AU2012232984B2 - Methods and devices for providing prolonged drug therapy - Google Patents

Abstract

Methods and devices for maintaining a desired therapeutic drug effect over a prolonged therapy period are provided. In particular, oral dosage forms that release drug within the gastrointestinal tract at an ascending release rate over an extended time period are provided. The dosage forms may additionally comprise an immediate-release dose of drug. Fig. 2 14j FIG. 2

Description

- 1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL Name of Applicant: Alza Corporation Actual Inventors: Atul D. Ayer and Diane R. Guinta and Lawrence G. Hamel and Zahedeh Hatamkhany and Andrew C. Lam and Samuel R. Saks and Padmaja Shivanand and Richard G. Weyers and Jeri D. Wright and Carol A. Christopher and Suneel K. Gupta Address for Service is: SHELSTON IP 60 Margaret Street Telephone No: (02) 9777 1111 SYDNEY NSW 2000 Facsimile No. (02) 9241 4666 CCN: 3710000352 Attorney Code: SW Invention Title: Methods and devices for providing prolonged drug therapy Details of Original Application No. 2010249205 dated 07 Dec 2010 The following statement is a full description of this invention, including the best method of performing it known to me/us: File: 30060AUP05 la BACKGROUND OF THE INVENTION 1. Field of the Invention This invention pertains to methods and devices for maintaining a desired 5 therapeutic drug effect over a prolonged therapy period. In particular, the invention is directed to methods and devices that provide drug release within the gastrointestinal tract at an ascending release rate over an extended time period. In this manner, drug is ) released at an ascending rate during a portion of the drug administration period sufficient.to maintain a desired therapeutic drug effect throughout a prolonged therapy 10 period. Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. To produce its pharmacological effects, a drug must be made available in Is appropriate concentrations at its site of action within the body. This availability is affected by numerous factors including the quantity of the drug 2 administered, the extent and rate of its absorption from its administration site its distribution, binding or localization within tissues, its biotransformation and its excretion. One commonly-used indicator of drug availability is the concentration of drug that is obtained within the blood or plasma, or other 5 appropriate body fluid or tissue, of a patient following administration of the drug. For convenience, this concentration may be referred to as "plasma drug concentration" hereinafter which is intended to be inclusive of drug concentration measured in any appropriate body fluid or tissue. Plasma drug concentration measurements provide very useful information including, for 1o example, comparative information with regard to different drug dosage forms and/or different drug administration routes. In addition, for many drugs, various drug effects including both desired pharmacological effects, i.e., therapeutic drug effects, and undesired pharmacological effects, i.e., side effects, have been correlated with specific plasma drug concentrations or 15 ranges of plasma drug concentrations. For orally administered drug dosage forms, absorption occurs within the gastrointestinal ("g.i.") tract and is affected by many factors including the physicochemical properties of the local microenvironment, such as surface area, blood flow and membrane characteristics (which vary significantly in the 20 different portions of the g.i. tract), the physicochemical properties of the drug entity, drug concentration, the existence and activity of drug-specific transport mechanisms, etc. One important factor in the rate of absorption of drug administered as an oral dosage form is the rate at which drug is released from the dosage form. Drug release rates for oral dosage forms are typically 25 measured as an in vitro rate of dissolution, i.e., a quantity of drug released from the dosage form per unit time. Conventional oral dosage forms can be described as "immediate release" because, generally, essentially the entire dose of drug is released from the dosage form within a very short period, i.e., minutes, following 30 administration. As this bolus of released drug is absorbed, the plasma drug concentration typically rapidly rises to a maximal or peak concentration and 3 subsequently declines as the drug is distributed, bound or localized within tissues, biotransformed and/or excreted. The time period for this decline varies for different drugs and depends on many factors but this time period will be characteristic of a particular drug. Generally, during some portion of 5 the time period in which the plasma drug concentration rises, peaks and declines, the drug provides its therapeutic effects, i.e., the plasma drug concentration achieves or exceeds an effective concentration. Moreover, at some point during this time period, the therapeutic effects disappear, i.e., when the plasma drug concentration declines to a level that is below an 10 effective concentration. In addition, often, during a portion of this time surrounding the time the peak concentration is attained, i.e., when the plasma drug concentration is in its highest range, undesired side effects may become apparent. In view of the above, it will be appreciated that continued drug 15 effectiveness occurs during the time period when the plasma drug concentration is within the effective plasma drug concentration range. Because the plasma drug concentration declines overtime, however, multiple doses of the immediate-release drug dosage form must be administered at appropriate intervals to ensure that the plasma drug concentration remains in 20 or, again, rises to, the effective concentration range. At the same time, however, there is a need to avoid or minimize plasma drug concentrations that rise to, and/or that remain for too long within, the higher ranges where side effects become apparent. Accordingly, for many drugs, multiple, separate doses of the immediate-release dosage form must be administered 25 at appropriate intervals to maintain a satisfactory balance of desired and undesired pharmacological effects over a prolonged therapy period. One focus of efforts to improve drug therapy has been directed to providing non-immediate-release oral drug dosage forms that affect absorption of the drug primarily by altering the release rate of the drug from 30 the dosage form. Examples of such non-immediate-release delivery systems include delayed-release and sustained-release systems. Sustained-release 4 dosage forms generally release drug for an extended time period compared to an immediate-release dosage form. There are many approaches to achieving sustained release of drugs from oral dosage forms known in the art. These different approaches include, for example, diffusion systems such as 5 reservoir devices and matrix devices, dissolution systems such as encapsulated dissolution systems (including, for example, "tiny time pills") and matrix dissolution systems, combination diffusion/dissolution systems, osmotic systems and ion-exchange resin systems as described in Remington's Pharmaceutical Sciences, 1990 ed., pp. 1682-1685. 10 It is believed to be particularly desirable to provide sustained-release oral dosage forms that provide drug release at a substantially constant release rate over an extended time period. In this manner, for many drugs, the plasma drug concentration initially ascends for a short period of time as drug release begins and then remains substantially constant over an 15 extended time period as drug release continues at a constant rate. For many drugs, this substantially constant plasma drug concentration correlates with substantially constant drug effectiveness over a prolonged therapy period. In addition, because an initial relatively high peak plasma drug concentration is avoided, side effects may be less of a problem. Accordingly, advantages of 20 constant-release dosage forms include decreasing the number of doses of a drug that need to be administered over time and providing a better balance of desired and undesired pharmacological effects of the drug. Osmotic dosage forms, in particular, have been notably successful at providing constant-release of drugs over extended time periods. Osmotic 25 dosage forms, in general, utilize osmotic pressure to generate a driving force for imbibing fluid into a compartment formed, at least in part, by a semipermeable wall that permits free diffusion of fluid but not drug or osmotic agent(s), if present. A substantially constant rate of drug release can be achieved by designing the system to provide a relatively constant osmotic 30 pressure and having suitable exit means for the drug formulation to permit the drug formulation to be released at a rate that corresponds to the rate of fluid 5 imbibed as a result of the relatively constant osmotic pressure. A significant advantage to osmotic systems is that operation is pH-independent and thus continues at the osmotically-determined rate throughout an extended time period even as the dosage form transits the gastrointestinal tract and s encounters differing microenvironments having significantly different pH values. Surprisingly simple but highly effective osmotic devices comprising drug in a mixture with excipients, optionally including osmotically active component(s), within the compartment are known in the art. Although 1o effective for many drugs, the release rate in these devices often declines over time and complete delivery of the drug load may not occur. A more sophisticated type of osmotic device comprises two component layers within the compartment formed by the semipermeable wall. One component layer comprises drug in a mixture with excipients, optionally including osmotically 15 active component(s), that will form a deliverable drug formulation within the compartment and the second component layer comprises osmotically active component(s) but does not contain drug. The osmotically active component(s) in the second component layer typically comprise osmopolymer(s) having relatively large molecular weights and which exhibit 20 "swelling" as fluid is imbibed such that release of these components through ) the drug formulation exit means does not occur. The second component layer is referred to as a "push" layer since, as fluid is imbibed, the osmopolymer(s) swell and push against the deliverable drug formulation of the first component layer to thereby facilitate release of the drug formulation 25 at a substantially constant rate. The above-described devices are known, for example, from the following US Patents, owned by Alza Corporation: 4,327,725; 4,612,008; 4,783,337; and 5,082,668, each of which is incorporated in its entirety by reference herein. Although constant-release dosage forms have proven effective for 30 many different drug therapies, there are clinical situations where these have not been entirely satisfactory. It has been observed that for some patients -6 treated with constant-release dosage forms for some conditions or diseases, the therapeutic effectiveness of the drug decreases at time periods before the end of the desired therapy period despite the maintenance of substantially constant drug release that would be expected to provide continued effectiveness. Accordingly, there remains 5 a need to provide methods and devices for maintaining a desired therapeutic drug effect over a desired prolonged therapy period when sustained-release dosage forms that release drug at a substantially constant rate over an extended time period are not satisfactory. BRIEF SUMMARY OF THE INVENTION 10 It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. To this end, a first aspect of the present invention provides a method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder comprising administering a longitudinally compressed, capsule-shaped dosage form to 15 said subject, wherein said dosage form comprising a pharmaceutically acceptable composition comprising methylphenidate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a patient in a manner that achieves an ascending release rate of said methylphenidate beginning with a first periodic interval that begins at time t = 0 and continuing through about 5.5 hours following said 20 administration. Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". 25 A second aspect of the present invention provides a method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject - 6a comprising orally administering a longitudinally compressed, capsule-shaped dosage form to said subject, wherein said dosage form comprises: an immediate release coating comprising methylphenidate hydrochloride; and a sustained release portion comprising methylphenidate hydrochloride and a 5 pharmaceutically acceptable carrier, wherein: said dosage form provides release of said methylphenidate hydrochloride over a period comprising first, second, third, and fourth sequential, one-hour time intervals; said sustained release portion releases more of said methylphenidate 10 hydrochloride during said second interval than during said first interval, more of said methylphenidate hydrochloride during said third interval than during said second interval, and more of said methylphenidate hydrochloride during said fourth interval than during said third interval; and the methylphenidate hydrochloride released during said first interval only includes methylphenidate hydrochloride released from said immediate 15 release coating. A third aspect of the present invention provides a method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising orally administering a longitudinally compressed, capsule-shaped dosage form to said subject, wherein said dosage form comprises 20 an immediate release portion comprising methylphenidate or a pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein: 25 said dosage form releases said methylphenidate over a period comprising first, second, and third sequential one-hour time intervals, and - 6b said sustained release portion releases more of said methylphenidate during said second interval than during said first interval, and more of said methylphenidate during said third interval than during said second interval. A fourth aspect of the present invention provides a method for effectively treating 5 Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising orally administering a longitudinally compressed, capsule-shaped dosage form to said subject, wherein said dosage form comprises: an immediate release portion comprising methylphenidate or a pharmaceutically effective salt thereof; and 10 a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 8 hours following administration. 15 A fifth aspect of the present invention provides a method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising orally administering a longitudinally compressed, capsule-shaped dosage form to said subject, wherein said dosage form comprises: an immediate release portion comprising methylphenidate or a pharmaceutically 20 effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to 25 about 8 hours following administration; - 6c wherein said dosage form provides a blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof that is greater at 4 hours following administration than at 2 hours following administration, and is greater at 5.5 hours following administration than at 4 hours following administration; 5 wherein said blood plasma at a time up to 4 hours following administration comprises said methylphenidate or pharmaceutically effective salt thereof from said immediate release portion; and, wherein said blood plasma at a time after 4 hours following administration does not comprise methylphenidate or pharmaceutically effective salt thereof from said 10 immediate release portion. A sixth aspect of the present invention provides a longitudinally compressed, capsule-shaped dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a pharmaceutically 15 effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to 20 about 8 hours following administration. A seventh aspect of the present invention provides a longitudinally compressed, capsule-shaped dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a pharmaceutically 25 effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, - 6d wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 8 hours following administration; wherein said dosage form provides a blood plasma concentration of said 5 methylphenidate or pharmaceutically effective salt thereof that is greater at 4 hours following administration than at 2 hours following administration, and is greater at 5.5 hours following administration than at 4 hours following administration; wherein said blood plasma at a time up to 4 hours following administration comprises said methylphenidate or pharmaceutically effective salt thereof from said 10 immediate release portion; and, wherein said blood plasma at a time after 4 hours following administration does not comprise methylphenidate or pharmaceutically effective salt thereof from said immediate release portion. According to another aspect of the present invention there is provided a method 15 for treating Attention-Deficit Disorder or Attention-Deficit Hyperactivity Disorder in a patient, wherein the method comprises administering a pharmaceutically acceptable composition comprising 100 ng to 500 mg of methylphenidate and a pharmaceutically acceptable carrier to said patient in a manner that achieves a substantially ascending methylphenidate plasma drug concentration over a time period of about 5.5 hours 20 following said administration. Preferably, the substantially ascending methylphenidate plasma drug concentration is over a time period of about 5.5 to about 8 hours following the administration. Preferably, the substantially ascending methylphenidate plasma drug 25 concentration is over a time period of about 5.5 to about 9.5 hours following the administration.

