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US 2004O224020A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub. Date: Nov. 11, 2004 (54) ORAL DOSAGE FORMS WITH (22) Filed: Dec. 18, 2003 THERAPEUTICALLY ACTIVE AGENTS IN CONTROLLED RELEASE CORES AND Related U.S. Application Data IMMEDIATE RELEASE GELATIN CAPSULE COATS (60) Provisional application No. 60/434,839, filed on Dec. 18, 2002. (76) Inventor: Grant L. Schoenhard, San Carlos, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................... A61K 9/24 Janet M. McNicholas (52) U.S. Cl. .............................................................. 424/471 McAndrews, Held & Malloy, Ltd. 34th Floor (57) ABSTRACT 500 W. Madison Street Chicago, IL 60661 (US) The present invention relates to oral dosage form with active agents in controlled release cores and in immediate release (21) Appl. No.: 10/742,672 gelatin capsule coats. Patent Application Publication Nov. 11, 2004 Sheet 1 of 3 US 2004/0224020 A1 r N 2.S Hr s Patent Application Publication Nov. 11, 2004 Sheet 2 of 3 US 2004/0224020 A1 r CN -8 e N va N . t Cd NOLLYRILNONOO Patent Application Publication Nov. 11, 2004 Sheet 3 of 3 US 2004/0224020 A1 US 2004/0224020 A1 Nov. 11, 2004 ORAL DOSAGE FORMS WITH released formulations, a long t is particularly disadvan THERAPEUTICALLY ACTIVE AGENTS IN tageous to patients Seeking urgent treatment and to maintain CONTROLLED RELEASE CORES AND MEC levels. A second difference in the pharmacokinetic IMMEDIATE RELEASE GELATIN CAPSULE profiles of controlled release in comparison to immediate COATS release drug formulations is that the duration of Sustained plasma levels is longer in the controlled release formula CROSS REFERENCED APPLICATIONS tions. The longer duration of Such Sustained plasma levels facilitated by controlled release formulations are advanta 0001. None applicable. geous to all patients, prolonging the desired biological effect. Therefore, although the controlled release formula BACKGROUND OF THE INVENTION tion facilitates a Substantially longer period of time in 0002 The maximum time of effectiveness of many oral maintaining plasma levels of drug or active metabolite(s), it dosage forms is only a few hours. While it is often desirable Suffers from the drawback of requiring longer periods of to reach an effective dose quickly, in order to maximize time to achieve the C, when compared to immediate patient compliance, it is also considered desirable to reduce release formulations. Thus, there remains a long felt need for the frequency of dosing, thereby reducing the number of improved controlled release formulations, including dosage doses a patient must take in order to attain effective therapy. formulations that might have one or more desirable charac In the case of combination therapy where two drugs may be teristics of both immediate release and controlled release given in the same dosage form (e.g., tablets, capsules, etc.), formulations. the frequency of dosing is further reduced. SUMMARY OF THE INVENTION 0.003 For any given dosage form of an agent, such as a 0006 The present invention is directed to novel oral drug, the amount of the agent from the dosage form that is dosage forms with therapeutically active agents in both available to reach the circulation System depends first on the controlled release cores and immediate release gelatin cap rate and extent of release from the dosage form. Following Sule coats. The agents have different release profiles from oral administration, drug or prodrug is released from the the cores and gelatin capsule coats. The controlled release dosage form containing the drug or prodrug in the gas cores optionally comprise additional components for the trointestinal (GI) tract and free drug is absorbed. The extent immediate release of a portion of therapeutically active of release determines the amount of drug available for agent from the core. Such gelatin capsule encapsulated absorption. The rate of release gives the amount of drug controlled release oral dosage forms constitute improved available for absorption per unit time. Drug dosage forms controlled release dosage forms and achieve a rate of release that rapidly release the drug into the GI tract are termed and an extent of release not previously achieved by either immediate release or IR formulations. The time, t to immediate release or controlled release dosage forms of reach to maximum plasma concentrations (C) of the drug therapeutically active agent(s). Soft gelatin capsules, such as in the body ranges from a few minutes to two plus hours for Softgels, with at least one therapeutically active agent are Such immediate release formulations. During the absorption preferred for encapsulating the cores. The invention further phase, the drug is distributing throughout the body, and in relates to pharmaceutical formulations useful in the prepa most cases are beginning and/or simultaneously being elimi ration of Such dosage forms, as well as to methods of making nated from the body. Thus, the pharmacokinetic profile (the and administering Such dosage forms. Gelatin capsule graph of drug in blood or plasma concentration vs. time) for encapsulated controlled release cores of at least one thera repeated administration of immediate release formulations peutically active agent, including liquid, tablet, or Solid cycle from minimum or trough plasma concentrations C min cores, wherein the gelatin capsule encapsulating Such con to peak plasma concentrations, C, and back to minimum trolled release core comprises an immediate release formu or trough plasma