MXPA00011908A

MXPA00011908A - Methods and devices for providing prolonged drug therapy

Info

Publication number: MXPA00011908A
Application number: MXPA/A/2000/011908A
Authority: MX
Inventors: Atul D Ayer; Carol A Christopher; Diane R Guinta; Suneel K Gupta; Lawrence G Hamel; Zahedeh Hatamkhany; Andrew C Lam; Samuel R Saks; Padmaja Shivanand; Richard G Weyers; Jeri D Wright
Original assignee: Alza Corporation
Priority date: 1998-06-03
Filing date: 2000-11-30
Publication date: 2002-03-26

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.

Description

METHODS AND DISPOSTTTVQS TO PROVIDE PROLONGED THERAPY WITH DRUGS BACKGROUND OF THE INVENTION 1. Field of the Invention This invention pertains to methods and devices for maintaining a desired therapeutic effect and drug during a period of prolonged therapy. In particular, the invention relates to methods and devices that provide drug release within the gastrointestinal tract at an upward release rate over a prolonged period of time. In this manner, the drug is released at an upward rate during a portion of the drug administration period sufficient to maintain a desired therapeutic drug effect throughout a prolonged period of therapy. 2. Description of Related Art, Including Disposable Information in Accordance with Title 37 of the Code of Federal Regulations, Sections 1.97 and 1.98 To produce its pharmacological effects, a drug must be available in appropriate concentrations at its site of action within the body . This availability is affected by numerous factors, including the amount of the drug administered, the degree and speed of its absorption from its administration site, its distribution, its link or location within the tissues, its biotransformation, and its excretion. A commonly used indicator of drug availability is the concentration of the drug that is obtained within the blood or plasma, or another appropriate body fluid or tissue, from a patient, following the administration of the drug. For convenience, this concentration can be referred to as "plasma drug concentration" hereinafter, which is intended to include the concentration of the drug measured in any appropriate body fluid or tissue. Plasma drug concentration measurements provide very useful information, including, for example, comparative information with respect to different dosage forms of the drug, and / or different routes of drug administration. In addition, for many drugs, different effects of the drug have been correlated, including both the desired pharmacological effects, i.e., the effects of the therapeutic drug, and the undesired pharmacological effects, i.e., the side effects, with plasma drug concentrations. or ranges of specific plasma drug concentrations. For orally administered dosage forms of the drug, absorption occurs within the gastrointestinal tract ("gi"), and is affected by many factors, including the physicochemical properties of the local micro-environment, such as surface area, flow blood, and the membrane characteristics (which vary significantly in different portions of the gastrointestinal tract), the physicochemical properties of the drug entity, the concentration of the drug, the existence and activity of specific drug transport mechanisms, and so on. . An important factor in the rate of absorption of the drug administered as an oral dosage form is the rate at which the drug is released from the dosage form. Drug release rates for oral dosage forms are usually measured as the dissolution rate in vi tro, ie, an amount of drug released from the dosage form per unit of time. Conventional oral dosage forms can be described as "immediate release", because, in general, essentially the entire dose of the drug is released from the dosage form within a very short period, i.e. minutes, right after your administration. As this bolus of drug released is absorbed, the concentration of the drug in plasma normally rises rapidly to a peak or peak concentration, and subsequently declines as the drug is distributed., it is bound, or it is located inside the tissues, it is biotransformed, and / or it is excreted. The period of time for this decline varies for different drugs, and depends on many factors, but this time period will be characteristic of a particular drug. In general, during some portion of the time period in which the concentration of the drug in plasma rises, reaches the peak, and declines, the drug provides its therapeutic effects, i.e. the concentration of the drug in plasma reaches or exceeds a concentration effective Moreover, at some point during this period of time, the therapeutic effects disappear, that is, when the concentration of the drug in plasma declines to a level that is below an effective concentration. In addition, often during a portion of this time around the time when the peak concentration is reached, ie, when the concentration of the drug in plasma is in its highest range, unwanted side effects may be observed. In view of the foregoing, it will be appreciated that a continuous effectiveness of the drug occurs during the period of time in which the concentration of the drug in plasma is within the effective plasma drug concentration range. However, because the concentration of the drug in plasma declines over time, multiple doses of the immediate release drug dosage form must be administered at appropriate intervals to ensure that the concentration of the drug in plasma remains in, or again rise up, the effective concentration range. However, at the same time there is a need to avoid or minimize concentrations of the drug in plasma that rise up to, and / or remain for a long time within, the highest ranges where side effects may occur. Accordingly, for many drugs, multiple separate doses of the immediate release dosage form should be administered at appropriate intervals to maintain a satisfactory balance of desired and undesired pharmacological effects during a prolonged therapy period. An approach to the efforts to improve drug therapy has been directed to provide dosage forms of oral drugs that are not immediate release, which affect the absorption of the drug primarily by altering the rate of release of the drug from the drug. dosage form. Examples of these delivery systems that are not immediate release include delayed release and sustained release systems. Sustained-release dosage forms generally release the drug for a prolonged period of time, compared to an immediate-release dosage form. There are many approaches to achieve sustained release of drugs from oral dosage forms known in the art. These different approaches include, for example, diffusion systems, such as deposit devices and matrix devices, dissolution systems, such as encapsulated dissolution systems (including, for example, "small time pills"), and dissolution systems. of matrix, diffusion / dissolution systems in combination, osmotic systems, and ion exchange resin systems, as described in Remington's Pharmaceutical Sciences, 1990 Edition, pages 1682-1685. It is believed to be particularly desirable to provide oral sustained release dosage forms that provide drug release at a substantially constant release rate over a prolonged period of time. Thus, for many drugs, the concentration of the drug in plasma initially rises for a short period of time when drug release is initiated, and then remains substantially constant for a prolonged period of time when the release of the drug continues at a rate constant. For many drugs, this concentration of substantially constant plasma drug correlates with the effectiveness of the substantially constant drug during a prolonged therapy period. In addition, because an initial concentration of the drug in relatively high peak plasma is avoided, side effects are no longer a problem. Accordingly, the advantages of constant release dosage forms include reducing the number of doses of a drug that need to be administered over time, and providing a better balance of the desired and undesired pharmacological effects of the drug. In particular, osmotic dosage forms have been notoriously successful in providing a constant release of drugs for extended periods of time. Osmotic dosage forms generally use osmotic pressure to generate a pulse force to imbibe fluid in a compartment formed, at least in part, by a semipermeable membrane that allows free diffusion of the fluid but not of the drug or osmotic agents , if they are present. A substantially constant rate of drug release can be achieved by designing the system to provide a relatively constant osmotic pressure, and having a suitable exit element for the drug formulation, in order to allow the formulation of the drug to be released to a velocity corresponding to the velocity of the imbibed fluid as a result of a relatively constant osmotic pressure. A significant advantage of the osmotic system is that the operation depends on the pH, and therefore, it continues at the osmotically determined rate throughout a prolonged period of time, even when the dosage form transits the gastrointestinal tract and encounters different micro-environments that have significantly different pH values. Surprisingly, simple but highly effective osmotic devices comprising drug in a mixture with excipients, optionally including osmotically active components within the compartment, are known in the art. Although effective for many drugs, the rate of release in these devices often declines over time, and a full supply of the drug load may not occur. A more sophisticated type of osmotic device comprises two component layers inside the compartment formed by the semipermeable wall. A component layer comprises the drug in a mixture with excipients, optionally including osmotically active components, which will form a drug formulation available within the compartment, and the second component layer comprises osmotically active components but does not contain drug. The osmotically active components of the second component layer usually comprise osmopolymers having relatively large molecular weights, and exhibiting "swelling" as the fluid is imbibed, so that the release of these components through the carrier element does not occur. exit of the drug formulation. The second component layer is referred to as a "push" layer, because, as the fluid is imbibed, the osmopolymers swell and push against the supply drug formulation of the first component layer, thereby facilitating the release of the drug formulation at a substantially constant rate. The devices described above are known, for example, from the following United States of America 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 the constant release dosage forms have proven to be effective for many different drug therapies, there are clinical situations where these have not been entirely satisfactory. It has been observed that, for some patients who are treated with constant release dosage forms for some conditions or diseases, the therapeutic effectiveness of the drug decreases in the periods of time before the end of the desired therapy period, despite the maintenance of a substantially constant drug release that would be expected to provide continued effectiveness. In accordance with the above there remains a need to provide methods and devices for maintaining a desired therapeutic drug effect during a desired prolonged therapy period, when sustained release dosage forms that release the drug at a substantially constant rate over a period of time. of long time are not satisfactory.

