WO2014144115A1 - Fixed dose combination treatment for schizophrenia - Google Patents

Fixed dose combination treatment for schizophrenia Download PDF

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Publication number
WO2014144115A1
WO2014144115A1 PCT/US2014/028394 US2014028394W WO2014144115A1 WO 2014144115 A1 WO2014144115 A1 WO 2014144115A1 US 2014028394 W US2014028394 W US 2014028394W WO 2014144115 A1 WO2014144115 A1 WO 2014144115A1
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dose
amphetamine base
equivalent
risperidone
dose equivalent
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PCT/US2014/028394
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French (fr)
Inventor
Amir Shojaei
Peter Haynes Hutson
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Shire Llc
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • 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
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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 1- homoarginine-d-amphetamine or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof, 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.
  • 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. Pietrzak et al., Hum Psychopharmacol. 2010;Jun;25(4):353-8; Barch DM, Carter CS, Schizophr Res. 2005;77(l):43-58.
  • 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.
  • Other adverse effects of atypical antipsychotic treatment include sedation, somnolence, hyperprolactinemia, and hypotension.
  • 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, 1 -homoarginine-d-amphetamine (KP-106) or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof, together and thereby improve compliance with atypical antipsychotic drug treatment and avoid self-medication with KP-106 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) KP-106 or a pharmaceutically acceptable salt thereof; (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 KP-106 or a pharmaceutically acceptable salt thereof and a fixed dose of the olanzapine as follows: KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 2.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 7.5mg, KP- 106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base
  • 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 KP-106 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 KP-106.
  • a fixed dosage unit according to the present invention may include KP-106 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 KP-106 and the fixed dose of risperidone in the fixed unit dosage of the present invention include: KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 4mg, KP-106 in a dose equivalent
  • 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 KP-106 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 KP-106.
  • fixed dosage units of the present invention are administered in the morning.
  • the patient is treated for persistent negative symptoms of schizophrenia.
  • 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 1 -homoarginine-d- amphetamine ("KP-106"), 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.
  • KP-106 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.
  • Amphetamines are known to be drugs of abuse. This risk is less with KP-106. However, the possibility remains that a patient may choose to self-administer KP-106 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 KP- 106 is unopposed by a counter effect of the atypical antipsychotic drug. These problems are addressed by the present invention, which provides a fixed dosage unit so that the KP-106 and atypical antipsychotic drug are necessarily administered together.
  • a fixed dosage unit of the present invention is formulated such the KP-106 component and the atypical antipsychotic component(s) are not easily distinguishable or separable. Accordingly, a patient attempting to inappropriately separate and self-administer the KP-106 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.
  • KP-106 (KemPharm Inc.) is 1-homoarginine-d-amphetamine. Published patent applications relating to KP-106 include U.S. Patent Publication No. 2009/239949; U.S. Patent Publication No. 2008/0139653; U.S. Patent Publication No. 2009/234018; WO 2008/073928; and WO 2008/098151. The contents of these published patent applications are hereby incorporated by reference.
  • a fixed dosage unit according to the present invention encompasses pharmaceutically acceptable salts of KP-106.
  • pharmaceutically acceptable salts include a mesylate, 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. Heinrich Stahl & Camille G. Wermuth, Wiley-VCH, 2002, the contents of which are incorporated by reference.
  • the dose of KP-106, or a pharmaceutically acceptable salt thereof may be, for example, the amount of KP-106, or a pharmaceutically acceptable salt thereof, that is equivalent to an amphetamine free base amount of 24mg, 30mg, 36mg, 42mg, and 48mg.
  • 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 1 Omg 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 KP-106 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 KP-106 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 KP-106 and an atypical antipsychotic drug.
  • Specific fixed dosage units according to the present invention may include, for example, the following dosage amounts of KP-106 and an antitypical antipsychotic drug.

