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  • 专利说明
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    • 专利摘要:
    A dosage form and a method are disclosed and claimed for administering a drug in a sustained and constantly ascending rate per unit time to provide an intended therapeutic effect while concomitantly lessening the development of unwanted effects.
    公开号:CA2515884A1
    申请号:C002515884
    申请日:1997-09-16
    公开日:1998-04-09
    发明作者:Suneel K. Gupta；Diane R. Guinta；Carol A. Christopher；Samuel R. Saks
    申请人:Alza Corporation；Suneel K. Gupta；Diane R. Guinta；Carol A. Christopher；Samuel R. Saks；
    IPC主号:A61K31-4458
    专利说明:
    [1" class="description-paragraph] WO 98114168 PCTlUS97/16599 DOSAGE FORM AND METHOD FOR ADMINISTERING DRUGz s FIELD OF THE INVENTION This invention pertains to both a novel dosage form and to a novel s method for administering a drug for producing a therapeutic effect. The invention concerns more specifically a dosage form that administers at a a sustained and continuously ascending rate a drug to produce a given therapy, s and more specifically a method for producing a therapeutic effect by io administering over a predetermined period at a sustained and continuously " ascending rate a drug to produce a given therapy. The invention relates also ,z to a dosage form and to a method for achieving a therapeutic effect by ,s administering an initial dose of drug followed by a sustained and increasing ,a dose of drug over an extended time.,s BACKGROUND OF THE INVENTION,~~a For a long time, pharmacy and medicine in every society used ,s drugs that produce effects on pain, mood, thought, feeling, behavior, zo and psychological personality. These drugs are represented by opioids, z, barbiturates, hypnotics, central nervous system stimulants, central nervous zz system depressants, psychostimulants, alcohols, cannabinoids, and zs catecholamines. In present medicine, one class of these drugs has become z4 the standard invention for the management of Attention-Deficit Disorder, z5 that is, the central nervous system stimulants. While this invention presents zs central nervous system drugs in greater detail, it is understood the invention z~ is generic and embraces drugs broadly administered using the dosage forms za and the method of the invention.zs The benefits perceived by parents, teachers, physicians, so psychologists, social workers, and clinicians are dramatic for central nervous system drugs, and this has resulted in the widespread and acceptable use
    [2" class="description-paragraph] 2 1 of central nervous system medication to treat Attention-Deficit Disorder.2 In 1994, the latest period for collecting data, it was observed that about two ' s percent of the school-aged female population and about six percent of the a school-aged male population, for a total of about two million patients, were s administered the medication for Attention-Deficit Disorder.s Prior to the advent of this invention, the dosage form and the method z for administering a drug, for example, a central nervous system acting drug, 8 consisted in using a standard pharmaceutical dosage form. For example, s one prior art dosage form and method for administering a drug, such as the ,o central nervous system drug methylphenidate, consists in using an immediate ~, release tablet containing the drug. This immediate release farm delivers the ,z drug by instant dumping of the drug and this produces uneven blood levels ~s characterized by peaks and valleys. For an immediate release form ~a containing methylphenidate which is characterized by a rapid onset and a ~s short half-life to produce the intended therapy, multiple doses are needed ,s each day that can result in swings in behavior and in attention as the 1~ medication loses its therapeutic effect. This dosage form does not provide is the needed therapy over an extended time.s Another prior art dosage form for dispensing a drug is the sustained-zo release dosage form. A drug dispensed from a prior art sustained-release z, dosage form may ascend initially but not over the entire dosing interval, and it zz actually may decline over time. That is, these sustained-release dosage forms zs dispense a drug in a nonascending profile over time, as they do not provide a z4 continuously increasing release rate per hour throughout the extended dosing zs period. This dosage form, additionally, may not provide the required duration zs of therapy and the appropriate blood pattern. For drugs that act on the central z~ nervous system, like methylphenidate, dispensed from a sustained-release za nonascending dosage form, the patient often develops an acute tolerance to zs the drug manifested by a shortened duration and a decrease in the intensity of so the therapeutic effect needed for acceptable therapy. The prior sustained-
    [3" class="description-paragraph] 3 1 release delivery is also devoid of means that compensate for its shortcomings z inherent therein.' s The above presentation teaches that a critical need exists for a novel a dosage form and for a novel method for administering a drug that overcomes s the shortcomings known to the prior art. This long-felt need exists for a dosage s form and for a method for (1 ) administering the drug at a sustained-increasing ~ rate that simultaneously reduces or eliminates the frequency of daily dosing;a for (2) a dosage form and a method for administering the drug in a sustained-s compensating dose to substantially compensate for acute tolerance to the drug ' 1o thereby maintaining a preselected clinical response; for (3) a dosage form that o administers the drug in a sustained-ascending profile clinically indicated for the 1z management of Attention-Deficit Disorders; and, for (4) a dosage form and a 1s method for administering the drug initially and in a sustained-ascending profile 1a throughout the entire school day.1s OBJECTS OF THE INVENTION 1e Accordingly, in view of the above presentation, it is an immediate 1s object of this invention to make available a dosage form that overcomes the zo shortcomings known in the prior art.21 Another object of the invention is to provide a novel and unique dosage z2 form that delivers a drug in a controlled increasing dose to a patient over time.z3 Another object of the invention is to provide a dosage form that za administers a dose of drug to maintain the therapeutic effect of the drug in a zs patient that acquires tolerance to the drug by delivering the drug in a controlled-zs increasing dose over time to maintain the therapeutic effect, while z~ concomitantly substantially avoiding the development of acute tolerance.za Another object of the invention is to make available a dosage form that zs delivers a dose of drug that essentially avoids or lessens the development of 3o acquired tolerance in a patient administered a drug that leads to acute