BRIEF COMPENDI OF THE INVENTION One aspect of the present invention pertains to providing better drug therapy for clinical situations wherein the therapeutic effectiveness of a therapy with a drug administered unexpectedly decreases in the periods of time before the end of the intended therapy period . Surprisingly, it has been found that, in an exemplary clinical situation, the administration of the drug at a release rate that is ascending, rather than being substantially constant, over a prolonged period of time, provided a therapeutic efficacy that does not decreased before the end of the extended therapy period. With the discovery that administration of the drug at a release rate that is substantially ascending provides better drug therapy, there is a need for sustained release oral dosage forms adapted to provide this rate of release over a prolonged period of time. suitable. In accordance with the foregoing, other aspects of the present invention include providing oral sustained release dosage forms that provide a rate of upward drug release over a prolonged period of time, methods for making these dosage forms, and methods for using these dosage forms in order to maintain therapeutic effectiveness during a desired prolonged therapy period. Surprisingly, it has been found that oral osmotic dosage forms can be achieved that exhibit a rate of upward drug release over a prolonged period of time. In particular, the present invention relates to osmotic dosage forms having two-layered or three-layered tablet cores that are adapted to provide ascending drug release rates over a prolonged period. In addition, to provide a rapid initial establishment of the action of the drug, the present invention also relates to dosage forms that additionally comprise a dose of drug for immediate release. Oral osmotic dosage forms in two layers of the present invention include a first component layer, comprising a selected drug and excipients for forming a dispensable drug composition when hydrated, and a second thrust layer, comprising an expandable osmopolymer with fluid and excipients, contained within a compartment formed by a semipermeable membrane, and having an exit element for the release of the drug from the compartment. The two layers are compressed into two-layer tablet cores before the semipermeable membrane is applied, and a suitable orifice is formed for release of the drug therethrough. It is important that the two-layer tablet cores disclosed herein are formed when two component layers are compressed together to provide a longitudinally compressed tablet core ("LCT") having a "capsule-shaped" configuration, with a different layer on each narrow end. The combination of features, including the osmotic properties of the component layers, the fluid flow properties of the semipermeable membrane, and the tablet core configuration, ensures that the drug is released at an upward rate for a prolonged period of time. In a preferred embodiment, sufficient activity in the push layer is achieved by the use of a relatively large concentration (at least about 35 percent) of the osmotically effective solute, or osmagent, such as sodium chloride. In addition, sorbitol is preferably included in the first component layer. Oral osmotic dosage forms in three layers of the present invention include a novel three-ply tablet core surrounded by a semi-permeable membrane, and that has an appropriate exit element to release the drug formulation through the semipermeable membrane. The novel three-ply tablet core has a first drug-containing layer, a second drug-containing layer, and a third push layer. In the operation, through the cooperation of the components of the dosage form, the drug is successively released from the first drug-containing layer, and then from the second drug-containing layer. It has been found that a drug concentration gradient facilitates the achievement of an ascending drug release rate over a prolonged period of time. Accordingly, the other excipients in the drug-containing layers can be more flexibly varied and adjusted for other purposes, such as for manufacturing convenience and pharmaceutical elegance. In this manner, dosage forms that exhibit a reliable drug release having the desired sustained and upward rate over a prolonged period of time can be manufactured in a reliable and efficient manner. It is preferred to use the longitudinally compressed tablet core configuration, as described above, to improve the hydration of the core in three layers. In addition, a flow improving agent is preferably included in the semipermeable wall composition. In a currently preferred embodiment, the combination of features, including the core configuration in three layers of longitudinally compressed tablet, a suitable drug concentration gradient between the first and second component layers, the osmotic properties of the component layers, and the properties fluid flow of the semipermeable membrane, achieve the desired upward rate of drug release over a prolonged period of time. There are numerous clinical situations and drug therapies that could be improved with the use of dosage forms that provide a sustained and ascending release rate over a prolonged period of time. Exemplary dosage forms, as disclosed herein, include drugs that act on the central nervous system and drugs of cardiovascular action. Those skilled in the art will appreciate that the invention is applicable to many other types of drugs and drug therapy. Examples of suitable types of drugs include, but are not limited to, anti-infectives, analgesics, anesthetics, antiarthritics, antiasthmatics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antihistamines, anti-inflammatories, anti-migraines, antineoplastic, antiparkinsonisms, anti- pruritic, antipsychotic, antipyretic, antispasmodic, anticholinergic, sympathomimetic, calcium channel blocker, beta blockers, antiarrhythmic, antihypertensive, ACE inhibitors, diuretics, vasodilators, decongestants, hormones, hypnotics, immunosuppressants, parasim-patomimetics, prostaglandins, proteins, peptides , sedatives, and tranquilizers. The exemplary clinical situation described herein involves the treatment of ADHD with methylphenidate therapy. In accordance with the foregoing, the present invention also pertains to the manufacture of sustained release oral dosage forms of methylphenidate which provide a sustained and upward release rate of a drug over a prolonged period of time. In addition, it has been found that sustained release oral dosage forms of methylphenidate that provide a rate of upward release of a drug over a prolonged period of time can be used to provide effective once-a-day therapy for ADHD. Accordingly, the present invention also pertains to improving drug therapy for ADHD, by eliminating the need for multiple daily doses of methylphenidate, and yet, it provides therapeutic efficacy throughout the day, which is compared with the therapeutic efficacy provided by multiple doses of immediate release methylphenidate. The features and advantages described above, as well as others, will become clearer from the following detailed disclosure of the invention, and from the accompanying claims. Although the present invention is illustrated herein by exemplary dosage forms containing specific exemplary drugs, methods for making these dosage forms, and methods for using dosage forms containing methylphenidate to provide a desired therapeutic result, the invention is not it is limited by the example modalities. The invention broadly encompasses sustained release oral dosage forms that provide a rising drug release rate over a prolonged period of time, methods for manufacturing these dosage forms, and methods for using these dosage forms to maintain therapeutic effectiveness for a period of time. desired prolonged therapy period with respect to any drugs and appropriate drug therapies that are apparent to a person skilled in the art, in view of the disclosure herein.

BRIEF DESCRIPTION OF THE DIFFERENT VIEWS OF THE DRAWINGS Figure 1 is a cross-sectional view of an osmotic dosage form in two layers according to the present invention. Figure 2 is a cross-sectional view of a three-layer osmotic dosage form, further comprising an immediate-release drug overcoat, and an aesthetic overcoat, in accordance with the present invention. Figure 3 is a graph illustrating the amount of drug released over time from a preferred embodiment of the present invention, as described in Example 6. Figure 4 is a graph illustrating plasma drug concentration over time, obtained immediately after the administration of methylphenidate, according to an experimental regimen (hollow diamonds), and a standard regimen (filled circles), as described in Example 7.

