CONTROLLED DOSE DRUG DELIVERY SYSTEM

Abstract

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising a pharmaceutically active amphetamine salt covered with an immediate-release coating and a pharmaceutically active amphetamine salt covered with an enteric coating wherein the immediate release coating and the enteric coating provide for multiple pulsed dose delivery of the pharmaceutically active amphetamine salt. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

Claims

1-32. (canceled)

33. A pharmaceutical composition comprising: at least one amphetamine salt and a pharmaceutically acceptable carrier; wherein the composition provides an about bioequivalent plasma level of amphetamine in a patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®.

34. The composition of claim 33, wherein the composition provides an about bioequivalent plasma level of d-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®.

35. The composition of claim 33, wherein the composition provides an about bioequivalent plasma level of l-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL® and an immediate; release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®.

36. (canceled)

37. A sustained release pharmaceutical composition comprising: (a) at least one amphetamine salt, (b) a sustained release coating, and (c) a delayed release coating, wherein the at least one amphetamine salt is released about 4 to about 6 hours after oral administration to a patient.

38. The pharmaceutical composition of claim 37, wherein the sustained release coating is external to the delayed release coating.

39. The pharmaceutical composition of claim 37, wherein about 50% of the at least one amphetamine salt is released at about six hours at a pH of about 7.5.

40. The pharmaceutical composition of claim 37, comprising: (a) at least one amphetamine salt layered onto a core, (b) a delayed release coating layered onto the at least one amphetamine salt; (c) a sustained release coating layered onto the delayed release coating, and (d) a protective coating layered onto the sustained release coating.

41. The pharmaceutical composition of claim 37, wherein the at least one amphetamine salt comprises dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate, and mixtures thereof.

42. The pharmaceutical composition of claim 37, wherein the delayed release coating is selected from the group consisting of: cellulose acetate phthalate; cellulose acetate trimellitate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; carboxymethylethylcellulose; co-polymerized methacrylic acid/methacrylic acid methyl esters, EUDRAGIT® L12.5, L100; EUDRAGIT® S12.5, S100; and EUDRAGIT® FS30 D.

43. The pharmaceutical composition of claim 37, wherein the sustained release coating is selected from the group consisting of: polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and esters thereof, alkyl alcohols, waxes, zein (prolamine from corn), EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLICOAT® SR30D, and cellulose acetate latex.

44. The pharmaceutical composition of claim 42, wherein the delayed release coating is EUDRAGIT® FS-30D.

45. The pharmaceutical composition of claim 43, wherein the sustained release coating is SURELEASE®.

46. The pharmaceutical composition of claim 37, comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine AUC (0-inf) of about 367 ng.Math.hr/mL.

47. The pharmaceutical composition of claim 37, comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an l-amphetamine AUC (0-inf) of about 125 ng.Math.hr/mL.

48. The pharmaceutical composition of claim 37, wherein the composition comprises 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of at least one amphetamine salt and has an AUC (0-inf) that is linearly proportional to the AUC (0-inf) for a 12.5 mg at least one amphetamine salt composition.

49. The pharmaceutical composition of claim 37, comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine Cmax of about 18.67 ng/mL.

50. The pharmaceutical composition of claim 37, comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an l-amphetamine Cmax of about 5.64 ng/mL.

51. The pharmaceutical composition of claim 37, wherein the composition comprises 18.75 mg, 25 mg, 37.5 mg, or 50 mg of at least one amphetamine salt and has a Cmax that is linearly proportional to the Cmax for a 12.5 mg at least one amphetamine salt composition.

52. The pharmaceutical composition of claim 37, comprising 12.5 mg of the at least one amphetamine salt; wherein the composition has an d-amphetamine Tmax of about 8.83 hours.

53-58. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIG. 1, is a graph showing the dissolution profiles for a typical sustained release formulation (PD0149-124) and a sustained release formulation of the present invention (PD0149-120). HFS is the formulation exemplified in Example 2, infra; HIR is the formulation exemplified in Example 1, infra; and FS is EUDRAGIT® FS30 D.

[0076] FIG. 2 illustrates the construction of the sustained release bead.

[0077] FIG. 3 illustrates a 3-bead controlled dose drug delivery system of the present invention, including an immediate release component (IR bead), a delayed pulsed release component (DR1 bead) and a sustained release component (DR2 bead).

[0078] FIG. 4 is a graph showing the dissolution profile of a 12.5 mg mixed amphetamine salt 3-bead composition according to the invention.

[0079] FIG. 5 is a graph showing the dissolution profile of a 25 mg mixed amphetamine salt 3-bead composition according to the invention. The following pH conditions were used: at 0-2 hours, pH 1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.

[0080] FIG. 6 is a graph showing the dissolution profile of a 37.5 mg mixed amphetamine salt 3-bead composition according to the invention. The following pH conditions were used: at 0-2 hours, pH 1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.

[0081] FIG. 7 is a graph showing the dissolution profile of a 50 mg mixed amphetamine salt 3-bead composition according to the invention. The following pH conditions were used: at 0-2 hours, pH 1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.

[0082] FIG. 8 is a graph showing the dissolution profile of a SPD465 sustained release bead (HDR2). The following pH conditions were used: at 0-2 hours, pH 1.1; at 2-3 hours, pH 6.0; at three hours and greater, pH 7.5.

[0083] FIG. 9 graphically illustrates the mean d-amphetamine plasma concentration of SPD465 37.5 mg compared to ADDERALL XR® 25 mg followed by immediate release mixed amphetamine salts 12.5 mg 8 hours later.

[0084] FIG. 10 graphically illustrates the mean l-amphetamine plasma concentration of SPD465 37.5 mg compared to ADDERALL XR® 25 mg followed by immediate release mixed amphetamine salts 12.5 mg 8 hours later.

[0085] FIG. 11 graphically illustrates mean d-amphetamine plasma concentrations over time following administration of a single dose and seven once-daily doses of 12.5 mg SPD465 to healthy subjects.

[0086] FIG. 12 graphically illustrates mean d-amphetamine plasma concentrations over time following administration of seven once-daily doses of SPD465 to healthy subjects.

[0087] FIG. 13 graphically illustrates the power model analysis of mean and individual Day 7 Cmax values for d-amphetamine by dose.

[0088] FIG. 14 graphically illustrates the power model analysis of mean and individual Day 7 AUC.sub.0-24 values for d-amphetamine by dose.

[0089] FIG. 15 graphically illustrates mean l-amphetamine plasma concentrations over time following administration of a single dose and seven once-daily doses of 12.5 mg SPD465 to healthy subjects.

[0090] FIG. 16 graphically illustrates mean d-amphetamine plasma concentrations over time following administration of seven once-daily doses of SPD465 to healthy subjects.

[0091] FIG. 17 graphically illustrates the power model analysis of mean and individual Day 7 Cmax values for l-amphetamine by dose.

[0092] FIG. 18 graphically illustrates the power model analysis of mean and individual Day 7 AUC.sub.0-24 values for l-amphetamine by dose.

DETAILED DESCRIPTION OF THE INVENTION

[0093] Various types of controlled drug release and release profiles are contemplated by the present invention.

[0094] The terms “bead” and “pellet” refer to a discrete component of a dosage form. For example, a capsule shell is filled with a plurality of beads or pellets. As used herein, bead and pellet encompass any discrete component of a dosage form.

[0095] “Immediate” and “delayed” release” refer to the onset of release in relationship to administration of the drug. “Immediate” means that the release of drug begins very soon, within a relatively short time after administration, e.g. a few minutes or less. “Delayed” means that the release of drug is postponed, and begins or is triggered some period of time after administration (e.g., the lag time), typically a relatively long period of time, e.g. more than one hour.