    [4" class="description-paragraph] 4 tolerance by the dosage form administering the drug in a sustained and z increasing dose over time.s Another object of the invention is to provide a dosage form for a administering a central nervous system drug that overcomes the shortcomings s known to the prior art.s Another object of the invention is to provide an improvement in a dosage ~ form, wherein the improvement comprises the dosage form administering the a drug in a sustained and constantly ascending profile over time for treating s Attention-Deficit Disorder.o Another object of the invention is to provide a pharmacological ~ composition as a solid dosage form comprising 1 mg to 500 mg of drug in ~z admixture with a pharmaceutically acceptable carrier that is released in a ~s sustained release and increasing dose for use in the treatment of psychological ~a personalities.,s Another object of the invention is to provide a dosage form for increasing is the administration of a central nervous system acting drug per hour throughout ,~ a school day of 4 to 8-1I2 hours.,s Another object of the invention is to provide a dosage form for s administering a drug possessing central nervous system therapy in a zo sustained-increasing rate and at a minimum dose per day.z~ Another object of the invention is to provide a dosage form for zz administering a central nervous system acting drug in a drug delivery zs pattern that compensates for acquired tolerance associated with the drug.za Another object of the invention is to provide a dosage form that zs administers a drug for treating Attention-Deficit Disorder that comprises zs administering orally to a human diagnosed as having the disorder the drug in a z~ sustained and increasing dose of 100 ng to 375 mg over 16 hours for treating za the disorder in a human.zs Another object of this invention is to provide a novel and unique method so for maintaining the therapeutic effect of a drug in a patient that acquires s, tolerance to the drug, wherein the method comprises administering a dosage form to the patient that delivers the drug in a controlled increasing dose over an a extended time to maintain the therapeutic effect, while concomitantly s substantially avoiding the development of acute tolerance in the patient.4 Another object of the invention is to make available a method for s essentially avoiding or lessening the development of the acquired tolerance s in a patient administered a drug that develops acute tolerance in the patient, z wherein the method comprises administering the drug in a sustained and a increasing dose over time to produce the intended effect.s Another object of the invention is to provide an improvement in a method ' ~o for administering a drug, wherein the improvement comprises administering the drug in a sustained and constantly ascending profile over an extended time for ~z treating Attention-Deficit Disorder.~s Another object of the invention is to provide a method for administering a ,n central nervous system acting drug in a continuously increasing release rate ,s per hour throughout a school day of 4 to 8-1/2 hours.is Another object of the invention is to provide a novel method to ~~ compensate for acute tolerance development associated with a drug ,a possessing the ability to produce tolerance in a patient, by administering the ,s drug orally in a sustained-ascending dose to substantially lessen the unwanted zo effects of acute tolerance.z~ Another object of the invention is to provide an improvement in a method 22 for administering a drug possessing central nervous system stimulant therapy, zs wherein the improvement comprises administering the drug in a sustained and za ascending pattern over an extended time for treating Attention-Deficit Disorders zs and additionally provides therapeutic compensation for acquired tolerance zs associated with the drug.z~ Another object of the invention is to provide a method for treating za Attention-Deficit Disorder comprising administering orally to a human diagnosed zs as having the disorder at a sustained and increasing dose of 100 ng to 500 mg so over 16 hours a central nervous system drug for treating the disorder in a s~ human patient and at a minimum number of doses per day. WO 98/14168 PCTlUS9~I16599 Another object of the invention is to administer a central nervous system z acting drug by a method wherein the drug ascends initially and continuously ' s over the entire dosing interval for treating Attention-Deficit Disorder, ADD, and a Attention-Deficit Hyperactivity Disorder, ADHD.s These objects, as well as other objects, features, and advantages of the s invention will become more apparent from the following detailed disclosure of ~ the invention and the accompanying claims.a s DRAWING FIGURES PROVIDED BY THE INVENTIONIn Figure 1, the solid line depicts the plasma concentration for a central ~z nervous system stimulant administered from an immediate release form, and 13 the dotted line denotes the plasma concentration for a central nervous system ~a stimulant released from a sustained nonascending form.In Figure 2, an immediate release dosage form is depicted by the solid ~s line comprising a peak and a valley depicted against a sustained release i~ ascending dose shown by the dotted line.