‘W6 93£'1S?S2
`
`‘
`
`—~ 9 ~
`
`?C'}.‘!US93.»‘{}28{i€}
`
`cc:smp€:en—e:=r1ts
`
`inslurie 1ecithi.n; i:~::.<s:¢:mNu;L«a8, E:>2:r:UR:sN 3.2::
`
`{Lucas Meyer, Germany} which is a mixture cf abmut ?a% mi
`
`ghosphatifiylchaline,
`
`12% phosphatidylethaholamine anfl
`
`abmut 15% athar phcsphalipids; QVOTHIR 166 {Lamas Meyer,
`
`5 Germany} which is a mixfiura somgrisinq about 58%
`
`phasphatifiylchaline, 18% phcsphatidylethanolamine anfi 12%
`
`uther phesphclipids; Q purified phasphGli§i§ mixture;
`
`L$PDZD.E~?5 at LIFQID EH30 {$i§oifi, Germany} which is a
`
`phnspho1ipifi.mixtura comprising abaut 80%
`
`10 phosphatidylcholina,
`
`8% phosphatidylethanolamine, 3.6%
`
`nmn~p0l&r iigids anfi about 2% sphinqomyelin. Furifiad egg
`
`ymlk phospha1i§ids, sayhaan nil phnsgholipids 5: ether
`§urifiad phosphalipifi mixtures are useful as this
`
`ccmpenent. This listing is rapresantative anfi nut
`
`is
`
`limiting, as ether phasphalipid materials which ara knawn
`
`tn thcse skilled in the art can be usefi.
`
`The surfactant chosen shoulfi prafarahly be nonwimnifi
`
`ta minimiza irritatien, and one ski11e& in tha art can
`
`cmndmct tests to rautinely select spacific surfactants for
`
`2% this purpase. Generally, the surfactant is a nmn~ionic
`
`alkylene nxifie camiansate wf an arganic cnmgnunfl which
`
`contains Qua a: mare yfiruxyl graups. Far example,
`
`athaxylatefi andfmr progexylatad almohml er ester campuunfis
`
`or mixtures tharecf are scmmnnly available and_ara wall
`
`25
`
`knawn to those skilled in the art.
`
`suitabla smrfactants
`
`include; but are net limitad to, TYLOXAPQL; PQLGXAMER
`
`é0?G; POLOXAMER 188; PDLYQXYL 40 Stearate; EflflLFDR ELMEQG,
`PGL¥SDRBATE 88,
`an&‘PQLYSQRBATE 39, as well as variaus
`
`campaunds said under the trafie name TWEEN {ICE American
`
`33
`
`Inc., Wilmington, Qelaware, U.S.A,},
`
`§LURGNXC Fwéé (trade
`
`’
`
`V
`
`name af BASE, Ludwigshafen, Garmany fur a co§olymer cf
`
`polyoxyethylene and p0lyuxypropylen&}¢ At this time,
`
`PLHRGNIC Fwaa and the FDLGXAMER 188 are preferred.
`
`Tha
`
`TYLOxA?QL.anfl TNEEN surfactants are also prefarrafi because
`
`35
`
`they are FB&.a§prQvefi for human use.
`
`The aqueaus cumpanent will be the continuaus §hase of
`
`the emulsimn anfi may be watsr, saline 6: any ether
`
`
`
`TEVA—EXHmHrum4@ART20Fm
`
`0228
`
`0228
`
`TEVA - EXHIBIT 1004 (PART 2 OF 5)
`
`

`
`W0 93!‘ I812
`
`.— la .——
`
`;PCTffiS§.3?G§§3{§B
`
`suitable aqueous solutian which can yield an isatonic and
`
`pH cantrmllad preparatimn.
`
`In aafiitian,
`
`the ccmgositions of fine invantiun may
`
`alse cemprise canvantinnal additives such as preservatives
`
`anfi anziomiéants.
`
`Typical preservativas inelude
`
`Thimermsal, ehlorhutanclg anfl mathyl, ethyl, groyyl or
`
`hutyl garabfins.
`
`The prsferred ail phase antioxidant is
`
`awtccopnaral ax &~tmca§heral suscinata.
`
`The aquaaus ghase
`
`may also include an antiaxidant at a ahelatimg agent of a
`yolyamine carbcxylic acifi such as etnylana diamine
`
`lfi
`
`tetraacatic acid {“EETA"), er a pharmaceutically
`
`acaeptahla salt tharaaf+
`
`The drug; cnsmetic, 3: active ingrefiiant, alene er
`
`with the oily excigiants, are mixad with a sufficient
`
`amaunt sf surfactants anfifor disgarsinq and suspending
`
`agents ta allnw dispersibility within the desired aize
`
`range in aqueouE madinm. The surfactant{s} may be any
`
`pharmaceutically acceptable una{5§ that enah1e{s} adequata
`
`disyazsibility anfi stability mf the draplets in aqueoua
`
`medium,
`
`in-a farm af stable submicron size«range draplets.
`
`The drug, with ax withaut aily exeipients,
`
`ia vigcrously
`
`mixed with an aquaous sciutian that may contain
`
`surfastants,
`
`to rasult in suhmicrun droplets afi the firug
`
`If neefied, a high shear mixer and E high
`and excipients.
`grassure hemoganiaar are emplayed ta awhieve the daSired
`&ra§lat aize.
`Smnicatimn is an alternative methufl ta
`
`achieve the aasired submicran drapiet size.
`
`15
`
`Qfi
`
`ES
`
`Riqhly efficient dalivary af the $ubmicran firaplats
`
`tn the skin is ehtained with a-dmsaqe iarmVwhi¢h is semiw
`
`35
`
`selifi.
`
`To prefiuce a semiwsaxid campesitian, many methcfis
`
`may he agpliad; afiditian of gelling agants, such as
`aarb¢§als and adjusting to a §H, arganic fihickening agents
`such as §a1yvinyl pyrrelidane {PVP} at a hydraxygropyl
`
`35
`
`methyl uellulese {HERE} palymar, Q: catostearyl alcohcl
`and‘nthar waxes that may riqifiify, solidify ur inmraa$a
`the viscasity mf the aquaaus disparsimn ta the fiesired
`
`cansistency level.
`
`Inmrganic thigkening agents such as
`
`0229
`
`0229
`
`

