Methods and compositions for treating attention deficit disorder

Abstract

To provide therapeutic compositions and methods for treating attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD). [Solution] Compositions and methods for the treatment of attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) include a dosage form that delivers a therapeutic amount of an active drug in a delayed-release and controlled-release formulation. This dosage form can be administered overnight, and the release of the drug is delayed for 3 to 8 hours, thereafter with a gradually increasing release rate.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 61 / 591,129 filed on 26 January 2012, U.S. Provisional Patent Application No. 61 / 561,763 filed on 18 November 2011, and U.S. Provisional Patent Application No. 61 / 466,684 filed on 23 March 2011, the contents of which these U.S. Provisional Patent Applications are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Background of the Invention Attention-deficit-hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms such as impulsivity, hyperactivity, and / or inattention. Hyperactivity is common in children with ADHD but tends to disappear in adulthood. However, the majority of children with ADHD continue to experience some degree of attention deficit throughout their lives.

[0003] Stimulant therapy is widely used as a pharmacological treatment for ADHD. Stimulants have been shown to be safe in appropriately selected patients over the short term, and appear to be well-tolerated over a 5-year treatment period. Currently, the active pharmaceutical agents approved for use in the treatment of ADHD or ADD in the United States are primarily dopamine or norepinephrine pathway activators. Approved drugs include amphetamine and methylphenidate, dextroamphetamine prodrugs, lisdexamfetamine dimesylate, and salts and isomers of atomoxetine.

[0004] One of the challenges in treating ADHD and other CNS stimulant-responsive conditions is delivering and maintaining effective concentrations in patients throughout the day, particularly during the morning hours when cognitive abilities and concentration are needed for school or work, and often in the evenings or nights when students do their homework. Early formulations relied on two immediate-release doses daily, which presented compliance problems. Various long-acting formulations have been developed and are now available that have been shown to be effective for 8–14 hours in clinical trials (Non-Patent Literature 1). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Brams et al., Current Medical Research and Opinion, Vol. 26, No. 8, pp. 1809-1825, August 2010. [Overview of the Initiative] [Means for solving the problem]

[0006] overview The compositions and methods disclosed herein provide novel formulations and methods for treating diseases or conditions responsive to central nervous system stimulants. Such conditions include, but are not limited to, attention deficit disorder, attention deficit hyperactivity disorder, narcolepsy, excessive daytime sleepiness, major depressive disorder, bipolar depression, negative symptoms of schizophrenia, chronic fatigue, chemotherapy-related fatigue, or binge eating disorder. The compositions and methods are effective for treating adult, pediatric, and adolescent populations requiring such treatment.

[0007] The compositions and methods of this disclosure provide a convenient method of administration in which a single dose can be taken typically before bedtime in the evening or at any time during a long period of sleep, and the release of the drug is delayed in one example by 4 to 12 hours, and then released in a controlled or sustained manner. In some specific embodiments, the composition is a water-soluble capsule containing coated particles such as beads or mini-tablets. Such particles have a drug-containing core coated with an outer delayed-release coating and an inner sustained-release coating. Delayed release allows the subject to sleep, and the drug begins to be released slowly as the outer layer of the composition dissolves and the sustained-release layer begins to lose some of its integrity. This ensures that a low but therapeutic level of the drug is delivered into the patient's serum, even if the patient wakes up as usual and prepares for the day. After this slow release, the rate of drug release increases over a period of approximately 8 to 10 hours or more, and a therapeutic amount continues to be delivered, typically during the active hours of the day. Therefore, the compositions and methods disclosed herein provide a single dose that can be easily taken before sleep and provides a therapeutic effect throughout the productive hours of the day, starting from when the subject wakes up normally.

[0008] While the composition of this invention is described as effective with a once-daily dose, it should be understood that additional doses may be administered as needed, under the direction of a physician. The description herein primarily relates to the treatment of individuals with a typical schedule, such as going to bed between 9 p.m. and midnight and sleeping for 6 to 9 hours. However, it should be understood that the use and effectiveness of the composition and method are not limited to such a schedule and can be adopted for use with different daily schedules, such as night shift workers or individuals with longer, shorter, or more variable sleep patterns.

[0009] In some specific embodiments, the compositions disclosed herein may include, but are not limited to, tablets, minitablets, or beads (encapsulated in water-soluble capsules). Minitablets or beads may comprise a drug-containing core or a drug-coated inert bead core, where the drug core or drug layer may also comprise an optional disintegrant, osmagent, or pore-forming agent. In some specific embodiments, the disintegrant may be a superdisintegrant. In some specific embodiments, the drug layer or core is encapsulated by a sustained-release layer, which may comprise a water-insoluble and water-permeable polymer layer that controls the rate of water absorption and drug release. An outer delayed-release layer is coated on top of the sustained-release layer. The delayed-release layer may comprise a plasticizer whose solubility is pH-dependent (or). Thus, the delayed-release layer may be a pH-dependent layer that is insoluble in aqueous solutions with a pH below 5.0 and soluble at higher pH levels in the ileum or colon, or it may be a pH-independent layer. In some specific embodiments, the outer pH-dependent layer dissolves at the higher pH within the ileum or colon. Then, as the sustained-release layer loses its integrity, it ruptures, releasing any remaining drug within the core.

[0010] Examples of active ingredients include central nervous system stimulants effective in treating ADD and ADHD or other conditions associated with dopamine or norepinephrine pathways. These active ingredients include, but are not limited to, amphetamines and amphetamine salts, such as salts of dextroamphetamine, and active isomers of methylphenidate and its active salts, all of which may be used as racemic mixtures or as pure isomers (such as d-threomethylphenidate). Furthermore, the compositions of this disclosure may include one or more prodrugs of central nervous system stimulants, such as, but are not limited to, amino acid conjugate-type active ingredients including, for example, l-lysine-d-amphetamine.

[0011] Accordingly, in some specific embodiments, the compositions and methods of the present disclosure include a therapeutic dose of a central nervous system stimulant, at least one pharmaceutically acceptable excipient and, if necessary, a disintegrant. A solid oral pharmaceutical composition comprising a core containing a drug, osmagent, or a pore-forming agent; a sustained-release layer coating the core; and a delayed-release layer encapsulating the sustained-release layer, wherein when the composition is placed in a simulated gastric environment, the combination of the sustained-release and delayed-release layers results in a delay of 3–8, 10, or even 12–13 hours, during which less than 10% of the central nervous system stimulant is released. The term "simulated gastric environment" is intended in this specification to represent its common meaning as understood in the art, and should be understood in a broad sense to mean a three-stage environment consisting of a low pH (e.g., 1–5) aqueous environment followed by a higher pH aqueous environment with immersion (e.g., pH 6.8, etc.) after a period of up to about 2 hours, or a low pH followed by an intermediate pH of about 6 (the environment is maintained at about 37.0°C). Alternatively, in some specific embodiments, the simulated gastric environment is described as being a USP Apparatus I (Baskets) with stirring, in which the composition is placed in 700 ml of an aqueous solution of 0.1 N HCl (pH 1.1, v) for up to 2 hours, followed by 2 to 6 hours in sodium phosphate buffer at pH 6.0; followed by 6 to 20 hours in sodium phosphate buffer at pH 7.2 (adjusting the pH to 7.2 by adding NaOH).

[0012] Any of the solid oral pharmaceutical compositions disclosed herein may be in the form of coated beads, or compressed into tablets or minitablets. The beads or minitablets may then be dispensed in single doses into water-soluble gelatin capsules or into liquid or gel-like suspensions for administration.

[0013] Also, one aspect of the compositions and methods of the present disclosure is a solid oral pharmaceutical composition comprising a core containing a therapeutic amount of a central nervous system stimulant and at least one pharmaceutically acceptable excipient, wherein the core substantially does not contain a disintegrant, osmagen or pore-forming agent; a sustained release layer coating the core; and a delayed release layer encapsulating the sustained release layer, wherein when the composition is placed in a simulated gastric environment, the combination of the sustained release layer and the delayed release layer provides a delay of 3 to 12 hours, during which time the central nervous system stimulant released is 10% or less, and can be described as such a solid oral pharmaceutical composition.

[0014] The solid oral pharmaceutical compositions of this disclosure may be described as formulations in which the in vitro dissolution rate of the dosage form, when the composition is placed at 37°C ± 0.5°C and measured by USP Apparatus I (Baskets) with stirring, is 0 to about 20% of the drug released after 8 hours, about 2 to about 30% after 10 hours, about 10 to about 65% after 12 hours, and 45% to 95% after 15 hours, with the amount of active ingredient released per hour increasing from the period between 20% and 65% release. Furthermore, the compositions and methods disclosed herein are solid oral pharmaceutical compositions in which the in vitro elution rate of the dosage form is measured by USP Apparatus I (Baskets) with the composition placed at 37°C ± 0.5°C and stirred, with the composition in 700 ml of aqueous solution of 0.1N HCl (pH 1.1,v) for up to 2 hours, followed by sodium phosphate buffer at pH 6.0 for 2 to 6 hours; followed by sodium phosphate buffer at pH 7.2 for 6 to 20 hours (with NaOH added to adjust the pH to 7.2), with the amount of drug released being 0 to about 10% after 6 hours, about 15 to about 28% after 10 hours, about 40 to about 60% after 12 hours, and about 80% to about 95% after 15 hours, with the amount of active ingredient released per hour increasing from between 20% and 65% release, or the composition being 0.1N Soak in 700 ml of aqueous solution of HCl (pH 1.1) for up to 2 hours, followed by 2-6 hours in sodium phosphate buffer at pH 6.0; then in sodium phosphate buffer at pH 7.2 for 6-20 hours. When adjusted to pH 7.2 by adding NaOH, placed at 37°C ± 0.5°C, and measured by USP Apparatus I (Baskets) with stirring, the drug released within 6 hours when the composition is administered to humans is about 10% or less, the drug released within 12 hours is about 50% or less, and it can be described as a solid oral pharmaceutical composition described as having a single maximum value between 12 and 20 hours after administration for the plot of plasma concentration against time after administration.

[0015] Also, the solid oral pharmaceutical composition of the present disclosure may, in some specific embodiments, include a plurality of core pellets that are substantially spherical beads. The core may consist essentially of a central nervous system stimulant and one or more excipients, or the core may consist essentially of the stimulant and one or more excipients coated on an inert non-pareil bead. This core is then coated with two or more release control layers to produce a population of particles for drug delivery. However, in order to obtain a more consistent coating and a reproducible release profile of the active ingredient from the population of particles, it is advantageous to provide a core that is as smooth and spherical as possible, which is one aspect of the compositions and methods of the present disclosure.

