US20090087490A1 - Extended release formulation and method of treating adrenergic dysregulation - Google Patents

Extended release formulation and method of treating adrenergic dysregulation Download PDF

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US20090087490A1
US20090087490A1 US12/134,444 US13444408A US2009087490A1 US 20090087490 A1 US20090087490 A1 US 20090087490A1 US 13444408 A US13444408 A US 13444408A US 2009087490 A1 US2009087490 A1 US 2009087490A1
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dosage form
oral dosage
amount
clonidine
receptor agonist
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Henry Joseph Horacek
Min Michael He
Moise A. Khayrallah
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Shionogi Inc
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Addrenex Pharmaceuticals Inc
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Assigned to ADDRENEX PHARMACEUTICALS, INC. reassignment ADDRENEX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KHAYRALLAH, MOISE ANTUN, HE, MIN MICHAEL, HORACEK, HENRY JOSEPH
Publication of US20090087490A1 publication Critical patent/US20090087490A1/en
Priority to US12/560,648 priority patent/US20100209510A1/en
Priority to US12/615,477 priority patent/US7884122B2/en
Assigned to SHIONOGI PHARMA, INC. reassignment SHIONOGI PHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADDRENEX PHARMACEUTICALS, INC.
Priority to US13/082,724 priority patent/US20110245314A1/en
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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Definitions

  • compositions and methods of treatment and prevention of adrenergic dysregulation are disclosed.
  • Adrenergic dysregulation refers to abnormal neuronal activation or secretion of the hormone adrenaline and/or the neurotransmitter noradrenaline. Adrenergic dysregulation may occur at both baseline levels of stimulation and in response to external stress. Excessive adrenergic stimulation results in symptoms such as high blood pressure, hyperactivity, physical aggression, motor tics, and insomnia.
  • Time release hydrophilic matrices are known in the field of drug formulations.
  • one such hydrophilic matrix is hydroxypropyl methylcellulose (HPMC).
  • An intact gel layer may provide predictable release of an incorporated drug from the matrix by migration through the gel layer.
  • electrolytes present in the surrounding medium may modify the release profile of drugs from HPMC matrices. Modification of the release profile of a drug resulting from differences in matrix environment may be detrimental to the therapeutic usefulness of a drug.
  • Drug release from an oral solid extended release dosage form and subsequent absorption of the drug from the gastro-intestinal tract into the blood stream is dissolution-rate dependent and may be slow and irregular especially in the case of sparingly water soluble, slightly water soluble, very slightly water soluble, practically water insoluble, or a water insoluble drug, as defined according to the United States Pharmacopeia 24, p 10.
  • Additives may be added to hydrophilic matrixes to modify the gelling rate and/or the release rate of an incorporated drug.
  • the nature of the interaction of a particular drug with the matrix and additive is not generally predictable. This is particularly problematic for drugs administered in low dosages or drugs with limited solubility. It is also difficult to correlate the release rate of a drug with its serum or blood concentration when complex matrix/additive systems are used.
  • the traditional oral dosage formulations of ⁇ 2 -adrenergic receptor agonists have disadvantages.
  • the release profile of the traditional oral dose is typically a rapid and bolus release followed by rapid and complete absorption.
  • the traditional oral formulation of clonidine has side-effects including sedation about an hour after the given dose, when the patient may become transiently sedated or fall asleep. Because of the rapid absorption of the drug, the half-life of this dosage form of clonidine is essentially the same as the biological half-life of about four to six hours.
  • the therapeutic effect may wear off too soon and possibly be accompanied with rebound hyperarousal. This may occur in the middle of the night causing insomnia and nightmares.
  • a capsule containing microcapsule having a range of differing release profiles has been used as a sustained release formulation of clonidine.
  • This formulation is known as Catapresan-Perlonget and is available in Europe.
  • the sustained release formulation contains different membrane coated nuclei of the drug. One nuclei releases the drug rapidly while the others release more slowly over 3 or 6 hours, respectively.
  • FIGS. 1A and 1B depict the mean Clonidine concentration-time profiles after administration of Clonicel-Fasted (Treatment A), Clonicel-Fed (Treatment B) and Catapres-Fasted (Treatment C).
  • FIG. 2 is a graphical representation of predicted area under the curve (AUC) blood plasma levels of an exemplary extended release composition embodiment disclosed herein in comparison with an immediate release composition.
  • AUC area under the curve
  • FIG. 3 depicts the mean clonidine concentration-time profiles by treatment group for days 23 and 25. Average concentrations for the 3 treatment groups ranged from approximately 400 pg/mL to 1800 pg/mL. Plasma concentrations increased proportionately with increase in dose, stayed fairly even throughout the inter-dosing interval, and were very similar between Days 23 and 25.
  • FIG. 4 depicts the mean ( ⁇ SD) steady-state trough clonidine concentrations on days 23, 25 and 26.
  • the relationship between dose and derived PK parameters was explored by plotting C max , C min , AUC ⁇ , and CL/F values for Day 25 as a function of the administered dose. As the figure shows, the three exposure parameters appeared to increase proportionately with the dose, and CL/F decreased slightly over the dosing range.
  • FIG. 5 depicts a sigmoidal E max relationship between effect on systolic blood pressure and clonidine C max .