`
`W€393fI8?:'§2
`
`_. 1; .. "
`
`FW?TfUS93!fi28fi8
`
`fumed silica QAERSSIL Qt CABDSIL}, alumina, clay Gt ether
`
`similar calloidal particles can be used ta ineraase the
`
`viscnsity mi the farmulation.
`
`It i3 also §c$sib1e tn use
`
`mi; cQncantrati0nS an the higher and of the disclesed
`
`ranga tn achiave higher visE0sity.campa5itians. Howevar,
`
`use cf greater than 30% mil causes difficulty in achiaving
`
`tha desired firaplet-size.‘
`
`chemical skin penetratian enhancers may ha
`
`incarpwratefi
`
`intm thaԤurmulation ta enhance penetraticn
`
`af the activa imgrefiiant through the skin.
`
`In this
`
`regard, DMSG, desyl methyl sulfoxida, N~dodecyl
`
`yyrrolidane, decanml, dedacanal, an Qrganic acid such as
`
`oleie acid, or the like can be used. Qverall
`
`pnarmacmlmgieai effacts achieved with the sombination of
`
`chemical enhancers anfl submicron fircplets are greater than
`
`far either somgonant used by itself.
`
`This inventicn prcvifies submicran spheres {or
`
`areplets} that are an insoluble assembly af unique
`
`antitiesTéispersefi in an aquemus §hase with tha aid mf
`
`ayprcpriate surfactants or emulsifying agents.
`
`The
`
`emulsifying agent amfi surfactant farm a pratective layer
`
`arcunfi the fircplets thus enabling efficient disgersian aha
`
`guspensien af the wily phase in watar. This layer is a
`
`monaiayer, pmlar by virtue of the surfactants.
`
`The
`
`preseni drwplets are naither vesicles net lipasamas aince
`nu hilayers ragembling the hilayer farming the living $311
`
`wall is farmed. Eicellas may be fwrmefi anfi be p:&sent,
`
`but may accaunt for only a vary small fractian uf the
`surfactants and insuluhla matter af the formula anfi
`in
`
`neg1igible.quantities, usually lass than ahaut 1% of the
`
`tatal mas$ af insalubla matter and surfaatants or
`
`flispersing agents.
`Expariments cafriefi nut and measurements by means cf
`
`13
`
`15
`
`28
`
`25
`
`30
`
`ghotmn Sorrelatinn spactrascagy {Cou1tar N4MD3 and lasar
`
`35
`
`diffraction qcwulter Lsggag indicated that the droplat
`
`size in the ccmpasitians of the inventian is in the size
`range sf ahaut 5.82 ta aboufi D.5.micruns. Preferably, the
`
`0230
`
`0230
`
`

`
`WIT) 93.338752
`
`4.. 12 ..
`
`P-C’1‘fUS93f{328fii}
`
`size range is mainly in the 3.1 to Q.3 miuren {i.e., 193
`
`tn 390 nm}
`
`range.
`
`V
`
`fiayenéing an the ifiherent activity afi the active
`
`ingredient its quantity has ta be afljustad flax each
`
`sgecififi firug,
`
`ccmpasitiuns accarfling ta the invention fa: tapical
`
`apglicatimn to abtain a tdpical or systemic effect,
`
`ncntain, far axamgle as active ingredient: steraids er
`
`nanwsteraifial anti~inflammatary‘arugs, antibintiss,
`
`antifungalg, antiviralsi antihistamines, antineaplastics
`
`or local anesthetics. Specific examgles wauid include
`
`substancas such as clatrimazmla, bifanazcle,
`
`tatracyclina,
`
`miccnazale,
`
`triamcinoiane, amghetericin gentamicin,
`
`hydrocartisone,
`
`iedmxuridine,
`
`fiiphenhyfiramine, minmxidil,
`
`lidocaina,
`
`tatracaine and clinflamycin.
`
`Ear systemic.effeuts,
`
`the follawing cateqerias of
`
`aruqs are suitable: hypnctics, sedativesf anxiolytics,
`
`antifiepressants, anticonvulsants, anti~inf1ammatury flrugs,
`
`anti~fiunga1s, prestanoids, prostanaifi agonista, prastanaié
`
`antagonists, analgesics, hormcnes anfi vitamins. Specific
`
`examples wmulfi include lipoghi1icT§egtides, barbiturates,
`
`banzodiazepines, ghanothiazines, cyclaspnrin,
`
`éiphenoxylate, ghysmtigmine,
`
`tacrina, fiiclofanac,
`
`IE
`
`3.5
`
`20
`
`dexamathasana, prastaglanfiins, nifefiigina, nitrsglycerine,
`
`25
`
`atrapine, verapamil, fantanyl, 1ipaphilic_peptides,
`
`ketatifen, phenytmin, micanazwla and katncmnaanla.
`
`For caametic effiects;
`
`tha active ingredient might ha
`
`for example vitamin a, vitamin E, a palyunsaturated fatty
`
`acid such as eicnsapentansi: acid, retinoids, caratanas
`
`343
`
`and ban3oy& geroxida.
`
`Insteafl at a viscous Cempasitimn,
`
`tha droglats af the
`
`invehtimn can be tagiaally and_transdermal1y ap§1ied by_an
`
`articla which incluflas the flrcglets, an active ingredient
`
`35
`
`and a sugport far retaining tha aomgnsitian therean. The
`supycrt wauld inalude an adhasive far securing the artislé
`ta the skin cf a subject.
`A wide variety ef active
`
`ingradients,
`
`inalufiing steroids such as astrafiisl,
`
`0231
`
`0231
`
`