- 6e A further aspect of the present invention provides a method for treating Attention Deficit Disorder or Attention-Deficit Hyperactivity Disorder in a patient, wherein the method comprises administering a pharmaceutically acceptable composition comprising 100 ng to 500 mg of methylphenidate and a pharmaceutically acceptable carrier to said 5 patient in a manner that achieves a substantially ascending methylphenidate plasma drug concentration over a time period of about 8 hours following said administration. A further aspect of the present invention provides a method for treating Attention Deficit Disorder or Attention-Deficit Hyperactivity Disorder in a patient, wherein the method comprises administering a pharmaceutically acceptable composition comprising 10 100 ng to 500 mg of methylphenidate and a pharmaceutically acceptable carrier to said patient in a manner that achieves a substantially ascending methylphenidate plasma drug concentration over a time period of about 9.5 hours following said administration. A further aspect of the present invention relates to providing improved drug therapy for those clinical situations where therapeutic effectiveness of an administered 15 drug therapy unexpectedly decreases at time periods before the end of the intended therapy period. It has been surprisingly discovered that, in an exemplary clinical situation, administration of drug at a release rate that is ascending, rather than substantially constant, over an extended time period provided therapeutic efficacy that did not decrease before the end of the prolonged therapy period. 20 With the discovery that administration of drug at a release rate that is substantially ascending provides improved drug therapy, a need arises for sustained-release oral dosage forms adapted to provide such a release rate over a suitable extended time period. Accordingly, the present invention also relates to providing oral sustained release dosage forms that provide an ascending drug release rate over an extended 25 time period, methods of making such dosage forms and methods of using such dosage forms to maintain therapeutic effectiveness for a desired prolonged therapy period.

- 6f It has been surprisingly discovered that oral osmotic dosage forms exhibiting an ascending drug release rate for an extended time period can be ' 7 achieved. In particular, the present invention is directed to osmotic dosage forms having bi-layer or tri-layer tablet cores that are adapted to provide ascending drug release rates over an extended period. In addition, to provide for an initial rapid onset of drug action, the present invention is also related to 5 dosage forms that additionally comprise a dose of drug for immediate release. The bi-layer oral osmotic dosage forms of the present invention include a first component layer, comprising a selected drug and excipients for forming a deliverable drug composition when hydrated, and a second push layer, comprising a fluid-expandable osmopolymer and excipients, contained within 10 a compartment formed by a semipermeable membrane and having exit means for drug release from the compartment. The two layers are compressed into bi-layer tablet.cores before the semipermeable membrane is applied and a suitable orifice for drug release therethrough is formed. Importantly, the bi-layer tablet cores disclosed herein are formed when two 1s component layers are compressed together to provide a longitudinally compressed tablet ("LCT") core having a "capsule-shaped" configuration with a different layer at each narrow end. The combination of features including the osmotic properties of the component layers, the fluid flux properties of the semipermeable membrane 20 and the configuration of the tablet core ensures that drug is released at an ascending rate over an extended time period. In a preferred embodiment, sufficient activity in the push layer is achieved by use of a relatively large concentration (at least about 35%) of osmotically effective solute, or osmagent, such as sodium chloride. In addition, sorbitol is preferably 25 included in the first component layer. The tri-layer oral osmotic dosage forms of the present invention include a novel tri-layer tablet core surrounded by a semipermeable membrane and having suitable exit means for releasing drug formulation through the semipermeable membrane. The novel tri-layer tablet core has a first drug 30 containing layer, a second drug-containing layer and a third push layer. In operation, through the cooperation of the dosage form components, drug is 8 successively released from the first drug-containing layer and then from the second drug-containing layer. It has been discovered that a drug concentration gradient facilitates the achievement of an ascending drug release rate for an extended time period. Consequently, the other excipients 5 in the drug-containing layers may be more flexibly varied and adjusted for other purposes such as manufacturing convenience and pharmaceutical elegance. In this manner, dosage forms that exhibit reliable drug release having the desired sustained and ascending rate over an extended time period can be reliably and efficiently manufactured. 10 It is preferred to use the LCT core configuration, as described above, to enhance hydration of the tri-layer core. In addition, a flux-enhancing agent is preferably included in the semipermeable wall composition. In a presently preferred embodiment, the combination of features including the LCT tri-layer core configuration, a suitable drug concentration gradient between the first 15 and second component layers, the osmotic properties of the component layers and the fluid flux properties of the semipermeable membrane achieves the desired ascending rate of drug release over an extended time period. There are numerous clinical situations and drug therapies that could be improved with the use of dosage forms that provide a sustained and 20 ascending release rate over an extended time period, Exemplary dosage forms, as disclosed herein, comprise CNS-acting drugs and cardiovascular acting drugs. It will be appreciated by persons of skill in the art that the invention is applicable to many other types of drugs and drug therapies. Examples of suitable types of drugs include, but are not limited to, anti 25 infectives, analgesics, anesthetics, antiarthritics, antiasthmatics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antihistamines, antiinflammatories, antimigraines, antineoplastics, antiparkinsonisms, antipruritics, antipsychotics, antipyretics, antispasmodics, anticholinergics, sympathomimetics, calcium channel blockers, beta blockers, antiarrythmics, 30 antihypertensives, ACE inhibitors, diuretics, vasodilators, decongestants, 9 hormones, hypnotics, immunosuppresives, parasympathomimetics, prostaglandins, proteins, peptides, sedatives and tranquilizers. The exemplary clinical situation described herein involves treatment of ADHD with methylphenidate therapy. Accordingly, the present invention also 5 pertains to making oral methylphenidate sustained release dosage forms that provide a sustained and ascending release rate of a drug over an extended time period. It has further been discovered that oral methylphenidate sustained release dosage forms that provide an ascending release rate of a drug over 10 an extended time period can be used to provide effective once-a-day therapy for ADHD. Thus, the present invention also pertains to improving drug therapy for ADHD by eliminating the need for multiple daily doses of methylphenidate yet providing therapeutic efficacy throughout the day that compares to the therapeutic efficacy provided by multiple doses of immediate 15 release methylphenidate. The above-described features and advantages, as well as others, will become more apparent from the following detailed disclosure of the invention and the accompanying claims. Although the present invention is illustrated herein by exemplary 20 dosage forms containing specific exemplary drugs, methods of making such dosage forms and methods of using methylphenidate-containing dosage forms to provide a desired therapeutic outcome, the invention is not limited by the exemplary embodiments. The invention broadly embraces oral sustained release dosage forms that provide an ascending drug release rate over an 25 extended time period, methods of making such dosage forms and methods of using such dosage forms to maintain therapeutic effectiveness for a desired prolonged therapy period with respect to any appropriate drugs and drug therapies as would be apparent to a person of skill in the art in view of the disclosure herein. 30 9a Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