DETAILED DESCRIPTION OF THE INVENTION Many effective drug therapies utilize immediate release oral dosage forms administered at separate intervals to provide and maintain a desired therapeutic effect during a prolonged period of therapy. In addition, sustained release dosage forms for many drugs are known, and in particular, oral dosage forms of constant release are known. There are many examples of effective drug therapies that use constant release oral dosage forms to provide a desired therapeutic effect during a prolonged period of therapy. In many cases, these drug therapies offer advantages over drug therapies using oral release forms of immediate release administered at separate intervals. However, there are clinical situations where the constant release dosage form has unexpectedly exhibited reductions in therapeutic effectiveness in periods of time before the end of the desired prolonged therapy period. An example of a clinical situation where the therapy of drugs with oral dosage forms of sustained release drug that provide a substantially constant rate of drug release over a prolonged period has not been entirely satisfactory, is with the use of stimulant drugs of the drug. Central nervous system (CNS) to treat different conditions and disorders, including Attention Deficit Disorder (ADD) and Attention Deficit Disorder Disorder (ADHD). These disorders are commonly diagnosed in children, but they can also occur in adults. The treatment of these and other psychological conditions with stimulant drugs of the central nervous system has a long history. Approximately 25 years ago, methylphenidate replaced amphetamine, as the primary stimulant prescribed to treat ADHD in children. Methylphenidate therapy has been studied extensively in children with ADHD, and the efficacy and safety of this treatment is well established. It has been shown that methylphenidate therapy is very effective in reducing the symptoms of hyperactivity, inattention, and impulsivity in children with ADHD. The goal of drug therapy is to control behavioral symptoms during the time of day while the patient is in school or otherwise involved in activities where symptom control benefits the patient's ability to catch and / or participate in another way beneficially in the activities.

However, due to concerns related to side effects, drug therapy is usually discontinued for at least a portion of the evening and through the night in most patients. Depending on the particular circumstances of the patient, drug therapy may or may not be discontinued also on weekends. The treatment commonly uses immediate release methylphenidate administered two or three times during the day. For several reasons, patients frequently experience difficulty in complying with this administration program. Because of the potential for abuse, methylphenidate is a controlled substance, and therefore, access to the drug is a special concern. This dosage regimen generally requires that at least one dose be administered during the school day, and as a rule, children are not allowed to self-administer the drug at school. For this reason, authorized school personnel generally take responsibility for administering the drug to children during the school day; however, this approach presents issues of medical privacy and potential stigmatization of children by their peers. In addition, the compliance issue becomes additionally complicated, since the transport, storage, and supply of the drug must be documented and / or monitored normally, and the programs of the different parties involved must be coordinated and accommodated. say, the child, educators, and authorized school personnel. The unfortunate result is that the doses may be given late, or they may be lost altogether, resulting in reduced efficacy of the therapy. For all the above reasons, it would appear that a sustained release oral dosage form of methylphenidate, which would provide substantially constant drug release over a prolonged period, to thereby eliminate the need for dose administration during the school day, It would be a welcome improvement. In fact, this sustained release dosage form of methylphenidate has been commercially available for several years. However, clinical experience with this dosage form has been disappointing, because the behavioral symptoms in patients taking the controlled release dosage form are controlled less later in the day, compared to patients who take multiple doses of medication. the immediate release dosage form. In addition, the slower setting of action of the controlled release dosage form, compared to the immediate release dosage form, is unsatisfactory for many patients.

Surprisingly, it has been found that the administration of methylphenidate at a release rate that is substantially upward, rather than substantially constant, over a prolonged period of time, provides therapeutic efficacy similar to the efficacy obtained with multiple doses of the dosage forms of immediate release methylphenidate. The details of this discovery are disclosed in pending U.S. Patent Application Number 920,593, filed July 31, 1997, of which the present application is a request for partial continuation. To briefly review, in a clinical study, a comparison was made of the efficacy in behavior, attention, and knowledge of a placebo and methylphenidate administered according to three different release rate regimes, ie, immediate release, constant release, and ascending release. The immediate release methylphenidate was administered as two separate doses. The constant release regimen was administered as an initial loading dose, the remaining total amount being administered in equal small doses at closely spaced intervals, extending beyond the time of administration of the second immediate release dose. The ascending release regimen was administered as an initial loading dose, the remaining total amount being administered in small increasing doses at closely spaced intervals, extending beyond the time of administration of the second immediate release dose. In this study, it was observed that the constant release regimen has reduced the clinical effectiveness, comparing with the immediate release regimen in the evaluation periods following the administration of the second dose of immediate release. On the other hand, the ascending release regimen demonstrated clinical efficacy comparable to the immediate release regimen during these evaluation periods. Accordingly, the ascending release regimen eliminated the reduction in therapeutic efficacy seen with the constant release regimen at later time periods during the prolonged therapy period. With the discovery that the effectiveness of the drug can be improved during a prolonged therapy period in some circumstances with the administration of the drug at an upward release rate over a prolonged period, there is a need for sustained release oral dosage forms adapted for provide this release speed. In one aspect of the present invention, it has surprisingly been found that oral osmotic dosage forms can be adapted in two layers to meet this need. In another aspect, it has been discovered in a surprising manner that sustained release oral osmotic dosage forms can be produced having novel three-layer cores, which also achieve sustained release of drug formulations at an upward rate for a period of time. of prolonged time. As is known in the prior art, osmotic dosage forms comprising compressed tablet cores require a short period of time following their administration, in which they reach enough hydrate to begin releasing the drug. For some drug therapies, the slight delay in the initial release of the drug is unsatisfactory. This problem is overcome with the addition of an initial dose of drug delivered in an immediate release overcoat applied to the surface of the semipermeable membrane. In the preferred embodiments of the present invention, as disclosed herein, this immediate release drug overcoat is applied to the surface of the osmotic dosage forms in two layers or in three layers. For the purposes of this disclosure, the following definitions will be applied: For greater clarity and convenience in the present, the convention of designating the time of administration of the drug is used as the zeros hours (t = 0 hours), and the times after administration in units of time appropriate, for example, t = 30 minutes or t = 2 hours, etcetera. As used herein, the term "drug" generally refers to a pharmacologically active substance which, when delivered to a living organism, produces a desired, usually beneficial, effect. The drug compositions are generally used clinically in the form of a pharmaceutically acceptable salt thereof. In addition, some drug compositions exhibit chirality, and therefore, have more than one optical isomer. Because different optical isomers may exhibit different pharmacological effects, it may be convenient to use a substantially pure form of an 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 and a pharmaceutically acceptable salt of the drug composition. same. Although a limited number of drugs are represented in the exemplary embodiments herein, the invention should not be limited by the exemplary embodiments, but is fully applicable to other suitable drugs, as would be understood by those skilled 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, and the desired administration period, for example every 12 hours, every 24 hours, and so on. Depending on the doses of the drug to be administered, one or more of the dosage forms may be administered. A "release rate" of the drug refers to the amount of drug released from a dosage form per unit of time, eg, milligrams of drug released per hour (mg / hr). The rates of drug release are calculated under dissolution test conditions in the in-dose dosage form known in the art. As used herein, a rate of drug release obtained in a specified time "following administration" refers to the rate of drug release in vi tro obtained in the specified time following the implementation of a dissolution test. appropriate The dissolution test used in the examples described herein was performed on dosage forms placed in metal coil sample containers connected to a USP Type VII batch indicator, and immersed in approximately 50 milliliters of acidified water (pH = 3) balanced in a water bath at a constant temperature at 37 ° C. Aliquots of the release rate solutions were injected into a chromatographic system to quantitate the amounts of drug released during the test intervals. A reference measurement commonly used to evaluate the release of the drug from the oral dosage forms is the time when 90 percent of the drug has been released into a dosage form. This measurement is referred to as "T90" for the dosage form. An "immediate release" dose of a drug refers to a dose that is released in a substantially complete manner within a period of time of about 1 hour or less, and preferably, of about 30 minutes or less. An immediate release dose of the 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 carrier to form a coating solution that is will dissolve quickly after being administered, to thereby provide an immediate release dose of the drug. As is known in the art, these immediate-release drug overcoats may contain the same or a drug or drugs different from those contained within the underlying dosage form. A "periodic release rate" refers to the amount of drug released from a dosage form during a specified periodic interval, as the end of that specified periodic interval is determined, ie, at each periodic interval when a determination, and the amount of drug released represents the rate of periodic release during that periodic interval. For example, the amount of drug released as determined at t = 1 hour represents the rate of periodic release from the dosage form during the first hour following administration, and the amount of drug released as determined at t = 2 hours, represents the. periodic release rate during the second hour after administration, and so on. An "ascending release rate" refers to a periodic release rate that increases above 1 the immediately preceding periodic release rate, wherein the periodic intervals are equal. For example, when the amount of drug released from a dosage form is measured at hourly intervals, and the amount of drug released during the fifth following administration (determined at t = 5 hours) is greater than the amount of the drug. drug released from the dosage form during the fourth hour following administration (determined at t = 4 hours), an ascending release rate has been presented from the fourth hour to the fifth hour. It will be appreciated that the first periodic release rate measured, for example, the periodic release rate at t = 1 hour (unless equal to 0), will always be greater than the rate of release during the preceding period, for example, the hour before the dosage form was administered, and therefore, the first periodic release rate always constitutes a presentation of an ascending release rate. The ascending release rates disclosed herein relate to the rate of release from a dosage form adapted to provide sustained release of the drug, and do not include release of the drug from an immediate release drug coating that can be applied to the dosage form. In embodiments of the dosage forms which additionally comprise an immediate release dose of a drug applied as a coating on the underlying dosage form, the release of the drug measured at t = 1 hour will generally reflect both the drug released from the coating of immediate-release drug, with any drug released from the underlying dosage form; however, the amount of drug released from the drug overcoat is not considered in the determination of whether the rate of drug release at t = 2 hours is greater than the release of the drug at t = 1 hour. As used herein with reference to the period of time during which an ascending release rate is provided, "a prolonged period of time" refers to a period of time starting at t = 0 hours, and continuing until when minus the midpoint, and preferably beyond the midpoint, of the relevant T90 of the dosage form. Because the dosage forms of the present invention are intended to provide sustained release of the drug, a T90 suitable for the purposes of this invention is at least about 6 hours, and consequently, the "extended period of time" during which provides an ascending release rate from at least 3 hours. In accordance with the above-mentioned definitions, an "ascending release rate over a prolonged period of time" refers to the ascending release rates of the drug obtained from the time of administration of the dosage form to, and preferably beyond of, the midpoint of the T90 relevant to the dosage form. To illustrate, consider a situation where a dosage form has a T90 of about 8 hours. In this situation, an "ascending release rate over a prolonged period of time" is reached when the rate of release in each hour until t = 4 hours is greater than the release rate in the immediately preceding hour. Preferably, the rate of release continues to rise during periods of time beyond t = 4 hours. Two-layer oral osmotic dosage forms, and methods for making and using these dosage forms, are known in the art, for example, as described and claimed in the following US patents.