[0016] Furthermore, the solid oral pharmaceutical compositions of this disclosure may include central nervous system stimulants that can generally be defined as chemical entities that affect the dopamine or norepinephrine neural pathways. Preferred pharmaceutically active ingredients include, but are not limited to, amphetamine, dextroamphetamine, active isomers of amphetamine and amphetamine salts (e.g., dextroamphetamine salt), methylphenidate and its active salts, or combinations thereof, all of which may be used alone or in combination as racemic mixtures, or as pure isomers (e.g., d-threomethylphenidate), or as any prodrug or pharmaceutical salt or mixed pharmaceutical salt thereof. The compositions of this disclosure may also include prodrugs, for example, but are not limited to, active ingredients conjugated with amino acids (e.g., l-lysine-d-amphetamine). Suitable excipients in the core of the pharmaceutical composition include polyvinylpyrrolidone, hydroxypropyl methylcellulose, lactose, sucrose, microcrystalline cellulose, or any combination thereof.

[0017] One embodiment of the compositions of the present disclosure is that the delayed-release layer may contain a pH-dependent polymer or copolymer that is insoluble in aqueous media with a pH lower than 5.5. Examples of such a delayed-release layer include, but are not limited to, cellulose phthalate acetate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic polymer, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose succinate acetate, cellulose trimellitate acetate, shellac, methacrylic acid copolymer, Eudragit L30D, Eudragit L100, Eudragit FS30D, Eudragit S100, or any combination thereof. The delayed-release layer may also contain plasticizers, or in some specific embodiments, the delayed-release layer may contain methacrylic acid copolymer type B, mono- and diglycerides, dibutyl sebacate, and polysorbate 80.

[0018] In some specific embodiments of the solid oral pharmaceutical compositions of the present disclosure, the sustained-release layer comprises a water-insoluble and water-permeable polymer, and may further comprise a water-soluble polymer. In some specific embodiments, the sustained-release layer comprises, but is not limited to, a cellulose ether derivative, an acrylic resin, a copolymer of esters of acrylic acid and methacrylic acid having a quaternary ammonium group, a copolymer of esters of acrylic acid and methacrylic acid, or any combination thereof, or may comprise ethylcellulose, hydroxypropylcellulose, dibutyl sebacate, and magnesium stearate.

[0019] In some specific embodiments, the core may include a disintegrant, and may also include corn starch, potato starch, pregelatinized starch, modified starch, sweeteners, clay, bentonite, microcrystalline cellulose, carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polyacrilin potassium, alginate, sodium starch glycolate, gum, agar, guar, carob, karaya, pectin, tragacanth, crospovidone, or low-substituted hydroxypropylcellulose. The composition may also contain a disintegrant, osmagent, or pore-forming agent, which may be a salt, acid, base, chelating agent, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, polyol, mannitol, sulfatol, xylitol, carbohydrate, carbonate, bicarbonate, electrolyte, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, α-d-lactose monohydrate, glucose, α-hydroxy acid, citric acid, ascorbic acid, or any combination thereof. A further aspect of the present disclosure is that the formulations of the present disclosure may contain an abuse deterrent, which may be a capsaicinoid or a nasal stimulant such as sodium lauryl sulfate.

[0020] In some specific embodiments, an optional disintegrant, osmagent, or pore-forming agent constitutes 0 to about 75% by weight of the core. The composition may also include a swellable layer or a sealing layer positioned between the core and the sustained-release layer. The swellable layer may contain a super-disintegrant, an osmotic agent, or a combination thereof, and in some specific embodiments, a hydrophilic polymer (such as polyethylene oxide) and a binder, and may further include a drug-containing layer between the swellable layer and the sustained-release layer, and a sealing portion may be included between the swellable layer and the drug-containing layer.

[0021] In some specific embodiments, the compositions and methods of the Disclosure may be described as methods for treating a condition in a subject having a disorder or condition responsive to administration of a central nervous system stimulant, comprising the step of orally administering a solid oral pharmaceutical composition of the Disclosure. The treatment method may include the step of administering one or two dosage forms per day, depending on the needs of a particular patient. One aspect of the compositions and methods of the Disclosure is such that administration of a dosage form on a once-daily basis results in a delayed release of about 4 to about 12 hours, followed by an increase in the plasma concentration profile, resulting in a single maximum serum concentration (Cmax) during a 24-hour period from the start of administration of the dosage form, which appears at least 12, at least 14, or at least 15 hours after administration.

[0022] Furthermore, the compositions and methods of this disclosure may, in some specific embodiments, be described as solid oral pharmaceutical compositions comprising a therapeutic dose of a central nervous system stimulant, which, when administered orally to humans, result in a delayed release of 4 to 12 hours, an increase in serum concentration of the central nervous system stimulant over 7 to 12 hours, and a maximum serum concentration (Cmax) 10 to 16 hours after administration. In some specific embodiments, the serum concentration exhibits a single maximum value.

[0023] Furthermore, in some specific embodiments, the compositions and methods of the present disclosure may be described as solid oral pharmaceutical compositions comprising a core (substantially free of disintegrants, osmagents, or pore-forming agents) containing a therapeutic dose of a central nervous system stimulant and at least one pharmaceutically acceptable excipient; a sustained-release layer coating the core; and a delayed-release layer encapsulating the sustained-release layer, wherein, when the composition is placed in a simulated intragastric environment, the combination of the sustained-release and delayed-release layers results in an average delay of 3 to 12 hours, during which 10% or less of the central nervous system stimulant is released, and resulting in an average gradual increase in the release of the central nervous system agent 8 to 16 hours after being placed in the simulated intragastric environment.

[0024] Conditions or disorders that can be treated include, but are not limited to, attention deficit disorder, attention deficit hyperactivity disorder, excessive daytime sleepiness, major depressive disorder, bipolar depression, negative symptoms of schizophrenia, chronic fatigue, chemotherapy-related fatigue, or binge eating disorder. Attention deficit disorder is characterized by hyperactivity, impulsivity, or inattentional symptoms that impair social, academic, or occupational functioning and are often present in two or more settings, such as school (or work) and home. The inattentional type is characterized by at least six of the following symptoms, which have persisted for at least six months: lack of attention to detail / careless mistakes; lack of sustained attention; poor listening skills; inability to complete tasks; poor organization; avoidance of tasks requiring sustained mental effort; losing things; being easily distracted; and forgetfulness. In the hyperactive-impulsive type, at least six of the following symptoms are present for at least six months: squirming; leaving one's seat; running / climbing in inappropriate places; difficulty with quiet activities; "on the go"; excessive talking; blurting answers; inability to wait one's turn; and meddlesome behavior. The combined type includes both inattentive and hyperactive-impulsive behaviors.

[0025] As used herein, the term "treatment" is not limited to the cure or resolution of any condition or disorder, nor is it limited to the achievement of certain milestones or improvement criteria in a particular subject. It should be understood that the term encompasses the administration of any drug for the purpose of obtaining a positive effect with respect to cognitive or behavioral function, symptoms, or side effects. All such activities are considered treatments, whether the improvement (if any) is immediately observable or measurable or not.

[0026] For example, it is well known that certain side effects can occur with the administration of CNS stimulants. Such side effects may include, but are not limited to, headache, nausea, dizziness, facial flushing, loss of appetite, insomnia, abdominal discomfort (stomach pain), dry mouth, rapid heartbeat, nervousness, mood swings, irritability, weight loss, or simply feeling unwell. Treatment with the formulations of this disclosure is expected to result in a reduction in the frequency or severity of side effects compared to treatments in which the active agent is rapidly released into the stomach. Therefore, treatment may include not only the reduction of symptoms of the condition or disorder, but also the reduction of side effects.

[0027] The compositions and active agents of this disclosure are administered in “effective amounts,” “effective doses,” or “therapeutic effective amounts or doses.” “Effective” amounts or “therapeutic effective amounts” or doses of a drug or pharmacologically active agent are intended to be sufficient amounts of the drug or agent to produce the desired effect without toxicity. In this disclosure, “effective amount” is the amount of a composition or active agent that is effective in improving, ameliorating, or preventing one or more symptoms of the condition being treated. The “effective” amount varies from subject to subject depending on the individual’s age and general health condition or the specific active agent. The therapeutic or effective dose or amount is determined by a physician and is often based on empirical data obtained by administering escalating doses until the best balance of benefits versus side effects is achieved.

[0028] Effective doses of the compositions of this disclosure for the treatment of (particular) ADHD include doses that have been shown to be effective in the treatment of these conditions by oral administration, such as, but not limited to, 5, 9, 10, 15, 18, 20, 25, 27, 30, 35, 36, 45, or 54 mg once or twice daily. It should also be understood that other dosage ranges may be effective for conditions or symptoms other than ADHD, and therefore the therapeutically effective drug concentration in the compositions of this disclosure may be between 0.1 and 1000 mg (including any specific concentration within that range).

[0029] As used herein, the term “pharmaceutically acceptable salt” means a non-toxic, pharmaceutically acceptable salt as previously reported (see International J.Pharm., 1986, 33, 201-217; J.Pharm.Sci., 1997 (January), 86, 1, 1). However, other salts well known to those skilled in the art may also be useful in the preparation of the compositions of this disclosure, and include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharic acid, or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0030] Furthermore, the compositions and methods of this disclosure may, in some specific embodiments, be described as solid oral pharmaceutical compositions comprising a therapeutic dose of a central nervous system stimulant, wherein when administered orally to humans, the composition exhibits a delayed release of 3 to 8 hours, a gradual increase in the rate of central nervous system stimulant release over 7 to 12 hours, and a serum concentration Cmax 10 to 16 hours after administration, with a plot of serum concentration against time after release showing a single maximum value. The solid oral pharmaceutical may further be defined as having 10% or less of the central nervous system stimulant released within 6 hours after administration.