~s In Figures 3, 4, and 5, the release results are depicted for a central ~s nervous system drug wherein the clear circles denote a placebo, the dark zo circles denote an immediate release form, the dark squares denote a zi sustained-nonascending release profile, and clear squares denote a sustained zz ascending release rate profile.23 In Figure 6, a sustained-ascending release plasma concentration is za depicted by the solid line and compared with an immediate-release plasma zs concentration depicted by the dash line comprising the peaks and valleys.zs In Figure 7, the solid circles denote a placebo, the clear circles a z~ sustained-ascending profile, and the solid squares a three-times-a-day program za for the same central nervous system drug. 1 Figure 8 depicts a placebo given three times a day comprising dark z circles, an immediate-release depicted by solid squares, and a sustained-' 3 ascending release essentially free of tolerance by clear circles for the same 4 drug.s Figures 9-11 depict the plasma methylphenidate concentration obtained s by administering the drug three times a day, in an ascending dose, and by a dosage form that controls the delivery profile.a Figures 12-16 depict the plasma methylphenidate concentration s obtained by administering the drug from a dosage form comprising an external overcoat initial dose of drug followed by an internal ascending dose of drug over time.,z 1s DETAILED DISCLOSURE OF SPECIFICATION ,s In accordance with the practice of this invention, it has now been found ,s that a dosage form and a method can be provided that administers a drug in a 1~ novel program that substantially lessens or completely compensates for ,a tolerance in a patient. Tolerance, as defined in Pharmacology in Medicine, ,s by Brill, p. 227 (1965) McGraw-Hill, is characterized as a decrease in effect zo followed by administering a drug. When tolerance develops following a single z1 dose or a few doses over a very short time, it is referred to as acute tolerance.zz When the drug is administered over a more protracted period of time to show a z3 demonstrable degree of tolerance, it is referred to as chronic tolerance. The z4 medical literature, as exemplified in, The Pharmacological Bases of zs Therapeutics, by Goodman and Gilman, 8th Ed., p. 72 (1990) Pergamon Press, zs reported tolerance may be acquired to the effects of many drugs and this 27 literature classifies tolerance as acute or chronic based on when it is acquired.zs That is, acute tolerance develops during a dosing phase of one dose or on one 29 day, and chronic tolerance is acquired due to chronic administration typically so weeks, months, and years. Tolerance as presented in medical literature most s1 frequently denotes chronic tolerance as seen by administering larger doses over a long time, often necessitated by an increase in body dimensions, hepatic z enzyme involved in biotransformation, and the like.3 The invention comprises dosage forms for providing an ascending dose a of drug. Representative of a dosage form comprises a hydrogel matrix s containing a plurality of tiny pills. The hydrogel matrix comprises a hydrophilic s polymer selected from the group consisting of a polysaccharide, agar, agarose, natural gum, alkali alginate including sodium alginate, carrageenan, fucoidan, a furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, gum s tragacanth, locust bean gum, pectin, amylopectin, gelatin and a hydrophilic ~o colloid. The hydrogel matrix comprises a plurality of 4 to 50 tiny pills, each tiny ~ pill comprising an increasing dose population of from 100 ng ascending in dose ,z such as 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, etc. The tiny pills s comprise a release rate controlling wall of 0.0 mm to 10 mm thickness to a provide for the timed ascending release of drug. Representative of wall-forming ~s materials include a triglyceryl ester selected from the group consisting of ~s glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl » laureate, glyceryl didecenoate and glyceryl tridecenoate. Other wall forming ~a materials comprise polyvinyl acetate phthalate, methylcellulose phthalate, and s microporous vinyl olefins. Procedures for manufacturing tiny pills are disclosed zo in U.S. Patent Nos. 4,434,153; 4,721,613; 4,853,229; 2,996,431; 3,139,383 z~ and 4,752,470.zz The dosage form of the invention for delivering an ascending dose of zs drug comprises drug releasing beads. The drug releasing beads are za characterized by a dissolution profile wherein 0 to 20% of the beads undergo zs dissolution and release the drug in 0 to 2 hours, 20 to 40% undergo dissolution zs and release the drug in 2 to 4 hours, 40 to 60% exhibit dissolution and release z~ in 4 to 6 hours, 60 to 80% in 6 to 8 hours, and 80 to 100% in 8 to 10 hours.za The drug releasing beads comprise a central composition or core comprising a zs drug and pharmaceutically acceptable composition forming ingredients so including a lubricant, antioxidant, and buffer. The beads comprise increasing s~ doses of drug, for example, 1 mg, 2 mg, 5 mg, and 10 mg, increasing to 40 mg. The beads are coated with a release rate controlling polymer that can be z selected utilizing the dissolution profile disclosed above. The manufacture of s beads is disclosed in Inter. J. of Pharm., by Liu, Vol. 112, pp. 105-116 (1994);a Inter. J. of Pharm., by Liu and Yu, Vol. 112, pp. 117-124 (1994); Pharm. Sci., s by Remington, 14th Ed. pp. 1626-1628 (1970); J. Pharm. Sci., by Fincher, s Vol. 57, pp. 1825-1835 (1968); and U.S. Patent No. 4,083,949. A dosage form provided by the invention comprises a concentration s gradient of drug from 1 mg to 100 mg coated from the former low dose to the s latter high dose on a polymer substrate. The polymer can be erodible or a ,o nonerodible polymer. The coated substrate is rolled about itself from the latter ~, high dose at the center of the dosage form, to the former low dose at the ,z exposed outer end of the substrate. The coated substrate is rolled from the ,3 high dose to the low dose to provide for the release of from low to high dose ~a as the substrate unrolls or erodes. For example, 1 mg to 25 mg of ,s methylphenidate is coated onto an erodible polymer such as an polypeptide, ,s collagen, gelatin, or polyvinyl alcohol, and the substrate rolled concentrically ,~ from the high dose rolled over and inward to adapt a center position, and then ,a outward towards the low dose to form an outer position. In operation, the ,s dosage form erodes dispensing an ascending dose of methylphenidate that Zo is released over time.z, Another dosage form provided by the invention comprises a multiplicity z2 of layers, wherein each layer is characterized by an increasing dose of drug.z3 The phrase "multiplicity of layers" denotes 2 to 6 layers in contacting lamination.z4 The multiplicity of layers are positioned consecutively, that is, one layer after z5 another in order, with a first exposed layer, the sixth layer in contact with the zs fifth layer and its exposed surface coated with a drug impermeable polymer.z~ The sixth layer is coated with a drug impermeable polymer to insure release of za drug from the first layer to the sixth layer. The first layer comprises 1 to 5 mg of zs drug and each successive