10 BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figure 1 is a cross-section view of a bi-layer osmotic dosage form in accord with the present invention. s Figure 2 is a cross-section view of a tri-layer osmotic dosage form, additionally comprising an immediate-release drug overcoat and an aesthetic overcoat, in accord with the present invention. Figure 3 is a graph illustrating the quantity of drug released over time from a preferred embodiment of the present invention as described in Example ) 10i 6. Figure 4 is a graph illustrating the plasma drug concentration over time obtained following administration of methylphenidate in accord with an experimental regimen (open diamonds) and a standard regimen (closed circles) as described in Example 7. 15 DETAILED DESCRIPTION OF THE INVENTION Many effective drug therapies utilize immediate-release oral dosage forms administered at spaced intervals to provide and maintain a desired 20 therapeutic effect over a prolonged therapy period. In addition, sustained release dosage forms for many drugs are known and, in particular, constant release oral dosage forms are known. There are many examples of effective drug therapies that utilize constant-release oral dosage forms to provide a desired therapeutic effect over a prolonged therapy period. In many cases, 25 these drug therapies offer advantages over drug therapies that utilize immediate-release oral dosage forms administered at spaced intervals. There are clinical situations, however, where the constant-release dosage form has unexpectedly exhibited decreases in therapeutic effectiveness at time periods before the end of the desired prolonged therapy period. 30 One example of a clinical situation where drug therapy with sustained release oral drug dosage forms that provide a substantially constant rate of 11 drug release for an extended period has not been entirely satisfactory is with the use of central nervous system (CNS) stimulant drugs to treat various conditions and disorders including Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD). These disorders are 5 commonly diagnosed in children but can also occur in adults. Treatment of these and other psychological conditions with CNS stimulant drugs has a long history. About 25 years ago, methylphenidate replaced amphetamine as the primary stimulant prescribed to treat ADHD in children. Methylphenidate therapy in children with ADHD has been extensively - 1o studied and the efficacy and safety of this treatment is well-established. Methylphenidate therapy has been shown to be very effective in reducing symptoms of hyperactivity, inattention and impulsivity in children with ADHD. The goal of drug therapy is to control the behavioral symptoms during the daytime while the patient is in school or otherwise involved in activities where 15 symptom control benefits the patient's ability to learn and/or otherwise beneficially participate in activities. Because of concerns related to side effects, however, drug therapy is typically discontinued during at least a portion of the evening and through the night in most patients. Depending on the patient's particular circumstances, drug therapy may or may not be 20 discontinued over the weekends as well. Treatment commonly utilizes immediate-release methylphenidate administered two or three times during the day. For various reasons, patients often experience difficulty complying with this administration schedule. Because of abuse potential, methylphenidate is a controlled substance and 25 thus drug access is a special concern. This dosage regimen generally requires that at least one dose is administered during the school day and, as a rule, children are not permitted to self-administer the drug at school. For this reason, authorized school personnel generally take on the responsibility for administering the drug to children during the school day, however, this 30 approach raises issues of medical privacy and potential stigmatizing of the child by peers. In addition, the compliance issue becomes further 12 complicated as transportation, storage and supply of the drug typically must be documented and/or monitored and the schedules of the different parties involved, i.e., the child, the educators and the authorized school personnel, must be coordinated and accommodated. The unfortunate result is that 5 doses may be given late or missed altogether resulting in decreased efficacy of the therapy. For all of the above reasons, it would appear that a sustained-release oral dosage form of methylphenidate that provided substantially constant drug release over an extended period to thereby eliminate the need for dose 10 administration during the school day would be a welcome improvement. In fact, such a sustained-release dosage form of methylphenidate has been commercially available for several years. Clinical experience with this dosage form, however, has been disappointing in that behavioral symptoms in patients taking the controlled-release dosage form is less well-controiled later 1s in the day compared to those patients taking multiple doses of the immediate release dosage form. In addition, the slower onset of action of the controlled release dosage form compared to the immediate-release dosage form is unsatisfactory for many patients. It has been surprisingly discovered that administration of 20 methylphenidate at a release rate that is substantially ascending, rather than substantially constant, over an extended time period provided therapeutic efficacy similar to the efficacy obtained with multiple doses of immediate release methylphenidate dosage forms. Details of this discovery are disclosed in copending U.S. Application No. 910,593, filed July 31, 1997, of 25 which the present application is a continuation-in-part application. To briefly review, in one clinical study, a comparison of the. behavioral, attentional, and cognitive efficacy of placebo and methylphenidate administered according to three different release rate regimens, i.e., immediate-release, constant release and ascending-release, was performed. The immediate-release 30 methylphenidate was administered as two spaced-apart doses. The constant-release regimen was administered as an initial loading dose with the 13 remaining total quantity administered in equal small doses at closely-spaced intervals extending past the time of administration of the second immediate release dose. The ascending-release regimen was administered as an initial loading dose with the remaining total quantity administered in increasing 5 small doses at closely-spaced intervals extending past the time of administration of the second immediate-release dose. In this study, the constant-release regimen was observed to have decreased clinical effectiveness compared to the immediate-release regimen at evaluation periods following administration of the second immediate 10 release dose. On the other hand, the ascending-release regimen demonstrated comparable clinical efficacy to the immediate-release regimen during these evaluation periods. Thus, the ascending-release regimen avoided the decrease in therapeutic efficacy seen with the constant-release regimen at later time periods during the prolonged therapy period. 15 While not making any assertions with respect to mechanism(s) of action of the present invention, it is noted that the development of acute tolerance to methylphenidate has been proposed as an explanation for the unsatisfactory decrease in therapeutic effectiveness that has been observed in some cases. Support for this theory was demonstrated in a second clinical 20 study wherein a decrease in effectiveness of methylphenidate was seen over a prolonged therapy period both when a constant-release regimen was utilized as well as when very closely-spaced doses of immediate-release methylphenidate dosage forms were administered. An ascending-release regimen, however, was shown to maintain therapeutic efficacy throughout the 25 prolonged therapy period. With the discovery that drug effectiveness over a prolonged therapy period may be improved in some circumstances with administration of drug in an ascending release rate over an extended period, a need arises for sustained-release oral dosage forms adapted to provide such a release rate. 30 In one aspect of the present invention, it has been surprisingly discovered that bi-layer oral osmotic dosage forms can be adapted to meet this need. In 14 another aspect, it has been surprisingly discovered that sustained-release oral osmotic dosage forms having novel tri-layer cores can be produced that also achieve sustained release of drug formulations at an ascending rate for an extended time period. 5 As is known in the prior art, osmotic dosage forms comprising compressed tablet cores require a short time period following administration in which to become hydrated sufficiently to begin releasing drug. For some drug therapies, the slight delay in initial drug release is unsatisfactory. This problem is overcome with the addition of an initial dose of drug supplied in an 10 immediate-release overcoat applied to the surface of the semipermeable membrane. In preferred embodiments of the present invention, as disclosed herein, such an immediate-release drug overcoat is applied onto the surface of the- bi-layer or tri-layer osmotic dosage forms. For purposes of this disclosure, the following definitions shall apply: 15 For clarity and convenience herein, the convention is utilized of designating the time of drug administration as zero hours (t = 0 hours) and times following administration in appropriate time units, e.g., t = 30 minutes or t = 2 hours, etc. As used herein, the term "drug" generally refers to a pharmacologically 20 active substance that, when delivered into a living organism, produces a desired, usually beneficial, effect. Drug compositions are generally utilized clinically in the form of a pharmaceutically acceptable salt thereof. In addition, some drug compositions exhibit chirality and, thus, have more than one optical isomer. Because the different optical isomers may exhibit 25 different pharmacological effects, it may be advantageous to utilize a substantially pure form of one optical isomer of a drug, or a pharmaceutically acceptable salt thereof. Accordingly, the term "drug" refers to a clinically useful form of a drug composition including a pharmaceutically acceptable salt thereof and including a substantially pure isomer of the drug composition 30 and a pharmaceutically acceptable salt thereof. Although a limited number of drugs are represented in the exemplary embodiments herein, the invention is 15 not to be limited by the exemplary embodiments but is fully applicable to other suitable drugs as would be understood by persons of skill in the art. The amount of drug incorporated in the dosage forms of the present invention varies depending on the particular drug, the therapeutic indication s and the desired administration period, e.g., every 12 hours, every 24 hours, etc. Depending on the dose of drug desired to be administered, one or more of the dosage forms may be administered. A drug "release rate" refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr). 10 Drug release rates are calculated under in vitro dosage form dissolution testing conditions known in the art. As used herein, a drug release rate obtained at a specified time "following administration" refers to the in vitro drug release.rate obtained at the specified time following implementation of an appropriate dissolution test. The dissolution test utilized in the Examples 15 described herein were performed on dosage forms placed in metal coil sample holders attached to a USP Type VII bath indexer and immersed in about 50 ml of acidified water (pH = 3) equilibrated in a constant temperature water bath at 37 0 C. Aliquots of the release rate solutions were injected into a chromatographic system to quantify the amounts of drug released during the 20. testing intervals. A commonly-used reference measurement for evaluating drug release from oral dosage forms is the time at which 90% of drug within a dosage form has been released. This measurement is referred to as the "T" 90 for the dosage form. 25 An "immediate-release" dose of a drug refers to a dose that is substantially completely released within a time period of about 1 hour or less and, preferably, about 30 minutes or less. An immediate-release dose of drug applied as a coating on the surface of a dosage form, as used herein, refers to a dose of a drug prepared in a suitable pharmaceutically acceptable 30 carrier to form a coating solution that will dissolve rapidly upon administration to thereby provide an immediate-release dose of drug. As is known in the art, 16 such immediate-release drug overcoats may contain the same or a different drug or drugs as is contained within the underlying dosage form. A "periodic release rate" refers to the quantity of drug released from a dosage form during a specified periodic interval as determined at the end of s that specified periodic interval, i.e., at each periodic interval when a determination is made, the quantity of drug released represents the periodic release rate during that periodic interval. For example, the quantity of drug released as determined at t = 1 h represents the periodic release rate from the dosage form during the first hour following administration and the quantity 10 of drug released as determined at t = 2 h represents the periodic release rate during the second hour following administration, etc. An "ascending release rate" refers to a periodic release rate that is increased over the immediately-preceding periodic release rate, where the periodic intervals are the same. For example, when the quantity of drug 15 released from a dosage form is measured at hourly intervals and the quantity of drug released during the fifth hour following administration (determined at t = 5 hours) is greater than the quantity of drug released from the dosage form during the fourth hour following administration (determined at t = 4 hours), an ascending release rate from the fourth hour to the fifth hour has occurred. 20 It will be appreciated that the first periodic release rate measured, e.g., the periodic release rate at t = 1 hour (unless equal to 0), will always be greater than the release rate during the preceding period, e.g., the hour before the dosage form was administered, and, thus, the first periodic release rate always constitutes an occurrence of an ascending release rate. 25 The ascending release rates described herein refer to the release rate from a dosage form adapted to provide sustained release of drug and do not include release of drug from any immediate-release drug coating that may be applied to the dosage form. In dosage form embodiments additionally comprising an immediate-release dose of a drug applied as a coating onto the 30 underlying dosage form, the drug release measured at t = 1 hour will generally reflect both the drug released from the immediate-release drug 17 coating and any drug released from the underlying dosage form, however, the quantity of drug released from the drug overcoat is disregarded in determining whether the drug release rate at t = 2 hours is greater than the drug release at t = 1 hour. s As used herein with reference to the time period during which an ascending release rate is provided, "an extended time period" refers to a time period beginning at t = 0 hours and continuing through at least the mid-point, and preferably beyond the mid-point, of the relevant T90 of the dosage form. - *Because the dosage forms of the present invention are intended to provide 10 sustained release of drug, a suitable T., for purposes of this invention is at least about 6 hours and, consequently, the "extended time period" during which an ascending release rate is provided is at least 3 hours. In accord with the above-recited definitions, an "ascending release rate over an extended time period" refers to ascending release rates of drug 15 obtained from the time of administration of the dosage form through, and preferably beyond, the mid-point of the relevant T, for the dosage form. To illustrate, consider a situation where a dosage form has a T,( of about 8 hours. In this situation, an "ascending release rate over an extended time period" is achieved when the release rate at each hour through t = 4 hours is 20 greater than the release rate in the immediately-preceding hour. Preferably, the release rate continues to ascend during time periods beyond t = 4 hours. Bi-layer oral osmotic dosage forms and methods of making and using such dosage forms are known in the art, for example, as described and claimed in the following US Patents, owned by Alza Corporation: 4,327,725; 25 4,612,008; 4,783,337; and 5,082,668, each of which is incorporated in its entirety by reference herein. The prior art bi-layer osmotic dosage forms achieve sustained release of drug formulations wherein a relatively brief initial period of ascending release rates is followed by substantially constant release rates over a major portion of the T 90 period. The achievement of an 30 ascending release rate for an extended time period of at least 50% of the T 90 period is not found within the prior art. The dosage forms of the present 18 invention are useful for providing continuous effective drug therapy over a prolonged therapy period without exhibiting a decrease in effectiveness during the latter portion of the prolonged therapy period. The bi-layer oral osmotic dosage forms of the present invention include 5 a first component layer, comprising a selected drug and excipients for forming a deliverable drug composition when hydrated, and a second push layer, comprising a fluid-expandable osmopolymer and excipients, wherein the two layers are compressed into bi-layer tablet cores before the semipermeable membrane is applied and a suitable orifice for drug release therethrough is ) ) 10 formed. The combination of features including the osmotic properties of the component layers, the fluid flux properties of the semipermeable membrane and the configuration of the tablet core ensures that drug is released at an ascending rate over an extended time period. Importantly, the bi-layer tablet cores of the present invention are 15 configured such that each component layer is substantially round in cross dimension with a circumferential width and a length between a top and a bottom end. The two layers are compressed together longitudinally such that the resulting bi-layer tablet core has the same circumferential width as the component layers and a length that combines the lengths of the component 20 layers. The overall configuration can be described as "capsule-shaped" ) wherein the bi-layer tablet core has a circumferential width that is less than its length and has a rounded "narrow" top end and a rounded "narrow" bottom end and wherein each narrow end comprises a different component tablet layer. 25 For purposes of this disclosure, the above-described tablet cores are referred to as longitudinally compressed tablet ("LCT") cores. This LCT configuration ensures that, as the push layer expands longitudinally within the compartment formed by the semipermeable membrane, the surface area of the push layer in contact with the semipermeable membrane is increased 30 more than when other configurations are used.