[0031] In some specific embodiments, the compositions and methods of the present disclosure may be defined as solid oral pharmaceutical compositions comprising a core containing a therapeutic dose of a central nervous system stimulant and at least one pharmaceutically acceptable excipient; a sustained-release layer coating the core; and a delayed-release layer encapsulating the sustained-release layer, wherein the core is substantially free of disintegrants, osmagents, or pore-forming agents; and when the composition is administered to a human, the combination of the sustained-release and delayed-release layers results in: an average delay of 3 to 8 hours during which 10% or less of the central nervous system stimulant is released; and an average increase in the serum concentration of the central nervous system agent from the start of absorption to 12 to 16 hours post-administration, with the serum concentration showing a single maximum value. [Brief explanation of the drawing]

[0032] The following drawings constitute part of this specification and are included to illustrate further examples of particular embodiments of the invention. This disclosure may be better understood by referring to one or more of these drawings in combination with the detailed descriptions of specific embodiments presented herein. [Figure 1] Figure 1A is a schematic diagram of a pharmaceutical composition of beads having a drug-containing core surrounded by a sustained-release layer and a delayed-release layer. Figure 1B is a schematic diagram of composition 1A having an additional swellable layer positioned between the sustained-release layer and the delayed-release layer. [Figure 2]Figure 2A is a schematic diagram of a pharmaceutical composition of a minitablet having a drug-containing core surrounded by a sustained-release layer and a delayed-release layer. Figure 2B is a schematic diagram of composition 2A having an additional swellable layer positioned between the sustained-release layer and the delayed-release layer. [Figure 3] Figure 3 is a schematic diagram of the pharmaceutical composition of a bead, which includes a core surrounded by four layers, an inert inner core, a swellable polymer, a drug layer, a sustained-release layer, and an enteric-coated layer. [Figure 4] Figure 4 shows graphs of the elution profiles for DOE1-8. [Figure 5] Figure 5 shows graphs of the elution profiles for DOEs 9, 10, 11, 3, and 4. [Figure 6] Figure 6 is a graph of the stability elution profile of DOE4. [Figure 7] Figure 7 is a graph of the stability elution profile of DOE3. [Figure 8] Figure 8 is a graph of the elution profile of the enteric coating in DOE3 (3 stages). [Figure 9] Figure 9 is a graph showing the elution of the DOE3 coating. [Figure 10] Figure 10 is a graph of the elution profile for lot 2009-138-45 (weight increase of 30%). [Figure 11] Figure 11 is a graph of the stability and dissolution profile over two weeks. [Figure 12] Figure 12 is a graph of the elution profile of DOE3 (lot 2009-138-45) cured at 50°C. [Figure 13] Figure 13 is a graph of the elution profile of DOE3 (lot 2009-138-45) cured at 55°C. [Figure 14] Figure 14 is a graph showing the stability of the elution profile of DOE3 (lot 2009-138-45) cured at 55°C. [Figure 15] Figure 15 is a graph of the elution profile of DOE3 (lot 2009-138-45), which is stable for 8 months. [Figure 16]Figure 16 is a graph of the dissolution profiles of the formulations described in Examples 14 to 18. [Figure 17] Figure 17 is a graph showing the serum concentration of healthy volunteers after ingesting the formulations of Examples 14-18. [Figure 18] Figure 18 compares the data from Figure 17 with that of commercially available formulations. [Modes for carrying out the invention]

[0033] Detailed description of the invention This disclosure provides therapeutic compositions and methods for treating attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or other conditions or disorders responsive to central nervous system stimulants by providing dosage forms that deliver a therapeutic dose of an active drug in a delayed and controlled release pattern so that a therapeutic dose of the drug is maintained throughout the day's activity hours. In pediatric patients (including adolescent patients), and also in adults, the therapeutic dose is preferably administered upon waking, in the morning, and in the afternoon when work or homework needs to be done.

[0034] The formulations of this disclosure can deliver a therapeutic dose of the drug over an extended period throughout the day with a single administration. The dosage form provides delayed release, allowing for convenient administration before the patient goes to sleep. A small proportion of the drug may be released during the first 6-8 hours after administration, so that the patient has already received a minimum therapeutic dose upon normal waking. Consequently, the patient does not need to take a pill after waking up and then eat breakfast to prepare for the day before receiving the therapeutic effect.

[0035] Furthermore, the formulations disclosed herein also result in a gradual increase in drug release over the next 8 to 16 hours after the delayed release, or up to 16 hours after administration of the dosage form. Thus, after the delayed release, the dosage form may yield a sigmoid release curve as shown in Figures 3 and 5 of the attached drawings.

[0036] Central nervous system stimulants Stimulant medications (e.g., methylphenidate and amphetamines, as well as prodrugs) are often prescribed to treat individuals diagnosed with attention deficit hyperactivity disorder (ADHD). According to the National Institutes of Health Sciences, all stimulants work by increasing dopamine levels in the brain. Dopamine is a brain chemical (or neurotransmitter) associated with pleasure, movement, and attention. The therapeutic effect of stimulants is achieved through a slow, steady increase in dopamine, similar to the brain's natural production. Doses prescribed by physicians start at low doses and are gradually increased until the therapeutic effect is achieved.

[0037] Stimulant therapy for ADHD, often in combination with psychotherapy, helps improve ADHD symptoms as well as the patient's self-esteem, cognition, and social and family relationships. Commonly prescribed medications include amphetamines and methylphenidate. These medications have a paradoxical sedative "focusing" effect on individuals with ADHD. Researchers hypothesize that methylphenidate amplifies dopamine release, thereby potentially improving attention and focus in individuals with weak dopamine signals.

[0038] Useful amphetamines in the formulations and methods of this disclosure include amphetamine and its isomers, such as dextroamphetamine, d,l-amphetamine, and pharmaceutically acceptable salts thereof (e.g., sulfates, saccharates, and aspartates). Amphetamine is a sympathetic amine that is a noncatecholamine with CNS excitatory activity. Peripheral effects include increased systolic and diastolic blood pressure, as well as weak bronchodilation and respiratory excitatory effects.

[0039] Dextroamphetamine is a dextrorotatory isomer of the compound d,l-amphetamine sulfate and is a sympathetic amine in the amphetamine group. Chemically, dextroamphetamine is d-α-methylphenethylamine. Dextroamphetamine may be used in the practice of this disclosure, but various pharmaceutically acceptable salts of dextroamphetamine may also be used.

[0040] Methylphenidate Methylphenidate is another central nervous system (CNS) stimulant that has been used since the 1960s to treat ADD, ADHD, fatigue, and narcolepsy. Methylphenidate can be formulated as a racemic mixture of dextrorotatory and levorotatory conformations, or as a pure dextrorotatory isomer. Methylphenidate has two chiral centers in its molecule and can therefore be further purified to enrich the d-threoisomer. The use of pharmaceutically acceptable salts of methylphenidate (such as methylphenidate hydrochloride) is also envisioned by this disclosure.

[0041] It should be understood that the active pharmaceutical components of this disclosure may exist as prodrugs that are activated in the user's body. One example of a prodrug form is one having an amino acid conjugated to the active component. When this amino acid is enzymatically cleaved, the active drug is released. Prodrugs containing lysyl, isoleucyl, or aspartyl conjugates are assumed to be useful in the implementation of this disclosure.

[0042] formulation The formulations disclosed herein are designed to produce a novel release and serum profile, including an initial delay phase followed by a sigmoid release phase. This profile allows the dosage form to provide a sustained and long-lasting therapeutic effect with once-daily administration. Based on the release characteristics of the dosage form, which pass through the stomach before release, the formulations disclosed herein are expected to offer further advantages, at least including less variability in stomach emptying, lower dependence on nutritional status (postprandial or fasting), lower risk of sudden dose dumping, and lower intra-individual and inter-individual variability.

[0043] The first example of a dosage form is a single bead cluster, which can be administered as a capsule or liquid or gel suspension containing the beads. Examples of bead structures 10 are schematically shown in Figures 1A and 1B. In Figure 1A, the inner circle represents the drug-containing core, which contains the active ingredient or prodrug, appropriate excipients, and optionally a superdisintegrant or osmagent. The core may contain, for example, an active agent, a disintegrant, osmagent or pore-forming agent, and a binder. An exemplary core contains about 20-25% active agent, about 45-60% microcrystalline cellulose, about 10-30% potassium chloride, and about 3-5% binder (e.g., polyvinyl chloride). The drug-containing core may contain (for example, nylpyrrolidone or hydroxypropylcellulose). The drug-containing core may be produced by various processes known in the art, such as wet granulation, extrusion, and spheroidization. In this embodiment, two layers coat the core. The first layer is a sustained-release layer, and the outer layer is a delayed-release layer, which is pH-dependent as needed. In some specific embodiments, the core shown in Figure 1A may be inert nonpareil beads. The inner core may be sugar and starch beads, or composed of microcrystalline cellulose. Any spherical beads suitable for forming the core beads and pharmaceutically acceptable may be used. In such embodiments, the drug and excipient of the core are laminated on the core beads to obtain a three-layer formulation.

[0044] The outermost layer 14 is a delayed-release or enteric coating. In some specific embodiments, this layer comprises a water-soluble polymer, a water-insoluble polymer, a plasticizer, and a lubricant. The duration of drug release delay is controlled by the ratio of water-soluble to insoluble polymers, the concentration of the plasticizer, the amount of lubricant, and the weight increase due to the coating (which can be up to 35-45%). Alternatively, this layer may be a pH-dependent polymer that dissolves at pH above 5.0.

[0045] The sustained-release layer 16 is designed to provide a slower initial release rate, which increases over a period of 8–10 hours after the layer is exposed to an aqueous environment. An increase in the drug profile can be achieved by a membrane that becomes more permeable over time. Examples of sustained-release layers include water-soluble polymers, water-insoluble polymers, plasticizers, and lubricants. The drug release rate can be controlled or sustained by varying the ratio of water-soluble to water-insoluble polymers and by varying the coating thickness (up to a weight increase of 15–45%).

[0046] An alternative embodiment is shown in Figure 1B. In this figure, a swollen layer 18 containing a super-disintegrant or osmotic agent is positioned between the core and the sustained release layer.

[0047] In some specific embodiments, the compositions and methods of the present disclosure include a four-layer formulation 30 as shown in Figure 3. This formulation may include an internal core 15 of nonpareil beads and four concentric layers described from the inside out as a swellable polymer layer 18, a drug layer 12, a sustained-release layer 16, and a pH-dependent delayed-release layer 14 (which may be a pH-dependent layer).

[0048] In some specific embodiments, this four-layer composition may be prepared in a stepwise manner. In the first step, a hydrophilic polymer suspended in ethanol with a binder is coated onto nonpareil beads until a weight increase of 30-50% is achieved. In some specific embodiments, PolyOx Coagulant SFP (PEO) (commercially available from Dow Chemical Company) is the hydrophilic polymer, and hydroxypropyl cellulose (HPC) is used. LF) is added as a binder. The PolyOx layer is then sealed with hydroxypropyl cellulose (such as Klucel® EF) until the weight increase reaches 10%. The API is then suspended in ethanol with the binder and coated onto these layered beads, thereby applying the sustained-release coating and the delayed-release coating as described herein.

[0049] Figures 2A and 2B show embodiments in which the core is a mini-tablet 20 instead of a bead. The cores and layers in Figures 2A and 2B are functionally identical to the layers with similar numbers on the beads in Figures 1A and 1B, except that there is no optional inert core.

[0050] Various water-soluble polymers may be used in the formulations of this disclosure. Such polymers include, but are not limited to, polyethylene oxide (PEO), ethylene oxide-propylene oxide copolymer, and polyethylene-polypropylene glycol (e.g., poloxamer). Examples include carbomer, polycarbophil, chitosan, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxyalkylcellulose (such as hydroxypropylcellulose (HPC), hydroxyethylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose), sodium carboxymethylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, polyacrylates, for example, carbomer, polyacrylamide, polymethacrylamide, polyphosphatidine, polyoxazolidine, polyhydroxyalkyl carboxylic acid, alginic acid and its derivatives (such as carrageenate alginate, ammonium alginate, and sodium alginate), starch and starch derivatives, polysaccharides, carboxypolymethylene, polyethylene glycol, natural gums (such as guar gum, acacia gum, tragacanth gum, karaya gum, and xanthan gum), povidone, and gelatin.