layer comprises an additional 1 to 5 mg of drug.ao The biodegradable polymers undergo chemical decomposition to form soluble s, monomers or soluble polymer units. The biodegradation of polymers usually WO 98/14168 PCTlUS97/16599 ~ involves chemically or enzymatically catalyzed hydrolysis. Representative of z biodegradable polymers acceptable for an increase drug loading in each layer s of from 5 to 50 wt% over the first and successive layers wherein the first layer a comprises 100 ng. Representative biodegradable polymers comprise a s member selected from the group consisting of biodegradable poly(amides), s poly(amino acids), poly(esters), poly(lactic acid), poly(glycolic acid), ~ poly(orthoesters), poly(anhydrides), biodegradable poly(dehydropyrans), and 8 poly(dioxinones). The polymers are known to the art in Controlled Release of s Druas, by Rosoff, Ch. 2, pp. 53-95 (1989); and in U.S. Patent Nos. 3,811,444;~0 3,962,414; 4,066,747; 4,070,347; 4,079,038; and 4,093,709.1~ The invention further employs a dosage form comprising a polymer that ,z releases a drug by diffusion, flux through pores, or by rupture of a polymer is matrix. The drug delivery polymeric system comprises a concentration ~4 gradient, wherein the gradient is an ascent in concentration from a beginning ~s or initial concentration to a final, or higher concentration of 100 ng to 250 mg.~s The dosage form comprises an exposed surface at the beginning dose and a ~~ distant nonexposed surface at the final dose. The nonexposed surface is ~e coated with a pharmaceutically acceptable material impermeable to the ~s passage of drug. The dosage form structure provides for a flux increase zo delivery of drug ascending from the beginning to the final delivered dose.z~ The dosage form matrix can be made by procedures known to the zz polymer art. In one manufacture, 3 to 5 or more casting compositions are zs independently prepared wherein each casting composition comprises an za increasing dose of drug with each composition overlayered from a low to the z3 high dose. This provides a series of layers that come together to provide a zs unit polymer matrix with a concentration gradient. In another manufacture, z~ the higher does is cast first followed by laminating with layers of decreasing zs dose to provide a polymer matrix with a drug concentration gradient. An zs example of providing a dosage form comprises blending a pharmaceutically so acceptable carrier, like polyethylene glycol, with a known dose of drug, like a s~ central nervous system stimulant, at an elevated temperature, like 37°C, and 1 adding it to a silastic medical grade elastomer with a cross-linking agent, like z stannous octanoate, followed by casting in a mold. The step is repeated for ' s each successive layer. The system is allowed to set, for 1 hour, to provide the a dosage form. Representative polymers for manufacturing the dosage form s comprise a member selected from the group consisting of olefin and vinyl s polymers, condensation polymers, carbohydrate polymers, and silicon polymers as represented by poly(ethylene), poly(propylene), polyvinyl acetate), a poly(methyi acrylate), poiy(isobutyi methacrylate), poly(alginate), poly(amide), s and poly(silicone). The polymers and manufacturing procedures are known in to Polymers, by Coleman et al., Vol. 31, pp. 1187-1230 (1990); Drug Carrier Systems, by Roerdink et al., Vol. 9, pp. 57-109 (1989); Adv. Drua Delivery Rev., ,z by Leong et al., Vol. 1, pp. 199-233 (1987); Handbook of Common Pol mers, ,3 Compiled by Roff et al., (1971) published by CRC Press; and U.S. Patent ~a No.3,992,518.,s Further in accord with the practice of the present invention, the method ,s of this invention uses the disclosed dosage forms for administering a drug to a ~7 patient that may acquire acute or chronic tolerance for decreasing and/or ,e avoiding said tolerance, and presently the method is indicated for treating ~s patients that may acquire acute tolerance. Further, in accordance with the zo practice of this invention, in one embodiment, it has also been found a method z, can be provided that administers a drug for treating Attention-Deficit Disorder, zz to a human orally as a function of time to achieve the desired drug zs concentration over time. The concentration of drug relates to the dose of drug za in mg per hour delivered per unit time in hours for absorption into the systemic zs circulation. The method of the invention uniquely provides a method for zs maintaining a desired drug effect by adjusting continually the drug delivery z~ rate when the therapeutic effect declines during acquired acute tolerance.z8 It is standard medical practice, that a drug should provide a therapeutic zs effect throughout the dosing interval. However, when tolerance develops or is so acquired to a drug, the prior art approach to ensure a therapeutic response is to 31 increase the dose administered in an immediate dose dumping manner, and for this type of dosing, where associated side effects are likely to occur, tolerance 2 may develop unequally to all the effects, and the therapeutic index may s decrease. Another approach used by the prior art to lessen the occurrence of 4 tolerance is to administer drug doses less frequently so that acquired tolerance s is avoided, but with this approach there is an absence of therapy for a given s time.fn medicine, it is generally accepted that central nervous system acting $ drugs are useful for the management of Attention-Deficit Disorders. The drugs s useful for this therapy are the mild central nervous system stimulants, and they ~o include catecholamines and drugs that can mimic their action. The drugs useful for this therapy comprise a member selected from the group consisting ~z of amphetamine, dextro-amphetamine, methamphetamine, methylphenidate, ~3 racemic methylphenidate, threo-methylphenidate, phenylisopropylamine, ~4 risperidone, and pemoline. The drugs include also their pharmaceutically ~s acceptable salts such as a member selected from the group consisting of ~s hydrochloride, sulfate, phosphate, acetate, hydrobromide, pamoate, and maleate. A patient receiving these drugs typically acquires tolerance to the ~e effects of the drugs. For example, a patient on methylphenidate and receiving ~s a 5 mg dose twice a day acquires tolerance, and a larger dose must be zo administered due to the single large dose needed to overcome the tolerance 21 development which would give rise to unwanted side effects. In