PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 97144039
`(51) International Patent Classification 6 :
`A61K 31/505
`27 November 1997 (27.11.97)
`
`(It) International Publication Number:
`
`At
`
`(43) International Publication Date:
`
`(21) International Application Number:
`
`PCT/EP97/02504
`
`(22) International Filing Date:
`
`12 May 1997 (12.05.97)
`
`(30) Priority Data:
`20 May 1996 (20.05.96)
`96201429.6
`( 34) Countries for which the regional or
`international application was filed:
`
`EP
`
`DE et a!.
`
`(81) Designated States: AL, AM, AU, BA, BB, BG, BR, CA, CN,
`CU, CZ, EE, GE, HU, IL, IS, JP, KG, KR, LC, LK, LR,
`LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, SG,
`Sl, SK, TR, TT, UA, US, UZ, VN, ARIPO patent (GH, KE,
`LS, MW, SD, SZ, UG), Eurasian patent (AM, AZ, BY, KG,
`KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, DE,
`DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE),
`OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR,
`NE, SN, TD, TG).
`
`(71) Applicant (for all designated States except US):
`JANSSEN Published
`With international search report.
`PHARMACEUTICA N.Y. [BE/BE]; Tumhoutseweg 30, B-
`Before the expiration of the time limit for amending the
`2340 Beerse (BE).
`claims and to be republished in the event of the receipt of
`amendments.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): FRAN<;:OIS, Marc, Karel,
`Jozef [BFJBE]; Janssen Pharmaceutica N.Y., Tumhout-
`seweg 30, B-2340 Beerse (BE). EMBRECHTS, Roger,
`Carolus, Augusta [BFJBE]; Janssen Pharmaceutica N.Y.,
`Tumhoutseweg 30, B-2340 Beerse (BE). BORGHIJS, Her-
`man, Karel [BFJBE]; Janssen Pharmaceutica N.Y., Tum-
`houtseweg 30, B-2340 Beerse (BE). MONBALIU, Johan
`[BE/BE]; Janssen Pharmaceutica N.Y., Turnhoutseweg 30,
`B-2340 Beerse (BE).
`
`(54) Title: AQUEOUS SUSPENSIONS OF 9-HYDROXYRISPERIDONE FATTY ACID ESTERS
`
`(57) Abstract
`
`The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via
`intramuscular or subcutaneous injection, comprising: (1) as an active ingredient a therapeutically effective amount of a 9-hydroxyrisperidone
`fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof and (2) a pharmaceutically acceptable carrier; wherein
`the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein; and with a process of preparing such
`a composition. The invention further concerns such a pharmaceutical composition for use as a medicament in the treatment of
`schizophrenia, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g.
`in dementia,
`behavioural disturbances in mental retardation and autism, bipolar mania, depression, anxiety.
`
`LUYE1028
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`FOR THE PURPOSES OF INFORMATION ONI.Y
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`-BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`cz
`DE
`OK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`C<'lte d 'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`1<'1
`FR
`GA
`GB
`GE
`Gil
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`Ll
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`1-U
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Sl
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YV
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`lJ zbekistan
`VietNam
`Yugoslavia
`Zimbabwe
`
`LUYE1028
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`wo 97/44039
`
`PCT/EP97/02504
`
`-1-
`
`AQUEOUS SUSPENSIONS OF 9-HYDROXYRISPERIDONE
`FATTY ACID ESTERS
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`The present invention is concerned with a pharmaceutical composition suitable as a
`depot formulation for administration via intramuscular or subcutaneous injection,
`comprising :
`(I) as an active ingredient a therapeutically effective amount of a 9-hydroxy-
`risperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture
`thereof and
`(2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable
`carrier is water and the active ingredient is suspended therein ;
`and with a process of preparing such a composition. The invention further involves
`such a pharmaceutical composition for use as a medicament in the treatment of
`schizophrenia, non-schizophrenic psychoses, behavioural disturbances associated with
`neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental
`retardation and autism, bipolar mania, depression, anxiety.
`
`Risperidone is generic to 3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-
`6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The preparation and
`pharmacological activity thereof are described in EP-0, 196,132 (corresponding to
`US-4,804,663). Various conventional pharmaceutical dosage forms, including tablets,
`capsules, drops, suppositories, oral solutions and injectable solutions are exemplified
`therein. In practice, risperidone is normally administered as the base in a tablet or in a
`buffered, oral or intramuscular solution. Particular solutions for oral or intramuscular
`administration are described in W0-96/0 1652.