19 In a preferred embodiment, sufficient activity in the push layer is achieved by use of a relatively large concentration (at least about 35%) of osmotically effective solute, or osmagent, such as sodium chloride. Consequently, the size of the push layer is relatively large and may be slightly s larger than the first component layer containing the drug and excipients. In addition, for certain embodiments, sorbitol was found to be a useful excipient in the first component layer. It has been surprisingly discovered that the combination of features described above, including the LCT core configuration, the relatively high percent of osmagent and, in some exemplary 10 embodiments, the use of sorbitol as an excipient provides the desired ascending release rate over an extended time period from bi-layer oral osmotic dosage forms. Exemplary embodiments of such bi-layer osmotic dosage forms are detailed below in Examples I - 3. An embodiment of a bi-layer oral osmotic dosage form 15 is shown in 15 cross-section in Figure 1. The components are not drawn to scale. The bi layer LCT core comprises a first component layer 21, containing drug and selected excipients, and a second push layer 29, containing at least one fluid expandable osmopolymer and optionally containing at least one osmagent along with selected excipients. Suitable excipients are known in the art and 20 include diluents, carriers, binders, fillers and processing aids. A semipermeable membrane 57 surrounds the bi-layer tablet core to form a compartment and a suitably sized orifice 55 is formed through the semipermeable membrane and into the first component layer 21 to permit drug formulation to be released from within the compartment. As illustrated, 25 the orifice 55 is preferably formed in the narrow end of the dosage form comprising the first component layer. In operation, through cooperation of the bi-layer osmotic dosage form components, drug is released from the first drug-containing layer at an ascending release rate for an extended time period. Although not shown in Figure 1, an immediate-release dose of a drug 30 may be provided by applying a drug-containing overcoat to a bi-layer dosage form, if desired, as described elsewhere herein.

20 In addition to the above-described bi-layer osmotic dosage forms, it has been surprisingly discovered that oral osmotic dosage forms exhibiting an ascending drug release rate for an extended time period can also be achieved with a novel tr-layer tablet core surrounded by a semipermeable s membrane and having suitable exit means for releasing drug formulation through the semipermeable membrane. The novel tri-layer tablet core has a first drug-containing layer, a second drug-containing layer and a third push layer. In operation, through the cooperation of the dosage form components, drug is successively released, in a sustained and controlled manner, from the 10 first drug-containing layer and then from the second drug-containing layer such that an ascending release rate over an extended time period is achieved. It has been discovered that a drug concentration gradient between the first and second drug-containing layers of the tri-layer core facilitates the 15 achievement of an ascending drug release rate for an extended time period from the tri-layer osmotic dosage form. Consequently, the other excipients in the drug-containing layers may be more flexibly varied and adjusted for other purposes such as manufacturing convenience and pharmaceutical elegance. For example, the tri-layer osmotic dosage forms preferably avoid the use of 20 sorbitol as an excipient. This provides manufacturing efficiency and product shelf-life advantages since sorbitol is very hygroscopic and attracts moisture during storage which can pose difficulties in handling and manufacturing as well as longer-term stability concerns. In addition, sufficient activity in the push layer may be achieved with the use of a relatively lower concentration 25 (less than about 25%) of osmotically effective solute such that the size of the push layer can be smaller relative to the size of the two drug-containing layers. Preferably, the push layer is smaller than the combined size of the first and second drug-containing layers. An advantage to a smaller-sized push layer is that larger doses of drug, if desired, can be accommodated 3o without the overall size of the dosage form becoming so large as to engender manufacturing challenges and/or to become unpalatable to patients.

21 In a presently preferred embodiment, the hydration rate of the tri-layer osmotic dosage form is improved with the inclusion of a flux-enhancing agent in the semipermeable membrane. In addition, it is preferred to use the longitudinally compressed tablet ("LCT") core configuration, as described s above, for the tri-layer osmotic dosage forms to also enhance hydration. In a presently preferred embodiment, the combination of features including the LCT tri-layer core configuration, a suitable drug concentration gradient between the first and second component layers, the osmotic properties of the component layers and the fluid flux properties of the semipermeable to membrane achieves the desired ascending rate of drug release over an extended time period. Advantageously, such preferred embodiments exhibit consistent and reliable operation and can be efficiently manufactured on a large-scale basis. A preferred embodiment of a tri-layer oral osmotic dosage form 15 additionally comprising an immediate-release dose of drug applied as an overcoat and an aesthetic overcoat 14 is shown in cross-section in Figure 2. The tri-layer LCT core comprises a first component layer 20, containing a selected drug in a pharmaceutically acceptable form along with selected excipients; a second component layer 18, containing a higher concentration 20 of drug along with selected excipients; and a third push layer 28, containing at least one osmopolymer and optionally containing at least one osmagent along with selected excipients. A semipermeable membrane 56 surrounds the tri layer tablet core to form a compartment and a suitably sized orifice 54 is formed through the semipermeable membrane and into the first component 25 layer to permit drug formulation to be released from within the compartment. As illustrated, the orifice 54 is preferably formed in the narrow end of the dosage form comprising the first component layer.. In operation, through cooperation of the tri-layer osmotic dosage form components, drug is successively released, in a sustained and controlled manner, from the first 30 drug-containing layer and then from the second drug-containing layer at an ascending release rate for an extended time period.

22 As shown in Figure 2, the preferred embodiment further comprises ah immediate-release dose of drug contained within an overcoat 60 applied onto the surface of the tri-layer osmotic dosage form. The drug is mixed with suitable excipients such as, for example, hydroxypropylmethylcellulose, to. 5 prepare a solution for coating onto the surface of the semipermeable membrane of the tri-layer osmotic dosage form that will rapidly dissolve and release drug following administration. As shown in Figure 2, it is also preferred to provide an optional aesthetic overcoat 62 applied onto the surface of the drug-containing 10 overcoat 60. As known in the art, such aesthetic overcoats provide advantages including taste-masking, improved appearance and "glidability" for facilitating swallowing and further processing steps such as printing, packaging, etc. Exemplary embodiments of tri-layer osmotic dosage forms that exhibit a substantially ascending release rate over an extended time 15 period are detailed below in Examples 4 - 6 and Examples 8 and 9. The continued maintenance of therapeutic effectiveness over a prolonged therapy period by the administration of the oral osmotic dosage forms that exhibit an ascending release rate over an extended time period of the present invention has been demonstrated. An exemplification is 20 described below in Example 7. In particular, it has been discovered that such osmotic dosage forms containing methylphenidate can be used to provide effective once-a-day therapy for ADHD. This discovery represents an important improvement in drug therapy for ADHD by eliminating the need for multiple daily doses of methylphenidate yet providing therapeutic efficacy. 25 throughout the day that compares to the therapeutic efficacy provided by multiple doses of immediate release methylphenidate. The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of the invention in any way, as these examples, and other equivalents thereof, will become 30 apparent to those versed in the art in the light of the present disclosure and the accompanying claims.

