HK1022272A - Dosage form and method for administering drug - Google Patents

Description

Dosage form and method of administration

The present invention relates to novel dosage forms and novel methods of administration for producing a therapeutic effect. More particularly, the present invention relates to dosage forms that are administered at a sustained ascending rate to produce a particular therapy and to methods of producing a therapeutic effect by administering at a sustained ascending rate over a predetermined time to produce a particular therapy. The invention also relates to a dosage form and a method for achieving therapeutic efficacy by administering an initial dose of a drug followed by a sustained ascending dose of the drug over time.

Drugs that have an effect on pain, mood, thinking, feeling, behavior and psychological personality have long been used in medicine and medicine in every society. These drugs are opioids, barbiturates, hypnotics, central nervous system stimulants, central nervous system depressants, psychostimulants, alcohols, cannabinoids and catecholamines. In current medicine, one class of these drugs has become the standard invention for the treatment of attention deficit disorder, namely central nervous system stimulants. While the present invention is presented in more detail with respect to central nervous system drugs, it is to be understood that the present invention has general applicability and includes drugs that are widely administered using the dosage forms and methods of the present invention.

Parents, teachers, physicians, psychologists, social workers and clinicians have seen significant benefits of central nervous system drugs, which have led to the generally accepted use of central nervous system drug therapy to treat attention deficit disorder. In 1994, the most recent time data was collected, approximately 2% of the school-age female population and approximately 6% of the school-age male population (approximately two million patients in total) were found to receive medication to treat attention deficit disorder.

Prior to the advent of the present invention, dosage forms and methods of administration (e.g., CNS-acting drugs) were the use of standard pharmaceutical dosage forms. For example, one prior art dosage form and method of administering a drug (e.g., the central nervous system drug methylphenidate) is to use an immediate release tablet containing the drug. The immediate release dosage forms deliver the drug by releasing the drug instantaneously, which results in unstable blood levels characterized by peaks and troughs. In the case of an immediate release dosage form containing methylphenidate, characterized by rapid onset and short half-life, to produce the desired therapeutic effect, multiple doses per day are required, which leads to fluctuations in behavior and attention as the medication loses its therapeutic effect. The dosage form cannot provide a desired therapeutic effect for a long period of time.

Another prior art dosage form for administration is a sustained release dosage form. The drug delivery from the prior art sustained release dosage forms may be gradual starting, but will not increase over the dosing interval, and in fact may decrease over time. That is, these sustained release dosage forms deliver the drug in a non-increasing distribution over time because they do not provide a continuously increasing release rate per hour over the course of prolonged administration. Furthermore, the dosage form may not provide the desired treatment period and proper blood pattern. With respect to central nervous system-affecting drugs (e.g., methylphenidate) administered from sustained release non-ascending dosage forms, patients often develop acute tolerance to the drug as evidenced by the shortened duration and the reduced intensity of the therapeutic effect required for acceptable therapy. Previous sustained release delivery also lacks a means to compensate for the inherent disadvantages therein.

The foregoing description suggests that there is an urgent need for new dosage forms and new methods of administration that overcome the disadvantages known in the prior art. This long standing need for dosage forms and for methods requires: (1) administering at a continuously increasing rate while reducing the number of administrations per day; (2) dosage forms and methods for administering at a continuously compensating dose to substantially compensate for acute tolerance to the drug, thereby maintaining a preselected clinical response; (3) dosage forms administered in a continuously increasing profile for the clinical need to treat attention-deficit disorder, and (4) dosage forms and methods for initiating administration and administering in a continuously increasing profile throughout school days.

Accordingly, in view of the above, it is an instant object of the present invention to provide a dosage form which overcomes the disadvantages known in the prior art.

It is another object of the present invention to provide a novel and unique dosage form which provides for the administration of a controlled incremental dose to a patient over time.

It is a further object of the present invention to provide a dosage form which provides a single dose of drug to a patient who has acquired tolerance to the drug to maintain therapeutic efficacy, i.e., by administering in controlled incremental doses over time to maintain therapeutic efficacy, while substantially avoiding the development of acute tolerance.

It is a further object of the present invention to provide a dosage form that delivers a dose of drug that substantially avoids or reduces the development of tolerance acquired by patients who develop acute tolerance from administration by which the drug is administered in a sustained ascending dose over time.

It is a further object of the present invention to provide a dosage form for administration to the central nervous system which overcomes the known disadvantages of the prior art.

It is a further object of the present invention to provide improvements in dosage forms wherein the improvements include dosage forms for administration in a sustained constant ascending distribution for the treatment of attention deficit disorder.

It is a further object of the present invention to provide a pharmaceutical composition in solid dosage form comprising 1mg to 500mg of a drug in admixture with a pharmaceutically acceptable carrier, the drug being released in sustained and ascending dose form for the treatment of psychological personality disorders.

