PCI‘
`
`International Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`
`(11) International Publication Number:
`
`WO 92/08459
`
`A6lK 31/485, 47/00, 9/70
`
`(43) International Publication Date:
`
`29 May 1992 (2905.92)
`
`(21) International Application Number:
`
`PCT/SE91/00760
`
`(74) Agents: TANNERFELDT, Agneta et al.; Kabi Pharmacia
`AB, S-112 87 Stockholm (SE).
`
`(22) International Filing Date:
`
`11 November 1991 (11.11.91)
`
`(30) Priority data:
`9003665-8
`
`16 November 1990 (16.1 1.90) SE
`
`(for all designated States except US): KABI
`(71) Applicant
`PHARMACIA AB [SE/SE]; S-751 82 Uppsala (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only) : BUNDGAARD, Hans
`[DK/DK]; Tjtirnevej 36, DK-2970 Htirsholm (DK).
`CHRISTRUP, Lona [DK/DK]; Svend Géingesvej 36,
`DK-2700 Bronskig (DK). DRUSTRUP, Jtirn [DK/DK];
`Hvidkildevej 36 A, DK-2400 Kopenhamn (DK). FULL-
`ERTON, Ann [DK/DK]; Gronbakken 5, DK-2720 Van-
`lose (DK). NICKLASSON, Martin [SE/SE]; Bréinnin-
`gestrandsvéigen 72, S-151 39 Sodertéilje (SE).
`
`(81) Designated States: AT (European patent), AU, BE (Euro-
`pean patent), CA, CH (European patent), DE (Euro-
`pean patent), DK (European patent), ES (European pa-
`tent), FI, FR (European patent), GB (European patent),
`GR (European patent), IT (European patent), JP, LU
`(European patent), NL (European patent), NO, SE (Eu-
`ropean patent), US.
`
`'
`Published
`With international search report.
`
`TOPICAL COMPOSITIONS FOR TRANSDERMAL DELIVERY OF PRODUG DERIVATIVES OF MOR-
`PHINE
`
`iooo
`
`750
`
`§'
`
`
`
`
`
`Amountpenetrated(I19/cm?)
`
`(57) Abstract
`
`Time
`
`(h)
`
`The invention relates to topical composition for transdermal delivery of morphine. The composition comprises an effective
`amount of a morphine ester in association with a topical pharmaceutical carrier which gives solutions, suspensions, ointments, lo-
`tions, creams, gels, pastes, jellies, sprays and aerosols and/or together with a medical device. The invention also relates to the use
`of the morphine esters for the manufacture of a topical medicament for transdermal delivery for relieving pain or tranquilizing a
`mammal.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 1
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 1
`
`

`
`FOR THE PURPOSES OF INFORMATTON ONLY
`
`Codes used to identify States party to the PC!‘ on the front pages of pamphlets publishing international’
`applications under the PCI‘.
`_
`
`AT
`AU
`BB
`BE
`BF
`BC
`BJ
`BR
`CA
`CF
`CG
`CH
`Cl
`
`,
`
`'
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Canada
`Central African Republic
`Congo
`7
`Switzerland
`can d'Ivoire
`Cameroon
`Czechoslovakia
`Germany
`Denmark
`
`'
`
`'
`
`ES
`Fl
`I’-‘R
`GA
`GB
`GN
`' GR
`HU
`I1‘
`JP
`KP
`
`KR
`LI
`LK
`LU
`MC
`
`,
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Guinea
`Greece
`Hungary
`Italy
`Japan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Liechtenstein
`Sri lanka
`Luxembourg
`Monaco
`
`Madagascar
`Mali
`Mongolia
`Mauritania
`Malawi
`Netherlands
`Norway
`Poland
`Romania
`Sudan
`Sweden
`Senegal
`Soviet Union
`Chad
`Togo
`United States of America
`
`+ a Any designation of “SU” has effect in the Russian Federation. It is not yet known whether
`any such designation has effect in other States of the former Soviet Union.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page2
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 2
`
`

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`W0 92/08459
`
`T
`
`PCT/SE91 /00760
`
`Topical compositions for transdermal delivery of prodrug derivatives
`of morphine
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`The present invention relates to the use of prodrug derivatives of
`morphine in effecting transdermal delivery of morphine to the
`systemic circulation of a mammal.
`
`the term "prodrug" denotes a
`For purposes of this specification,
`derivative of morphine which, when administered topically to warm-
`blooded animals, e. g. humans,
`is converted into the proven drug,
`i. e.