23 Example 1 Bi-layer oral osmotic dosage forms were made in accord with conventional manufacturing processes known in the art and disclosed in detail in copending U.S. Application No. 967,606, filed November 10, 1997, of s which the present application is a continuation-in-part application. Briefly, a first component layer, containing methylphenidate hydrochloride and selected excipients, and a second push layer, containing suitable osmopolymers, 40% by weight of an osmagent and selected excipients, were separately prepared by granulation methods. Next, the first component layer and the second push 10 layer granulation preparations were longitudinally compressed together to form bi-layer LCT cores. A selected semipermeable membrane was then coated around the bi-layer LCT cores and a suitable 30 mil orifice for drug release was formed therethrough and into the first component layer. Each dosage form as prepared comprised: 15 First component layer 14.08 mg methylphenidate hydrochloride 90.26 mg poly(ethylene)oxide (200,000 number-average 20 molecular weight) 5.5 mg poly(vinylpyrrolidone) (40,000 number-average molecular weight) 0.11 mg magnesium stearate 0.555 mg butylated hydroxy toluene 25 Second nush layer 71.032 mg poly(ethylene)oxide (7,000,000 number-average molecular weight) 30 52.8 mg sodium chloride 6.6 mg poly(vinylpyrrolidone) (40,000 number-average molecular weight) 24 1.32 mg red ferricoxide 0.132 mg magnesium stearate 0.555 mg butylated hydroxy toluene 5 Semipermeable Membrane 15.3 mg cellulose acetate (39.8% acetyl content) 1.7 mg poly(ethylene glycol) (3350 number-average molecular weight 10 The periodic release rates from the dosage form were determined hourly for ten hours using in vitro dissolution testing. A residual quantity of drug of 0.72 mg remained in the dosage form. The results are shown in Table I along with an indication of whether an ascending release rate 15 occurred. Table 1 Ascending Time (hours) Quantity of drug Release Rate released (mg) . Occurrence 1 0.22 YES 2 1.45 YES 3 1.72 YES 4 1.84 YES 5 2.05 YES 6 2.21 YES 7 2.13 NO 8 1.26 NO 9 0.39 NO 10 0.09 NO 25 As seen from Table 1, drug was released from the dosage forms at an ascending rate for an extended time period, i.e., more than 90% of the drug was released by t = 8 hours and ascending release rates occurred through t = 6 hours, an extended period of time well beyond the mid-point of the T,. 5 Example 2 Bi-layer oral osmotic dosage forms were made in accord with conventional manufacturing processes known in the art and disclosed in detail in copending U.S. Application No. 967,606, filed November 10, 1997, of 1o which the present application is a continuation-in-part application. Briefly, a first component layer, containing methylphenidate hydrochloride, sorbitol and selected excipients, and a second push layer, containing suitable osmopolymers, 40% by weight of an osmagent and selected excipients, were separately prepared by granulation methods. Next, the first component layer 15 and the second push layer granulation preparations were longitudinally compressed together to form bi-layer LCT cores. A selected semipermeable membrane was then coated around the bi-layer LCT cores and a suitable 30 mil orifice for drug release was formed therethrough. Each dosage form as prepared comprised: 20 First component layer (110 mq) 12.8% methylphenidate hydrochloride 54.75% poly(ethylene)oxide (200,000 number-average 25 molecular weight) 25.4% sorbitol 5% hydroxypropylmethylcellulose (11,200 number average molecular weight) 2% magnesium stearate 30 0.05% butylated hydroxy toluene 26 Second push layer (132 mq) 53.85% poly(ethylene)oxide (7,000,000 number-average molecular weight) 5 40% sodium chloride 5% hydroxypropylmethylcellulose (11,200 number average molecular weight) 1 % red ferric oxide 0.1% magnesium stearate ) 10 0.05% butylated hydroxy toluene Semipermeable Membrane (42 mq) 47.5% cellulose acetate (39.8% acetyl content) 15 47.5% cellulose acetate (32% acetyl content) -5% poly(ethylene glycol) (3350 number-average molecular weight The periodic release rates from the dosage form were determined 20 hourly for twelve hours. No residual quantity of drug remained in the dosage form. The results are shown in Table 2 along with an indication of the occurrences of an ascending release rate.

27 Table 2 Ascending Time (hours) Quantity of drug Release Rate released (mg) Occurrence 1 0.13 YES 2 1.16 YES 3 1.53 YES 4 1.61 YES 5 1.75 YES 6 1.79 YES 7 2.13 YES 8 2.18 YES 9 1.07 NO 10 0.43 NO 11 0.17 NO 12 0.13 NO As seen from Table 2, more than 90% of the drug was released by t = 9 hours and ascending release rates occurred through t = 8 hours, an extended time period well beyond the mid-point of the T9. -5 Example 3 Bi-layer oral osmotic dosage forms additionally comprising an immediate-release dose of drug applied as an overcoat onto the semipermeable membrane were made in accord with conventional 10 manufacturing processes known in the art and disclosed in detail in copending U.S. Application No. 967,606, filed November 10, 1997, of which the present application is a continuation-in-part application. Briefly, a first component layer, containing methylphenidate hydrochloride, sorbitol and selected excipients, and a second push layer, containing suitable 1s osmopolymers, 39.8% by weight of an osmagent and selected excipients, were separately prepared by granulation methods. Next, the first component 28 layer and the second push layer granulation preparations were longitudinally compressed together to form bi-layer LCT cores. A selected semipermeable membrane was then coated around. the bi-layer LCT cores and a suitable 30 mil orifice for drug release was formed therethrough. A drug-containing s overcoat mixture was prepared and coated onto the semipermeable membrane of the osmotic dosage form. Optionally, a taste-masking overcoat is also applied. Each osmotic bi-layer dosage form as prepared comprised: 10 First component layer 14 mg methylphenidate hydrochloride 61 mg poly(ethylene)oxide (2,000,000 number-average molecular weight) 15 27.5 mg sorbitol 5.5 mg polyvinylpyrrolidone 2.2 mg magnesium stearate 0.055 mg butylated hydroxy toluene 20 Second Dush layer )) 72 mg poly(ethylene)oxide (7,000,000 number-average molecular weight) 53 mg sodium chloride 25 6.6 mg polyvinylpyrrolidone 1.3 mg red ferric oxide 0.132 mg magnesium stearate 0.066 mg butylated hydroxy toluene 30 29. Semipermeable Membrane 20 mg cellulose acetate (39.8% acetyl content) 20 mg cellulose acetate (32% acetyl content) 5 2 mg poly(ethylene glycol) (4000 number-average molecular weight) An immediate-release drug-containing overcoat comprising 60% hydroxypropylmethylcellulose and 40% methylphenidate hydrochloride is 1n prepared and a final solution of 10 mg (i.e., containing 4 mg of methylphenidate salt) is coated onto the semipermeable membrane of the osmotic dosage form. The periodic release rates from the drug overcoat and the osmotic dosage form were determined at 30 minutes, 1 hour and then hourly for the 15 next nine hours. The 4 mg of methylphenidate contained within the drug overcoat was released within the first 30 minutes and the periodic release rate shown at t = 1 hour of 0.41 mg constitutes drug released from the bi layer osmotic dosage form during the second 30-minute interval. No residual quantity of drug remained in the dosage form. The hourly results are shown 20 in Table 3 along with an indication of the occurrences of an ascending release rate.

30 Table 3 Ascending Time (hours) Quantity of drug Release Rate released (mg) Occurrence 1 0.41 YES 2 1.05 YES 3 1.49 YES 4 1.57 YES 5 1.71 YES 6 1.75 YES 7 2.09 YES 8 2.14 YES 9 1.32 NO 10 0.48 NO As seen from Table 3, exclusive of the immediate-release drug overcoat, more than 90% of the drug was released by t = 9 hours and ascending release rates occurred through t = 8 hours, an extended period of 5 time well beyond the mid-point of the T 90 . Example 4 Tri-layer oral osmotic dosage forms were made in accord with conventional manufacturing processes known in the art and disclosed in 10 detail in copending U.S. Application No. 937,336, filed August 19, 1997, of which the present application is a continuation-in-part application. Briefly, a first component layer, containing pseudoephedrine hydrochloride and selected excipients, a second component layer, containing a higher concentration of pseudoephedrine hydrochloride and selected excipients, and 15 a third push layer, containing suitable osmopolymers, an osmagent and selected excipients, were separately prepared by granulation methods. Next, the first component layer, second component layer and the third push layer granulation preparations were longitudinally compressed together to form tri- 31 layer LCT cores. A selected semipermeable membrane was then coated around the tri-layer LCT cores and a suitable 30 mil orifice for drug release was formed therethrough. Each dosage form as prepared comprised: 5 First component layer 4.4 mg pseudoephedrine hydrochloride 15.3 mg poly(ethylene)oxide (300,000 number-average 10 molecular weight) 1.1 mg hydroxypropylmethylcellulose (9,200 number average molecular weight) 1.1 mg polyoxyethylene 40 stearate 0.11 mg. magnesium stearate 15 Second component layer 13.5 mg pseudoephedrine hydrochloride 2.59 mg poly(ethylene)oxide (300,000 number-average. 20 molecular weight) 0.9 mg hydroxypropylmethylcellutose (9,200 number average molecular weight) 0.9 mg polyoxyethylene 40 stearate 0.018 mg red ferric oxide 25 0.09 mg magnesium stearate Third push layer 22.2 mg poly(ethylene)oxide (7,000,000 number-average 30 molecular weight) 12 mg sodium chloride 32 2 mg hydroxypropylmethylcellulose (9,200 number average molecular weight) 2 mg polyoxyethylene 40 stearate 1.2 mg cross-linked acrylic acid polymer 5 0.4 mg red ferric oxide 0.2 mg magnesium stearate Semipermeable Membrane 10 11.4 mg cellulose acetate (39.8% acetyl content) 0.6 mg polyethylene glycol (3350 average number molecular weight) The periodic release rates from the osmotic dosage form were 15 determined hourly for 7 hours and results are shown in Table 4 along with an indication of the occurrences of an ascending release rate. Table 4 Ascending Time (hours) Quantity of drug Release Rate released (mg) Occurrence 1 0.13 YES 2 0.65 YES 3 2.2 YES 4 2.78 YES 5 3.24 YES 6 3.14 YES 7 3.43 YES As seen from Table 4, about 87% of drug was released during the first 20 7 hours and ascending release rates were achieved throughout this period.