`
`\V{}§3!i8752
`
`1
`
`F‘ L»)
`
`I
`
`’PCTFr"L§S93f{§18{li3
`
`nisutine er nitraqlycarine, can ha administered by this
`
`artic1a, which would genarally be in the farm cf an
`
`occlusive dressing ar an aénesiva gatch.
`
`In the fallmwing descriptimn, cmnaentratians wilk he
`
`indicatad by % which flenates the cencentratian by weight
`
`oi the campmnent per 190 unifis valume Sf entire
`enmpasitibn. All indicatefi cmncanttatians shauld he
`
`underatoma as standing each hy itself, and net cumulative.
`
`It should be apgreciated by tha artisan, however,
`
`that
`
`there is soma dapenfiency between the cancentrations of tha
`
`campanants, e.g., higher concentratinns of the ail will
`
`generally require higher cancentrations cf the emulsifier
`
`anfl surfactant.
`
`“
`
`The emulsian usad in the mampoaitions of the present
`
`invantian may cnmprise about 0.5 ta 33% mil, abaut 8.1 ta
`
`16% emulxifiar anfi about 8.35 ta 5% surfactanta.
`
`Generally,
`
`inaraasing the_ccncantratién af the nanwaquecus
`
`phage, i.e., the cmmbined cmnaentraticn sf the Qily and
`
`the amphighilic phasa,
`
`increases viscasity of the
`
`mompasitian.
`
`in urder to obtain a viscmus camgasiticn,
`
`the cancentratisn cf the nil ceulfl ha increasefi to about
`
`23 to 36%. As noted abave, another way to increase the
`
`viszosity is ta add a pharmaceutically acceptable gelling
`
`(5!
`
`lb
`
`15
`
`2*?
`
`or thickening agent, such as Carbopcl or tha like. These
`
`25
`
`viscqus ccmpmsitians are useful as creams Gr aintmants.
`
`Preferred ccncentrations of tha c3m§anants are as
`,m11_ows: abrzmt 5 tan 26% oil; assist (2.2 ta 5% mi the
`
`emulsifier! with ahmut 3.2 tn 1% being particularly
`
`grefierréd; anfi abaut 9.2 ta §% for the surfactant,—with
`
`about Gez ta 1% haing particularly preffirrafi.
`
`far a
`
`visaaus efimgasitimn, about 0.2 ta 15% of the gelling qr
`thickaning agent can ha included.
`
`The drug fir casmetic agent {the &ctive ingrediént} i5
`
`yresant in an amaunt Qf about 6.65 ta 5% by weight of tha
`
`campmsitian, preferably abcut 0.1 ta 2.5%.
`
`aepanding ugan
`
`whether tha active ingredient is hydrcphilic or
`
`hydraghebic, it will be physically present in tha oily
`
`39
`
`35
`
`0232
`
`0232
`
`

`
`VH393H8?52
`
`4* 13$
`
`*~
`
`PCTfs"L‘»S93f{§380£}
`
`the pH of fihase
`$153,
`yhase at the aqueaus mompanent.
`camfiasiticns shuuld be in a range which is suitable fer
`
`the stability of the active ingrefiient, but slightly
`
`acidia.or as clQS&~tQ neutral as pasaible far
`
`campatihility with the skin.
`
`‘Tha inventing is iilustrataa with reference to the
`
`abavewmentienefl examgiea, which are to be cunstruad in a
`
`striatly nan~1imitative*mannar¢
`
`13
`
`EEAMELES
`
`The enhanced tagical and transdermal effects sf firugs
`
`administerefi 13 emulsians comprised of suhmicrmn size
`draplets in cmmparison ta standarfi cream furmulaticns and
`
`cnmmaraial yreparatimns was establighed in several tafit
`systems. Antiinflammatory agants were testefi utilizing
`
`15
`
`the carrageeman infiuced yaw adema in guinea pigs.
`
`Tranguilizers wera assessed in guinea gigs utilizing
`
`behavi§ra;.te5ts indicative cf aedation. Local
`
`anesthetics ware tested in healthy human volunteers an the
`
`33
`
`basis mi less of lama: senaatian fnllawinq apglicatimn of
`
`varicus pregaratians.
`
`The fallmwing summarizes the systems used and rasuits
`
`nhtainefi with the formulatisna tested.
`
`fha fmllmwing
`
`cases axa ta be cnnstruea as exam§les in a strictly ncn~
`
`25
`
`limitative mannar.
`
`§gumLE;:
`
`A diazepam.submicron craam pregaratinn was
`
`mafia as follaws:
`
`9.5 g af diazapam are mixaé with § q of
`
`mafiium cnain triglycerida {HST} ail and 1 g af lecithin
`
`SO
`
`until an hamugenecus wily gnasa 15 achieved.
`
`?ha oily
`
`phasa is thgn disgarseé intn 96 ml sf an—aquaaus phase
`which includes 3 q mi PLUROKIC Fwfis and 3.1 g sf a mixtura
`
`cf mathy1.an§ gropyl parabens by initial mixing with.a
`
`35
`
`magmatic stirrer fullmwefi by a high shaar mixer {Paiytran
`K3806} far 5 minutes at Qsflfiaa EPM ta farm an emulsion.
`Eartha: treatmanfi cf tha emulsicn is canfiuctad in a-nigh
`pressure homageniaar {AF$ ~ Gauiiny at 880 bar fax 5
`
`0233
`
`0233
`
`