[0096] “Rapid” and “slow” release refer to the rate of release after onset. Once delivery of the drug begins, it may be released relatively quickly or relatively slowly. A rapid release indicates that, after onset, a maximum or peak dose is reached in a relatively short period of time. A slow release indicates that, after onset, a maximum or peak dose is reached in a relatively long period of time. Once reached, the maximum dose may fall off at any pace (e.g. fast, slow, or constant).

[0097] “Sustained” or “continuous” refers to the period of on-going release, and means that the delivery of drug goes on (it continues or is sustained) for an extended period of time after initial onset, typically more than one hour, whatever the shape of the dose release profile. For example, the drug release is sustained between a maximum and minimum value (more than zero) for some relatively long period of time. This release may be at a constant dose, or at a dose which diminishes over time.

[0098] “Constant” release refers to the dose that is being released, and means that a drug is delivered at a relatively constant dose over a moderate or extended period of time. This can be represented by a dose release profile that is relatively flat or only gently sloped after initial onset, i.e. without highly distinct peaks and valleys. Thus, a constant release will typically be sustained or continuous, but a sustained or continuous release may not be constant.

[0099] “Pulsed” release means that a drug is delivered in one or more doses that fluctuate between a maximum and minimum dose over a period of time. This can be represented by a dose release profile having one or more distinct peaks or valleys. However, two or more pulsed releases may produce an overlapping, overall, or composite release profile that appears or effectively is constant. When two or more pulsed releases occur, there may or may not be a period of no release between pulses. Typically, pulsed release results in release of essentially all of a drug within about 60 minutes or less.

[0100] “Extended” release refers to a formulation which provides either a release of drug within a targeted dose range for a relatively long period, or a plasma level of drug within a targeted dose range for a relatively long period, without regard for the particular mechanism or character of release, e.g. as sustained, pulsed, or constant.

[0101] “Effective therapy” or “effective treatment,” as used herein, means to prevent, alleviate, arrest, or inhibit at least one symptom or sign of ADHD. Symptoms and signs of ADHD include, for example, inattention, hyperactivity and impulsivity.

[0102] “Food effect,” as used herein, means a significant difference in the bioavailability of a drug in a patient when the drug is administered in a fasted state compared to a fed state. “No food effect” means that there is no significant difference in the bioavailability of a drug in a patient when the drug is administered in a fasted state compared to a fed state.

[0103] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system, i.e., the degree of precision required for a particular purpose, such as a pharmaceutical formulation. For example, “about” can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0104] Drug release and drug release profiles are measures or representations of the manner and timing by which a formulation releases or delivers active ingredients (drug) to a receiving environment (e.g. the stomach, intestines, etc.) upon administration. Various methods are known for evaluating drug release and producing release profiles, including in vitro tests which model the in vivo behavior of a formulation. These include USP dissolution testing for immediate release and controlled release solid dosage forms.

[0105] Drug release profiles are distinct from plasma profiles. A plasma profile is a measure or representation of the dose or level of active ingredient (drug) in the bloodstream of a mammal, e.g. a patient receiving a drug formulation. Upon release of a drug from a formulation, e.g. into the gut of a mammal, the amount of drug that is present in the bloodstream over time can be determined.

[0106] A drug release profile may be designed to produce a desired or targeted plasma profile. Often, but not necessarily, a plasma profile will mimic a release profile. For example, it might be expected that a sustained release of drug would more likely produce a sustained dose in the plasma, or that a pulsed release would produce a pulsed (peak and valley) plasma profile. This is not necessarily so, however. For example, the half-life of the drug in the blood stream (its rate of decay) may be such that a sustained or continuous plasma profile could result from a pulsed delivery profile. Other factors may also play a role, such as bio-absorption, bioavailability, and first pass effect. The plasma profile produced by a particular release profile may also vary from patient to patient.

[0107] Measures of bioavailability well known in the art include the area under the plasma concentration-time curve (AUC), the concentration maximum (C.sub.max), and the time to C.sub.max (T.sub.max).

[0108] AUC is a measurement of the area under the plasma concentration-time curve, and is representative of the amount of drug absorbed following administration of a single dose of a drug (Remington: The Science and Practice of Pharmacy, (Alfonso R. Gennaro ed. 2000), page 999).

[0109] C.sub.max is the maximum plasma concentration achieved after oral drug administration (Remington, page 999). An oral drug administration results in one C.sub.max, but may result in greater than one “peak plasma concentration” or “plasma concentration peak” (for example, following the administration of a pulsed dose formulation).

[0110] T.sub.max is the amount of time necessary to achieve the C.sub.max after oral drug administration, and is related to the rate of absorption of a drug (Remington, page 999).

[0111] Bioequivalence is the absence of a significantly different rate and extent of absorption in the availability of the active ingredient when administered at the same dose under similar conditions. Bioequivalence can be measured by pharmacokinetic parameters such as, for example, AUC and Cmax.

[0112] A drug delivery system of the invention typically may comprise a core seed or matrix, which may or may not be loaded with drug, and one or more coating layers comprising drug, and/or comprising a layer have release characteristics which control the onset and release characteristics of the drug. An exemplary core is a sugar core. Exemplary matrixes include hydrophilic matrixes. Polymers useful for forming a hydrophilic matrix include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), poly(ethylene oxide), poly(vinyl alcohol), xanthan gum, carbomer, carrageenan, and zooglan. Other similar hydrophilic polymers may also be employed.

[0113] Coating layers can provide immediate release, delayed pulsed release or sustained release. Immediate release of the drug from the immediate-release layer can be achieved by any of various methods known in the art. One example is the use of a very thin layer or coating which by virtue of its thinness is quickly penetrated by gastric fluid allowing rapid leaching of the drug. Another example is by incorporating the drug in a mixture that includes a supporting binder or other inert material that dissolves readily in gastric fluid, releasing the drug as the material dissolves. A third is the use of a supporting binder or other inert material that rapidly disintegrates upon contact with gastric fluid, with both the material and the drug quickly dispersing into the fluid as small particles. Examples of materials that rapidly disintegrate and disperse are lactose and microcrystalline cellulose. An example of a suspending agent and binder is hydroxypropyl methylcellulose.

[0114] Enteric coatings for the delayed pulsed release component can be pH-dependent or pH-independent. Enteric coatings for the sustained release component are pH dependent. A pH dependent coating is activated to release drug within a known pH range, which typically is matched to the local pH of the environment where delayed release is desired. Exemplary pH dependent coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and, 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

[0115] A pH independent coating includes materials susceptible to enzymatic activation by azo-reductases in intestinal bacteria (i.e., azo-polymers) or materials susceptible to degradation by polysaccaridases in the colon (natural polysaccarides). Non-limiting examples of azo-polymers include co-polymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Non-limiting examples of natural polysaccharides include amylose, chitosan, chrondoitin, dextran, and xylan.

[0116] The sustained release component can include sustained release coatings, sustained release matrices, and sustained release osmotic systems. Sustained release coatings can be prepared using a water-insoluble polymer, a combination of water-insoluble polymers, or a combination water-insoluble and water-soluble polymers. Conventional sustained release polymers well known to those of ordinary skill in the formulary arts can be used for the sustained release matrix.

[0117] Exemplary sustained release coatings can include polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and esters thereof, alkyl alcohols, waxes, zein (prolamine from corn), and aqueous polymeric dispersions such as EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLICOAT® SR30D, and cellulose acetate latex.