United States of America, 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. Two-ply osmotic dosage forms of the prior art achieve a sustained release of drug formulations wherein a relatively short initial period of ascending release rates is followed by substantially constant release rates over a greater part of the T90 period. The range of an ascending release rate over a prolonged period of at least 50 percent of the T90 period is not found in the prior art. The dosage forms of the present invention are useful for providing an effective continuous drug therapy during a prolonged therapy period, without exhibiting a reduction in effectiveness during the latter part of the prolonged therapy period. Oral osmotic dosage forms in two layers of the present invention include a first component layer, comprising a selected drug and excipients for forming a dispensable drug composition when hydrated, and a second thrust layer, comprising an expandable osmopolymer with fluid and excipients, wherein the two layers are compressed into two-layered tablet cores before the semi-permeable membrane is applied and a suitable orifice is formed for release of the drug therethrough. The combination of features, including the osmotic properties of the component layers, the fluid flow properties of the semipermeable membrane, and the tablet core configuration, ensures that the drug is released at an upward rate for a prolonged period of time. It is important that the tablet cores in two layers of the present invention are configured in such a way that each component layer is of a substantially round transverse dimension, with a circumferential width and a length between an upper and a lower end. The two layers are pressed together longitudinally, such that the resulting two-layer tablet core has the same circumferential width as the component layers, and a length that combines the lengths of the component layers. The overall configuration can be described as "capsule shaped", wherein the tablet core in two layers has a circumferential width that is less than its length, and has a rounded "narrow" upper end, and a "narrow" lower end. "rounded, and wherein each narrow end comprises a different component tablet layer. For the purposes of this disclosure, tablet cores described above are referred to as longitudinally compressed tablet cores ("LCT"). This longitudinally compressed tablet configuration ensures that, when the pusher layer is longitudinally expanded within the compartment formed by the semipermeable membrane, the surface area of the pusher layer in contact with the semipermeable membrane is increased more than when other configurations are used. In a preferred embodiment, sufficient activity is achieved in the push layer by using a relatively large concentration (at least about 35 percent) of the osmotically effective solute, or osmagent, such as sodium chloride. Consequently, the size of the push layer is relatively large, and may be slightly larger than the first component layer containing the drug and the excipients. In addition, for certain embodiments, it was found that sorbitol is a useful excipient in the first component layer. Surprisingly, it has been found that the combination of features described above, including the configuration of the longitudinally compressed tablet core, the relatively high percentage of osmagent, and in some exemplary embodiments, the use of sorbitol as an excipient, provides the desired upward release rate over a prolonged period of time from the two-layer oral osmotic dosage forms. The exemplary embodiments of these two-layer osmotic dosage forms are detailed below in Examples 1 to 3. In Figure 1, a modality of an oral osmotic dosage form in two layers 15 is shown in cross-section. They are drawn to scale. The core of the tablet longitudinally compressed in two layers comprises a first component layer 21, containing selected drug and excipients, and a second thrust layer 29, containing at least one osmopolymer expandable with fluid, and optionally containing at least one osmagent. , together with selected excipients. Suitable excipients are known in the art, and include diluents, carriers, binders, fillers, and processing aids. A semi-permeable membrane 57 surrounds the tablet core in two layers to form a compartment, and an orifice of suitable size 55 is formed through the semipermeable membrane and in the first component layer 21, to allow the drug formulation to be released from inside the compartment. As illustrated, the orifice 55 is preferably formed at the narrow end of the dosage form comprising the first component layer. In the operation, through the cooperation of the components of the osmotic dosage form in two layers, the drug is released from the first drug-containing layer at an upward release rate over a prolonged period of time. Although not shown in Figure 1, an immediate release dose of a drug can be provided by applying a drug-containing overcoat to a two-layered dosage form, if desired, as described elsewhere in the literature. the present. In addition to the above-described two-layer osmotic dosage forms, it has surprisingly been found that oral osmotic dosage forms that exhibit a rising drug release rate over a prolonged period of time can also be achieved with a 3-layer novel tablet core surrounded by a semi-permeable membrane, and having a suitable outlet element for releasing the drug formulation through the semi-permeable membrane. The novel three-layer tablet core has a first drug-containing layer, a second drug-containing layer, and a third push layer. In the operation, through the cooperation of the components of the dosage form, it is successively released in drug, in a sustained and controlled manner, from the first drug-containing layer, and then from the second drug-containing layer, from such that an ascending release rate is achieved for a prolonged period of time. It has been found that a drug concentration gradient between the first and second drug-containing layers of the core in three layers facilitates the achievement of a rising drug release rate over a prolonged period of time from the osmotic dosage form in three layers. Accordingly, the other excipients in the drug-containing layers can be varied in a more flexible manner, and can be adjusted for purposes other than manufacturing convenience and pharmaceutical elegance. For example, osmotic dosage forms in three layers preferably eliminate the use of sorbitol as an excipient. This provides manufacturing efficiency and shelf-life advantages of the product, because sorbitol is very hygroscopic and attracts moisture during storage, which can present difficulties in handling and manufacturing, as well as longer-term stability concerns. . In addition, sufficient activity in the thrust layer can be achieved with the use of a relatively lower concentration (less than about 25 percent) of the osmotically effective solute, such that the size of the thrust layer can be smaller in relation 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 of a smaller size push layer is that larger doses of the drug can be accommodated, if desired, without the overall size of the dosage form becoming so large that it engenders manufacturing challenges and / or It becomes an unpleasant taste for patients. In a currently preferred embodiment, the hydration rate of the osmotic dosage form in three layers is improved with the inclusion of a flow enhancing agent in the semipermeable membrane. In addition, it is preferred to use the longitudinally compressed tablet core configuration ("LCT"), as described above, for the osmotic dosage forms in three layers, in order to also improve hydration. In a currently preferred embodiment, the combination of features, including the core configuration in three layers of longitudinally compressed tablet, a suitable drug concentration gradient between the first and second component layers, the osmotic properties of the component layers, and the properties Fluid flow of the semipermeable membrane achieves the desired upward rate of drug release over a prolonged period of time. Conveniently, these preferred embodiments exhibit a consistent and reliable operation, and can be manufactured in an efficient manner on a large scale basis. A preferred embodiment of a three layer oral osmotic dosage form further comprising an immediate release dose of the drug, applied as an overcoat, and an aesthetic overcoat 14, is shown in cross section in Figure 2. The core of the tablet longitudinally compressed in three layers comprises a first component layer 20, which contains a drug selected in a pharmaceutically acceptable form, together with selected excipients; a second component layer 18, which contains a higher concentration of the drug, together with selected excipients; and a third thrust layer 28, containing at least one osmopolymer, and optionally containing at least one osmagent, together with selected excipients. A semi-permeable membrane 56 surrounds the tablet core in three layers to form a compartment, and an appropriately sized hole 54 is formed through the semipermeable membrane and into the first component layer, to allow the drug formulation to be released. from inside the compartment. As illustrated, the orifice 54 is preferably formed at the narrow end of the dosage form comprising the first component layer. In the operation, through the cooperation of the components of the osmotic dosage form in three layers, the drug is released successively, in a sustained and controlled manner, from the first drug-containing layer, and then from the second drug-containing layer, at an upward release rate for a prolonged period of time. As shown in Figure 2, the preferred embodiment further comprises an immediate release dose of the drug contained within an overcoat 60 applied to the surface of the osmotic dosage form in three layers. In drug it is mixed with suitable excipients as such, for example, hydroxypropyl methylcellulose, to prepare a solution for coating on the surface of the semipermeable membrane of the osmotic dosage form in three layers, which will dissolve rapidly and release the drug. right after your administration. As shown in Figure 2, it is also preferred to provide an optional aesthetic overcoat 62 applied on the surface of the drug-containing overcoat 60. As is known in the art, these aesthetic overcovers provide advantages, including taste masking, improved appearance and possibility of brightness ", to facilitate swallowing, and other processing steps, such as printing, packaging, and so on. The exemplary embodiments of the three layer osmotic dosage forms exhibiting a substantially upward release rate over a prolonged period of time are detailed below in Examples 4 to 6 and Examples 8 and 9. The continuous maintenance of therapeutic effectiveness over a period of prolonged therapy by administration of oral osmotic dosage forms exhibiting an upward release rate over a prolonged period of time of the present invention. An exemplification is described below in Example 7. In particular, it has been found that these osmotic dosage forms containing methylphenidate can be used to provide effective therapy once a day for ADHD. This discovery represents a major improvement in the therapy of drugs for ADHD, by eliminating the need for multiple daily doses of methylphenidate, and nonetheless, it provides therapeutic efficacy throughout the day, which is compared with the therapeutic efficacy provided. by multiple doses of methylphenidate immediate release. 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, because these examples and other equivalents thereof will become more clear to those skilled in the art. technique in light of the present disclosure and the accompanying claims.