33 Example 5 Tri-layer oral osmotic dosage forms having a drug concentration gradient wherein the drug concentration was greater in the second component layer than the first component layer and also having viscosity 5 gradients wherein the viscosity of the first component layer was less than the viscosity of the second component layer and the viscosity of the second component layer was lower than the viscosity of the third push layer were made in accord with conventional manufacturing processes known in the art and disclosed in detail in copending U.S. Application No. 937,336, filed o August 19, 1997, of which the present application is a continuation-in-part application. Each dosage form as prepared comprised: First component layer (350 mq) 15 8.6% nicardipine 54.8% sorbitol 36.8% poly(ethylene)oxide (200,000 number-average molecular weight) 20 Second component layer (120 mg) 45% nicardipine 50% poly(ethylene)oxide (300,000 number-average 25 molecular weight) 5% hydroxypropylmethylcellulose (9,200 number average molecular weight) 30 34 Third push layer (350 mq) 68.75% poly(ethylene)oxide (7,000,000 number-average molecular weight) 5 20% sodium chloride 5% hydroxypropylmethylcellulose (9,200 number average molecular weight) 5% cross-linked acrylic acid polymer 1% ferric oxide 10 0.25% magnesium stearate Semipermeable Membrane (43.5 mg) 95% cellulose acetate (39.8% acetyl content) 15 5% polyethylene glycol (3350 average number molecular weight) The dosage forms had 25 mil exit orifices formed through the semipermeable membrane to permit release of drug formulation from within 20 the compartment. An ascending release rate for an extended time period of about 16 hours was achieved with the dosage forms of Example 5. Example 6 Preferred embodiments of the tri-layer osmotic dosage forms of the 25 present invention additionally comprising an immediate-release dose of drug applied as an overcoat, as shown in Figure 2, were prepared in accord with conventional osmotic tablet manufacturing processes. The first component layer contained the following (by weight percent): 9.40% methylphenidate hydrochloride, 83.71% polyethylene oxide (Polyox N 30 80 brand product of Union Carbide, Danbury, CT), 5% polyvinylpyrrolidone 35 (Kolidon 29-32 product of BASF Corp., Mt. Olive, NJ); 1.34% succinic acid; 0.5% stearic acid; and 0.05% butylated hydroxy toluene. The second component layer contained the following (by weight percent): 13.65% methylphenidate hydrochloride, 78.80% polyethylene oxide 5 (Polyox N-80 brand product of Union Carbide, Danbury, CT), 5% polyvinylpyrrolidone (Kolidon 29-32 product of BASF Corp., Mt. Olive, NJ); 1.95% succinic acid; 0.5% stearic acid; 0.05% butylated hydroxy toluene; and 0.05% yellow ferric oxide, as coloring agent. The third push layer contained the following (by weight percent): 73.7% 10 high molecular weight polyethylene oxide (Polyox 303 brand product of Union Carbide, Danbury, CT), 20% sodium chloride; 5% polyvinylpyrrolidone (Kolidon 29-32 brand product of BASF Corp., Mt. Olive, NJ); 0.25% stearic acid; 0.05% butylated hydroxy toluene; and 1% green ferric oxide, as coloring agent. 1s Each of the first component layer, second component layer and third push layer were separately prepared into granulated compositions in a fluid bed granulator. The granulated compositions were then compressed sequentially and longitudinally on a rotary tablet press to produce the tri-layer LCT cores. For each dosage form, 40 mg of the first component layer 20 granulation and 75 mg of the second component layer granulation were first sequentially filled and tamped at 100 newtons into the die. Then, 90 mg of the third push layer granulation to the die was added to the die and the final compression was performed at 1500 newtons. The composition of the semipermeable membrane was 83% by weight 25 cellulose acetate (CA 398-10, having an acetyl content of 39.8%, product of Eastman Chemical, Kingsport, TN) and 17% by weight copolymer of ethylene and propylene oxide (Poloxamer 188 brand product of BASF Corp., Mt. Olive, NJ, added as a flux-enhancer. The two ingredients were dissolved in a blend of 99.5% acetone and 0.5% water to form a 5% solids solution. In a pan 30 coater, the solution was then sprayed onto the tri-layer LCT cores to a weight of 25.7 mg and a thickness of 4-5 mil.

36 After the semipermeable membrane had been applied to form a compartment containing the tri-layer LCT cores, a 0.76 mm (40 mil) orifice was drilled through the semipermeable membrane at the narrow end of the compartment proximate to the first component layer to thereby form the 5 preferred tri-layer osmotic dosage forms, each containing 14 mg of methylphenidate. Each dosage form was approximately 12 mm long with an approximate diameter of 5.3 mm. The drug overcoat for providing an immediate-release initial dose of drug contains approximately 30% by weight methylphenidate hydrochloride, 10 approximately 70% by weight hydroxypropylmethylcellulose (Methocel E3 brand name product of Dow Chemical Co., Midland, MI), and a trace amount of phosphoric acid (i.e., 20 ml of phosphoric acid added to 87 kg of drug in solution). An aqueous coating solution is prepared by dissolving and mixing the ingredients in water to form a solution with a 10% solids composition. In a 15 pan coater, the solution was then sprayed onto the semipermeable membranes of the tri-layer osmotic dosage forms to a weight of about 14.0 mg comprising an immediate-release dose of methylphenidate of about 4mg. The final aesthetic overcoat composition weighed 16.9 mg and contained an underlayer of Opadry II, yellow (brand name product of 20 Colorcon, West Point, PA and an overlayer of Opadry, clear, with a trace amount of carnauba wax, a glidant, prepared and applied as follows: first, Opadry 11 (10%) is suspended in water (90%) and sprayed onto the drug overcoated dosage forms; next, clear Opadry (5%) is suspended in water (95%) and sprayed onto the drug- and Opadry l-overcoated dosage forms; 25 finally, the dosage forms are tumbled in the coater with the carnauba wax for ten minutes to allow about 100 ppm of wax to be uniformly distributed onto the clear Opadry overcoat. Many pharmaceutical dosage forms utilize drug in salt form such as the hydrochloride salt of methylphenidate utilized herein. Such salt forms of 30 drugs prepared in aqueous solution, however, are prone to degradation and, thus, often have stability and shelf-life problems. It has been discovered that 37 the addition of an appropriate pH-adjusting agent to the aqueous solution decreases undesired degradation and improves the stability of the product. In particular, in preferred embodiments tri-layer osmotic dosage forms comprising methylphenidate hydrochloride, it has been discovered that 5 degradation of the drug ingredient can be minimized by the addition of suitable antidegradation agents, i.e., succinic acid in the first and second component layers and phosphoric acid in the drug overcoat. Other suitable antidegradation agents include compounds that dissolve in an aqueous medium are pharmaceutically acceptable, i.e., nontoxic and suitable for oral 10 administration to humans, and that exhibit sufficient pH-adjusting ability, i.e., have a pH no greater than 4 and preferably of 3 or below. Additional examples include potassium phosphate, sodium phosphate, fumaric acid, citric acid, tartaric acid, malic acid, hydrochloric acid, aspartic acid, glutamic acid, oxalic acid, lactic acid, malonic acid, glyceric acid and ascorbic acid. 15 Periodic release rates for twenty-four sample dosage forms prepared as described were determined hourly for 12 hours and are presented in grapn form in Figure 3. The mean quantities released each hour are shown in Table 5 along with an indication of the occurrences of an ascending release rate. It is noted that the entire 4 mg immediate-release dose was essentially released 20 within the first hour and this quantity is disregarded with respect to the determination that an ascending release rate occurred at t = 2 hours, i.e., the mean quantity at t = 2 hours was compared to the mean quantity at t = 1 hours less 4 mg representing the immediate-release dose.