It is still another object of the present invention to provide a dosage form for increasing the hourly dosage of cns-acting drugs in 4 to 8.5 hours on school days.

It is a further object of the present invention to provide a dosage form for administering a drug therapeutically effective in the central nervous system at a sustained rate of increase and at a minimum dosage per day.

It is yet another object of the present invention to provide a dosage form for administration of a cns-acting drug in a drug delivery profile that compensates for the acquired drug-related tolerance.

It is a further object of the present invention to provide a dosage form for the administration of a medicament for the treatment of attention deficit disorder which comprises orally administering to a person diagnosed with the disorder the medicament in an ascending dose of 100ng to 375mg administered continuously over 16 hours to treat the disorder in the person.

It is a further object of the present invention to provide a novel and unique method for maintaining the therapeutic efficacy of a drug in a patient who has acquired tolerance to the drug, wherein the method comprises administering to the patient a dosage form that delivers the drug in controlled, ascending doses over time to maintain the therapeutic efficacy while substantially avoiding the development of acute tolerance in the patient.

It is a further object of the present invention to provide a method for substantially avoiding or reducing the development of acquired tolerance in a patient to whom a drug that develops acute tolerance in the patient has been administered, wherein the method comprises administering the drug at a dose that is continuously increasing over time to produce the intended effect.

It is a further object of the present invention to provide improvements in methods of administration, wherein the improvements include administration in a sustained, constant ascending distribution over time to treat attention deficit disorder.

It is yet another object of the present invention to provide a method of administering a cns-acting drug at an hourly continuously increasing release rate throughout school day of 4 to 8.5 hours.

It is yet another object of the present invention to provide a new method to compensate for the development of acute tolerance associated with drugs that can produce tolerance in patients by orally administering at sustained ascending doses to greatly reduce the effects of unwanted acute tolerance.

It is a further object of the present invention to provide an improvement in a method of administering a drug having central nervous system stimulating therapeutic effects wherein the improvement comprises administering the drug in sustained ascending fashion over time to treat attention deficit disorder and additionally to provide therapeutic compensation for acquired tolerance associated with the drug.

It is a further object of the present invention to provide a method of treating attention-deficit disorder which comprises orally administering to a human diagnosed with the disorder a central nervous system drug in a continuously increasing dose of 100ng to 500mg over 16 hours to treat the disorder in the human patient, and in a minimum number of doses per day.

It is a further object of the present invention to treat Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) by administering a centrally acting drug by a method in which the drug is initially increased and continuously increased throughout the dosing interval.

These and other objects, features and advantages of the present invention will become more fully apparent from the following detailed disclosure of the invention and appended claims.

In fig. 1, the solid line depicts the plasma concentration of the cns stimulant administered from the immediate release dosage form and the dashed line represents the plasma concentration of the cns stimulant released from the sustained non-augmented dosage form.

In fig. 2, a solid line including peaks and valleys depicts an immediate release dosage form and a dashed line depicts a sustained release ascending dosage form.

In fig. 3, 4 and 5, the release results of the central nervous system drug are depicted, wherein open circles indicate placebo, black circles indicate immediate release, black squares indicate sustained non-increasing release profile, and open squares indicate sustained increasing release rate profile.

In fig. 6, the solid line depicts sustained incremental release plasma concentrations and the dashed line including peaks and troughs depicts immediate release plasma concentrations.

In figure 7, filled circles represent placebo, open circles represent a sustained ascending distribution, and filled squares depict the three-daily dosing regimen of the same cns drug.

FIG. 8 depicts: the black circles represent placebo three times a day, the black squares represent immediate release, and the open circles represent sustained ascending release that is substantially intolerant to the same drug.

FIGS. 9-11 depict plasma methylphenidate concentrations obtained by administration in three ways: three times a day, in ascending doses, and by controlling the delivery profile.

FIGS. 12-16 depict plasma methylphenidate concentrations obtained by administration of a dosage form comprising: an outer coating of an initial dose of drug, followed by an inner layer of an ascending dose of drug over time.

In accordance with the practice of the present invention, it has now been found that a dosage form and a method for administration in accordance with the novel regimen can be provided which substantially reduces or completely compensates for patient tolerance. The ` tolerance ` defined by Brill in "Pharmacology in Medicine" p.227(1965) McGraw-Hill indicates a decrease in efficacy following administration. When tolerance develops after one dose or after several doses over a very short period of time, it is called acute tolerance. When a significant degree of tolerance is exhibited for a longer period after administration, it is referred to as chronic tolerance. The medical literature, such as The "pharmacologic basis of therapeutics" by Goodman and Gilman, 8 th edition, p.72(1990) Pergamon Press, reports that tolerance can be achieved from The effects of many drugs, which classifies tolerance as acute or chronic based on The time at which it is achieved. That is, acute tolerance is established in a single dose or over a period of one day, while chronic tolerance is achieved as a result of prolonged administration (typically weeks, months and years). The tolerance proposed in the medical literature most often refers to chronic tolerance, as found in longer-term administration of larger doses, often due to increased body size, liver enzymes involved in biotransformation, etc.