`morphine.
`
`The prodrug forms of morphine of this invention are certain
`derivatives of morphine which possess a desirable high lipophilicity
`and biphasic solubility in comparison to the parent compound,
`morphine, and which are cleaved enzymatically to morphine.
`
`Description of
`
`the Prior Art
`
`is generally known and an accepted practice to administer
`It
`morphine to control chronic pain. Morphine plays a prominent role in
`the control of pain associated with chronic diseases, especially the
`chronic pain of cancer, and acute pain, especially the acute pain
`experienced post-operatively. However, such prior art uses of
`morphine are subject to serious problems.
`In addition to the obvious
`problems associated with potential abuse and addiction, the oral and
`parenteral administration of morphine for pain control
`frequently
`involve wide swings in the pharmacodynamics of the drug over each
`dosing interval. Furthermore, morphine has a short duration of action
`and is inefficiently and variably absorbed orally due to first-pass
`metabolism in the intestine and liver.
`During recent years much attention has been paid to the development
`of transdermal delivery systems as a means of mitigating many of
`the drawbacks associated with the parenteral or oral route of
`administration. (Sloan K B, Adv. Drug Delivery Rev. (1989), 67-101)
`A prerequisite for the development of a transdermal delivery system
`of morphine and other opioids is, however, that the drugs are capable
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 3
`
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 3
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`

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`WO 92/08459
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`2
`
`PCT/SE91/00760
`
`of penetrating the skin at a sufficiently high rate and are not
`metabolized during the percutaneous absorption. Morphine which
`remains the analgesic drug of choice for the treatment of severe
`pain, unfortunately exhibits, a very limited skin permeability which
`makes it unsuited for transdermal delivery. For instance,
`the steady-
`state flux of morphine through human skin in vitro has been reported
`to be only 6 ng/cm?/h when applied in the form ofra saturated
`solution (pH 7.4). (Roy, S.D., and Flynn, G.L.,Transdermal delivery of
`narcotic analgesicszgcomparatlve permeabilities of narcotic
`analgesics through human cadaver skin.Pharm. Res. 6 (1989) 825-
`832). These poor skin-penetration properties of morphine led to the
`conclusion that morphine is totally unsuited for transdermal delivery.
`The very poor ability of morphine to permeate into andthrough the
`skin can mainly be ascribed to its poor lipophilicity. Thus,
`the log P,
`P value for morphine is only -0.15 where P is the partition coefficient
`between octanol and aqueous buffer of pH 7.4 (Roy and Flynn 1989)
`It has now surprisingly been found that transdermal delivery of
`morphine can be achieved by the prodrug approach proposed in
`accordance with the present invention.
`F
`
`SUMMARY OF THE INVENTION
`
`topical compositions for
`The present invention provides novel
`transdermal delivery comprising an effective amount of a compound
`represented by the following general Formula I
`F
`
`(I)
`
`
`
`where R1 and R2 are the same or different and are hydrogen and a
`member selected from the group of physiologically hydrolyzable
`chemical groups consisting of alkylcarbonyl, alkenylcarbonyl
`arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl and
`heteroaryloxycarbonyl groups wherein the alkyl moiety consists of
`unsubstituted or substituted, straight-chain and branched-chain and
`cyclic alkyl groups having 1-20 carbon atoms, wherein the alkenyl
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 4
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 4
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`

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`W0 92/08459
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`PCT/S E91 /00760
`
`moiety consists of unsubstituted and substituted, straight-chain and
`branched-chain and cyclic alkenyl groups having 2-20 carbon atoms,
`wherein the aryl moiety consists of
`unsubstituted and substituted
`phenyl, and phenalkyl groups wherein the alkyl moiety contains 1-3
`carbon atoms and the phenyl moiety is unsubstituted or substituted,
`and the heteroaryl moiety is an aromatic 5- or 6-membered
`heterocyclic ring containing one or two heteroatoms selected from
`the group consisting of nitrogen, oxygen, and sulfur;
`and nontoxic pharmaceutically acceptable acid addition salts thereof,
`with the proviso that if R1 = hydrogen then R2 a: hydrogen, and if R2 =
`hydrogen then R1 :# hydrogen
`in association with a topical pharmaceutical carrier for solutions,
`suspensions, ointments, "lotions, creams, gels, pastes,
`jellies, sprays
`and aerosols and/or together with a medical device.