some patients, z2 the therapeutic response to methylphenidate declines in 4 to 5 hours despite 23 the maintenance of methylphenidate in a nonascending constant concentration.2a That is, tolerance is acquired to the behavioral and psychological effects of 2s methylphenidate and generally to psychostimulants. This invention has found is also that a sustained release product that dispenses a noncompensating but 2~ constant concentration of a drug will not be clinically effective, as a sustained-zs release dosage form designed to produce a constant plasma of, for example, zs methylphenidate concentration, lacks efficacy particularly against acquired so tolerance. WO 98/141b8 PCT/IJS97/1G599 This invention among its objects provides a dosage form and method for z treating Attention-Deficit Disorders, which include Attention-Deficit/Hyperactivity s Disorder, combined type, predominantly inattentive type, predominantly a hyperactive impulsive type and which are known also as minimal brain s dysfunction, hyperkinetic child syndrome, behavioral syndrome, minimal s cerebral dysfunction and minor cerebral dysfunction, as disclosed in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, pp. 49-56 a (1987) published by the American Psychiatric Association, Washington, D.C., s by making available both a dosage form and a method of treatment that ,o substantially negates the unwanted results of the prior art by providing » continuous compensation of drug to essentially eliminate acute tolerance, ~z thereby producing a stabilization of the therapeutic effect.~s The pharmacological effect of a drug is related to its receptor site ,4 concentration. Thus, when the effect of a drug is considered as a function (f) ~ s of delivery time (t), the kinetics of stabilization for some drugs can be rapid, ~s and for other drugs the effect does not stabilize as a diminution in response 1~ expressed as tolerance develops to the drug. This latter condition applies to ,a central nervous system acting drugs such as methylphenidate. This invention ,s compensates for acquired-acute tolerance by providing an optimal drug delivery zo profile for its management. For some drugs the onset of tolerance is quick, 2~ for instance, tolerance develops for methyiphenidate within hours after its zz administration. A management program for this is provided by this invention by zs making available a drug delivery pattern that initially delivers a dose of drug to za achieve instant therapy and accompanied by a sustained-ascending release zs dose over time to maintain the effect.is The drug methylphenidate is commercially available in a sustained z7 release dosage form Ritalin~-SR, and the methylphenidate dispensed by this zs commercial form can lead to acute tolerance. When acute tolerance is is acquired a drug-free washout period of several hours is needed before a repeat so administration is likely with the dosage form. The present invention however, WO 98/14168 PCTlUS97/16599 1 compensates for the loss of a therapeutic effect of a drug, such as 2 methylphenidate, by providing a method of delivery rate in mg per hour s that continually compensates for the development of acute tolerance, a by considering the clinical effect (E) of a drug at time (t) as a function of the drug concentration (C) according to Equation 1: 7 Effect = f(t, C) Eq. 1 s In addition, the rate of drug delivered (A), in mg per hour is directly 1o proportional to the concentration times the clearance of the drug. As the 11 effect varies with time and the functionality is expressed, then according 12 to this invention (A} can be governed to ensure the therapeutic effect is ~s maintained at a clinical value. If the effect from a drug is found clinically to 1a decrease with time, this decline could be linear as expressed by Equation 2:ss Effect ~o = Effect i,~~ - kE*t Eq. 2 1e wherein, Effect C"~ is the clinical effect observed initially at the start of drug 1s administration and Effect ~t~ is the effect observed at time (t) hours, kene~, is a 2o proportionality constant ascertained by measuring the clinical effect (E1 ) 21 at time (t1 ) hours and (E2) at time (t2} hours while maintaining a constant 22 plasma concentration followed by dividing (E1) minus (E2) by (t1) minus (t2).2s In order to maintain a constant effect, (A) must be adjusted with the same 2a functionality according to Equation 3:26 A~t~ _ ~inp + ksttect*t Eq. 3 2e wherein A~;~;~ is the initial drug input in mg per hour at the start of the therapy 2s and A~t~ is the drug input at time (t) hours, and kE"~, is the proportionality so constant presented above. If the therapeutic effect is found to decline s1 exponentially with time, this relationship is expressed by Equation 4: z Effect ~,~ = Effect~,~;, *expt-ks"e"n~ Eq. 4 a wherein Effecti;";~ and Effectn~ are as defined before, kE~,~, is a rate constant s (h''), a unit of reciprocal hours, ascertained by measuring the clinical effect s (E 1 ) at time (t1 ) hours and (E2) at time (t2) hours while maintaining a 7 constant plasma concentration followed by dividing natural log of (E1) s minus natural log of (E2) by (t1) minus (t2). To maintain a constant effect, s (A) must be adjusted according to Equation 5:~o ~, Ann ' Aon~~ * exp~'~n~~~u Eq. 5 ~2 ,s wherein Ai,~;~ and A« is as defined before. kE,~ is the rate constant (h'') ~a presented above. The equations are presented in Pharmac. Ther., Vol. 16, ~s pp. 143-166 (1982) by Holford N.H.G. and Sheiner, L.E.s The effects defined herein refer to the pharmacological effects ,~ exhibited by the drug as ascertained by clinical subjective observation such ~s as SKAMP and CLAM, or as ascertained by objective activity monitoring such ~s as mathematic tests and school accomplishments. The CLAM Test is a zo behavior rating that indicates social conformity or rebellion as developed by z~ Conners, Lonez, and Milch and SKAMP is a rating that also measures 22 behavior as developed by Swanson and reported in Psychopharmacological zs Bulletin, Vol. 21, pp. 887-890 (1985).za The effect measurements in this study were: (1) observer ratings on zs SKAMP scale (during classroom time) and (2) performance on the is computerized mathematics test. Each child was tested on the mathematics z~ test before the study began, and based on this pre-test during the study, a za mathematics test appropriate for each child's ability was given. The morning zs and evening parent CLAM assessments were used to identify unusual so behaviors. The evening parent CLAM was used to determine the presence of a, treatment effects in the evening hours, particularly treatment effects on the WO 98114168 PC1'/US97/16599 i time the child fell asleep, and whether the child's sleep was interrupted. All of z the children also wore an activity monitor (Actigraph) which records the s movements of the child throughout the day. The activity (number of a movements per minute) is recorded electronically and modeled as a function of the drug effect.s DETAILED DISCLOSURE OF EXAMPLESa PROVIDED BY THE INVENTIONs ,o The following examples are merely illustrative of the present invention ,~ and they should not be considered as limiting the scope of this invention in ~z any way, as these examples and other equivalents thereof will become ,s apparent to those versed in the art in the light of the present disclosure ~4 and the accompanying claims.