[0118] Principles of sustained release formulation technology applicable to this invention, include those disclosed in R. K. Chang and J. R. Robinson, chapter 4: “Sustained Drug Release from Tablets and Particles Through Coating,” in Pharmaceutical Dosage Forms: Tablets, volume 3, edited by H. A. Lieberman, L. Lachman, and J. B. Schwartz, Marcel Dekker, Inc., 1991; R. J. Campbell and G. L. Sackett, chapter 3: “Film coating,” in Pharmaceutical Unit Operations: Coating, edited by K. E. Avis, A. J. Shukla, and R. K. Chang, Interpharm Press, Inc., 1999.

[0119] The present invention comprises a core or starting seed, either a prepared or commercially available product. The cores or starting seeds can be sugar spheres, spheres made from microcrystalline cellulose and any suitable drug crystals.

[0120] The materials that can be employed in making drug-containing pellets are any of those commonly used in pharmaceutics and should be selected on the basis of compatibility with the active drug and the physicochemical properties of the pellets. The additives except active drugs are chosen below as examples:

[0121] Binders such as cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer and the like.

[0122] Disintegration agents such as corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®), and any disintegration agents used in tablet preparations.

[0123] Filling agents such as lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0124] Surfactants such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, PLURONIC® line (BASF), and the like.

[0125] Solubilizers such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate and sodium carbonate and the like.

[0126] Stabilizers such as any antioxidation agents, buffers, acids, and the like, can also be utilized.

[0127] Methods of Manufacturing the Core Include

[0128] a. Extrusion-Spheronization—Drug(s) and other additives are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size screen. The extrudates are spheronized in a marumerizer. The resulting pellets are dried and sieved for further applications.

[0129] b. High-Shear Granulation—Drug(s) and other additives are dry-mixed and then the mixture is wetted by addition of a binder solution in a high shear-granulator/mixer. The granules are kneaded after wetting by the combined actions of mixing and milling. The resulting granules or pellets are dried and sieved for further applications.

[0130] c. Solution or Suspension Layering—A drug solution or dispersion with or without a binder is sprayed onto starting seeds with a certain particle size in a fluid bed processor or other suitable equipment. The drug thus is coated on the surface of the starting seeds. The drug-loaded pellets are dried for further applications.

[0131] For purposes of the present invention, the core particles have a diameter in the range of about 50-1500 microns; preferably 100-800 microns.

[0132] These particles can then be coated in a fluidized bed apparatus with an alternating sequence of coating layers.

[0133] The core may be coated directly with a layer or layers of at least one pharmaceutically active amphetamine salts and/or the pharmaceutically active amphetamine salt may be incorporated into the core material. Pharmaceutically active amphetamine salts contemplated to be within the scope of the present invention include amphetamine base and salts thereof. Preferred pharmaceutically active amphetamine salts include dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate.

[0134] A protective layer may be added on top of the pharmaceutical active containing layer and also may be provided between active layers. A separation or protective layer may be added onto the surface of the active-loaded core, and then the enteric delayed pulsed or sustained release layer is coated thereupon. Another active layer may also be added to the enteric delayed pulsed or sustained layer to deliver an initial dose.

[0135] A protective coating layer may be applied immediately outside the core, either a drug-containing core or a drug-layered core, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30D, OPADRY® and the like. The suggested coating levels are from 1 to 6%, preferably 2-4% (w/w).

[0136] The enteric delayed pulsed release or sustained release coating layer is applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. Suitable coaters are well known in the art. For example, any commercially available pH-sensitive polymer can be used. With such a polymer, the pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but is not limited to this value. The pharmaceutical active should become available when the pH-sensitive layer dissolves at the greater pH; after a certain delayed time; or after the unit passes through the stomach.

[0137] Suitable enteric polymers for the delayed pulsed release component and sustained release component include, for example, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and, 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

[0138] The enteric delayed pulsed release and sustained release polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive. Examples of such coating products include the neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names EUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without any functional groups, sold under the trade names EUDRAGIT® NE30D; and other pH independent coating products.

[0139] The modifying component of the protective layer used over the enteric delayed pulsed release or sustained release coating can include a water penetration barrier layer (semipermeable polymer) which can be successively coated after the enteric coating to reduce the water penetration rate through the enteric coating layer and thus increase the lag time of the drug release. Coatings commonly known to one skilled in the art can be used for this purpose and applied by conventional techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. For example, the following materials can be used, but not limited to: cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, waxes, zein, and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, cellulose acetate latex. The combination of above polymers and hydrophilic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose (KLUCEL®, Hercules Corp.), Hydroxypropyl methylcellulose (METHOCEL®, Dow Chemical Corp.). Polyvinylpyrrolidone can also be used.

[0140] An overcoating layer can further optionally be applied to the composition of the present invention: OPADRY®, OPADRY II® (Colorcon) and corresponding color and colorless grades from Colorcon can be used to protect the pellets from being tacky and provide colors to the product. The suggested levels of protective or color coating are from 1 to 6%, preferably 2-3% (w/w). Talc can also be used for this purpose, e.g., a 2% w/w talc treatment can be applied.

[0141] Many ingredients can be incorporated into the overcoating formula, for example to provide a quicker immediate release, such as plasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutylsebacate, triacetin, polyethylene glycols, propylene glycol and the others; lubricants: talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, and the like.

[0142] The composition, preferably in beadlet form, can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. A lubricant can further be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.

[0143] The composition can be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a table that can accept the particles but will not allow their destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®), pre-gelatinized starches (STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).

[0144] In addition, disintegrants are added in order to disperse the beads once the tablet is ingested. Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), and cross-linked polyvinylpolypyrrolidone (Plasone-XL). These materials should be present in the rate of 3-15% (w/w), with a preferred range of 5-10% (w/w).

[0145] Lubricants can be added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).

[0146] Tablets are formed, for example, as follows. The particles are introduced into a blender along with AVICEL®, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.

[0147] A tablet according to the present invention can be constructed in three layers, wherein the immediate release component is dry blended, and the delayed pulsed release and the sustained release components are wet granulated. The tablet is then formed in a one layer or a three layer compression. Upon dissolution of the layers in the one layer or three layer tablet, each component is released and acts in its own way (i.e., the immediate release particles provide immediate release, the delayed pulsed release particles provide delayed pulsed release, and the sustained release particles provide sustained release after a lag time).

[0148] It will be appreciated that the multiple dosage form of the present invention can deliver rapid and complete dosages of pharmaceutically active amphetamine salts to achieve the desired levels of the drug in a recipient over the course of about 14 hours to about 16 hours with a single oral administration.

[0149] This invention also encompasses the use of a longer-day amphetamine composition to treat conditions other than ADHD. These conditions include, but are not limited to, Alzheimer's disease and other memory disorders, fibromyalgia, chronic fatigue, depression, obsessive compulsive disorder, alone or in combination with a SSRI; oppositional defiant disorder (ODD), with or without ADHD and with or without any compositions or formulations of guanfacine or buproprion; anxiety, with or without ADHD and alone or in combination with an anxiolytic or SSRI; resistant depression; stroke rehabilitation; Parkinson's disease; mood disorder; schizophrenia; Huntington's disorder; dementia, e.g. AIDS dementia and frontal lobe dementia; movement dysfunction; apathy; fatigue; Pick's disease; sleep disorders, e.g., narcolepsy, cataplexy, sleep paralysis and hypnagogic hallucinations; etc.

