(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`13 April 2006 (13.04.2006)
`
`PCT
`
`(10) International Publication Number
`WO 2006/037342 A2
`
`(51) International Patent Classification:
`
`Not classified
`
`(21) International Application Number:
`PCT ID K2005/000648
`
`MULLER, Bernd, W. [DE/DE]; Schlotfeldtsberg 14a,
`(DE). ROBINSON, Joseph, R.
`D-24220 Flintbek
`[US/US]; 41 Chequamegon Bay, Madison, WI 53719
`(US).
`
`(22) International Filing Date: 7 October 2005 (07.10.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`PA 2004 01546
`PA 2004 01736
`PA 2005 00211
`PA 2005 00419
`60/691,513
`
`8 October 2004 (08.10.2004) DK
`10 November 2004 (10.11.2004) DK
`11 February 2005 (11.02.2005) DK
`23 March 2005 (23.03.2005) DK
`16 June 2005 (16.06.2005) us
`
`(71) Applicant
`(for all designated States except US):
`ADITECH PHARMA AB [SE/SE]; Medeon - Malmo
`Science Park, P.A. Hanssonsvag 41, S-205 12 Malmo (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): NILSSON, Henrik
`[SE/DK]; Cort Adelersgade 4, st.th., DK-1053 Copen(cid:173)
`hagen (DK). SCHONHARTING, Florian [DK/SE];
`Sundspromenaden 27, 3, s., S-211 16 Malmo (SE).
`
`INSPICOS A/S; Boge Alie 5, P.O. Box 45,
`(74) Agent:
`DK-2970 Hprsholm (DK).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY,
`MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO,
`NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK,
`SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`[Continued on next page}
`
`iiiiiiii
`
`!!!!!!!! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`(54) Title: CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING A FUMARIC ACID ESTER
`
`-iiiiiiii
`!!!!!!!! --
`== -
`== -
`!!!!!!!! -
`
`iiiiiiii
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`100
`
`90
`
`80
`
`70
`
`"' "-
`'C " "' ., 60
`" ~
`u.
`::;;
`c
`1:
`" 0
`E 30
`<(
`
`50
`
`40
`
`20
`
`10
`
`0
`
`____.
`~
`
`/
`
`/
`
`/
`
`/
`
`I
`I
`I
`
`/
`
`M
`~
`~ r-....
`~
`Q
`..........
`\0
`Q
`0
`(57) Abstract: The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as
`M active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory
`0 or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations
`> of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction
`
`0
`
`100
`
`200
`
`300
`Time (min)
`
`400
`
`500
`
`60
`
`~ in gastro-intestinal related side-effects.
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 1
`
`

`

`W 0 2006/03 7 34 2 A2
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll lllll lllll llll lllllll 111111111111
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 2
`
`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING A FUMARIC ACID
`
`ESTER
`
`Field of the invention
`
`The present invention relates to controlled release pharmaceutical compositions comprising a
`
`5
`
`fumaric acid ester as an active substance. The compositions are suitable for use in the
`
`treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders
`
`and are designed to release the fumaric acid ester in a controlled manner so that local high
`
`concentrations of the active substance within the gastrointestinal tract upon oral
`
`administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related
`side-effects.
`
`10
`
`Background of the invention
`
`Fumaric acid esters, i.e. dimethylfumarate in combination with ethylhydrogenfumarat have
`
`been used in the treatment of psoriasis for many years. The combination is marketed under
`
`the tradename Fumaderm®. It is in the form of tablets intended for oral use and it is
`
`15
`
`available in two different dosage strengths (Fumaderm® initial and Fumaderm®):
`
`Fumaderm® Initial
`
`Fumaderm®
`
`Dimethylfumarate
`
`30 mg
`
`120 mg
`
`Ethylhydrogenfumarate,
`
`calcium salt
`
`67 mg
`
`87 mg
`
`20
`
`Ethylhydrogenfumarate,
`
`Magnesium salt
`
`5 mg
`
`5 mg
`
`Etylhydrogenfumarate,
`
`Zinc salt
`
`3 mg
`
`3 mg
`
`25
`
`The two strengths are intended to be applied in an individually based dose regimen starting
`
`with Fumaderm® initial in an escalating dose, and then after e.g. three weeks of treatment
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 3
`
`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`2
`
`switching to Fumaderm®. Both Fumaderm® initial and Furn aderm® are enteric coated
`tablets.
