(12) United States Patent
`(10) Patent N0.:
`US 6,555,544 B2
`
`Francois et al.
`(45) Date of Patent:
`*Apr. 29, 2003
`
`US006555544B2
`
`(54) AQUEOUS SUSPENSIONS 0F SUBMICRON
`9-HYDROXYRISPERIDONE FATTY ACID
`ESTERS
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`(75)
`
`Inventors: Marc Karel Jozef Francois, Kapellen
`(BE); Willy Maria Albert Carlo Dries,
`Merksplas (BE); Esther Dina Guido
`Basstanie, Zandhoven (BE)
`
`(73) Assignee: Janssen Pharmaceutica, N.V. (BE)
`
`(*) Notice:
`
`This patent issued on a continued pros-
`ecution application filed under 37 CFR
`1.53(d), and is subject to the twenty year
`patent
`term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/530,687
`
`(22) PCT Filed:
`
`Nov. 10, 1998
`
`(86) PCT No.:
`
`PCT/EP98/07321
`
`§ 371 (C)(1),
`(2), (4) Date: May 2, 2000
`
`(87) PCT Pub. No.: WO99/25354
`
`PCT Pub. Date: May 27, 1999
`
`(65)
`
`Prior Publication Data
`
`US 2003/0064998 A1 Apr. 3, 2003
`
`(30)
`
`Foreign Application Priority Data
`
`NOV. 17, 1997
`
`(EP) ............................................ 97203568
`
`(51)
`Int. Cl.7 ....................... A01N 43/90; A61K 31/519
`(52) US. Cl. ......................... 514/259.41; 514/259.1
`
`(58) Field of Search ..................... 424/422; 514/259.41,
`514/259.1
`
`5,158,952 A * 10/1992 Janssen et a1.
`6,077,843 A *
`6/2000 Francois et al.
`
`.............. 514/258
`............ 514/528
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`W0
`
`368388
`W0 97/44039
`
`* 10/1989
`11/1997
`
`* cited by examiner
`
`Primary Examiner—Alton Pryor
`(74) Attorney, Agent, or Firm—Mary Appollina
`
`(57)
`
`ABSTRACT
`
`The present invention is concerned with a pharmaceutical
`composition suitable as a depot formulation for administra-
`tion via intramuscular or subcutaneous injection, compris-
`ing:
`(1) 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 in submicron form 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 com-
`position for use as a medicament in the treatment of psy-
`chosis, schizophrenia, schizoaffective disorders, non-schizo-
`phrenic psychoses, behavioural disturbances associated with
`neurodegenerative disorders, e.g. in dementia, behavioural
`disturbances in mental retardation and autism, Tourette’s
`syndrome, bipolar mania, depression, anxiety.
`
`7 Claims, N0 Drawings
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 001
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 001
`
`

`

`US 6,555,544 B2
`
`1
`AQUEOUS SUSPENSIONS 0F SUBMICRON
`9-HYDROXYRISPERIDONE FATTY ACID
`ESTERS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a National Stage application under 35
`U.S.C. §371 of PCT/EP98/07321 filed Nov. 10, 1998, which
`claims priority from EP 97.203.568.7, filed Nov. 17, 1997.
`The present invention is concerned with a pharmaceutical
`composition suitable as a depot formulation for administra-
`tion via intramuscular or subcutaneous injection, compris-
`ing:
`(1) 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 in submicron form 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
`psychosis, schizophrenia, schizoaffective disorders, non-
`schizophrenic psychoses, behavioural disturbances associ-
`ated with neurodegenerative disorders, e.g.
`in dementia,
`behavioural disturbances in mental retardation and autism,
`Tourette’s syndrome, 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 prepara-
`tion and pharmacological activity thereof are described in
`EP-0,196,132 (corresponding to US. Pat. No. 4,804,663).
`Various conventional pharmaceutical dosage forms, includ-
`ing 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 WO-96/01652.
`Risperidone is a highly potent drug having a relatively
`narrow therapeutic index. It may produce undesirable side
`effects on overdosage, most notably extra pyramidal syn-
`drome (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 typically ranges from about 0.5 to about 2 mg.
`Inter-individual differences and co-medication may neces-
`sitate dose titrating in patients.
`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. Pat. Nos. 5,158,952
`and 5,254,556). Said esters are considered to be potentially
`valuable prodrugs of the active metabolite of risperidone for
`use in depot formulations.
`For a number of reasons, it is desirable to administer
`risperidone in a sustained or delayed release (depot) formu-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`lation which is effective over an extended period of time,
`preferably about 3 weeks or more, in particular about 1
`month.
`
`WO-94/25460 (corresponding to EP-0,697,019) 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 subop-
`timal. The release of the active ingredient from the formu-
`lations 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 truly effective depot formulation.