`
`\¥I}§3f}S?S2
`
`¥W3T?{fl§93fQ2SBO
`
`minutes {ahuut 10 cycles) at %5~5E”E. Tharaafter,
`
`the
`
`emulsinn was Cocled ta ream temgerature and the mean
`
`draplet 313% was measurefi siae to ha 12¢ nanameters having
`
`a very narrow distributian with yractifially nc draplets
`
`abave mne micron {less than 0.5%} being detactefi.
`
`CARBQPGL is added ta.a final csncentratian of 3.3%‘
`
`Finally,
`
`the pH is~elavatafl with sodium hydrmxida tn ? and
`
`a samiwsulié submicran drsplet pra§aration ig aehievefi.
`
`EXAMELEQ;
`
`Example 1 was regeatad using 6 g MET oil anfi
`
`3 g oleic acifl.
`nanometers.
`
`The mean drcpiat size—was fauna ta be 158
`
`§§AEFLE 3:
`
`{Cmmparativa}
`
`A formulatinn was made in the
`
`same manner as Example 2 but withnmt the §ro:edur& to
`
`reduce the &rop1at giza.
`
`The finalfidroplat size was
`
`between 5 and 55 miurans,
`
`EKAMELEA4:
`
`{Camparativa}
`
`A conventicnal fiiazegam cream
`
`waa pragarefi as follewsz
`
`diazepam 0.5 g, MET mil 9 g,
`
`emulsifying wax 9 g. hat water a1 ml.
`
`& classical
`
`technique was usad whereby the wax was melted,
`
`the mil and
`
`firuq were added,—and than the hot water was added with
`
`ll}
`
`15
`
`EU
`
`Tha mean drcplet size Qf tha cream was
`vigormus stirring.
`between E anfi SC micrans.
`
`25
`
`ECESRIIPLE 5-:
`
`The systemic tranquiliaing effest af tapically
`
`appliafi diaaapam creams uf the first faur examples were
`
`inveatigated and comyared to the systemic administratimn
`
`cf fiiaaapam, as fallaws.
`Materials ana Methmds
`
`GuinEaǤigE, males and iamalas, having a bedy waight
`
`mi about 259 g were shaved E4 haurs before application of
`
`the craams.
`
`The fsllowing farmulatians ware applied:
`
`{a} diaaepam 9.3% ~ small firags {Example 1};
`
`{b3 diazepam
`
`8_5% ~ small firags with a1eic‘acifi {Exampla 2};
`
`35
`
`35
`
`
`
`0234
`
`0234
`
`

`
`W0 93353331.
`
`‘
`
`_,
`
`1,5.
`
`__
`
`P{I.‘Tz'"US93fi}2S9_i¥
`
`{G} diazagam G,§% ~ largg drmps with Qleic acid {EHam§le
`
`{d} diamepam 9.5% in a canvantimnal cream mi large
`3};
`droplet size {Example 4}.
`Fiva grams cf each preparatian
`was agplied an the ahavafi area, i.e., abaut 28 egg Rf each
`
`guinaa pig.
`
`Cmmm&ruial1y availahla paranteral yrayarations w$re
`
`alga used as cmntrals, as fgllsws: {e} diaaegam 5 mggml
`
`{vials mfi 2 mi), 19 mgfkg administered intramuscularlyg
`
`and if} the same praparatian afiministered suhsutaneausly
`
`3.0
`
`£15 mgfkg}.
`
`Clinical appaarancs, fallowing agglicatian or
`
`injeatimn, was checkefi anfi recorfiedé
`
`The anset and
`
`tarminatimn times of the effects were recorfiad.
`
`Three basic bahavimral tests,
`
`infiicating lave; cf
`
`15
`
`seaatianf were use&
`
`ED
`
`25
`
`{a} Righting reflex: animals are pcsitionafi on their back
`and tha time that is requirafi tn raturn ta narmal pasiticn
`
`was xacorded. Threa levels af sadaticn are scared:
`
`law
`
`{scare 1) ~ animal returns immediately ta mutual §osition;
`
`mmderate.{scare 2} u up tn 35 sacands are needed ta return
`
`ta narmal pnsitien; severewfieap {score 3} w more than 38
`
`secanfls are needed to regain narmal position.
`
`{b}
`Snap tast: animals are §asitianed an a S cm high
`step, with the farelsqs an the step.
`Eng time interval
`for changing this gmsitian was measured far each animal.
`
`The same course sf time that was used for scaring Qf
`righting reflex was use&.hara.
`b
`leg3, their
`{3} Animals were.pasiti0nad on their hinfi
`feralegs put an tha tsp sf tnair cage {EU cm high}. The
`
`39
`
`time intarval far changing this §a$itimn was measnred far
`
`Each animal.
`
`Tha same scaring methcéolegy as abmve was
`
`usafi hare.
`
`A tutal aggragate scare fer each animai was
`{d}
`calculataa ta Shaw tha.stata of sedatian far this stuay.
`
`35
`
`The results are shawn in Table 1. It was fuunfi that
`
`tapically apgliad aiazegam is very afifactive when
`dalivered in submicran draplets.
`A s3st9mi$~lik& effect
`
`0235
`
`0235
`
`

`
`wan 93x:s:7s2
`
`7
`
`_ 417, _
`
`P{I¥’!L?S§¥3i{}28{¥i7}
`
`may be acniaved with this yraparation, but the sama fiase
`
`in larga droglet farmulatian was nut effectiva. Alas,
`inclusion cf claim acid in the furmulatian reéucas the
`
`the
`
`time for enset af activity and fiuration,
`
`
`
`xabig ix
`
`Efiicacy of fiifferant tayinal anfi Sysiamic
`fiiazepam Furwulatians in Guiuaa Pigfi.
`
`Treatment
`
`
`T
`
`ND. cf
`Animala
`
`scare
`
`T
`
`fime nf
`Rctivity
`{min}
`
`Diazapam.
`
`i.m.,
`
`1G mgfkg
`
`Diaae§am, 5.2.! 18 mgfkg
`
`Diazagam $.S% cxeam {S gg
`suhmicran drape
`
`Diazepam G.§% arefim {E Q)
`gubmicran drcpa with Qlaic
`atid
`
`Biazegam 3.5% eraam (S g}
`large firmgs with 912;: acid
`
`é
`
`4
`
`S
`
`fl
`
`E
`
`39.0
`
`52.8
`
`£?.S
`
`15~120
`
`lfimlifl
`
`éS~24O
`
`$3.?
`
`Eflwlfifl
`
`3.8
`
`~~
`
`~~
`~w
`S
`CLass;:al diaaegam Q.S%
`cream {E 93
`
`EXAMELE 6: Example 1 was repeatefl using TWBEN~S0
`
`instead
`
`Di PLSRONIC F*68.
`
`The mean dxoglet size was :70
`
`nancmetars and an enhancafi txanquiiizinq affect
`
`substantially equivalent ta that of Examgle 1 wag
`fletecteé.
`
`gggfiggfi ?:
`
`Example 1 was rapaated using EHULFGR EL*62B
`
`instead 0f PLEEQNIC F~fiS.
`
`Tha mean draplet size was.faunfi
`
`te—be 180 nafimmeters anfi the activity wa5 Qnmyarable tn
`that m? ‘ E.‘«£am_p.1».-'~: 1.
`
`
`EXAEELE 8:
`
`Example 1 was again regaatad excapt that the
`fmrmulatian cmntained 23 g MET mil.
`
`Tha mean drnylet siza
`
`was —f»::m.mi to be 21.0 nanam_eters, but the at:-'3;ivi.ty was
`
`significantly increased 1% uamparison ta Camyarativa
`
`Example A anfi was as gama as that sf Example 1.
`
`0236
`
`13
`
`15
`
`ES
`
`25
`
`30
`
`35
`
`0236
`
`