`
`Another marketed composition is Fumaraat 120® containing 120 mg of dimethylfumarate
`
`and 95 mg of calcium monoethylfumarate (TioFarma, Oud-Beijerland, Netherlands). In a
`
`5
`
`recent publication (Litjens et al. Br. J. Clin. Pharmacol. 2004, vol. 58:4, pp. 429-432), the
`
`pharmacokinetic profile of Fumaraat 120® is described in healthy subjects. The results show
`
`that a single oral dose of Fumaraat 120® is followed by a rise in serum monomethylfumarate
`
`concentration and only negligible concentrations of dimethyl fumarate and fumaric acid is
`
`observed. The results indicate that dimethylfumarate is rapidly hydrolyzed to
`
`10 monomethylfumarate in an alkaline environment, but according to the authors not in an acid
`
`environment. As the composition is enteric coated, it is contemplated that the uptake of
`
`fumarate takes place mainly in the small intestine, where di methylfumarate before uptake is
`
`hydrolysed to the monoester due to an alkaline environment, or it may rapidly be converted
`
`due to esterases in the circulation. Furthermore, the study shows that tmax and Cmax are
`
`15
`
`subject to food effect, i.e. tmax is prolonged (mean for fasted conditions is 182 min, whereas
`
`for fed conditions mean is 361 min) [lag time is 90 min for rasted and 300 min for fed] and
`
`Cmax is decreased (fasted: 0.84 mg/I, fed: 0.48 mg/I) by concomitant food-intake. Another
`
`study (Reddingius W.G. Bioanalysis and Pharmacokinetics of Fumarates in Humans.
`Dissertation ETH Zurich No. 12199 (1997)) in healthy subjects with two tablets of
`
`20
`
`Fumaderm® P forte revealed Cmax values (determined as m onoethyl- or
`
`monomethylfumarate) in a range from 1.0 to 2.4 µg/ml and a tmax in a range of from 4.8 to
`
`6.0 hours.
`
`US 6,277,882 and US 6,355,676 disclose respectively the use of alkyl hydrogen fumarates
`
`and the use of certain fumaric acid mono alkyl ester salts for preparing micro tablets for
`
`25
`
`treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn. US
`
`6,509,376 discloses the use of certain dialkyl fumarates for the preparation of pharmaceutical
`
`preparations for use in transplantation medicine or the therapy of autoimmune diseases in
`
`the form of micro tablets or pellets. US 4,959,389 disclose compositions containing different
`
`salts of fumaric acid monoalkyl ester alone or in combination with dialkyl fumarate. GB
`
`30
`
`1,153,927 relates to medical compositions comprising dimethylmaleic anhydride and/or
`
`dimethylmaleic acid and/or a dimethylfumaric acid compounds. The Case report "Treatment
`
`of disseminated granuloma annulare with fumaric acid esters" from BMC Dermatology, vol. 2,
`
`no.5, 2002, relates to treatment with fumaric acid esters.
`
`However, therapy with fumarates like e.g. Fumaderm® frequently gives rise to gastro-
`
`35
`
`intestinal side effects such as e.g. fullness, diarrhea, upper abdominal cramps, flatulence and
`
`nausea.
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 4
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`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`3
`
`Accordingly, there is a need to develop compositions comprising one or more therapeutically
`
`or prophylactically active fumaric acid esters that provide an improved treatment with a
`
`reduction in gastro-intestinal related side effects upon oral administration.
`
`Furthermore, the present commercially available products contain a combination of two
`
`5
`
`different esters of which one of the esters (namely the ethylhydrogenfumarate which is the
`
`monoethylester of fumaric acid) is present in three different salt forms (i.e. the calcium,
`
`magnesium and zinc salt). Although each individual form may have its own therapeutic
`
`profile it would be advantageous to have a much simpler product, if possible, in order to
`
`obtain a suitable therapeutic effect.