  • FIGS. 6A , 6 B and 6 C depict the mean daytime SBP (systolic blood pressure), DBP (diastolic blood pressure), and change from Baseline to day 26.
  • FIGS. 7A and 7B depict the mean daytime systolic and diastolic blood pressure observations at Baseline and for Days 26 to 28. As is evident from the data, both SBP and DBP daytime values gradually returned to Baseline levels over the 48 hours post-dosing without overshoot even though study medication had been withdrawn abruptly.
  • FIGS. 8A , 8 b and 8 C depict the mean SBP profiles by treatment at baseline and day 26 .
  • FIGS. 9A , 9 B and 9 C depict the mean DBP profiles by treatment at baseline and day 26 .
  • FIG. 10A , 10 B and 10 C depict the mean heart rate profiles by treatment at baseline and day 26 .
  • an oral dosage form comprising: (a) an ⁇ 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of said oral dosage form; and (b) a pharmaceutically acceptable hydrophilic matrix comprising: (i) at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of the oral dosage form; (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of the oral dosage form; and (iii) a metal alkyl sulfate; wherein after administration of the oral dosage form no more than once about every 12 hours to a subject having a steady state plasma concentration of the ⁇ 2 -adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.
  • a method of treating adrenergic dysregulation in a subject in need thereof comprises orally administering to the subject no more than once about every 12 hours the oral dosage formulation described herein, which provides a plasma peak-to-trough ratio no greater than about 1.9, wherein the adrenergic dysregulation is treated.
  • an oral dosage form comprises an ⁇ 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of the oral dosage form; a pharmaceutically acceptable hydrophilic matrix comprising a mixture of at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of the oral dosage form; at least one of starch, lactose, or dextrose in an amount between 80 wt % and 20 wt % of the oral dosage form; a release-retardant of a metal alkyl sulfate; and optionally a metal stearate and/or colloidal silica.
  • an oral dosage form comprising: (a) an ⁇ 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of said oral dosage form; and (b) a pharmaceutically acceptable hydrophilic matrix comprising: (i) at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of the oral dosage form; (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of the oral dosage form; and (iii) a metal alkyl sulfate; wherein after administration of the oral dosage form no more than once about every 12 hours to a subject having a steady state plasma concentration of the ⁇ 2 -adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.
  • an oral dosage form comprising: (a) an ⁇ 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of the oral dosage form; and (b) a pharmaceutically acceptable hydrophilic matrix comprising: (i) at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of said oral dosage form; (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of the oral dosage form; and (iii) a metal alkyl sulfate; wherein after a first administration to a subject of the dosage form, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9 for any subsequent administration of the dosage form, wherein the subsequent administration is no more than once about every 12 hours.
  • a solid oral dosage form for treating and/or reducing an adrenergic dysregulation condition in a subject in need thereof.
  • the solid oral dosage form comprises, a) an ⁇ 2 -adrenergic receptor agonist; b) a pharmaceutically acceptable hydrophilic matrix providing a release rate of the ⁇ 2 -adrenergic receptor agonist; and c) a release-retardant in an amount such that the release rate of the ⁇ 2 -adrenergic receptor agonist from the hydrophilic matrix is decreased.
  • a method of treating an adrenergic dysregulation condition in a subject in need thereof comprises, orally administering to a subject a formulation comprising an effective amount of an ⁇ 2 -adrenergic receptor agonist, the ⁇ 2 -adrenergic receptor agonist admixed within a pharmaceutically acceptable hydrophilic matrix comprising a release-retardant; and providing an extended release rate of the ⁇ 2 -adrenergic receptor agonist from the formulation; wherein the extended release rate of the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein is less than a release rate for the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix without the release-retardant admixed therein.
  • the method can further include, providing (i) a plasma concentration level of the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix; and (ii) a peak plasma level concentration of the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix; wherein the plasma concentration level of ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein provides an extended plasma concentration level of the ⁇ 2 -adrenergic receptor agonist and a reduced peak plasma level concentration of the ⁇ 2 -adrenergic receptor agonist than a pharmaceutically acceptable hydrophilic matrix and the ⁇ 2 -adrenergic receptor agonist without the release-retardant admixed therein.
  • the extended release rate of the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix is zero-order to first-order.
  • a method of treating adrenergic dysregulation in a subject in need thereof comprises orally administering to the subject a formulation comprising an effective amount of an ⁇ 2 -adrenergic receptor agonist the ⁇ 2 -adrenergic receptor agonist admixed within a pharmaceutically acceptable hydrophilic matrix comprising a release-retardant.
  • the method provides an extended release rate of the ⁇ 2 -adrenergic receptor agonist.
  • the extended release rate of the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein is less than a release rate for the ⁇ 2 -adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix without the release-retardant admixed therein.
  • a method of treating adrenergic dysregulation in a subject in need thereof comprising: administering an oral dosage form as described herein to a subject no more than once about every 12 hours, wherein the subject has a steady state plasma concentration of the ⁇ 2 -adrenergic receptor agonist, and wherein after the administering, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9; wherein the adrenergic dysregulation is treated.