`
`V¥I)§3!}8?§2
`
`I
`
`,
`
`3.4 {)3
`
`PCT! {.?S93fi}28i}E1
`
`§xgmPLE <: Example 1 was repeated except that 30 g MST
`nil end 1 g eiezepam were ueed. The mean droplet size was
`258 nenemeters and the.§reparetien exhibited increasefi
`activity cempered to that sf Cemparative.Exam§le é‘whieh
`was at least as game as-that af Examgle 1.
`
`Example 1 was again reeeated but 1 g eleie
`Exhfiggfimlez
`The mean droplet siee was 100
`acid was inczludefi .
`
`nanometers an& the cmmpesitien was ficunfi te he as active
`
`M3
`
`as that of Examgle 1.
`
`EXRMPLE 11: Example 1 was repeated using TWEE§~$E instead
`of lecithin.
`The mean dreplet size was founfi to be 256
`
`nenameters and the fermuletien was much more active {a
`
`15
`
`scare cf 35} than that of Example 4.
`
`EXAMFLE 1.2 :
`
`Exemele 1 was repeated ueing MDfiTafifiL—Sa
`
`instead cf lecithin.
`
`The mean flreglet size was feund fie
`
`be 300 nenemetere and the fermuletien was mueh mere active
`
`25
`
`{a score of 36)
`
`than that ef Example 4.
`
`exaxeL§ 13:
`
`ineteee ef MST ail.
`
`Example 1 was repeated using eeyheen oil
`The mean dreplet size wee feunfi ta be
`
`183 nenemeters and tee formulatian was as active as that
`
`35
`
`ef Example 1 {e eeere ef 45).
`
`Example 1 wee repeated with the addition of
`Exggeifi 1%:
`The mean éroplet size was
`e~teee§hexe1 as an antioxidant.
`fauna te be 188 nenemefiers anfi the fermuletion was as
`
`33
`
`active ae that ef Example 1.
`fauna ta be suitable far administering exifietien.eeneitive
`
`This fermuletien wee elem
`
`aruqe such as nifedieine.
`
`35
`
`Exemgle 1 was again repeated but E g ef
`‘J:
`
`AER§SiL.ei1ica and hydregyyrepyl cellulese, respectively,
`were ineludefl
`ineteefi ef CERBGFQL, and the pH was edjuetefi
`tn 5.§.
`The mean éreylet size fer each examele was feund
`
`0237
`
`0237
`
`

`
`I¥31YiE§93f628§fi
`
`ta ha 188 nanamaters and the C§m§GSitiQfiS were fauna tm—be
`
`as active as that of Examgla 1.
`
`an imdumethacin_suhmicrmn craam preparation
`§§AfiELE 1?;
`was made a fullaws:
`indomathacin 9.5 g, MET mil 1? g,
`lecithin 8.8 g, EMULFGR EL~fi2O 1.5 g, CAREGFOL~1.? g anfi
`water 78 ml.
`The §racadure af Example 1 was féllawefi ta
`
`attain a mean flraplet size mi 13$ nanametar$.
`
`18
`
`large droplat
`A conventicnal,
`{Comparative}
`§Xg§PLE.1§:
`sise indomethacin cream was prepared as fnllawsz
`
`indsmethacin 9,5 g; MC? mil :5 g, emu15ifyinq wax 9-q,
`water ?§ mi, The cmmpasitian was yragared as in Exampie
`
`Be
`
`The mean firoglet size was found ta be between 5~5a um.
`
`15
`
`Tha toyical antiwinflammatary effect af
`EX§MP;E.13:
`tcgicallymapplied indametnaain areams cf Examples
`1?—18 were investigated anfi aomyarad far their antiw
`inflammatary effgct versus systemic afiministration.
`
`25
`
`Animals and Materials
`
`éuinea gigs (QBQ g}.
`{a}
`Indamethacin 8.3% in submicrmn cream {Example 1?}.
`{E}
`Indmmethacin 8.5% in cnnventional cream {Examgle 13}.
`{a}
`{d3 Enésmathacin 9.5% in salutian.
`
`25
`
`Study Pracedura
`
`{a} All animals received
`
`an injactiun of Sq: ml
`
`carrageenan 3.1% into the
`taken frmm the area cf injactimn and falluwed far up ta 5
`
`hinfi paw. Measuremants were
`
`RQRIS.
`
`3Q
`
`35
`
`The above creams were afiministared at carrageenan
`{b}
`afiministration site and the soluticn of indamethacin was
`administerad intramuscularly 15 minutes prim: ta
`
`Carrageenan administratiun.
`{c}
`The circumferance sf the yaw was again measured anfl
`thfi change in size was camparad far tha different
`treatment5.
`The volume chang&s were maasured.by a
`plathysmameter gfigc, Baselfi.‘
`
`
`
`0238
`
`