`
`Risperidone is a highly potent drug having a relatively narrow therapeutic index. It
`may produce undesirable side effects on overdosage, most notably extra pyramidal
`syndrome (EPS) and to a lesser extent hypotension (due to peripheral alpha-adrenergic
`activity). For the purpose of producing an antipsychotic effect in a patient the total
`daily dose of risperidone ranges from about 2 to about 8 mg ; for the alleviation of
`behavioral disturbances associated with neurodegenerative disorders the total daily
`dose is usually less and typica1ly ranges from about 0.5 to about 2 mg. Inter-individual
`differences and co-medication may necessitate dose titrating in patients.
`
`For a number of reasons, it is desirable to administer risperidone in a sustained or
`delayed release (depot) formulation which is effective over an extended period of time,
`
`LUYE1028
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
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`

`

`wo 97/44039
`
`-2-
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`preferably about 3 weeks or more.
`
`PCT/EP97/02504
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`W0-94/25460 (corresponding to EP-0,697 ,0 19) relates to a first such depot
`formulation and concerns the risperidone pamoate salt, a poorly water-soluble salt form
`of risperidone, which may be suspended in a pharmaceutically acceptable carrier, such
`as water or an oil, and may be administered subcutaneously or intramuscularly. This
`salt, however, has pharmacokinetic properties which are suboptimal. The release of the
`active ingredient from the formulations appears to be too rapid, which results in
`relatively high initial plasma levels and an inadequate mean duration of action, both
`characteristics which should be improved upon in a tmly effective depot formulation.
`
`W0-95113814 concerns sustained release formulations for parenteral administration
`wherein risperidone is microencapsulated in a biocompatible, biodegradable wall-
`forming material (e.g. a polymer such as dl-(polylactide-co-glycolide)). The micro-
`encapsulated formulations have suitable pharmacokinetic properties, but require
`sophisticated processes of preparation in a purpose-built plant.
`
`Consequently, there is still a need for an effective and readily available depot
`formulation of risperidone or a risperidone-Iike compound.
`
`It is known that risperidone is metabolized to 9-hydroxyrisperidone which has a
`pharmacological profile and potency comparable with that of the parent drug
`risperidone, but which has a longer elimination half-life. Risperidone is distributed to
`and eliminated from the brain tissues more rapidly than its metabolite 9-hydroxy-
`risperidone. 9-hydroxyrisperidone, its enantiomeric forms and the C2-20 alkanoic acid
`esters thereof are described in EP-0,368,388 (corresponding to US-5, 158,952 and
`US-5,254,556). Said esters are considered to be potentially valuable prodrugs of the
`active metabolite of risperidone for use in depot formulations.
`
`In addition, the problems associated with the genetic polymorphism in the metabolism
`of risperidone to its active metabolite 9-hydroxyrisperidone can possibly be avoided by
`administration of the metabolite or a long-acting prodrug thereof, instead of risperidone
`itself.
`
`Indeed, in the metabolism of risperidone, debrisoquine-type genetic polymorphism
`plays a distinct role. As a consequence, humans can be phenotyped as poor,
`intermediate or extensive metabolizers on the basis of their metabolic ratio. Said
`metabolic ratio is defined as the ratio of urine recovery of debrisoquine to that of the
`4-hydroxymetabolite of debrisoquine over a period of 8 hours after an oral intake of
`
`LUYE1028
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`W097/44039
`
`-3-
`
`PCTIEP97/02504
`
`10 mg debrisoquine. In oriental people more than 99% of the population can be
`phenotyped as extensive metabolizers and poor metabolizers are rather seldom. In the
`Caucasian race however only about 90% of the population can be phenotyped as either
`extensive or intermediate metabolizers. Approximately 10% of the population are poor
`5 metabolizers and have deficient amounts of the debrisoquine-hydroxylase enzyme.
`
`The duration of action and the peak plasma levels of active agents (risperidone and
`9-hydroxyrisperidone) are dependent on the debrisoquine metabolic ratio of the human
`subject treated with risperidonc. More in particular, in poor metabolizers high transient
`peak levels of risperidone are likely to be attained when the total daily amount is
`administered in a single dose. This may give rise to undesired side-effects such as
`extra pyramidal syndrome (EPS) and hypotension.
