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`A CETA M [D E DER IVATIVE HAVING
`DEFINED PARTICLE SIZE
`
`Apr. 27. 1994) discloses the use of modafinil to treat urinary
`incontinence.
`»
`
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`BACKGROUND OF THE INVENTION
`
`Publications cited in this'docurnent are incorporated
`herein by reference.
`This invention relates to the acetamide derivative modali-
`nil. Modafinil (Clsl-leOzS). is 2-(benzhydrylsuliinyl)ac-
`etamidc. and is also known as 2-[(diphcnylmcthyl)sulfinyl]
`acetamide.
`
`Modafinil has been described as presenting a “neuropsy~
`chopharmacological spectrum characterized by the presence
`of excitation with hyperactivity and of hypcnnotility; and by
`the absence of stereotypy (except in high doses) and of
`potentialisation of the cfl’eets of apomorphine and amphet—
`”amine" (U.S. Pat. No. 4.177.290; hereinafter the “'290
`patent." which is incorporated herein by reference). Asingle
`administration of modafinil results in increased locomotor
`aetivity in mice and increased nocturnal activity in monkeys
`(Duteil ct al.. Eur. J. PltamtacoL 18049 (1990)). The
`neuropsycbophannacological profile of modafinil has been
`distinguished from that of amphetamines (Saletu et al.. Int.
`J. Clin. Pirarm. Res. 9:l83 0989)). Modalinil is thought to
`modulate the central postsynaptic alpha,-adncncrgic recup-
`ror. without participation of the doparninergic system (Dutcil
`er al.. supra). Modafinil has been successfully tested in
`humans for treatment of idiopathic hypersornnia and narco~
`lepsy (Bustuji er al.. Prug. Noam-Psych. Biol. Psych. 121695
`0983)).
`
`Narcolepsy is a chronic disorder characterized by inter-
`mittcnt sleep attacks. persistent. excessive daytime slocpi~
`ness and abnormal rapid eye movement (“REM") sleep
`marril‘esuuions. such as sleep—onset REM periods. cataplexy.
`sleep paralysis and hypnagogic hallucinations. or both
`(Assoc. of Sleep Disorders Centers. Sleep 2:] (1979)). Most
`patients with narcolepsy also have disrupted nocturnal sleep
`(Montplaisir. in Guillerninault er al. eds. Narcolepsy. Spec-
`Uum Pub. New York. pp. 43-56). Pathological somnolence.
`whether due to narcolepsy or other causes. is disabling and
`potentially dangerous. Causes of pathological somnolencc.
`other than narcolepsy. include chronic sleep loss (Carskadon
`ct 31.. Sleep, 5:573 (1982); Carskadon et al.. Psyclrophysi-
`olagy, 18:107 ([98 1)): sleep apnea (Kryger et al.. Pn‘ncr‘pler
`and Practice ofSleep Medicine. W. B. Saunders Co.. Phila-
`delphia. Pa. (l 989)); and other sleep disorders (International
`Classification of Sleep Disorders: Diagnostic and Coding
`Manual. American Sleep Disorder Association. Rochester.
`Minn. (1990)). Whether due to narcolepsy or other ca-u'ses.
`pathological somnolence produces episodes of unintended
`sleep. reduced attention. and performance errors. Conse-
`quently,
`it
`is linked to a variety of transportation and
`industrial accidents (Mitler er al.. Sleep ll:lOO (1988)). A
`therapeutic agent that reduces or eliminates pathological
`somnolencc would have important implications not only for
`individual patients. but also for public health and safety.
`Other uses of modafinil have been presented. US. Pat.
`No. 5.180.745 discloses the use of modatinil for providing
`a neuroprotcctivc ell‘ect in humans. and in particular for the
`treatment of Parkinson's disease. The levorotatory form of
`modafrnil. i.c.. (—)ben7.hydrylsulfinyl~acctamidc. may have
`porcntial benefit for treatment of depression. hypersomnia
`and Alzheimer‘s disease (L28. PaL No. 4.927.855). Euro-
`pcan Published Application 547952 (published Jun. 23.