`WO-95/13814 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 suit-
`able pharmacokinetic properties, but require sophisticated
`processes of preparation in a purpose-built plant.
`PCT/EP97/02504 discloses aqueous suspensions of
`9-hydroxyrisperidone fatty acid esters in water wherein the
`prodrug of the active ingredient
`is in micronized fonn.
`Unexpectedly, these formulations prove to be far too lon-
`glasting in humans to be therapeutically useful.
`Consequently, there is still a need for an effective and
`readily available depot formulation of risperidone or a
`risperidone-like compound.
`Nanoparticles are well known in the prior art, having been
`described, for example, in EP-A-0,499,299. These particles
`consist essentially of a crystalline drug substance having a
`surface modifier absorbed on the surface of the particles
`such that the effective average particle size is less than about
`400 nm. It is also known that said particles are particularly
`useful to formulate poorly water soluble active ingredients.
`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 therapeu-
`tically effective for at least three weeks or more, in particular
`about 1 month. By the expression “effective for at least three
`weeks or more”, one means that the plasma level of the
`active ingredient, 9-hydroxyrisperidone (free alcohol liber-
`ated by hydrolysis from the alkanoic acid ester), should be
`above approximately 10 ng/ml. On the other hand, said
`plasma level 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.
`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 occur-
`rence of undesirable side effects after each administration
`
`will undoubtedly improve the patients’ compliance with the
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 002
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 002
`
`

`

`US 6,555,544 B2
`
`4
`
`(i.e. corresponding to an average particle size of less than
`2,000 nm), preferably the specific surface area >6 m2/g, and
`in particular is in the range from 10 to 16 m2/g. Useful
`surface modifiers are believed to include those which physi-
`cally adhere to the surface of the active agent but do not
`chemically bond thereto.
`Suitable surface modifiers can preferably be selected from
`known organic and inorganic pharmaceutical excipients.
`Such excipients include various polymers, low molecular
`weight oligomers, natural products and surfactants. Pre-
`ferred surface modifiers include nonionic and anionic sur-
`
`factants. Representative examples of excipients include
`gelatin, casein,
`lecithin (phosphatides), gum acacia,
`cholesterol, tragacanth, stearic acid, benzalkonium chloride,
`calcium stearate, glyceryl monostearate, cetostearyl alcohol,
`cetomacrogol emulsifying wax, sorbitan esters, polyoxyeth-
`ylene allcyl ethers, e.g., macrogol ethers such as cetomac-
`rogol 1000, polyoxyethylene castor oil derivatives, polyoxy-
`ethylene sorbitan fatty acid esters, e.g., the commercially
`available TweensTM, polyethylene glycols, polyoxyethylene
`stearates, colloidal silicon dioxide, phosphates, sodium
`dodecylsulfate, carboxymethylcellulose calcium, carboxym-
`ethylcellulose
`sodium, methylcellulose,
`hydroxyethylcellulose, hydroxypropylcellulose, hydrox-
`ypropylmethylcellulose phthalate, noncrystalline cellulose,
`magnesium aluminate silicate,
`triethanolamine, polyvinyl
`alcohol (PVA), poloxamers, tyloxapol and polyvinylpyrroli-
`done (PVP). Most of these excipients are described in detail
`in the Handbook of Pharmaceutical Excipients, published
`jointly by the American Pharmaceutical Association and The
`Pharmaceutical Society of Great Britain, the Pharmaceutical
`Press, 1986. The surface modifiers are commercially avail-
`able and/or can be prepared by techniques known in the art.
`Two or more surface modifiers can be used in combination.
`
`Particularly preferred surface modifiers include polyvi-
`nylpyrrolidone; tyloxapol; poloxamers, such as PluronicTM
`F68, F108 and F127 which are block copolymers of ethylene
`oxide and propylene oxide available from BASF;
`poloxamines, such as TetronicTM 908 (T908) which is a
`tetrafunctional block copolymer derived from sequential
`addition of ethylene oxide and propylene oxide to ethylene-
`diamine available from BASF; dextran;
`lecithin; Aerosol
`OTTM (AOT) which is a dioctyl ester of sodium sulfosuc-
`cinic acid available from Cytec Industries; DuponolTM P
`which is a sodium lauryl sulfate available from DuPont;
`TritonTM X-200 which is an alkyl aryl polyether sulfonate
`available from Rohm and Haas; TweensTM 20, 40, 60 and 80
`which are polyoxyethylene sorbitan fatty acid esters avail-
`able from ICI Speciality Chemicals; SpanTM 20, 40, 60 and
`80 which are sorbitan esters of fatty acids; ArlacelTM 20, 40,
`60 and 80 which are sorbitan esters of fatty acids available
`from Hercules, Inc.; CarbowaxTM 3550 and 934 which are
`polyethylene glycols available from Union Carbide; Crod-
`estaTM F110 which is a mixture of sucrose stearate and
`sucrose distearate available from Croda Inc.; CrodestaTM
`SL-40 which is available from Croda, Inc.; hexyldecyl
`trimethyl ammonium chloride (CTAC); bovine serum albu-
`min and SA90HCO which is C18H17CH2(CON(CH3)CH2
`(CHOH)4CH20H)2. The surface modifiers which have been
`found to be particularly useful
`include tyloxapol and a
`poloxamer, preferably, PluronicTM F108 and PluronicTM
`F68.