~s EXAMPLE 1 m ~e A commercially available immediate release tablet consisting of 5 mg ~s of methylphenidate was administered twice a day to 36 school children, and zo the predicted plasma concentration in nglml graphed against time as seen in z~ the solid black line in Figure 1. The tablet exhibits a peak and valley plasma zz concentration for the methylphenidate. A sustained-release nonascending zs program that administered 20 mg of methylphenidate consisting of 8.3 mg za at zero hour followed by 0.9 mg at 1.5 hours, 0.9 mg at 2 hours, 0.9 mg 2.5 hours, 0.9 mg at 3 hours, 0.9 mg at 3.5 hours, 0.9 mg at 4 hours, 0.9 mg zs at 4.5 hours, 0.9 mg at 5 hours, 0.9 mg at 5.5 hours, 0.9 mg at 6 hours, z7 0.9 mg at 6.5 hours, 0.9 mg at 7 hours, and 0.9 mg at .5 hours produced zs the sustained-release dotted line parallel to the x-axis as seen in Figure 1.zs The immediate release tablet and the sustained-release dosage form were so compared to a sustained-release dosage form that administered methylphenidate in an ascending profile. The sustained-release ascending profile corresponds to administering 4.2 mg at zero hour, 1.1 mg at 1.5 hours, z 1.1 mg at 2 hours, 1.2 mg at 2.5 hours, 1.2 mg at 3.0 hours, 1.3 mg at ' s 3.5 hours, 1.3 mg at 4 hours, 1.5 mg at 4.5 hours, 1.5 mg at 5 hours, 1.8 mg a at 5.5 hours, 1.8 mg at 6 hours, and 2.0 mg at 6.5 hours, to produce the s sustained-ascending release dotted line profile seen in Figure 2.s The results of the clinical studies demonstrated patients administered a dosage form free of methylphenidate, a placebo, exhibited high, elevated s swings in behavior, such as activity, inappropriate behavior, low attention, s lower mathematical scores and a disinterest in school. The patients ~o administered a sustained-nonascending dose of methylphenidate exhibited a o decrease in activity, higher mathematical scores and a lessening of ~z inappropriate behavior. However, these effects were accompanied by the ,s development of acute tolerance in the patient. The patient administered ,a methylphenidate, according to this invention, in a controlled-sustained s ascending profile exhibited the desired therapeutic effect without tolerance.,s The accompanying figures present the results of the above-described study.In Figures 3, 4, and 5, the line with a clear circle denotes a placebo, the dark ,$ circle an immediate release dosage form administered twice a day, the dark ,s squares a sustained release nonascending dosage profile, and the clear zo squares the sustained ascending release profile provided by this invention.z, The SKAMP Score and CLAM Score were defined earlier in the specification, zz and the times are as indicated on the figures. Figure 3 denotes the observed za behavior, Figure 4 denotes the inattention overactivity, and Figure 5 denotes za the combined attention results of the study.zs EXAMPLE 2 z~zs The results of a clinical study that comprises administering zs methylphenidate according to two distinct delivery programs are reported in so this example. In the study, a sustained-ascending profile corresponds to s~ administering methylphenidate as follows: 8 mg at zero hours, 1.4 mg at WO 98114168 PCT/t1S97116599 1.5 hours, 1.4 mg at 2.0 hours, 1.7 mg at 2.5 hours, 1.7 mg at 3.0 hours, z 2.0 mg at 3.5 hours, 2.0 mg at 4.0 hours, 2.2 mg at 4.5 hours, 2.2 mg at s 5.0 hours, 2.2 mg at 5.5 hours, 2.2 mg at 6.0 hours, 2.4 mg at 6.5 hours, a 2.4 mg at 7.0 hours, 2.6 mg at 7.5 hours, and 1.9 mg at 8.0 hours. The methylphenidate was administered in overcoated capsules comprising a s tots! of 36 mg of methylphenidate with 22% in the exterior overcoat. The 7 ascending dose was administered with the first dose at 0730 followed by s ascending doses every 30 minutes until 1530 to produce the intended s ascending plasma concentration. The study included the delivery of ,o methylphenidate in immediate dosage form three times a day with 10 mg of ~, methylphenidate delivered at 0730, 1130, and 1530 hours. The study was ~2 done with 32 children with attention deficient hyperactivity disorder. Is Accompanying Figure 6 depicts the plasma concentration for methylphenidate ,a wherein the dot-dash line is produced by the sustained-ascending ,s administration program, and the dash line is produced by the immediate ~s dosage form. In accompanying Figure 7, the solid circles denote placebos, ,7 the clear circles denote the sustained-ascending program, the solid squares ~s denote the three times a day program, and the parameter observed was ,s behavior with an absence of acquired tolerance for the sustained ascending zo program. Accompanying Figure 8 depicts the combined attention parameter z~ wherein the solid circle is a placebo with acquired tolerance, the solid square z2 is the three daily immediate release delivery with acquired tolerance, and the zs clear circle is the sustained-ascending release essentially free of developed za tolerance.zs zs EXAMPLE 3 zs A method for administering the central nervous system stimulant is methylphenidate in a sustained and ascending dose for the management of sa attention deficient disorder accompanied by a lessening of acquired tolerance s, is provided by administering a dosage form shaped as an orally administered 1 tablet. The dosage form comprises a film of polyanhydride polymer of z sebacic and azelaic acids coated with a composition comprising 20 mg of ' s methylphenidate blended with pharmaceutically acceptable gelatin. The a pharmaceutically acceptable film is coated with the methylphenidate s composition in increased thickness spirally wound about itself. Following oral s administration into the gastrointestinal tract the composition comprising the methylphenidate is dispensed at constantly increasing rate as the film erodes s over time. The polymer of the dosage form is described in U.S. Patent s Nos. 2,668,162 and 2,676,945, and the dosage form is described in ~o U.S. Patent No. 3,625,214. 