[0051] In some specific embodiments, at least the delayed release layer is, for example, an acrylic polymer, an acrylic copolymer, a methacrylic polymer, or a methacrylic copolymer, for example, but not limited to Eudragit® L100, Eudragit® L100-55, Eudragit® L30 The following polymers are included: D-55, Eudragit® S100, Eudragit® 4135F, Eudragit® RS, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkylamine methacrylate copolymer, polymethyl methacrylate, polymethacrylic anhydride, polymethacrylate, polyacrylamide, polymethacrylic anhydride, and glycidyl methacrylate copolymer, alkylcellulose, such as ethylcellulose, methylcellulose, calcium carboxymethylcellulose, certain substituted cellulose polymers, such as hydroxypropyl methylcellulose phthalate, as well as hydroxypropyl methylcellulose succinate acetate, cellulose butyrate acetate, cellulose phthalate acetate, and cellulose trimmaleate acetate, polyvinyl acetate phthalate, polyester, wax, shellac, zein, and one or more other polymers.

[0052] EUDRAGIT is a well-known polymer and a useful copolymer for controlled-release applications. EUDRAGIT® grades for enteric coatings are based on an anionic polymer of methacrylic acid and methacrylate. It contains the -COOH functional group. It is soluble in the pH range of 5.5 to 7. EUDRAGIT® FS 30 D is an aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid. It is insoluble in acidic media but dissolves above pH 7.0 by salt formation. EUDRAGIT L100-55 and L30-55 are soluble at pH above 5.5. EUDRAGIT L100 and S100 are soluble at pH above 6.0.

[0053] Sustained-release EUDRAGIT® formulations are used in many oral dosage forms to enable sustained, controlled release of the active ingredient. Drug delivery can be controlled throughout the gastrointestinal tract for increased therapeutic efficacy and patient compliance. Various combinations of EUDRAGIT® RL (easily permeable) and RS (difficult to permeate) grade polymers allow for customized release profiles, providing a wide range of choices to achieve desired drug delivery performance. EUDRAGIT® NE polymers are neutral ester dispersions, requiring no plasticizers, and are particularly suitable for granulation processes in the manufacture of matrix tablets and sustained-release coatings.

[0054] Examples of osmagents or osmotic agents include organic and inorganic compounds, such as salts. Examples include acids, bases, chelating agents, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, α-d-lactose monohydrate, glucose, combinations thereof, and other similar or equivalent substances widely known in the art.

[0055] As used herein, the term “disintegrant” is intended to mean a compound used in a solid dosage form to facilitate the breakdown of a solid mass (layer) into smaller particles that are more readily dispersed or dissolved. Examples of disintegrants include, but are not limited to, starches (corn starch, potato starch, and their gelatinized and modified forms), sweeteners, clay, bentonite, and microcrystalline cellulose (e.g., Avicel). TM ), carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polyacrylate potassium (for example, Amberlite TMExamples include alginates, sodium starch glycolate, gums, agar, guar, carob, karaya, pectin, tragacanth, crospovidone, and other substances known to those skilled in the art. Superdisintegrants are fast-acting disintegrants. Exemplary superdisintegrants include crospovidone and low-substitution HPCs.

[0056] In preferred embodiments, plasticizers are also included in the oral dosage form. Suitable plasticizers for use in the present invention include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, low molecular weight organic polymers, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, singleblock polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, and glycerin. Other examples of such plasticizers include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, triethyl citrate, tributyl citrate, and allyl glycolate.

[0057] Furthermore, one aspect of the compositions and methods of the present disclosure may incorporate into the formulation or dosage form one or more components that press the formulation in powder form and inhibit or prevent abuse of the active ingredient by inhalation. Accordingly, a nasal stimulant may be incorporated into the sustained-release layer or core of the dosage form, either as a separate layer or incorporated within the outer layer. Examples of stimulants, but not limited to, include sodium lauryl sulfate (also known as sodium dodecyl sulfate) or capsaicinoids (e.g., capsaicin and synthetic capsaicin). In some specific embodiments, the dosage form contains 1 to 10% sodium lauryl sulfate.

[0058] Furthermore, the compositions of this disclosure may also include one or more functional excipients, such as lubricants, thermal lubricants, antioxidants, buffers, alkalizing agents, binders, diluents, sweeteners, chelating agents, colorants, flavorings, surfactants, solubilizers, wetting agents, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic substances, absorption enhancers, preservatives, absorbents, crosslinking agents, bioadhesive polymers, retarders, pore-forming agents, and fragrances.

[0059] In the present invention, useful lubricants or thermal lubricants include, but are not limited to, fatty acid esters, glyceryl monooleate, glyceryl monostearate, waxes, and carnauba wax. Examples include oxalic acid, beeswax, vitamin E succinate, and combinations thereof.

[0060] As used herein, the term “antioxidant” is intended to mean an agent used to inhibit oxidation and thus prevent deterioration of a preparation by oxidation due to the presence of oxygen free radicals or free metals in the composition. Examples of such compounds include, but are not limited to, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), hypophophorous acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, and sodium metabisulfite, as well as others known to those skilled in the art. Other suitable antioxidants include, for example, vitamin C, sodium bisulfite, vitamin E and its derivatives, propyl gallate, or sulfite derivatives.

[0061] Suitable binders for use in the present invention include beeswax, carnauba wax, cetyl palmitate, glycerol behenate, glyceryl monostearate, glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil, microcrystalline wax, paraffin wax, stearic acid, stearyl alcohol, stearate 6000 WL1644, gelucire 50 / 13, poloxamer 188, and polyethylene glycol (PEG) 2000, 3000, 6000, 8000, 10000, or 20000.

[0062] Buffers are used to suppress changes in pH during dilution or the addition of acids or alkalis. Examples of such compounds include, but are not limited to, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and sodium citrate dihydrate, salts of inorganic or organic acids, salts of inorganic or organic bases, and others known to those skilled in the art.

[0063] As used herein, the term “alkalizing agent” is intended to mean a compound used to provide an alkaline medium for the stability of the product. Examples of such compounds include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine, as well as others known to those skilled in the art.

[0064] Exemplary binders include: polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinyl acetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co(co)-polypropylene; alkylcellulose and cellulosic derivatives, e.g., low-substituted HPC (L-HPC), methylcellulose; hydroxyalkylcellulose, e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkylalkylcellulose, e.g., hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; starch, pectin; PLA and PLGA, polyester (shellac), wax, e.g., carnauba wax, beeswax; polysaccharides, e.g., cellulose, tragacanth, gum arabic, guar gum, and xanthan gum.

[0065] Examples of chelating agents include EDTA and its salts, alpha hydroxy acids such as citric acid, polycarboxylic acids, polyamines, their derivatives, and others known to those skilled in the art.

[0066] As used herein, the term “coloring agent” is intended to mean a compound used to color a solid (e.g., tablet) pharmaceutical preparation. Such compounds include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide (red), other FD&C dyes, as well as natural coloring agents, such as grape skin extract, sugar beet red powder, beta-carotene, annatto, carmine, turmeric, paprika, and other substances known to those skilled in the art. The amount of coloring agent used may vary as desired.

[0067] As used herein, the term “flavoring” is intended to mean a compound used to impart a fragrant flavor, often an aroma, to a pharmaceutical preparation. Examples of flavorings include synthetic flavor oils and aromatic and / or natural oils, extracts of plants, leaves, flowers, fruits, and combinations thereof. Other examples may include cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, thuja oil, nutmeg oil, sage oil, bitter cinnamon oil, and cassia oil. Other useful flavors include vanilla, citrus oils, e.g., lemon, orange, grape, lime, and grapefruit, and fruit essences, e.g., apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, and apricot. Flavors that have been found particularly useful include commercially available orange, grape, cherry, and bubblegum flavors and mixtures thereof. The amount of flavoring may depend on several factors, such as the desired sensory effect. The flavor is present in any amount desired by those skilled in the art. Specific flavors include grape and cherry flavors, as well as citrus flavors (such as orange).

[0068] Suitable surfactants include polysorbate 80, sorbitan monooleate, polyoximers, sodium lauryl sulfate, or others known in the art. Soaps and synthetic detergents may also be used as surfactants. Suitable soaps include alkali metal, ammonium, and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents, e.g., dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, e.g., alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, e.g., fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphoteric detergents, e.g., alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

[0069] Wetting agents are agents that reduce the surface tension of a liquid. Examples of wetting agents include alcohols, glycerin, proteins, peptides, water-miscible solvents such as glycols, hydrophilic polymers such as polysorbate 80, sorbitan monooleate, sodium lauryl sulfate, alkali metal fatty acid salts, ammonium and triethanolamine salts, dimethyldialkylammonium halide, alkylpyridinium halide, and alkylamine acetates; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphoteric detergents such as alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

[0070] Examples of solubilizing agents include cyclodextrin, povidone, combinations thereof, and others known to those skilled in the art.

[0071] Examples of waxes include carnauba wax, beeswax, microcrystalline waxes, and others known to those skilled in the art.

[0072] Examples of absorption enhancers include dimethyl sulfoxide, vitamin E PGS, sodium cholate, and others known to those skilled in the art.

[0073] Examples of preservatives include compounds used to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercury nitrate, and thimerosal, as well as others known to those skilled in the art.

[0074] Examples of absorbents include sodium starch glycolate (Explotab). TM Primojel TM ) and croscarmellose sodium (Ac-Di-Sol TM ), cross-linked PVP (Polyplasdone TM XL 10), beegum, clay, alginate, PVP, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose (e.g., Avicel TM ), polaritrin potassium (for example, Amberlite TM Examples include sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, cellulose-based agents, montmorillonite clay (e.g., bentonite), gum, agar, carob gum, karaya gum, pectin, tragacanth, and other disintegrants known to those skilled in the art.

[0075] A crosslinking agent is defined as any compound that forms crosslinks between portions of the polymer. Examples of crosslinking agents include, but are not limited to, organic acids, α-hydroxy acids, and β-hydroxy acids. Preferred crosslinking agents include tartaric acid, citric acid, fumaric acid, succinic acid, and others known to those skilled in the art.

[0076] Examples of bioadhesive polymers include polyethylene oxide, KLUCEL (hydroxypropylcellulose), CARBOPOL, polycarbophil, GANTREZ, poloxamer, and combinations thereof, as well as others known to those skilled in the art.

[0077] The retarder is an insoluble or sparingly soluble polymer having a glass transition temperature (Tg) higher than 45°C or higher than 50°C before being plasticized by other agents in the formulation (e.g., other polymers and other excipients required for processing). Examples of such excipients include waxes, acrylics, cellulose derivatives, lipids, proteins, and glycols.