`1993) discloses the use of modalinil as an anti-ischcrnic
`agent. [European Published Application 594507 (published
`
`55
`
`60
`
`65
`
`
`
`SUMMARY OF THE lNVENTlON
`
`Our invention discloses a pharmaceutical composition
`comprising modafirtil in the form of particles of a defined
`size. and the use of such composition. We have discovered
`that
`the size of modafinil particles is important
`to the
`potency and safety profile of the drug.
`_
`“Particle." as used herein. refers to an aggregated physical
`unit of the acetamidc compound. i.c.. a piece or a grain of
`aoetarnide. For example. FIGS. 2—5 provide photographic
`representations of various modafinil particles from Lots 5-D
`and L4.
`
`IO
`
`15
`
`As used herein. the term "mean." when used in reference
`to the size of modafinil'particles. refers to the sum of the size .
`measurements of all measurable panicles measured divided
`by the total number of particles measured For example. for
`live measurable particles which could be measured. and
`were determined to have diameters of 20 microns. 73
`microns. 20 microns. 35 microns and 20 microns. the mean
`diameter would be 23.6 microns. As used herein. the term
`"diameter" is a volurrretn‘c measurement based on the pre—
`sumed spherical shape of modafinil particles.
`As used herein, the term “median." when used in refer-
`ence to the size of modafinil particles. indicates that about
`50% of all measurable particles measured have a particle
`size less than the defined median particle size value. and that
`about 50% of all measurable particles measured have a
`particle size greater than the defined median particle size
`value. For example. for the five particle values listed above.
`the median diameter would be 20 microns.
`As used herein. the term “mode." when used in reference
`to the size of modnfinil particles. indicates the most fre-
`quently-occurring particle size value. For example. for the
`live particle values listed above. the mode diameter would
`be 20 microns.
`
`As used herein. the term “percent cumulative." when used
`in reference to the size of modafrnil particles. refers to an
`aggregate of the individual percent values for all measurable
`particles measured at specified diameters.
`As used herein. “about" means plus or minus approxi-
`mately ten percent of the indicated value. such that “about
`20 microns" indicates approximately 18 to 22 microns. The
`size of the particle can be determined. e.g.. by the methods
`provided below. and by conventional methods known to
`those of skill in the art
`
`In accordance with the invention disclosed herein. the
`mean particle size for a modaiinil particle preferably ranges
`from about 2 microns to about 19 microro. more preferably
`from about 5 microns to about 18 microns. and most
`preferably from about l0 microns to about 17 microns.
`in accordance with the invention disclosed herein. the
`median particle size for modafinil preferably ranges from
`about 2 microns to about 60 microns. more preferably from
`about 10 microns to 50 microns. and most preferably from
`about 20 microns to about 40 microns.
`
`in accordance with the invention disclosed herein. the
`mode particle size for modafinil preferably ranges from
`about 2 microns to about 60 microns. more preferably from
`about 10 microns to about 50 microns. and most preferably
`from about 20 microns to about 40 microns.
`We view the median measurement as having greater
`importance compared to the mode or mean values in that the
`
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`median value provides an indication of the distribution of
`the particles measured in a given population. While not
`necessarily a limitation but rather an indicator of the con-
`sistency of the population measured. the ratio of median:
`moan: mode would ideally be lzlzl; however. a ratio of
`median to mean of 1:250 to 1:050 is acceptable. and a ratio
`of median to mode of 1:15!) to 1:0.50 is acceptable. Ideally.
`the standard deviation between the mean. median and mode
`measurements of a modafinil population would approach
`zero. indicating that every particle in the population mea-
`sured was substantially identical or met the criteria for an
`ideal, normalized distribution. A standard deviation of less
`than about 25 between the mean. median and mode mea-
`surements is acceptable as an indication of the consistency
`of the population of the particles measured.