`
`Further inter-individual differences among humans, as far as the metabolism of
`risperidone is concerned, are due to the fact that in clinical practice the human subjects
`to be treated with risperidone will usually receive additional medication, e.g.
`tranquillizers such as phenothiazines, neuroleptica such as haloperidol, antidepressiva
`etc., all of which may compete with risperidone for the debrisoquine-hydroxylase
`enzyme. These drug interactions may seriously affect the metabolism of risperidone,
`especially in extensive metabolizers, and may result in the occurrence of adverse effects
`in patients receiving such additional medication.
`
`The present invention results from the investigations into the development of an
`efficient, well-tolerated, sustained or delayed release (depot) formulation of a
`9-hydroxyrisperidone alkanoic acid ester which is therapeutically effective for at least
`three weeks or more. By the expression "effective for at least three weeks or more",
`one means that the plasma levels of the active ingredient, 9-hydroxyrisperidone (free
`alcohol liberated by hydrolysis from the alkanoic acid ester), should be above
`approximately 10 ng/ml. On the other hand, said plasma levels should remain at all
`times below a threshold value of approximately 100 ng/ml in order for one to call the
`formulation "efficient". The threshold value is the mean plasma level during a
`considerable period of time, e.g. for more than 15 minutes, above which patients may
`experience undesirable side effects, or conversely, the value of the plasma level under
`which the systemic tolerance of the formulation in question is still acceptable. The
`threshold value does not hold for transient, high plasm levels during a short period of
`time, e.g. for less than 15 minutes, which are due, for example to unexpected burst-
`release of the active ingredient.
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`W097/44039
`
`-4-
`
`PCT IEP97/02504
`
`Both of the foregoing features - plasma levels above a minimal therapeutical
`concentration but below a side-effect producing threshold value -are considered to be
`basic requirements that a contemporary depot formulation should fulfil in order to be
`acceptable for the intended patients. Limiting the number of drug administrations and
`the occurrence of undesirable side effects after each administration will undoubtedly
`improve the patients' compliance with the therapy. However, beyond these basic
`requirements, a number of further desiderata can be identified which would further
`improve patients' compliance ; the two most notable being good local tolerance and
`ease of administration.
`
`Good local tolerance means minimal irritation and inflammation at the site of injection;
`ease of administration refers to the size of needle and length of time required to
`administer a dose of a particular drug formulation. In addition, depot formulations
`should be stable and have a shelf-life of at least two years under normal conditions.
`
`The investigations into the development of an efficient, well-tolerated, sustained or
`delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester
`which fulfils the above mentioned requirements, led to the finding that a
`pharmaceutical composition suitable as a depot formulation for administration by
`intramuscular or subcutaneous injection should comprise :
`(I) as an active ingredient a therapeutically effective amount of a 9-hydroxy-
`risperidone fatty acid ester having the formula
`0
`
`O)lR
`Cr~N
`
`0
`
`F
`
`or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R
`represents a straight C9• 19alkyl radical ; and
`(2) a pharmaceutically acceptable carrier;
`characterized in that the pharmaceutically acceptable carrier is water and the active
`ingredient is suspended therein.
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`wo 97/44039
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`-5-
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`PCT/EP97/02504
`
`Surprisingly, it appears that aqueous suspensions of 9-hydroxyrispcridone
`C10-20 alkanoic acid esters (wherein R represents a straight C9-19 alkyl radical) are
`comparable and in some respects far better depot formulations than corresponding
`suspensions in non-aqueous, oily suspensions. This is quite unexpected since it is
`somewhat of a tenet in the art that depot formulations must comprise lipophilic drugs
`dissolved or suspended in a lipophilic medium. Hitherto, the 9-hydroxyrisperidone
`C10-20 alkanoic acid esters were therefore formulated in oils suitable for intramuscular
`administration, in particular in sesame oil. C 10-2oalkanoic acids are selected from the
`group consisting of decanoic (capric), undecanoic, dodecanoic (lauric), tridecanoic,
`tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic,
`octadecanoic (stearic), nonadecanoic and eicosanoic acid. Due to their limited aqueous
`solubility, it was generally believed that the esters had to be suspended into oils. The
`ester having a C15 (pentadecyl) chain and the active ingredient corresponding thereto
`being the 9-hydroxyrisperidone palmitate ester was found to be the superior ester from
`a pharmacokinetic, as well as from a tolerance point of view.