  • the ⁇ 2 -adrenergic receptor agonist can be any compound or composition of matter that binds to the ⁇ 2 -adrenergic receptor of a cell to produce a central ⁇ -adrenergic stimulation within the cell.
  • ⁇ 2 -adrenergic receptor agonists include epinephrine, noradrenaline, isoprenaline, clonidine, guanfacine, lofexidine, xylazine, or their salts.
  • the agonist is clonidine or a pharmaceutically acceptable salt thereof. Most preferably, the agonist is clonidine hydrochloride.
  • the aforementioned agonists may be supplied as pure compounds, or in a form of a pharmaceutically active salt, isomer, a racemic mixture, or in any other chemical form or combination that, under physiological conditions, provides for therapeutically effective treatment of adrenergic dysregulation.
  • clonidine refers to a 9-carbon, two-ringed imidazoline derivative.
  • the term “clonidine” denotes generally one or more of 2,6-dichloro-N-2-imidazolidinylidene benzeneamine, or benzeneamines structurally and functionally related thereto that are described in U.S. Pat. No. 3,454,701. U.S. Pat. No. 3,454,701, is incorporated herein by reference for its disclosure of such structurally and functionally related benzeneamines.
  • lofexidine refers to 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole or structurally and functionally related imidazoles.
  • xylazine refers to 2-(2,6-dimethylphenylamino)-5,6-dihydro-4H-thiazine or structurally and functionally related thiazines.
  • clonidine denotes 2,6-dichloro-N-2-imidazolidinylidene benzeneamine, and its various tautomers and rotomers. In a preferred embodiment, it has the following structure:
  • the amount of ⁇ 2 -adrenergic receptor agonists that is included per oral dosage form may vary widely.
  • the therapeutically effective dose range for the ⁇ 2 -adrenergic receptor agonist clonidine is about 0.025 mg to about 0.40 mg per dosage form for most of the symptoms of the clinical disorders listed above.
  • the therapeutically effective dose range of about 0.025 mg to about 0.40 mg per dosage form typically controls most of the symptoms of adrenergic dysregulation.
  • Adrenergic dysregulation refers generally to conditions of cardiovascular, analgesic, neurologic/psychiatric, or gastrointestinal/renal origin resulting from abnormal neuronal activation or secretion of adrenaline and/or noradrenaline.
  • cardiovascular conditions include those conditions manifested in hypertension, atrial fibrillation, congestive heart failure, and orthostatic hypotension.
  • Analgesic conditions include those conditions manifested in intraoperative and postoperative pain, intractable cancer pain, headaches, labor pain, and reflex sympathetic dystrophy.
  • Neurologic/psychiatric conditions include those conditions manifested in akathisia, peripheral neuropathy, neuropathic orofacial pain, diabetic gastroparesis, essential tremor, postepidural shivering, postanesthesia shivering, restless legs syndrome, hypertonicity, hyperkinetic movement disorders, Tourette's syndrome, substance withdrawal, acute anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), conduct disorder, bipolar disorder, aggression, narcolepsy, panic disorder, posttraumatic stress disorder, sleep disorders, social phobia, and schizophrenia.
  • Gastrointestinal/renal conditions include those conditions manifested in ulcerative colitis and proctitis, emesis, and cyclosporine-induced nephrotoxicity.
  • Endocrine/hormonal conditions include those conditions manifested in hyperthyroidism, growth delay in children, excessive sweating, post-menopausal flushing, and hot flashes.
  • Attention Deficit Hyperactivity Disorder and ADHD refer to any etiological or pathological symptom associated with the disorder. Such symptoms and etiology include inattention, hyperactivity and impulsivity. Generally, a subject will exhibit significant impairment occurring in at least two settings and/or consistently display such characteristic behaviors over an extended period of time. The terms also include Attention Deficit Disorder (ADD).
  • ADD Attention Deficit Disorder
  • Hypertension refers generally to any etiological or pathological symptom manifested in blood pressure that is chronically elevated. Such symptoms include low-renin levels, insulin resistance, sleep apnea, excess serum sodium levels, obesity and genetic disposition.
  • Useful amounts of agonist present in the formulation are between about 0.001 wt % and 0.5 wt % of the dosage form. Preferably, the amount is between about 0.01 wt % and about 0.3 wt %. More preferably, the amount is between about 0.05 wt % and 0.2 wt %.
  • Useful amounts of the hydroxypropyl methylcellulose ether(s) are between about 20 wt % and 80 wt % of the dosage form. Preferably, the amount is between about 30 wt % and 50 wt %. More preferably, the amount is between about 40 wt % and 60 wt %. Most preferably, the amount is between about 20 wt % and 40 wt %, or 60 wt % and 80 wt %.
  • Useful amounts of starch, lactose or dextrose are between about 20 wt % and 80 wt % of the dosage form. Preferably, the amount is between about 50 wt % and 70 wt %. More preferably, the amount is between about 40 wt % and 60 wt %. Most preferably, the amount is between about 20 wt % and 40 wt %, or 60 wt % and 80 wt %.
  • metal alkyl sulfate are between about 1 wt % and 8 wt % of the dosage form. Preferably, the amount is between about 1 wt % and 7 wt %. More preferably, the amount is between about 2 wt % and 6 wt %. Most preferably, the amount is about 2 wt %.
