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  Pharmaceutical Patents  

 

Title:  Extended release formulation and method of treating adrenergic dysregulation
United States Patent: 
7,884,122
Issued: 
February 8, 2011

Inventors: 
Horacek; Henry Joseph (Charlotte, NC), He; Min Michael (Ellicott City, MD), Khayrallah; Moise A. (Morrisville, NC)
Assignee:
Shionogi Pharma, Inc. (Atlanta, GA)
Appl. No.: 
12/615,477
Filed: 
November 10, 2009


 

Pharm Bus Intell & Healthcare Studies


Abstract

A composition and method of treating adrenergic dysregulation by administering the composition is disclosed, wherein the composition comprises a a2-adrenergic receptor agonist; a pharmaceutically acceptable hydrophilic matrix and a release-retardant of a metal alkyl sulfate. In embodiments, the composition provides a sustained release of the agonist, wherein after administration of the composition no more than once about every 12 hours to a subject having a steady state plasma concentration of the a2-adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.

Description of the Invention

SUMMARY

Described herein is an oral dosage form comprising: (a) an .alpha..sub.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 .alpha..sub.2-adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.

In another embodiment, a method of treating adrenergic dysregulation in a subject in need thereof is disclosed. The method 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.

DETAILED DESCRIPTION

In one embodiment, an oral dosage form is provided. The dosage form comprises an .alpha..sub.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.

In another embodiment, an oral dosage form is disclosed, wherein the oral dosage form comprises: (a) an .alpha..sub.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 .alpha..sub.2-adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.

In another embodiment, disclosed is an oral dosage form comprising: (a) an .alpha..sub.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.

In yet another embodiment, a solid oral dosage form for treating and/or reducing an adrenergic dysregulation condition in a subject in need thereof is disclosed. The solid oral dosage form comprises, a) an .alpha..sub.2-adrenergic receptor agonist; b) a pharmaceutically acceptable hydrophilic matrix providing a release rate of the .alpha..sub.2-adrenergic receptor agonist; and c) a release-retardant in an amount such that the release rate of the .alpha..sub.2-adrenergic receptor agonist from the hydrophilic matrix is decreased.

In another embodiment, a method of treating an adrenergic dysregulation condition in a subject in need thereof is disclosed. The method comprises, orally administering to a subject a formulation comprising an effective amount of an .alpha..sub.2-adrenergic receptor agonist, the .alpha..sub.2-adrenergic receptor agonist admixed within a pharmaceutically acceptable hydrophilic matrix comprising a release-retardant; and providing an extended release rate of the .alpha..sub.2-adrenergic receptor agonist from the formulation; wherein the extended release rate of the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein is less than a release rate for the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix without the release-retardant admixed therein. In this embodiment, the method can further include, providing (i) a plasma concentration level of the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix; and (ii) a peak plasma level concentration of the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix; wherein the plasma concentration level of .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein provides an extended plasma concentration level of the .alpha..sub.2-adrenergic receptor agonist and a reduced peak plasma level concentration of the .alpha..sub.2-adrenergic receptor agonist than a pharmaceutically acceptable hydrophilic matrix and the .alpha..sub.2-adrenergic receptor agonist without the release-retardant admixed therein. In this embodiment, the extended release rate of the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix is zero-order to first-order.

In another embodiment, a method of treating adrenergic dysregulation in a subject in need thereof is provided. The use of the present formulations may provide for improved therapies for symptoms manifesting from adrenergic dysregulation conditions by systemic control of catecholamines. The method comprises orally administering to the subject a formulation comprising an effective amount of an .alpha..sub.2-adrenergic receptor agonist the .alpha..sub.2-adrenergic receptor agonist admixed within a pharmaceutically acceptable hydrophilic matrix comprising a release-retardant. The method provides an extended release rate of the .alpha..sub.2-adrenergic receptor agonist. The extended release rate of the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix with the release-retardant admixed therein is less than a release rate for the .alpha..sub.2-adrenergic receptor agonist from the pharmaceutically acceptable hydrophilic matrix without the release-retardant admixed therein.

