WO 93/18752
`
`9
`
`PCT/ US93/02800
`
`components include lecithin? MO.HTANOL-68f EPICURON 120
`{Lucas Meyer, Germaay) which is a mixture of about 70% of
`phosphatiaylcholiite, 12% phosphatidylethaholajnine and
`about 15% othar phospholipids; OVOTHIH 160 (Lucas Meyer,
`S Germany) which is a mixtare comprising about 60%
`phosphatidylcholine, 18% phosphatidylethanolaaine and 12%
`other phospholipids; a purified phospholipid snijcture;
`LIPOID E-75 or LIPOID E~S0 (Lipoid, Germany) which is a
`phospholipid liixtttire comprising about 86%:
`10 phosphatidylcholine, 8% phosphatidylethanolamins, 3.S%
`ttoi3*-polar lipids and about 2% sphingomy el in. Purified egg
`yolk phospholipidsj soybean oil phosphoiipids or other
`purified phospholipid siKtures are ussful as this
`component. This listing is representative and not
`15 limiting, as other phospholipid materials which are known
`to those skilled in the art can be ttssd.
`The surfactant chosen should preferably be non-ionic
`to minimize irritation, and one skilled in the art can
`conduct tests to routinely select specific surfactants for
`20 this purpose. Generally^ the surfactant is a non-ionic
`alkylene oxide conisnsate of an organic compound which
`contains one or moti hydroxyI groups, for example,
`ethoxylated and/or propoxylated alcohol or ester compounds
`or mixtures thereof are commonly available and are well
`25 known to those •skilled in the art, Suitable surfactants
`include? bat are not limited to, T^LOXAPOL; P0L0XM1ER
`4070? mwxmm isa/ PGLYOXYL 40 Stearate? EMOLFOR EL~620,
`PGLfSORBATE 80, and POLYSORBATE 20, as well as various
`compounds sold under the trade name TWEES (IC1 American
`30 inc., Wilmington, Delaware, U.S.A,}, PLmmtC F-SS (trade
`name of BASF, Ludvigshafen, Germany for a copolymer of
`poiyoxyethy 1 erse and poiyoxypropylene}. At this time,
`PLUROSIC F-~68 and the POLOXAMSR 1S8 are preferred. The
`TYLOXAPOL and TWEEN surfactants are also preferred because
`JS they are PDA approved for human use.
`The aqueous component will be the continuous phase of
`the emulsion and may be water, saline or any other
`
`0228
`
` EXHIBIT 1004 (Part 2 of 5)
`
`

`
`WO 93/18752
`
`- 10 ~
`
`PCr/US93/0280fi
`
`suitable aqueoiis solation which .can yielsi an isotetiic and
`pH controlled preparation.
`In addition, the compositions of the invention may
`also comprise conventional additives such as preservatives
`$ and antioxidants. Topical preservatives include
`Thisierosai, chlorbutanol, and methyl, ethyl, propyl or
`butyl parabans - The preferred oil phase antioxidant is
`a-tocopherol or ^-tocopherol succinate. The aqueous phase
`my also include an antioxidant or a chelating agent of a
`10 polyamine carboxyliq acid such as ethylene diamine
`tetraacetic acid ("SDTA"), or a pharmaceutically
`acceptable salt thereof,
`The drug, cosmetic, or active ingredient, alone or
`with the oily excipients, are sjixed with a sufficient
`IS amount of surfactants and/or dispersing and suspending
`agents to allow dispersibility within the desired size
`range in aqueous medium. The surfactant(s) may be any
`pharmaceutically acceptable one{s5 that enable(s) adequate
`dispersibility and stability of IShe droplets In aqueous
`20 medium, in a form of stable sutoroicron si£e~range droplets.
`The drug, with or without oily excipients, is vigorously
`mixed with an aqueous solution that may contain
`surfactants, to result in submicron droplets of the drug
`and excipients. if needed, a high shear mixer and a high
`25 pressure hoRiogeniser are eaplaved to achieve the desired
`droplet size. Sonication is an alternative method to
`achieve the desired submicron droplet size,
`Highly efficient delivery of the submicron droplets
`to the skin Is obtained with a dosage form which is semi-*
`30 solid. To produce a semi-solid composition, many methods
`may be applied; addition of gelling agents, such as
`carbopols and adjusting to a pH, organic thickening agents
`such as polyvinyl pyrrolidone (PVPJ or a hydroxypropyl
`methyl cellulose (HPMC) poller, or cetostearyl alcohol
`35 and other waxes that may rigidify, solidify or increase
`the viscosity of the aqueous dispersion to the desired
`consistency level, inorganic thickening agents such as
`
`0229
`
`

`
`WO 93/18752
`
`« 11
`
`PCT/i!S93/(J28(H>
`
`18
`
`is
`
`20
`
`fased silica {AEROSIL or CMOSIL)alaaifta
`clay or other
`sijnilar eolloidal particles can be used to iacrfease
`viscosity of the formuiatidn. It is also possible to use
`oil concentrations on the higher end of the disclosed
`S range to achieve higher viscosity cosspositions. However.,
`use of greater than 30% oil causes difficulty in achieving
`the desired siroplet size.