  • Metal alkyl sulfates are known in the art and include, for example, ammonium lauryl sulfate, magnesium laureth sulfate, sodium dodecyl sulfate (sodium lauryl sulfate), sodium laureth sulfate, sodium myreth sulfate and sodium pareth sulfate.
  • the metal alkyl sulfate is sodium lauryl sulfate (SLS).
  • the useful and preferred values of the dosage form are also useful and preferred values when used in the methods described herein.
  • the peak-to-trough ratio is defined as the highest blood plasma concentration divided by the lowest blood plasma concentration within a dosing interval.
  • the dosing interval is the time from the administration of a dose to the time of the next administration. Determining the time at which blood plasma can be measured to ensure the highest and lowest concentrations are determined is within the purview of a skilled artisan.
  • a useful peak-to-trough ratio is no greater than about 1.9.
  • the ratio is no greater than about 1.6.
  • the ratio is between about 1.3 and 1.6.
  • the most preferred ratio is about 1.4. The lower the ratio, the less fluctuation and, therefore, there are fewer associated side effects.
  • Steady-state is defined as the plasma concentration levels after about five half-lives. Thus, steady-state is reached at different times for different actives. Clonidine's half-life is about 12 to 17 hours. Therefore, clonidine steady-state is reached at about day four.
  • the hydrophilic matrix provides for a controlled pharmacokinetic release profile of the ⁇ 2 -adrenergic receptor agonist.
  • the hydrophilic matrix provides for a zero- to first-order release profile of the ⁇ 2 -adrenergic receptor agonist.
  • the ratio of the components may influence the release profile of the ⁇ 2 -adrenergic receptor agonist from the matrix.
  • ⁇ 2 -adrenergic receptor agonist for example, clonidine
  • the ratio of the components may not be predictable or determinable.
  • the release profile of the ⁇ 2 -adrenergic receptor agonist may be adjusted or more easily tailored to a particularly advantageous therapeutically effective profile.
  • therapeutically effective profiles of up to and including 24 hour dosing of the ⁇ 2 -adrenergic receptor agonist is provided with reduction or elimination of undesirable side effects, such as hyperarousal.
  • the formulation disclosed herein provides minimal fluctuation of plasma concentrations of an ⁇ 2 -adrenergic receptor agonist, such as clonidine at steady-state.
  • the data provided herein show that the present formulation provides plasma concentrations at steady state that are predictable from day to day. Further, when measured on two days separated by 48 hours, the concentrations were very similar on a patient by patient basis indicating consistent performance between individual drug units.
  • the narrow peak-to-trough plasma concentrations provide a therapeutically effective amount of active without the roller-coaster effect that comes with the high peak-to-trough fluctuations seen in prior art formulations.
  • the present formulation provides blood levels achieved from the clonidine patch in an oral sustained-release tablet.
  • FDA noted that the peak to trough ratio in steady state concentrations observed with the clonidine patch averaged about 1.33 whereas the corresponding fluctuation with the immediate release clonidine tablet averaged 2.10.
  • Data from the present study show average ratios with Clonicel of about 1.4 to about 1.5, which are ratios that are much closer to the clonidine patch than to the immediate release tablet.
  • hydrophilic matrix refers to one or more natural or synthetic materials that are hydrophilic, but not necessarily water-soluble.
  • hydrophilic matrix include polymer or polymers having affinity for absorbing water such as cellulose ethers (e.g., hydroxypropyl methylcellulose), mono or disaccharides (for example, dextrose or lactose), starch, derivatives thereof, alone or in combination.
  • starch refers generally to a mixture of polysaccaharides of plant origin, the polysaccarides including amylose and amylopectin.
  • Starch includes, for example, sorghum, plantain and corn starches.
  • starch includes material that has been chemically- and/or mechanically-processed in the presence of water and subsequently dried.
  • starch includes pregelatinized starch, which encompasses completely chemically- and/or mechanically-processed starch or mixtures of partially and completely chemically- and/or mechanically-processed starches.
  • Partially pregelatinized starch includes, for example a mixture comprising one or more of a modified starch and one or more of an unmodified starch, each starch independently selected from sorghum, plantain and corn starches.
  • lactose refers to a chemical compound comprising a ⁇ -D-galactose and a ⁇ -D-glucose molecule linked through a ⁇ 1-4 glycosidic chemical bond, and derivatives thereof. Lactose may be provided in any form, e.g., spray dried, modified spray dried, or hydrated.
  • Dextrose refers to a chemical compound comprising a glucose molecule and derivatives thereof. D-glucose is preferred. Dextrose may be provided in any form, e.g., spray dried, modified spray dried, or hydrated.
  • treatment refers to the alleviation or elimination of etiological or pathological symptoms and include, for example, the elimination of such symptom causation either on a temporary or permanent basis, or to alter or slow the appearance of such symptoms or symptom worsening.
  • treatment includes alleviation or elimination of causation of symptoms associated with, but not limited to, adrenergic dysregulation or its related-complications described herein. Treatment includes the prevention of the associated condition.