[0150] The invention also contemplates combinations of the longer-day amphetamine compositions of this invention with other therapeutic agents. The drugs can be formulated in the same dosage form as the longer-day amphetamine composition dose of the invention or can be formulated separately, in which case, the drugs can be administered sequentially in any order or simultaneously. Typically, dosages can be in the same ranges as for each drug used separately or, where synergistic effects occur, one or more of the combined drugs can be used in lower dosages.

[0151] The other therapeutic agents can include e.g., for Alzheimer's: galanthamine, tacrine, donepezil, rivastigmine, memantine, human growth hormone, selegiline hydrochoride, estrogen, clioquinol, ibuprofen, and Gingko bilboa; for ADHD: methylphenidate (e.g., RITALIN®, CONCERTA®), amphetamine, pemoline, clonidine, guanfacine, etc; for depression: fluoxetine hydrochloride, sertraline HCL, paroxetine HCL, reboxetine, bupropion HCL, olanzapine, fluoxetine hydrochloride, amitriptyline, imipramine, nortriptyline, phenelzine, tranylcypromine sulfate, trazodone, and venlafaxine; for mood disorder: thorazine, haloperidol, thiothixene, thioridazine, risperadone, clozapine, risperidone, and olanzapine; for fatigue: benzodiazepines, naproxen, fluoxetine hydrochloride, sertraline HCL, paroxetine HCL, venlafaxine, and trazodone; for fibromyalgia: phenytoin, carbamazepine, valproate, divalproex, desipramine, nortriptyline, amitryptiline, doxepin, and non-steroidal inflammatory drugs; for oppositional defiant disorder (ODD): clonidine, risperidone, and olanzepine; for apathy: amisulpride, olanzapine, visperidone, quetiapine, clozapine, and zotepine; for Parkinson's disease: levodopa, bromocriptine, pergolide, and pramipexole; for schizophrenia: clozapine, olanzepine, quetiapine fumarate, and risperidone; for Huntington's disorder: haloperidol and clonzepam; for dementia: thioridazine, haloperidol, risperidone, tacrine, donepezil, and rivastigmine; for narcolepsy: modafinil, amphetamine, modafinil and RITALIN®; for cataplexy: sodium oxybate; for hallucinations: clozapine, risperidone, olanzepine, and quetiapine fumarate; for sleep paralysis: PEROCET®, VICODIN®, and LORCET®; for obsessive compulsive disorder: clomipramine, fluoxetine hydrochloride, sertraline HCL, paroxetine HCL, fluvoxamine; and for anxiety: amitryptiline, amoxepine, bupropion HCL, carbamazepine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, VENTYL®, trimipramine etc; selective serotonin reuptake inhibitors (SSRIs) including fluoxetine hydrochloride, fluvoxamine, nefazodone, paroxetine HCL, sertraline HCL venlafaxine, etc., benzodiazepines, including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, oxazepam, triazolam, etc., monamine oxidase inhibitors including moclobemide, phenelzine, tranylcypromine sulfate, etc.

[0152] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0153] The following examples are presented for illustration and do not limit the invention.

EXAMPLES

Example 1

Immediate Release Formulation (HIR)

[0154] Sugar sphere seeds (30/35 Mesh, NF) were put into a FLM-15 fluid bed processor with a 9-Wurster column and fluidized at 60° C. A suspension of a mixture containing amphetamine aspartate; amphetamine sulfate, USP; dextroamphetamine saccharate; and dextroamphetamine sulfate, USP with Hypromellose 2910, USP/NF as a binder was sprayed onto the seeds under suitable conditions. After drying, an OPADRY® Beige, YS-1-17274-A seal coating was applied. The ingredients are listed by weight percent in Table 1.

TABLE-US-00001 TABLE 1 Ingredient Weight % Amphetamine aspartate 4.75 Amphetamine sulfate, USP 4.75 Dextroamphetamine saccharate 4.75 Dextroamphetamine sulfate, USP/NF 4.75 Sugar sphere 30/35 mesh, USP/NF 78.00 OPADRY ® Beige, YS-1-17274-A 2.00 Hypromellose 2910, USP/NF 1.00 Purified water, USP * Total 100.00 * removed during processing

Example 2

Intermediate Formulation (HFS)

[0155] The following formulation was used to coat the immediate release mixed amphetamine salt pellets from Example 1 with EUDRAGIT® FS30D (also referred to herein as EUDRAGIT® 4110D) (Rohm Pharma, Germany) coating dispersion. The immediate release pellets of Example 1 were loaded in a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt). The coating dispersion was prepared by dispersing triethyl citrate, USP/NF; talc, USP/NF and EUDRAGIT® FS30D into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized mixed amphetamine salt pellets. The spraying was continued until the targeted coating level of 25-30 weight percent (wt %) was achieved. The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. After drying, the pellets were coated with OPADRY® Beige, YS-1-17274-A. The ingredients are listed by weight percent in Table 2.

TABLE-US-00002 TABLE 2 Ingredients Weight (%) Immediate release pellets (Example 1) 65.50 MAA/MA/MMA Copolymer Suspension 27.77 (EUDRAGIT ® FS30 D)* Triethyl citrate, USP/NF 1.35 Talc, USP/NF 3.38 OPADRY ® Beige, YS-1-17274-A 2.00 Water ** Total 100.00 *MAA/MA/MMA Copolymer Suspension is Methyl Acrylate, MethylMethacrylate, and Methacrylic Acid Copolymer (EUDRAGIT ® FS30D) ** removed during processing

Example 3

Delayed Release Formulation (HDR)

[0156] The following formulation was used to coat the immediate release mixed amphetamine salt pellets from Example 1 with EUDRAGIT® L30 D-55 coating dispersion. The immediate release pellets of Example 1 were loaded in a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt). The coating dispersion was prepared by dispersing Triethyl citrate, USP/NF; Talc, USP/NF and EUDRAGIT® L30D-55 into water and mixing for at least 30 minutes. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized mixed amphetamine salt pellets. The spraying was continued until the targeted coating level of 27-32 weight percent was achieved. The coated pellets were dried at 30-35° C. for 5 minutes before stopping the process. After drying, the pellets were coated with OPADRY® Beige, YS-1-17274-A. The ingredients are listed by weight percent in Table 3.

TABLE-US-00003 TABLE 3 Ingredients Weight (%) Immediate release pellets (Example 1) 63.00 Methacrylic Acid Copolymer Dispersion, 29.03 USP/NF (EUDRAGIT ® L30 D-55)* Triethyl citrate, USP/NF 2.94 Talc, USP/NF 3.04 OPADRY ® Beige, YS-1-17274-A 2.00 Water ** Total 100.01 *Methacrylic Acid Copolymer Dispersion, USP/NF (EUDRAGIT ® L30 D-55) is supplied as a 30% aqueous dispersion. ** removed during processing

Example 4

Sustained Release Formulation (HDR2)

[0157] Intermediate formulation pellets from Example 2 were loaded into a fluid bed processor with a reduced Wurster column (GPGC-15, Glatt). The coating dispersion was prepared by mixing SURELEASE®, talc, USP/NF and water for at least 15 minutes prior to spraying. Under suitable fluidization conditions, the coating dispersion was sprayed onto the fluidized pellets. The spraying was continued until the targeted coating level of 7-9 weight percent of SURELEASE® solids was achieved. The coated pellets were then dried at 35-40° C. for 10 minutes before discharging from the bed. The ingredients are listed by weight percent in Table 4. The dissolution profile for the HDR2 sustained release bead is shown in FIG. 8.

