US 2003.0056896A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0056896 A1 Jao et al. (43) Pub. Date: Mar. 27, 2003 (54) EFFECTIVE THERAPY FOR EPILEPSIES (22) Filed: Sep. 30, 2002 (76) Inventors: Frank Jao, San Jose, CA (US); Patrick Related U.S. Application Data S.-L. Wong, Palo Alto, CA (US); Evangeline Cruz, Hayward, CA (US); (63) Continuation of application No. 08/440,378, filed on Eduardo C. Sy, Union City, CA (US); May 12, 1995, now abandoned. Anthony L. Kuczynski, Mountain View, CA (US) Publication Classification Correspondence Address: (51) Int. C.7 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - C09. 1/00 ALZA CORPORATION (52) U.S. Cl. .............................................................. 156/327 POINTELLECTUAL BOX 7210 PROPERTY DEPARTMENT (7) ABSTRACT MOUNTAIN VIEW, CA 940397210 A dosage form is disclosed for delivering an antiepileptic drug, which dosage form comprises for maintaining the 21) Appl.pp No.: 10/262,153 integritygrily of the dosage9. form and of the antiepilepticpilep drug.9. Patent Application Publication Mar. 27, 2003 Sheet 1 of 5 US 2003/0056896A1 F. G. F. G. 2 F. G. 3 3 10 3 O ?: 11 2 14 2 C Z s AN-20 N 6 S N I NZ 19 LN N N is78 SN:N NY-20N3 28 N2 -26 N-22 A-2 Q 24 al O / AYAGA2DY AS Patent Application Publication Mar. 27, 2003 Sheet 2 of 5 US 2003/0056896 A1 3 O O- | I O 6 TIME (HOURS) F. G.6A : 00 O O TME (HOURS) F.G. 6B Patent Application Publication Mar. 27, 2003 Sheet 3 of 5 US 2003/0056896 A1 00 9 O 80 70 60 50 40 30 20 O O O 2 4 6 8 IO 2 4 6 8 20 22 24 TIME (HOURS) F. G. 7 100 90 80 70 60 50 40 30 20 O 0 2 4 6 8 O 2 4 6 8 20 22 24 TIME (HOURS) Y O Patent Application Publication Mar. 27, 2003 Sheet 4 of 5 US 2003/0056896 A1 Co eSir S Co CO -N hE O) N1 OO CE CD umb L Co e CN Co Co Co Cd O C Cd CN O CO CO e CNU (6) SWR NOAN-Hc Patent Application Publication Mar. 27, 2003 Sheet 5 of 5 US 2003/0056896 A1 O o N o o C co o O C o e-r - O o er C a LL CD E amo O n?) O O N O O - a \ C Co Cd Cd Cd Co Cd Co Co Co Cd CP Cd C CO N- co d S- n CN - (%) OSW3 9? O CZW WON US 2003/0056896 A1 Mar. 27, 2003 EFFECTIVE THERAPY FOR EPILEPSIES followed by a decrease in drug concentration as a result of drug absorption, distribution, metabolism, and elimination. FIELD OF THE INVENTION The concentration difference in dosing intervals is related to 0001. This invention pertains to novel and unobvious the presence and to the absence of administered drug, which dosage forms for administering a drug effective in the is a major disadvantage associated with conventional dosage therapy of the epilepsies. The invention concerns also a forms. Conventional dosage forms and their mode of opera pharmaceutical composition comprising an antiepileptic tion are discussed in Pharmaceutical Sciences, Remington, drug and a pharmaceutical carrier. The invention relates 18th Ed., pp 1676-1686 (1990), Mack Publishing Co.; The further to the manufacture of a dosage form for administer Pharmacological and Clinical Pharmacokinetics, 3rd Ed., ing a drug useful for treating epilepsies. Additionally the pp. 1-28 (1984), published by Lea & Febiger, Philadelphia, invention pertains to a method for producing antiepileptic Pa.; and in U.S. Pat. Nos. 3,598,122 and 2,598,123, both therapy in a patient in need of antiepileptic therapy. issued to Zaffaroni. BACKGROUND OF THE INVENTION 0006 The above presentation dictates of the critical need for a dosage form that overcomes the Shortcomings of 0002 The term epilepsies is a collective designation for conventional dosage forms, including tablets, capsules, elix a group of central nervous System disorders having in irs and Suspensions. These conventional dosage forms pro common the repeated occurrence of Sudden and transitory duce peaks and Valley patterns, and they do not provide for episodes of abnormal phenomena of motor, convulsion, dosage-regulated drug therapy over an extended period of Sensory, autonomic, or psychic origin. The Seizures are time. The drug, as delivered by the prior art is dosed twice nearly always correlated with abnormal and excessive dis or thrice a day, which does not lend itself to controlled and charges in the brain which can be recorded by an electro Sustained therapy. This prior art pattern of drug administra encephalogram. tion Speaks of the need for a dosage form that can administer 0.003 Epilepsy afflicts millions of people worldwide, and the drug in a rate-controlled pattern over an extended time the disease is more common in children than in adults. For to provide constant therapy and thereby eliminate the peaks the purposes of drug treatment, it is useful to classify and Valleys and eliminate the need for multiple uncontrolled patients