1
`
`EX 1018
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`2l?.
`
`J.C. Chaumeil
`
`the area of
`on the dissolution conditions; 5 is
`Contact between the powder and the solvent; Cs is
`the concentration of the drug at saturation; Ct is the
`concentration of the amount ofdissolved drug at
`the time of measurement. All of these parameters
`are constant. except for S and CL
`increasing 8 allows. to st first approximation,
`an improvement in the rate of dissolution. S is
`inverseiy proportional to the extent of granulation
`of the powder. it can thus be increased by reducing
`particle size.
`
`MICRONIZATION: A METHOD OF
`REDUCING PARTICLE SIZE
`
`The process used to reduce size of particles and
`aggregates must be chosen according to the
`powder characteristics (strucmre, hardness. and
`chemical stability) and the particle size required.
`'I'he‘gn1nulation of a powder can be defined as the
`average particle size measured using an ap-
`propriate device: a screen down to a few tens of
`rrticrometers, a particle size counter, or electronic
`or laser diffraction for smaller granules (2).
`the
`Theoretically,
`the smaller
`the particles,
`the
`higher the rate of dissolution. Practically,
`energy of the process can create a disequilibrium in
`the electric charges of the pt1t‘1iClt'.5 and cnuse
`aggregation of the smaller particles. This means
`that
`the minimum particle
`size
`is
`a
`few
`micrometers.
`The best devices For reducing particle size nre
`those which spmad out the energy. However, it
`is
`rarely possible to obtain the required particle size
`using only one operation. High-energy equipment
`that could reduce a raw material with large
`particles to one with micrometer-sized particles
`would release a large amount of heat, which could
`cause partial destruction of less stable molecules.
`Processes for reducing particle size must therefore
`be carried out in successive steps. The apparatus
`used for reducing particle size can be classified
`into three broad categories (i): i) coarse crushers;
`iileintermediate grinders; iii] fine grinding mills.
`Briefly. rnicroniaers are part ofthe last category
`and can only be used with the powders that are first
`reduced to particles to few millimeters in size.
`
`
`
`Fig, 1, jar mitt. titupnntcd with |1t'r‘ltti.-L\'it1tl liutu l.c Hit. A.
`Phannnri: galéniuuu. (tlh l-itlitimt. h‘l:tm1:I |'1‘)3.J
`
`Generally. two types of rnicrttttizurs are used:
`First. pebble orjur mills operate hy the principle of
`attrition or impact. The material to be ground is
`placed in a cylindrical jut cunlttining pebbles or
`balls of flint. porcelain. or stainless steel (Fig.
`it.
`The jnr revolves hurl‘/.nnlul|y on its long iutis.
`which tumbles the pebbles or balls with the
`particles. which are pulveri'r.cd. This grinding can
`be currictl out with the raw material uluuc or in
`suspcnsioit
`in :1
`(nunsttlvcnt)
`liquid: Suuttttdly.
`lluitl energy mills are used to uhtuin cxlrctncly line
`particles. The particle size is reduced by sulijecling
`the material to high-speed jets til‘ air or into gas
`(Fig. 2).
`Like the other mctltutls ol‘ rcdttuing paniclc
`size, nricroni‘/.ntion does not produce a powder
`with a uniform particle size. Size distrlhutiun is it
`
`Exit Pulvetization
`
`zone
`
`|'nun la:
`FIG. 2, Fluid energy mill (lit-printed with |!UI‘l'IIln.¥illIl
`Hit. A. Phamiauit gnldnirpm.fitl1lElilinn.Mnsuni l'l'J'.‘.l
`
`‘..-'a
`ii
`3'..:41‘.
`
`2
`
`

`
`
`Micmnizart'on.' Impmving the lrioavailobility ofpnorly soluble drugs
`213
`
`FREQUENCY
`
`Flli. J. Size ruttgcs ufpttrticli.-s
`
`statistical concept. For regular particles, diameter
`is used to dclittc the extent of granulation,
`regarding the particles as h'pltt:rt1.\‘. The size range
`of the particles is usually normally distributed
`around tl
`ttt:.tJtlIIl.ll|Tl. which is dclincd as
`the
`particle size and which is the tnctliutt value of the
`real measured size (Fig. .'t'J.
`
`APl’l.lCA’I‘t0N OI-' MICRONIZA-'l‘i0N TO
`P()()Rt.Y S0t.UBl.li DRUGS WITH
`A LOW |tl()A‘v'AI1.Alllt.lTY
`
`rat‘ several sparingly
`The rate of dismlttlitttt
`soluble drugs has been improved by micronization.