`Che&sicaX skin penetration enliancers jnay £>&
`incorporated into the formulation to enhance penetration
`In this
`of the active ingredient through the skin.
`decyl methyl sulfoxide, N-dodecyl
`regard, DMSO
`pyrrolidone, dscanoi, dod&cancl, an orfanic acid such as
`oleic acid, or the like can be used, overall
`pharmaco1ogica1 effects achieved with the combination of
`chemical enhancers and sutanicrcn droplets are greater than
`for either coatponent used by itself.
`This invention provides submioron spheres (or
`droplets) that are an insoluble assembly of unique
`entities dispersed in an aqueous phase with the aid of
`appropriate surfactants or emulsifying agents. The
`emulsifying agent and surfactant form a protective layer
`around the droplets thus enabling efficient dispersion and
`suspension of the oily phase in water. This layer is a
`monolayer, polar by virtue of the surfactants. The
`present .droplets- are neither vesicles nor liposomes since
`no biiayers resembling the biiayer forroing the living cell
`wall is formed. Micelles may be formed and be present,
`but ®ay account for only a very small fraction of the
`surfactants and insoluble aatter of the formula and in
`nsgligibXe quantities, usually lass than about 1% of the
`total mass of insoluble matter and surfactants or
`dispersing agents.
`Experiments carried out and measurements by means of
`photon oorreiation spectroscopy (Coulter N4MD) and laser
`diffraction (Coulter LS13G) indicated that the droplet
`size in the compositions of the invention is in the size
`range of about 0«02 to about 0,5. microns. Preferably, the
`
`25
`
`30
`
`35
`
`0230
`
`

`
`WO 93/18752
`
`12
`
`PCT/US'B/OISOO
`
`size rang® is mainly in the 0.1 to 0-3 micron (i.e., 1Q0
`to 300 nia) range.
`Depending sn the inherent activity of the active
`incfrediftRt its quantity has to be a&jasted: £or each
`5 specific drug.
`Compositions according to the invention for topical
`application to obtain a topical or s^steBiio effect,
`contain, for example as active ingredient: steroids or
`non-steroidal anti~inflasmiatory drugs, antiisiotxcs,
`3.0 antifungals, antivirals, antihistaMnes, antineoplastics
`or local anesthetics. Specific examples would include
`s«festances such as clotrimazole, bifonazole, tetracyclirie
`miconazole, triamcinolone, amphotericin gentajjiicin,
`hydrocortisone, iodaxuridine, diphenhydramine, minoKMil,
`IS lidocaine, tetracaine and clindamycin.
`For systamic effects, the following categories of
`drugs are suitable: hypnotics, sedatives, aMxlolyfcics,
`antideprassanfes, anticonvulsants, anti-inflaMaatory arugs,
`anti-fungals, prostanoids, prostanoid agonists, prostanoid
`20 antagonists, analgesics, hormones and vitamins. Specific
`examples would include lipophilic peptides# barbiturates,
`benzodiazepines, phenothiazines, cyclosporin,
`diphenoxylate, physatigmine, tacrine, diclofenac,
`dexaiaethasone, prostaglandins, nifedipine, nitroglycerine,
`25 atropine, verapamil, fentanyl, lipophilic peptides,
`ketotif en, phenytoin, miconaKOle and Jcetoconaaole.
`For cosmetic effects, the active ingredient might be
`for example Vitamih A, Vitamin E, a polyunsaturated fatty
`acid such as ei.cosapentanoic acid, retinoids, carotenes
`30 aM ben 2oy 1 peroxide.
`Instead of a viscous composition, the droplets of the
`invention can be topically and transdermally applied by an
`article which includes the droplets, an active ingredient
`and a support for retaining the composition thereon. The
`35 support Would" include an adhesive for securing the article
`to the skin of a subject. A wide variety of active
`ingredients, including steroids such as estradiol,
`
`0231
`
`

`
`WO 93/18752
`
`- 13 -
`
`PCr/US93/9»
`
`nicotine or nitroglycerine, can be administered by this
`article, which would generally foe In the forja of an
`occlusive dressing or an adhesive patch-
`In the following description, concentrations will be
`5 indicated by % which denotes the concentration by weight
`of the component per 100 units volume of entire
`compositiGn* All indicated concentrations should be
`understood as standing each toy itself, and not cumulative.