`
`“fl39$flS7§2
`
`- 21‘) ~
`
`£'US!)32’{§28£}&
`
`The results yresented in-Table 2 demanstrata that a
`
`lmcal agpliaation of indumathaain in suhmicran drsglet
`
`cream wag the mmat affective in reducing the edema caused
`
`by fiha carraqeanan injactian, and was mare efifective than
`
`large flraplats of indamethacin mraam at the same dnse
`
`administerafl intramusuuiarly.
`
`
`
`Tabie 2:
`
`Earfarmance cf niffsrent Indomethscin Farmulatians
`in Faw E&ema.Madal in Guinea fiigs
`
`kverage change of circumference.
`77 mar CE at
`Bcurs after cazrageenan
`injecticn
`
`N8. of
`
`Treatment
`Animals
`1.
`1
`3
`Q T
`5
`
`15
`
`central
`{Carrageenan}
`
`4
`
`17
`
`32
`
`51
`
`8%
`
`33
`
`1Q
`
`29
`
`25
`
`30
`
`35
`
`Indnmethaain fl.§%,
`in cream small
`dxaglats
`Indnmethacin in
`cream. Larga
`dxaglets
`Inanmethacin 15
`mgfkg i.m.
`in
`
`sclutian
`
`0
`
`3.3
`
`24
`
`32
`
`35
`
`15
`
`SS
`
`8?
`
`4?
`
`39
`
`19
`
`22
`
`23
`
`3%
`
`33
`
`4
`
`4
`
`4
`
`EXAMELE 20:
`
`A lifioaaina submicron cream preparatian was
`
`mafia a3 fcllawsz
`
`1idacaina.4 g, MC? oil §.5 mg;
`
`lecithin
`
`Q.E g, EMU&FOR Efiwfififi 1.5 q, water ?g ml and CAREQFQL
`
`1.? g.
`
`.Aqain,
`
`tha.prmcedures were the same as in Exampies
`
`m and 1?.
`
`Thg mean fircylet size was found ta he 15G—nm.
`
`EXAMPLE 21:
`
`{C5mparative)
`
`A ccnventimnai,
`
`large draglet
`
`$i3e lidacaine craam was prepared as per Examgle 3 except
`
`with iidocaine Q g; MET ail 5.5 U, emulsifying wax 8 g,
`
`petraleum 14 q, watar 69 ml.
`
`The mean fireplat size was
`
`qreatar than $8 micruns.
`
`§§g§§;§Qg4;
`
`A small draglet siae eutectic local
`
`anasthatic was grepared as fellews.
`
`Egg g lidccaina,
`
`O39
`
`0239
`
`

`
`““’9G”‘3753
`
`~ 2:M—»
`
`Iwrrrusasrazaaa
`
`3.2 g tatracaine,
`
`2 g PLURGXIC F~5.,
`
`89 g water, aha
`
`«
`
`V
`
`carhmpal 415 g.
`Tha preparatian procedure was as per
`Examgie 1,
`the pH was adjusted tn 7.5 and the mean firoplat
`size was faund ta be 258 nancmeters.
`
`EXAMFLE 33:
`
`{Comparative}
`
`A conventional,
`
`large &rw§1et
`
`size eutacti: iacal anesthetic was gregared as fallaws.
`
`The same fmrmulatimn as in_Example 23 was praparefi—but
`withmut the pracedura ts refiuce tha druplet siaa.
`Tha
`
`in
`
`final firaplat size was fauna he be between 2B~10G gmi
`
`EXAMPLE 24:
`
`Tha iacal anesthetic effect mf ta§i:ally
`
`apglied liflocaine creams 05 Examples 2G~23 were
`invasziqated and comparafi.
`Each preparation was applied
`
`15
`
`tn the farearm of 4 male human valunteers ané the fiegree
`
`of lanai anesthesia with tima was mafiitored.
`
`A gentle
`
`tauch was made with a sharg needle anfi the sensitivity of
`
`an adjacent {untreated} araa was camparafi to the
`
`applicatian site to estimate the effectiveness of tha
`teatafl pre§aratinn.
`The experiment was blinfi fer the
`
`23
`
`volunteers. The sensitivity at the site af applicatian
`
`was given a scare af intensity cf 1 ta 4 and an average
`
`dasaqe form performance was calculatefi. The results ara
`
`shown in Table 3.
`
`E5
`
`HmmHHmmm_”Nm___MflN“~w**__N_#_mmmmmmmm_,__w__***mflflm
`
`Tabla 3:
`
`3verage scare {Effectiveness} of smal1‘vsfl
`Large Braylet size Lidncaing Craams
`
`ara§lats—
`
`V
`
`j
`
`Small
`
`Large
`
`Exam§le #
`Brag Cmnc., %
`
`3Q
`
`.
`
`Dxaplet sige, mm
`
`Delay, hears
`
`Duration,
`
`finurs
`
`35
`
`Effectiveness
`{Average Score§
`
`_
`
`lfi
`é
`
`@425
`
`84$
`
`@.S
`
`28
`
`20
`4
`
`10Ȥa
`
`1
`
`3
`
`1?
`
`.w................M
`
`‘
`
`0240
`
`0240
`
`