TABLE-US-00004 TABLE 4 Ingredients Weight (%) Intermediate formulation (Example 2) 90.00 Talc, USP/NF 2.00 SURELEASE ® Clear E-7-19010* 8.00 Water ** Total 100.00 *SURELEASE ® Clear E-7-19010 is supplied as a 24.5% solids aqueous dispersion ** removed during processing

[0158] A 12.5 mg mixed amphetamine salt sustained release bead (lot no. B02013) produced according to this Example was administered to 12 subjects aged 18-55 years old and compared to ADDERALL® 10 mg in a crossover study (Clinical Study 101). Two other prototype beads were also tested. A parametric (normal theory) general linear model was applied to the calculation of AUC, Cmax, Tmax and t.sub.1/2 for each of the formulations. AUC and Cmax were also analyzed on a log scale to assess bioequivalence between test treatments. The results for the sustained release bead and the reference ADDERALL® are shown in Table 5.

TABLE-US-00005 TABLE 5 AUC (0-inf) AUC (0-t) Cmax Tmax (ng.hr/mL) (ng.hr/mL) (ng/mL) (hr) d-amphetamine 12.5 mg mixed 367.19* 353.64* 18.67 8.83* amphetamine salt sustained release bead 10 mg 280.59  266.70  18.62 2.17  ADDERALL ® (reference) ratio of test to  1.03   1.05  0.80 reference (90% CI) (0.97-1.11)** (0.98-1.12)** (0.76-0.84) l-amphetamine 12.5 mg mixed 125.23* 112.44* 5.64 9.33* amphetamine salt sustained release bead 10 mg 100.64   87.93  5.53 2.50  ADDERALL ® (reference) ratio of test to  0.99   1.02  0.81 reference (90% (0.91-1.08)** (0.93-1.11)** (0.76-0.87) CI) *p < 0.05 compared to 10 mg ADDERALL ® **90% confidence interval fell within recommended 0.80-1.25 limits of bioequivalence when analyzed on logarithmic scale.

[0159] The results of this pharmacokinetic study showed that a single dose of the sustained release formulation had a Tmax significantly longer than a single dose of ADDERALL®. Additionally, the AUCs of the sustained release formulation were equivalent to that of dose-adjusted ADDERALL® for both d- and l-amphetamine.

Example 5

Controlled Release Capsules (SPD465 25 mg/Capsule)

[0160] A controlled release capsule was produced by combining the immediate release pellets of Example 1, and delayed release pellets of Example 3 and Example 4. The theoretical milligram/capsule of components for controlled release capsules, 25 mg/capsule are listed in Table 5. The theoretical potency of each pellet type was derived based on the starting ingredients for manufacture. Based on the actual manufacturing process, along with observation of process losses, the target potency value was: 170 mg/gram for Example 1 immediate release pellets, 107.1 mg/gram for Example 3 delayed release pellets, and 100.2 mg/gram for Example 4 delayed release pellets. The components are listed by theoretical milligrams/capsule in Table 6.

TABLE-US-00006 TABLE 6 Theoretical Components milligram/capsule Immediate release pellets of Example 1* 43.86 Delayed release pellets of Example 3** 69.62 Delayed release pellets of Example 4*** 74.40 Capsule shell 61.00 Total 248.88 *The theoretical fill weight was calculated based on the theoretical potency of Example 1 immediate release pellets, 190 mg/gram. **The theoretical fill weight was calculated based on the theoretical potency of Example 3 delayed release pellets, 119.7 mg/gram. ***The theoretical fill weight was calculated based on the theoretical potency of Example 4 delayed release pellets, 112.0 mg/gram.

[0161] The dissolution profile for SPD465 25 mg (lot no. A03547A) is shown in FIG. 5.

Example 6

Controlled Release Capsules (SPD465 37.5 mg/Capsule)

[0162] A controlled release capsule was produced by combining the immediate release pellets of Example 1, and the delayed release pellets of Example 3 and Example 4. The theoretical milligram/capsule of components for controlled release capsules, 37.5 mg/capsule are listed in Table 7. The theoretical potency of each pellet type was derived based on the starting ingredients for manufacture. Based on the actual manufacturing process, along with observation of process losses, the target potency value was: 170 mg/gram for Example 1 immediate release pellets, 107.1 mg/gram for Example 3 delayed release pellets, and 100.2 mg/gram for Example 4 delayed release pellets. The components are listed by theoretical milligrams/capsule in Table 7.

TABLE-US-00007 TABLE 7 Theoretical Components milligram/capsule Immediate release pellets of Example 1* 65.79 Delayed release pellets of Example 3** 104.43 Delayed release pellets of Example 4*** 111.6 Capsule shell 81.00 Total 362.82 *The theoretical fill weight was calculated based on the theoretical potency of Example 1 immediate release pellets, 190 mg/gram. **The theoretical fill weight was calculated based on the theoretical potency of Example 3 delayed release pellets, 119.7 mg/gram. ***The theoretical fill weight was calculated based on the theoretical potency of Example 4 delayed release pellets, 112.0 mg/gram.

Example 7

Controlled Release Capsules (SPD465 50 mg/Capsule)

[0163] A controlled release capsule was produced by combining the immediate release pellets of Example 1, and delayed release pellets of Example 3 and Example 4. The theoretical milligram/capsule of components for controlled release capsules, 50 mg/capsule are listed in Table 8. The theoretical potency of each pellet type was derived based on the starting ingredients for manufacture. Based on the actual manufacturing process, along with observation of process losses, the target potency value was: 170 mg/gram for Example 1 immediate release pellets, 107.1 mg/gram for Example 3 delayed release pellets, and 100.2 mg/gram for Example 4 delayed release pellets. The components are listed by theoretical milligrams/capsule in Table 8.

TABLE-US-00008 TABLE 8 Theoretical Components milligram/capsule Immediate release pellets of Example 1* 87.72 Delayed release pellets of Example 3** 139.24 Delayed release pellets of Example 4*** 148.80 Capsule shell 96.00 Total 471.76 *The theoretical fill weight was calculated based on the theoretical potency of Example 1 immediate release pellets, 190 mg/gram. **The theoretical fill weight was calculated based on the theoretical potency of Example 3 delayed release pellets, 119.7 mg/gram. ***The theoretical fill weight was calculated based on the theoretical potency of Example 4 delayed release pellets, 112.0 mg/gram.

[0164] The dissolution profile for SPD465 50 mg (lot no. A03536B) is shown in FIG. 7.

Example 8

A Phase I Pharmacokinetic Study in Healthy Adult Volunteers to Evaluate the Pharmacokinetic Profile of the 37.5 mg Controlled Release Composition of Example 6 Relative to 25 mg ADDERALL XR®+12.5 mg Mixed Amphetamine Salts IR (-Clinical Study 103)

[0165] The objective of this study was to assess the pharmacokinetics (PK) of the 37.5 mg controlled release composition of Example 6 compared to a reference treatment of ADDERALL XR® 25 mg followed by a 12.5 mg dose of the mixed amphetamine salts immediate-release (IR) formulation disclosed in Example 1 administered 8 hours later.

[0166] This was an open-label, randomized, single-dose, 2-way crossover, 2-period, phase I study with at least a 7-day washout between each period. In period 1, subjects were randomized to receive a single morning dose of one of the two study formulations. Each subject was crossed over to receive the alternate treatment in the subsequent period. In Treatment A, subjects received a single 37.5 mg dose of the controlled release composition of Example 6. In Treatment B, subjects received a single 25 mg dose of ADDERALL XR® followed by a 12.5 mg dose of the mixed amphetamine salts immediate release formulation of Example 1 administered 8 hours later. See Table 9.