`The most suct:cssl'ttl examples involve otttifungal,
`ltnrtttnttul and vunrttttrtic drugs.
`(}rist:t:l'u|viit has at puniculurly low solubility
`and was thus studied as it ll1it:rUlti‘1.L‘|J powder with
`a median particle si‘/.t.‘
`til‘ 3 micrometers (3).
`Muustttutttcttt or the tttttuuut dissolved in waiter
`tr-r.rtr.r
`time using a Ittls3rtJnl7.£U powder showed
`that the rule nl'di.wJlutitm depcttdcd on the area of
`contact. which is
`related to the particle size.
`
`increasing this area was the best way of increasing
`the rate of dissolution of this drug (4).
`In the field of hormones. progesterone has had
`limited clinical use because of its poor digestive
`absorption due to its low aqueous solubility. To
`improve its hioavailabitity, progesterone was
`micronized and placed in sott gelatin capsules
`containing nrachidonic oil as a dispersion excipient
`(5). A new formulation of progesterone is now
`available for hormonal therapies. A comparison of
`oral micronized progesterone administration (200
`mg per dose)
`and injectable administration
`(intramuscular route) of an oily solution (50 mg
`per dose) in postmenopausal women thawed that
`after a I-day treatment. the relative bioavajlability
`of
`the micronized progesterone was 8.6%
`compared with the intramuscular progesterone
`(‘Table I). Mean Cm values for oral administration
`of progesterone were 30% of those obtained after
`intramuscular administration, and Tm occurred
`significantly earlier with the oral administration
`(6). These resulLs could be due to the low diffusion
`rate of pmgcsterone from its oily solvent after
`injection. After the second day of the treatment.
`progesterone was shown to aocumulateafter the
`multiple
`intramuscular
`doses;
`no_
`such
`accumulation
`was
`observed
`after
`oral
`
`I
`I
`administration.
`The use of micronization for progesterone has
`made it possible to administer this hormone by the
`digestive route, providing a significant benefit to
`patients.
`advantages have also been
`Comparable
`obtained with rnicrortized spironolactonc, which
`has an enhanced in vltm dissolution (7). The
`bioavuilubility in 24 healthy male subjects
`
`'t‘Alll.t-2 l. tfntupitrtsun or ptturtnucuttlnt.-tic parameters for mlcmnizcd pmgtuttcrunc administered orally and progesterone
`In ull tll|IItlIll.\'|t:l‘t'tl lItl:1Itt1us'ctt|I1r3y for day I ortt 2-tlny regimen.
`
` Micrnnizetl prugt:stemt1t:' lntmtnuscular progesterone"
`
`154-53 I319
`ll7.»$ 2 I732
`MJ(',____., tttgjtftttlt
`14-3 t I-0
`ti‘.| 1- to?
`l'”___ (Itp'III|3
`8.7 1: 2.U#
`2.5: L6
`‘|'__“‘ {In
`from comspoading values after
`tJV-.iluc:.- oftur inn-.mm_n_-ulur pmgptenmc significantly t.lil'l'erent
`‘Jill! ting; "Sit mg in nil:
`:niL'rutI1fL'u| ping.-xii-mnu |r|,‘IlI|l'l|_'||l rp < l).lJ5l.
`nch vttluc is the mean : SEM uidulairum153ulJjttls.RcpI'tnl€i1 by pennsssmo tram
`Iltt‘ /\!IlI.'tiL':ttI Smell’ for Itrpntdttctivu Mcdtunu ti-‘mi:'iJ_vumt.i‘trfit‘t'-'_v i‘)‘J.'l. 6.1: 26-13).
`
`3
`
`

`
`H4
`
`LC. Chaumcii
`
`TABLE 2. atuavnltnbutty or mir:.t'm1i12d spimnotnctonc to standard splmnulnctnnc tnblcu.
`
`"E-ruépmijun
`
`lliuuvniinbility ['3'-P .i_
`By 96huu: AUC"
`By %~huw min.-try umrcnuni: earn.-tiun"‘
`HS.) (El)3.0-|1‘).7]
`IILH i‘i‘J.{t-Iliii)
`|||.l (lD|.H-121.5)
`IIJL4 (37.2-I lT.‘})
`l|d1fi (103.0-i'li.h]
`HJTJI [‘)ii.l-i|(I.Hi
`
`.
`
`15 mg tablets
`H30 mg tablets
`Ovt:mJ]
`‘
`'Figurc.sin pnrrnthscs nr: 95% mrtl'td:nr:t: iimits.