`
`fiK}$¥iKEE
`
`—— 22 ~ ‘
`
`IUS93.’{1’38fl{}
`
`These data show that lifiocaine alane in eleaginous
`
`basa er in regular cream sf emulsifying wax {i.a;, ane
`
`having a draplet size mi greatar than fin micrans}, was nut
`effective as local anesthetic. Hawaver,
`the small armpiet
`
`size graparatimn mi lidauaine pravided lanai anasthesia
`and gerfiarmed battar than larger dro§1et—siaa which was
`very gawr. Meremver,
`the small drnglet siza'Eutectic
`mixtura §&:fcrmed better than the same formulation but
`
`with iarga drogiat size, aa Shawn in Tabla 4‘
`
`10
`
`
`
`
`
`
`
`Table 4: Average s¢cre {Bffect£veness} of small vs.
`Earge Braplet size Eutaati: fiscal
`Anesthetic Mixture creams
`
`Draglats
`
`W
`
`13
`
`Example #
`
`Erug Cuna., %
`
`small
`
`21
`
`4.é
`
`Droplet size; gm
`
`8.295
`
`20
`
`Belay; hours
`
`Duratien, hears
`
`Effactiveness
`iaveraga score}
`
`0.3
`
`6
`
`S3
`
`Large
`
`TTTTTTTTTfl
`
`22
`
`4.4
`
`2G~1DB
`
`9.5
`
`&,5
`
`48
`
`Ex§MP£E 25:
`
`R fliclofenac suhmicrmn cream was prepared as
`
`fellows: Gil ghase ~ diclafenac diethylammanium 1292 g,
`MCT ail 1?0 g, LIPGEB E~8C 3% g, awtacepheral succinate
`
`25
`
`8.4 g; aqueaus ghase w ESTA diswflium salt 1 g, Efi§LFQR
`ELHSEQ
`25 g, glycerol ;?‘S g, prasarvatives {methyl and
`prapyl parahens} 0.5 gg reverse esmosis gurified water ta
`
`1053 g.
`
`3&1
`
`és
`
`The uqmpasitiun was §ra§ared as.ful1ows.
`?he
`amulgicn was pre§arefi by cambining the mil and aqueous
`phasas tagether'wit§ a magmatic stirrer fer § minutes,
`fol1Qwad.hy a highespeafi, nigh«shear mixar {Polytrun
`
`K3086} far 5 minutes at 3389 RPM. The emulsion which was
`
`vmbtainefi was traated by & high gresaura hamngenizer {APV~
`
`Gaulin} at 89$ bar {6 minutes, ahaut la cyclas} at
`
`0241
`
`0241
`
`

`
`&%1}931I87§2
`
`EN:T?1fiS93!8233Q
`
`4SwSE “C.
`
`After hamnqanizaticn;
`
`fihe emulsien was alluwefi
`
`ta can} ta ream temperaturey fiha particle size
`
`distributian was daterminaa ané the emulsion was then
`Q.4§ micron pore—size filter funimmdali
`
`filtereé thrcuqh a
`siEe after 8 cy:1es;80U bar is 139 3 39 mm, with tha fiust
`bafereifiltratimn being in the range cf a~¢%.
`
`To
`The cream fmrmulatinfi was prepared as fullows:
`1300 g af the emulsiun,
`in q mf
`;u% CARBGPQL gas, which
`was prewswallen in purifiied water, was adaefi aha mixeé
`thcruughiy with the Polytron K3GGS device at S*1fl,GQO RPM
`for 2»3 minutes. Pure triethanalamine was afided drnpwise
`with mixing ta adjust—the QE to &~5.§.
`A final mixing
`with the Pmlytrcn K3690 device at the same conditions
`prmduaes a cream which cmntains 1.15% Diclofenac EBA
`iwhish is equal to a 3% selutiun cf safiium diclafenac}.
`After pfl, visccsity and drug cmntent testing, the cream is
`
`packed intm aluminum tubes.
`
`EXAMPLE 2%:
`
`A tagical efiama treatmant by fiiclafenac in
`
`different aroplet siza fmrmulaticns was evaluated‘
`A farmulation cantaining suhmicram droplets of diclufenac
`{Example 25} was camgared to stanfiard pre§aratinn using
`the carragaenan paw edema moael {guinea pigs}.
`ml sf 3.1% solufiian} wag injected inta
`
`Carragaanan {G~l
`hinfi*gaw {at time=o)+ Start size sf edema at time Zara
`was taken as lGfi% laval. Surfaae of adfima was treated
`immediately after carraqeenan ihfiectian by test
`preparatimns:
`V
`a)
`1.1&% éiclafenau diethylammania {equivalent ta 1.0%
`Diclmfenac smdium)
`in suhmicran emulsien (§O—1§G mm
`draglets)
`{Example 25}.
`‘
`b}
`VQLTAREE EMULGE& {Ciba~Geigy} w as a reference
`cam§ssitisn with known aativity,
`cg 1.1s% diclafenac
`diethylammmnia in large flraglets {5*18 gm}.
`Changes in voluma were mafia using a ylathysmometar iflga,
`31
`Basel}, anfi the rasults are shown in Fig. &.
`
`15
`
`15
`
`3Q
`
`35
`
`33
`
`35
`
`0242
`
`