concentrations, C. lation of at least one therapeutically active agent are 0004) To achieve Sustained concentration of circulating improved dosage forms with Surprising advantages. Such drug or active metabolite(s) or conjugate(s) of drug over a gelatin capsule encapsulating wherein the gelatin capsule longer period of time between doses, controlled release contains at least one therapeutically active agent, enables the (alternative constant release (SR) or extended release) drug increase of the rate of release of the therapeutically active formulations were developed. These controlled release (CR) agent(s) from oral dosage forms of the invention and/or formulations require approximately from 2 to 3 hours to increases the apparent extent of exposure to Sustained blood/ achieve C, and the minimum effective concentration plasma concentrations of the agent(s) and/or metabolites or (MEC) of drug in the circulation, and can maintain MEC conjugates of Such agent(s), as well as the related pharma levels from about 12 to about 22 hours before declining codynamic response, for example, when at least one of the exponentially because no more drug is being released from therapeutically active agents is the same in the gelatin the dosage form and Systematically absorbed. Thus, the capsule coating and in the core. pharmacokinetic profile of controlled release formulations 0007 Novel oral dosage forms according to the invention have a shape Similar to a hyperbole, with a slow and gradual comprise (i) an controlled release core, and (ii) an immediate increase in drug blood levels to a plateau, followed by a release gelatin capsule around the controlled release core, decline in plasma concentrations. wherein the controlled released core comprises at least one 0005. When comparing the pharmacokinetic profiles of therapeutically active agent and at least one controlled immediate release with controlled release drug formulations, release material, and wherein the immediate release gelatin there are two major differences. First, the time to achieve the capsule comprises at least one therapeutically active agent. C in the plasma is often longer in the controlled release Such oral dosage forms have at least one therapeutically Versus the immediate release formulation. In controlled active agent in the controlled release core that is the same as US 2004/0224020 A1 Nov. 11, 2004 or different from at least one therapeutically active agent in agonists, alone or in combination with opioid antagonists. the immediate release gelatin capsule. Preferred dosage The present invention thus provides controlled release phar forms according to the invention have the same therapeuti maceutical formulations in the form of a liquid, tablet, or cally active agent in both the core and the immediate release capsule as a controlled release core, wherein the core gelatin capsule and optionally may have other agents in comprises one or more therapeutically active agents and one either or both of the core and gelatin capsule. Such gelatin or more controlled release materials. Optionally, the core capsule encapsulated controlled release dosage forms as additionally comprises one or more therapeutically active described herein, achieve an increased rate of release of the agents and one or more immediate release components. therapeutically active agent via the immediate release gela Preferably, at least one active agent is in both a controlled tin capsule and an increased extent of duration of exposure release and an immediate release form in Such a core. A core to Stable blood/plasma concentration of the therapeutically is then encapsulated with an immediate release gelatin active agent(s) and/or active metabolite(s) or conjugate(s) capsule comprising immediate release pharmaceutical for via the combination of the release of active agents from the mulations of one or more therapeutically active agents. The immediate
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  • Adrenoceptor (1) Antibiotic (2) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Serotonin (8) Other (9) Phosphorylation (7) Ca2+

    Adrenoceptor (1) Antibiotic (2) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Serotonin (8) Other (9) Phosphorylation (7) Ca2+

    Supplementary Fig. 1 Lifespan-extending compounds can show structural similarity or have common substructures. Cl NO2 H doxycycline (2) N N NH 2 O H O H O O H O O O O O H O NH NH Cl O O 2 N N guanfacine (1) O H N N H H H nitrendipine (3) S Cl N H promethazine (9) NO2 F N NH2 F N demeclocycline (2) O H O O H O O F N NH O O H O O Cl S N NH N guanabenz (1) O O 2 fluphenthixol (5) Br CN O H N H N nicardipine (3) S N H Cl O H N N propionylpromazine (5) O O H O H O O H O O O H Cl N S Br LFM−A13 (7) NH2 S S O H H H chlorprothixene (5) thioridazine (5) N N O H minocycline (2) HO S O β-estradiol (6) O H H N H N H O H O danazol (6) N N cyproterone (6) H N H O H O methylergonovine (5) HO H pergolide (5) O N O O O N O HN O O H O N N H 3C H H O O H Cl H O H C H 3 O H N N H N H N H H O metergoline (8) dihydroergocristine (5) Cortexolone (5) HO O N (R,R)−cis−Diethyltetrahydro−2,8−chrysenediol (6) O H O H N O vincristine (9) N H N HN H O H H N H O N N N N O N H O O O N N dihydroergotamine (8) H O Cl O H O H O nortriptyline (1) S O mianserin (8) octoclothepin (5) loratadine (9) H N N Cl N N N cinnarizine (3) O N N N H Cl N Cl N N N O O N loxapine (5) N amoxapine (1) oxatomide (9) O O Adrenoceptor (1) Antibiotic (2) Ca2+ Channel (3) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Phosphorylation (7) Serotonin (8) Other (9) Supplementary Fig.