In yet another embodiment, disclosed is 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 .alpha..sub.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 .alpha..sub.2-adrenergic receptor agonist can be any compound or composition of matter that binds to the .alpha..sub.2-adrenergic receptor of a cell to produce a central .alpha.-adrenergic stimulation within the cell. Examples of .alpha..sub.2-adrenergic receptor agonists include epinephrine, noradrenaline, isoprenaline, clonidine, guanfacine, lofexidine, xylazine, or their salts. In preferred embodiments, 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.

As used herein, "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. As used herein, lofexidine refers to 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole or structurally and functionally related imidazoles. As used herein, xylazine refers to 2-(2,6-dimethylphenylamino)-5,6-dihydro-4H-thiazine or structurally and functionally related thiazines. With respect to the preferred embodiments of the present invention, the term "clonidine" denotes 2,6-dichloro-N-2-imidazolidinylidene benzeneamine, and its various tautomers and rotomers. In a preferred embodiment, it has the following structure -- see Original Patent.

The amount of .alpha..sub.2-adrenergic receptor agonists that is included per oral dosage form may vary widely. For example, the therapeutically effective dose range for the .alpha..sub.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. By way of example, 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).

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 %.

Useful amounts of 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. Preferably, 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.

Minimizing the fluctuation in plasma concentration yields beneficial results. The leveling of the blood plasma concentrations over a dosing interval and, consequently, over the course of potentially long-term therapy provides the consistent plasma levels necessary to treat or ameliorate .alpha..sub.2-adrenergic dysregulation. A useful peak-to-trough ratio is no greater than about 1.9. Preferably, the ratio is no greater than about 1.6. Also preferred is a ratio between about 1.1 and about 1.6. Most preferably, 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 .alpha..sub.2-adrenergic receptor agonist. The hydrophilic matrix provides for a zero- to first-order release profile of the .alpha..sub.2-adrenergic receptor agonist. When using a combination of components for the hydrophilic matrix, the ratio of the components may influence the release profile of the .alpha..sub.2-adrenergic receptor agonist from the matrix. For a low dose .alpha..sub.2-adrenergic receptor agonist (for example, clonidine) the ratio of the components may not be predictable or determinable. By adjusting the amount of hydrophilic polymer and/or release-retardant compared to the .alpha..sub.2-adrenergic receptor agonist, the release profile of the .alpha..sub.2-adrenergic receptor agonist may be adjusted or more easily tailored to a particularly advantageous therapeutically effective profile. By releasing the drug over a longer period of time, therapeutically effective profiles of up to and including 24 hour dosing of the .alpha..sub.2-adrenergic receptor agonist is provided with reduction or elimination of undesirable side effects, such as hyperarousal. More specifically, the formulation disclosed herein provides minimal fluctuation of plasma concentrations of an .alpha..sub.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. In its review of data from the clonidine patch, 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.

The term "hydrophilic matrix" refers to one or more natural or synthetic materials that are hydrophilic, but not necessarily water-soluble. Examples of a 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.

The term "starch" refers generally to a mixture of polysaccharides of plant origin, the polysaccharides including amylose and amylopectin. Starch includes, for example, sorghum, plantain and corn starches. The term "starch" includes material that has been chemically- and/or mechanically-processed in the presence of water and subsequently dried. By way of example, the term "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.

The term "lactose" refers to a chemical compound comprising a .beta.-D-galactose and a .beta.-D-glucose molecule linked through a .beta..sub.1-4 glycosidic chemical bond, and derivatives thereof. Lactose may be provided in any form, e.g., spray dried, modified spray dried, or hydrated.

The term "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.

As used herein, the term "treatment" and its grammatical equivalents refer 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. For example, the term "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. For example, any reduction in blood pressure of a subject suffering from hypertension would be considered an ameliorated symptom. Likewise, any inhibition or suppression of inattention, hyperactivity and impulsivity would also be considered amelioration of ADHD. Furthermore, 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.