38 Table 5 Ascending Time (hours) Quantity of drug Release Rate released (mg) Occurrence 1 4.098 YES 2 1.138 YES 3 1.650 YES 4 1.993 YES 5 2.043 YES 6 2.099 YES 7 1.966 NO 8 1.763 NO 9 0.428 NO 10 0.174 NO 11 0.084 NO 12 0.061 NO As seen from Table 5, exclusive of the immediate-release drug overcoat, more than 90% of the drug was released by t = 8 hours and ascending release rates occurred through t = 6 hours, an extended period of 5 time well beyond the mid-point of the T 90 . )i Example 7 Therapeutic effectiveness of single doses of tri-layer osmotic dosage forms containing 14 mg of methylphenidate and additionally comprising an io immediate-release drug overcoat containing 4 mg of methylphenidate was studied and-compared to multiple doses of immediate-release methylphenidate. Safety and therapeutic efficacy parameters were evaluated for a 12-hour period in the same subjects treated with the following regimens on different days: the experimental regimen wherein the tri-layer osmotic dosage form 1s was administered once at t = 0 hours and the standard regimen wherein immediate-release methylphenidate (Ritalin@) was administered three times, 39 at t = 0 hours, t = 4 hours, and t = 8 hours. Because the subjects were current methylphenidate users, the doses of methylphenidate administered during each regimen varied somewhat to match as closely as possible the "usual dose" each subject was routinely administered. For comparative 5 purposes, the actual doses were normalized to a single 18 mg dose of the tri layer osmotic dosage and to 15 mg of Ritalin@ administered as three 5 mg doses. Plasma drug concentrations were determined in all subjects at the same times during the study periods for each regimen. The selected times 10 corresponded to the time just prior to, and 1.5 hours and 2.5 hours following, administration of the first two doses of immediate-release methylphenidate (i.e., at t = 0 hours, t = 1.5 hours, t = 2.5 hours, t = 4 hours, t = 5.5 hours, t 6.5 hours), and just prior to, and 1.5 hours and 3.5 hours following, administration of the third dose (i.e., at t = 8 hours, t = 9.5 hours and t = 11.5 15 hours). In Figure 4, plasma drug concentrations obtained from one group of study participants (n = 16) while treated with the experimental regimen (represented by open diamonds) and while treated with the standard regimen (represented by closed circles) are shown in graph form. A comparison of 20 Figures 3 and 4 demonstrates a correlation between the in vitro release rates through about t = 8 hours and the in vivo plasma drug concentrations through about t = 9.5 hours. As shown in Figure 4, the plasma drug concentration following each administration of an immediate-release dose rises relatively rapidly and then 25 declines at a generally characteristic rate until the next dose is administered. The plasma drug concentration following administration of the tri-layer osmotic dosage form also exhibits an initial relatively rapid rise due largely to release of drug from the immediate-release drug overcoat. Subsequently, however, the plasma drug concentration does not decline but continues to 30 substantially ascend (save for a slight "dip" between t = 5.5 hours and t = 6.5 hours) through a time period of 9.5 hours. Particularly striking is the 40 difference during the time periods within about 1 hour before and about 1.5 hours following administration of the second and the third immediate-release dose. With the standard regimen, during these periods, the plasma drug concentration declines to a trough concentration and then rises again to a 5 peak concentration. With the experimental regimen, during. these same time periods, the plasma drug concentration is substantially smoothly ascending and exhibits no peaks and troughs. Safety and therapeutic parameters, including behavioral, attentional and cognitive functions, were assessed hourly during the first three hours and 10 the last three hours of the study period and at two-hour intervals in between. The clinical effectiveness of the experimental regimen was closely comparable to the clinical effectiveness of the standard regimen throughout the twelve-hour study period. An effective once-a-day therapy for ADHD proVides many advantages and offers a significant improvement in drug 15 therapy by eliminating the need for multiple daily doses of methylphenidate while providing continued therapeutic efficacy throughout the day. Example 8 Tri-layer oral osmotic dosage forms were made in accord with the 20 manufacturing processes of Example 6 but comprising twice as much methylphenidate, i.e., a total of 28 mg of methylphenidate contained within the first and second component layers and 8 mg of methylphenidate in the drug overcoat. All of the remaining ingredients are also doubled so that the weight percents are the same as in Example 6. The third push layer is also 25 doubled. The semipermeable membrane had the same composition as in Example 6 but was applied to a weight of about 34 mg. These dosage forms exhibit release of 36 mg of methylphenidate with about 8 mg released immediately and the remaining 28 mg released at an ascending release rate over an extended time period. 30 41 Example 9 Tri-layer oral osmotic dosage forms were made in accord with the manufacturing processes of Example 6 but comprising a total of 42 mg of methylphenidate contained within the first and second component layers and 5 12 mg of methylphenidate in the drug overcoat. The first component layer contained the following (by weight percent): 11.5% methylphenidate hydrochloride, 81.6% polyethylene oxide (Polyox N-80 brand product of Union Carbide, Danbury, CT), 5% polyvinylpyrrolidone (Kolidon 29-32 product of BASF Corp., Mt. Olive, NJ); 1.3% succinic acid; 0.5% stearic acid; 0.05% 10 butylated hydroxy toluene; and 0.05% yellow ferric oxide, as coloring agent. The second component layer contained the following (by weight percent): 19.8% methylphenidate hydrochloride, 72.7% polyethylene oxide (Polyox N 80 brand product of Union Carbide, Danbury, CT), 5% polyvinylpyrrolidone (Kolidon 29-32 product of BASF Corp., Mt. Olive, NJ); 1.95% succinic acid; 15 0.5% stearic acid; and 0.05% butylated hydroxy toluene. The third push layer is doubled from Example 6 and the semipermeable membrane had the same composition as in Example 6 but was applied to a weight of about 34 mg. These dosage forms exhibit release of 54 mg of methylphenidate with about 12 mg released immediately and the remaining 42 mg released at an 20 ascending release rate over an extended time period. While there has been described and pointed out features and advantages of the invention, as applied to present embodiments, those skilled in the art will appreciate that various modifications, changes, additions, and omissions in the descriptions within the specification can be made without 25 departing from the spirit of the invention.

Claims (93)

1. An osmotic dosage form comprising: a capsule-shaped longitudinally compressed tablet core containing a plurality of layers wherein drug is contained in at least one layer and at least one other layer 5 comprises a suitable fluid-expandable polymer; a semipermeable wall surrounding said longitudinally compressed tablet core to thereby form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting said semipermeable wall into said compartment; and 10 an orifice formed through said semipermeable wall and into said longitudinally compressed tablet core to permit drug to be released from within said compartment into said external fluid environment.

2. The dosage form described in claim 1 wherein said longitudinally compressed tablet core comprises two layers and wherein said orifice is formed through said 15 semipermeable wall at a location adjacent to said layer wherein said drug is contained.

3. The dosage form described in claim 1 wherein said longitudinally compressed tablet core comprises three layers and a portion of said drug is contained within a first layer and the remaining portion of said drug is contained within a second layer, wherein the concentration of drug contained within said first layer is less than the concentration 20 of drug contained within said second layer, and wherein said fluid-expandable polymer is contained within a third layer and said orifice is formed through said semipermeable wall at a location adjacent to said first layer.

4. The dosage form described in claim 2 or 3 further comprising an immediate release dose of a drug applied as a coating onto the outer surface of said osmotic 25 dosage form.

5. The dosage form described in claim 1 wherein said CNS-stimulant drug is methylphenidate.

6. The dosage form described in claim 1 wherein said semipermeable membrane comprises cellulose acetate and a flux-enhancing agent. - 43

7. A dosage form comprising: a first drug layer comprising drug; a second drug layer comprising an additional quantity of said drug, wherein the quantity of said drug in said second layer is greater than the quantity of said drug in 5 the first layer; a third layer comprising a composition that expands and displaces the first drug layer followed by the second drug layer from the dosage form; a wall that surrounds the three layers, which wall is permeable to fluid and impermeable to drug; and 10 a passageway in the wall communicating with the first drug layer for delivering the first drug layer followed by the second drug layer from the dosage form wherein said drug layers and wall are shaped and adapted to interact cooperatively such that drug is released from the dosage form at an ascending release rate beginning with a first periodic interval that begins at time t = 0 and continuing up to at least about 15 5.5 hours following administration of said dosage form.

8. The dosage form of claim 7 wherein said drug is a CNS-stimulant drug selected from the group consisting of methylphenidate, d-threo-methylphenidate, amphetamine, dextroamphetamine, methamphetamine, and pemoline.

9. The dosage form of claim 7 further comprising a drug layer overcoat. 20

10. The dosage form of claim 7 wherein the third layer further comprises at least one osmagent.

11. The dosage form of claim 7 wherein said wall further comprises an immediate-release dosage of the drug applied as a coating onto the outer surface.

12. The dosage form of claim 7 wherein said wall further comprises cellulose 25 acetate and a flux-enhancing agent.

13. A dosage form comprising a capsule shaped tablet core comprising two layers, wherein: a first of said two layers comprises a portion of drug, a second of said layers comprises a suitable fluid-expanding polymer and is 30 adjacent said first layer, - 44 a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment, and an orifice formed through the semipermeable membrane and into the capsule 5 shaped tablet core at a location adjacent to the first layer to permit the drug to be released from within the compartment into the external fluid environment, and wherein the dosage form releases the drug at an ascending release rate beginning with a first periodic interval that begins at time t = 0 and continuing up to at least about 5.5 hours following administration of said dosage form. 10

14. The dosage form of claim 13 wherein the drug layer comprises methylphenidate or pharmaceutically acceptable salt thereof.

15. The dosage form of claim 13 that further comprises a drug layer overcoat.

16. The dosage form of claim 13 wherein the second layer further comprises at least one osmagent. 15

17. The dosage form of claim 16 that is a bi-layer dosage form comprising a drug layer and a push layer.

18. The dosage form of claim 13 further comprising an outer surface and an immediate-release dosage of the drug applied as a coating onto the outer surface.

19. The dosage form of claim 13 wherein the semipermeable membrane further 20 comprises cellulose acetate and a flux-enhancing agent.

20. A method comprising orally administering an osmotic dosage form comprising: a capsule-shaped longitudinally compressed tablet core containing a plurality of layers wherein drug is contained in at least one layer and at least one other layer 25 comprises a suitable fluid-expandable polymer; a semipermeable wall surrounding said longitudinally compressed tablet core to thereby form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting said semipermeable wall into said compartment; and - 45 an orifice formed through said semipermeable wall and into said longitudinally compressed tablet core to permit drug to be released from within said compartment into said external fluid environment.

21. A method comprising orally administering a capsule shaped dosage form 5 comprising: a first drug layer comprising drug; a second drug layer comprising an additional quantity of said drug, wherein the quantity of said drug in said second layer is greater than the quantity of said drug in the first layer; 10 a third layer comprising a composition that expands and displaces the first drug layer followed by the second drug layer from the dosage form; a wall that surrounds the three layers, which wall is permeable to fluid and impermeable to drug; and a passageway in the wall communicating with the first drug layer for 15 delivering the first drug layer followed by the second drug layer from the dosage form wherein said drug layers and wall are shaped and adapted to interact cooperatively such that drug is released from the dosage form at an ascending release rate beginning with a first periodic interval that begins at time t = 0 and continuing up to at least about 5.5 hours following administration of said dosage form. 20

22. A method comprising orally administering a dosage form comprising a capsule shaped tablet core comprising two layers, wherein: a first of said two layers comprises a portion of a drug, a second of said layers comprises a suitable fluid-expanding polymer and is adjacent said first layer, 25 a semipermeable membrane surrounding the capsule shaped tablet core to form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting the semipermeable membrane into the compartment, and an orifice formed through the semipermeable membrane and into the capsule shaped tablet core at a location adjacent to the first layer to permit the drug to be 30 released from within the compartment into the external fluid environment, and wherein the dosage form releases the drug at an ascending release rate beginning with a first periodic interval that begins at time t = 0 and continuing up to at least about 5.5 hours following administration of said dosage form. - 46

23. A dosage form comprising a capsule shaped tablet core comprising: two layers, wherein a first of said two layers comprises a portion of drug, wherein said drug comprises-methylphenidate hydrochloride, and wherein a second of said layers comprises a suitable fluid-expanding polymer; 5 a semipermeable membrane that surrounds the capsule shaped tablet core to form a compartment that has an osmotic gradient that drives fluid from an external fluid environment contacting the semipermeable membrane into the compartment; and an orifice that is formed through the semipermeable membrane at a location adjacent to the first layer that permits the drug to be released from the compartment into 10 the external fluid environment, wherein the dosage form releases the drug over a period comprising a first, second, and third sequential time intervals of equal duration, and wherein the dosage form releases more of said drug during said second interval than during said first interval and more of said drug during said third interval 15 than during said second interval.