`In accordance with the invention disclosed herein. it is
`preferable that not more than about 5% of the cumulative
`total (percent cumulative) of modafinil particles in any one
`dose provided to a mammal have particle sizes greater than
`about 200 microns: it is more preferable that not more than
`about 5% of the cumulative total (percent cumulative) of
`modzrfinil particles in any one dose provided to a mammal
`have particle sizes greater than about I90 microns; it is most
`preferable that not more than about 5% of the cumulative
`total (percent cumulative) of modafinil particles in any one
`dose provided to a mammal have particle sizes greater than
`about
`ISO microns. “us. a “substantially homogeneous
`mixture" of modafinil particles. as utilized herein. refers to
`a mixture of modafinil particles in which at least about 95%
`of the particles in that mixture are less than a defined size.
`The value ranges defined above are based upon mcasurc~
`ments matte utili7ing technology and instruments developed
`by the Hiac/Royko Division of Pacific Scientific (1180]
`Tech Road. Silver Spring. Md. 20904. United States of
`America). As those in the art may appreciate. different 35
`instruments manufactured by different companies may pro-
`vide difi'ercnt measurements for the same particles. For
`example. in a characteristic modafinil lot (Lot L-2).
`the
`mean. median. and mode particle measurements obtained
`using a Coultcr Counter TA II sizing counter were 43. 31.
`and 29 microns. respectively. Using a Hiac/Royko Model
`9064 sizing counter. the mean. median and mode particle
`measurements obtained for Lot L-Z were 18.75. 31.41 and
`25.31 microns. respectively. These differences are presum.
`ably predicated upon the different approaches used in mea-
`suring particles of such diminutive sizes. Thus. the value
`ranges provided above are relative and are most preferably
`to be considered in view of utilization of instruments and
`operating systems manufactured by Hiac/Royko.
`for
`example. and preferably. the Hiac/Royko Model 9064 sys- 5°
`tern sizing counter.
`Modafinil particles of the invention can be in the form of
`a phan-nacologically acceptable salt. e.g.. an acidic or basic
`addition salt.
`
`5
`
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`
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`
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`
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`
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`tive amount of a pharmaceutical composition of the inven»
`tion is useful for enhancing alertness. or increasing regulars
`ity of sleep rhythms.
`A “pharmaceutical composition”. a used herein. means a
`medicament for use in treating a mammal that comprises
`modafinil of a defined particle size prepared in a manner that
`is appropriate for administration to a mammal. A pharma-
`ceutical composition according to the invention may also.
`but does not of necessity. include a non-toxic pharntaceuti~
`cally acceptable carrier.
`The pharmaceutical composition of the invention can
`contain at least about 50 mg. preferably at least about 100
`mg, or more preferably at least about 200 mg of modafinil
`having a particle size as defined above. The pharmaceutical
`composition preferably contains no more than about 700
`mg; more preferably. no more than about 600 mg; and most
`preferably. no more than about 400 mg. of ntodafinil having
`a particle size as defined above.
`Other features and advantages of the invention will be
`apparent from the following detailed description and from
`the claims.
`
`DETAILED DESCRIPTION
`
`We first briefly describe the drawings.
`I. Drawings FIG. I Is a graph dcpicdng particle size distri-
`butions for six lots of modafinil: Lots L-l. L—2. ILA. E-B.
`E-C and ED.
`FIG. 2 is a scanning clectrou micrograph of a sample of
`modafinil Lot E~D at 50x magnification.
`FIG. 3 is a scanning electron micrograph of a sample of
`modafinil Lot 8-!) at 100x magnification.
`FIG. 4 is a scanning electron micrograph of a sample of
`modafinil Lot L-l at 50x magnification.
`FIG. 5 is a scanning clecrron micrograph of a sample of
`modafinil Lot L-l at 100x magnification.
`'
`FIG. 6 is a graph depicting the dissolution rate of modali-
`nil particles from Lot E-D (median particle size 94.05 pm)
`and Lot L-l (median particle size 50.18 um).-
`FIG. '7 is a graph depicting the dissolution rate of modali-
`nil particles from Lot E-B (median particle size 89.10 pm).
`Lot ED (median particle size 94.05 pm) and Let L]
`(median particle size 50.18 pm).