`
`10
`
`The present inventors contemplate that an improved treatment regimen may be obtained by
`
`administration of a pharmaceutical composition that is designed to deliver the active
`
`substance in a controlled manner, i.e. in a manner that is prolonged, slow and/or delayed
`
`compared with the commercially available product. Furthermore, it is contemplated that
`
`instead of using a combination of different fumaric acid esters, a suitable therapeutic
`
`15
`
`response may be achieved by use of a single fumaric acid ester alone such as
`
`dimethylfumaric acid.
`
`Short description of the figures
`
`Fig. 1 shows an example of an in vitro dissolution profile of a capsule prepared as described
`
`in example 5.
`
`20
`
`Fig. 2 shows an example of an in vitro dissolution profile of a sample of a tablet (before the
`
`enteric coating is applied) prepared as described in example 16.
`
`Fig. 3 shows an example of an in vitro dissolution profile of a sample of a tablet (before the
`
`enteric coating is applied) prepared as described in example 17.
`
`Disclosure of the invention
`
`25
`
`Accordingly, the present invention relates to a pharmaceutical composition comprising as an
`active substance one or more fumaric acid esters selected from di-(C1-C5)alkylesters of
`fumaric acid and mono-(Ci-C5)alkylesters of fumaric acid, or a pharmaceutically acceptable
`salt thereof, which - upon oral administration and in comparison to that obtained after oral
`
`administration of Fumaderm® tablets in an equivalent dosage - gives a reduction in GI
`
`30
`
`(gastro-intestinal) related side-effects.
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 5
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`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`4
`
`As mentioned above, the present inventors contemplate that a suitable way of reducing the
`
`gastro-intestinal related side-effects is by administration of the active substance in the form
`
`of a controlled release composition.
`
`Accordingly, the present invention relates in a further aspect to a controlled release
`
`5
`
`pharmaceutical composition for oral use comprising as an active substance one or more
`fumaric acid esters selected from di-(C1-C5)alkylesters of fumaric acid and mono-(Ci(cid:173)
`C5)alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, wherein the
`
`release of the fumaric acid ester - when subjected to an in vitro dissolution test employing
`
`0.1 N hydrochloric acid as dissolution medium during the first 2 hours of the test and then
`
`10
`
`0.05 M phosphate buffer pH 6.5 as dissolution medium - is as follows:
`
`within the first 3 hours after start of the test at the most about 70% w/w of the total amount
`
`of the fumaric acid ester contained in the composition is released, and/or
`
`within the first 4 hours after start of the test at the most about 92% w/w of the total amount
`of the fumaric acid ester is released, and/or
`
`15
`
`within the first 5 hours after start of the test at the most about 94% w/w of the total amount
`of the fumaric acid ester is released, and/or
`
`within the first 6 hours after start of the test at the most about 95% w/w of the total amount
`of the fumaric acid ester contained in the composition is released, and/or
`
`within the first 7 hours after start of the test at the most about 98% w/w of the total amount
`of the fumaric acid ester contained in the composition is released, and/or
`
`20
`
`within the first 9 hours after start of the test at the most about 99% w/w of the total amount
`of the fumaric acid ester contained in the composition is released and/or
`
`within the first 12 hours after start of the test at the most about 99% w/w of the total
`amount of the fumaric acid ester contained in the composition is released.
`
`25
`
`In the present context, a controlled release composition is a composition that is designed to
`
`release the fumaric acid ester in a prolonged, slow and/or delayed manner compared to the
`
`release of the commercially available product Fumaderm®, when tested under comparable
`conditions (e.g. for in vivo studies: dose equivalents, with or without standardized meal etc.,
`or for in vitro studies: dose equivalents, dissolution test apparatus and working conditions
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 6
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`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`5
`
`including e.g. composition, volume and temperature of dissolution medium employed,
`rotation speed etc.).