[0078] Examples of pore-forming materials include water-soluble polymers (such as polyethylene glycol, propylene glycol, polaxamer, and povidone); binders (e.g., lactose, calcium sulfate, calcium phosphate); salts (e.g., sodium chloride, magnesium chloride); combinations thereof, as well as other similar or equivalent substances widely known in the art.

[0079] As used herein, the term “sweetener” is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, but are not limited to, aspartame, dextrose, glycerin, mannitol, sodium saccharin, Examples include sorbitol, sucrose, fructose, and other such substances known to those skilled in the art.

[0080] It should be understood that compounds used in the field of pharmaceutical formulations generally serve a variety of functions or purposes. Therefore, if a compound named herein is mentioned only once, or if it is used to define more than one term herein, its purpose or function should not be construed as being limited only to the named purpose(s) or function(s).

[0081] One aspect of the compositions and methods of the present disclosure is that the pharmaceutical formulations of the present disclosure provide a novel release profile when administered orally to humans in vivo. In some specific embodiments, the formulations provide a delay time of 4 to 12 hours, followed by the release of 85% of the drug over a subsequent 9 hours with escalating doses.

[0082] The elution profile is obtained under conditions designed to mimic the gastric environment or the environment faced by an oral composition swallowed by a human. While gastric residence times vary, a typical test involves placing the composition in a low-pH solution of 0.1N HCl for 2 hours to mimic the residence time in gastric acid. The composition is then placed in a higher-pH aqueous solution at approximately pH 6 for 2–6 hours, followed by a typical pH 6.8, to mimic the ileum and colon. As used herein, simulated gastric conditions encompass both the initial acidic stage and the subsequent higher pH stage of the normal human gastrointestinal tract.

[0083] After a delay period, serum concentrations increase over approximately 9–10 hours, reaching their peak serum concentration (Cmax). Based on this release profile, a dose ingested at 9:00 PM would begin to be released around 3:00 AM with a 6-hour delay, reaching its peak serum concentration approximately 16 hours later. At this point, the drug is eliminated from the body at essentially the same rate as it was absorbed.

[0084] A further aspect of the compositions and methods of the present disclosure is that the drug can begin to be slowly released during the lag time. This release is determined by the composition of the delayed release layer described herein. An example of a small amount of release during the lag time is one in which the drug released during a lag of 3 to 12 hours is about 10% or less. It should also be understood that as the delayed release layer becomes more permeable, a greater percentage, 12%, 15%, 18% or even 20% may be released.

[0085] Therefore, there is disclosed herein a pharmaceutical preparation for once-daily administration of such a drug for the treatment of conditions responsive to central nervous system stimulants, such as ADD, ADHD, bipolar depression, narcolepsy, sleep disorders and fatigue. The dosage drug is formulated to be taken before bedtime and release is initiated after a lag of several hours, so that the patient absorbs an amount of the drug sufficient to have a therapeutic effect while waking up and preparing to go to work or school. A further aspect of the formulation is that the drug is released in a gradually increasing dose throughout the day to resolve the acute tolerance effect, if any, and maintain a therapeutic level of the drug.

[0086] One embodiment of the compositions and methods of the present disclosure is a dosage form comprising a single population of beads or a capsule encapsulating mini-tablets, including a core and two or more coatings coating the core. The inner core is beads or mini-tablets containing an active pharmaceutical ingredient (API) and one or more excipients. The core is encapsulated by a sustained release layer and an outer delayed release layer.

[0087] In some particular embodiments, the sustained release layer comprises a combination of a water-soluble polymer and a water-insoluble polymer. The sustained release coating may contain, for example, polyethylene oxide and ethyl cellulose, or a combination of hydroxypropylmethylcellulose and ethyl cellulose. The ethyl cellulose product that can be used in the dosage form of the present disclosure is Ethocel TM(Commercially available as a trademark of The Dow Chemical Company). The elution rate of the sustained-release layer can be controlled by adjusting the ratio of water-soluble polymers to water-insoluble polymers in the coating or layer. The weight ratio of water-insoluble polymers to water-soluble polymers can be adjusted to, for example, 90:10-10:90, 80:20-20:80, 75:25-25:75, 70:30-30:70, 67.5:33.5-33.5:67.5, 60:40-40:60, 56:44-44:56, or 50:50.

[0088] Furthermore, the sustained-release coating may contain a plasticizer such as triethyl citrate (TEC) at a level of 3% to 50% of the combined weight of the polymers. Other additives to the coating may include titanium dioxide, talc, colloidal silicon dioxide, or citric acid.

[0089] Several examples of sustained-release layers are shown in the table below. These various formulations include variations in the ratio of water-insoluble polymers to water-soluble polymers, and the reverse of this ratio. Citric acid was added to the formula to inhibit the dissolution of HPMCAS-LF (which dissolves at ≥ pH 5.5), thus causing a delay in the initial part of the dissolution curve, and maintaining a low microenvironmental pH within the film. In some specific embodiments, the active ingredient or API may be included in the sustained-release layer. In initial tests, the model drug metronidazole was micronized and added to the formulation as a suspension. However, any suitable API disclosed may be added to the sustained-release layer.

[0090] [Table 1] An exemplary core shown in Table 2 was synthesized. In this example, an osmotic agent was added to the core.

[0091] [Table 2] Sustained-release layers with the formulations shown in the right-hand column (F) of Table 1 were synthesized on API-containing beads. The formulations were named 2009-043-10A when they resulted in a 25% weight increase in the sustained-release layer, and 2009-043-10 when they resulted in a 35% increase. Further layers shown in columns A and B of Table 1 were synthesized. For the formulations in column B, the formulations in column A were modified by removing colloidal silicon dioxide and increasing the plasticizer to polymer levels of 50% w / w. All other ratios shown in column A were maintained.

[0092] Furthermore, the formulation in column A was modified to obtain the sustained release layer in column C of Table 1. In this formulation, colloidal silicon dioxide was removed and citric acid was added. The Ethocel:HPMCAS ratio was reduced from 75:25 to 56:44. This formulation was expected to result in a lower pH in the microenvironment and an increased delay time. A layered sample resulting in a 25% weight increase and another sample with a 45% weight increase were subjected to dissolution tests.

[0093] Another embodiment of the sustained-release layer was prepared, incorporating a drug or API into the sustained-release layer. This layer is shown in column D of Table 1. In this formulation, the ratio of Ethocel to HPMCAS was 75:25. A finely powdered drug was added to the formulation as a suspension. Samples with a 25% weight increase were subjected to dissolution testing.

[0094] The core tablets shown in Table 2 were coated with a sustained-release layer formulated as shown in column A of Table 1. This formulation exhibited slow initial drug release (3% in the first 3 hours).

[0095] A sustained-release coating of another embodiment was designed with a polyethylene oxide (PEO) to ethylcellulose ratio of 37.5:62.5. Additionally, 10% talc was added to one sample to improve the coating process. The presence of talc did not affect drug release. The release profiles of these formulations, processed with weight increases of 25% and 40%, were also determined. These formulations showed a 1-hour delay, with the drug being substantially completely released within 9 hours.

[0096] The compositions of the present disclosure, which contain a single group of beads or minitablets having a sustained-release layer and an outer delayed-release layer, are shown herein to be an effective delivery system with novel release properties and remarkably low variability in absorption when administered to humans; however, it should be understood that alternative compositions may also be used in view of the present disclosure.

[0097] In some specific embodiments, the drug-containing core beads or mini-tablets are coated with a delayed-release layer comprising one or more water-insoluble polymers, one or more water-soluble polymers, and a silicone oil to obtain a desired delay or lag time before release, as in the present disclosure. The lag time and release are controlled by the ratio of the two types of polymers and the thickness of the layer. In such embodiments, the delayed-release layer may include, but is not limited to, cellulose phthalate acetate, cellulose acetate trimalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic polymer, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose succinate acetate, cellulose trimellitate acetate, shellac, methacrylic acid copolymer, Eudragit L30D, Eudragit L100, Eudragit FS30D, Eudragit S100, or any combination thereof. The delayed-release layer may also include a plasticizer, or in some specific embodiments, the delayed-release layer may include methacrylic acid copolymer type B, mono- and diglycerides, dibutyl sebacate, and polysorbate 80. Furthermore, the delayed-release layer may contain a cellulose ether derivative, an acrylic resin, a copolymer of esters of acrylic acid and methacrylic acid having a quaternary ammonium group, a copolymer of esters of acrylic acid and methacrylic acid, or any combination thereof. The layer may also further contain powder components such as talc as a carrier for the silicone oil.

[0098] In some specific embodiments of the present invention, a central nervous system stimulant may be included in a delayed-release and / or controlled-release capsule. In such embodiments, the water-insoluble capsule comprises one or more compartments in which the drug or active agent is held. Furthermore, one or more absorbents, superabsorbents, or osmagents are included in the drug-containing compartments. The capsule also comprises one or more pores sealed with a water-soluble polymer, at least one of which is fluidly in communication with a delayed-release layer enclosing each compartment and the entire capsule.

[0099] In such embodiments, the length of the initial delay can be controlled by the composition and thickness of the outer delayed-release layer. This layer may be pH-dependent or pH-independent, as disclosed herein. When the capsule is administered to a human, the delayed-release layer begins to lose integrity as the capsule passes through the gastrointestinal tract. As the water-soluble plug is exposed and dissolves, the aqueous fluid enters the drug-containing compartment(s) and is absorbed by the absorbent or osmagent, thus pushing the active drug out of the capsule through the pore. This release profile can be controlled by the concentration and absorption characteristics of the absorbent or osmagent such that a desired profile is obtained.

[0100] Sustained-release coating for dextroamphetamine sulfate pellets A formulation of the present disclosure is prepared in which a hydrophobic excipient is introduced to obtain further delay in drug release. The plasticizer level is Ethocel TM Maintain the level at 7.26%. The formulation is shown in Table 3.

[0101] [Table 3] These formulations were coated to a 30% weight increase level, and the samples were tested at a free base capsule dose of 10 mg of the free base. Dissolution tests were performed in a pH 7.0 buffer at a paddle speed of 75 rpm.

[0102] Lot 2009-066-51 has a water-insoluble component ratio of 80:20. This results in a significantly faster release profile. API release is 25% in the first hour. In subsequent formulations, talc was omitted and replaced with magnesium stearate.

[0103] In lot 2009-066-53, which contained magnesium stearate, initial release was significantly delayed. In lots -59 and -64, Ethocel TM Further changes include raising the level and lowering the Klucel® level. Ethocel vs. Klucel® in lots -59 and -64. TM The ratios are 86:14 and 97:3, respectively. This change was predicted to slow the release from lot 53, but in reality, its dissolution release time increased. Lot 67 contains a reduction in magnesium stearate and Ethocel compared to Klucel®. TM This included reducing the ratio (returning it to 80:20). This resulted in faster emission than the model profile suggested.