EXAMPLE 1 Oral osmotic dosage forms were made in two layers according to the conventional manufacturing processes known in the art, and disclosed in detail in pending U.S. Patent No. 967,606, filed on October 10, November 1997, of which the present application is a request for partial continuation. Briefly, a first component layer, containing methylphenidate hydrochloride and selected excipients, and a second thrust layer, containing appropriate osmopolymers, 40 percent by weight of an osmagent, and selected excipients, were prepared separately by granulation methods. . Next, the granulation preparations of the first component layer and the second push layer were compressed longitudinally together to form longitudinally compressed tablet cores in two layers. It was then coated with a semi-permeable membrane selected around the tablet cores longitudinally compressed in two layers, and a 0.762 millimeter orifice was formed suitable for release of the drug therethrough, and into the first component layer. Each dosage form already prepared included: First component layer 14.8 milligrams of methylphenidate hydrochloride. 90.26 milligrams of poly (ethylene) oxide (number average molecular weight of 200,000). 5.5 milligrams of poly (vinylpyrrolidone) (number average molecular weight of 40,000) 0.11 milligrams of magnesium stearate 0.555 milligrams of butylated hydroxytoluene Second push layer 71,032 milligrams of poly (ethylene oxide) (number average molecular weight of 7,000,000). 52.8 milligrams of sodium chloride 6.6 milligrams of poly (vinylpyrrolidone) (number average molecular weight of 40,000). 1.32 milligrams of red ferric oxide. 0.132 milligrams of magnesium stearate. 0.555 milligrams of butylated hydroxytoluene.

Semipermeable membrane 15.3 milligrams of cellulose acetate (acetyl content of 39.8 percent) 1.7 milligrams of poly (ethylene glycol) (number average molecular weight of 3,350). Periodic release rates were determined from the dosage form every hour for 10 hours, using the in vi tro dissolution test. A residual drug amount of 0.72 milligrams remained in the dosage form. The results are shown in Table 1, along with an indication of whether an ascending release rate occurred.

As seen in Table 1, the drug was released from the dosage forms at an upward rate for a prolonged period of time, i.e., more than 90 percent of the drug was released at t '= 8 hours, and ascending release rates were presented up to t = 6 hours, a prolonged period of time well beyond the midpoint of T90.

EXAMPLE 2 Oral osmotic dosage forms were made in two layers according to the conventional manufacturing processes known in the art, and disclosed in detail in the pending United States Patent Application Number 967,606, filed on October 10, November 1997, of which the present application is a request for partial continuation. Briefly, a first component layer, containing methylphenidate hydrochloride, sorbitol and selected excipients, and a second pusher layer containing suitable osmopolymers, 40 percent by weight of an osmagent, and selected excipients were prepared separately by methods of granulation. Next, the granulation preparations of the first component layer and the second thrust layer were longitudinally compressed together to form tablet cores longitudinally compressed in two layers. It was then coated with a semi-permeable membrane selected around the tablet cores longitudinally compressed in two layers, and a suitable 0.762 millimeter hole was formed for the release of the drug therethrough. Each prepared dosage form comprised: First component layer (110 milligrams) 12.8 percent methylphenidate hydrochloride. 54.75 percent poly (ethylene oxide) (number average molecular weight of 200,000). . 4 percent sorbitol. 5 percent hydroxypropylmethylcellulose (number average molecular weight of 11,200). 2 percent magnesium stearate. 0.05 percent of butylated hydroxytoluene.

Second push layer (132 milligrams) 53.85 percent poly (ethylene) oxide (number average molecular weight of 7,000,000). 40 percent sodium chloride. 5 percent hydroxypropylmethylcellulose (number average molecular weight of 11,2000). 1 percent red ferric oxide. 0.1 percent magnesium stearate. 0.05 percent of butylated hydroxytoluene.

