophrenia including both positive and negative symptoms and general psychopathology.
  • the PANSS yields nine separate scores along clinical dimensions, which help to define the severity and predominance of positive versus negative symptoms.
  • the CGI-S and CGI-C tests permit a global evaluation of the subject's severity and change over time.
  • Guy W 1976 ECDEU assessment manual for psychopharmacology, revised, U.S. Department of Health, Education and Welfare Pub. No. (ADM) 76-338, NIMH, Rockville, MD (incorporated by reference herein in its entirety).
  • the Investigator rated the severity of a subject's condition on a 7-point scale ranging from 1 (Normal, not at all ill [no symptoms]) to 7.
  • Change at visits 1 -10 were compared to the CGI-S at baseline (Visit 0) using a CGI-C assessment, a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Change at Visits 1 1-14 was compared to the CGI-S at randomization (Visit 10).
  • NSA-16 Negative Symptoms Assessment
  • SANS-25 represents the standard SANS criteria.
  • SANS- 18 is a customized metric that was also employed because the SANS- 18, as discussed supra, does not include the attention markers.
  • Table 7, below the open-label SANS change scores for subjects receiving each of the base antipsychotic medications are shown by Table 7, below. For all of the SANS change scores reported below, the higher the negative number, the better the clinical result.
  • LOCF refers to "last observation carried forward” method for missing data present during the open-label phase. The last non-missing response before the missing
  • FAS refers to the full analysis set and is defined as all enrolled subjects who take at least one dose of investigational product and have one post baseline primary efficacy assessment in the open-label phase.
  • the SANS-18 change scores were determined relative to the subjects' SANS-18 scores (of >55) at the start of the ten week testing period. From this data, it can be concluded that adjunctive therapy with LDX, in addition to the base antipsychotic medication, substantially reduced the SANS-18 scores in the subject groups. The significance of the reduction in the SANS- 18 scores is that this modified SANS avoids measures of attention. Thus, the improvement in the subjects' scores is not based simply on improvements to attention. Two alternative statistical methods were employed simultaneously, because the LOCF method has been criticized, e.g., by Streiner, 2008, EBMH l l(l):3-5, incorporated by reference herein. This allows for the results to be appreciated with the benefit of LOCF, FAS and observed case methods.
  • aripiprazole had a -0.9 (SD 0.9) mean change in global affective flattening score
  • - olanzapine had a -0.8 (SD 0.8) mean change in global affective flattening score
  • olanzapine had a -0.7 (SD 0.7 mean change in global alogia score
  • risperidone/paliperidone had a -0.8 (SD 0.7) mean change in global alogia score.
  • aripiprazole had a -0.8 (SD 0.7) change in global avolotion-apathy score
  • olanzapine had a -0.4 (SD 0.7) mean change in global avolition -apathy score
  • SANS negative symptom domains which include three core DSM-IV defined negative symptoms in schizophrenia namely alogia, avolition and affective flattening.
  • SANS alogia and affective flattening symptom domains the greatest change was observed in the aripiprazole (a partial dopamine agonist) and risperidone (a2 receptor blockade) groups.
  • Table 10 confirms that across all antipsychotic medications there was improvement on all 3 PANSS scale scores (positive, negative, general psychopathology, as described by Kay et al., Id. supra) with all antipsychotic medications
  • a Phase 1, double-blind, dose-escalating, inpatient study of multiple doses in stable schizophrenia patients was conducted.
  • the doses included in this study were LDX 50, 70, 100, 150, 200, and 250mg daily, each over 5 days treatment.
  • This study assessed the safety, tolerability, and pharmacokinetics of LDX in 31 subjects with schizophrenia who were clinically stable on their current antipsychotic treatment.
  • Subjects were treated with LDX or matching placebo starting at 50mg daily and gradually titrated up to a maximum dose of 250mg daily, as tolerated.
  • Example 3 provides evidence that treatment of schizophrenia with LDX in combination with an atypical antipsychotic drug, relative to the atypical antipsychotic treatment alone, avoids or reduces the degree of weight gain, hypotension, elevation in serum prolactin, and elevation in high sensitivity CRP in subjects receiving such treatment.
  • Example 5 provides evidence that treatment of schizophrenia with LDX in combination with an atypical antipsychotic drug, relative to the atypical antipsychotic treatment alone, avoids or reduces the degree of weight gain, hypotension, elevation in serum prolactin, and elevation in high sensitivity CRP in subjects receiving such treatment.
  • Subjects were screened for approximately 2 weeks to establish eligibility for initial study participation. Subjects that met the eligibility criteria and had 3 binge days/week during the prior 2 weeks were randomized to 1 of the 4 treatment groups. Subjects were instructed to take investigational product daily at 7:00 AM.
  • Eligible subjects were randomized in a 1 : 1 :1 :1 ratio to 1 of 4 treatment groups: LDX 30, 50 or 70mg/day or placebo. All subjects randomized to LDX started at a dose of 30mg/day. Those randomized to 50mg were titrated to that dose over a 1-week period; those randomized to 70mg were titrated to that dose over a 2-week period.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une unité posologique fixe, ainsi que des méthodes pour le traitement de la schizophrénie consistant à administrer l'unité posologique fixe. Plus spécifiquement, la présente invention concerne une unité posologique fixe qui réduit l'incidence ou le degré des effets indésirables qui sont associés à une pharmacothérapie antipsychotique atypique. La présente invention se rapporte au domaine des formes posologiques pharmaceutiques et aux méthodes de traitement. Plus particulièrement, cette invention concerne une unité posologique fixe incluant du dimésylate de lisdexamfétamine et un médicament antipsychotique atypique, ainsi que des méthodes de traitement de la schizophrénie consistant à administrer l'unité posologique fixe.
PCT/US2014/028283 2013-03-15 2014-03-14 Polythérapie à dose fixée pour la schizophrénie Ceased WO2014168727A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361793983P 2013-03-15 2013-03-15
US61/793,983 2013-03-15