As used herein, "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. In 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.

As used herein, 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. For purposes of prevention, 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. Preferably, the mammal is a human, horse, dog or cat.

As used herein, 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. In addition, the terms include any subject who requires a reduction in the side-effects of a therapeutic agent. Furthermore, 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. Examples of such 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. By way of example, the pharmaceutically acceptable hydrophilic matrix is a cellulose ether derivative. The cellulose ether derivative is a hydroxypropyl methylcellulose.

The hydrophilic matrix may include hydroxypropyl methyl cellulose (HPMC). Different viscosity grades of HPMC are commercially available. The 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.RTM., 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 CARBOPOL.TM. 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.

The HPMC may be admixed with additional hydrophilic polymers, for example, starch, pregelatinized starch, monosaccharides, or disaccharides. By way of example, the HPMC may be admixed with dextrose, sucrose, lactose, lactulose, trehalose, maltose, mannitol, sorbitol or combinations thereof. For example, 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, WI). 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 .mu.m. The hydrophilic matrix may comprise a HPMC admixed with a partially gelatinized starch or a combination/admixture of lactose and partially gelatinized starch. By way of example, Starch 1500.RTM. NF (Colorcon, West Point, Pa.) which is described by the manufacturer as a partially gelatinized starch, may be used.

Extended release periods of the .alpha..sub.2-adrenergic receptor agonist may be provided by manipulation of the hydrophilic matrix or manipulation of the hydrophilic matrix and a release retardant. By way of example, an eight hour release period for the .alpha..sub.2-adrenergic receptor agonist may be provided using a hydrophilic matrix comprising Methocel.RTM. 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. By way of example, a twelve hour release period for the .alpha..sub.2-adrenergic receptor agonist may be provided using a hydrophilic matrix comprising Methocel.RTM. 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. By way of example, up to a twenty four hour release period for the .alpha..sub.2-adrenergic receptor agonist may be provided using a hydrophilic matrix comprising, for example, Methocel.RTM., 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. For example, 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. Such 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. Among 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.RTM., dextroamphetamines, Dexedrine.RTM., modafinil, Provigil.RTM., amineptine (Survector.RTM.); 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.RTM.), bupropion (Wellbutrin.RTM.); and combinations thereof. The compounds and pharmaceutical formulations described herein may be used with known methods for treating hypertension, such as: ACE inhibitors such as captopril, enalapril, fosinopril (Monopril.RTM.), lisinopril (Zestril.RTM.), quinapril, ramipril (Altace.RTM.); angiotensin II receptor antagonists: e.g., irbesartan (Avapro.RTM.), losartan (Cozaar.RTM.), valsartan (Diovan.RTM.), candesartan (Atacand.RTM.); alpha blockers such as doxazocin, prazosin, or terazosin; beta blockers such as atenolol, labetalol, metoprolol (Lopressor.RTM., Toprol-XL.RTM.); calcium channel blockers such as amlodipine (Norvasc.RTM.), diltiazem, verapamil; diuretics, such as bendroflumethiazide, chlortalidone, hydrochlorothiazide; and combinations thereof.

Methods of diagnosing and monitoring the presence or change of adrenergic dysregulation condition are generally known. To assess whether the formulations disclosed herein are useful to treat, reduce, or prevent an adrenergic dysregulation condition, any method known in the art may be used. For example, 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.
 

Claim 1 of 10 Claims

1. An oral dosage form comprising: (a) clonidine or a pharmaceutically acceptable salt thereof in an amount between about 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 said oral dosage form; (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of said oral dosage form; and (iii) sodium lauryl sulfate in an amount of about 5 wt % of said oral dosage form; wherein after administration of said dosage form no more than once about every 24 hours to a subject having a steady state plasma concentration of clonidine, the clonidine plasma concentration peak-to-trough ratio is no greater than about 1.9.

 

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