TABLE-US-00009 TABLE 9 Route of Treatment Composition Dose Administration A Composition of Example 6 1 × 37.5 mg Oral (Batch no. A03383-002L) B ADDERALL XR ® and the 1 × 25 mg ADDERALL XR ® Oral immediate release bead of (Batch no. A02936B) Example 1 followed 8 hours later by 1 × 12.5 mg bead of Example 1 (Batch no. A03383-003L)

[0167] At screening, each subject provided a medical and medication history. A 12-lead electrocardiogram (ECG), vital signs, height, and weight were obtained. Blood and urine samples were collected for routine clinical laboratory analysis, antibody screening for Human Immunodeficiency Virus (HIV), Hepatitis B and C, and urine alcohol and drug screen. A serum pregnancy test was conducted on all women of child-bearing potential (WOCP) during screening.

[0168] For each treatment period, subjects reported to the clinic the morning prior to dosing at which time continued eligibility was confirmed by urine alcohol and drug screen, urine pregnancy test for WOCP, weight, routine clinical laboratory analysis, 12-lead ECGs, and vital signs. Subjects also underwent a physical examination, and a brief medical and medication history was completed.

[0169] Blood samples for the determination of plasma d- and l-amphetamine concentrations were collected at specified times in each treatment period. Vital sign measurements were obtained prior to dosing and at 2, 4, 8, 12, 24, and 60 hours post-dose. Adverse events (AEs) and concomitant medications were reported throughout each treatment period. Twelve-lead ECG measurements were collected prior to dosing and at 2, 4, 8, 12, 24, and 60 hours post-dose.

[0170] Exit assessments at the end of each treatment period included a physical examination, 12-lead ECG, routine clinical laboratory measurements, vital signs, and AE assessment. A serum pregnancy test for WOCP was performed at study exit/withdrawal. A follow-up telephone call to assess AEs was made to all subjects 30±2 days after last exposure to study medication.

[0171] Duration of study: 11 days (two treatment periods, each with four days of confinement and a 7-day washout period between study medication dosing).

[0172] Pharmacokinetics: d- and l-amphetamine concentrations were determined in plasma samples collected at the following times: 30 minutes prior to dosing (Time 0) on Day 1, and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours post-dose for each treatment. Plasma d- and l-amphetamine concentrations were measured with a validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) method.

Statistical Methods:

[0173] Pharmacokinetic parameters were compared between treatment groups using an analysis of variance (ANOVA) with sequence, period, and treatment as fixed effects, and subject nested within sequence as a random effect. This analysis was performed for the natural log transformations of maximum plasma concentration (C.sub.max), area under the plasma concentration-time curve from time 0 to time infinity (AUC.sub.(0-inf), and area under the plasma concentration-time curve from time 0 to last measured time (AUC.sub.(0-last)) using SAS PROC MIXED.

[0174] For C.sub.max, AUC.sub.(0-inf), and AUC.sub.(0-last), exponentiated least squares (LS) means for each treatment were obtained by taking the antilog of the LS means on the log scale. Ratios of the exponentiated LS means for the test treatment (SPD465 37.5 mg) relative to the reference treatment (25 mg ADDERALL XR® followed by 12.5 mg mixed amphetamine salts IR 8 hours later) and 90% confidence intervals (CIs) of the ratios were provided. The 90% CIs were obtained by taking the antilog of the 90% CIs for the difference between the LS means on the log scale.

[0175] C.sub.max, AUC.sub.(0-last), AUC.sub.(0-inf), terminal half-life (t½), terminal phase rate constant (λ.sub.Z), and time of maximum plasma concentration (t.sub.max) were summarized descriptively for each treatment.

[0176] Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 7.1 adverse event dictionary. The frequency of treatment-emergent adverse events (TEAE) was tabulated by body system and preferred term for each treatment. AEs were further summarized by severity, relationship to study drug, gender, and ethnicity. AEs leading to study withdrawal were summarized separately by body system, preferred term, and treatment group.

[0177] Clinical laboratory evaluations were summarized by treatment and visit. Hematology and biochemistry were summarized using descriptive statistics; discrete urinalysis measurements were summarized using frequencies and percents and continuous urinalysis measurements were summarized using descriptive statistics. Laboratory data outside the normal range was flagged in the subject data listings.

[0178] Vital signs, including pulse, systolic and diastolic BP, and respiration rate, were summarized by treatment for each measured time point using descriptive statistics. Change from baseline was also calculated and summarized for each post baseline time point.

Results:

[0179] Subject Demographics:

[0180] The overall gender distribution was 60% (12/20) females and 40% (8/20) males. The overall racial distribution was 90% (18/20) White and 10% (2/20) Black/African-American. The age of the study subjects ranged from 21-50 years with an overall mean age (SD) of 30.0 years (8.83). Subjects weighed between 61 kg and 97 kg with a mean weight (SD) of 73.8 kg (10.15), and height ranged between 158 cm-188 cm with a mean height (SD) of 172.6 cm (8.05). Body Mass Index ranged between 20.1 kg/m.sup.2-29.2 kg/m.sup.2 with a mean BMI (SD) of 24.75 (2.267).

Pharmacokinetic Results:

[0181] FIG. 9 shows the d-amphetamine plasma concentration profile of SPD465 37.5 mg compared to ADDERALL XR® (25 mg) followed by immediate release mixed amphetamine salts (12.5 mg) eight hours later. Exposure to d-amphetamine, as described by C.sub.max and AUC values, was comparable following Treatment A and Treatment B. The 90% CI of the test-to-reference ratios were within the bioequivalence range of 80%-125%.

[0182] FIG. 10 shows the l-amphetamine plasma concentration profile of SPD465 37.5 mg compared to ADDERALL XR® (25 mg) followed by immediate release mixed amphetamine salts (12.5 mg) eight hours later. C.sub.max and AUC values of l-amphetamine following a dose of Treatment A were similar to those following Treatment B; 90% CI of the test-to-reference ratios were within the bioequivalence range of 80%-125%.

[0183] The elimination half lives of d- and l-amphetamine were similar for both treatments. See Table 10.

TABLE-US-00010 TABLE 10 Plasma Pharmacokinetic Parameters for d- and l-Amphetamine After a Single Dose of 37.5 mg SPD465 (Treatment A) or 25 mg ADDERALL XR ® + 12.5 mg Mixed Amphetamine Salts (Treatment B) Exponentiated Treatment A Treatment B LS Mean Mean LS Mean LS Ratio % Parameters n (±SD) Mean n (±SD) Mean (A)/(B) 90% CI d-Amphetamine C.sub.max 20 50.3 49.7 19 49.3 49.2 101.0  (96.9, 105.3) (ng/mL) (7.5) (7.4) AUC.sub.(0-last) 20 1058.0 1042.4 19 997.9 1000.8 104.2 (100.2, 108.3) (ng .Math. hr/mL) (184.5) (172.9) AUC.sub.(0-inf) 20 1084.9 1067.8 19 1019.5 1022.5 104.4 (100.3, 108.7) (ng .Math. hr/mL) (196.2) (181.3) T.sub.max 20 8.2 19 9.7 (hr) (2.0) (2.1) l-Amphetamine C.sub.max 20 14.7 14.6 19 16.0 16.0 90.9 (87.5, 94.4) (ng/mL) (2.2) (2.3) AUC.sub.(0-last) 20 353.5 347.6 19 364.1 364.6 95.3 (91.0, 99.8) (ng .Math. hr/mL) (66.0) (66.5) AUC.sub.(0-inf) 20 372.8 365.9 19 382.3 383.9 95.3 (91.2, 99.6) (ng .Math. hr/mL) (73.5) (69.0) T.sub.max 20 8.4 19 10.7 (hr) (2.1) (1.3) LS = Least squares

Conclusions:

[0184] Treatment A and Treatment B were bioequivalent with respect to C.sub.max and AUC of d- and l-amphetamine. All treatments were well tolerated and all reported AEs were expected.