  • “Therapeutically effective” refers qualitatively to the amount of an agent or agents in combination for use in adrenergic dysregulation therapy that is nontoxic but sufficient to provide the desired effect that will achieve the goal of preventing, or improvement in the severity of the symptoms.
  • Adrenergic dysregulation or its related complication symptoms is considered prevented or improved if any benefit is achieved, irrespective of the absolute magnitude of the amelioration or improvement.
  • any reduction in blood pressure of a subject suffering from hypertension would be considered an ameliorated symptom.
  • any inhibition or suppression of inattention, hyperactivity and impulsivity would also be considered amelioration of ADHD.
  • any reduction or elimination in side-effects such as “peak and trough” side effects of transient sedation at peak serum levels and rebound exacerbation of symptoms at trough levels of a subject on an ADHD therapy is considered an ameliorated symptom.
  • therapeutically effective amount refers to an amount of an active agent.
  • the therapeutically effective amount varies according to the patient's sex, age and weight, the route of administration, the nature of the condition and any treatments, which may be associated therewith, or any concurrent related or unrelated treatments or conditions of the patient.
  • determining the effective amount or dose a number of factors are considered by the attending diagnostician, including, but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
  • Therapeutically effective amounts may be determined without undue experimentation by any person skilled in the art or by following the exemplary guidelines set forth in this application.
  • the term “subject” for purposes of treatment or prevention includes any subject, and preferably is a subject who is in need of an adrenergic dysregulation treatment, or who needs treatment of an adrenergic dysregulation related complication.
  • the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, an adrenergic dysregulation condition or its related complications.
  • the subject is typically an animal, more typically is a mammal.
  • the mammal is a human, horse, dog or cat.
  • the terms “subject in need thereof” and grammatical equivalents refer to any subject who is suffering from or is predisposed to an adrenergic dysregulation condition or its related complications.
  • the terms include any subject that requires a lower dose of therapeutic agents.
  • the terms include any subject who requires a reduction in the side-effects of a therapeutic agent.
  • the terms include any subject who requires improved tolerability to any therapeutic agent for an adrenergic dysregulation therapy.
  • the pharmaceutically acceptable hydrophilic matrix as herein disclosed may comprise polysaccharides, for example, cellulose derivatives.
  • polysaccharides include alkylcelluloses, such as, methylcellulose; hydroxyalkylcelluloses, for example, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses, such as, carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses, such as, sodium carboxymethylcellulose; carboxyalkylalkylcelluloses, such as, carboxymethylethylcellulose; carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic polysaccharides, such as, alginic acid, alkali metal and ammonium salts thereof.
  • the pharmaceutically acceptable hydrophilic matrix is a cellulose ether derivative.
  • the hydrophilic matrix may include hydroxypropyl methyl cellulose (HPMC). Different viscosity grades of HPMC are commercially available.
  • HPMC may have a hydroxypropoxyl substitution of from about 7 to about 12 weight percent, a methoxyl substitution of from about 28 to about 30 weight percent, a number average molecular weight of about 86,000 and a 2% aqueous solution viscosity of about 4000 cps.
  • the HPMC may have a hydroxypropoxyl substitution of from about 7 to about 12 weight percent, a methoxyl substitution of from about 19 to about 24 weight percent, a number average molecular weight of about 246,000 and a 2% aqueous solution viscosity of about 100,000 cps. Mixtures of the above HPMC's may be used.
  • the hydrophilic matrix may comprise a hydroxypropyl methylcellulose such as Methocel®, which is manufactured by the Dow Chemical Company, U.S.A.
  • the hydrophilic matrix may also comprise polyacrylic acids and the salts thereof, crosslinked acrylic acid-based polymers, for example CARBOPOLTM polymers (Lubrizol Corp., Wickliffe, Ohio); polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
  • polyacrylic acids and the salts thereof crosslinked acrylic acid-based polymers
  • CARBOPOLTM polymers Librizol Corp., Wickliffe, Ohio
  • polymethacrylic acids and the salts thereof methacrylate copolymers
  • polyvinylalcohol polyvinylpyrrolidone, copolymers of polyvinylpyrroli
  • the HPMC may be admixed with additional hydrophilic polymers, for example, starch, pregellatinized starch, monosaccharides, or disaccharides.
  • the HPMC may be admixed with dextrose, sucrose, lactose, lactulose, trehalose, maltose, mannitol, sorbitol or combinations thereof.
  • the lactose or lactose monohydrate may be used. Different grades of lactose may be used.
  • the lactose is a modified spray-dried lactose monohydrate ( 316 . Fast Flow, Wis.). Other lactose monohydrates, may also be used.
  • the particles of lactose monohydrate may be such that 98% (w/w) of the particles are smaller than 850 ⁇ m.
  • the hydrophilic matrix may comprise a HPMC admixed with a partially gellatinized starch or a combination/admixture of lactose and partially gellatinized starch.
  • Starch 1500® NF Colorcon, West Point, Pa.
  • Starch 1500® NF which is described by the manufacturer as a partially gellatinized starch, may be used.
  • Extended release periods of the ⁇ 2 -adrenergic receptor agonist may be provided by manipulation of the hydrophillic matrix or manipulation of the hydrophillic matrix and a release retardant.