`
`PluronicTM F108 corresponds to poloxamer 338 and is the
`polyoxyethylene, polyoxypropylene block copolymer that
`conforms generally to the formula HO[CH2CH20]X[CH
`(CH3)CH20]y[CH2CH20]ZH in which the average values of
`x, y and z are respectively 128, 54 and 128. Other commer-
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`3
`therapy. However, beyond these basic requirements, a num-
`ber 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 inflam-
`
`mation at the site of injection; ease of administration refers
`to the size of needle and length of time required to admin-
`ister 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) formu-
`lation 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 for-
`mulation for administration by intramuscular or subcutane-
`ous injection should comprise:
`a dispersion of particles consisting essentially of a thera-
`peutically effective amount of
`a crystalline
`9-hydroxyrisperidone fatty acid ester having the for-
`mula
`
`N
`
`/N\O
`
`O O
`
`iR
`
`CH3
`
`N
`/ |
`N
`
`O
`
`or a salt, or a stereoisomer or a stereoisomeric mixture
`thereof, wherein R represents a straight C9_19alkyl
`radical; having a surfactant absorbed to the surface
`thereof in an amount effective in maintaining a specific
`surface area >4 m2/g (corresponding to an effective
`average particle size of less than 2,000 nm),
`in a
`pharmaceutically acceptable carrier comprising water.
`Surprisingly,
`it appears that aqueous suspensions of
`micronized 9-hydroxyrisperidone C10_20 alkanoic acid esters
`(wherein R represents a straight C9_19 alkyl radical) have an
`exceptionally longlasting effect in humans, but not in test
`animals, in particular dogs. This is quite unexpected since
`the pharmacokinetics of drugs in humans and in dogs are
`often comparable. The pharmacokinetic properties in
`humans of the aqueous suspensions of 9-hydroxyrisperidone
`alkanoic acid esters depend on the particle size to a much
`larger extent than previously held possible.
`C10_20alkanoic acids are selected from the group consist-
`ing of decanoic (capric), undecanoic, dodecanoic (lauric),
`tridecanoic, tetradecanoic (myristic), pentadecanoic, hexa-
`decanoic (palmitic), heptadecanoic, octadecanoic (stearic),
`nonadecanoic and eicosanoic acid. 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.
`The nanoparticles of the present invention have a surfac-
`tant or surface modifier adsorbed on the surface thereof in an
`
`amount sufficient to maintain a specific surface area >4 m2/g
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 003
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 003
`
`

`

`US 6,555,544 B2
`
`5
`cial names of poloxamer 338 are Hodag NonionicTM 1108-F
`available from Hodag, and SynperonicTM PE/F 108 available
`from ICI Americas.
`The optimal relative amount of the antipsychotic agent
`and the surface modifier depends on various parameters. The
`optimal amount of the surface modifier can depend, for
`example, upon the particular antipsychotic agent and surface
`modifier selected, the critical micelle concentration of the
`surface modifier if it forms micelles, the surface area of the
`antipsychotic agent, etc. The specific surface modifier pref-
`erably is present in an amount of 0.1 to 1 mg per square
`meter surface area of the antipsychotic agent. In case 9-hy-
`droxyrisperidone palmitate is used as antipsychotic agent
`and PluronicTM F108 as a surface modifier, a relative amount
`(w/w) of both ingredients of approximately 6:1 is preferred.
`As used herein, an effective average particle size of less
`than 2,000 nm means that at least 90% of the particles have
`a diameter of less than 2,000 nm when measured by art-
`known conventional techniques, such as sedimentation field
`flow fractionation, photon correlation spectroscopy or disk
`centrifugation. With reference to the effective average par-
`ticle size,
`it
`is preferred that at
`least 95% and, more
`preferably, at least 99% of the particles have a particle size
`of less than the effective average particle size, e. g. 2,000 nm.
`Most preferably, essentially all of the particles have a size of
`less than 2,000 nm.