`
`In order to improve the tolerance further. several suspensions with different size
`particles of 9-hydroxyrisperidone palmitate ester in sesame oil, optionally in the
`presence of aluminum monostearate, were next considered. No significant difference
`between small or large prodrug particles could be established. The presence of the
`aluminum monostearate only affected the viscosity of the formulation and its ease of
`administration. In yet another set of experiments, it was found that upon decreasing the
`prodrug concentration in the depot formulation, the tolerance to the administered
`formulation improved still further. Because the oil suspensions proved difficult to take
`up in a syringe, experiments with less viscous carriers were initiated, in particular with
`a medium-chain triglyceride (Miglyol™). and contrary to what the tenet holds, with
`water as a carrier. The Miglyol™ formulations exhibited considerably less systemic
`and local tolerance than the sesame oil based formulations. To our big surprise,
`however, the aqueous suspensions of the 9-hydroxyrisperidone palmitate ester
`outperformed the sesame oil based formulations. They have not only an appropriate
`duration of action, but also acceptable systemic and local tolerance, and a strikingly
`limited inter-individual variability of pharmacokinetic properties.
`
`The pharmacok.inetic properties of the aqueous suspensions according to the present
`invention further may depend to a limited extent on the physico-chemical properties of
`the 9-hydroxyrisperidone palmitate ester solid, such as the particle .size and crystal
`form.
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`wo 97/44039
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`PCT/EP97/02504
`
`Aqueous compositions according to the present invention conveniently further
`comprise a suspending agent and a wetting agent, and optionally one or more of a
`preservative, a buffer and an isotonizing agent. Particular ingredients may function as
`two or more of these agents simultaneously, e.g. behave like a preservative and a
`buffer, or behave like a buffer and an isotonizing agent.
`
`Suitable suspending agents for use in the aqueous suspensions according to the present
`invention are cellulose derivatives, e.g. methyl cellulose, sodium carboxymethyl
`cellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginates,
`chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene- and polyoxy-
`propylene ethers. Preferably sodium carboxymethyl cellulose is used in a concentration
`of 0.5 to 2%, most preferably I% (w/v). Suitable wetting agents for use in the aqueous
`suspensions according to the present invention are polyoxyethylene derivatives of
`sorbitan esters, e.g. polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and
`polyoxypropylene ethers, sodium deoxycholate. Preferably polysorbate 20 is used in a
`concentration of 0.05 to 0.3%, more preferably 0.05 to 0.2 %, most preferably 0.1%
`(w/v).
`
`Preservatives are antimicrobials and anti-oxidants which can be selected from the group
`consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated
`hydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol,
`metacresol, benzethonium chloride, myristyl-y-piccolinium chloride, phenylmercuric
`acetate and thimerosal. In particular, it is benzyl alcohol which can be used in a
`concentration up to 2% (w/v), preferably up to 1.5% (w/v). Isotonizing agents are, for
`example, sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate. The
`suspensions conveniently comprise from I to 10% (w/v) isotonizing agent. Preferably,
`mannitol is used in a concentration from 2 to 7%, more preferably about 5%. Most
`preferably, however, from about I to about 3 % (w/v), especially from about 1.5 to
`about 2 % (w/v) of one or more electrolytes are used to render the suspension isotonic,
`apparently because ions help to prevent flocculation of the suspended ester. In
`addition, particular electrolytes have the further advantage of buffering the aqueous
`suspension. Particularly preferred is the use of a mixture of disodium hydrogen
`phosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogen phosphate
`monohydrate (typically about 0.6% (w/v)) for rendering the solution isotonic, neutral
`and less prone to flocculation of the suspended ester therein.