  • an eight hour release period for the ⁇ 2 -adrenergic receptor agonist may be provided using a hydrophilic matrix comprising Methocel® E4M which has a hydroxypropoxyl substitution of from about 7 to about 12 weight percent, a methoxyl substitution of from about 28 to about 30 weight percent, a number average molecular weight of about 86,000, a 2% aqueous solution of viscosity of about 4000 cps and 95% by weight may pass through a 100 mesh screen.
  • a twelve hour release period for the ⁇ 2 -adrenergic receptor agonist may be provided using a hydrophilic matrix comprising Methocel® K100M, which has a hydroxypropoxyl substitution of from about 7 to about 12 weight percent, a methoxyl substitution of from about 19 to about 24 weight percent, a number average molecular weight of about 246,000, a 2% aqueous solution of viscosity of about 100,000 cps and at least 90% by weight may pass through a 100 mesh screen.
  • up to a twenty four hour release period for the ⁇ 2 -adrenergic receptor agonist may be provided using a hydrophilic matrix comprising, for example, Methocel®, and a release retardant.
  • the formulation disclosed may also optionally comprise pharmaceutically acceptable formulating agents in order to promote the manufacture, compressibility, appearance and taste of the formulation.
  • These formulating agents comprise, for example, diluents or fillers, glidants, binding agents, granulating agents, anti-caking agents, lubricants, flavors, dyes and preservatives.
  • the formulation may contain other pharmacologically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, taste or odor of the formulation.
  • the formulation may contain still other pharmacologically-acceptable excipients for modifying or maintaining the stability of one or more compounds of the composition.
  • excipients are those substances usually and customarily employed to formulate dosages for administration in either unit dose or multi-dose form.
  • the formulation herein described may be a solid oral dosage form.
  • the solid oral dosage form is generally a tablet, capsule or gelcap.
  • the optional formulating agents that further may be comprised in the matrix formulation may include, for example polyvidone; acacia gum; gelatin; alginic acid, sodium and calcium alginate; ethylcellulose; glidants such as colloidal silica, or talc; lubricants such as magnesium stearate and/or palmitate, calcium stearate, stearic acid, and polyethylene glycol.
  • the method can also include co-administering a therapeutically effective amount of a compound or formulation described herein and at least one other additional therapeutic agent.
  • the composition may be co-formulated or administered with one or more additional therapeutic agents. Any therapeutic agent that is typically used in the treatment, prevention, and reduction of adrenergic dysregulation may also be administered or co-formulated with the formulations herein disclosed.
  • the additional therapeutic agents may be administered within (either before or after) 14 days, 7 days, 24 hours, 12 hours, 1 hour, or simultaneously with the composition and/or formulations herein disclosed. Any suitable additional therapeutic agent may be co-formulated with the composition herein described or administered to the mammal being treated with this composition at concentrations known to be effective for these agents.
  • the formulation with or without the additional agents may be administered orally or parenterally by injection, although other effective administration forms, such as intra-articular injection, intradermal injection, inhalant mists, transdermal iontophoresis or suppositories are also envisioned.
  • the compounds and pharmaceutical formulations described herein may be used with other methods of treating and/or preventing ADHD.
  • Other methods of treating and/or preventing ADHD include, for example, stimulants such as methylphenidate, Ritalin, Concerta, amphetamines, Adderall®, dextroamphetamines, Dexedrine®, modafinil, Provigil®, amineptine (Survector®); anti-depressants such as bupropion; nonstimulants such as Selective Norepinephrine Reuptake Inhibitors (SNRIs); tricyclic anti-depressants; Selective Serotonin Reuptake Enhancers (SSREs) such as tianeptine (Stablon®), bupropion (Wellbutrin®); and combinations thereof.
  • stimulants such as methylphenidate, Ritalin, Concerta, amphetamines, Adderall®, dextroamphetamines, Dexedrine®, modafinil, Provigil®, amineptine (Survector®); anti-depressants such as bupropion; nonstimulants such
  • ACE inhibitors such as captopril, enalapril, fosinopril (Monopril®), lisinopril (Zestril®), quinapril, ramipril (Altace®); angiotensin II receptor antagonists: e.g., irbesartan (Avapro®), losartan (Cozaar®), valsartan (Diovan®), candesartan (Atacand®); alpha blockers such as doxazosin, prazosin, or terazosin; beta blockers such as atenolol, labetalol, metoprolol (Lopressor®, Toprol-XL®); calcium channel blockers such as amlodipine (Norvasc®), diltiazem, verapamil; diuretics, such as bendroflumethiazide
  • a medically desirable result for an ADHD or hypertension condition may be a reduction of impulsiveness or blood pressure, respectively.
  • ADHD or hypertension may be diagnosed and/or monitored, for example, by physical examination of the subject before, during and after administration of the herein disclosed formulations.
  • a preblend was prepared as follows: API (clonidine HCl, USP; Spectrum Chemical, New Brunswick, N.J.); hydroxypropyl methylcellulose (Hypromellose, USP; Methocel® K100M Premium, Dow Chemical), lactose monohydrate NF 316 .
  • Fast Flow® (Formost Farms, Wis.) pre-screened through 20 mesh was used (Tablets 1 and 2), the lactose carrier, were mixed in a V-blender, and then collected.