`
`The release in vivo may be tested by measuring the plasma concentration at predetermined
`time periods and thereby obtaining a plasma concentration versus time profile for the fumaric
`
`5
`
`acid ester in question or, if relevant, a metabolite thereof. (E.g. in the case of
`
`dimethylfumarate, the active substance is envisaged to be methylhydrogenfumarate, i.e. the
`
`monomethyl ester of fumaric acid). Furthermore, it is contemplated that metabolism already
`
`takes place within the gastro-intestinal tract or during passage of the gastro-intestinal
`
`mucosa, or upon first passage through the hepatic circulation. Accordingly, when
`
`10
`
`dimethylfumarate is administered, the relevant component to search for in the plasma may
`
`be the monomethyl ester and not the dimethylester of fumaric acid.
`
`Other tests may also be used to determine or to give a measure of the release of the active
`substance in vivo. Thus, animals (e.g. mice, rats, dogs etc.) may be used as a model. The
`animals receive the compositions under investigation and after specified periods of time, the
`
`15
`
`animals are sacrificed and the content of the active ingredient (or metabolite thereof, if
`
`relevant) is determined in plasma or specific organs or extracted from the intestinal contents.
`
`Another test involves the use of a specific segment of an animal intestine. The segment is
`
`placed in a suitable dissolution apparatus containing two compartments (a donor and a
`
`receiver) separated by the segment, and the composition under investigation is placed in a
`
`20
`
`suitable medium in one compartment (the donor compartment). The composition will release
`
`the active substance that subsequently is transported across the intestinal segment.
`
`Accordingly, at suitable time intervals, the concentration of the active substance (or, if
`
`relevant, the metabolite) is measured in the receiver compartment.
`
`A person skilled in the art will be able to adapt the above-mentioned method to the specific
`
`25
`
`composition.
`
`With respect to iri vitro methods, well-established methods are available, especially methods
`described by official monographs like e.g. United States Pharmacopeia (USP) or the European
`
`Pharmacopoeia. A person skilled in the art will know which method to choose and how to
`select the specific conditions to carry out the in vitro test. For instance, the USP prescribes in
`vitro tests be carried out at 37 +/- 1.0 such as 37 +/-0.5 degrees Celsius/Centigrade. A
`suitable dissolution test is, for example as described in example 29, for capsules, wherein the
`
`30
`
`dissolution profile is determined as described in the United States Pharmacopoeia at 37°C
`
`using a rotating basket at 100 rpm employing 0.1 N hydrochloric acid as dissolution medium
`
`during the first 2 hours of the test and then followed by 0.05 M phosphate buffer pH 6.5 as
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 7
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`

`

`WO 2006/037342
`
`PCT/DK2005/000648
`
`6
`
`dissolution medium for the remaining test period, and, for example as described in example
`30, for tablets wherein the dissolution profile is determined as described in the United States
`
`Pharmacopoeia at 37°C using a paddle dissolution apparatus at 100 rpm employing 0.1 N
`hydrochloric acid as dissolution medium during the first 2 hours of the test and then followed
`
`5
`
`by 0.05 M phosphate buffer pH 6.5 as dissolution medium for the remaining test period.
`
`As mentioned above, the in vivo release of the active substance is prolonged, slow and/or
`
`delayed compared with the commercially available Fumaderm® composition. In the present
`
`context, the term "prolonged" is intended to indicate that the active substance is released
`
`during a longer time period than Fumaderm® such as at least during a time period that is at
`
`10
`
`least 1.2 times, such as, e.g., at least 1.5 times, at least 2 times, at least 3 times, at least 4
`
`times or at least 5 times greater than that of Fumaderm®. Thus, if e.g. 100% of
`
`dimethylfumarate is released from Fumaderm® tablets 3 hours after the start of a suitable
`
`test, then 100% of dimethylfumarate in a composition according to the invention is released
`
`at least 3.6 hours after the start of a suitable test.
`
`15
`
`In the present context the term "delayed" is intended to indicate that the release of the
`
`active substance starts at a later point in time compared with that of Fumaderm® (such as at
`
`30 min or more later such as, e.g., 45 min or more later, 1 hour or more later or 1.5 hours or
`
`more later, alternatively, that the initial release during the first 2 hours is much less
`
`compared with that of Fumaderm® (i.e. less than 80% w/w such as, e.g., less than 70%
`
`20
`
`w/w, less than 60% w/w or less than 50% of that of Fumaderm®).