`FIG. 8 is a graph depicting mean plasma concentration of
`modaftnil in dogs following single oral doses of modafinil
`from lots with dificrcnt particle sizes.
`FIG. 9 is a graph depicting mean plasma concentration of
`modafinil equivalents.
`i.e.. modafinil and modafinil acid
`metabolite. in dogs. following single oral doses of modafinil
`from lots with different particle sizes.
`.
`II. The Invention
`The invention results from our discovery that the particle
`size. and the consistency of the particle size. of modafinil
`can have a significant effect on its potency and safety profile.
`The first human trials for the use of modafinil to treat
`narcolepsy took place outside of the United States of
`America. The modafinil used in the initial studies was
`
`prepared in non—commercial scale lots (referred to herein as
`"early" or “E" lots). Pursuant to our discovery of the prcSent
`invention. it was observed that the early lets had a median
`particle size of between 80 microns (“um") and 150 pm. In
`the initial safety Studies conducted outside of the United
`States. early lot modafinil was administered to, humans .
`\vitlrout reports of clinically significant adverse events in'
`acute administration.
`
`‘
`
`
`
`the invention features a method of
`In another aspect.
`altering a somnolcnt state. c.g.. narcolepsy. idiopathic hyper-
`sontnia and related sleep disorders. using modafiail particles
`of a defined size: The method involves administering to a
`mammal a pharmaceutical composition comprising an effec- 60
`tive amount of modafinil in the form of particles of a defined
`size.
`.
`“An effective amount". as used herein. is an amount of the
`phanrntccutical composition that is effective for treating a
`sontnolcnt or somnolcsccnt state. i.c.. an amount of modafi-
`nil of a defined particle size that
`is able to reduce or
`eliminate the symptoms of a somnolcsccnt state. An ct'fcc.
`
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`SCParate safety and eflicacy studies of modafim‘l were
`Subsequently conducted in the United States under the
`dtrecdon of Ccphalon. Inc. using modafinil lots prepared by
`a method scaled up for commercial production (referred to
`herein as "late" or "L" lots). When the late lots of modafinil
`were administered to humans in the United States. the initial
`clinical
`trial
`revealed the occurrence of unanticipated
`adverse events at a dose level (800 mg/day) previously
`determined to be acceptable during studies conducted out-
`side of the United States. We discovered that the late lots had
`
`a median particle size of between 30 and 50 um. Thus. the
`initial human trials conducted in the United States were
`
`10
`
`perfonned with modafinil having a significantly smaller
`particle size.
`
`15
`
`lots comprising a
`As m subsequently discovered,
`smaller particle size resulted in an increase in the potency of
`nuxlafirtil. leading us to conclude that the drug can be more
`readily absorbed when compared to modafinil derived from
`lots comprising a larger particle size. Therefore. modafinil
`particles of a defined size provide at least two significant and
`unexpected advantages. First. potency is increased. A
`smaller average particle 5in allows achievement of a given
`mtvlaftnil plasma concentration at a lower oral dose. Second.
`with the knowledge of the importance of particle size on
`potency. the safety profile of the drug can be more accurately
`controlled because dosing with consistent and defined par-
`ticle sizes allows for greater reliability in the dosing of the
`drug necessary to achieve a desired resulL
`lil. Human Clinical Safety Studies—Foreign
`The safety and phannacodynamics of modafinil were
`initially cltaractcriycd in several studies conducted outside
`the United States using modafinil obtained from the early
`lots. During these studies. modafinil in amounts of up to
`4.500 mg have been ingested without the occurrence of
`significant clinical side effects (see. for example. Bastuji.
`supra; see also Lyons. T. .l. and French, .1. Aviation. Space
`and Euviromnenlul Medicine May. 1991. 432). No statisti-
`cally or clinically significant hemodynamic changes in heart
`rate or blood pressure in patients or in healthy volunteers
`using modafinil doses tested in the foreign studies have been
`reported.
`1V. Human Clinical Safety Studies—United States
`While significant testing of modaftnil had already been
`conducted outside the United States. new drug candidates.