The invention includes pharmaceutical dosage forms that provide incremental doses. A typical dosage form comprises a hydrogel matrix containing a plurality of tiny pellets. The hydrogel matrix comprises a hydrophilic polymer selected from the group consisting of: polysaccharides, agar, agarose, natural gums, alkaline alginates (such as sodium alginate), carrageenan, fucoidan, furcellaran, laminarin, sargassum, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, pectin, pullulan, gelatin, and hydrocolloids. The hydrogel matrix comprises a plurality of 4-50 tiny pellets, each tiny pellet comprising an increasing dose from 100ng up to, for example, an increasing dose population of 0.5mg, 1mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, etc. The tiny pill comprises a release rate control wall with the thickness of 0.0 mm-10 mm so as to ensure the release amount of the medicine to be increased at regular time. Representative wall-forming materials include triglycerides selected from the group consisting of: glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl laurate, glyceryl didecenoate, and glyceryl tridecenoate. Other wall-forming materials include poly (vinyl acetate phthalate), methyl cellulose phthalate, and porous vinyl olefins. Methods for preparing tiny pellets are disclosed in U.S. patent nos.4,434,153; 4,721,613, respectively; 4,853,229, respectively; 2,996,431, respectively; 3,139,383 and 4,752,470.

Dosage forms of the invention for delivering an ascending long dose of drug comprise drug-releasing beads. The drug releasing bead is characterized by a dissolution curve in which 0 to 20% of the bead undergoes dissolution and releases the drug within 0 to 2 hours, 20 to 40% undergoes dissolution and releases the drug within 2 to 4 hours, 40 to 60% shows dissolution and releases the drug within 4 to 6 hours, 60 to 80% is within 6 to 8 hours, and 80 to 100% is within 8 to 10 hours. The drug-releasing beads include a central composition or core that includes a drug and pharmaceutically acceptable composition ingredients (including lubricants, antioxidants, and buffers). The beads include increasing doses of drug, e.g., 1mg, 2mg, 5mg, and 10mg, up to 40 mg. The beads are coated with a release rate controlling polymer which can be selected using the dissolution profiles disclosed above. The following documents disclose the preparation of such beads: liu, journal of international pharmaceuticals (inter.j.of Pharm.), vol.112, pp.105-116 (1994); liu and Yu, journal of International pharmaceuticals, Vol.112, pp.117-124 (1994); remington, pharmaceutical science (pharm. sci.), 14 th edition, pp.1626-1628 (1970); fincher, journal of pharmaceutical science (J.Pharm.Sci.), Vol.57, pp1825-1835 (1968); and U.S. patent No.4,083,949.

The present invention provides a dosage form comprising a drug concentration gradient from 1mg to 100mg, from a low dose of the former to a high dose of the latter, coated on a polymer matrix. The polymer may be an erodable or non-erodable polymer. The coated matrix wraps itself from the latter high dose in the center of the dosage form to the former low dose at the exposed outer ends of the matrix. The coated substrate is wrapped from a high dose to a low dose to ensure release of the drug from the low dose to the high dose upon release or erosion of the substrate. For example, 1mg to 25mg of methylphenidate is coated onto an erodible polymer (e.g., polypeptide, collagen, gelatin, or polyvinyl alcohol), the matrix is wrapped coaxially, rolled inward from a high dose to conform to a central site, and then rolled outward to a low dose to form an outer site. In use, the dosage form is eroded to deliver an ascending dose of methylphenidate released over time.

Another dosage form provided by the present invention comprises a plurality of layers, wherein each layer is characterized by an ascending dose of drug. The term "many layers" means 2 to 6 layers of superimposed contacts. The plurality of layers are placed in series, i.e., one after the other in the order of a first layer exposed, a sixth layer in contact with the fifth layer, and the exposed surface of the sixth layer coated with a drug impermeable polymer. The sixth layer is coated with a drug impermeable polymer to ensure release of the drug from the first to sixth layers. The first layer comprises 1-5 mg of the drug and each successive layer comprises an additional 1-5 mg of the drug. The biodegradable polymer undergoes chemical decomposition to form soluble monomer or soluble polymer units. Biodegradation of polymers typically involves chemocatalytic or enzymatically catalyzed hydrolysis. Representative biodegradable polymers are suitable for increasing drug loading in each layer by 5% to 50% by weight over the first and adjacent layers, wherein the first layer contains 100 ng. Typical biodegradable polymers include one selected from the group consisting of: biodegradable polyamides, polyamino acids, polyesters, polylactic acids, polyglycolic acids, polyorthoesters, polyanhydrides, biodegradable poly (dehydropyrans) and poly (dioxinones). These polymers are known in the art and are described in the following references: rosoff, "Controlled Release of Drugs" (Controlled Release of Drugs), Chapter 2, pp.53-95 (1989); and U.S. patent nos.3,811,444; 3,962,414; 4,066,747, respectively; 4,070,347, respectively; 4,079,038, and 4,093,709.