`It should be appreciated by the artisan, however, that
`there is sojne dependency between the concentrations of the
`coroponeiyts, e.g., higher concentrations of the oil will
`
`10
`
`is
`
`20
`
`25
`
`36
`
`35
`
`and surfactant-
`The emulsion used in the compositions of the present
`invention^ may comprise about 0.5 to 30% oil, about 0.1 to
`10% eniulsifier and about 0,05 to 5% surfactants.
`Genera1ly, increasing the concentration of the non-aqueous
`phase, i.e., the combined concentration of the oily and
`the am&hiphilic phase, increases viscosity of the
`composition, In order to obtain a viscous composition,
`the concentration of the oil could be increased to about
`20 to 30%. M noted above, another way to increase the
`viscosity is to add a pharmaceuticalIy acceptable gelling
`or thickening agent, such as Carfoopol or the like. These
`viscous compositions are useful as creams or ointroents.
`preferred concentrations of the components are as
`follows; afeput ,5 to 201 oil; about 0.2 to s% of the
`esjulsifier, with about 0.2 to 1% being particularly
`preferred; and about 0.2 to 5% for the surfactant, with
`about 0.2 to 1% feeing particularly preferred. For a
`viscous coiaposition, about 0,2 to 15% of the gelling or
`thickening agent can be included.
`The drug or cosmetic agent (the active ingredient) is
`present in an amount of about 0,05 to 5% by weight of the
`composition, preferably about o.i to 2.5%, Depending upon
`Whether the active ingredient is hydrophilic or
`hydrophobic, it will be physicaily present in the oily
`
`0232
`
`

`
`^0:'93/t8752
`
`^ 14
`
`rwmm/mm
`
`phase or the aqueous component, Msb, the pH of these
`coiRpasitions should b& in a ra^ge which is suitable for
`the stability of the active ingredient, but slightly
`acidic or as close to netitxal as possible for
`5 cosipatibxliry with the skin.
`Uhe invention is illustrateci with reference to the
`above-raent ioned examples r which are to be construed in a
`strictly non~ 1 iirdtati.ve manner.
`
`y:-
`
`10
`
`The enhanced topical and transdermal effects of drugs
`adsiinistered in emlsions comprised of submicroxi size
`droplets in comparison to standard cream formulations and
`cojBHjercial preparations was estatolished in several test
`15 systems,
`Antiinflammatory agents were tested utiliging
`the carrageenan induced paw edema in guinea pigsx
`Tranquilizers were assessed in guinea pigs utilizing
`behavioral, tests indicative of sedation. Local
`anesthetiGs were tested in healthy human volunteers on the
`basis of loss of local sensation following application of
`various freparations:.
`The following sumiaarises the systeals used and results
`obtained with the formulations tested* The following
`cases are to be construed as examples in a strictly non-
`limitative fanner.
`
`ao
`
`25
`
`SXMPI.E it A diazepam submicron cream prssparation was
`macie -as fQllows: 0.S g of diazepaai are mixed with 9 q of
`jnediuju chain triglyceride {MCf.} oil and 1 g of lecithih
`until an homogeneous oily phase is achieved. The oily
`phase is then dispersed into 90 al of an aqueous phase
`•Which includes 2 g of PLURONIC F-6S and 0,1 g of a mixture
`of jnethy 1 and propyl parabens by initial mixing with a
`magnetic stirrer followed by a high shear mixer {Polytroh
`K30QQ} for 5 Hiinutes at ao^ooo mm to form an emulsion-
`Farther treatment of the emuisioh is conducted in a high
`pressure homogenisar {APV - C-aulin) at 800 bar for 6
`
`3.0'
`
`'3'S
`
`0233
`
`

`
`WO 93/18752
`
`IS
`
`PCr/US<B/028Oft
`
`minutes (about 10 cycles) at 45-55"C. Thereafter* the
`emulsion was cooled to room temjoeratiire and the aiean
`droplet size was measured size to be 120 nanometers having
`a very narrow distribution with practically no droplets
`S above one micron (lass than 0.5%) being detected.
`CARBOPOL is added to a final concentration of 0.3%,
`Finally, the pH is elevated with sodiu® hydroxide to ? and
`a seBi-solid submicron droplet preparation is achieved.
`
`10 EXAMPLE 2 i
`Example 1 was repeated using 6 g MCT oil and
`The mean droplet size was found to be 150
`3 g oleic acid-
`nanometers.