`such as modafinil. typically undergo clinical research in the
`United States in order to combat-ate the information
`obtained in foreign studies. 'lhc first United States clinical
`evaluation of modafinil was a double-blind. ascending dose
`Study involving oral administration of modafinil to healthy
`males (i.e.. physically and mentally healthy male subjects 18
`to 50 years of age: average body weight of 40% to +15%
`of normal weight for age. height. frame and sex; 2101).
`The planned doses for the first United States clinical trial
`were 200. 400. 600. 800. 1000. 1200 and 1400 mg/day of
`modafinil or placebo. These dose levels were based upon the
`safety profile observed during the foreign clinical testing of
`modafmil. Subsequent doses were given only when it was
`determined that the previously administered dose was safe
`
`
`
`
`
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`
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`and‘wcll tolerated. For example. the safely’data f6r’th'c 200‘
`rug study dose was reviewed and assessed before oth:r
`volunteers received the 400 mg dose.
`In this first United States Phase 1 clinical study. modafinil
`from Lot L-l was utilized. Complete data were obtained for
`three of the seven modafinil dose levels intended for testing.
`i.e.. 200. 400. and 600 mg/day. However. elevations in heart
`rate and blood pressure were nored in two of the volunteers
`at the 800 mg dose level. These symptoms resolved without
`treauncnt or sequclae following drug discontinuation. This
`was surprising and completely unexpected. given the esca-
`lation of modafinil dosing observed in the foreign studies.
`Because these results were unexpected and because they
`occurred in healthy volunteers. these adverse events led to
`discontinuation of dosage progression at the 1000. 1200 and
`1400 tug/day levels until the cause of such results was
`determined.
`‘
`.
`V. Discrepancy Between the Foreign and United States
`Results
`in searching for the cause of the discrepancy, we corn-
`parcd plasma levels of modafinil measured in the first United
`States study and the preceding foreign studies. We found that
`at a given oral dose. when compared to subjects in the
`foreign studies. subjects in the United States study had
`higher peak modafinil plasma levels.
`The modalinil tablets used in the foreign studies were
`based upon early lots of modafinil. while the modalinil
`tablets used in the United States study were based upon late
`lots of modafinil. We theorized that a differencc'in bioavail-
`
`ability of the different lots of modafinil was responsible for
`the differences in maximum tolerable dose observed in the
`
`foreign and United States clinical studies. Although not
`obvious or readily apparent. one of several possible expla-
`nations which wc posited was a possible difference in the
`modafinil particle size used in the foreign and the United
`States studies.
`
`V1. Particle Size Analysis
`Following this assumption. We compared various param-
`eters from lots of the bulk drug; such comparisons had not
`been conducted previously. given the assumption that the
`modafinil being tested in the United States was the "same"
`as that investigated outside of the United States. Particle size
`distribution of the bulk drug was among the parameters
`examined. We have performed modaiinil particle size analy-
`ses with a Hiac/Royko Model 9064 sizing counter. a Coultcr
`Counter sizing counter. by optical microscopy and by scan-
`ning electron microscopy.
`Our particle size measurements were obtained using a
`lilac/Royce Model 9064 sizing counter following manufac-
`turer instructions (400 um aperture: saturated water with
`modafinil solution; PDAS program). A summary of the
`results of these measurements is presented in Table l. which
`includes the mean. median and mode particle sizes for six
`representative lots of modafinil. For comparative purposes.
`the standard deviation values derived from the mean.
`
`median and mode measurements are provided. as are the
`ratio values of mediammcanzmode. Lots BA. 513. BC and
`BB were among the so-called early lots. and Lots L-l and
`L-2 were among the so-callcd late lots.
`
`026
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`MODAFINIL PARTICLE DIAMETERN
`STD DEVIATION
`MEAN‘
`MEDMN'
`MODE‘
`BETWEEN MEAN.