Semipermeable membrane (42 milligrams) 47.5 percent cellulose acetate (acetyl content of 39.8 percent). 47.5 percent cellulose acetate (32 percent acetyl content). 5 percent poly (ethylene glycol) (number average molecular weight of 3,350). Periodic release rates were determined from the dosage form every hour for 12 hours. No residual amount of drug remained in the dosage form. The results are shown in the Table 2, together with an indication of the presentations of an ascending release velocity.

As seen in Table 2, more than 90 percent of the drug was released at t = 9 hours, and ascending release rates were presented up to t = 8 hours, a long period of time well beyond the midpoint of T90- EXAMPLE 3 Oral osmotic dosing forms were made in two layers which additionally comprised an immediate release drug dose applied as an overcoat on the semipermeable membrane, according to the conventional manufacturing processes known in the art and disclosed in detail in U.S. Patent Application Pending Number 967,606, filed November 10, 1997, of which the present application is a request for partial continuation. Briefly, a first component layer, containing methylphenidate hydrochloride, sorbitol, and selected excipients, and a second thrust layer, containing appropriate osmopolymers, 39.8 percent by weight of an osmagent, and selected excipients, were prepared separately by granulation methods. Next, the granulation preparations of the first component layer and the second component layer were longitudinally compressed together to form longitudinally compressed tablet cores in two layers. It was then coated with a semi-permeable membrane selected around the tablet cores longitudinally compressed in two layers, and a suitable 0.762 mm orifice was formed for the release of the drug therethrough. An overcoat mixture containing drug was prepared and coated on the semipermeable membrane of the osmotic dosage form. Optionally, a taste masking overcoat is also applied. Each prepared two-layer osmotic dosage form comprised: First component layer 14 milligrams of methylphenidate hydrochloride 61 milligrams of poly (ethylene oxide) (number average molecular weight of 2,000,000). 27.5 milligrams of sorbitol. 5.5 milligrams of polyvinyl pyrrolidone 2.2 milligrams of magnesium stearate. 0.055 milligrams of butylated hydroxytoluene.

Second push layer 72 milligrams of poly (ethylene) oxide (number average molecular weight of 7,000,000) 53 milligrams of sodium chloride 6.6 milligrams of polyvinylpyrrolidone. 1.3 milligrams of red ferric oxide. 0.132 milligrams of magnesium stearate. 0.066 milligrams of butylated hydroxytoluene. Semipermeable membrane 20 milligrams of cellulose acetate (acetyl content of 39.8 percent). 20 milligrams of cellulose acetate (32 percent acetyl content). 2 milligrams of poly (ethylene glycol) (number average molecular weight of 4), 000). An overcoat containing immediate release drug comprising 60 percent hydroxypropylmethylcellulose and 40 percent methylphenidate hydrochloride is prepared and coated with a final solution of 10 milligrams (ie, containing 4 milligrams (ie, containing 4 milligrams of the methylphenidate salt) on the semipermeable membrane of the osmotic dosage form Periodic release rates were determined from the drug overcoat and the osmotic dosage form at 30 minutes, one hour, and then every hour for the next 9 hours The four milligrams of methylphenidate contained within the drug overcoat were released within the first 30 minutes, and the rate of periodic release was demonstrated at t = 1 hour of 0.41 milligrams, and constitutes the drug released from the osmotic dosage form in two layers, during the second interval or 30 minutes.No residual amount of drug remained in the dosage form. The hourly results are shown in Table 3, along with an indication of the presentations of an ascending release rate.

As seen in Table 3, excluding the overcoat of immediate release drug, more than 90 percent of the drug was released at t = 9 hours, and rising-release rates were presented up to t = 8 hours, a period of time prolonged well beyond the midpoint of the T90.

EXAMPLE 4 Oral osmotic dosage forms were made in three layers according to the conventional manufacturing processes known in the art and disclosed in detail in U.S. Patent Application Pending Number 937,336, filed Aug. 19. of 1997, of which the present application is a request for partial continuation. 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 a third thrust layer, containing suitable osmopolymers, were prepared separately. , an osmagent, and selected excipients, by means of granulation methods. Next, the granulation preparations of the first component layer, the second component layer, and the third thrust layer were longitudinally compressed together to form longitudinally compressed tablet cores in three layers. It was then coated with a semipermeable membrane selected around the tablet cores longitudinally compressed in three layers, and a suitable 0.762 millimeter hole was formed through it. Each prepared dosage form comprised: First component layer 4.4 milligrams of pseudoephedrine hydrochloride. 15.3 milligrams of poly (ethylene) oxide (number average molecular weight of 300,000). 1.1 milligrams of hydroxypropylmethylcellulose (number average molecular weight of 9,200). 1.1 milligrams of polyoxyethylene stearate 40. 0.11 milligrams of magnesium stearate.

Second component layer 13.5 milligrams of pseudoephedrine hydrochloride 2.59 milligrams of poly (ethylene oxide) (number average molecular weight of 300,000). 0.9 milligrams of hydroxypropylmethylcellulose (number average molecular weight of 9,200). 0.9 milligrams of 40 polyoxyethylene stearate. 0.018 milligrams of red ferric oxide. 0.09 milligrams of magnesium stearate.

Third push layer 22.2 milligrams of poly (ethylene) oxide (number average molecular weight of 7,000,000). 12 milligrams of sodium chloride 2 milligrams of hydroxypropylmethylcellulose (number average molecular weight of 9,200). 2 milligrams of polyoxyethylene stearate 40. 1.2 milligrams of crosslinked acrylic acid polymer. 0.4 milligrams of red ferric oxide. 0.2 milligrams of magnesium stearate.

Membrane Semipermeable 11.4 milligrams of cellulose acetate (acetyl content of 39.8 percent). 0.6 milligrams of polyethylene glycol (number average molecular weight of 3,350).

Periodic release rates were determined from the osmotic dosage form every hour for 7 hours, and the results are shown in Table 4, along with an indication of the presentations of an ascending release rate.

As seen in Table 4, approximately 87 percent of the drug during the first 7 hours, and ascending release rates were reached throughout this period.

EXAMPLE 5 Oral osmotic dosage forms were made in three layers having a drug concentration gradient, wherein the concentration of drug was higher in the second component layer than in the first component layer, and they also had viscosity gradients, in where the viscosity of the first component layer was lower than the viscosity of the second component layer, and the viscosity of the second component layer was lower than the viscosity of the third layer of thrust, according to the conventional manufacturing processes known in the subject matter and disclosed in detail in the pending United States Patent Application Number 937,336, filed August 19, 1997, of which the present application is a request for partial continuation. Each prepared dosage form comprised: First component layer (350 milligrams) 8.6 percent nicardipine. 54.8 percent of sorbitol. 36.8 percent poly (ethylene) oxide (number average molecular weight of 200,000).

Second component layer (120 milligrams) 45 percent nicardipine. 50 percent poly (ethylene) oxide (number average molecular weight of 300,000). 5 percent hydroxypropylmethylcellulose (number average molecular weight of 9,200).

Third push layer (350 milligrams) 68.75 percent poly (ethylene oxide) (number average molecular weight of 7,000,000). 20 percent sodium chloride. 5 percent hydroxypropylmethylcellulose (number average molecular weight of 9,200). 5 percent crosslinked acrylic acid polymer. 1 percent ferric oxide. 0.25 percent magnesium stearate. Membrane Semipermeable (43.5 milligrams) 95 percent cellulose acetate (acetyl content of 39.8 percent). 5 percent polyethylene glycol (number average molecular weight of 3,350). Dosage forms had 0.635 mm exit holes formed through the semipermeable membrane to allow release of the drug formulation from within the compartment. An upward release rate was achieved for a prolonged period of about 16 hours with the dosage forms of Example 5.