Example 9

A Phase I Study to Evaluate the Pharmacokinetic Profile of SPD 465 50 mg Under Fed, Fasted, and Sprinkled Conditions in Healthy Adult Volunteers (Clinical Study 105)

[0185] This was an open-label, randomized, single-dose, 3-way crossover, 3-period study with a minimum 7-day washout between each study drug dosing. Sixteen healthy male and female subjects between the ages of 18 and 55 participated in the study. This study was designed to evaluate (1) the effect of a high fat meal on the PK of SPD465 50 mg compared to a reference treatment and (2) the effect of a SPD465 50 mg capsule sprinkled on applesauce compared to a reference treatment. The reference treatment was a 50 mg dose of SPD465 following an at least 10-hour fast. See Table 11. The primary objective of this study was to assess the effect of a high fat meal on the bioavailability of SPD465 relative to the fasted state.

TABLE-US-00011 TABLE 11 Treatment Study Drug Dosage Treatment A SPD465 1 × 50 mg capsule (reference) (batch no. A03445- after an at least 10 001L) hour fast Treatment B SPD465 1 × 50 mg capsule (batch no. A03445- following a high fat 001L) meal Treatment C SPD465 1 × 50 mg capsule (batch no. A03445- sprinkled on 1 001L) tablespoon of applesauce

[0186] The study included three single-dose treatment periods separated by a minimum 7-day washout period between study drug dosing. On study day 1 of each period, according to the randomization schedule, the subjects were administered a single dose of SPD465 50 mg following an at least 10-hour fast, SPD465 50 mg following a standard high fat meal or the contents of a SPD465 50 mg capsule sprinkled on applesauce.

[0187] Blood samples for the determination of plasma d- and l-amphetamine concentrations were collected 30 minutes prior to drug administration (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours after dosing in each treatment period.

[0188] Results:

[0189] d-Amphetamine

[0190] d-Amphetamine plasma levels as described by C.sub.max, AUC.sub.(0-last), and AUC.sub.(0-inf) were highest in fasted subjects, slightly lower in subjects receiving SPD465 sprinkled on applesauce, and lowest in subjects pretreated with a high-fat meal. See Tables 12 and 13. The 90% CI of the test-to-reference ratios, with fasted as the reference treatment, were within the typically acceptable bioequivalence range of 80% to 125%, which indicates that the there were no significant differences across the unfed/fed conditions. The CIs on the ratios between subjects receiving the high-fat meal and fasted subjects were less than 100%.

[0191] The median time to maximum d-amphetamine plasma concentrations (T.sub.max) in fasted subjects and those who received SPD465 sprinkled on applesauce was 7 and 7.5 hours, respectively. The T.sub.max in subjects who received SPD465 following a high-fat meal was delayed approximately 4 to 5 hours with a median value of 12 hours.

TABLE-US-00012 TABLE 12 d-Amphetamine Plasma Pharmacokinetic Parameters Following a Single Dose Administration of 50 mg SPD465 Fasted (A) High Fat Meal (B) Sprinkled (C) Parameter n = 14 n = 16 n = 16 C.sub.max (ng/ml) 72.3 60.0 67.3 Mean (SD) (13.72) (7.09) (7.69) T.sub.max (hr) 7.0 12.0 7.5 Median (Min, Max) (6.0, 10.0) (8.0, 14.0) (5.0, 9.0) AUC.sub.(0-last) (hr*ng/ml) 1531.9 1382.6 1450.8 Mean (SD) (292.36) (289.85) (253.28) AUC.sub.(0-inf) (hr*ng/ml) 1589.5 1433.8 1497.9 Mean (SD) (359.98) (339.50) (300.83) λz (1/hr) 0.07 0.07 0.07 Mean (SD) (0.014) (0.011) (0.012) t.sub.1/2 (hr) 10.9 10.5 10.6 Mean (SD) (2.60) (2.11) (2.22)

TABLE-US-00013 TABLE 13 Statistical Analysis Results of Plasma d-Amphetamine Following a Single Dose Administration of 50 mg SPD465 Exponentiated LS Means High- Fat Ratio Fasted Meal Sprinkled of LS (A) (B) (C) Means 90% CI Parameter n = 14 n = 16 n = 16 B/A C/A B/A C/A AUC.sub.(0-inf) 1528.3 1392.5 1463.7 91.1 95.8 86.7, 91.1, (hr * ng/mL) 95.8 100.6 AUC.sub.(0-last) 1484.2 1350.3 1424.5 91.0 96.0 86.7, 91.5, (hr * ng/mL) 95.5 100.7 C.sub.max 69.6 59.4 66.7 85.3 95.8 80.4, 90.3, (ng/mL) 90.5 101.6 LS = Least squares

[0192] l-amphetamine

[0193] l-Amphetamine plasma levels as described by C.sub.max, AUC.sub.(0-last), and AUC.sub.(0-inf) were highest in fasted subjects, slightly lower in subjects receiving SPD465 sprinkled on apple sauce, and lowest in subjects pretreated with a high-fat meal. See Tables 14 and 15. The 90% CI of the test-to-reference ratios, with fasted as the reference treatment, were within the typically acceptable bioequivalence range of 80% to 125%, which indicates that the there were no significant differences across the unfed/fed conditions. The CIs on the ratios between subjects receiving the high-fat meal and fasted subjects were less than 100%.

[0194] The median time to maximum l-amphetamine plasma concentrations (T.sub.max) in fasted subjects and those who received SPD465 sprinkled on applesauce was 7.5 and 8 hours, respectively. The T.sub.max in subjects who received SPD465 following a high-fat meal was delayed approximately 4.5 hours with a median value of 12 hours.

TABLE-US-00014 TABLE 14 l-Amphetamine Plasma Pharmacokinetic Parameters Following a Single Dose Administration of 50 mg SPD465 Fasted (A) High Fat Meal (B) Sprinkled (C) Parameter n = 14 n = 16 n = 16 C.sub.max (ng/ml) 21.1 17.6 20.0 Mean (SD) (3.74) (2.21) (2.50) T.sub.max (hr) 7.5 12.0 8.0 Median (Min, Max) (6.0, 12.0) (8.0, 14.0) (5.0, 12.0) AUC.sub.(0-last) (hr*ng/ml) 506.9 448.3 479.2 Mean (SD) (107.92) (107.79) (100.83) AUC.sub.(0-inf) (hr*ng/ml) 545.2 481.7 511.4 Mean (SD) (147.92) (138.43) (127.13) λz (1/hr) 0.05 0.06 0.06 Mean (SD) (0.014) (0.013) (0.011) t.sub.1/2 (hr) 13.6 12.8 13.0 Mean (SD) (3.70) (3.30) (3.22)

TABLE-US-00015 TABLE 15 Statistical Analysis Results of Plasma l-Amphetamine Following a Single Dose Administration of 50 mg SPD465 Exponentiated LS Means High- Fat Ratio Fasted Meal Sprinkled of LS (A) (B) (C) Means 90% CI Parameter n = 14 n = 16 n = 16 B/A C/A B/A C/A AUC.sub.(0-inf) 522.3 463.4 495.0 88.7 94.8 83.9, 89.6, (hr * ng/mL) 93.9 100.3 AUC.sub.(0-last) 492.2 436.1 468.1 88.6 95.1 83.8, 90.0, (hr * ng/mL) 93.7 100.5 C.sub.max 20.4 17.4 19.8 85.2 96.9 80.2, 91.2, (ng/mL) 90.6 103.0 LS = Least squares

[0195] Conclusion

[0196] There were no statistically significant differences in plasma d- or l-amphetamine levels when SPD465 50 mg was administered to subjects in a fasted state, following a high-fat meal, or when the SPD465 was administered with applesauce. The pharmacokinetic findings indicate that in the presence of a high-fat meal, the rate of absorption of d- and l-amphetamines is decreased but the extent of absorption is unaffected. Thus, these results show that SPD465 administered with food was bioequivalent to SPD465 administered without food.