`MEDIANrML-ZANNODE
`LOT (I‘m)
`(um)
`(sun)
`MEDIAN. MODE
`
`13.15131
`E-A 34.60 +l- 5.21
`143.65 +/-— 3.26
`176.48 +/‘- 5.32
`74.27
`
`1.19721.l3
`15-!) 29.99 +I— 1.09
`89.10 +/- 4.28
`78.59 +l~ 160
`31.53
`111792.78
`E-C 28.27 +l— 4.10
`79.00 +I- 3.78
`101.“) #~ .30.92
`37.30
`1:415:59
`[ED 2214 +I— 0.76
`94.05 +I- 13.75
`158.63 N— 63.81
`68.28
`1:134:39
`L] 21.40 44- 2.52
`50.18 H— 12.57
`56.56 V- 22.39
`13.73
`
`
`1’2 18.75 +4- 1.89
`31.41 «I— 3.57
`15.31 H— 1.34
`636
`
`15
`
`cumulative parti
`Lots E-A. E-B. E-C, and.E-D.
`particle size for Lots L] and 1.2 was between approxi-
`' mately 30 um and approximately
`50 um. while the 50 29
`Lots E-A. E—B. E-C, and
`
`VII. Effect of Modafinil Particle Size on Rate of Modnfinil
`Dissolution
`We investigated the oll‘cct ofmodafrnil panicle size oil the
`rate of dissolution. The results or‘ these experiments are
`summarized in FIG. 6 and FIG. 7.
`In the first experiment. 500 ml ofdeionized water was put
`in a l-liter beaker and 50 mg of E-D or L-l was added. The
`suspension was stirred constantly with a 5 cm Tciioncoated
`75 magnetic stir bar and a magneti
`
`ar.
`
`sample being replaced with 1 ml
`of deionized water. The stir
`plate speed setting was “2"
`for the first 20 minutes. and "7"
`
`gy. Re
`ticle size and morp
`presentativc scanning electron
`micrographs of early Lot 13-
`D are shown in FIG. 2 (50x
`magnification) and in FIG. 3
`(100x magnification). Repre-
`sentativc scanning electron rn
`icrographs of late Lot L—l are
`shown in FIG. 4 (50x mag
`nificau'on) and FIG. 5 (100x
`from 20to60 minutes Each sample was immediately filtered
`magnification).
`3°
`through a 0.45 pm filter. to remove undissolved particles.
`It is noted that the size of modafinil particles may be
`The filtered samples wereassayed for modafinil. by high
`determined by any ofseveral conventional methods. Meth~
`meat;ratatrnrrzzrn‘a?imam? magnummmegnw
`.
`.'
`.’
`.
`..
`‘.
`o naconet..
`tr‘oflmlag.D 4:
`(l 4.;odn—
`gllflcgggggfafiflgfizgfifi: ngfigfiglii‘gv‘fi'opucgl 35 nil Lot L-l (median: 50.18 um) had a fasterdissolution rate
`ability. electron rnicroSCopy. scanning electron'microscopy
`than d'd modalinil Lot5‘1) (mean: 94105um). Themum of
`and Coulter Counter techniques. For a general review of
`the first ”‘me are summarized m FIG‘ 6'
`methods for determining particle size. see Martin et al..
`A second dissolution rate expcnmcnt was conducted to
`[mm-m1 Mammy, 3rd Ed, ”a & Febigcr, Philadelphia ‘0 determine relative dissolution rates of modafinil from the
`(1983). See also O'Connor in
`1X.
`Remington 's, infra. Section
`capsules used in the dog
`study (described below) of plasma
`modafinil levels followi
`ng oral administration of modafinil
`from Lots E-B. E-D an
`d L-l. in the second dissolution rate
`experiment. the solven
`t was 900 ml of 0.0m HCl, main-
`
`Optical microscopy is us
`ment
`in the range of 0.2
`
`eful for particle size measure-
`ttm to l00 pm. For optical
`
`trained at 37° C. Each sample placed into the solvent con~
`microscopy. anemulsion orsuspcnsion. dilutedorundiluted. <5
`sisted of 200 mg of modafinil packed in a gelatin capsule.
`is mounted on aslidc orruledcell. Themicroscopeeyepiece
`Stainless steel coils were attached to the capsules to prevent
`ts fitted with a micrometerby which the size ofthe parucles
`them from floating. A stir-ring paddle was used at 100 rpm.