EXAMPLE 6 The preferred embodiments of the osmotic dosage forms were prepared in three layers of the present invention, which additionally comprised an immediate release dose of the drug, applied as an overcoat, as shown in Figure 2, according to the process of making conventional osmotic tablets. The first component layer contained the following (in percent by weight): 9.40 percent methylphenidate hydrochloride, 83.1 percent polyethylene oxide (brand product Polyox N-80 from Union Carbide, Danbury, CT), 5 percent polyvinyl pyrrolidone (Kolidon product 29-32 from BASF Corp., Mt. Olive, NJ); 1.34 percent succinic acid; 0.5 percent stearic acid; and 0.5 percent of butylated hydroxytoluene. The second component layer contained the following (in percent by weight): 13.65 percent methylphenidate hydrochloride, 78.80 percent polyethylene oxide (product brand Polyox N-80 from Union Carbide, Danbury, CT), 5 percent polyvinylpyrrolidone (Kolidon product 29-32 from BASF Corp., Mt. Olive, NJ); 1.95 percent succinic acid; 0.5 stearic acid; 0.05 percent butylated hydroxytoluene; and 0.05 percent yellow ferric oxide, as a coloring agent. The third thrust layer contained the following (in percent by weight): 73.7 percent high molecular weight polyethylene oxide (product brand Polyox 303 from Union Carbide, Danbury, CT), 20 percent sodium chloride; 5 percent polyvinylpyrrolidone (Kolidon brand product 29-32 from BASF Corp., Mt. Olive, NJ); 0.25 percent stearic acid; 0.05 percent butylated hydroxytoluene; and 1 percent green ferric oxide as a coloring agent. Each of the first component layer, the second component layer, and the third thrust layer were prepared separately in granular compositions in a fluid bed granulator. The granulated compositions were then compressed in sequence and longitudinally on a rotary tablet press, to produce the tablet cores longitudinally compressed in three layers. For each dosage form, first 40 milligrams of the granulation of the first component layer were filled in sequence 75 milligrams of the granulation of the second component cap, and were rammed to 100 Newtons in the punch. Then 90 milligrams of the granulation of the third thrust layer was added to the punch, and the final compression was performed at 1,500 Newtons. The composition of the semipermeable membrane was 83 weight percent cellulose acetate (CA 398-10, with an acetyl content of 39.8 percent, product of Eastman Chemical, Kingsport, TN), and 17 weight percent of ethylene oxide and propylene copolymer (product brand Poloxamer 188 of BASF Corp., Mt. , NJ), added as a flow improver. The two ingredients were dissolved in a mixture of 99.5 percent acetone and 0.5 percent water to form a 5 percent solids solution. In a pan coater, the solution was then sprayed onto the cores of tablets longitudinally compressed in three layers to a weight of 25.7 milligrams and a thickness of 0.102 to 0.127 millimeters. After the semi-permeable membrane had been applied to form a compartment containing the tablet cores longitudinally compressed in three layers, a 0.76 millimeter (40 mil) hole was drilled through the semipermeable membrane at the narrow end of the compartment next to the first component layer, to thereby form the osmotic dosage forms in three preferred layers, each containing 14 milligrams of methylphenidate. Each dosage form was approximately 12 millimeters long, with an approximate diameter of 5.3 millimeters. The overcoat of drug to provide an initial dose of immediate release of the drug contains about 30 weight percent methylphenidate hydrochloride, about 70 weight percent hydroxypropylmethylcellulose (product brand name Methocel E3, from Dow Chemical Co. ., Midland, MI), and a trace amount of phosphoric acid (ie, 20 milliliters of phosphoric acid added to 87 kilograms 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 percent solids composition. In a pan coater, the solution was then sprayed onto semipermeable membranes of the osmotic dosage forms in three layers to a weight of about 14.0 milligrams, comprising an immediate release dose of methylphenidate of about 4 milligrams. The final aesthetic overcoated composition weighed 16.9 milligrams, and contained a sub-layer of yellow Opadry II (product brand name of Colorcon, West Point, PA), and a transparent Opadry overlay with a trace amount of carnauba wax, a brightener, prepared and applied as follows: first the Opadry II (10 percent) is suspended in water (90 percent), and sprayed on the overcoated dosage forms with drug; then transparent Opadry (5 percent) in water (95 percent) is suspended and sprayed over dosage forms coated with drug and Opadry II; finally, the dosage forms are stirred in the coater with the carnauba wax for 10 minutes to allow approximately 100 ppm of wax to be evenly distributed over the transparent Opadry coating. Many pharmaceutical dosage forms use drug in salt form, such as the hydrochloride salt of methylphenidate used herein. These salt forms of the drugs, prepared in aqueous solution, however, are susceptible to degradation, and consequently, often have problems of stability and shelf life. It has been found that the addition of an appropriate pH adjusting agent to the aqueous solution reduces unwanted degradation and improves the stability of the product. In particular, in the three-layer osmotic dosage forms of the preferred embodiments, which comprise methylphenidate hydrochloride, it has been found that degradation of the drug ingredient can be minimized by the addition of suitable anti-degradation agents, ie, acid. succinic in the first and second component layers, and phosphoric acid in the drug overcoat. Other suitable anti-degradation agents include compounds that are dissolved in an aqueous medium and that are pharmaceutically acceptable, ie, non-toxic and suitable for oral administration to humans, and that exhibit sufficient pH-adjustability, ie, do not have a pH greater than 4, and preferably of 3 or less. 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. Periodic release rates were determined for sample dosage forms of 20 hours prepared as described, each hour for 12 hours, and are presented as a graph in Figure 3. The average amounts released every hour are shown in Table 5 , along with an indication of the presentations of an ascending release velocity. It is noted that the entire 4 milligram immediate release dose was released essentially within the first hour, and this amount is not taken into account with respect to the determination that an ascending release rate has been presented at t = 2 hours, that is, the average amount at t = 2 hours was compared with the average amount at t = 1 hour minus 4 milligrams representing the immediate release dose.

As seen in Table 5, excluding the overcoat of immediate-release drug, more than 90 percent of the drug was released at t = 8 hours, and ascending release rates were presented up to t = 6 hours, a prolonged period of time well beyond the midpoint of T90.

EXAMPLE 7 The therapeutic effectiveness of individual doses of osmotic dosage forms in three layers containing 14 milligrams of methylphenidate, and further comprising an overcoat of immediate release drug containing 4 milligrams of methylphenidate, was studied and compared with multiple doses of methylphenidate. Methylphenidate immediate release. The parameters of safety and therapeutic efficacy were evaluated during a period of 12 hours in the same subjects treated with the following regimens in different days: the experimental regime in which the osmotic dosage form in three layers was administered once at t = 0 hours , and the standard regimen where immediate release methylphenidate (Ritalin®) was administered three times, 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 with the "usual dose" routinely administered to each subject. For comparative purposes, the actual doses were normalized to a single dose of 18 milligrams of the osmotic dosage in three layers, and up to 15 milligrams of Ritalin® administered as three doses of 5 milligrams. Plasma drug concentrations were determined in all subjects at the same times during the study periods for each regimen. The selected times corresponded to the time just before, and 1.5 hours and 2.5 hours after, the administration of the first two doses of immediate release methylphenidate. (that is, 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 before, and 1. 5 hours and 3.5 hours after administration of the third dose (ie, at t = 8 hours, t = 9.5 hours, and t = 11.5 hours). In Figure 4, plasma drug concentrations obtained from a group of study participants (n = 16) are shown, while treated with the experimental regimen (represented by the diamond eggs), and while treated with the standard regime (represented by filled circles) in graphic form.