`
`V§T}§3I}S?52
`
`5
`
`& T
`{*3 ..r¥='-
`
`.r~*£:r;'us9.3Ie“2sm:
`
`§§§ELE 2?:
`
`A girmxicam small draplet cream was preparefi
`
`from the fallmwing cmmpanentsz
`
`yiroxicam 0.35 g, MCT ail
`
`§.S g,
`
`lecithin 8;5 q, Twaenwsfi 9.5 g} water 33.4 g,
`
`carbopol 0.3 g,
`
`triethylamine G.£*gi
`
`The compositien was
`
`greparad aa in Example 1. The mash firmplat sisa was fannfl
`to he 13? nm.
`
`EX&HPLE gs:
`
`{Comparative} A conventianai piroxicam ilarga
`
`drcplet} cream was yregareé as fnllnwa:
`
`piraxicam
`
`G.l?8 g, MC? mil 5 g, aetosteryl aicmhal 2.? g, scflium
`
`fiadecylsulfata 9.3 g, water 2? q. Aiter melting togather
`
`the catasteary; alcohol with sodium éedecylsulfate,
`
`the
`
`£CT oil was addedg Qiraxicam was mixed with ready hat ail
`
`ghase, and than 27 ml uf hailing water was adfied and mixad
`
`tnormughly. Aftar sealing to room temgeratura,
`
`the cream
`
`was ehtained,
`
`EXAMFLE 25:
`
`£ tagical efiema traatment by §irmxicam in
`
`fiifferent emulsicn farmulatians was studiad.. The
`
`submicrcn draglets of piraxicam ffixamgle 2?} was Campared
`
`ta stanflarfi cream (Example 28} using the carragaenan paw
`
`edema medal {guinea pigs} mi Example 26. As shown in Fig.
`
`3, giroxicam in the cream of Example 2? demcnstrates
`
`relatively law antiinflammatcry activity, while the
`
`formulaticn of Example 26 was found t$ be much mare
`affective.
`
`EXAM?LE 36:
`
`A tnpical naprcxen submicron firaam was
`
`greparad fram the fcllowing csmgonentsz
`
`napxaxen lg;
`
`Miglyol 318 l?g; LIPGID E«80 3g; a~tocm§hera1 Euccinate
`
`fi.G¢g; EHULFDR Egusza 2.5g; glycaral 1.?5g; Efifa diso&ium
`
`flihydrata 6.1g; CARBOPUL 348 U,5g;
`
`triethanw1amine‘D.§g;
`
`and pure water to lung.
`
`The naprexan, MIGEYGL 810, LIPQID
`
`E~8G anfi a~tucnpher0l succinata ware mixed tngathar at
`
`45°C until cempletely diss$:vsd ta farm an oil phase‘
`
`The
`
`EMULFOR, glycara; and EBT& were dissmlvad in water anfi
`
`mixed thurmughiy with the nil phase in a high shear mixer
`
`15
`
`20
`
`E5
`
`30
`
`35
`
`O43
`
`0243
`
`

`
`W'€193i18‘?'53.
`
`N 25 _m
`
`INTTfiES93£GZ8flfi
`
`{golytran K33flQ3 far 5 minutes at abaut 28,303 REM to farm
`an emulsian. Further treatmant ef the emulsian is
`ccnfiucted in a high pressure.hnmmgenizer (&FV ~ Saulin} at
`380 bar far 8 cycles in a drcplat sisa af ahaut 10U~15D
`am. After filtratian through a a.¢5 micrmh filtar,
`CARBGFOL in the form 0f 3 graswallen gel
`(18% in watar}
`was afided an&‘mixefi
`in thé Palytron device far 2 minutes
`at 5900 RPM.
`fine triathanolamina was afidefi ta a final pH
`at 5.5~e.5 and the fcrmulatian was mixed in the Palytrun
`device until a hommganemus cream was ahtained.
`
`
`EXMEPLE 31:
`
`A tnpiaal adama treatment by naprnxen in
`A submicrsn.draplet
`flifferent farmulatiens was studied.
`cream of napraxen {Example 36} was aompared to a standard
`cream using tha carrageanan paw edema moflel {guinea pig$)
`of Examyleg 26 anfi 29 far the follawinq farmulatinns:
`a) Napraxen in a suhmiaron emulsion {lGB~1§G nm aroplets
`as per Example 30) applied tnpically.
`h} Naprcxen in a canventional cream {dreplats larger than
`an micruns} agpliefi tapically.
`
`The results are illustrated in Fig. 3
`
`l3
`
`15
`
`28
`
`25
`
`30
`
`35
`
`0244
`
`

`
`“H}93H8?52
`
`—~ 25 ~*
`
`I’C;'I‘.2’US93fiL?.-8{10
`
`fl.§:::__.é...§;..c2_l_a.;«L::.1s—:<i_.;_% :
`
`SHE §&§;fi§
`
`1.
`
`A campnaitien far topical a§§li:atian af
`
`pnarmacauticals Gr casmatics cmmprising submicran size
`
`firaylats comyrising abmut 0.5 ta 33% uf a firat comganaut
`
`af an oily liquid, abaut‘0.1 to 33% of a secmnd cumpanant
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`cf an emulaifier and ahaut $.05 tn 5% cf a nmn~ionic
`
`surfactant, said draglets having a maan érogiet size in
`
`tha range sf 3.35 ts 5.3 gm, wherein said camgositicn
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`prmvides an enhanced tapical andfor transdermal systemic
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`effeat cmmpared tn the same compositimns which have larger
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`5izeLdrmpletsf
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`2.
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`The campositimn Of claim 1 wherain the.mean
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`druplat size is hatwaen about 0.1 and 0.3 um.
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`3.
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`The eampmsition of claim 1 wherein tha first
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`cumymnent cmmprises a mefiium chain triglyaarida oil having
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`a chain length cf abnut 8'ta 12 carhans, a vegetable mil,
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`a mineral nil, an ail sf animal saurce, a synthetic
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`fierivativa thereof, or mixtures thsremf.
`
`4‘
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`Tha campasiticn of claim 3 wharein the first
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`campanent is present in an ammunt of abaut 20 ta 33% to
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`form a viscaus cumgcsitian.
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`E.
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`[The eomgnsitian af claim 1 wherein the
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`emulsifier is a ghoaghalipid compauné er a mixtura of
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`1.13
`
`15
`
`23
`
`25
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`phuaghmlipids.
`
`é.
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`The cmmpmsitian cf claim 5 wherein the
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`phnsgholigid is lecithin, yhmsghatiaylchcline,
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`phosghatidylethanmlamine or mixtures thereof.
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`30'
`
`35
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`?.
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`$h& comgositimh cf claim 5 wherein the
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`emulsifiar is'prasent in an amaunt of ahnut 8&2 ta 5%.
`
`a.
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`?ha Cflmpmsition sf claim 1 wherein the
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`surfactant is a nan~ianic alkylana uxide candensata af an
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`organic comgound wniah $mntainE cue §r:mare hydrmxyl
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`graugs.
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`9.
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`The campasitisn cf claim 8 whexein the
`
`surfactant is an ethoxylatad alcmhsl at ester camgauné.
`
`0245
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`

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`W8 93! I 8352
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`PCTi‘f£ES9.3f{i28iI¥U
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`16.
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`The comyesiticn mf nlaim 9 wherain the non~innic
`
`ssurfac