`my be estimated.
`Solution samples were taken at o, 5, 10, 15_ 20, 25, 30, 40
`Mechanical sieving uses a series ofstandard sieves cali-
`bmted by the National Bureau 0‘ Standards. Mechanical 5° and 60minutes The results of the modafinil capsule disso-
`Sicv“ may be “5°11 for screening material 3‘ fine 35 44 um
`lotion experiment are summarized in FIG. 7.
`(N°- 325 sieve). Sicves manufactured by photo-etching and
`VIII. Efl’cct ofModafmil Particle Size on Modafinil Plasma
`clcctrofomting are available with apertures from 90 run to 5
`Concentration
`”Measurementsobtained using instruments and techniques 55
`Given the disparity tn results between the foreign and
`' g what was presumed to be “idem
`tical" modafrnil. additional non-human analyses were nec~
`essary prior to continuation of human clinical trials. Accord-
`ingly. animal studies in dogs were carried out to determine
`the in vivo phannacokinetics of modafinil with different
`average particle size diameters, roughly designated as hav-
`ing "small" (Lot LI) and "large" (Lots BB and E-D)
`median particle sizes. Nine male dogs were randomly
`assigned. according to body weight to three dose groups.
`Each group was given a single oral dose or 200 of mg
`modafinil weekly for three weeks in a randomized. cross—
`over design, as described in Table 2.
`
`
`
`developed by HiacJRoyko are
`preferred. A Hiac/Royco
`sizing counter utilizes the pri
`nciple of light~cxtinction
`(obscuration)
`for particle size
`detection. The principle
`involved is that when a particle su
`spended in a liquid passes
`through a sensor microcell wh
`ere a laser beam is directed
`through a window at the cell.
`the particles in the fluid block
`the laser beam from a light
`extinction photodiode (photo-
`detcctor) resulting in a loss of light intensity. This loss of
`light intensity detected by the photodetector produces an
`'
`particle. These pulses are propor- 65
`tional in amplitude to th
`c light intensity (light extinction)
`le size.
`which is a measure of panic
`
`..
`
`
`
` .
`
`02'?
`
`
`
`

`

`9
`
`5,618,845
`
`10
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`~~~
`caster 7‘
`WM—
`BULK DRUG LOT
`NUMBER or
`AND MEDIAN
`
`
`
`DOGS WEEK PARTICLE SIZE.caour 5W
`l
`3
`1
`5-D (94.05 pm)
`2
`1,1 (50.18 pm)
`3
`an (89. IO pm)
`1
`or (50.18 pm)
`2
`15.13 (59.10 pm)
`3
`13-!) (94.05 pm)
`1
`on (89.10 tan)
`2
`E-D (sans pm)
`3
`1,1 (50.13 jun)
`WW
`
`
`
`3
`
`3
`
`2
`
`3 .
`
`m
`
`patent. and then subjeCting the modafinil or undefined par
`ticle size to conventional methods of milling and sieving.
`Methods for comminution (i.e.. the mechanical'proccss of
`reducing the size of particles or aggregates) are known to
`those in the an. Examples are provided in O'Connor or at.
`Chpt. 88. Reminglorr's Pharmaceutical Sciences, 18th Edi~
`tion. Mack Publishing Co.. Easton. Pa (1990). Following
`comrninution. the particles can be separated into a series of
`sieve cuts by passing the particles downward through an
`agitated vertical stack of sieves ofdecreasing mesh sizes and
`collecting the granules retained on each sieve or in the
`bottom part. Particles which fall outside of a desired range
`can again be subjected to milling and sieving.
`X. Formulation and Administration
`An appropriate dosage for modafinil having a defined
`particle size is between about 50 mg and about 700 mg of
`modafinil.