`
`3,5
`
`EXAMPLE 3: •{Comparative) A formulation was made in the
`same manner as Example 2 but without the procedure to
`reduce the droplet size. The £inal-.droplet size was
`between 5 and 50 microns.
`
`{Coisparative) A conventional diazepam crsaat
`was prepared as follows: diazepam 0,5 g, MCT oil 9 q,
`emulsifying wax 9 g, hot water 81 si, A classical
`technique was used whereby the wax was iselted, the oil and
`drug were added, and then the hot water was added with
`vigorous stirring» The mean droplet sise of the cream was
`between S and 50 microns.
`
`20
`
`25
`
`SXMIPLE 5 ;
`The systeitiic tranguili^ing effect of topically
`applied diazepam Greams of the first four examples ware
`investigated and compared to the systemic administratiGn
`SO of diaaapam, as follows.
`Materials and Methods
`Guinea pigs, wales, and females, having a body weight
`of about 250 g wero shaved 24 hours before appliaation of
`the creams. The following formulations were applied;
`35 (a) diazepam 0.5% - small drops (Example 1}; (b) diazepam
`0xS% - small drops with oleic acid (Example 2);
`
`0234
`
`

`
`WO 93/18752
`
`16 -
`
`PO7US93/O28O0
`
`10
`
`IB
`
`(c) diaaepas 0.5% - large drops with oleic acid (Ejeasple
`(d) diaaepa® 0.5% in a convantianal cream of larg-®
`3K?
`five graias of each preparation
`droplet size. {Example 4)..
`was applied on the shaved area, i.e., about 20 c% of each
`5 gmnss pig.
`CoEteiercially availafeie par©nt«raX preparations wers
`also used as controls, as follows.(e) diaaepam 5 ucf/ml
`{vials of 2 ml), 10 ag/fcg administered intra»tiscularly#
`a.nd (f) the same preparation administered subcutaneously
`(10 sg/Jcg).
`Clinical appearance, following application or
`The onset and
`injection, was checked and recorded,
`tsrs-iination times of the effects were recorded.
`Three basic behavioral tests, indicating level of
`sedationf were used
`Eighting reflejc: animals are positioned on their back
`(a)
`and. the time that is required to return to normal position
`Three levels of sedation are scored; low
`was recorded.
`(score 1) - animal returns iramedlately to normal position;
`moderate, (score 2) - up to 30 seconds are needed to return
`to normal position; severe-deep (score 3} ~ more than 30
`seconds are needed to regain normal position.
`Step test: animals are positioned on a S cm high
`m
`step, with the forelegs on the step,
`The time interval
`for changing- this position was measured for each animal.
`The sa»e course of time that was used for scoring of
`righting reflex was used here.
`Animals were positioned on their hind legs, their
`(c)
`The
`forelegs put on the top of their cage (20 cm high)-
`time interval for changing this position was measured for
`The same scoring methodology as above was
`each animal.
`used here.
`m
`k total aggregate score for each animal was
`calculated to show the state of sedation for this study.
`The results are shown in Table 1. It was found that
`topically applied diazepam is very effective when
`delivered in submicron droplets, A systsmic-like effect
`
`20
`
`25
`
`38
`
`35
`
`0235
`
`

`
`Bffica<sy of Differeat ©Epical aod Systemic
`DiazepaK Poraulstioas ia Guiaea Pigs,
`score Time of
`So, Sf
`Animals
`Activity
`froin)
`1S-120
`15-120
`45-240
`30-120
`
`j{|
`
`4
`
`39.0
`52.8
`47.5
`43.7
`
`WOMIS752
`
`- I? -
`
`PCT/USSB/0280ft
`
`my 'be achieved with tihis preparation.t but the same dos®
`in large droplet foxrmiiiation was not effective,. Also, the:
`inclusion of oleic acid in the formulation reduces the
`time for onset, of activity and duration.
`
`§
`
`table 4;
`
`T:E'®atmsnt:
`
`10 Siizepam, i,®,., 10 iftg/kg
`Siaseg'Sm,
`/ 10 mg/.kg
`Diazepam O-S'*, crea.'ts fS g)
`$ujs»tcror5 drops
`Diazepam O.S% cream (5 g)
`subrrii.cron drops with oleic
`acid
`Diazepam 0.5% crease (S g)
`large drops with oleic acid
`Classical diasepam Q.2%
`cream (S g)
`EXAMPLE 6: iEJcaaiisle 1 was repeated using TWSEN-S0 instead
`of PLURORIC :F-68. The sean droplet, size was I?G
`nanometers and an enhanced tranquili^ing effect
`substantially equivalent to that of Example l was
`deteGted.
`Example i was repeated using EMULFDR EL-620
`mmhz ?-
`The mean droplet size was: found
`instead of PLURONIp F-68.