[0104] Replacing the hydrophilic plasticizer TEC with the hydrophobic plasticizer dibutyl sebacate (DBS) resulted in a significantly longer delay before initial release. Lot 2009-066-69 was the first lot to use DBS as a plasticizer. With the addition of DBS and the removal of Klucel®, initial drug release was less than 2% over 8 hours.

[0105] In lot 2009-066-72, Klucel® was added to the formulation as before. Ethocel in relation to Klucel® TMThe ratio was 95:5. The elution profile was similar to that of lot 2009-066-69. In lot 2009-066-75, Ethocel was used in relation to Klucel®. TM The ratio was reduced from 95:5 to 90:10. This change did not result in a different release profile compared to the previous two formulations.

[0106] Lot 2009-066-78 is for Ethocel (registered trademark) against Klucel (registered trademark). TM The ratio was reduced to 80:20, and the level of water-soluble polymer was increased. Formulation 2009-066-78 showed increasing release, with 20% drug release in 4 hours, followed by release exceeding 80%.

[0107] DOE Sustainable Emission Coatings The Design of Experiment (DOE) is based on Ethocel®, a registered trademark of Klucel. TM The ratios were set up in three ratios: 70:30, 75:25, and 80:20. The coating was applied using a GPCG2 with a 1.0 mm spray nozzle. 650.0 g of pellets were used for the DOE coating run. The pellets consisted of an 80% w / w placebo pellet and a 20% dextroamphetamine sulfate pellet. The pellets were diluted to retain the D-amphetamine sulfate pellet. The DOE formulations are shown in Table 4. Each coating formulation contained 12% w / w solids. The solvent consisted of ethanol to deionized water in a 95:5 ratio.

[0108] [Table 4] Each DOE formulation was coated until it increased in weight by 30%, and then the sample was placed in a capsule containing a 13.6 mg dose (equivalent to a 10.0 mg dose of free base) and subjected to dissolution testing in pH 7.2 phosphate buffer at a paddle speed of 75 rpm (this was the paddle speed used in all dissolution tests).

[0109] We have developed the following standard mixing procedure for sustained-release coating preparations: Pour ethanol into a beaker of appropriate size. Place this beaker under a laboratory mixer fitted with a Cowles blade. Increase the mixing rate to create a vortex, and then Ethocel TM Add Klucel® and DBS to this ethanol. Reduce the mixer speed until the vortex disappears and dissolve the excipients. Mix until the excipient is dissolved. Once the excipient is dissolved, vortexing may be performed for the addition of magnesium stearate. Mix the magnesium stearate for at least 30 minutes or until no agglutinations remain. Adding deionized water to this mixed dispersion is the final step of this process. The first eight DOE elution profiles are shown in Figure 4.

[0110] As shown in Figure 5, DOE9 is Ethocel for Klucel®. TM The ratio of 75:25 resulted in faster dissolution and release. In DOE10, Ethocel was used in relation to Klucel®. TM The ratio was 80:20, and the magnesium stearate level was reduced from 40% w / w / to 25% w / w. Making these changes shifts the dissolution profile much further to the right than the model profile. The DOE11 formulation is similar to lot 2009-066-78 (see Tables 3 and 4 for formulations). DOE11, 3, and 4 have release profiles close to the model profile. All three are Ethocel compared to Klucel®. TM The ratio is 80:20, but the percentage w / w of the hydrophobic excipient differs. The DOE3 coating had the profile closest to the model.

[0111] DOE3 and DOE4 Stability For stability testing, capsules containing 13.6 mg (equivalent to 10.0 mg of free base) were placed in HDPE bottles and immersed in test stability chambers at 40°C / 75%RH, 25°C / 60%RH, and 30°C / 65%RH. Pellets without capsules were also placed in HDPE bottles at 40°C / 75%RH for open-container testing. After 2-4 weeks for the open-container testing at 40°C / 75%RH, the pellets were eluted in phosphate buffer at pH 7.2. The elution results are shown in Figures 6 and 7.

[0112] The elution profiles at various stable time points all exhibited similar drug release profiles, demonstrating the stability of the sustained-release coating. The next step in this development was to apply a pH-dependent coating to the surface of the sustained-release coating.

[0113] pH-dependent coating For the pH-dependent coating test, DOE3 pellets were used. A 13.6 mg dose (10.0 mg of free base) sample was placed inside a capsule. Dissolution tests were performed in 0.1N HCl for 2 hours (T=0-2 hours), then in pH 6.0 phosphate buffer for 4 hours (T=2-6 hours), and finally in pH 7.0 phosphate buffer for the remaining time. The formulations are shown in Table 5.

[0114] [Table 5] The S 100 coating was prepared using 94.4% w / w alcohol / 5.6% w / w deionized water as the solvent, while the FS 30 D coating was prepared using aqueous solution only. The elution profiles are shown in Figure 8.

[0115] Lot 2009-104-78 showed a rapid release following a 6-hour delay. Subsequently, the S 100 formulation with 10% w / w GMS (Imwitor 900 K) was coated onto DOE3 pellets. Lot 2009-138-25B showed a delay at the onset of drug release, followed by a release curve similar to the model profile.

[0116] pH-dependent / SR-coated DOE3 pellets Tests on pH-dependent coatings on DOE3 SR coatings were repeated with 100% active core pellet batches (without placebo pellets). The coating parameters are shown in Table 6.

[0117] [Table 6] Figure 9 shows the activity of the DOE3 coating and the elution profile of the placebo-diluted pellet.

[0118] Next, a pH-dependent coating containing GMS (lot 2009-138-45) was coated onto a sustained-release DOE3 coating. The pellets were coated until they reached a 30% weight increase, and the sample was obtained at a 25% weight increase. The pellets were divided into appropriate amounts into 13.6 mg capsules (10.0 mg of free agent) and tested in a three-stage dissolution test. The coating parameters are shown in Table 7, and the dissolution profile is shown in Figure 10.

[0119] [Table 7] At 10 hours, 20% of the drug had been released from DOE3, which closely matched the target profile. A portion of the DOE3 (lot 2009-138-45) pellet was encapsulated in gelatin capsules up to a dose of 13.6 mg (equivalent to a 10 mg free base dose) and stabilized. Sixteen capsules were filled into bottles and placed under the following conditions: four bottles at 40°C / 75% relative humidity, four bottles at 30°C / 65% relative humidity, and one bottle at 25°C / 60% relative humidity. Two bottles containing only pellets equivalent to the 16 capsules were placed at 40°C / 75% relative humidity for accelerated testing in open-dish containers. After stabilization for two weeks, the samples were withdrawn from open-dish containers, 30°C / 65% relative humidity, and 40°C / 75% relative humidity. The elution profiles for these samples are shown in Figure 11.

[0120] The open-container pellets, which had been in use for two weeks, began releasing the drug at the 4-hour mark. Drug release did not begin in the initial pellets and other sealed-container samples until the 6-hour mark. In the two sealed-container samples, drug release was slower than in the initial release. The pellets had absorbed moisture... It was suspected that this caused GMS (Imwitor®) to become unstable, resulting in faster drug release in the open container test. To attempt to stabilize GMS, a sample from lot 2009-138-45 was placed in a furnace and cured at 50°C for 12, 24, and 48 hours. The elution results are shown in Figure 12.

[0121] At 50°C, curing time did not affect drug release. Another curing test was set up in a furnace set to 55°C. Samples from lot 2009-138-45 (DOE3) were cured for 24, 48, and 108 hours (4.5 days). The elution profiles are shown in Figure 13.

[0122] Drug release after hardening of pellets at 55°C was not directly dependent on time. For samples hardened at 55°C, the pellets were divided into appropriate amounts into gelatin and HPMC capsules (free base doses of 13.6 mg / 10.0 mg). Each bottle of HPMC capsules contained 1 gram of desiccant to absorb any excess moisture. The samples were hardened at 50°C, divided into appropriate amounts into HPMC capsules only, and placed in each bottle with 1 gram of desiccant. Sixteen capsules were placed in each bottle. Stability conditions are shown in Table 8.

[0123] [Table 8] After 2 and 4 weeks, samples cured at 55°C were withdrawn and elution tests were performed on them. The elution results for the stable samples are shown in Figure 14.

[0124] In pellets cured at 55°C and encapsulated in HPMC capsules, similar dissolution profiles were obtained for initial, 2-week, and 4-week samples. This indicates the stability of the product under these conditions. In gelatin-loaded capsules, a slightly slower dissolution profile was obtained for the 2-week and 4-week samples compared to the initial release.

[0125] HPMC capsules containing lot 2009-138-45 (DOE3, SR, and pH coated) were left with a desiccant at 40°C / 75%RH (sealed container) for 8 months. Samples were withdrawn at 2, 3, and 8 months for dissolution testing. The dissolution profiles for HPMC capsules containing D-amphetamine sulfate pellets are shown in Figure 15.

[0126] After 8 months of accelerated stability, D-amphetamine sulfate exhibits a profile similar to its initial release profile (T=0). The only difference is a slower release over a period of 7-10 hours. [Examples]

[0127] Example 1 An example of a core pellet described herein includes the following components (when produced in a 5 kg batch):

[0128] Batch size: 5,000 grams Solid content of granulation medium: 6%

[0129] [Table 1e] During the processing stage, excess water is added to the granulation medium. The amount of water is 47.12% of the dry blend batch size. The granulation medium weighs 2506.0 grams, and the spraying rate is 418 ± 20 g / min.

[0130] Example 2 An example of a sustained-release coating to be applied to a core pellet is prepared using the following components.

[0131] Core batch size - 1100.0g Weight increase due to coating - 30% Solids content - 12.0%

[0132] [Table 2e] Example 3 The S100 pH-dependent coating, formulated with a 30% weight increase, is formulated using the following components.

[0133] Weight increase due to coating - 30% Solids content - 10.0% Batch size - 715g Core pellet quantity - 550g

[0134] [Table 3e] Example 4 The S100 pH-dependent coating, formulated with a 50% weight increase, contains the following components:

[0135] Weight increase due to coating - 50.0% Solids content - 10.0% Batch size - 715g Core pellet quantity - 550g

[0136] [Table 4e] Example 5 Formulations were prepared using a pellet core as in Example 1, a sustained-release coating as in Example 2, and a pH-dependent coating with a 30% weight increase as in Example 3.

[0137] [Table 5e] Example 6 Formulations were prepared using a pellet core as in Example 1, a sustained-release coating as in Example 2, and a pH-dependent coating with a 50% weight increase as in Example 3.

[0138] [Table 6e] Example 7 To obtain a faster release profile, an example of a sustained-release coating with a different ratio of water-soluble polymer (Klucel) to water-insoluble polymer (Ethocel) is prepared using the following components.