Abstract

The present invention relates to a fixed dosage unit, and methods for treating schizophrenia comprising administering the fixed dosage unit. More specifically, the present invention relates to a fixed dosage unit that reduces the incidence or degree of adverse effects that are associated with atypical antipsychotic drug therapy. The present invention relates to the field of pharmaceutical dosage forms and methods for treatment.

Description

FIXED DOSE COMBINATION TREATMENT FOR SCHIZOPHRENIA
Field of the Invention
[001] 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 1- homoarginine-d-amphetamine or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof, and methods for treating schizophrenia comprising administering the fixed dosage unit.
Background
[002] 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%).
[003] 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. McGurk et al, Mental Health Services Research, 2004;6(3): 185-8; Buchanan R, Schizophrenia Bulletin, 2007;33(4): 1013-1022. In addition to these symptom domains, diminished cognitive abilities are recognized as distinct core features of schizophrenia and are not an epiphenomenon of positive and negative symptoms. Keefe et al., Arch Gen Psychiatry, 2007;64(6):633-647.
[004] The prevalence of negative symptoms varies in the literature depending on whether primary, secondary, or persistent negative symptoms are being described. Primary negative symptoms are enduring, occur in all phases of illness, and form part of the deficit syndrome. Secondary negative symptoms are more broadly defined and include all negative symptoms that may be caused by positive, mood, or extrapyramidal symptoms, and environmental deprivation. Persistent negative symptoms include both primary and secondary negative symptoms that have failed to respond to treatment, persist during clinical stability, and interfere with role function. Buchanan RW., Schizophr Bull, 2007;33(4):1013-22. The CLAMORS Study Collaborative Group has described a sample of 1452 outpatient schizophrenia subjects taking antipsychotic medications and found that 1 or more negative symptoms present in 57.6% of subjects and primary negative symptoms in 12.9% of subjects. Bobes et al., J Clin Psychiatry, 2010;71(3):280-6. Buchanan et al (2007) estimate that primary negative symptoms represent 20- 30% of subjects in clinical samples. According to these authors the prevalence of persistent negative symptoms, which includes persistent primary and secondary negative symptoms, would be higher, but reliable estimates are not available.
[005] There is no known single cause of schizophrenia. Studies suggest that a combination of genetic, neurobiological, environmental, and psychological factors contribute to the cause. 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. Abi-Dargham A. Int J Neuropsychopharmacol.,2004; Suppl l :Sl-5.
[006] 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. These 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. Pietrzak et al., Hum Psychopharmacol. 2010;Jun;25(4):353-8; Barch DM, Carter CS, Schizophr Res. 2005;77(l):43-58.
[007] In a study of compliance with atypical antipsychotics among patients with schizophrenia in two Canadian provinces, adults with a diagnosis of schizophrenia who filled at least 1 prescription for risperidone, olanzapine, or quetiapine were identified in the Quebec public prescription drug insurance plan database and the Saskatchewan Health database. Compliance was assessed based on the medication possession ratio, which was estimated as the proportion of days for which medication was available over each month of follow-up (> or = 80% = good compliance; 50%-79% = moderate compliance; < 50% = poor compliance). The association between the early and long-term effects of compliance and the risks of hospitalization, suicide, and death were examined. Poor compliance was seen in 23% of 41,754 of patients from Quebec and 34% 3,291 of those from Saskatchewan. Compared with poor compliance, the long-term effect of good compliance was associated with a significantly decreased risk of all-cause hospitalization and psychosis-related hospitalization. Ward et al., Clin Ther. 2006;28(1 1): 1912-21.
[008] 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. Ananth et al., Curr Pharm Des. 2004; 10(18):2219-29. 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. Other adverse effects of atypical antipsychotic treatment include sedation, somnolence, hyperprolactinemia, and hypotension.