The invention further contemplates a dosage form comprising a polymer that releases a drug by diffusion, through a pore, or by rupture of the polymer matrix. The drug delivery polymer system comprises a concentration gradient, wherein the gradient is a concentration increase from a starting or initial concentration to a final or higher concentration, i.e., a concentration increase of 100ng to 250 mg. The dosage form includes an exposed surface for an initial dose and a remote unexposed surface for a final dose. The unexposed surface is coated with a pharmaceutically acceptable substance that is impermeable to the drug. The dosage form configuration ensures an increased flux of the delivered drug, from the beginning of the increment to the last delivered dose.

The dosage form matrix may be prepared by methods known in the polymer art. In one manufacturing process, 3 to 5 or more casting compositions are independently prepared, wherein each casting composition comprises an incremental drug dose, and each composition is layered from a low dose to a high dose. This provides a series of layers which together constitute a unitary polymer matrix having a concentration gradient. In another method of preparation, a higher dose is cast and then laminated with a decreasing dose to provide a polymer matrix with a gradient in drug concentration. One example of providing such a dosage form includes: a pharmaceutically acceptable carrier, such as polyethylene glycol, is blended with a known dose of a drug, such as a central nervous system stimulant, at an elevated temperature, such as 37 deg.C, and added to a silicone rubber pharmaceutical grade elastomer containing a cross-linking agent, such as stannous octoate, followed by casting in a mold. This step is repeated for each subsequent layer. The system was left for 1 hour to provide the dosage form. Representative polymers for preparing the dosage form include one selected from the group consisting of: olefin polymers and vinyl polymers, polycondensates, carbohydrate polymers and silicone polymers, for example polyethylene, polypropylene, polyvinyl acetate, polymethyl acrylate, polyisobutyl methacrylate, polyacrylates, polyamides and polysiloxanes. These polymers and methods of preparation are known and are described in the following documents: coleman et al, Polymer (Polymers) Vol.31, pp.1187-1230 (1990); roerdink et al, Drug Carrier Systems (Drug Carrier Systems), Vol.9, PP.57-109 (1989); leong et al, reviews on the progress of drug Delivery (adv. drug Delivery Rev.), vol.1, pp.199-233 (1987); edited by Roff et al, "Handbook of Common Polymers" (Handbook of Common Polymers), (1971) published CRC Press; and U.S. patent No.3,992,518.

Furthermore, in accordance with the practice of the present invention, the methods of the present invention employ the disclosed dosage forms to administer to a patient who is likely to acquire acute or chronic tolerance to reduce and/or avoid such tolerance, and have been shown to be useful in treating patients who are likely to acquire acute tolerance. Also, in accordance with the practice of the present invention, in one embodiment, it has also been found that a method can be provided for orally administering to an individual for the treatment of attention deficit disorder, i.e., administering as a function of time to achieve a desired concentration of drug over time. Drug concentration is related to the drug dose (expressed in mg/h) which is the dose delivered per unit time (in hours) for absorption into the systemic circulation. The method of the present invention uniquely provides a means to maintain the desired drug effect by continuously adjusting the rate of drug delivery as the therapeutic effect declines during the acute tolerance attained.

It is common medical practice that a drug should provide therapeutic efficacy throughout the dosing interval. However, when tolerance to drugs is developed or obtained, prior art methods of ensuring therapeutic response are to increase the dose administered in an immediate dose-dumping manner, and in the case of such administration, there is a high probability of associated side effects, tolerance to all effects may be varied, and the therapeutic index may be lowered. Another method of the prior art for reducing the incidence of tolerance is to administer fewer drug doses and thus avoid achieving tolerance, but the use of this method lacks treatment at the prescribed time.

In medicine, it is widely accepted that cns-acting drugs are suitable for the treatment of attention deficit disorder. Suitable drugs for this therapy are mild central nervous system stimulants, including catecholamines and drugs that mimic their action. The drug suitable for the therapy comprises a substance selected from the group consisting of: amphetamine, dextroamphetamine, methamphetamine, methylphenidate, racemic methylphenidate, threo methylphenidate, phenylisopropylamine, lispirone, and pemoline. The medicaments also include their pharmaceutically acceptable salts, for example one selected from the group consisting of: hydrochloride, sulfate, phosphate, acetate, hydrobromide, pamoate and maleate. Patients receiving these drugs often gain tolerance to the effects of the drug. For example, patients receiving a 5mg dose of methylphenidate twice daily acquire tolerance and must therefore administer larger doses, as a single large dose is required to overcome tolerance development, which can cause undesirable side effects. In some patients, the therapeutic response to methylphenidate decreased within 4-5 hours, despite maintaining the methylphenidate at a non-increasing constant concentration. That is, tolerance to the behavioral and psychological effects of methylphenidate and, in general, psychostimulants is obtained. The present invention also finds that sustained release formulations that dispense uncompensated but constant concentrations of drug may not be clinically effective because sustained release dosage forms designed to produce constant plasma concentrations of, for example, methylphenidate, in particular lack the effect against acquired tolerance.