[0139] Core batch size - 1100.0g Weight increase due to coating - 30% Solids content - 12.0%

[0140] [Table 7e] Example 8 Formulations were prepared using a pellet core as in Example 1, a sustained-release coating as in Example 7, and a pH-dependent coating with a 30% weight increase as in Example 3.

[0141] [Table 8e-1]

[0142] [Table 8e-2] Example 9 Pellet core as in Example 1, sustained release coating as in Example 7 Formulations were also prepared using pH-dependent coatings having a 50% weight increase, as in Example 4.

[0143] [Table 9e] Example 10 Another example of a sustained-release coating according to this disclosure is prepared using the following components.

[0144] Core batch size - 1100.0g Weight increase due to coating - 30% Solids content - 12.0%

[0145] [Table 10e] Example 11 Pellet core as in Example 1, sustained release coating as in Example 10 Formulations were prepared using pH-dependent coatings having a 30% weight increase, as in Example 3.

[0146] [Table 11e] Example 12 An example of a core pellet described herein that does not contain starch or osmagenta includes the following components (when produced in a 2 kg batch). This core pellet is used in Examples 17-21.

[0147] [Table 12e] Example 13 Examples of slow-release coatings described herein for use in slow-release formulations (1 and 2) 25% SR + 20% or 30% pH coatings.

[0148] [Table 13e] Example 14 Examples of slow-release enteric coatings described herein for use in 25% SR + 20% or 30% pH coatings of slow-release formulations (1 and 2)

[0149] [Table 14e-1]

[0150] [Table 14e-2] Example 15 Examples of medium-release coatings described herein for use in medium-release formulations (1 and 2) with 20% SR + 20% or 30% pH coatings.

[0151] [Table 15e-1]

[0152] [Table 15e-2]

[0153] [Table 15e-3] Example 16 Example of a rapid-release coating for a 20% SR + 20% pH coating of a rapid-release formulation.

[0154] [Table 16e-1]

[0155] [Table 16e-2] Example 17 Example of a dextroamphetamine sulfate composition having the core described in Example 12, a 25% weight increase due to sustained-release coating, and a 20% weight increase due to delayed-release (enteric-coated) coating, 30 mg capsule (slow-release formulation 1)

[0156] [Table 17e-1]

[0157] [Table 17e-2] Example 18 An example of a dextroamphetamine sulfate composition having a core, a 25% weight increase due to sustained-release coating, and a 30% weight increase due to delayed-release (enteric-coated) coating, as in Example 12, 30 mg capsule (slow-release formulation 2)

[0158] [Table 18e-1]

[0159] [Table 18e-2] Example 19 An example of a dextroamphetamine sulfate composition having a core, a 20% weight increase due to sustained-release coating, and a 20% weight increase due to delayed-release (enteric-coated) coating, as in Example 12, 30 mg capsule (medium-rate release formulation 1)

[0160] [Table 19e-1]

[0161] [Table 19e-2] Example 20 An example of a dextroamphetamine sulfate composition having a core, a 20% weight increase due to sustained-release coating, and a 30% weight increase due to delayed-release (enteric-coated) coating, as in Example 12, 30 mg capsule (medium-rate release formulation 2)

[0162] [Table 20e-1]

[0163] [Table 20e-2] Example 21 An example of a dextroamphetamine sulfate composition having a core, a 20% weight increase due to sustained-release coating, and a 20% weight increase due to delayed-release (enteric-coated) coating, as in Example 12, 30 mg capsule (rapid-release formulation).

[0164] [Table 21e-1]

[0165] [Table 21e-2] Example 22 The five formulations described in Examples 17-21 were subjected to the dissolution tests described below. The dissolution data is shown in the table below.

[0166] [Table 22e] A graph of the dissolution data is shown in Figure 16. As can be seen from this graph, the formulation produced a delayed release of 6 to 10 hours, followed by a sustained increase in release over the next 10 hours.

[0167] Example 23 A parallel, five-arm, open-label, single-dose fasting study of 30 mg capsules of dextroamphetamine was conducted in healthy, non-smoking male subjects. Between each trial, 56 healthy male volunteers (aged 18-45 years) were administered the five formulations described in Examples 13-17.

[0168] During the clinical trial, five different formulations were administered orally: Treatment A: 1 capsule of dextroamphetamine sulfate, 30 mg, CII (20%) SR, 30% ER coating, medium velocity release; Treatment B: 1 capsule of dextroamphetamine sulfate, 30 mg, CII (25% SR, 20% ER coated, slow-release); Treatment C: 1 capsule of dextroamphetamine sulfate, 30 mg, CII (20% SR, 20% ER coated, rapid release) Treatment D: 1 capsule of dextroamphetamine sulfate, 30 mg, CII (25% SR, 30% ER coated, slow-release); Treatment E: One capsule of dextroamphetamine sulfate, 30 mg, CII (20% SR, 20% ER coated, medium-rate release).

[0169] The pharmaceutical was administered daily at 8:00 AM, and serum amphetamine concentrations were measured hourly for 20 hours. Using a validated method (D24 version 00), dextroamphetamine and its internal standard amphetamine-d5 were extracted from human plasma (200.0 μL) using potassium ethylenediaminetetraacetate (K2EDTA) as an anticoagulant by liquid-liquid extraction, evaporation under nitrogen, and reconstitution in 200.0 μL of mobile phase (0.05% trifluoroacetic acid:acetonitrile, 80:20, v / v). Aliquots of the extract were injected into a high-performance liquid chromatography (HPLC) system and detected using an API 3000 with an HSID tandem mass spectrometer, and quantified by the peak area ratio method.

[0170] The sensitivity and selectivity of the method were achieved by detecting the different ion mass transitions from precursor to product for dextroamphetamine (136.2 → 119.1) and its internal standard amphetamine-d5 (141.2 → 124.1) under reverse chromatography conditions at specified retention times.

[0171] The assay was evaluated (using predefined criteria) by creating an 8-point calibration curve (excluding zero concentration) encompassing the range of 0.200 ng / mL to 51.200 ng / mL for dextroamphetamine in human plasma. The slope and intercept of the calibration curve were analyzed using weighted linear regression (1 / concentration). 2The concentrations were determined by the following method. Two calibration curves and a double QC sample (at three concentration levels) were analyzed along with the test sample from each batch. The concentrations of the standard, quality control sample, and unknown test sample were determined from the calibration curve using the peak area ratio.

[0172] Serum concentrations are shown in Figure 17. In this figure, the start time of the day is set to 9:00 PM. In Figure 18, pharmacokinetic data for three commercially available formulations—dexedrine, Adderall XR, and Vyvanse—are overlaid on the data in Figure 17.

[0173] As shown in the table below, the highest levels were observed in Treatment A at 0-6 hours and 0-10 hours of initial exposure, which correlated with the early dissolution observed with this formulation. max In terms of exposure, treatment A was slightly higher than the other treatments, but more variable than treatments B and C. Treatment C was higher than B, but more variable. In treatment D, exposure ranged from 0 to T. max The overall AUC was relatively high. 0~無限大 (Considering this,) the T of treatment D max The values ​​appeared later than those from other treatments.

[0174] [Table 23e-1] The initial exposures (0-6 and 0-10) obtained with these formulations are AUC 0~無限大 It is significantly lower compared to the following table, and the AUC 0~Tmax Along with the AUC of each of the five treatments 0~無限大 These are shown as percentages of the average values ​​of these partial exposure metrics relative to the average value of the total value.

[0175] [Table 23e-2] Exposure was less than 2% for all treatments (0-6 hours), and AUC (0-10 hours) was less than 5% for all treatments except treatment A (6.4%).

[0176] During the trial, a total of 25 adverse events ("AEs") occurred in 17 subjects. The most frequently observed AE is shown as a fraction of the total number of AEs that occurred after each treatment.

[0177] No adverse events (AEs) were reported more than once after administration of Treatment A [Dextroamphetamine sulfate capsules, 30 mg, CII (20% SR, 30% pH coated, medium-rate release)], Treatment C [Dextroamphetamine sulfate capsules, 30 mg, CII (20% SR, 20% pH coated, rapid release)], and Treatment D [Dextroamphetamine sulfate capsules, 30 mg, CII (25% SR, 30% pH coated, slow-release)].

[0178] Following the administration of treatment B (dextroamphetamine sulfate capsules, 30 mg, CII (25% SR, 20% pH coated, slow-release)), the most common adverse events were headache (2 / 7) and somnolence (2 / 7).

[0179] Treatment E [(Dextroamphetamine sulfate capsules, 30 mg, CII (20% SR)] After administration of [20% pH coated, medium-rate release], the most common adverse event (AE) was dry mouth (2 / 8).

[0180] No adverse events (AEs) were reported after the test was completed.

[0181] Five cases of adverse events (AEs) were "probably" related to the test drug, and twelve cases of AEs were "not necessarily unrelated" to the test drug. All subjects who experienced AEs during this study made full recovery.

[0182] No serious adverse events (SAEs) were reported.

[0183] Example 24 Methylphenidate composition, 54 mg capsules (slow-release formulation, 25% weight increase due to SR + 30% pH-dependent weight increase)

[0184] [Table 24e-1]

[0185]

Table 24e-2

[0186]

Table 25e-1

[0187]

Table 25e-2

[0188] All of the compositions and methods disclosed herein and claimed are capable of being made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods and to the steps or sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that certain agents, which are chemically or physiologically related, may be substituted for the agents described herein, yet the same or similar results may be obtained. All such similar substitutes and modifications apparent to those skilled in the art are to be included within the spirit, scope, and concept of the invention as defined by the appended claims.