24. The dosage form according to claim 23 wherein said period of release comprises a fourth sequential time interval, and wherein the dosage form releases more of said drug during said fourth interval than during said third interval.

25. The dosage form according to claim 23 further comprising an immediate 20 release dosage of the drug applied as a coating on an outer surface of the dosage form.

26. The dosage form according to claim 25 wherein the dosage form releases more of said drug during said second interval than during said first interval, not including drug released from said coating during said first interval.

27. The dosage form according to claim 23 or wherein the drug released during 25 said first interval does not include any drug released from said capsule shaped tablet core.

28. The dosage form according to claim 23 further comprising a third layer comprising an additional portion of said drug, wherein said third layer is disposed between said first layer and said second layer. - 47

29. A method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising orally administering a dosage form to said subject, wherein said dosage form comprises: an immediate release portion comprising methylphenidate or a 5 pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 10 2.5 hours following administration to 5.5 hours following administration.

30. The method according to claim 29 wherein said immediate release portion and said sustained release portion each comprise D-methylphenidate or methylphenidate hydrochloride.

31. The method according to claim 29 wherein said dosage form provides a 15 substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration.

32. The method according to claim 29 wherein said blood plasma at a time up to 4 hours following administration comprises said methylphenidate or pharmaceutically effective salt thereof from said immediate release portion. 20

33. A tablet dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically 25 effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 2.5 hours following administration to 5.5 hours following administration.

34. The dosage form according to claim 33 wherein said immediate release 30 portion and said sustained release portion each comprise D-methylphenidate or methylphenidate hydrochloride. - 48

35. The dosage form according to claim 33 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration.

36. The dosage form according to claim 33 wherein said blood plasma at a time 5 up to 4 hours following administration comprises said methylphenidate or pharmaceutically effective salt thereof from said immediate release portion.

37. The dosage form according to claim 33 wherein said blood plasma at a time after 4 hours following administration does not comprise said methylphenidate or pharmaceutically effective salt thereof from said immediate release portion. 10

38. The method according to claim 29 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 2.5 hours following administration to 6.5 hours following administration.

39. The method according to claim 29 wherein said dosage form provides a 15 substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 6.5 hours following administration.

40. The method according to claim 33 wherein the methylphenidate hydrochloride in said immediate release coating is released primarily during said first interval.

41. The dosage form according to claim 33 wherein said dosage form provides a 20 substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 6.5 hours following administration.

42. A tablet oral dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a 25 pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein: - 49 said dosage form releases said methylphenidate over a period comprising first, second, third, fourth, fifth, sixth, and seventh sequential one-hour time intervals, and said sustained release portion releases more of said methylphenidate during said second interval than during said first interval, more of said methylphenidate during said 5 third interval than during said second interval, and more of said methylphenidate during said fourth interval than during said third interval.

43. The dosage form according to claim 42 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration. 10

44. The dosage form according to claim 42 wherein said sustained release portion comprises methylphenidate hydrochloride.

45. A tablet oral dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a 15 pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 20 2.5 hours following administration to 5.5 hours following administration.

46. The dosage form according to claim 45 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration.

47. The dosage form according to claim 45 wherein said dosage form portion 25 releases said methylphenidate over a period comprising first, second, third, fourth, fifth, sixth, seventh, and eighth sequential 30 minute time intervals.

48. The dosage form according to claim 47 wherein said sustained release portion releases more of said methylphenidate during said eighth interval than during said seventh interval. - 50

49. The dosage form according to claim 45 wherein said dosage form releases said methylphenidate over a period comprising first, second, and third sequential two hour time intervals.

50. The dosage form according to claim 49 wherein said sustained release 5 portion releases more of said methylphenidate during said second interval than during said first interval.

51. The dosage form according to claim 49 wherein said sustained release portion releases more of said methylphenidate during said third interval than during said second interval. 10

52. The dosage form according to claim 51 wherein said dosage form releases said methylphenidate over a period comprising first, second, third, and fourth sequential two-hour time intervals.

53. The dosage form according to claim 52 wherein said sustained release portion releases more of said methylphenidate during said second interval than 15 during said third interval, and releases more of said methylphenidate during said fourth interval than during said third interval.

54. The dosage form according to claim 52 wherein said sustained release portion releases more of said methylphenidate during said second interval than during said third interval, but releases less of said methylphenidate during said fourth 20 interval than during said third interval.

55. The dosage form according to claim 45 wherein said sustained release portion comprises methylphenidate hydrochloride.

56. A tablet oral dosage form for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising: 25 an immediate release portion comprising methylphenidate or a pharmaceutically effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein: - 51 said dosage form releases said methylphenidate over a period comprising at least a first and a second sequential time intervals, and said sustained release portion releases more of said methylphenidate during said first interval than during said second interval. 5

57. The dosage form according to claim 56 wherein said dosage form releases said methylphenidate over a period comprising first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and thirteenth sequential 30 minute time intervals.

58. The dosage form according to claim 57 wherein said sustained release 10 portion releases more of said methylphenidate during said eighth interval than during said fifth interval.

59. The dosage form according to claim 57 wherein said sustained release portion releases more of said methylphenidate during said eighth interval than during said seventh interval. 15

60. The dosage form according to claim 57 wherein said sustained release portion releases more of said methylphenidate during said ninth interval than during said eighth interval.

61. The dosage form according to claim 56 wherein said dosage form releases said methylphenidate over a period comprising first, second, and third sequential two 20 hour time intervals.

62. The dosage form according to claim 61 wherein said sustained release portion releases more of said methylphenidate during said second interval than during said first interval.

63. The dosage form according to claim 62 wherein said sustained release 25 portion releases more of said methylphenidate during said third interval than during said second interval.

64. The dosage form according to claim 56 wherein said sustained release portion comprises methylphenidate hydrochloride. - 52

65. A method for effectively treating Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder in a subject comprising orally administering a dosage form to said subject, wherein said dosage form comprises: an immediate release portion comprising methylphenidate or a pharmaceutically 5 effective salt thereof; and a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 10 2.5 hours following administration to 5.5 hours following administration and wherein: said dosage form releases said methylphenidate over a period comprising at least a first and a second sequential time intervals, and said sustained release portion releases more of said methylphenidate 15 during said first interval than during said second interval.

66. The method according to claim 65 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration.

67. The method according to claim 65 wherein said dosage form provides a 20 substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 6.5 hours following administration.

68. The method according to claim 65 wherein said period of release comprises a third sequential time interval.

69. The method according to claim 68 wherein said period of release comprises 25 first, second, and third two-hour time intervals.

70. The method according to claim 69 wherein the sustained release portion releases more of said methylphenidate during said third interval than during said second interval. - 53

71. The method according to claim 68 wherein said period of release comprises a fourth sequential time interval, and wherein the sustained release portion releases more of said methylphenidate during said fourth interval than during said third interval.

72. The method according to claim 71 wherein said period of release comprises 5 first, second, third, and fourth one-hour time intervals.

73. The method according to claim 65 wherein said dosage form releases said methylphenidate over a period comprising first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and thirteenth sequential 30 minute time intervals. 10

74. The method according to claim 73 wherein said sustained release portion releases more of said methylphenidate during said eighth interval than during said fifth interval.

75. The method according to claim 73 wherein said sustained release portion releases more of said methylphenidate during said eighth interval than during said 15 seventh interval.

76. The method according to claim 73 wherein said sustained release portion releases more of said methylphenidate during said ninth interval than during said eighth interval.

77. The method according to claim 65 wherein said immediate release portion 20 and said sustained release portion each comprise D-methylphenidate or methylphenidate hydrochloride.

78. The method according to claim 65 wherein the methylphenidate hydrochloride in said immediate release coating is released primarily during said first interval.

79. A tablet oral dosage form for effectively treating Attention Deficit Disorder or 25 Attention Deficit Hyperactivity Disorder in a subject comprising: an immediate release portion comprising methylphenidate or a pharmaceutically effective salt thereof; and - 54 a sustained release portion comprising methylphenidate or a pharmaceutically effective salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 5 2.5 hours following administration to 5.5 hours following administration and wherein: said dosage form releases said methylphenidate over a period comprising at least a first and a second sequential time intervals, and said sustained release portion releases more of said methylphenidate 10 during said first interval than during said second interval.

80. The dosage form according to claim 79 wherein said dosage form provides a substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof from 1.5 to 5.5 hours following administration.

81. The dosage form according to claim 79 wherein said dosage form provides a 15 substantially ascending blood plasma concentration of said methylphenidate or pharmaceutically effective salt thereof up to about 6.5 hours following administration.

82. The dosage form according to claim 79 wherein said period of release comprises a third sequential time interval.

83. The dosage form according to claim 82 wherein said period of release 20 comprises first, second, and third two-hour time intervals.

84. The dosage form according to claim 83 wherein the sustained release portion releases more of said methylphenidate during said third interval than during said second interval.

85. The dosage form according to claim 79 wherein said period of release 25 comprises first, second, third, and fourth one-hour time intervals.

86. The dosage form according to claim 79 wherein said dosage form releases said methylphenidate over a period comprising first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and thirteenth sequential 30 minute time intervals. - 55

87. The dosage form according to claim 86 wherein said sustained release portion releases more of said methylphenidate during said eighth interval than during said fifth interval.

88. The dosage form according to claim 86 wherein said sustained release 5 portion releases more of said methylphenidate during said eighth interval than during said seventh interval.

89. The dosage form according to claim 86 wherein said sustained release portion releases more of said methylphenidate during said ninth interval than during said eighth interval. 10

90. The dosage form according to claim 79 wherein said immediate release portion and said sustained release portion each comprise D-methylphenidate or methylphenidate hydrochloride.

91. The dosage form according to claim 79 wherein the methylphenidate hydrochloride in said immediate release coating is released primarily during said first 15 interval.

92. The dosage form according to any one of claims 33, 42, 45, 56 or 79, wherein the dosage form is osmotic.

93. The dosage form according to any one of claims 33, 42, 45, 56 or 79, wherein the dosage form is non-osmotic. 20