`The invention also provides a composition containing a non-toxic
`additive acting as a skin penetration enhancer.
`Another subject of the invention is topical dosage forms
`consisting of a matrix type or reservoir type patch system containing
`a compound as defined in Formula I or this compound in combination
`with a penetration enhancing delivery device/process such as
`iontophoresis. Reservoir type patch systems and lontophoresis are
`both well known systems for transdermal delivery.
`combined
`The composition according to the invention can also be
`with an additional drug delivery device such as patches, gauze or
`
`compresses.
`The invention further includes the use of the esters according to
`Formula I
`in the manufacure of a topical medicament for transdermal
`delivery with the intention of for relieving pain or tranquilizing a
`mammal and the use of these esters for transdermal delivery.
`Also claimed is a process for achieving transdermal delivery of
`morphine, which comprises applying to mammalian skin an effective
`amount of a composition according to Formula I.
`include
`Examples of suitable straight-chain alkyl groups in Formula I
`methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, dodecyl, palmityl
`and the like groups.
`
`Examples of suitable branched-chain alkyl groups include isopropyl,
`sec-butyl,
`t-butyl, 2- methylbutyl, 2-pentyl, 3-pentyl and the like
`
`groups.
`
`cyclic alkyl groups include cyclopropyl,
`Examples of suitable
`cyclobutyl, cyclopentyl and cyclohexyl groups.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 5
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 5
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`

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`W0 92/08459
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`PCT/SE91 /00760
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`Examples of suitable "alkenyl"groups include vinyl (ethenyl), 1-
`gpropenyl,
`i-butenyl, pentenyl, hexenyl, n-decenyl and c-pentenyl and
`the like.
`
`The groups may be substituted, generally with 1 or 2 substituents,
`wherein the substituents are independently selected from halo,
`hydroxy, alkoxy, amino, mono- and dialkylamino, nitro, carboxyl,
`alkoxycarbonyl, and cyano groups.
`
`By the expression "phenalkyl groups wherein the alkyl moiety
`contains 1-3 carbon atoms "
`is meant benzyl, phenethyl and 1
`phenylpropyl groups wherein the phenyl moiety may be substituted.
`When substituted,
`the phenyl moiety of the phenalkyl group may
`, contain, independently from 1
`to 3 alkyl, hydroxy, alkoxy, halo, amino,
`mono- and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano
`groups.
`
`Examples of suitable "heteroaryl" are pyridinyl,
`
`thienyl or imidazolyl.
`
`As noted herein, the expression "halo" is meant
`sense to include F, Cl, Br, and l.
`
`in the conventional
`
`The term "non-toxic pharmaceutically acceptable acid addition salts"
`as used herein generally includes the non-toxic addition salts of
`7
`compounds of Formula I, formed with non-toxic inorganic or organic
`acids. For example, the salts include those derived from inorganic
`acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, nitric,
`phosphoric and the like; and the salts with organic acids such as
`acetic, propionic, succinic,
`fumaric, maleic,
`tartaric, citric, glycolic,
`lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic,
`glutamic, salicylic, sulphanilic, methanesulphonic, and the like.
`
`The inventive method for relieving pain and for tranquilizing
`mammals comprises the application of the above compositions to
`mammalian skin and in particular, provides for inducing and
`maintaining analgesia by administering through an area of intact skin
`a morphine prodrug of the Formula I at an analgetically effective rate
`and continuing the administration of said material at said rate for an
`extended period of time at least sufficient to induce analgesia. Said
`compositions may contain any type of absorption enhancers, such as
`ifatty acids, fatty acid esters and fatty alcohols as well as any type
`of pharmaceutical additive commonly used for topical or dermal
`preparations and/or delivery systems such, as transdermal patches.
`
`lt
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 6
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 6
`
`

`
`W0 92/08459
`
`5
`
`PC!‘/SE91/00760
`
`is an object of the present invention to provide an improved method
`of treating and controlling acute and/or chronic pain.
`It
`is a further object of the present invention to enable pain to be
`controlled over a sustained period of time by administering
`transdermally a morphine prodrug of Formula I.
`According to the present
`invention,
`the permeability coefficients and
`fluxes of the compounds and compositions through mammalian skin
`tissue are established as being sufficient
`in magnitude to be
`practical
`for direct
`transdermal applications, producing time-
`sustained dosage rates consistent for pain suppression and
`tranquilizing effects over prolonged periods of
`time.