according to the type of Seizure the patient experi dosing of the drug. ences. The generally accepted classification of epileptic 0007. The prior art provided controlled-release dosage Seizures comprises partial Seizures consisting of focal and forms that can administer a drug continuously over time for local Seizures, and generalized Seizures consisting of con controlled-rate therapy, as in, for example, U.S. Pat. No. Vulsive or nonconvulsive Seizures. Partial Seizures are clas 4,327,725 issued to Cortese and Theeuwes, and in U.S. Pat. sified further as Simple partial Seizures, complex partial Nos. 4,612,008; 4,765,989; and 4,783,337 issued to Wong, Seizures, and partial Seizures Secondarily generalized. Gen Barclay, Deters and Theeuwes. The dosage forms disclosed eralized Seizures are classified further as absence Seizures, in these patents provide a controlled-rate drug delivery over atypical absence Seizures, myoclonia Seizures, clonic Sei an extended time to provide constant drug therapy and Zures, tonic Seizures, tonic-clonic and atonic Seizures. The thereby eliminate the need for multiple dosing of the drug. epilepsies are presented in The Pharmacological Basis of These dosage forms can deliver many drugs for their Therapeutics, 8th Ed, Chapter 19 (1990), Editors Gilman intended therapy, but there are certain drugs that are not and Rail, Pergamon Press. readily manufactured and delivered from dosage forms. For 0004 Antiepileptic drugs are available for treating epi example, phenytoin Sodium converts to practically insoluble lepsies, as disclosed in Pharmaceutical Sciences, Reming phenytoin in the gastrointestinal pH range of 1 to 8 and the ton's, 18th Ed., pp 1072-1081 (1990) published by Mack release of unprotected drug in this range is incomplete and Publishing Co., and while the drugs are useful for treating this abstracts from acceptable therapy. the epilepsies, there are many shortcomings associated with these drugs. For instance, the drugs often are poorly Soluble 0008. It is immediately apparent, in the light of the above in aqueous and biological fluids, which property makes it presentation, that an urgent need exists for a dosage form difficult to both provide and dispense the drugs from a endowed with controlled-release delivery for the adminis dosage form in a known dose over and extended time. The tration of an antiepileptic drug for antiepileptic therapy. The drugs also can be extremely hygroscopic and they may need exists for this dosage form for delivering an antiepi liquify rapidly, which physical-chemical characteristic dic leptic drug in a controlled-Sustained dose in a therapeutic tates against their delivery from a dosage form at a con antiepileptic range and for Simulateously providing trolled rate over a prolonged period of time. Then too, many extended therapy. It will be appreciated by those versed in drugs exhibit a short half-life that can lead to fluctuations in the dispensing antiepileptic drug art, that Such a dosage form blood antiepileptic drug levels. These properties can inter that can administer an antiepileptic drug in a controlled-rate fere with manufacture and the release of the drugs from dose over time, and it would be a major advancement in the dosage form and from pharmaceutical compositions, and therapy of the epilepsies. these shortcomings are Serious drawbacks in the manage ment of epilepsies. DISCLOSURE OF OBJECTS OF THE INVENTIONS 0005 Prior to this invention, the prior art administered an antiepileptic drug in conventional forms like a Standard 0009. Accordingly, in view of the above presentation, it nonrate tablet or a common dose-dumping capsule at repeti is an immediate object of this invention to provide a dosage tive dosing intervals. The prior art modes of therapy leads to form for delivering an antiepileptic drug for treating epilep a drug concentration in the blood during the dosing interval, sies that overcomes the shortcomings known to the prior art. US 2003/0056896 A1 Mar. 27, 2003 0.010 Another object of the present invention is to pro 0023. Another object of the present invention is to pro vide a dosage form that delivers an antiepileptic drug in a vide a method for administering an antiepileptic drug for continuous-release dose over time. mulation in a therapeutic range while Simultaneously-avoid 0.011) Another object of the present invention is to pro ing a toxic range of the antiepileptic drug formulation. vide a dosage form for administering an antiepileptic drug as 0024. Another object of the invention is to provide a a controlled-rate in a therapeutic-dose over an extended method for administering an antiepileptic drug formulation period of time.