`
`" Cnnrcnon: AUC after micmniud tablets x I00
`Canntncne AUC nflet stnndan! Inhlcts
`'”Un'n.tLry cmuennne cx.t:n:tion aflet micronizctl tablets
` xtmi
`Urinary canrmnn: ucrctiun after stundnrd tnbkts
`
`tkzpmducad with pcrmi:-:'mn from Mclnnts. G.‘[‘. at 11].! t'.‘.'iu Pimnatut-at 1982. 22: Iiili-4|7. D l.ippunL1i|t-Rm-cit PL'thIi.\‘]'lEI.\'],
`
`inlhlinnlabaujpiinnflfi]
`
`Mkmrtlwd ilimwaln 71'/I
`
`Nnnrnizmnizcddirmniii I7‘).
`
`G
`
`‘
`
`T1
`
`Tim: (linunl
`
`FIG. 4. Intcstinal nlmrption of micmnizcd and nursmicmniml
`diosmin.
`
`receiving tablets manufactured with either
`micronized material or the standard material was
`
`irnprovamnt “ri-
`N
`.
`
`studied by ntcusurcmcnt an the plttimmuultittctics
`of
`the main metabolite of
`spirotuiltw-tnnc:.
`czmrcnonc, for 96 it after treatment (8). Table 2
`sttuws
`the rclutioiwhip of the blunt]
`tuvelx tit’
`cnnrenmtc (AUC) and its urinttry cxcrctinn with
`the pnrticlc size of spiruimlnt-time; the L”iTI2F|3!ll.‘L'.\'
`um statistically significttttt.
`A phttrmtiunitigicul study WLLR curried uut by
`Juhrtstun at at’. (9) to investigate the cttcctx tit"
`micmnizutitm on the digestive uhttttrption of Lt
`flctvtmoid. Liiuxtnin. This study showed that the
`absorption of tniuruuizcd din.-imin is four time.-t
`greater than thut tit‘ nunmit-mni'.r::d din-tmin (Fig.
`4).
`
`
`
`U Illuonlud fllostrl-'\
`
`FIG. 5. lmprcvtmcnt in the clinical symptorns of vmnus ittsufficicncy with mii::uni1n.-d .'Ltld titminicniniml Liitmnin.
`
` .':.:~:.,-.,"...-.r.:.a.'-=.':.£t:L:.‘:+:."r”‘
`
`
`
`4
`
`

`
`Mi'4:nmi.‘.n!Fr)r1: Impm w':I,1: the bimiw:¢'i'u1'J:'I'ir,v ufpmrr."_v .\'rJ.’ubie u':'it,:,J.r
`
`2 I5
`
`Anulher sludy demonxlrdlcd the beiter clinicul
`cifiuncy nf miuronized ”d:'Ei.-{min after 60 days at‘
`(ruminant
`(p<U.D|)
`(10).
`Plelhysinngruphic
`ineusurcmcnts showed :1 significantly higher
`venutnnic activity for micrnnized diusmin.
`in
`terms ufvenuux dislensihilily and emptying rims.
`The Superiority of n1icmni;'.ed dio.-cmin. cun1p.'m:d
`with an equivalent du.-ie (II nunmicmnizcd diosm'II1.
`has been demnnstrutcd bmh ph:Inn:iuoiugiuu|iy
`nnd in [crime :1! the clinical symplmns uf” vcnuu.\'
`insu mu-i:ncy (Fig. 5).
`
`CONCLUSIONS
`
`Thcse findings nn the influence 0|’ particle .-'i'.r.::
`show that reducing pailticle size by Inicnuiizutinn
`uun imprnvc lhc nuc uf Ui.'ih‘()iL1li(1n of pimriy
`sulublc mutcriuls. Such in mm results may be
`uxci'u'l t'nmpIimi7.in_1_: drug Fnrmulutinn.-1' in impruvc
`the hinuvuiluhilily of ponrly .\'uiub1e drugs.
`
`REFERIENCES
`
`,uru1in¢nrr.v u'¢'
`flmlrn'.\'
`I.
`|.i: Hir. A. I'Imrmuw': ,1,-irfiiiifqiir.
`.fl-'-"I'I'nIrimn. Vihlidilinn. Mun’
`‘ Puris IUW. 275-83.
`2. 2-Iurupcull £’|mrn|uu:|x:;i, Jnl Eilliliiin.
`(ilmtcr. M.
`J. Nyxmlm. ('.. Mumur. J.. BJ:!rm:Ll. M.l..