`
`A particularly desirable feature for an injectable depot formulation relates to the ease
`with which it can be administered. In particular such an injection should be feasible
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`W097/44039
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`-7-
`
`PCT/EP97/02504
`
`using a needle as fine as possible in a span of time which is as short as possible. This
`can be accomplished with the aqueous suspensions of the present invention by keeping
`the viscosity below about 75 mPa.s, preferably below 60 mPa.s. Aqueous suspensions
`of such viscosity or lower can both easily be taken up in a syringe (e.g. from a vial),
`and injected through a fine needle (e.g a 21 G 1 'h, 22 G 2 or 22 G 1 1.4 needle).
`
`Ideally, aqueous suspensions according to the present invention will comprise as much
`prodrug as can be tolerated so as to keep the injected volume to a minimum, and as
`little of the other ingredients as possible. In particular, such a composition will
`comprise by weight based on the total volume of the composition :
`(a) from 3 to 20 % (w/v) of the prodrug;
`(b) from 0.05 to 0.2% (w/v) of a wetting agent;
`(c) from 0.5 to 2% (w/v) of a suspending agent;
`(d) up to 2 % (w/v) preservatives;
`(e) optionally one or more isotonizing agents sufficient to render the composition
`isotonic with serum; and
`(f) water q.s. ad 100%.
`
`The aqueous suspensions according to the present invention can be prepared fol1owing
`art-known processes of preparing suspensions characterized by intimately mixing the
`active ingredient with the carrier.
`
`Such a process may comprise the steps of :
`(a) stirring the wetting agent with the water;
`(b) adding the preservative to the mixture while stirring;
`(c) dispersing the suspending agent in the mixture while stirring;
`(d) optionally dissolving the isotonizing agent in the mixture while stirring;
`(e) dispersing the active ingredient in the mixture while stirring, followed by
`homogenizing the mixture.
`
`In view of the usefulness of 9-hydroxyrisperidone in the treatment of a number of
`disorders, the present invention also concerns a pharmaceutical composition as
`described hereinbefore for use as a medicament in the treatment of schizophrenia, non-
`schizophrenic psychoses, behavioural disturbances associated with neurodegenerative
`disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism,
`bipolar mania, depression, anxiety.
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`wo 97/44039
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`PCT/EP97 /02504
`
`In addition, the present invention concerns the use of a composition as described
`hereinbefore for the preparation of a medicament for treating schizophrenia, non-
`schizophrenic psychoses, behavioural disturbances associated with neurodegenerative
`disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism,
`bipolar mania, depression, anxiety.
`
`The present invention further concerns a method of treating warm-blooded animals, in
`particular humans suffering from schizophrenia, non-schizophrenic psychoses,
`behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia,
`behavioural disturbances in mental retardation and autism, bipolar mania, depression,
`anxiety, said method comprising the administration of a therapeutically effective
`amount of an aqueous suspension as described hereinbefore. Typically, said
`formulation will be administered approximately every three weeks or even at longer
`intervals where possible. The dosage should range from about 2 to 4 mg/kg body
`weight.
`
`The following examples are intended to illustrate the present invention.
`
`Experimental Part
`A. Preparation of 9-hydroxyrisperidone palmitate ester.
`N,N -Dicyclohexylcarbodiimide ( 1.39 g ; 6.8 mmol) was added to a solution of
`hexadecanoic acid (1.54 g ; 6 mmol) in dichloromethane (140 ml) and stirred at room
`temperature for 10 minutes. 9-hydroxyrisperidone (2.13 g ; 5 mmol) was added to the
`reaction mixture, followed by 4-pyrrolidinopyridine (93 mg ; 0.63 mmol). The mixture
`was stirred for three days at room temperature. Water (200 ml) was added to the
`reaction mixture and this was extracted three times with chloroform (100 ml). The
`combined organic layers were dried (MgS04), filtered, and evaporated. The mixture
`was triturated in diisopropylether (100 ml), filtered and recrystalized in isopropanol (60
`ml). The crystals were filtered off and dried, yielding 9-hydroxyrisperidone palmitate
`ester (2.67g; 80.4%).
`
`B. Composition examples.
`Each of the formulations hereunder was prepared according to the following general
`recipe:
`The wetting agent was stirred with the water at room temperature and the preservative
`was added thereto. While stirring, the suspending agent was dispersed in the mixture,
`and the isotonizing agent - if any - was added. Next, the active ingredient was
`dispersed into the stirred mixture which was then homogenized and filled into sterile
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`LUYE1028
`Luye Pharma Group Ltd., et al. v. Alkermes Pharma Ireland Ltd.