[009] Despite some evidence for improvement of negative symptoms with amphetamine treatment in schizophrenia in the literature, the development of dopamine-enhancing agents such as amphetamine in the treatment of negative symptoms has not occurred mainly because of concerns about psychomimetic effects. A 2004 review of 54 scientific studies concluded that a single stimulant dose can produce a psychotic response in 50-70% of patients with schizophrenia and pre-existing acute psychotic symptoms, and 30% of schizophrenics without acute symptoms. Berman et al., Mol Psychiatry, 2009;14(2): 123-142. Other concerns include an adverse impact of amphetamine on cardiovascular parameters (blood pressure and heart rate) and potential abuse liability in a population that is already at risk for these adverse outcomes. Casey et al. (1961) described no benefit from lOmg through to 60mg per day of dexamphetamine combined with chlorpromazine and noted worsening of symptoms among withdrawn and hospitalized patients who had chronic schizophrenia. Casey et al., Am J Psychiatry, 1961 ;117, 997-1003.
Summary of the Invention
[0010] 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, 1 -homoarginine-d-amphetamine (KP-106) or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof, together and thereby improve compliance with atypical antipsychotic drug treatment and avoid self-medication with KP-106 alone.
[0011] 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.
[0012] 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.
[0013] An aspect of the present invention provides a fixed dosage unit including: (a) KP-106 or a pharmaceutically acceptable salt thereof; (b) an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable excipient or carrier.
[0014] In one embodiment, 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 KP-106 or a pharmaceutically acceptable salt thereof and a fixed dose of the olanzapine as follows: KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 2.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 7.5mg, KP- 106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine lOmg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine lOmg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 7.5mg, and KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine lOmg.
[0015] 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 KP-106 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 KP-106. [0016] A fixed dosage unit according to the present invention may include KP-106 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 KP-106 and the fixed dose of risperidone in the fixed unit dosage of the present invention include: KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 16mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 16mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 16mg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 16mg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone lOrng, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 15mg, and KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 16mg.
[0017] According to the present invention, a method is provided 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 KP-106 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 KP-106.
[0018] In an embodiment, fixed dosage units of the present invention are administered in the morning. In other embodiments of the invention, the patient is treated for persistent negative symptoms of schizophrenia.
Detailed Description
[0019] 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 1 -homoarginine-d- amphetamine ("KP-106"), 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. The administration of KP- 106 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.
[0020] Amphetamines are known to be drugs of abuse. This risk is less with KP-106. However, the possibility remains that a patient may choose to self-administer KP-106 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 KP- 106 is unopposed by a counter effect of the atypical antipsychotic drug. These problems are addressed by the present invention, which provides a fixed dosage unit so that the KP-106 and atypical antipsychotic drug are necessarily administered together. Further, a fixed dosage unit of the present invention is formulated such the KP-106 component and the atypical antipsychotic component(s) are not easily distinguishable or separable. Accordingly, a patient attempting to inappropriately separate and self-administer the KP-106 without the atypical antipsychotic will find it very difficult, if not impossible, to do so.
[0021] 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. In one embodiment, the patient is treated for persistent negative symptoms of schizophrenia.
KP-106
[0022] KP-106 (KemPharm Inc.) is 1-homoarginine-d-amphetamine. Published patent applications relating to KP-106 include U.S. Patent Publication No. 2009/239949; U.S. Patent Publication No. 2008/0139653; U.S. Patent Publication No. 2009/234018; WO 2008/073928; and WO 2008/098151. The contents of these published patent applications are hereby incorporated by reference.
[0023] A fixed dosage unit according to the present invention encompasses pharmaceutically acceptable salts of KP-106. Examples of pharmaceutically acceptable salts include a mesylate, 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. Heinrich Stahl & Camille G. Wermuth, Wiley-VCH, 2002, the contents of which are incorporated by reference.
[0024] The dose of KP-106, or a pharmaceutically acceptable salt thereof, may be, for example, the amount of KP-106, or a pharmaceutically acceptable salt thereof, that is equivalent to an amphetamine free base amount of 24mg, 30mg, 36mg, 42mg, and 48mg.