The present invention provides, in its objects, a dosage form and a method of treating attention-deficit disorder, including attention-deficit/hyperactivity disorder, conjunctive, primarily inattentive, primarily hyperactive impulsive, these also known as mild brain dysfunction, childhood hyperkinetic syndrome, behavioral syndromes, mild brain dysfunction and minor brain dysfunction, as disclosed in the "Diagnostic and Statistical handbook of mental disorders" (Diagnostic and Statistical Manual of mental disorders) 3 rd edition, pp.49-56 (1987), published by the american psychiatric Association, Washington, d.c., by providing a dosage form and method of treatment that substantially eliminates the undesirable effects of the prior art by providing continuous drug compensation that substantially eliminates acute tolerance, thus stabilizing the effect.

The pharmacological effect of a drug is related to its receptor site concentration. Thus, if the effect of a drug is viewed as a function (f) of delivery time (t), the stable kinetics of some drugs may be rapid, while for others the effect is unstable with decreasing response, indicating that tolerance to the drug is being developed. The latter case is suitable for centrally acting drugs (such as methylphenidate). The present invention compensates for the acute tolerance obtained by providing an optimal drug delivery profile for its operation. For some drugs, the onset of tolerance is rapid, e.g., methylphenidate develops tolerance within hours after administration. One treatment protocol provided by the present invention for this purpose is to provide a drug delivery profile that initially delivers a dose of drug to achieve immediate treatment, followed by a sustained release dose that increases over time to maintain the effect.

The drug methylphenidate can be in sustained release formulation Ritalin^SR commercial, applying the sameThe methylphenidate in its purifezed form can lead to acute tolerance. When acute tolerability is achieved, a drug free clearance period of several hours is required before repeated administration of the dosage form is possible. However, the present invention compensates for the loss of therapeutic efficacy of a drug, such as methylphenidate, by providing a delivery rate (expressed in mg/hr) method that continuously compensates for the development of acute tolerance by considering the clinical effect (E) of the drug at time (t) as a function of drug concentration (C) as shown in equation 1 below

Effect = f (t, C) equation 1

In addition, the rate of drug delivery (a) (expressed in mg/hour) is directly proportional to the concentration multiplied by the elimination rate of the drug. As the effect varies with time and the functionality is expressed, then according to the invention, (a) can be controlled to ensure that the therapeutic effect is maintained at clinical value. If the effect of a clinically found drug decreases over time, the decrease may be linear, as shown in equation 2:

effect_(t)Effect of = effect_(ini)-k_EffectX t equation 2 wherein_(ini)Is the clinical effect initially observed at the start of administration, the effect (t) is the effect observed over a period of time (t) hours, k_EffectIs the proportionality constant obtained by measuring the clinical effect (E1) at time (t1) hours and (E2) at time (t2) hours while maintaining a constant plasma concentration, and then dividing (E1) by (E2) by (t1) by (t 2). To maintain a constant effect, it is necessary to adjust (a) with the same functionality of equation 3:

A_(t)=A_(ini)+k_effectX t equation 3 where A_(ini)Is the initial dose of drug (in mg/hour) at the start of the treatment, A_(t)Is the amount of drug administered, k, over time (t) hours_EffectIs the proportionality constant set forth above. If the effect is found to decrease exponentially with time, this relationship is expressed by equation 4:

effect_(t)Effect of = effect_(ini)×exp^{(-k effect x t)}Equation 4 wherein the effect_(ini)And effects_(t)As defined above, k_EffectIs the rate constant (h)^-1) I.e. the reciprocal unit of the number of hours, can be obtained: the clinical effect (E1) was measured at time (t1) hours and (E2) at time (t2) hours while maintaining constant plasma concentrations, followed by dividing the natural logarithm of (E1) minus the natural logarithm of (E2) by (t1) minus (t 2). In order to maintain a constant effect, it is necessary to adjust (A) according to equation 5

A_(t)=A_(ini)×exp^{(k effect x t)}Equation 5 where A_(ini)And A_(t)As defined above. k is a radical of_EffectIs the rate constant (h) given above^-1). These equations are referred to in drug therapy (pharmac. ther.) vol.16, pp.143-166(1982) by Holford n.h.g and Sheiner, l.e.