Example 10

An Open-Label, Incomplete Block Randomization, Three-Period, Four Treatment, Dose Escalating Study of the Pharmacokinetics of SPD 465 Administered at Steady State in Healthy Adult Volunteers (Clinical Study 110)

[0197] The primary objective of this study was to determine the pharmacokinetics of SPD465 following repeat dose administration over a range of doses from 12.5 mg to 75 mg. All 18 subjects received SPD465 at a dose of 12.5 mg once daily for 7 days in Period 1. The dose was increased so that about half the subjects received 25 mg and the others received 50 mg once daily for the next 7 days (Period 2). In Period 3, all subjects were increased to 75 mg once daily for 7 days following Period 2.

[0198] Blood samples were collected from each subject on days 1, 5, 6 and 7 of each Period for the determination of d- and l-amphetamine concentrations. Blood and urine samples were collected on day 7 of Period 3 for metabolite identification.

[0199] Subjects were administered the SPD465 dosages described in Table 16.

TABLE-US-00016 TABLE 16 Mode of Batch Dose level administration Number 12.5 mg (Period 1) 1 × 12.5 mg capsule A08763A   25 mg (Period 2) 1 × 25 mg capsule A08767A   50 mg (Period 2) 1 × 50 mg capsule A08762A   75 mg (Period 3) 2 × 37.5 mg capsules A08761A

[0200] The calculated pharmacokinetic parameters included: [0201] Cmax: maximum plasma concentration [0202] Tmax: time of maximum plasma concentration [0203] AUC.sub.0-24: area under the plasma concentration-time curve from time 0 to time 24 hours [0204] Cmin: minimum plasma concentration [0205] CL/F: apparent oral clearance [0206] CL/F/Wt: weight adjusted apparent oral clearance [0207] R: accumulation ratio [0208] AUC.sub.0-24/AUC.sub.0-2412.5 mg: area under the plasma concentration-time curve from time 0 to time 24 hours on Day 7 at 25 mg, 50 mg, and 75 mg relative to the AUC.sub.0-24 on Day 7 at 12.5 mg.

[0209] Pharmacokinetic parameters were calculated by non-compartmental techniques using WinNonlin® Professional version 4.1. All calculations were based on actual sampling times. The pharmacokinetic parameters were determined from plasma concentration-time data measured using a validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) method.

[0210] The pharmacokinetic results are graphically illustrated in FIGS. 11-12 and 15-16 shown in Table 17.

TABLE-US-00017 TABLE 17 Single dose Multiple dose (Day 1) (Day 7) 12.5 mg 12.5 mg 25 mg 50 mg 75 mg Parameter Statistic (N = 18)* (N = 18)* (N = 9) (N = 8) (N = 17)* d-amphetamine Cmax Mean 17.0 22.4 48.5 94.2 153.5 (ng/mL) (SD) (2.9) (5.8) (4.6) (32.1) (24.6) Tmax Median 8.0 6.0 8.0 6.0 8.0 (hr) (min., (6.0, 9.0) (2.0, 10.1) (6.0, 9.0) (4.0, 12.1) (6.0, 12.0) max.) AUC.sub.0-24 Mean 248.5 351.3 742.0 1499.7 2526.2 (hr * ng/mL) (SD) (45.3) (87.5) (77.5) (504.9) (495.1) Cmin Mean — 7.6 17.2 38.2 66.8 (ng/mL) (SD) (2.9) (5.6) (10.5) (23.8) CL/F Mean 39.0 29.5 25.5 29.5 22.9 (L/hr) (SD) (7.2) (13.5) (2.8) (16.6) (3.7) CL/F/Wt Mean 0.51 0.40 0.35 0.40 0.31 (L/hr/kg) (SD) (0.09) (0.18) (0.05) (0.23) (0.06) R Mean — 1.4 — — — (SD) (0.30) AUC.sub.0-24/ Mean — — 2.2 4.2 8.0 AUC.sub.0-24 (SD) (0.4) (0.6) (4.0) 12.5 mg l-amphetamine Cmax Mean 5.2 7.6 15.9 30.2 52.0 (ng/ml) (SD) (0.9) (1.8) (1.6) (8.7) (9.6) Tmax Median 8.0 8.0 8.0 9.0 8.0 (hr) (min., (6.0, 10.0) (2.0, 10.1) (4.0, 9.0) (4.0, 12.1) (6.0, 12.0) max.) AUC.sub.0-24 Mean 81.3 126.4 261.5 514.7 899.3 (hr * ng/mL) (SD) (14.8) (29.9) (31.8) (148.5) (205.9) Cmin Mean — 3.0 6.6 14.8 26.8 (ng/mL) (SD) (1.0) (2.1) (4.3) (10.1) CL/F Mean 39.7 26.8 24.2 26.6 21.6 (L/hr) (SD) (7.1) (10.2) (3.1) (9.7) (3.9) CL/F/Wt Mean 0.52 0.36 0.34 0.36 0.30 (L/hr/kg) (SD) (0.08) (0.14) (0.05) (0.14) (0.07) R Mean — 1.6 — — — (SD) (0.3) AUC.sub.0-24/ Mean — — 2.2 4.1 7.8 AUC.sub.0-24 (SD) (0.4) (0.8) (3.4) 12.5 mg *N indicates the number of subjects in the safety population who took drug. Due to early termination or missing data, some subjects may not be contributing to the results at all time points.

[0211] The dose proportionality of the Cmax and AUC.sub.0-24 of SPD465 d- and l-amphetamine were analyzed using the power model and graphically by plotting individual subject and mean Day 7 Cmax and AUC.sub.0-24 against dose with the estimated power model regression line. See FIGS. 13-14 and 17-18.

[0212] These results showed that repeated doses of SPD465 led to the accumulation of d- and l-amphetamine in plasma consistent with the half-life and dosing of the compound. Further, the Cmax and AUC.sub.0-24 increased linearly with increasing doses of SPD465. Because SPD465 includes an immediate release bead, a delayed pulsed release bead, and a sustained release bead in a 1:1:1 ratio, the Cmax and AUC.sub.0-24 for the sustained release bead alone also increases linearly with increasing doses of SPD465 (e.g., the Cmax for 25 mg of the sustained release bead is twice the Cmax for 12.5 mg of the sustained release bead, and the Cmax for 37.5 mg of the sustained release bead is 3× the Cmax for 12.5 mg of the sustained release bead).

[0213] The disclosures of patents, patent applications, publications, product descriptions, and protocols cited throughout this application are incorporated by reference in their entireties.

[0214] It is to be understood that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.