`The morphine prodrug derivatives of the present
`invention are certain
`derivatives which show a higher lipophilicity and biphase solubility
`than the active parent drug and hence are better able to penetrate the
`skin of a human or non-human animal and which are capable of
`reverting to the active morphine during or after transportation
`through the skin. These characteristics make the derivatives useful
`for transdermal delivery of morphine.
`
`Figures 1 and 2 show the permeability of some morphine esters
`through human skin. The amount of morphine appearing in the receptor
`phase is plotted as a function of time from suspensions or solutions
`of 3,6-dipropionyl morphine (A),
`(figure 1) and dihexanoyl morphine
`(B), (figure 2) in 0.05 M phosphate buffer of pH 7.0 (O) and isopropyl
`myristate(-).
`3,6-Dipropionyl morphine was applied in the form of suspensions in
`both buffer and IPM whereas 3,6-dihexanoyl morphine was applied in
`buffer and as a solution (200mg/ml) in IPM.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Among the compounds represented by the general Formula I, preferred
`compounds are such in which R1 and R2 are the same and is one of the
`following groups:
`acetyl
`.
`propionyl
`butyryl
`valeryl
`hexanoyl
`isobutyryl
`methoxyacetyl
`ethoxyacetyl
`benzoyl
`nicotinoyl
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 7
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 7
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`

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`W0 92/08459
`
`1
`
`z
`
`6
`
`PCT/SE9l/00760
`
`methoxycarbonyl
`ethoxycarbonyl
`propoxycarbonyl
`butoxycarbonyl
`hexyloxycarbonyl
`octyloxycarbonyl
`imidazolylcarbonyl
`
`Other preferred compounds are such in which R1 is hydrogen and R2 is
`one of the groups listed above, or R2 is hydrogen and R1 is one of
`these, groups.
`9
`7
`
`7
`
`The compounds of Formula I are esters (carboxylic acid or carbonate
`esters) of morphine formed either at C3 or C5, or at both hydroxyl
`groups. Several esters of morphine have long been known including
`the -3,6-diacetyl ester (heroin) and 3,6-dinicotinoyl ester
`(nicomorphine).
`Information on the preparation or pharmacological
`8
`activity of various esters of morphine can thus be found in the
`5
`following references: Beckett and Wright (1875), Hesse (1884), Merck
`(1899), Emde (1930), Mannich and Siewert (1939), Welsh (1954), Zirm
`and Pongratz (1959), Pongratzand Zirm (1957, 1964), Voldeng et al.
`(1968), Selmeci et al. (1968), Borowitz and Diakiw (1975), May and
`Jacobsen (1977), Andrew et al. (1984), Owen et al. (1984), Sy et al.
`(1986), Broekkamp et al. (1988) and Whitehouse et al. (1990). See
`reference list on page 12.
`However,
`these references or other information in the literature do
`not disclose orindicate any utility of esters or other derivatives of
`morphine as prodrug forms suitablefor transdermal delivery of
`morphine, nor any properties of the compounds that might indicate
`such utility.
`Asuwill be described below it has now surprisingly been found that
`compounds of Formula I
`-
`in contrast to morphine itself — are highly
`useful
`to achieve transdermal delivery of morphine at an
`analgetically effective rate and extent.
`
`7
`
`6
`
`Emparatign gf Qgmpgunds of Formula I
`
`4 The compounds of Formula I can be prepared by various methods as
`already described in the literature for a number of morphine esters
`(see the references cited above). Thus, we prepared 3,6-dipropionyl,
`3,6-diisobutyryl and 3,6-dihexanoyl morphine by reacting morphine
`with an excess of the corresponding acid anhydride, following the
`method described by Owen et al.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 8
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`

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`W0 92/08459
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`PCT/S E9 1 /00760
`
`and the
`6-Propionyl morphine was prepared as described by Sy et al.
`3-propionyl, 3-isobutyryl and 3-hexanoyl esters as described by
`Welsh.
`
`Detailed descriptions of the preparation of some morphine esters are
`given in Examples 1-5.
`
`F¢a.m.o_|e_1
`
`3,6-dipropionyi morphine (Formula l, R1 = R2 = C2H5CO)
`
`A mixture of morphine (2.0 g) and propionic anhydride (5.0 ml) was
`stirred at 90 °C for 4 h.-Upon cooling to room temperature water (40
`ml) was added. After 1 h the solution was partitioned between ether
`(50 ml) and 10 % potassium hydroxide solution (40 ml). The ether
`phase was separated, washed with water, dried over anhydrous
`sodium sulphate and evaporated in vacuo. The residue obtained was
`crystallized form ethanol-water to yield 2.7 g of the title compound,
`m.p. 106-107 °C.