1z EXAMPLE 4 1a A method for treating Attention-Deficit Disorder with hyperactivity 1s supported by psychological and educational guidance by administering 1s pemoline for a stabilizing effect in children accompanied by an apparent 1~ absence of acquired tolerance is provided by administering a bioerodible 1a dosage form according to the invention, comprising the central nervous ~s stimulant pemoline. The dosage form comprises 5 contacting layers of Zo bioerodible poly(lactide-co-glycolide) with each Payer containing an increased 21 amount of 4, 6, 8, 10 and 12 mg of pemoline. The layers are compressed into 2z a laminated tablet-shaped arrangement with a single opened surface to is expose the layer containing 2 mg of pemoline with the remainder of the tablet za surrounded with nonbiaerodible copolymeric ethylene-vinyl acetate. So the zs layers bioerode in constant succession, a corresponding constantly is increasing dose of pemoline is dispensed over time. The bioerodible 27 polymers are known in U.S. Patent No. 3,773,919; EPO 0-052-510; and za Canadian Patent No. 1,169,090. z s A method for administering a drug in a sustained-increasing release a rate is provided by administering a dosage form manufactured as a s pharmaceutically acceptable gelatin two-piece joined capsule comprising a s multiplicity of spherical beads. The capsule comprises a series of beads z consisting of a progression of 1, 1.25, 1.5, 1.75, 2 and 2.25 mg of drug in a each different bead coated correspondingly with a progression of 0.5, 1, s 1.5, 2.5, 3, and 3.25 mm of polymeric poly(2.2-dioxo-trans-1, 4-cyclohexane ~o dimethylene tetrahydrofuran). As the beads erode in the environment of the gastrointestinal tract they dispense drug in a sustained-ascending release ~z rate over time. The drugs that can be dispensed by this method comprise a ~s member selected from the group consisting of amphetamine, a dextroamphetamine, methamphetamine, methylphenidate, ,s phenylisopropylamine and pemoline. Procedures for coating are disclosed in ~s J. Am. Phar. Assoc., Sci. Ed., Vol. 48, pp. 451-454 (1959); and U.S. Patent » No.2,799,241. s EXAMPLE 6 zo ii A delivery system is provided by the invention which releases the drug zz resulting in an ascending plasma methylphenidate concentration time profile 23 that substantially overcomes tolerance and maintains the desired as pharmacological ef#ect of the stimulant methylphenidate for the desired duration. For example, to achieve an effect-time profile similar to the three zs doses of immediate release given every 4 hours for 12 hours every day, z~ TID (three times a day), a delivery system which results in the plasma za methylphenidate concentrations between the ranges as fisted below will zs overcome tolerance and maintain pharmacological effects. To make a so delivery system which is equal to two doses of immediate release given every 31 4 hours the release rate can be truncated, and similarly, for the longer a duration the concentration can be increased. The delivery profile exemplifies z the drug and pharmacological effect. However, the concept of increasing ' a concentration still remains the same.a Table 1 provides this range as a fraction of the simulated TIDs concentrations. The attached figures show the ascending profile variations s superimposed on the TID and the reference ascending (ASCEND) treatment profiles. Time TID ConcentrationAscending Profile (h) (nglMl) Range (Fraction of T1D Concentration) Low High 1.5 4.8 (peak) 0.75 0.90 3.0 3.8 1.071.37 4.0 2.8(trough) 1.32 2.29
    [5" class="description-paragraph] 5.5 6.5(peak) 0.80 1.20 7.0 4.8 1.42 1.81 8.0 3.6(trough) 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 ~o The accompanying drawing figures depict the therapeutic benefits obtained by the invention. Figure 9 illustrates a simulated plasma ~z methylphenidate concentration profile for three-times-a-day 30 mg dose ~s {solid line), an ascend treatment of 36 mg (dash line), and an osmotic ~a controlled 36 mg dose (dot-dash line). Figure 10 depicts the plasma ~s methylphenidate concentration as in Figure 9, except in Figure 10 the osmotic ~s controlled dose is 38 mg. Figure 11 depicts the plasma methylphenidate ~~ concentration as in Figure 9, except in Figure 11, the osmotic controlled dose WO 98/14168 PCTNS97l16599 ~ is 40 mg. Figure 12 illustrates 30 mg delivered three times a day by the solid z line, an ascend dose from a dosage form comprising 36 mg of drug once a s day by the dash line, and a dosage form comprising an immediate 8 mg dose a and a sustained 26 mg ascending dose illustrated by the dot-dash line.s Figure 13 depicts a plasma methylphenidate concentration like Figure 12, s except the dosage form represented by the dot-dash line comprises an z instant-release dose of 9 mg of methylphenidate and an ascending dose of a 24 mg of methylphenidate. Figure 14 is similar to the previous Figures except s the dot-dash line depicts an instant release dose of 8 mg and an ascending ' ~o dose of 25 mg of methylphenidate. Figure 15 is similar to the above Figures, ~, except the dot dash fine illustrates an immediate dose of methylphenidate of ,z 8 mg followed by a sustained ascending dose of 25 mg of methylphenidate.~s Figure 16 is similar to the above Figures with the clinical conditions as set ~a forth, except in this study the dot-dash lines illustrate an immediate dose of ~s 8 mg of methylphenidate, followed by a controlled-ascending dose of 24 mg is of methylphenidate. The method of the invention provides further for administering a drug ~a according to the above examples, wherein the drug is administered by the ~s dosage form of this invention in a controlled-rate and in a sustained release 2o pattern throughout a school day of up to 8 hours, or up to 12 hours.z~ While there has been described and pointed out features and 2z advantages of the invention, as applied to present embodiments, those skilled 2s in the medical art will appreciate that various modifications, changes, z4 additions, and omissions in the method described in the specification can zs be made without departing from the spirit of the invention.