`I'i'I_\'.\_fu'uu‘hrmfruI n.qm:'Lw nf:i'ru_:: rrh-uirr. I. I)J'.\'.wht.'1'm| mrr
`umuumncnrir wf .vpun'n_g-f_I‘ IrJ.’uI>.'|'
`|'u.InpuumI.r with my
`('i=rnl1rr('nmurr'l"r| II. J Pllunn Plmnnucul P235, 37; 21'.‘-
`1|.
`
`:'Ii_v.\fi::-rlmuirul
`(5., Ny.~':n1:n. C.. Aidan. M.
`4.5j¢'ikvis:,
`r1.tpn'.'.r if drug m'm.n-. IX.
`.'umn';,-uiirm n_f' .uuu.rju:'rurx
`mm izrqwirciinwziixrirrri rifrlrmesfunu ,uurn'cu.'urr dixjwrion
`,|'_|'.\':'.l'fll-I‘. iniJPhurm l9NU.54: lbl-ii).
`5. Silruk-Wnrc, R., Briruirc. C.. Dc Li_;nic.r:s, B. ‘funcvn, H.,
`Mu1wni.~‘.—Jarvis.
`P.
`(Jmi'
`uu'i.'nuu':n.' _nn:;:r.r|ernn:.
`Cnntm.'i:p1iuu |‘)K7,3fa: .'|'.‘3-35.
`6. Simun, J.A., Rubirwln. D.E., Amiraws. M.C.. lliidcbmnd,
`J.R.. Ruwi Jr.. M.l... Blukc, R.E..
`ilndgcn, (].D.
`"1119
`m':.rw;uu'un 1;! um! nn'n'nmf:nf pn:_i,-¢-.\'rmme.' [luv 1-_fl2-1'1 rJ
`Irma’.
`du.t¢'
`pn:,um1lm:u.'iI'_l'. mm’
`:'nm,I1m‘i.rm|
`u-il.'r
`mnwnn.rrui'n.r ,urugrm-nuw. Fenil Slcril Ii)‘-L1. (ill: 1h-J3.
`'1'. (.‘|u;liu. J.M., Rntmxay. LIE. Shcllun. J.R.. Tsdd. MJ..
`Murrny. 5.. Pulnm. RJ‘.
`l"nt'rnr.r :'r[,'1nm:“fi|_g- rmnpun:.'|'w-
`n'JJ'uum1'i'¢J.'11'lf.'_i'.qf1pinumi‘rii'!mIr!u.':.'r.'.1. I l‘h'.|.rnI Sci l')Tn'.
`hfi: E42941.
`R. Mulnncx. G.'l'.. Aslmry. M..T.. Ranuny. Eiil. Shcllnn. LR.
`1‘-IT!” Iin"J'Uf='nIIH':nrr'rm mr rhr .'u'miwrr‘Jiri'n'.':'.'_v umim-riw'.'_v inf
`.\‘_iu‘Jrlmztm-rnur.J Clill Pllnriiiuwl W32. 21: -1 HM.
`ry‘
`9.J'IIhn:«lun. A.M., Pnul. H.J.. Ynuug. C.(i.
`Jifli-cw:
`mh-nuu':uliuJJ mt
`n'1'_i,-t.>'rfL'r
`u.'r.n-n';:.|l'rm of Jin.\'tI':.'.'I.
`E’h|L*huluL:y l9‘)4{.‘>'upp|
`I1: -i-ix.
`lin-
`.rmn'_v Hf
`Hl.E‘n.\-piu.'. M..
`Iluminiui. A.
`.'Juni'ni':--hi'i:m'
`phur11uI:'m.!1':I:lmf(' um? i'FiJli¢':II in‘.'J1'1'rr'tu' af 53132 .W:' in
`nwnmx iu.|'rq_[,fii-1'rm~_r.
`/1rh‘uJuugi'.\‘
`:31" Um m-Ir mJ'rnm:':rri'
`fruvu. Em Aragiul
`I'M‘), MlSu|ipI 4): rul-5.
` &:
`Adilruxc Inr L-ornspuudcncc: LC. Clruiuncil.
`l.uImrutuirL- LIL:
`Fh.-irmm:nIci:|IaIic cl IJun:mphnrn1uiL' FAD l.'i')'.'. Fm.‘l.J|IE ilc
`Scicriucs !’l|ni1n1:1uuu|iqrJu‘ I:|
`!ii«iingi:|ucx. Univcrshé Rm!-
`Dum.-unm. 4. nvc-mic du |‘()1m-rvulnim. 7527!] Paris Ccdex D6,
`Iimnsm.
`
`-a
`
`5