`
`Example 2
`
`3-propionyl morphine (Formula I, R1 = C2H5CO,R2 =H)
`
`Propionic anhydride (13.1 ml, 100 mmol) was added while stirring to
`a mixture of sodium bicarbonate (20 g, 240 mmol) and morphine
`hydrochloride(3.75g, 10mmol)
`in water (200 ml). After complete
`addition the mixture was stirred for 90 min and extracted with
`
`chloroform (2 x 100 ml). The combined extracts were dried over
`anhydrous sodium sulphate and evaporated in vacuo to yield the title
`compound as a colorless oil
`in 95% yield. The compound crystallized
`from petroleum ether at -18°C, m.p. 85-86°C( Anal.
`: calc./w
`C2oH23NO4: C,70.36; H,6.79; N,4.10. Found: C,70.35; H,6.89, N,4.19.).
`The hydrochloric acid salt of the compound was prepared by adding a
`methanolic HCl solution to a solution of the base in ether, m.p. 157-
`158 °C (monohydrate).
`
`Exam.o.le_.3
`
`3,6-diisobutyryl morphine (Formula I, R1 = R2 = (CH3)2CH2CO)
`
`The compound was prepared essentially as described in Example 1,
`using isobutyric anhydride instead of propionic anhydride. The
`
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`W0 92/08459
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`PCT/SE91 /00760
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`compound was recrystallized from ether-petroleumeether, m.p. 96-97
`°C.
`0
`6
`
`x m l 4
`
`3,6—dlhexanoylTmorphine (Formula I, R1 = R2 = CH3(CH2)4CO)
`
`The compound was prepared essentially as described in Example 1,
`using hexanoic anhydride instead of propionic anhydride. The
`compound was a colorless oil.
`
`g
`
`3-hexanoyl morphine (Formula I, R1 = CH3(CH2)4CO, R2= H)
`
`The compound was prepared essentially as described in Example 2,
`using the equivalent amount of hexanoic anhydride instead of
`propionic anhydride. The compound was a colorless oil.
`
`0
`r.
`fMrhin
`hilii
`Li
`n
`ili
`l
`in water at
`The solubility of the compounds, given in Examples 1-5,
`pH 7 and in isopropyl myristate and their partition coefficients
`between octanol and pH 7.4 aqueous buffer (P) are shown in Table 1.
`The experimental methods used for these determinations are
`described below.
`1
`6
`
`Table 1 §olubilities and gagtition goefficignjgs
`
`(P) of morphine and
`
`v
`
`I
`
`r
`
`r
`
`r
`
`1 6°
`
`4
`
`Compound
`
`0
`
`log P 51
`
`Morphine.
`.3-Propionyl-morphine
`3,6-Dipropionyl-morphine
`3-Hexanoyl-morphine
`P 3,6-Diisobutyryl-morphine
`3,6-Dihexanoyl-morphine
`
`-0.06
`0.66
`1.66
`2.04
`2.60
`>4
`
`§olubility
`In Water
`
`4
`
`(mg/ml)
`ln IPM b
`
`.
`
`at
`
`pH 7.0
`
`1.8 P
`21
`3.6
`2.6
`0.6
`0.02
`
`0.023
`7 9
`4 1
`>150
`8 0
`
`>200
`
`a Between octanol and pH 7.4 aqueous buffer.
`b IMP:
`isopropyl myristate
`1
`
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`W0 92/08459
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`
`The solubilities of morphine and morphine esters were determined in
`triplicate in a phosphate buffer solution of pH 7.0 and in isopropyi
`myristate (IPM) at 21 °C by placing excess amounts of the compounds
`in 5 ml of the solvent. The mixtures were placed in an ultrasonic bath
`for 10 min and then rotated on a mechanical spindle for 24 h and
`filtered. After rotation for 1
`h the pH of the phosphate buffer
`mixtures was adjusted to 7.0. An aliquot of the filtrates was diluted
`with water or acetonitrile and analyzed by HPLC.
`
`The apparent partition coefficients (P) of morphine and the various
`esters were determined at 21°C in an octanol-0.02 M phosphate
`buffer (pH 7.4) system. The concentration of the compounds in the
`aqueous phase before and after partitioning was determined by HPLC
`analysis, and the partition coefficients determined.