    权利要求:
    Claims (20)
    [1] 1. A dosage form tablet comprising 100 ng to 500 mg of methylphenidate in admixture with a pharmaceutically acceptable carrier that releases the methylphenidate in a sustained and increasing dose over a prolonged time period.
    [2] 2. A dosage form tablet comprising 100 ng to 500 mg of a member selected from the group consisting of methylphenidate and its pharmaceutically acceptable salts mixed with a pharmaceutically acceptable carrier that is delivered in a controlled and increasing dose over a prolonged time period.
    [3] 3. A dosage form comprising a pharmaceutically acceptable polymer, a dose of methylphenidate in the polymer in a low to high dose, and wherein the dosage form when in operation provides a sustained-release of a low to a higher dose of methylphenidate.
    [4] 4. The dosage form according to claim 3, wherein a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline replaces the methylphenidate in the dosage form.
    [5] 5. A dosage form comprising a multiplicity of compositions comprising a pharmaceutically acceptable carrier, a dose of methylphenidate in an increasing dose in the compositions, and wherein the dosage form when in operation provides a sustained-release of methylphenidate in an increasing dose over a prolonged time period.
    [6] 6. The dosage form according to claim 5, wherein the compositions are in layers.
    [7] 7. The dosage form according to claim 5, wherein the pharmaceutically acceptable carrier is a polymer.
    [8] 8. The dosage form according to claim 5 wherein a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline replaces the methylphenidate in the dosage form.
    [9] 9. A dosage form a plurality of layers comprising a composition comprising a different pharmaceutically acceptable polymer; a dose of a member selected from the group consisting of methylphenidate and its pharmaceutically acceptable salt in an increasing dose in the compositions, and wherein the dosage form when in operation provides a sustained-release increasing dose of methylphenidate.
    [10] 10. The dosage form according to claim 9, wherein methylphenidate is replaced by a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline.
    [11] 11. A dosage form for delivering methylphenidate comprising: a pharmaceutically acceptable composition comprising a bioerodible polymer; a dose of 1 mg to 500 mg of a member selected from the group consisting of methylphenidate and its pharmaceutically acceptable salt in the dosage form;and wherein the dosage form, when in operation, provides a sustained-release increasing dose of methylphenidate.
    [12] 12. The dosage form for delivering methylphenidate according to claim 11 wherein methylphenidate is replaced by a member selected from the group consisting of amphetamine, dextroamphetamine, methaphetamine, phenylisopropylene, and pemoline.
    [13] 13. A dosage form for orally delivering methylphenidate in a sustained-release and ascending dose wherein the dosage form comprises: a multiplicity of layers comprising a pharmaceutically acceptable bioerodible polymer, a 1 mg to 500 mg ascending dose of methylphenidate in the layers, whereby the dosage form, when in operation provides a sustained-release ascending dose of methylphenidate.
    [14] 14. The dosage form for orally delivering methylphenidate according to claim 13, wherein methylphenidate is replaced in the dosage form by a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline.
    [15] 15. A dosage form for orally delivering a sustained-release and ascending dose of methylphenidate wherein the dosage form comprises a plurality of layers comprising a different pharmaceutically acceptable bioerodible polymer, a 1 mg to 500 mg dose of a member selected from the group consisting of methylphenidiate and its pharmaceutically salt in the layers, whereby the dosage form delivers a sustained-release and ascending dose of methylphenidate.
    [16] 18. The dosage form for orally delivering methylphenidate according to claim 15, wherein methylphenidate is replaced by a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline.
    [17] 17. A dosage form for orally delivering a sustained-release and increasing dose of methylphenidate, wherein the dosage form comprises: a plurality of tiny pills comprising a dose of a member selected from the group consisting of methylphenidate and its pharmaceutically acceptable salt, and a wall of varying thickness to provide for an increasing release rate of methylphenidate, whereby, the dosage form delivers a sustained-release and increasing dose of methylphenidate.
    [18] 18. The dosage form for orally delivering methylphenidate according to claim 17, wherein the dosage form comprises a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline that replaces methylphenidate in the dosage form.
    [19] 19. A dosage form tablet comprising 100 ng to 500 mg of a member selected from the group consisting of methylphenidate and its pharmaceutically acceptable salts mixed with a pharmaceutically acceptable carrier that achieves an ascending plasma concentration profile following administration to a patient.
    [20] 20. The dosage form according to claim 19, wherein a member selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, phenylisopropylamine, and pemoline replaces the methylphenidate in the dosage form.
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    同族专利:
    公开号 | 公开日
    CA2515884C|2016-10-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2005-09-13| EEER| Examination request|
    2017-11-20| MKEX| Expiry|Effective date: 20170918 |
    优先权:
    申请号 | 申请日 | 专利标题
    US2872696P| true| 1996-09-30|1996-09-30||
    US60/028,726||1996-09-30||
    US3051496P| true| 1996-11-12|1996-11-12||
    US60/030,514||1996-11-12||
    US4412197P| true| 1997-04-22|1997-04-22||
    US60/044,121||1997-04-22||
    CA002264852A|CA2264852C|1996-09-30|1997-09-16|Use of methylphenidate or a pharmaceutically acceptable salt thereof|
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