`
`As used in the present invention, a gastrointestinal {GI) side effect may include, but is not
`
`limited to diarrhea, stomach ache, stomach pain, abdominal pain, abdominal cramps, nausea,
`
`flatulence, tenesmus, meteorism, an increased frequency of stools, a feeling of fullness and
`
`upper abdominal cramps.
`
`25
`
`In the present context, a reduction of GI related side effects is intended to denote a decrease
`
`in severity and/or incidence among a given treated patient population, compared to the GI
`
`side effects observed after administration of the composition according to the invention
`
`compared with that of Fumaderm®. A reduction in GI related side effects according to this
`
`definition could thus be construed as a substantial reduction in incidence of any of the GI side
`
`30
`
`effect listed above, such as at least a 10% reduction in incidence or more preferably at least
`
`20 % reduction in incidence or even more preferable a more than 30 % reduction in
`
`incidence. A reduction in GI related side effect can also be expressed as a substantial
`
`reduction in severity in any of the GI side effects listed above, such as a reduction in severity
`
`and/or frequency of diarrhea, stomach ache, stomach pain, abdominal pain, abdominal
`
`35
`
`cramps, nausea, flatulence, tenesmus, meteorism, increased frequency of stools, a feeling of
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 8
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`

`

`WO 2006/037342
`
`PCT /DK2005/000648
`
`7
`
`fullness or upper abdominal cramps. The reduction of GI related side effects, as described
`above, can be monitored in a clinical trial setting, either comparing the administration of the
`
`composition according to the invention head on with Fumaderm® or with placebo. In case of
`
`a placebo controlled trial, the incidence of GI related side effects in the patients receiving the
`
`5
`
`composition according to the invention compared to the placebo group, can be compared to
`historical trials comparing Fumaderm® to placebo (see e.g. Altmeyer et al, J. Am. Acad.
`Dermatol. 1994; full reference: Altmeyer PJ et al, Antipsoriatic effect of fumaric acid
`derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad.
`
`Dermatol. 1994; 30:977-81). Typically, patients suffering from psoriasis are included in such
`
`10
`
`a study, and typically more than 10% of the body surface area will be affected by psoriasis
`
`(severe psoriasis). However, patients in whom between 2 and 10 percent of the body surface
`
`area is affected can also be included (moderate psoriasis). Patients can also be selected
`
`based on the psoriasis area severity index {PASI). Typically, patients within a certain range of
`
`PASI are included, such as between 10 and 40, or such as between 12 and 30, or such as
`
`15
`
`between 15 and 25. Patients with any type of psoriasis may be included (chronic plaque type,
`
`exanthematic guttate type, pustular type, psoriatic erythroderma or palmoplantar type), but
`
`in some cases only patients with the chronic plaque type are included. About 15 to 20
`
`patients in each treatment group (composition according to the invention and Fumaderm® or
`
`placebo) are sufficient in most cases, but more preferably about 30 to 50 patients are
`
`20
`
`included in each arm of the study. Total study duration can be as short as one day to one
`
`week, but more preferably the study will run for 8 weeks to 12 weeks or up to 16 weeks. The
`
`side effects can e.g. be assessed as the total number of times a certain side effect was
`
`reported in each group (irrespective of how many patients have experienced the side effect),
`
`or the side effects can be assessed as the number of patients that have experienced a certain
`
`25
`
`side effect a certain number of times, such as at least once or at least twice or at least three
`
`times during the duration of the study. Furthermore, the severity of a side effect can be
`
`monitored, or a certain severity of a side effect can be required for it to qualify as a side
`
`effect in the study. A convenient way of assessing the severity of a side effect is via a visual
`
`analogue (VAS) scale.
`
`30
`
`Active substance
`
`The active substance in a composition of the invention is any fumaric acid ester. In one
`
`embodiment of the invention the fumaric acid ester is preferably selected from the group
`
`consisting of dimethylfumarate, diethylfumarate, dipropylfumarate, dibutylfumarate,
`
`dipentylfumarate, methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate,
`
`35 methyl-pentylfumarate, monomethylfumarate, monoethylfumarate, monopropylfumarate,
`
`monobutylfumarate and monopentylfumarate, including pharmaceutically acceptable salts
`
`thereof.