`
`After each weekly dose. blood samples (2 ml) were drawn 15
`from all animals by venepuncturc predose (within one hour
`of dosing), and at 0.5. l. 2. 3. 4. 6. 8. IO. 12, 18, 24. and 36
`hours post—dose. Blood samples were collected in heparin-
`,ized (lithium heparin) test tubes and centrifuged at 2.500 to
`3.000 rpm. The plasma was drawn off with a glass pipette. 20
`and stored frozen (-20° C.) until analyzed. The plasma
`concentration of modalinil. and its acid and sulfone metabo~
`lites were simultaneously determined by high-pressure liq-
`uid chromatography. according to the method of Moachon et
`til. (J. Chmmutag. B 654:9] (1994)).
`~
`Mean plasma modafinil levels in the nine dogs. at 0 to 36
`hours after modafinil administration. are depicted in FIG. 8.
`With "small" particles (Lot L-l).
`the plasma modafinil
`concentration peaked at l0 pg/ml. In contrast. with "larger"
`particles (Lots E-D or EB). the plasma modafinil concen-
`tration peaked at 8 pg/ml. Thus.
`tltc rnodafinil having a 3°
`median particle size of 50.18 pm resulted in a higher peak
`plasma concentration than that obtained with the same dose
`of modafinil administered in the form of larger particles.
`Similar results were observed regarding the acid metabolite
`of modafinil, 2-benzhydrylsulfinylacetic acid as depicted in 35
`FIG. 9.
`
`25
`
`> These results implicated the consequences of different
`particle sizes and the importance of controlling modafinil
`particle size. By controlling the particle size. safety concerns
`can be addressed. For example. a non-homogenous mixture 40
`of modafinil particle sizes may not provide consistent
`potency nor avoid undesired fluctuations in plasma modafi- ‘
`nil concentrations; such fluctuations can lead to undesired
`and unexpected events. Moreover.
`the use of modafinil
`particles having a defined size is more efiicient because a 45
`given plasma modafinil concentration can be achieved at a
`lower oral dose.
`After the discrepancy between the foreign and first United
`States studies was resolved and determined to be related to
`the differences in particle sizes. a second Phase 1 study was
`conducted in the United States. to further determine the 5°
`clinical safety. tolerance and phannacokinetic properties'of
`modafinil having a panicle size as defined. The second study
`involved normal young males and an experimental design
`similar to the first United States study (described above). in
`the second study. all subjects began at 200 mg/day using 55
`modafinil from Lots L-I or L~2. Dosage was then titrated. in
`200 mg/day inmments. up to the target dose. The results of
`this study suggested that 600 mglday was the maximum
`tolerable dose ("MTD'.') ol’ modafinil. with 800 mg/day
`being the minimum intolerable dose.
`'
`IX. Methods of Preparing Modafinil Having Defined Size
`Modalinil and modafinil~relatcd compounds can be pre-
`parcd by conventional methods. Methods for preparing
`modafinil and modafinil-related compounds appears in the
`’290 patent. Modafinil of the particle size defined herein 65
`may be obtained by :1 variety of approaches utilizing con-
`ventional methods, e.g.. the methods disclosed in the '290
`
`60
`
`The pharmaceutical composition described herein is most
`preferably adminiStered orally in the form of a vehicle such
`as a tablet. capsule. powder. pill. liquid/suspension or emul-
`sion. The administration vehicle may comprise a pharma-
`ceutically-acceptablc carrier. The carrier may comprise
`agents that aid solubility. absorption. flavor. color or texture
`of the vehicle or its contents. Topical administration via an
`epidermal patch or the like, or administration via direct
`injection of the drug, is also acceptable.
`A vehicle of the invention can include tic—15% of the
`modafinil particle. due to factors such as vehicle manufac»
`turing tolerances and expected shelf life of the modafinil.
`For example. a vehicle labeled as containing 50 mg can he
`initially prepared with. e.g.. 55 or 58 mg of modafinil. with
`the eXpectation that after one month to two years of storage.
`the active amount of modafinil
`therein has decreased.
`Vehicles prepared with such adjustments in order to com-
`pensate for the expected degradation of the drug fall within
`the scope of the invention.
`While the invention has been described in considerable
`detail. the invention disclosed herein is not to be limited to
`the actual description. but is to be afforded the full scope of
`the appended claims and all equivalents thereto. Although
`the specific exa