"effect" as defined herein refers to a pharmacological effect exhibited by a drug, as determined by clinical subjective observation (e.g., SKAMP and CLAM), or as determined by objective activity monitoring (e.g., math test and school performance). The CLAM test is a behavioral assessment method designed by Conners, Lonez and Milch, and represents social compliance or traitoricity; SKAMP is also an evaluation method for determining behavior, and was designed by Swanson and reported in Psychopharmacological Bulletin (Psychopharmacological Bulletin), Vol.21, PP.887-890 (1985).

The effect measurements in this study were: (1) observer assessment of SKAMP levels (in classroom hours) and (2) performance of computer-operated mathematical tests. The mathematical level of each child was tested before the study began, and mathematical tests appropriate to the abilities of each child were given based on the predictive test during the study. The morning and evening parental CLAM estimates were used to identify abnormal behavior. Night parent CLAM is used to determine the presence of a therapeutic effect during the night, particularly during the time the child sleeps, and whether the child's sleep is interrupted. All children wear activity monitors (actigraphs) which record the activity of the child throughout the day. The activity (number of activities per minute) was recorded by the electronic instrument and a functional model of the effect of the drug was established.

The following examples are merely illustrative of the present invention and are not to be construed as limiting the scope of the invention in any way, as these examples and their equivalents will be apparent to those skilled in the art in light of this disclosure and the appended claims. Example 1

36 school children were administered a commercially available immediate release tablet containing 5mg methylphenidate twice daily and the predicted plasma concentrations (in ng/ml) were plotted against time as shown by the solid black line in FIG. 1. The plasma concentration profile of the tablet, methylphenidate, appeared to peak and trough. A sustained release non-escalating regimen for the administration of 20mg methylphenidate included 8.3mg at 0 hours, followed by 0.9mg at 1.5 hours, 0.9mg at 2 hours, 0.9mg at 2.5 hours, 0.9mg at 3 hours, 0.9mg at 3.5 hours, 0.9mg at 4 hours, 0.9mg at 4.5 hours, 0.9mg at 5 hours, 0.9mg at 5.5 hours, 0.9mg at 6 hours, 0.9mg at 6.5 hours, 0.9mg at 7 hours, 0.9mg at 7.5 hours, forming a sustained release dashed line parallel to the x-axis, as seen in FIG. 1. The immediate release tablet and sustained release dosage form were compared to a sustained release dosage form presenting an increasing distribution of methylphenidate administration. The sustained release increasing profile corresponds to administration of 4.2mg at 0 hours, 1.1mg at 1.5 hours, 1.1mg at 2 hours, 1.2mg at 2.5 hours, 1.2mg at 3.0 hours, 1.3mg at 3.5 hours, 1.3mg at 4 hours, 1.5mg at 4.5 hours, 1.5mg at 5 hours, 1.8mg at 5.5 hours, 1.8mg at 6 hours, and 2.0mg at 6.5 hours, forming a sustained increasing release dashed graph, as seen in fig. 2.

Clinical study results show that patients administered a methylphenidate-free dosage form (placebo) exhibit high, elevated fluctuations in behavior such as activity, inappropriate behavior, low attention, lower mathematical scores, and disinterest in learning. Patients administered a sustained non-increasing dose of methylphenidate showed a reduction in mobility, a higher mathematical score and a reduction in inappropriate behavior. However, these effects are accompanied by acute tolerance in the patient. By administering methylphenidate in a controlled, sustained, ascending distribution to the patient according to the invention, the patient exhibits the desired therapeutic effect without tolerability. The results of the above studies are given in the figures. In fig. 3, 4 and 5, the line with open circles represents placebo, the black circles represent immediate release dosage forms administered twice a day, the black squares represent sustained release non-escalating dose profiles, and the open squares represent sustained, escalating release profiles provided by the present invention. The SKAMP score and the CLAM score have been defined earlier in this specification, with the times indicated in the figure. Fig. 3 shows the observed behavior, fig. 4 shows the inadvertent overactivity, and fig. 5 shows the combined attention results of the study. Example 2