`
`MYLAN PHARMS. INC. EXHIBIT 1008 PAGE 9
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`

`

`WO 2006/037342
`
`PCT /DK2005/000648
`
`8
`
`In a specific embodiment of the invention, the fumaric acid ester is a mono-(Ci-C5)alkylester
`of fumaric acid that is present in the form of a pharmaceutically acceptable salt. Suitable
`
`salts are e.g. metal salts such as a salt selected from alkali metal salts and alkaline earth
`
`metal salts including sodium, potassium, calcium, magnesium or zinc salt.
`
`5
`
`The term (C1-C5 )alkyl refers to a branched or un-branched alkyl group having from one to
`five carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-
`
`methyl-2-propyl, 2-methyl-1-propyl and pentyl.
`
`In another embodiment, the composition according to the invention comprises
`
`dimethylfumarate as the active substance.
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`10
`
`In a further embodiment, the composition according to the invention comprises
`
`monomethylfumarate as the active substance optionally in the form of a pharmaceutically
`
`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
`
`In another embodiment, the composition according to the invention consists essentially of
`
`dimethylfumarate as the active substance.
`
`15
`
`In another embodiment, the composition according to the invention consists of
`
`dimethylfumarate as the active substance.
`
`In a further embodiment, the composition according to the invention consists essentially of
`
`monomethylfumarate as the active substance optionally in the form of a pharmaceutically
`
`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
`
`20
`
`In a further embodiment, the composition according to the invention consists of
`
`monomethylfumarate as the active substance optionally in the form of a pharmaceutically
`
`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt.
`
`In a further embodiment, the composition according to the invention comprises
`
`dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically
`
`25
`
`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the
`
`active substances, in a weight ratio between about 1: 10 and about 10: 1.
`
`In a further embodiment, the composition according to the invention consists essentially
`
`of dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically
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`WO 2006/037342
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`PCT /DK2005/000648
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`9
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`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the
`
`active substances, in a weight ratio between about 1: 10 and about 10: 1.
`
`In a further embodiment, the composition according to the invention consists of
`
`dimethylfumarate and monomethylfumarate (optionally in the form of a pharmaceutically
`
`5
`
`acceptable salt like e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as the
`
`active substances, in a weight ratio between about 1: 10 and about 10: 1.
`
`Cosmetic and/or pharmaceutical compositions
`
`The problem the invention solves is related to the appearance of gastro-intestinal side-effects
`
`upon oral administration of fumaric acid esters. By prolonging and/or delaying the release of
`
`10
`
`the active substance from the composition it is envisaged that the local concentration of the
`
`active substance at specific sites of the gastro-intestinal tract is reduced (compared with that
`
`of Fumaderm®) which in turn leads to a reduction in gastro-intestinal side-effects.
`
`Accordingly, compositions that enable a prolonged and/or a slow release of a fumaric acid
`
`ester as defined above are within the scope of the present invention.
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`15
`
`Such compositions are well-known to the skilled artisan and include e.g. diffusion-controlled
`
`drug delivery systems, osmotic pressure controlled drug delivery systems, erodible drug
`
`delivery systems etc. Moreover, there are pharmaceutical companies that based on a specific
`
`technology (such as mentioned above) can provide a specific composition with specific
`
`release characteristics of the active substance. Accordingly, a person skilled in the art will
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`20
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`know how to obtain a suitable product once he has realized a specific need in respect of a
`
`particular drug substance. By way of example, Eurand is one of such companies that offer
`
`technical solutions in order to obtain a controlled release pharmaceutical composition
`
`containing a specific active substance and having specific requirements with respect to the
`
`release of the active substance from the composition (see e.g. http://www.eurand.com).