`to be 100 nanometers and the activity was eomparafele to
`that of Example i>
`30 EXAMPLE 8: Example 1 was again repeated except that the
`formilation contained 20 g MCT oil. Tile mean droplet size
`was found to be 210 nanometers, but the activity was
`significantly increased in coiftparison to CGissparative
`Example 4 ansa was as good as that of Example 1*
`
`3.0
`
`5
`
`C'
`
`IS
`
`2 0
`
`25
`
`35
`
`0236
`
`

`
`WO 93/18752
`
`^ i s
`
`PCr/l.!S93/02806
`
`EX&MgliE 9: Example 1 was repeated except that 20 g HOT
`oil and I g diazepams ware used, tee mean droplet size was
`250 nanometers and the preparation exhibited increased
`activity compared to that of Comparative ExaiapM 4 which
`s was at least as good as that of Example 1.
`
`EXAMPLE 101 Exaapis 1 was agairt defeated but l g oleic
`acid was includad, Tfee ssean droplet size, was 100
`nanometers and this compositioti Was found to foe as active
`1© as that of Example 1.
`
`EXAMPLE in Example i was repeated using TWEEN-65 instead
`of leeithiiu The aean droplet size was found to toe 250
`nanometers and the fariisulatiors was much sore active (a
`IS scors of 35} than that of Example 4.
`
`EXAMPLE 12; Exaapie 1 was repeated using MOHTANOL-68
`instead of lecjithin. The mean droplet size was found to
`be 300 nanometers and the formulation was much more active
`(a score of 30} than that of Example 4.
`
`ExaMipie 1 was repeated using soybean oil
`EKAMPLE 13;
`The mean droplet size was found to foe
`instead of KCT oil.
`ISO nanometers and the formulatiors was as active as that
`of Example 1 (a score of 45),
`
`28
`
`as
`
`EmMPLB 14;
`Example l was repeated with the addition of
`a-tocopherol as an antioxidant. The ciean droplet size was
`found to be ISO nanometers and the forimilation was as
`30 active as that of Example i„ This formulation was also
`found to b& suitable for administeriftg oxidation sensitive
`drugs such as nifedipine-
`EXAMPLES 15-16: ExaiB.ple i was again repeated but 2 g of
`35 AERO SIX. silica and hydroxy-propyl cellulose, respectively,
`were included instead of CARBOPQL, and the pH was adjusted
`to 5,5. The aean droplet size for each example was found
`
`0237
`
`

`
`WO 93/18752
`
`T ; b ; w
`*7
`
`vmwmmm
`
`to he, ISO nanometers and the compositions were found to be
`as active as that of Exaasple 1.
`
`An indosnethacin subalcron cream preparation
`5 was stacJe a followsx Indoaethacin 0,5 g, MCT oil l?
`lecithin 0.8 g, EMULFOR EL-620 1,6 g, CARBOPOL 1.7 q and
`water ?S sii. The procedure of Example 1 was followed to
`obtain a mean droplet size of 130 nanometers.
`
`10 EXAMPLE ISi {Comparative} A conventional, large droplet
`size indo^ethacin crearo was prepared as follows:
`inaomsthacin 0,5 <?, MCT oil 15 gf emulsifying pax 9 q,
`water 75 mi. The composition was prepared as in Exajspie
`2< The jsean droplet size was found to be hetw&eri 5-50 }m*
`
`IB
`
`'EXRSGPLE.' 19: The topical anti-iriX iaisiaatory effect of
`topically "-applied indomethacin creass of Examples
`17-i8 were investigated and compared for their atvti-
`inflasuaatory effect versus systwic adaiinistratian^
`20 Animals and Materials
`(a) Guinea pigs (250 g),
`(b) Indosiethacin 0.5% in submicron orearo (Bxample 17) >
`(c) indoHiethacin 0.5% in conventional creasa CExample IS}.
`(d) Indoroethacin 0.5% in solution.
`2S Study Procedure
`(a; All animals received an injection of 0.1 ml
`carrageenan 0.1% into the hind paw, Measurements were
`taken froia the area of injection and followed for up to 5
`hours.
`38 (b) The above creams ware administered at carrageenan
`administration site and the solution of indomethacin was
`administered intramuscularly IS ainutes prior to
`carrageenan administration,
`(c) The circumference of the paw was again measured and
`35 the change in size was compared for the different
`treatments. The volume changes were measured Jby a
`plethysmo&eter (Ugc, Basel).