The results of a clinical study involving the administration of methylphenidate according to two different delivery regimens are reported in this example. In this study, the sustained ascending distribution corresponded to the administration of methylphenidate as follows: 8mg at 0 hour, 1.4mg at 1.5 hours, 1.4mg at 2.0 hours, 1.7mg at 2.5 hours, 1.7mg at 3.0 hours, 2.0mg at 3.5 hours, 2.0mg at 4.0 hours, 2.2mg at 4.5 hours, 2.2mg at 5.0 hours, 2.2mg at 5.5 hours, 2.2mg at 6.0 hours, 2.4mg at 6.5 hours, 2.4mg at 7.0 hours, 2.6mg at 7.5 hours, 1.9mg at 8.0 hours. Methylphenidate is administered in the form of an outer gelatin capsule, which contains a total of 36mg methylphenidate, 22% in the outer coating. The ascending dose administered was the first dose at time 0730, followed by increasing doses every 30 minutes until time 1530, resulting in the expected ascending plasma concentration. The study included delivery of methylphenidate in an immediate dosage form three times daily, with 10mg of methylphenidate delivered at times 0730, 1130 and 1530. The study was performed on 32 children with attention deficit hyperactivity disorder. FIG. 6 shows the plasma concentrations of methylphenidate, where the dotted line is from a sustained ascending dosing regimen and the dashed line is from an immediate dosage form. In figure 7, filled circles represent placebo, open circles represent sustained ascending dosing regimens, filled squares represent three times daily dosing regimens, and the observed parameter is the behavior of the sustained ascending dosing regimen in the absence of acquired tolerance. FIG. 8 shows the combined attention parameters, where the filled circles are placebo, with tolerance achieved; solid squares are immediate release delivery three times a day with tolerance achieved; open circles are sustained ascending release, essentially free of established tolerance. Example 3

A method is provided for the treatment of attention deficit disorder by administering a dosage form formulated as an oral tablet for administration of the central nervous system stimulant methylphenidate in a sustained ascending dose with concomitant diminution of acquired tolerance. The dosage form comprises a film of polyanhydride polymer of sebacic and azelaic acids coated with a composition comprising 20mg of methylphenidate in admixture with pharmaceutically acceptable gelatin. The pharmaceutically acceptable film is coated with a methylphenidate composition in the form of an increased thickness that is spirally wound around itself. After oral administration into the gastrointestinal tract, the membrane is eroded over time, whereupon the composition comprising methylphenidate is released at a constant ascending rate. The polymers of this dosage form are described in U.S. Pat. Nos.2,668,162 and 2,676,945, and the dosage form is described in U.S. Pat. No.3,625,214. Example 4

A method is provided for treating attention deficit hyperactivity disorder by administering the bioerodible dosage forms of the invention comprising the central nervous stimulant pimulin, with the assistance of psychological guidance and educational guidance, with a stabilizing effect in children by administering pimulin, with a marked absence of acquired tolerance. The dosage form comprises 5 bioerodible poly (lactide-glycolide) contact layers, each layer containing incremental amounts of 4, 6, 8, 10 and 12mg of pimoline. The layers were compressed into a tablet configuration such that one layer was exposed on an open surface to the layer containing 2mg of pimulin, while the remaining layers of the tablet were surrounded by non-bioerodible ethylene vinyl acetate copolymer. The layers are then bioeroded in a constant order, releasing a constant increasing dose of pimulin over time. Such bioerodible polymers are known from U.S. Pat. Nos.3,773,919; EPO 0-052-510; and canadian patent No.1,169,090. Example 5

A method of administering a drug at a sustained, ascending release rate is provided by administering a dosage form prepared in the form of a pharmaceutically acceptable gelatin two-piece linked capsule comprising a plurality of spherical beads. The capsule comprises a series of beads, each distinct bead containing 1, 1.25, 1.5, 1.75, 2 and 2.25mg of drug in succession, which beads are coated with 0.5, 1, 1.5, 2.5, 3 and 3.25mm in succession of a polymer of poly (2, 2-dioxo-trans-1, 4-cyclohexanedimethylenetetrahydrofuran) respectively. As these beads erode in the environment of the gastrointestinal tract, they are administered at a sustained, increasing release rate over time. The drugs that can be administered by the present method include one selected from the group consisting of: amphetamine, dextroamphetamine, methamphetamine, methylphenidate, phenylisopropylamine, and pimulin. Methods of application are disclosed in journal of the american pharmaceutical association (j.am. phar. assoc.), sci.ed., vol.48, pp.451-454 (1959); and U.S. patent No.2,799,241. Example 6

The present invention provides a delivery system that releases drug resulting in an increasing plasma methylphenidate concentration over time, substantially overcoming tolerability and maintaining the desired pharmacological effect of the stimulant methylphenidate for a desired duration. For example, to achieve an effect-time profile similar to three immediate release doses per day (once every 4 hours for a total of 12 hours), i.e., TID (three times per day), a delivery system that results in plasma methylphenidate concentrations within the ranges set forth below would overcome tolerability and maintain pharmacological effects. To produce a delivery system equivalent to two immediate release doses given every 4 hours, the release rate can be reduced; similarly, the concentration may be increased for a longer duration. The delivery profile accounts for drug and pharmacological effects. However, the concept of increasing the concentration remains the same.

Table 1 provides the range as part of the simulated TID concentration. The figure shows incremental profile changes appended to the TID and reference incremental (ASCEND) processing profile.

