US 2005O112199A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0112199 A1 Padval et al. (43) Pub. Date: May 26, 2005 (54) THERAPEUTIC REGIMENS FOR Said application No. 10/947,455 is a continuation-in ADMINISTERING DRUG COMBINATIONS part of application No. 10/944,574, filed on Sep. 17, 2004, and which is a continuation-in-part of applica (76) Inventors: Mahesh Padval, Waltham, MA (US); tion No. 10/777,518, filed on Feb. 12, 2004. Peter Elliott, Marlboro, MA (US) (60) Provisional application No. 60/520,446, filed on Nov. Correspondence Address: 13, 2003. Provisional application No. 60/512,415, CLARK & ELBING LLP filed on Oct. 15, 2003. Provisional application No. 101 FEDERAL STREET 60/557,496, filed on Mar. 30, 2004. BOSTON, MA 02110 (US) Publication Classification (21) Appl. No.: 10/947,769 (51) Int. Cl. .................................................. A61K 9/22 (22) Filed: Sep. 23, 2004 (52) U.S. Cl. .............................................................. 424/468 Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 10/947,455, filed on Sep. 20, 2004, which is a continuation of The invention features dosing regimens for the administra application No. 10/777,517, filed on Feb. 12, 2004, tion of combination therapies, wherein one of the drugs of which is a continuation-in-part of application No. the combination is formulated for Sustained release, or 10/670,488, filed on Sep. 24, 2003. administered repeatedly, and compositions related thereto. Patent Application Publication May 26, 2005 Sheet 1 of 2 US 2005/0112199 A1 FIG. 1 1000 -O-Amoxapine -O-Prednisolone O 2 4 6 8 1 0 12 14 16 18 20 22 24 26 Time after administration (h) Patent Application Publication May 26, 2005 Sheet 2 of 2 US 2005/0112199 A1 FIG. 2 150 -O-Paroxetine -O-Prednisolone 125 S S. 5 100 of s 75 - C 50 O St 25 O 7. O O €1. OO-O-O O 2 4 6 8 10 12 14 16 18 20 22 24 26 Time after administration (h) US 2005/0112199 A1 May 26, 2005 THERAPEUTIC REGIMENS FOR 0008. The invention further features a pharmaceutical ADMINISTERING DRUG COMBINATIONS composition including a unit dosage form including a first drug selected from tricyclic compounds, SSRIs, SNRIs, CROSS-REFERENCE TO RELATED NSIDIs, antihistamines, and tetra-Substituted pyrimidopyri APPLICATIONS midines, and a Second drug formulated for Sustained release. 0001. This application is Continuation-in-part of U.S. 0009. The invention features a kit including: (a) a first Utility application entitled “Methods and Reagents for the drug not formulated for Sustained release, (b) a said Second Treatment of Diseases and Disorders Associated with drug formulated for Sustained release, and (c) instructions Increased Levels of Proinflammatory Cytokines, filed Sep. for administering Simultaneously, or within 30 minutes of 22, 2004, which is a Continuation of U.S. Utility application one another, Said first drug and Said Second drug. Ser. No. 10/777,517, filed Feb. 12, 2004, which is a Con 0010. In the above methods, compositions, and kits, the tinuation-in-part of U.S. Utility application Ser. No. 10/670, first drug or Second drug is desirably a tricyclic compound, 488, filed Sep. 24, 2003, and claims benefit of U.S. Provi SSRI, SNRI, NSIDI, antihistamine, corticosteroid, or a tetra sional Application No. 60/557,496, filed Mar. 30, 2004, each Substituted pyrimidopyrimidine. of which is incorporated herein by reference. 0011. In any of the above methods, compositions, and BACKGROUND OF THE INVENTION kits, the first drug and the Second drug are optionally formulated together in a unit dosage form. Unit dosage 0002 The invention relates to dosing regimens for the forms include, for example, a bilayer tablet having a first administration of combination therapies. layer including the first drug not formulated for Sustained release and a Second layer including the Second drug for 0.003 Combination therapy refers to the administration of mulated for Sustained release. The unit dosage form may two or more drugs for the treatment of a disease or disorder, also be a tablet having an inner core including the Second or two or more comorbid conditions. While in Some cases drug formulated for Sustained release and an outer coat each component of the combination is acting independently including the first drug not formulated for Sustained release. of the other(s), in other cases the two drugs may be acting Furthermore, the unit dosage form may be a capsule having in a combinatorial manner, e.g., a Synergistically, to produce beads including the Second drug formulated for Sustained a result that would not be achieved by the administration of release and beads including the first drug not formulated for the two drugs in a non-overlapping manner. Sustained release 0004) Notwithstanding the foregoing, it may be that combination therapy falling in the latter category may 0012 Any of the unit dosage forms described herein may include drugs having different pharmacokinetic properties further include the Second drug not formulated for Sustained (e.g., different Ta times). In these cases, the full benefit of release. the combination therapy is not being realized. 