Atypical antipyschotics
[0025] Atypical antipsychotic drugs are a class of medications that antagonize serotonin and dopamine receptors in the CNS. Among the psychotic disorders, 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.
1. Clozapine
[0026] 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. Despite its ability to trigger hypersalivation, clozapine is strongly anticholinergic; and its use results in nausea, vomiting, constipation, bloating, and abdominal pain. Weight gain can be particularly problematic. Leo and Del Regno, Prim Care Companion J Clin Psychiatry, 2000;2(6): 194-204.
2. Risperidone
[0027] 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. For women, increases in serum prolactin can result in amenorrhea, galactorrhea, and decreased libido. For men, hyperprolactinemia can result in erectile and ejaculatory dysfunction and decreased libido. The addition of prolactin-lowering agents, e.g., bromocriptine, may prove to be hazardous because they can exacerbate psychosis. Leo and Del Regno, Prim Care Companion J Clin Psychiatry, 2000;2(6): 194-204.
3. Olanzapine
[0028] 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.
4. Quetiapine
[0029] 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.
5. Ziprasidone
[0030] 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.
6. Amisulpride
[0031] 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.
7. Asenapine
[0032] Asenapine is available as a sublingual tablet. The starting dose is 5mg twice daily, and the recommended maintenance dose is 1 Omg twice daily. Adverse effects of asenapine include somnolence, weight gain, and orthostatic hypotension. See Asenapine Package Insert.
8. Paliperidone
[0033] 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.
9. Iloperidone
[0034] 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.
10. Zotepine [0035] 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.
11. Aripiprazole
[0036] 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.
12. Brexiprazole
[0037] Brexiprazole is currently in development for the treatment of schizophrenia. In a planned Phase 3 trial (NCTO 1668797), brexiprazole will be administered as a tablet at 1 to 4 mg/day.
13. Cariprazine
[0038] 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.
14. Lurasidone
[0039] 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.
Fixed doses of the invention [0040] A "fixed dosage unit" according to the present invention is a dosage form (solid or liquid) including KP-106 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). Thus, for example, a fixed dosage unit according to the present invention may be a capsule or compressed tablet comprised of an KP-106 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 KP-106 and an atypical antipsychotic drug.
[0041] Specific fixed dosage units according to the present invention may include, for example, the following dosage amounts of KP-106 and an antitypical antipsychotic drug.
Table 1
Figure imgf000020_0001
Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
24mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 7.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 7.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
42mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 7.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 7.5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
48mg
KP-106 Risperidone
KP-106 in a dose equivalent to 0.5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
24mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 4
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 7
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 11
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 13
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
24mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 0.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 7
an amphetamine base dose of
30mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 8
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 11
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 13
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 0.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
36mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 7
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 11
an amphetamine base dose of
36mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 12
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 13
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 0.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
42mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 7
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 11
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 13
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
42mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 16
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 0.5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of - 48mg
KP-106 in a dose equivalent to 5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 7
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
48mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 11
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 13
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
48mg
KP-106 Quetiapine
KP-106 in a dose equivalent to 25
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
24mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 125
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 175
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 275
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 25
an amphetamine base dose of
30mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 50
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 125
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 175
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 275
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 25
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 75
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 100
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 125
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 175
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
36mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 275
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 25
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 125
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 175
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
42mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 275
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 25
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 100
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 125
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 175
an amphetamine base dose of
48mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 200
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 275
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
48mg
KP-106 Ziprasidone
KP-106 in a dose equivalent to 20
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 60
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
24mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 120
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 140
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 60
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 140
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 60
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 140
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 20
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
42mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 60
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 80
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 140
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 160
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 20
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 60
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 100
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
48mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 140
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 180
an amphetamine base dose of
48mg
KP-106 Amisulpride
KP- 106 in a dose equivalent to 50
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
24mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
36mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 250
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 150
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 200
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 250
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
48mg
KP- 106 in a dose equivalent to 200