A comparison of Figures 3 and 4 demonstrates a correlation between in vitro release rates up to about t = 8 hours, and plasma drug concentrations in vivo up to about t = 9.5 hours. As shown in Figure 4, the concentration of the drug in plasma following each administration of an immediate release dose rises relatively quickly, and then declines at a generally characteristic rate, until the next dose is administered. The concentration of the drug in plasma following the administration of the osmotic dosage form in three layers also exhibits a relatively rapid initial rise, due in large part to the release of the drug from the overcoat of the immediate release drug. However, subsequently, the concentration of the drug in plasma does not decline, but continues to rise substantially (except for a slight "subsidence" between t = 5.5 hours and t = 6.5 hours) up to a time period of 9.5 hours. Particularly surprising is the difference during the time periods within about 1 hour before and about 1.5 hours following the administration of the second, and the third dose of immediate release. With the standard regimen, during these periods, the concentration of the drug in plasma declines to a concentration, and then rises again to a peak concentration. With the experimental regime, during these same periods of time, the concentration of the drug in plasma is rising in a substantially smooth manner, and does not exhibit peaks or valleys. The safety and therapeutic parameters were evaluated, including behavioral, attention and knowledge functions, during the first three hours and the last three hours of the study period, and at two-hour intervals between them. The clinical effectiveness of the experimental regimen was closely comparable with the clinical effectiveness of the standard regimen throughout the entire 12-hour study period. An effective once-a-day therapy for ADHD provides many advantages and offers a significant improvement in drug therapy, eliminating the need for multiple daily doses of methylphenidate while providing a continuous therapeutic efficacy throughout the day.

EXAMPLE 8 Oral osmotic dosage forms were made in three layers according to the manufacturing processes of Example 6, but comprising twice the methylphenidate, ie, a total of 28 milligrams of methylphenidate contained within the first and second component layers , and 8 milligrams of methylphenidate in the drug overcoat. All the remaining ingredients were also doubled, so that the percentages by weight were equal to those of Example 6. The third thrust layer also doubled. The semipermeable membrane had the same composition as in Example 6, but was applied to a weight of approximately 34 milligrams. These dosage forms exhibit a release of 36 milligrams of methylphenidate, with approximately 8 milligrams released immediately, and the remaining 28 milligrams released at an upward release rate over a prolonged period of time.

EXAMPLE 9 Oral osmotic dosage forms were made in three layers according to the manufacturing processes of Example 6, but they comprised a total of 42 milligrams of methylphenidate contained within the first and second component layers, and 12 milligrams of methylphenidate in the overcoat of drug. The first component layer contained the following (in percent by weight): 11.5 percent methylphenidate hydrochloride, 81.6 percent polyethylene oxide (product brand Polyox N-80 from Union Carbide, Danbury, CT), 5 percent polyvinylpyrrolidone (Kolidon product 29-32 from BASF Corp., Mt. Olive, NJ), 1.3 percent succinic acid; 0.5 percent stearic acid; 0.05 percent butylated hydroxytoluene; and 0.05 percent yellow ferric oxide, as a coloring agent. The second component layer contained the following (in percent by weight): 19.8 percent methylphenidate hydrochloride, 72.7 percent polyethylene oxide (product brand Polyox N-80 from Union Carbide, Danbury, CT), 5 percent polyvinylpyrrolidone (Kolidon product 29-32 from BASF Corp., Mt. Olive, NJ); 1.95 percent succinic acid; 0.5 percent stearic acid; and 0.05 percent butylated hydroxytoluene. The third push layer was doubled from Example 6, and the semipermeable membrane had the same composition as in Example 6, but was applied to a weight of approximately 34 milligrams. These dosage forms exhibit a release of 54 milligrams of methylphenidate, releasing approximately 12 milligrams immediately, and releasing the remaining 42 milligrams at an upward release rate over a prolonged period of time. Although the features and advantages of the invention have been described and pointed out, as they apply to the present embodiments, those skilled in the art will appreciate that various modifications, changes, additions, or omissions can be made in the descriptions within the specification, without departing from the spirit of invention.

Claims

1. A method for providing concentrations of methylphenidate in plasma that are ascending in a substantially smooth manner over a prolonged period of time, which comprises administering methylphenidate in a dosage form having a longitudinally compressed tablet core that provides a rate of drug release ascending for a prolonged period of time.

2. A dosage form comprising a pharmaceutically acceptable drug and vehicle, wherein the dosage form releases the drug at an upwardly releasing drug release rate over a prolonged period of time, which comprises: (a) a nucleus of longitudinally compressed tablet comprising three layers, wherein a portion of the drug is contained within a first layer, and the remaining portion of the drug is contained within a second layer, and a third layer comprises a polymer expandable with suitable fluid; (b) a semipermeable wall surrounding the longitudinally compressed tablet core to form a compartment having an osmotic gradient, for driving the fluid from an external fluid environment contacting the semipermeable wall into the compartment; and (c) an orifice formed through the semipermeable membrane and into the longitudinally compressed tablet core at a location adjacent to the first layer, to allow the drug to be released from within the compartment into the external fluid environment.

3. The dosage form according to claim 2, wherein the drug is released successively from the first layer, and then from the second layer.

4. The dosage form according to claim 3, wherein the dosage form further comprises an external surface and an immediate release dosage of a drug applied as a coating on the external surface.

5. A dosage form containing a drug acting on the central nervous system, and a pharmaceutically acceptable carrier, wherein the dosage form releases the drug acting on the central nervous system at an upward release rate over a period of time. prolonged time, which comprises: (a) a longitudinally compressed tablet core comprising three layers, wherein a portion of the drug is contained within a first layer, and the remaining portion of the drug is contained within the second layer, and a third layer comprises an expandable polymer with suitable fluid; (b) a semipermeable wall surrounding the longitudinally compressed tablet core, to thereby form a compartment having an osmotic gradient for driving fluid from an external fluid environment contacting the semipermeable wall into the compartment; and (c) a hole formed through the semipermeable wall and into the longitudinally compressed tablet core, in a location adjacent to the first layer, to allow the drug to be released from within the compartment into the external fluid environment.

6. The dosage form according to claim 5, wherein the drug is released successively from the first layer and then from the second layer.

The dosage form according to claim 6, wherein the drug acting on the central nervous system is a central nervous system stimulating drug selected from the group consisting of methylphenidate, d-threo-methylphenidate, amphetamine , dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline.

8. The dosage form according to claim 7, wherein the central nervous system stimulating drug is methylphenidate.

9. The dosage form according to claim 8, wherein the dosage form further comprises an external surface and an immediate release dosage of methylphenidate applied as a coating on the external surface.

10. The dosage form according to claim 9, wherein the coating comprises an anti-degradation agent.

11. The dosage form according to claim 10, wherein the anti-degradation agent is phosphoric acid.

12. The dosage form according to claim 11, wherein the semipermeable membrane further comprises cellulose acetate and a flow improver.

The dosage form described in claim 12, wherein the flow improver is a copolymer of ethylene oxide and propylene oxide.

14. The dosage form according to claim 2, wherein the dosage form is an osmotic dosage form.

15. The dosage form according to claim 5, wherein the dosage form is an osmotic dosage form.

16. A dosage form comprising methylphenidate and a pharmaceutically acceptable carrier, wherein the dosage form releases methylphenidate at an upwardly releasing drug release rate for a prolonged period of time, which comprises: (a) a tablet core longitudinally compressed comprising three layers, wherein a portion of the methylphenidate is contained within a first layer, and the remaining portion of the methylphenidate is contained within a second layer, and a third layer comprises an expandable polymer with suitable fluid; (b) a semipermeable wall surrounding the tablet core longitudinally compressed to form a compartment having an osmotic gradient for driving fluid from an external fluid environment contacting the semipermeable wall into the compartment; (c) a hole formed through the semipermeable wall and into the longitudinally compressed tablet core, in a location adjacent to the first layer, to allow the methylphenidate to be released from within the compartment and into the external fluid environment.

17. The dosage form according to claim 16, wherein the methylphenidate is released successively from the first layer, and then from the second layer.

18. The dosage form according to claim 17, wherein the dosage form further comprises an external surface and an immediate release dosage of methylphenidate applied as a coating on the external surface.