0013 In any of the above methods, compositions, and kits, the first drug may be a tricyclic compound and the 0005 Thus, there is a desire to develop better methods for Second drug may be a corticosteroid, Such as the combina combination therapy. tion of amoxapine and prednisolone or the combination of nortriptyline and budesonide; the first drug may be an SSRI SUMMARY OF THE INVENTION and the Second drug may be a corticosteroid, Such as the 0006. In a first aspect, the invention features a method of combination of paroxetine and prednisolone; the first drug enhancing the efficacy of a drug combination. The method may be dipyridamole and the Second drug may be a corti includes the steps of i) administering a first drug in an costeroid, Such as prednisolone; the fist drug may be an amount Sufficient to produce an effective plasma concentra NSIDI and the Second drug may be an antihistamine, Such as tion of the first drug for a period of time T, and ii) the combination of cycloSporin A and loratadine, or the first administering a Second drug in a manner Sufficient to pro drug may be dipyridamole and the Second drug may be an duce an effective plasma concentration of the Second drug antihistamine, Such as loratadine. for at least 70% of time T. Desirably, the second drug is 0014. The compositions can be formulated for any route administered in a manner Sufficient to produce an effective of administration. For example, the combination of nortrip plasma concentration of the Second drug for at least 75%, tyline and budesonide can be formulated for inhalation. 80%, 85%, or even 90% of time T. Optionally, some or all Desirably, the combination is formulated for oral adminis of the Second drug is formulated for Sustained release, and/or tration. the Second drug is administered more than once during time T. 0015 Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable 0007. The invention also features a method of adminis tering a drug combination. This method includes the Steps of forms, including isomerS Such as diastereomers and enanti administering Simultaneously, or within 30 minutes of one omers, Salts, esters, Solvates, and polymorphs thereof, as another, a first drug not formulated for Sustained release and well as racemic mixtures and pure isomers of the com a second drug formulated for Sustained release, wherein a) pounds described herein. the first drug produces a peak plasma concentration at Ta, 0016. The methods, compositions, and kits described b) the Second drug produces a peak plasma concentration at herein can also be used to generate information useful, for Ta2, and c) Ta2 is equal to or greater than Tinas, example, for increasing investment in a company or increas provided that if the second drug were not formulated for ing consumer demand for the methods, compositions, and/or Sustained release Tmax1 Tmax2: kits. US 2005/0112199 A1 May 26, 2005 0.017. The invention therefore features a method of mental approval includes, for example, the approval of a increasing consumer demand for a pharmaceutical compo drug application by the Food and Drug Administration, Sition, therapeutic regimen, or kit described herein. The among others. method includes the Step of disseminating information about 0024. By “SSRI” is meant any member of the class of the pharmaceutical composition, therapeutic regimen, or kit. compounds that (i) inhibit the uptake of Serotonin by neu 0.018. The invention further features a method of increas rons of the central nervous System, (ii) have an inhibition ing investment in a company Seeking governmental approval constant (Ki) of 10 nM or less, and (iii) a selectivity for for the Sale of a pharmaceutical composition, therapeutic Serotonin over norepinephrine (i.e., the ratio of Ki(norepi regimen, or kit described herein. The method includes the nephrine) over Ki(serotonin)) of greater than 100. Typically, Steps of i) disseminating information about the pharmaceu SSRIs are administered in dosages of greater than 10 mg per tical composition, therapeutic regimen, or kit, and ii) dis day when used as antidepressants. Exemplary SSRIs for use Seminating information about the intent of the company to in the invention are described herein. market the pharmaceutical composition, therapeutic regi 0025 By “corticosteroid” is meant any naturally occur men, or kit. ring or Synthetic compound characterized by a hydrogenated 0.019 Consumer demand for a pharmaceutical composi cyclopentanoperhydrophenanthrene ring System and having tion or kit described herein, optionally with instructions to immunosuppressive and/or antinflammatory activity.