`
`it can readily be seen that the
`From the data shown in Table 1
`morphine esters are more lipophilic than the parent drug in terms of
`octanol-aqueous buffer partition coefficients.
`It
`is also apparent
`that
`morphine esters showing both increased water and lipid solubility
`relative to morphine can be obtained. This higher biphasic solubility
`may be most favourable for skin penetration.
`
`kin
`
`rm
`
`i n
`
`i
`
`The feasibility of achieving transdermal delivery of morphine via the
`prodrugs of the present invention was evaluated by diffusion
`experiments in vitro using human skin samples.
`Whole abdominal human skin obtained under autopsy from two donors
`was used. The skin was stored at -18 °C and was allowed to thaw
`gradually at room temperature before use. All subcutaneous fat was
`removed and the skin cut into pieces. The excised skin was mounted
`in open Franz diffusion cells. They have an available diffusion area of
`0.70 cm?.
`The dermal side of the skin was exposed to the receptor medium (7.5
`ml of 0.05 M isotonic phosphate buffer of pH 7.2) which was stirred
`magnetically and kept at a constant temperature of 37 °C with a
`circulating water bath.
`The compounds studied were applied as solutions or suspensions (200
`microliter)
`in an aqueous buffer (pH 7.0) or in isopropyi myristate
`(lPM).
`The suspensions were stirred for 24 h prior to application to the skin
`surface. Samples of 2 ml were removed from the receptor phase and
`replaced with fresh buffer at appropriate intervals. The samples
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`PCT/SE91/00760
`
`were storedat -20 °C until analyzed for their morphine, di- and/or
`monoester content by HPLC as described below. The permeation
`studies of each compound were done in tri- or quadruplicate.
`P
`Reversed-phase HPLC procedures were used for the quantitative
`determination of morphine and its esters. A deactivated Supelcosil
`column was eluted with a mobile phase consisting of a mixture of
`acetonitrile (15-70 % v/v) and 0.01 M phosphate buffer solution of pH
`6.5. The concentration of acetonitrile was adjusted for each
`compoundito give a suitable compound retention time (3-10 min). The
`flow rate was 1.0 ml/min and the column effluent was monitored at
`215 or 280 nm.
`It was assured that in each case adequate separation
`of the ester from morphine and monoesters (in the case of the
`diesters) was achieved. Quantitation of the compounds was done from
`measurements of the peak heights in relation to those of standards
`chromatographed under the same conditions.
`in the case of morphine no measurable amounts of drug could be
`detected in the receptor phase during diffusion experiments lasting
`up to 200 h. The failure of morphine to penetrate human skin from the
`vehicles applied in significant amounts is in accordance with the
`g
`results obtained by Roy and Flynn (1989). These authors reported a
`steady—state flux of 0.006 ug /cm2/h for the permeation of morphine
`through human skin from a saturated solution of the drug in a pH 7.4
`buffer.
`the 3-hexanoyl, 3,6-dihexanoyl and other 3,6-dipropionyl
`in contrast,
`morphine esters readily penetrated human skin. The results obtained
`with some of these derivatives are shown in Fig.
`1
`in which the
`cumulative amounts (in mg morphine base) of morphine or ester
`measured in the receptor phase divided by the surface area of the
`diffusion cell are plotted against the time of ‘sampling. The steady-
`state fluxes were obtained from the slopes of the linear portions of
`these plots. The permeability coefficients (Km for the steady—state
`delivery were obtained by dividing the steady—state fluxes by the
`solubilities or concentrations of the compounds in the vehicle
`applied. The values obtained for various morphine esters, using
`morphine as a reference, are given in Table 2.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 12
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 12
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`

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`W0 92/08459
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`PCT/SE91 /00760
`
`1 1
`
`r
`f
`K
`i n
`ffi
`ili
`rm
`n
`Fl
`I
`phase gf delivery gf morphine thrgugh human skin frgm isoprogyl
`i
`I M
`n
`n
`ff
`r
`f H 7.