`IPR2016-01096
`
`

`

`wo 97/44039
`
`-9-
`
`PCT/EP97 /02504
`
`containers. All ingredients and apparatus used during the preparation of the aqueous
`suspensions were sterile. In the tables hereunder, all concentrations are expressed as %
`weight by volume of the total formulation [%(w/v)].
`
`5
`
`10
`
`15
`
`20
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`25
`
`30
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`35
`
`15.6 % ( 10 % 9-hydroxyrisperidone)
`0.2%
`2%
`1.5%
`100%
`
`Formulation I (F I)
`9-hydroxyrisperidone palmitate *
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzyl alcohol
`water q.s. ad
`* The ester was milled, but not sieved.
`
`Physico-chemical properties of Fl
`pH= 6.52
`viscosity= 20 mPa.s
`osmolality = ± 21 0 mOsrnlkg
`
`Formulation 2a, 2b and 2c (F2a. F2b, F2c)
`9-hydroxyrisperidone palmitate #
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzy I alcohol
`mannitol
`water q.s. ad
`
`7.8 % (5 % 9-hydroxyrisperidone)
`0.1%
`2%
`1.5%
`2%
`100%
`
`#The ester was milled and sieved into three fractions :
`F2a (particle size < I 0 J.lm)
`viscosity = 19 mPa.s
`viscosity = 29 mPa.s
`F2b ( 10 J.lm < particle size < 30 J.lm)
`F2c (particle size > 30 J.lm)
`viscosity= 32 mPa.s
`
`pH= 6.86
`osmolality = ± 280 mOsrnlkg
`
`Formulation3a, 3b and 3c (F3a. F3b. F3c)
`9-hydroxyrisperidone palmitate #
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzyl alcohol
`
`15.6% (10% 9-hydroxyrisperidone)
`0.2%
`1 %
`1.5 %
`
`LUYE1028
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`

`wo 97/44039
`
`mannitol
`water q.s. ad
`
`PCT/EP97/02504
`
`-10-
`
`2%
`100%
`
`5
`
`#The ester was miJled and sieved into three fractions :
`viscosity = ± 60 mPa.s
`F3a (particle size < 10 ).lm)
`viscosity = ± 60 mPa.s
`F3b ( 10 ).lm <particle size< 30 ).lm)
`viscosity = ± 60 mPa.s
`F3c (particle size > 30 ).lm)
`
`pH= 6.74
`osmolality = ± 280 mOsm/kg
`
`10
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`15
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`20
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`25
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`30
`
`Formulation 4 (F4)
`9-hydroxyrisperidone palmitate #
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzyl alcohol parenteral
`disodium hydrogen phosphate anhydrous
`sodium dihydrogen phosphate monohydrate
`water q.s. ad
`
`7.8 % (5 % 9-hydroxyrisperidone)
`0.2%
`1%
`1.5%
`0.9%
`0.6%
`100%
`
`# The ester was milled and sieved using appropriate nominal standard test sieves,
`yielding active ingredient having a particle size distribution as follows :
`90 % of the particles (by volume ) ~ 0.5 ).lm
`50 % of the particles (by volume ) ~ 5 ).lm
`10 % of the particles (by volume ) ~ 15 ).lm.
`The ester was sterilized by irradiation with 25 kGy IH'y and mixed with the solvent
`(filtered through a 0.22 ).lm membrane filter and autoclaved during 30 minutes at
`121 °C) under sterile conditions.
`
`pH= 7
`viscosity = ± I 0 mPa.s
`osmolality = ± 450 mOsm/kg
`The syringeability through a 22 G 1 114 needle posed no problem.
`
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`

`wo 97/44039
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`-11-
`
`Formula 5a, 5b and 5 c (F5a, F5b, F5c)
`
`9-hydroxyrisperidone palmitate #
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzyl alcohol parenteral
`disodium hydrogen phosphate anhydrous
`sodium dihydrogen phosphate monohydrate
`water q.s. ad
`
`F5a
`15.6%
`0.2%
`I%
`1.5%
`0.9%
`0.6%
`100%
`
`pH
`viscosity (mPa.s)
`osmolality (mOsm)/kg
`The syringeability through a 22 G 1 14 needle
`
`7
`12
`±450
`OK
`
`PCT/EP97/02504
`
`F5b
`23.4%
`0.2%
`1%
`1.5%
`0.9%
`0.6%
`100%
`
`7
`16
`±450
`OK
`
`F5c
`31.2%
`0.3%
`0.5%
`1.5%
`0.9%
`0.6%
`100%
`
`7
`16
`±450
`OK
`
`C. Pharmacological examples.