TABLE 1

Time (hours)	TID concentration (ng/MI)	Increasing distribution Range (part of TID concentration)
				Is low in	Height of
		1.5	4.8 (Peak)			0.75	0.90
3.0	3.8			1.07	1.37
		4.0	2.8 (minimal value)			1.32	2.29
5.5	6.5 (Peak)			0.80	1.20
		7.0	4.8			1.42	1.81
8.0	3.6 (Min)Value)			2.17	2.50
		9.5	7.0 (Peak)			1.10	1.23
11.0	5.2			1.00	1.38
		12.0	3.9			0.97	1.54
15.0	1.7			1.00	1.94

The figures depict the therapeutic benefits obtained by the present invention. Fig. 9 illustrates: simulated plasma methylphenidate concentration profiles for 30mg doses three times a day (solid line), 36mg augmentation treatment (dashed line), and osmotic controlled 36mg doses (dotted line). FIG. 10 plots plasma methylphenidate concentrations as in FIG. 9, except that the dose for osmotic control in FIG. 10 was 38 mg. FIG. 11 plots plasma methylphenidate concentrations as in FIG. 9, except that the dose for osmotic control in FIG. 11 is 40 mg. Fig. 12 illustrates a 30mg delivered three times a day (solid line), an escalating dose delivered once a day from a dosage form comprising 36mg of drug (dashed line), and a dosage form comprising an immediate 8mg dose and a sustained 26mg escalating dose (dotted line). FIG. 13 plots plasma methylphenidate concentrations similar to FIG. 12, except that the dosage form, shown by the dotted line, includes an immediate release dose of 9mg methylphenidate and an incremental dose of 24mg methylphenidate. FIG. 14 is similar to the previous figures except that the dotted line shows an immediate release dose of 8mg and an incremental dose of 25mg methylphenidate. FIG. 15 is similar to the previous figures except that the dotted line illustrates an immediate dose of 8mg methylphenidate, followed by a sustained ascending dose of 25mg methylphenidate. FIG. 16 is a graph similar to the previous figures except that the instant dose of 8mg methylphenidate is illustrated by a dotted line in this study, followed by a controlled incremental dose of 24mg methylphenidate.

The method of the present invention further provides for administering a drug as in the above examples, wherein the drug is administered in a dosage form of the present invention at a controlled rate and sustained release profile over a period of up to 8 hours or up to 12 hours of the day.

While features and advantages of the invention have been described and pointed out as applied to the described embodiments, those skilled in the medical arts will appreciate that various modifications, changes, additions, and deletions may be made to the methods described in this specification without departing from the spirit of the invention.

Claims (12)

1. A pharmaceutical composition in a dosage form comprising a dose of drug in a concentration gradient from a low dose to a high dose, whereby the dosage form releases drug in a low dose to high dose form.

2. The dosage form of claim 1 for delivering a drug, wherein the dosage form comprises: a composition comprising a polymer, a dose of a drug present in the composition in a concentration gradient from a low dose to a high dose, and wherein the dosage form releases the low dose of the drug followed by the high dose of the drug when administered.

3. The dosage form of claim 1 for delivering a drug, wherein the dosage form comprises: a plurality of layers comprising a polymeric composition, presenting an increasing dose of a dosage of a drug in the plurality of layers, and wherein the dosage form delivers an increasing dose of the drug over time as it is administered.

4. The dosage form of claim 1 for delivering a drug, wherein the dosage form comprises: comprising a plurality of layers of a composition comprising different polymers, presenting an increasing dose of a drug in the plurality of layers, and wherein the dosage form delivers an increasing dose of the drug over time as it is administered.

5. The dosage form of claim 1 for delivering a drug, wherein the dosage form comprises: a composition comprising a bioerodible polymer, a dose of a drug in the composition being present in an initial dose and a final dose, the dosage form thereby delivering the initial dose and the final dose over time.

6. The dosage form of claim 1 for delivering an ascending dose of drug, wherein the dosage form comprises: a plurality of layers comprising a bioerodible polymer, the layers presenting an incremental dose of drug, whereby the dosage form delivers an incremental dose of drug over time.

7. The dosage form of claim 1 for delivering an ascending dose of drug, wherein the dosage form comprises: a plurality of layers comprising different bioerodible polymers present incremental doses of drug in different layers, whereby the dosage form delivers incremental doses of drug over time.

8. The dosage form of claim 1 for delivering an ascending dose of drug, wherein the dosage form comprises tiny pellets containing drug that deliver over time an initial dose of drug and a successive ascending dose of drug.

9. The pharmaceutical composition of claim 1 in a dosage form, wherein the pharmaceutical composition comprises a dose of drug which is released in sustained and ascending dose form in admixture with a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 1mg to 500mg of drug.

11. The pharmaceutical composition of claim 1, wherein the drug is released in sustained ascending doses from 100ng to 375mg over a 16 hour period.

12. Use of the pharmaceutical composition of claim 1 for the treatment of psychological disorders.