`
`0238
`
`

`
`wo 93/38752
`
`- 20 -
`
`PCT7US93/O28O0
`
`T&e results pressnteci in Table 2 deiBonstrata that a
`local application of indomsthacin in stibmicron droplet;
`cream was the most sffsctiye in reducing fche edama caused
`by the- carrageatian injectionf and was more effective than
`S lar^e droplets of indomsthacin craam or 'the sa©e dosa
`administered intramascularly.
`
`X&bie 2;
`
`p«rfdnB&i»c« of Olffersat xndottstttacia- FartaalatioHs
`la Paw SdexsiSt Model is Guiaea gigs
`Average change of circumference,
`aercaM.
`Hours after carrageenan
`inject: ion
`
`EKfeKPLE 20; A lidocaine submicron cream preparation was
`macife as follows: lidooaine 4 g, MCT oil 6.5 sag", lecithin
`0.8 g, ESRJLFOR .EL-620 1.5 g, water 73 ml and CARBOPOL
`1,7 g. Again, the procedures were the same as in- Examples
`1 and 17. The issaa droplet size was found to be 160 nm.
`
`EXMMPltE 21: ^Comparative) Ik convantionai, large droplet
`sise lidocaine craam was prepared as per Example 3 except
`with lidocaihe 4 g, HOT oil 5.3 g, emulsifying wax 8 g,
`petroleum 14 gf water' 6$ mi. The meah droplet size was
`greater than SO- microns.
`
`EXAMPLE 22; A small droplet siee eutectic local
`anesthetic was prepared as follows. 2,2 g lidocaine>
`
`treatment*
`control
`{Carrsgseiiari)
`irsdoffiethaciR 0.5%,
`IH cream staaii
`droplets
`Indomethacin in.
`cream, Large
`droplets
`rndomethacin 10
`sag/kg ivm. is
`solation
`
`So. of
`« X!.i.ataXs
`
`4
`
`4
`
`4
`
`i
`
`17
`0
`
`3
`si
`
`24
`
`32
`
`7,3
`
`4
`so
`32
`
`16
`
`55
`
`67
`
`47
`
`13
`
`22
`
`25
`
`36
`
`S
`S3
`
`36
`
`39
`
`33
`
`10
`
`IS
`
`20
`
`25
`
`30
`
`35
`
`0239
`
`

`
`WO 93/18752
`
`- m -
`
`PCT/US93/02808
`
`2.2 g tetracaine, 2 « PLURObilC F-63, 89 g water, and
`carbopol 4 ,3 g> The preparatiorv procedure was as per
`Example l> the pH was adjusted to 7.5 and the mean dcoplet
`size was found to be 250 nanometers.
`
`EXAMPLE 23: (Coraparative} & conventional, large droplet
`sise eutectic local anesthetic was prepared as foMows.
`The sains formulation as in Example 22 was prepared but
`without the procedure to reduce the droplet sise. The
`final droplet size was found to be between 20~10S fm.
`
`The local anesthetic effect of topically
`EXAMPLE 24-
`applied lidocaine creams of Examples 20-23 were
`Each preparation was applied
`investigated and compared.,
`to the forearm of 4 male human volunteers and the degree
`of local anesthesia with time was monitored, ^gentle
`touch was made with a sharp needle and the sensitivity of
`an adjacent (untreated) area was compared to the
`application site to estimate the effectiveness of: the
`tested preparation. The experi»ent was blind for the
`volunteers. Ihe sensitivity at the site of application
`was given a score of intensity of 1 to 4 and an average
`dosage form perSormanGe Was calculated. The results are
`shown in l&hie 3.
`
`fabl® 3!
`Droplets
`Ejiaiaple #
`Drug Cone,, %
`Droplet sizej, ym
`Delay, hours
`Duration, hours
`Effectiveness
`(average Score)
`
`Average score {Effectiveness) of Small vs»
`targe Diroplet Size Xiidocaine creams
`Large
`small
`19
`•4
`0y2:5
`0.5
`4.5
`23
`
`1 ' - ' - ' - ' - ' - w w w w w w * — : t ' '
`
`4
`KHS'O
`3.
`3
`17
`
`10
`
`ts
`
`20
`
`25
`
`30
`
`35
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`These data, show that lidocaine alone in oleaginous
`base or In regular cream of emlsifylftg wax f i.e*, on<8:
`having a droplet size of greater than 50 mictons), was not
`effective as local anesthetic. However, the saall droplet
`5 siise prsparation of lidocaine provided local, anesthesia
`and performed better than larger droplet sis:® which was
`very poor. Moreover^ tha small droplet size ©utectic
`mixture psrforiaed better than the same foriauiafcion but
`with large droplet size, as shown in Table 4<
`
`10
`
`fable At Average Score (Effectiveness} of Small vs.