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 250
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
48mg
KP-106 Asenapine
KP-106 in a dose equivalent to 10
an amphetamine base dose of
24mg
KP- 106 in a dose equivalent to 20
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
42mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
48mg
KP-106 Paliperidone
KP-106 in a dose equivalent to 3
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
24mg
KP- 06 in a dose equivalent to 9
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 6
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
48mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 6
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 9
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
48mg
KP-106 Uoperidone
KP-106 in a dose equivalent to 2
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
24mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 16
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 18
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 22
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 24
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 18
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 22
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 24
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
36mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 10
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 18
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 20
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 22
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 24
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 2
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 6
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
42mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 12
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 18
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 22
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 24
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
48mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 4
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 6
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 8
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
48mg
KP- 106 in a dose equivalent to 12
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 14
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 16
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 18
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 22
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 24
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
48mg
KP-106 Zotepine
KP-106 in a dose equivalent to 50
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
42mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 100
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 50
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 75
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 100
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 150
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 225
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 300
an amphetamine base dose of
48mg
KP-106 Aripiprazole Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 2
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 30
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 30
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
36mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 30
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 10
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 30
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
48mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 10
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 15
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 20
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 30
an amphetamine base dose of
48mg
KP-106 Brexiprazole
KP-106 in a dose equivalent to 1
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
30mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 3
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 1
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
48mg
KP-106 in a dose equivalent to 2
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 3
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 4
an amphetamine base dose of
48mg
KP-106 Cariprazine
KP-106 in a dose equivalent to 1.5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 3.5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 4.5
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 1.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 3.5
an amphetamine base dose of Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
30mg
KP-106 in a dose equivalent to 4.5
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 1.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 3.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 4.5
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 1.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 3.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 4.5
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 1.5
an amphetamine base dose of
48mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 2.5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 3.5
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 4.5
an amphetamine base dose of
48mg
KP-106 Lurasidone
KP-106 in a dose equivalent to 40
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
24mg
KP-106 in a dose equivalent to 40
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
30mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
30mg Amount of KP-106 Amount of Atypical Antipsychotic Drug (mg)
KP-106 in a dose equivalent to 160
an amphetamine base dose of
30mg
KP- 106 in a dose equivalent to 40
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 80
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
36mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
36mg
KP- 106 in a dose equivalent to 40
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of
42mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 160
an amphetamine base dose of
42mg
KP- 106 in a dose equivalent to 40
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 80
an amphetamine base dose of Amount of KP-106 Amount of Atypical
Antipsychotic Drug (mg)
48mg
KP-106 in a dose equivalent to 120
an amphetamine base dose of
48mg
KP-106 in a dose equivalent to 160
an amphetamine base dose of
48mg
Dosage forms
[0042] 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 KP-106 component and the atypical antipsychotic drug component(s) are not easily distinguishable and not easily separable.
[0043] Thus, in one aspect of the invention, 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). 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.
[0044] 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., a KP-106 bead and an immediate release atypical antipsychotic drug bead; an KP-106 bead, an immediate release atypical antipsychotic drug bead, and a controlled release antipsychotic drug bead). In this case 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 KP-106 component from the antitypical antipsychotic component(s).
[0045] In fixed dosage units of the present invention including an atypical antipsychotic drug requiring bid dosing when administered alone, e.g., risperidone, 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. For example, 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). Alternatively, one atypical antipsychotic component may be formulated for sustained release and one atypical antipsychotic drug component may be formulated for delayed release. As used herein, "sustained release" means release that is maintained for a prolonged period of time, i.e., longer than immediate release. As used herein, "delayed release" means a release that does not begin immediately.
[0046] In fixed dosage units of the present invention including an atypical antipsychotic drug requiring tid dosing when administered alone, e.g., 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, 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. Any combination of different release profiles known in the art for the atypical antipsychotic components is encompassed by the present invention.
[0047] In embodiments of the invention including an atypical antipsychotic drug that is provided in an extended, delayed, sustained, or otherwise controlled release formulation when given alone, e.g., paliperidone, the 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. Thus, for example, a fixed dosage unit may be a capsule including KP-106 beads and extended release paliperidone beads.