`
`-
`
`Compound
`
`Flux(ug/cm?/h)
`
`Kp(cm/h)
`
`IMP
`
`Buffer
`
`lPM
`
`Buffer
`
`Morphine
`3.6-Dipropionyl-morphinea
`3,6-Dihexanoyl-morphine
`3-Hexanoyl-morphine
`3-Proprionyl-morphine
`3-Acetyl-morphine
`3-lsobutyryl-morphine
`3-Valeryl-morphine
`3-Butoxy-morphine
`
`<o.o1
`<o.o1
`2.5 -1; 0.5
`8.7 i 0.4
`1.7 : 0.2
`11.7 : 1.2b
`35.6 i12.0° 25.3 i 4.2
`37.7 i 4.1
`11.4 i 1.8b
`27.0 i 3.3b
`16.5 : 2.7b
`8.3 :t 2.2b
`
`<4.3 x 10'4
`3.0 x 1O'4
`>1.6 x 10-4
`>2.4 x 10-4
`
`<5.5 x 10‘5
`1.0 x 10-3
`0.14
`1.3 x 10'?
`
`Approximately 50 % of the amounts penetrated were present in the
`a
`receptor phase as morphine and 50 % as the 6-monoester. The flux values
`given were calculated in terms of total morphine equivalents.
`b
`The IPM solution applied was not saturated.
`It contained the
`compound at a concentration of 200 mg/ml
`c
`The IPM solution applied was not saturated.
`compound at a concentration of 125 mg/ml
`For all cases except the 3,6-diproprionyl ester, only morphine was
`found in the receptor phase, whereas for the 3,6-dipropionyl ester
`approximately 50 % of the amounts penetrated were present in the
`receptor phase as morphine and 50 % as the corresponding 6-
`monoester.
`it
`is of great interest to note the appreciable skin
`enzyme-mediated hydrolysis of the esters during diffusion.
`
`It contained the
`
`An experiment with 3-Proprionyl-morphine dissolved in ethanol-
`water (3:1 vol/vol) at a concentration of 620 mg/ml revealed a flux
`of 1021-8.0ug/cm2/h.
`
`The results obtained from the human skin permeation experiments
`show that it
`is possible to a very high degree improve the skin
`a
`penetration of morphine via prodrugs. Thus,
`the 3-hexanoyl ester
`afforded a more than 2.000-fold higher flux relative to morphine
`itself when delivered from an aqueous buffer vehicle, and
`progressevly greater enhancement was achieved when isopropyl
`myristate was used as a vehicle. The increased solubility of the
`esters in the vehicles (Table 1) combined with expected concomitant
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 13
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 13
`
`

`
`WO 92/08459
`
`1 2
`
`PCT/SE91/00760
`
`for transdermal delivery is 25 cm? and if a flux of 25
`example,
`microgram/h/cm? is used(see Table 2),
`it would be possible to
`deliver 0.625 mg morphine/h or 15 mg over 24 h. This amount is
`higher than that usually administrated (10 mg) parenterally during 24
`hours.
`
`The actual administration or use of the transdermal analgesic
`compositions according to the present invention can be in any
`conventional form and may follow any of the methods generally
`known to the art. For instance,
`the active narcotic analgetic
`compound (i.e., a morphine prodrug of Formula l) can be used in
`association with any pharmaceutical dosage form such as,
`for
`example, but not
`limited thereto, any solution, ointment,
`lotion,
`paste,
`jelly, gel, cream, spray or aerosol generally known tothe art.
`As such,
`the narcotic analgetic prodrug form in association with the
`pharmaceutical dosage formican be used directly as a topical
`composition or used in combination with an additional drug delivery
`device, for example, but not
`limited thereto, patches, gauze,
`compresses, or the like, again, as generally known in the art. The
`dosage forms may contain any type of absorption enhancers such as
`fatty acids, fatty acid esters and fatty alcohols or any other non-
`toxic compounds which are known to increase skin .permeability.
`in
`particular,
`the transdermal analgesic compositions can be
`administered in the form of a patch wherein the active morphine
`Vprodrug agent is present in a polymeric matrix or in a reservoir
`system combined with a polymeric rate controlling membrane.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 3 Page 14
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 14
`
`

`
`8 W0 92/08459
`
`PCT/SE9l/00760
`
`13
`
`B_e.fs=.m_0.e:-L._l1s.I
`
`Andrew, R., Tasker, R. and Nakatsu, K.
`Evaluation of 3,6-dibutanoylmorphine as an analgesic in vivo:
`comparison with morphine and 3.6-diacetyl morphine.
`Life Sci. 34 (1984) 1659-1667
`
`Beckett, G.H. and Wright, C.R.A.,
`Action of the organic acids and their anhydrides on the natural
`alkaloids. Part
`ll.