`Large Br op let Sisse Eutectic Local
`^aesthetic Mixture Cresms
`Small
`21
`4,4
`0.295
`0,3
`^5
`5S
`
`Large
`22
`4.4
`20-100
`0.5
`4,5
`40
`
`Droplets
`xs Exastple #
`Drxig Cone., %
`Groplet sise, m
`Delay, hours
`Duration, hours
`Effectiveness
`(Average Score)
`
`20
`
`EXAMPLE 25: A diclofenac submcron cream was prepared as
`follows; Oil phase - diclofenao diethylajsiaoniuro 12.2 g,
`MCT oil 17 0 g, LIPOID E-80 30 g, a-tocopherol succinate
`G,4 g? Aqueous phase - EDT.% disodiUK salt 1 g, EMJLFOR
`EL-62d 25 g, glycerol 17.5 g, preservatives {rr.ethyl and
`propyl parabenslp.Sf, reverse osmosis purified vater to
`1000 g»
`The composition was prepared as follows. The
`emulsion was prepared by combining the oil and aqueous
`phases together with a magnetic stirrer for 5 minutes,
`followed by a high-speed, high-shear stiaKsr (Folytron
`K3000} for S rainutes at 3000 RPM, The emulsion .which was
`obtained was treated by a high pressure homogenizer (APV-
`Gaulin) a-t 800 bar {6'ittinut^s, about 10 cycles) at
`
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`45-55 0C. After homogeniaation, the eauision was allowed
`to cool to room temperature/ the particle size
`distribution was determined and the emulsion was then
`filtered through a 0,4S micron pore sxz& filter (Onimodal)
`S size after 8 cycles/800 bar is 120 + 30 njs, with the dust
`before filtration being in the range of 2-4%.
`The creaifi formulation was prepared as follows; To
`1000 g of the emulsion, 50 g of 10% CABBOPOL 940, which
`was pre-swollen in purified water, was added and mixed
`is thoroughly with the Polytron K3OG0 device at 5-10,000 RPM
`for 2-3 ainutes. Pure trieth.anolamine was added drqpwise
`witi'i mixirsg to adjust the
`to 6~6.5. .A final fixing
`with; the Polytron K3000 deviGe at the saae conditious
`produces a cream which contaihs 1.16% Diclofenac DEA
`IS (which is squal to a i% solution of sodium diclofenac).
`After pH, viscosity and drug content testing, the cream is
`packed iftto aluminum tubes...
`
`20
`
`25
`
`30
`
`35
`
`EXAMPLE 26: h. topical edema treatsient by diclofenac in
`different droplet size formulations was evaluated.
`A forauiation contaiining submicron droplets of diclofenac
`(Example 25} was compared to standard preparation using
`the carrageenan paw edensa model (guinea pigs}.
`Carrageenan (0~i ml of 0.1% solution) was injected into
`hind paw (at tirae-o). Start size of edema at time zero
`was taken as 100% level. Surface of edema was treated
`imisediately after carrageenan injection by test
`preparations:
`a) 1.16% diclofenac diethylaaamotvia (equivalent to 1.0%
`Diclofenac sodium} in sutamicron aniuision (90-150 nm
`droplets) (EKaisple 23} .
`b) YOLTAREN EMDLGEL (Ciba-Geigy) - as a reference
`composition with fcrtown activity, c) 1.16% diclofenac
`diethylammonia in large droplets (5-10 Mm}.
`Changes in volume were made using a p 1 ethysaometer (tJgo,
`Basel), and the results are shown in Pig. 1-
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`EXAMPLE a?: A plrojcicaja small droplet; crea® was prepared
`frio» the following companents: piroxicast 0.25
`MOT oil
`9.5 q, lacitfelB 0-5 g, Tw&en-80 0,5 g, water 38,4 gt
`carbopol 0,2 g, triethylamine 0,2 g. The composition was
`$ prepared as in Example 1, The meajr droplet size was fblind
`to be 127 nm.
`
`(Comparativs) A conventional pirojiicais (large
`ersam was prepared as follows; piroxicam
`10 0.178 g, MC3? oil 5 g, mtmt&ryI alcohol 2,7 q, sodium
`dodecyisalfafca 0.3 g, water 27 g„ After melting toget&er
`the cstostearyl alcohol with sodium dodecy1su1fate, the
`MCT oil was added- Firoxicaat was mixed with ready hot oil
`phase f and then 27 m.X of bailing water was added and mixed
`15 thoroughly. After cooling to room temperature, the creaitt
`was obtained.
`
`£:XAMPli£ 291 A topical edejna treatment by piroxicam in
`different eiaulsion forKUiations was studied. The
`20 submicron droplets of piroxicam (Example 27} was compared
`to standard creais (Example 28) using the carrageenan paw
`©dema modeX (guinea pigs) of Example 26. As shown in Fig.