[0189] According to a preferred embodiment of the present invention, for example, the following are provided. (Item 1) A solid oral pharmaceutical composition comprising a plurality of particles, each of which: A core comprising a therapeutic amount of a central nervous system stimulant and at least one pharmaceutically acceptable excipient; A sustained emission layer enclosing the core; and Delayed emission layer enclosing the sustained emission layer Includes, Here, the composition, when placed in a simulated gastric environment, results in a period of 4 to 12 hours during which approximately 10% or less of the central nervous system stimulant is released. Solid oral pharmaceutical composition. (Section 2) The solid oral pharmaceutical composition according to item 1, wherein the core further comprises a disintegrant, osmagent, or pore-forming agent. (Section 3) The solid oral pharmaceutical composition described in item 1 above, wherein the in vitro dissolution rate of the dosage form is such that 0-10% of the drug is released after 8 hours, 2-30% after 10 hours, 15-60% after 12 hours, and 45-95% after 15 hours, where, The solid oral pharmaceutical composition according to item 1 above, wherein when measured in 75 ml of 0.1 N HCl aqueous solution at 75 rpm for 2 hours, followed by measurement in a pH 6.8 phosphate buffer solution and at 37°C ± 0.5°C using the USP Paddle Method, the amount of drug released at each time increases from a period between 20% and 65% release. (Section 4) A solid oral pharmaceutical composition as described in item 3 above, wherein the in vitro dissolution rate of the dosage form is such that 0-10% of the drug is released after 6 hours, 15-28% after 10 hours, 40-60% after 12 hours, and 80-95% after 15 hours, wherein the amount of active ingredient released per hour increases from between 20% and 65% release during the period measured by USP Apparatus I, which is placed in 700 ml of aqueous solution of 0.1N HCl, pH 1.1 for up to 2 hours, followed by 2-6 hours in sodium phosphate buffer at pH 6.0, and then 6-20 hours in sodium phosphate buffer at pH 7.2, at 37°C ± 0.5°C. (Section 5) A solid oral pharmaceutical composition as described in item 3 above, wherein 10% or less of the drug is released within 6 hours, 50% or less of the drug is released within 12 hours, and when placed in a 0.1N HCl aqueous solution for 2 hours, followed by a pH 6.8 phosphate buffer solution at 37°C ± 0.5°C, and when the composition is administered to a human, the plot of plasma concentration against time after administration shows a single maximum value between 12 and 20 hours after administration. (Section 6) The solid oral pharmaceutical composition according to item 1, wherein the core comprises substantially spherical beads. (Section 7) The solid oral pharmaceutical composition according to item 6, wherein the core comprises nonparel beads coated with a layer containing the central nervous system stimulant and at least one pharmaceutically acceptable excipient. (Section 8) The solid oral pharmaceutical composition according to item 1, wherein the core comprises amphetamine, dextroamphetamine, methylphenidate or any isomer thereof, a racemic mixture, a prodrug or a salt of a pharmaceutical product. (Section 9) The solid oral pharmaceutical composition according to item 8, wherein the core comprises a salt of amphetamine or a pharmaceutical product thereof. (Section 10) The solid oral pharmaceutical composition according to item 8, wherein the core comprises a salt of dextroamphetamine or a pharmaceutical product thereof. (Section 11) The solid oral pharmaceutical composition according to item 8, wherein the core comprises methylphenidate or a salt thereof. (Section 12) The solid oral pharmaceutical composition according to item 8, wherein the core comprises lisdexamfetamine dimesylate or a salt thereof. (Section 13) The solid oral pharmaceutical composition according to item 1, wherein the core comprises one or more excipients selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, lactose, sucrose, microcrystalline cellulose, and any combination thereof. (Section 14) The solid oral pharmaceutical composition according to item 1, wherein the pharmaceutically acceptable excipient is microcrystalline cellulose. (Section 15) The solid oral pharmaceutical composition according to item 1, wherein the delayed-release layer comprises a pH-dependent polymer or copolymer that is insoluble in an aqueous medium at a pH lower than 5.0. (Section 16) The solid oral pharmaceutical composition according to item 1, wherein the delayed-release layer comprises cellulose phthalate acetate, cellulose acetate trimalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic polymer, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose succinate acetate, cellulose trimellitate acetate, shellac, methacrylic acid copolymer, Eudragit L30D, Eudragit L100, Eudragit FS30D, Eudragit S100, or any combination thereof. (Section 17) The solid oral pharmaceutical composition according to item 1, wherein the delayed-release layer contains a plasticizer. (Section 18) The solid oral pharmaceutical composition according to item 17, wherein the plasticizer is dibutyl sebacate (DBS), tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, mineral oil, castor oil, or a fixing oil. (Section 19) The solid oral pharmaceutical composition according to item 10, wherein the delayed-release layer comprises methacrylic acid copolymer type B. (Section 20) The solid oral pharmaceutical composition according to item 10, wherein the delayed-release layer comprises methacrylate copolymer type B, mono- and diglycerides, dibutyl sebacate, and polysorbate 80. (Section 21) The solid oral pharmaceutical composition according to item 1, wherein the sustained release layer comprises a water-insoluble and water-permeable polymer. (Section 22) The pharmaceutical composition according to item 21, wherein the sustained-release layer further comprises a water-soluble polymer. (Section 23) The solid oral pharmaceutical composition according to item 1 above, wherein the sustained release layer contains a cellulose ether derivative, an acrylic resin, a copolymer of esters of acrylic acid and methacrylic acid having a quaternary ammonium group, a copolymer of esters of acrylic acid and methacrylic acid, or any combination thereof. (Item 24) The solid oral pharmaceutical composition according to item 1 above, wherein the sustained release layer contains ethyl cellulose, hydroxypropyl cellulose, and magnesium stearate. (Item 25) The solid oral pharmaceutical composition according to item 2 above, wherein the disintegrant, osmagen or pore-forming agent is corn starch, potato starch, pregelatinized starch, modified starch, sweetener, clay, bentonite, microcrystalline cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polyacrylic potassium, alginate, sodium starch glycolate, gum, agar, guar, lentil, karaya, pectin, tragacanth, crospovidone or low-substituted hydroxypropyl cellulose. (Item 26) The solid oral pharmaceutical composition according to item 2 above, wherein the disintegrant, osmagen or pore-forming agent is a salt, acid, base, chelating agent, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, lithium sulfate, polyol, mannitol, sulfitol, xylitol, carbohydrate, electrolyte, potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, α-d-lactose monohydrate, glucose, α-hydroxy acid, citric acid, ascorbic acid, or any combination thereof. (Item 27) The solid oral pharmaceutical composition according to item 1 above, further comprising an abuse deterrent. (Item 28) The solid oral pharmaceutical composition according to item 1 above, further comprising a nasal irritant. (Item 29) The solid oral pharmaceutical composition according to item 28, wherein the nasal irritant is a capsaicinoid or sodium lauryl sulfate. (Section 30) A water-soluble capsule containing the solid oral pharmaceutical composition described in item 1 above in a single dose. (Section 31) A water-soluble capsule preparation as described in item 30 above, wherein the single dose is 1 to 50 mg of a central nervous system stimulant. (Section 32) Furthermore, the solid oral pharmaceutical composition according to item 1, further comprising a sealing portion between the drug-containing core and the sustained-release layer. (Section 33) A method for treating a condition in a subject having a disorder or condition that is responsive to the administration of a central nervous system stimulant, comprising the step of orally administering an effective amount of the solid oral pharmaceutical composition described in item 1 above to the subject. (Section 34) The method according to item 33 above, wherein the effective dose is administered once a day. (Section 35) The method according to item 33, wherein administration of an effective dose on a once-daily basis results in a delayed release of the central nervous system stimulant over 4 to 12 hours, followed by an increase in plasma concentration, resulting in a single maximum serum concentration (Cmax) occurring within a 24-hour period following the initiation of the effective dose, which appears at least 12 hours after the administration. (Section 36) The method according to item 35, wherein Cmax appears at least 14 hours after the administration. (Section 37) The method according to item 35, wherein Cmax appears more than 15 hours after the administration. (Section 38) The method according to paragraph 33, wherein the disorder or condition is attention deficit disorder, attention deficit hyperactivity disorder, excessive daytime sleepiness, major depressive disorder, bipolar depression, negative symptoms of schizophrenia, chronic fatigue, chemotherapy-related fatigue, or binge eating disorder. (Section 39) A solid oral pharmaceutical composition comprising a therapeutic dose of a central nervous system stimulant, wherein, when administered orally to a human, the central nervous system stimulant is released with a delayed release of 4 to 12 hours and reaches a maximum serum concentration (Cmax) 10 to 16 hours after administration, and the plot of serum concentration against time after release shows a single maximum value. (Section 40) The solid oral pharmaceutical composition according to item 39 above, wherein when placed in a simulated gastric environment, approximately 10% or less of the central nervous system stimulant is released within 6 hours. (Section 41) The solid oral pharmaceutical composition according to item 39 above, wherein when placed in a simulated gastric environment, approximately 10% or less of the central nervous system stimulant is released within 8 hours. (Section 42) The solid oral pharmaceutical composition according to item 39 above, wherein when placed in a simulated gastric environment, approximately 10% or less of the central nervous system stimulant is released within 10 hours. (Section 43) The solid oral pharmaceutical composition according to item 39 above, wherein when placed in a simulated gastric environment, approximately 10% or less of the central nervous system stimulant is released within 12 hours. (Section 44) Area under the serum curve (AUC) 6 hours after administration 0~6 ) is the total AUC 0~∞ The solid oral pharmaceutical composition described in item 39 above, which is less than approximately 2% of the total. (Section 45) Area under the serum curve (AUC) 10 hours after administration 0~10 ) is the total AUC 0~∞ The solid oral pharmaceutical composition described in item 39 above, which is less than approximately 7% of the total. (Section 46) A solid oral pharmaceutical composition, A core comprising a therapeutic dose of a central nervous system stimulant and at least one pharmaceutically acceptable excipient; A sustained emission layer coating the core; and Delayed emission layer coating the sustained emission layer Includes, Here, the core is substantially free of disintegrants, osmagents, or pore-forming agents; Furthermore, the composition is a solid oral pharmaceutical composition in which, when administered to a human, approximately 10% or less of the central nervous system stimulant is detectable in the serum 3 to 12 hours after administration, and the serum concentration of the central nervous system drug increases from the start of absorption to 12 to 16 hours after administration. (Section 47) A solid oral pharmaceutical composition comprising a central nervous system stimulant, wherein the in vitro dissolution rate of the dosage form is 0-10% drug release after 8 hours, 2-30% release after 10 hours, 15-60% release after 12 hours, and 45-95% release after 15 hours, wherein the amount of active ingredient released at each time increases from between 20% and 65% release during the period measured by USP Apparatus I, which places the composition in 700 ml of 0.1N HCl, pH 1.1 aqueous solution for up to 2 hours, followed by 2-6 hours in sodium phosphate buffer at pH 6.0, and then 6-20 hours in sodium phosphate buffer at pH 7.2, at 37°C ± 0.5°C. (Section 48) A method for treating a condition in a subject having a disorder or condition that is responsive to the administration of a central nervous system stimulant, comprising the step of orally administering an effective amount of a solid oral pharmaceutical composition, The composition is A core comprising a therapeutic dose of a central nervous system stimulant and at least one pharmaceutically acceptable excipient; A sustained emission layer coating the core; and Delayed emission layer coating the sustained emission layer Includes, Furthermore, when the composition is administered to humans, approximately 10% or less of the central nervous system stimulant can be detected in the serum 4 to 12 hours after administration. method. (Section 49) The method according to paragraph 48, wherein the disorder or condition is attention deficit disorder, attention deficit hyperactivity disorder, excessive daytime sleepiness, major depressive disorder, bipolar depression, negative symptoms of schizophrenia, chronic fatigue, chemotherapy-related fatigue, or binge eating disorder.

Claims

[Claim 1] Preferred properties of a composition for treating a disorder.

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