Publications (1)

Publication Number Publication Date
WO2014168727A1 true WO2014168727A1 (fr) 2014-10-16

Family

ID=51689911

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/028283 Ceased WO2014168727A1 (fr) 2013-03-15 2014-03-14 Polythérapie à dose fixée pour la schizophrénie

Country Status (1)

Country Link
WO (1) WO2014168727A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3459538A1 (fr) 2017-09-20 2019-03-27 Sandoz AG Sels cristallins d'un promédicament de dextroamphétamine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100166889A1 (en) * 2007-09-13 2010-07-01 Lcs Group, Llc Method of treating depressive disorders
US20100189818A1 (en) * 2009-01-20 2010-07-29 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
WO2012056246A1 (fr) * 2010-10-28 2012-05-03 Shire Llc Traitement combiné d'un trouble dépressif majeur
WO2013028909A1 (fr) * 2011-08-25 2013-02-28 Sova Pharmaceuticals, Inc. Thérapie combinée pour le traitement de troubles respiratoires liés au sommeil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100166889A1 (en) * 2007-09-13 2010-07-01 Lcs Group, Llc Method of treating depressive disorders
US20100189818A1 (en) * 2009-01-20 2010-07-29 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
WO2012056246A1 (fr) * 2010-10-28 2012-05-03 Shire Llc Traitement combiné d'un trouble dépressif majeur
WO2013028909A1 (fr) * 2011-08-25 2013-02-28 Sova Pharmaceuticals, Inc. Thérapie combinée pour le traitement de troubles respiratoires liés au sommeil

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3459538A1 (fr) 2017-09-20 2019-03-27 Sandoz AG Sels cristallins d'un promédicament de dextroamphétamine
WO2019057765A1 (fr) 2017-09-20 2019-03-28 Sandoz Ag Sels cristallins d'un promédicament de dextroamphétamine

Similar Documents

Publication Publication Date Title
Gareri et al. Adverse effects of atypical antipsychotics in the elderly: a review
Bishara et al. Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability
Troost et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study
CA2580619C (fr) Utilisation de memantine (namenda) pour traiter l'autisme, les etats compulsifs et impulsifs
Stigler et al. Aripiprazole in pervasive developmental disorder not otherwise specified and Asperger's disorder: a 14-week, prospective, open-label study
Biederman et al. Aripiprazole in the treatment of pediatric bipolar disorder: a systematic chart review
TWI428130B (zh) 治療急性躁狂症之藥學組成物及方法
US20090068290A1 (en) Bifeprunox doses for treating schizophrenia
Argo et al. Aripiprazole, a novel atypical antipsychotic drug
US20020016334A1 (en) Pharmaceutical composition for the treatment of attention deficit hyperactivity disorder (ADHD)
Marino et al. Paliperidone extended‐release for the treatment of schizophrenia
US20060211686A1 (en) Alpha7 Neuronal nicotinic receptor ligand and antipsychotic compositions
CZ20004279A3 (cs) Lék pro léčení nepoddajné deprese a farmaceutická kompozice
US20030027817A1 (en) Combination therapy for treatment of bipolar disorders
Madhusoodanan et al. Clinical experience with aripiprazole treatment in ten elderly patients with schizophrenia or schizoaffective disorder: retrospective case studies
WO2008025781A1 (fr) Doses de biféprunox pour le traitement de la schizophrénie
Smith et al. Medical complications of psychiatric treatment
WO2014168727A1 (fr) Polythérapie à dose fixée pour la schizophrénie
JP2015502941A (ja) 少なくとも１つのｃｎｓ障害の治療、予防、および／または管理のためのルラシドン新規投与レジメンおよびその使用
WO2014144115A1 (fr) Polythérapie à doses prédéterminées pour la schizophrénie
Davison et al. Management of pain in chronic kidney disease
Rogers et al. Drug treatment of the psychoses
Preskorn Two in one: The venlafaxine story
Farmer et al. Pharmacological intervention for disruptive behaviors in intellectual and developmental disabilities: the glass is half full
JP7556031B2 (ja) 認知症患者の行動心理学的症状の治療

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14783516

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14783516

Country of ref document: EP

Kind code of ref document: A1