`3, piroxicam in the cream of Exaiaple 27 demonstrates
`relatively low antiinflammatory activity, while the
`25 t:orm«lation of Example 26 was found to he much more
`effective.
`
`BXA&ffLB 30: A topical naproxen submicron cream was
`prepared froiu the following components; naproxen ig;
`30 Miglyoi 810 i7g; LIPOID E^SO 3gf a-tocopherol succinate
`0.04g; EMDltFOR BL~62Q 2.5g; glycerol l«75g; SPTA disodxujs
`dihydrats O.lg? CARBOPOL 940 O.Sg; triethanola»ine G.Sg;
`and pure water to lODg. The naproxen, SIGLYOL SlStj. LIPOID
`E-86 and a-tocopheroi succinate ware mixed together at
`3S 45®C until completely dissolved to form an oil phase. The
`EMCLFQ-R, giycerol and, BDTA were dissolved in water and
`mixed thoroughly with the oil phase in a high sheat Mixer
`
`0243
`
`

`
`wmmmi
`
`"* 25 —
`
`PCT/VS93/82S08
`
`{Poiytron K3000) for S minutes at about 20,000 HPS to form
`an emulsion. Further treatmsrvt of the eaulsioH is
`conducted in a high pressure horoogenizer (APV - Gaulin} at
`800 teat: for S cycles to a droplet sis© of about iOd-159
`•n»» After filtratioft through a 0.45 Kicroft filtey,
`CARB0P0L In the form of a preswollen gel (10% in water)
`was added arid mixed in the Polytron device for 2 ainutes
`at 5000 RPM. The triethanoiaroine was added to a final pH
`of 5.5-6.5 and the forffiuiatian was mixed in the Polytron
`device until a homogeneous cream was obtained.
`
`SMEM-ll: A topical edema treatzaent by naproxen in
`differeht fprjsulations was studied. A subxnioron droplet
`creaB of naproxen (Example 30} was comparsd to a standard
`cream using the carrageenan paw edema model (guinea pigs)
`of Exawplss 26 and 29 for the following formulationss
`a) Naproxen in a submicron ataulsion {100-150 rm droplets
`as per Example 30} applied topically,
`b) Naproxen in a conventional creasi (droplets larger than
`20 ffiicrons) applied topically.
`The results are illustrated in Fig. 3
`
`10
`
`15
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`20
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`
`THE CLAIMS
`
`'What: is claimed is:
`A composition.for topical application of
`X A
`gharmacenticaXs or cosmetics, coaprising submicron size
`S droplets comprising about 0.5 to 30% of a first component
`of an oily liquid, about 0.1 to 10% of a second coinporient
`of an emulsifisr and about 0.05 to S% of a non-ionic
`surfactsnt, said droplets having a m&an droplet size in
`the range of 0.05 to 0.5 am., wherein said composition
`10 provides aft ©nbanced topical and/or transderaal systemic
`effect compared to the same compositions which have larger
`sis®: droplets
`The cOKposition of claim 1 Ssrherein the mean
`droplet siae is between aboat 0.1 and 0,.3 M®.
`The coittposition of clai® 1 whereiii the first
`component comprises a mediuia chain triglyceride oil having
`a chain length of about S to 12 carbons, a vegetable oil,
`a aineral oil, an oil of animal source, a synthetic
`derivative thereof, or mixtures thereof,
`fhe composition of claim 3 wherein the first
`4.
`component is present in an amount of about 20 to 30% to
`farm a viscous composition.
`The composition of claim I wherein the
`5 >
`sjjittlsifier is a phospholipid compound or a mixture of
`phospholipids.
`6.
`The composition of claim 5 wherein the
`phospholipid is lecithin, phosphatidylcholine,
`pho sphat i dyi eth an o 1 am ine or misitures thereof .
`The composition of claim 5 wherein the
`eraulsifiar is present, in an amount of about 0,2 to 5%.
`8.
`The composition of clai® 1 wherein the
`surfactant is a non-ionic aXkylene oxide condensate of an
`organic compound which contains one or more hydroxy!
`-C^roups *
`The composition of claim 8 wherein the
`9-
`surfactant is an ethoxylated alcohoior ester compound.
`
`'2 k
`
`IS
`
`20
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`30
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`
`10x The composition of claim 3 wherein the non~ionic
`surfactanl; is present in an amount of about 0,2 to 5%,
`11. The composition of ciiaim i which further
`comprises an active ingredient in an asaotant of 0.5 to 5%.
`12. 'The composition of claim 1 wherein the first
`component cbiaprises an active ingredient in the form of an
`essentially water-inso