  • the pre-blend from above was combined with pre-screened partially pregellatinized starch, NF (Starch 1500®; Colorcon, Pa.); sodium lauryl sulfate (Spectrum Chemical, N.J.) and colloidal silicon dioxide (Cab-O-Sil® M-5P; Cabot, Mass.) into a 2 qt. V-blender; and mixed for about 8 minutes; followed by a charge of pre-screened magnesium stearate and further mixing for 3 minutes.
  • the powder was pelletized using a Fette 1200i Tablet Press to provide Tablet 1.
  • the lactose carrier may be added before or after dry compaction of the powdered blend depending on the particular kind and particle size of the lactose.
  • additional Tablets 2-4 were prepared, and their compositions are summarized in Table 1. Tablet 5 was also prepared and its composition is summarized in Table 1.
  • the tablets may be film coated with art-known film coating compositions.
  • the coating may be applied to improve the aspect and/or the taste of the tablets and the ease with which they may be swallowed. Coating the tablets may improve stability and shelf-life.
  • Suitable coating formulations comprise a film-forming polymer such as, for example, hydroxypropyl methylcellulose, e.g. hypromellose 2910 , a plasticizer such as, for example, a glycol, e.g. propylene glycol or polyethylene glycol, an opacifier, such as, for example, titanium dioxide, and a film smoothener, such as, for example, talc.
  • Suitable coating solvents are water as well as organic solvents. Examples of organic solvents are alcohols, e.g.
  • the coating may contain a therapeutically effective amount of one or more API's to provide for an immediate release of the API(s) and thus for an immediate relief of the symptoms treated by the API(s).
  • An ethylcellulose coating such as Surelease® (Colorcon, Pa.) may be applied to the tablets in a pan coater or a fluidized bed coater.
  • FIG. 1 Experimental results of the dissolution of clonidine from the Tablets 2 and 3 using the USP paddle method (500 mL, 50 RPM) in a pH 2 medium are depicted in FIG. 1 .
  • the release profile is expressed as the % clonidine dissolved from the medium as a function of time.
  • the extended release profiles of clonidine from the hydrophilic matrix with and without release-retardant are shown graphically.
  • Tablet 3 with release retardant provides a zero- to first-order release profile of clonidine as compared to Tablet 2, which is absent the release-retardant.
  • the 90% confidence interval for comparing the maximum exposure of clonidine, based on ln(C max ), after Clonicel-fasted vs. Catapres is not within 80% to 125% limits.
  • the 90% confidence intervals for comparing total systemic exposure, based on ln(AUC last ) and ln(AUC inf ) are within the 80% to 125% limits, indicating the total systemic exposure to clonidine is similar after the administration of clonicel-fasted and catapres.
  • Clonidine plasma concentration-time profiles are similar after the administration of Clonicel under fasted and fed conditions.
  • T max values were 6.80 hours (fasted) and 6.50 hours (fed) and clonidine concentrations were comparable for administration under each condition.
  • Food had no effect on the elimination half-life of Clonicel (12.67 hours-fasted vs. 12.65 hours-fed).
  • the clonidine C max , AUC last , and AUC inf ratios (fed vs. fasted) are within the 90% confidence intervals of 80% to 125%, indicating that food does not have a significant effect on either the rate or extent of absorption of clonidine from the Clonicel formulation.
  • the plasma-concentration time profile of Clonicel was delayed and more sustained when compared to Catapres under fasted conditions and was unaffected by the presence of food. Data are shown in Tables 2, 3 and 4.
  • the doses in this study were chosen based on the recommended usual oral daily dose range for clonidine prescribed for hypertension and the expectation that the chosen doses would provide the range of plasma clonidine concentrations associated with efficacy in the treatment of hypertension (0.2 to 2.0 ng/mL). All doses were administered on a divided dose schedule, i.e., 0.1, 0.2, and 0.3 mg b.i.d., with 12 hours separating the doses.
  • Ambulatory blood pressure monitoring (ABPM) using an appropriate monitor, was performed at Baseline prior to dosing and on the last day of dosing (Day 26).
  • Ten blood samples to measure steady-state plasma concentrations of clonidine were collected pre-dose and for a 12-hour period following the morning dose on each of Days 23 and 25.
  • Blood samples at pre-specified intervals pre- and post study drug treatment were obtained on Days 23 and 25 for correlation of pharmacokinetics with results of ABPM obtained on Day 26-28 of the study.
  • Pharmacokinetic parameters for clonidine were calculated using noncompartmental analysis. Reported parameters, as defined herein, included: Maximum plasma concentrations of clonidine, observed by inspection of individual subject plots of plasma concentration versus time (C max ); Time (h) from dosing to C max , observed by inspection of individual subject plots of plasma concentration versus time (T max ); Minimum plasma concentrations of clonidine, observed by inspection of individual subject plots of plasma concentration versus time (C min ); The average concentration during a dosing interval at steady-state.
  • BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”.