[0048] 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. In a process for preparing a slow release composition, 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.
[0049] A fixed dosage unit of the invention may be a suspension or liquid. For example, 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.
[0050] All patents, published patent applications, and non-patent literature cited herein are incorporated by reference in their entirety.

Claims

We claim:
1. A fixed dosage unit comprising:
(a) 1-homoarginine-d-amphetamine (KP-106) or a pharmaceutically acceptable salt thereof;
(b) an atypical antipsychotic drug or a pharmaceutically acceptable salt thereof; and
(c) a pharmaceutically acceptable excipient.
2. The fixed dosage unit of claim 1, wherein the atypical antipsychotic drug is olanzapine.
3. The fixed dosage unit of claim 2, wherein the fixed dosage unit is formulated for once daily administration.
4. The fixed dosage unit of claim 3, wherein the fixed dose of the KP-106 and the fixed dose of the olanzapine is selected from the group consisting of: KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 2.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 5mg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and olanzapine lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and olanzapine lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and olanzapine lOmg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine 7.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and olanzapine lOmg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 2.5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine 7.5mg, and KP-106 in a dose equivalent to an amphetamine base dose of 48mg and olanzapine lOmg.
5. A method of reducing the incidence or degree of an adverse affect of olanzapine treatment in a patient suffering from schizophrenia, which comprises administering the fixed dosage unit of claim 4; wherein the adverse effect is selected from the group consisting of: hyperprolactinemia, weight gain, hyperlipidemia, sedation, and hypotension; and
wherein 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 KP-106 or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 wherein the fixed dosage unit is administered in the morning.
7. The method according to claim 5 wherein the patient has persistent negative symptoms of schizophrenia.
8. The fixed dosage unit of claim 1, wherein the atypical antipsychotic drug is risperidone.
9. The fixed dosage unit of claim 8, wherein the fixed dosage unit is formulated for once daily administration.
10. The fixed dosage unit of claim 9, wherein the risperidone is formulated for:
(a) immediate release and
(b) sustained or delayed release.
11. The fixed dosage unit of claim 10, wherein the fixed dose of the KP-106 and the fixed dose of the risperidone is selected from the group consisting of:
KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 0.5mg; KP- 106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 24mg and risperidone 16mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 30mg and risperidone 16mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 36mg and risperidone 16mg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 15mg, KP-106 in a dose equivalent to an amphetamine base dose of 42mg and risperidone 16mg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 0.5mg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone lmg; KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 2mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 3mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 4mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 5mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 6mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 7mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 8mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 9mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone lOmg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone l lmg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 12mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 13mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 14mg, KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 15mg, and KP-106 in a dose equivalent to an amphetamine base dose of 48mg and risperidone 16mg.
12. A method of reducing the incidence or degree of an adverse affect of risperidone treatment in a patient suffering from schizophrenia, which comprises administering the fixed dosage unit of claim 11 ; wherein the adverse effect is selected from the group consisting of: hyperprolactinemia, weight gain, hyperlipidemia, sedation, and hypotension; and
wherein 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 KP-106 or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12 wherein the fixed dosage unit is administered in the morning.
14. The method according to claim 12, wherein the patient has persistent negative symptoms of schizophrenia.
15. The method of claim 7 or 14, wherein the patient has persistent negative symptoms of schizophrenia following treatment with an atypical antipsychotic drug in the absence of KP-106.
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WO2018191311A1 (en) * 2017-04-10 2018-10-18 Shire Pharmaceuticals Inc. Methods of treatment using an amphetamine prodrug
EP3618877A4 (en) * 2017-04-10 2021-01-13 Shire Pharmaceuticals Inc. Methods of treatment using an amphetamine prodrug
CN109939112A (en) * 2019-05-10 2019-06-28 辽宁大学 Risperidone is preparing the application in blood lipid-lowering medicine

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