`C.1. Pharmacological testing of Fl and analogous oil formulations.
`Fl was administered intramuscularly at 2.5 mg/kg bodyweight to four beagle dogs
`using a 21 G needle. In the same experiment, a similar formulation based on Miglyol™
`(Fa.) and one based on sesame oil (F~) were used, as well as a suspension comprising
`9-hydroxyrisperidone decanoate in sesame oil (Fy). The Miglyol™ formulation was
`also administered using a 21 G needle, but both sesame oil based formulations had to
`be administered using a 19 G needle. The following pharmacokinetic parameters were
`calculated from the experimental data :
`
`Cmax
`(ng/ml)
`
`Tmax
`(h)
`
`AUC0-672h
`(ng.h/ml)
`
`Cav
`(ng/ml)
`
`C672h
`(ng/ml)
`
`Fl
`Fa.
`FP
`Fy
`
`54.6 (± 7.3)
`86.5 (± 33.2)
`21.9 (± 9.4)
`33.1 (± 18.2)
`
`276 (± 80)
`234 (± 82)
`210 (± 84)
`132 (± 42)
`
`18210 (± 1350)
`22082 (± 6319)
`7054 (± 3489}
`13875 (± 6208)
`
`27.1
`32.9
`10.5
`20.6
`
`8.8 (± 4.7)
`2.5 (::::; 2.0-7 .8)
`4.2 (::::; 2.0-6.5)
`12.0 (± 5.6)
`
`5
`
`10
`
`15
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`20
`
`25
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`30
`
`LUYE1028
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`
`

`

`W097/44039
`
`Claims
`
`-12-
`
`PCTIEP97/02504
`
`1. A pharmaceutical composition suitable as a depot formulation for administration by
`intramuscular or subcutaneous injection, comprising :
`(1) as an active ingredient a therapeutically effective amount of a 9-hydroxy-
`risperidone fatty acid ester having the formula
`
`5
`
`10
`
`15
`
`20
`
`F
`
`or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R
`represents a straight C9.t9alkyl radical ; and
`(2) a pharmaceutically acceptable carrier;
`characterized in that the pharmaceutically acceptable carrier is water and the
`active ingredient is suspended therein.
`
`2. A composition according to claim 1 wherein R represents a straight C 15
`(pentadecyl) chain and the active ingredient is 9-hydroxyrisperidone palmitate
`ester.
`
`3. A composition according to claim 1 wherein the composition further comprises a
`suspending agent and a wetting agent, and optionally one or more of a preservative,
`a buffer and an isotonizing agent.
`
`4. A composition according to claim 3 wherein the suspending agent is sodium
`carboxymethyl cellulose and the wetting agent is polysorbate 20.
`
`25
`
`5. A composition according to claim 4 wherein the preservative is benzyl alcohol and
`the isotonizing agent is mannitol or a phosphate buffer.
`
`30
`
`6. A composition according to claim 1 having a viscosity of less than 75 mPa.s.
`
`LUYE1028
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`IPR2016-01096
`
`

`

`wo 97/44039
`
`-13-
`
`PCT/EP97/02504
`
`7. A composition according to claim I comprising by weight based on the total volume
`of the composition :
`(a) from 3 to 20 % (w/v) of the prodrug;
`(b) from 0.05 to 0.2% (w/v) of a wetting agent;
`(c) from 0.5 to 2% (w/v) of a suspending agent;
`(d) up to 2 % (w/v) preservatives;
`(e) optionally one or more isotonizing agents sufficient to render the composition
`isotonic with serum; and
`(f) water q.s. ad 100%.
`
`8. A process of preparing a pharmaceutical composition as claimed in any one of
`claims 1 to 7, characterized by intimately mixing the active ingredient with the
`carrier.
`
`9. A process according to claim 8 comprising the steps of:
`(a) stirring the wetting agent with the water;
`(b) addin