  • Non-compartmental pharmacokinetic parameters were calculated from plasma concentrations of clonidine on Days 23 and 25 using WinNonlin® version 5.2 (Pharsight Corp). Since Clonicel was administered at fixed doses, independent of body weight or size, CL/F values were normalized to body weight on a per kg basis. All derived pharmacokinetic parameters and plasma concentrations at each scheduled assessment time point were summarized with descriptive statistics (mean, standard error of the mean, standard deviation, coefficient of variation, median, range and member of observations). Graphical displays of individual subject and mean (for a given dosage level) plasma concentration versus time data were also generated.
  • E (E max ⁇ C ⁇ )/(C ⁇ +EC 50 ⁇ ).
  • E is the observed magnitude of the pharmacological effect at a given concentration
  • C or AUC is the drug concentration or AUC producing the pharmacological effect
  • E max is the estimated, maximal pharmacological effect
  • EC 50 is the concentration at which the effect is 50% of the maximal effect
  • EC 90 is the concentration at which the effect is 90% of the maximal effect
  • ⁇ is the Shape factor (steepness of slope) for the E vs. C relationship.
  • Plasma concentrations are tabulated individually by patient and plotted in FIG. 3 . Average concentrations for the 3 treatment groups ranged from approximately 400 pg/mL to 1800 pg/mL. The figure shows that plasma concentrations increased proportionately with increase in dose, stayed fairly even throughout the inter-dosing interval, and were very similar between Days 23 and 25. Achievement of steady-state was confirmed by summarizing and plotting mean trough concentrations prior to the morning doses of Days 23, 25, and 26. Summary data are plotted in FIG. 4 .
  • Plasma concentrations at trough were also used to calculate intra-subject variability. It was important to investigate intra-subject variability in plasma concentration as an index of the consistency of pharmacokinetic performance between individual dosing units. The mean intra-subject coefficients of variation were very low and ranged from 10% to 12% for the three groups, thus indicating that the sustained-release formulation delivered clonidine consistently from day to day.
  • Steady-state noncompartmental pharmacokinetic parameters were calculated for each patient individually and summarized across treatment groups for Days 23 and 25. Table 6 shows the key parameters by treatment group and Day of treatment. Average C max values ranged from 553 pg/mL for the 0.2 mg group at Day 23 to 1980 pg/mL for the 0.6 mg group at Day 23. The same pattern was evident for C min and AUC ⁇ . T max averaged 4 to 5 hours at all dose levels, with an overall range for individual patients from 2 to 8 hours, although the majority (>60%) of the observed T max values occurred between 4 and 6 hours.
  • both systolic and diastolic blood pressures returned very closely to their baseline values without overshoot.
  • the effect on blood pressure was maintained over the entire 12-hour daytime dosing interval at all doses, albeit lesser in magnitude for the 0.2 mg/day dose and between 10 and 12 hours after dosing.
  • Table 8 summarizes the mean differences by treatment group and presents paired t-tests of the significance of these differences between Baseline and the last two measuring times. As the table shows, consistent statistically significant differences were maintained at the last 2 measuring times for SBP and DBP at the higher two dosing groups, but were more intermittent for the 0.2 mg/day group. With the exception of the difference between Hour 11 and Baseline at the 0.6 mg group, there were no statistically significant differences for HR at the last two measuring times.
  • Pharmacokinetic-pharmacodynamic modeling was conducted using the blood pressure response data and the C max , C min and AUC ⁇ values at Day 25 of dosing.
  • the sigmoidal E max model (WinNonlin PD Model 105) was used with the assumption that there is no pharmacological effect at zero drug concentration. The relationships between effect and exposure were similar for changes in diastolic and systolic blood pressure for each of the 3 exposure parameters.
  • a representative plot of the observed data, identified by Clonicel dose level, with the superimposed curve fit is displayed in FIG. 5 .
  • the sigmoidal E max model described well the relationship between blood pressure effects and clonidine concentration.
  • the slope of the concentration-response ( ⁇ ) is quite steep at the low concentrations provided by administration of the 0.2 mg daily dose of Clonicel.
  • Parameter estimates for the model fits for the effects on blood pressure are summarized in Table 9. These results indicate that the clonidine concentration required to produce 50% of the maximal response on systolic blood pressure is 458 pg/mL for C max and 359 pg/mL for C min . Concentrations of this magnitude were consistently achieved in the 0.4 and 0.6 mg groups, but not in the 0.2 mg group.
  • the estimated EC 90 for clonidine effects on systolic blood pressure indicated that C max and C min concentrations of 646 and 532 pg/mL, respectively, are required.
  • a sustained release profile for the Clonicel formulation of clonidine was confirmed by a delayed T max , a dampened C max , prolonged concentrations of clonidine over the 12-hour dosing interval, and low fluctuation of the plasma clonidine concentrations over the dosing interval.
  • the low fluctuation corresponds to the narrow peak-to-trough range provided by the sustained release formulation.
  • Low intra-subject variability in the clonidine plasma concentration-time profiles was established over two 12-hour dosing intervals at steady-state, indicates consistent delivery of clonidine by the formulation. Significant decreases in blood pressure were observed at all dose levels during treatment, with dose-related decreases at 0.2 and 0.4 mg/day but with no clinically significant additional benefit at 0.6 mg/day.

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US20100209510A1 (en) * 2007-06-08 2010-08-19 Henry Joseph Horacek Extended Release Formulation and Method of Treating Adrenergic Dysregulation
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