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`25
`
`Another company is MacroMed, Inc. that has developed a technology involving a so-called
`
`SQZgel™ (http://macromed.com, SQZgel™'s mechanism of action is a pH-sensitive polymer
`
`mixture combined with an outer coating. In the acidic environment of the stomach the
`
`polymer imbibes with water and swells, entrapping the drug. Upon entering the higher pH of
`
`the intestines, the polymer slowly shrinks, or "squeezes" at a "dialed-in" rate releasing the
`
`30
`
`active composition in a sustained manner), or Egalet a/s that has a specific extrusion based
`
`technology (http://www.eqalet.com, Key elements of the Egalet® technology are a
`
`biodegradable coat and a matrix, comprising the active drug, which is surface erodible,
`
`hydrophobic and composed of PEG-stearate. One of the Egalet® technologies is the 2K
`
`Egalet® constant release system, which is a 2-component production model consisting of
`
`35
`
`coat and matrix. The drug is evenly distributed throughout the Egalet® matrix for
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`WO 2006/037342
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`10
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`constant release over time. Also of interest in the present context are technologies like e.g.
`
`the Eurand technologies Diffucaps (Drug release profiles are created by layering active drug
`
`onto a neutral core such as sugar spheres, crystals or granules followed by a rate-controlling,
`
`functional membrane. Diffucaps/Surecaps beads are small in size, approximately lmm or less
`in diameter. By incorporating beads of differing drug release profiles into hard gelatin
`
`5
`
`capsules, combination release profiles can be achieved), Diffutabs (The Diffutab technology
`
`incorporates a bl end of hydrophilic polymers that control drug release through diffusion and
`
`erosion of a matrix tablet), Minitabs (Eurand Minitabs are tiny (2mm x 2mm) tablets
`
`containing gel-forming excipients that control drug release rate. Additional membranes may
`
`10
`
`be added to further control release rate), Orbexa (This technology produces beads that are of
`
`controlled size and density with a defined-based granulation extrusion and spheronization
`
`techniques. The resultant beads can be coated with release rate controlling membranes for
`
`additional release rate control and may be filled into capsules or provided in sachet form) and
`
`SDS (Eurand's SOS technology uses functional polymers or a combination of functional
`
`15
`
`polymers and specific additives, such as composite polymeric materials, to deliver a drug to a
`
`site of optimal absorption along the intestinal tract. In order to achieve this, Eurand first
`
`produces multiparticulate dosage forms such as Diffucaps or Eurand Minitabs, which
`
`incorporate the active drug. These dosage forms are then coated with pH
`
`dependent/independent polymeric membranes that will deliver the drug to the desired site.
`
`20
`
`These are then filled into hard gelatin capsules).
`
`Another interesting technology for use in formulating compositions according to the present
`
`invention is the so-called MeltDose® technology as described in WO 03/004001 (see
`
`http://www.lifecyclepharma.com. MeltDose® involves formulating solubilized, individual
`
`molecules into tablets. By formulating individual molecules, the primary limitation of oral
`
`25
`
`absorption of drugs with low water-solubility is removed, and a superior bioavailability can be
`attained). By employing this technology it is possible to obtain a particulate material that is
`suitable for processing into various pharmaceutical dosage forms e.g. in the form of pellets or
`
`tablets. Furthermore, the technology is suitable for use as it is possible to obtain a suitable
`
`release profile of the active substance, e.g. such as those release profiles described herein. In
`
`30
`
`one embodiment, pellets suitable for use may have a mean particle size larger than 2000 µm.
`
`In another embodiment, pellets suitable for use may have a mean particle size of from about
`0.01µm to about 250 µm.
`
`Another specific suitable formulation principle for use in the present context is formulation in
`
`a lipophilic environment such as, e.g., soft gelatin capsules. A suitable example of this
`
`35
`
`formulation principle is Vegicaps Soft from Scherer (a soft capsule technology based on
`
`carrageenan and starch, which despite being 100% plant-derived, still offers all the key
`
`attributes of traditional soft gelatin capsules. These include a soft and flexible dosage form
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`WO 2006/037342
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`11
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`that provides ease of swallowing.) (For further information see
`
`http://www.mscherer.de/page. ph p?pageID=94).
`
`A further specific example of a suitable formulation comprises the formulation of the active
`
`substance together with Vitamin E concentrate