`
`J. Chem. Soc. 28 (1875) 15-26
`
`|.J. and Diakiw, V.,
`Borowitz,
`The preparation and synthetic utility of 0-substituted
`normethylmorphines.
`J. Heterocycl. Chem., 12 (1975) 1123-1126.
`
`Broekkamp, C.L., Oosterloo, S.K. and Rijk, H.W.,
`Prodrug behaviour of nicotinoylmorphine esters.
`J. Pharm. Pharmacol. 40 (1988) 434-437.
`
`_E_mde,H.,
`Uber Diastereomerie VI. Konfiguration der Morphinalkaloide.
`Helv. Chim. Acta, 13 (1930) 1035-1058.
`
`Hesse, 0.,
`Studien iJber Morphin.
`Ann. Chem., 222 (1884),203-234.
`
`Mannich, C. and Siewert, G., Uber 6-Benzoyl-morphln.
`Arch. Pharm., 277 (1939) 128-130.
`
`May, E.L. and Jackson, A.E.,
`Chemistry and pharmacology of homologs of 6-acetyl and 3,6-
`diacetylmorphine.
`J. Pharm. Sci., 66 (1977) 285-286.
`
`Merck, E.,
`Ueber einige Morphinderivate.
`Arch. Pharm., 237 (1899) 211-222.
`
`Owen, J.A., Elliott, J., Jhamandas, K., and Nakatsu, K.,
`Morphine diesters,
`l. Synthesis and action on guinea pig ileum.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 15
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 15
`
`

`
`two 92/08459
`
`1 4
`
`PCT/SE91/00760
`
`Can. J. Physiol. Pharmacol., 62 (1984) 446-451.
`
`Pongratz, A. and Zirm, K.L.,
`Verfahren zur Darstellung des neuen 6-Morphin
`Mononicotinsaureesters.
`Osterr. Patentschrift Nr. 234,914 (1964).
`
`Pongratz, A. and Zirm, K.L.,
`Monatsh., 88 (1957) 330.
`
`VI
`
`Selmeci, G., Szlavik, L., Kaskoto, Z., Lepenyene, J.M. and Tothne, A.l.,
`Synthesis of new derivatives of morphine.
`ll. Production of
`benzoylmorphines with analgesic action and benzylmorphine
`possessing morphine-potentiating activity.
`Khim. Farm. Zh., 2 (7) (1968) 19-23
`
`Sy, W.-W., By, A.W., Neville, G.A. and Wilson, W.L.,
`Syntheses of 3-O- and 6-O-propanoylmorphine - a reinvestigation and
`correction.
`
`J. Pharm. Sci., 75 (1986) 787-789.
`
`Voldeng, A.N., Brandley, A., Kee, R.D., King, E.L. and (Melder, F.L.,
`Synthesis of adamantyl analoga of analgesics.
`J. Pharm. Sci., 57 (1968) 1053-1055.
`
`Welsh, L.H.,
`O3-Monoacetylmorphine.
`J. Org. Chem., 19 (1954) 1409-1415.
`
`Whitehouse, L.W., Paul, C.J., Gottschling, K.H., Lodge, B.A. and By, A.W.,
`Antinociceptive activity of propionyl esters of morphine: a
`reevaluation.
`1
`
`J. Pharm. Sci., 79 (1990) 349-350.
`
`Zirm, K.L.c and Pongratz, A.,
`Zur Wirkung des Pyridin-3-Carbonséiurebiesters des Morphines als
`Analgeticum.
`T
`Arzneim.-Forsch., 9 (1959) 511-513.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1020 — Page 16
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1020 - Page 16
`
`

`
`W0 92/08459
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`PCT/S E91 /00760
`
`15
`
`g\
`
`CLAIMS
`
`A topical composition for transdermal delivery of morphine
`1.
`comprising an effective amount of a compound of the formula:
`
`
`
`wherein R1 and R2 are the same or different and are hydrogen and a
`member selected from the group of physiologically hydrolyzable
`chemical groups consisting of alkylcarbonyl,alkenylcarbonyl
`arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl and
`heteroaryloxycarbonyl groups wherein the alkyl moiety consists of
`unsubstituted and substituted, straight-chain and branched-chain and
`cyclic alkyl groups having 1-20 carbon atoms, wherein the alkenyl
`moiety consists of unsubstituted and substituted, straight-chain and
`branched-chain and cyclic alkenyl groups having 2-2