`The particles of this invention can be prepared by a
`method comprising the steps of dispersing an antipsychotic
`agent in a liquid dispersion medium and applying mechani-
`cal means in the presence of grinding media to reduce the
`particle size of the antipsychotic agent
`to an effective
`average particle size of less than 2,000 nm. The particles can
`be reduced in size in the presence of a surface modifier.
`Alternatively, the particles can be contacted with a surface
`modifier after attrition.
`
`A general procedure for preparing the particles of this
`invention includes
`
`(a) obtaining an antipsychotic agent in micronized form;
`(b) adding the micronized antipsychotic agent to a liquid
`medium to form a premix; and
`(c) subjecting the premix to mechanical means in the
`presence of a grinding medium to reduce the effective
`average particle size.
`The selected antipsychotic agent in micronized form is
`obtained commercially or prepared using techniques known
`in the art.
`It
`is preferred that
`the particle size of the
`micronized antipsychotic agent be less than about 100 pm as
`determined by sieve analysis. If the particle size of the
`micronized antipsychotic agent is greater than about 100
`um, then it is preferred that the particles of the antipsychotic
`agent be reduced in size to less than 100 pm.
`The micronized antipsychotic agent can then be added to
`a liquid medium in which it is essentially insoluble to form
`a premix. The concentration of the antipsychotic agent in the
`liquid medium (weight by weight percentage) can vary
`widely and depends on the selected antipsychotic agent, the
`selected surface modifer and other factors. Suitable concen-
`
`trations of antipsychotic agent in compositions vary between
`0.1 to 60%, preferably is from 0.5 to 30%, and more
`preferably, is approximately 7% (w/v).
`A more preferred procedure involves the addition of a
`surface modifier to the premix prior to its subjection to
`mechanical means to reduce the effective average particle
`size. The concentration of the surface modifier (weight by
`weight percentage) can vary from 0.1% to 90%, preferably
`from 0.5% to 80%, and more preferably is approximately
`7% (w/v).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`to
`The premix can be used directly by subjecting it
`mechanical means to reduce the effective average particle
`size in the dispersion to less than 2,000 nm. It is preferred
`that the premix be used directly when a ball mill is used for
`attrition. Alternatively,
`the antipsychotic agent and,
`optionally,
`the surface modifier, can be dispersed in the
`liquid medium using suitable agitation such as, for example,
`a roller mill or a Cowles type mixer, until a homogeneous
`dispersion is achieved.
`The mechanical means applied to reduce the effective
`average particle size of the antipsychotic conveniently can
`take the form of a dispersion mill. Suitable dispersion mills
`include a ball mill, an attritor mill, a vibratory mill, a
`planetary mill, media mills—such as a sand mill and a bead
`mill. A media mill is preferred due to the relatively shorter
`milling time required to provide the desired reduction in
`particle size. For media milling, the apparant viscosity of the
`premix preferably is anywhere between 0.1 and 1 Pas. For
`ball milling, the apparant viscosity of the premix preferably
`is anywhere etween 1 and 100 mPa-s.
`The grinding media for the particle size reduction step can
`be selected from rigid media preferably spherical or par-
`ticulate in form having an average size less than 3 mm and,
`more preferably, less than 1 mm. Such media desirably can
`provide the particles of the invention with shorter processing
`times and impart less wear to the milling equipment. The
`selection of the material for the grinding media is believed
`not
`to be critical. However, 95% ZrO stabilized with
`magnesia, zirconium silicate, and glass grinding media
`provide particles having levels of contamination which are
`believed to be acceptable for the preparation of pharmaceu-
`tical compositions. Further, other media, such as polymeric
`beads, stainless steel, titania, alumina and 95% ZrO stabi-
`lized with yttrium, are useful. Preferred grinding media have
`a density greater than 2.5 g/cm3 and include 95% ZrO
`stabilized with magnesia and polymeric beads.
`The attrition time can vary widely and depends primarily
`upon the particular mechanical means and processing con-
`ditions selected. For rolling mills, processing times of up to
`two days or longer may be required.
`The particles must be reduced in size at a temperature
`which does not significantly degrade the antipsychotic
`agent. Processing temperatures of less than 30 to 40° C. are
`ordinarily preferred. If desired, the processing equipment
`may be cooled with conventional cooling equipment. The
`method is conveniently carried out under conditions of
`ambient temperature and at processing pressures which are
`safe and effective for the milling process.
`The surface modifier, if it was not present in the premix,
`must be added to the dispersion after attrition in an amount
`as described for the premix above. Thereafter, the dispersion
`can be mixed by,
`for example, shaking vigorously.
`Optionally, the dispersion can be subjected to a sonication
`step using, for example, a ultrasonic power supply.
`Aqueous compositions according to the present invention
`conveniently further comprise a suspending agent and a
`buffer, and optionally one or more of a preservative 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 sus-
`pensions 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 cellu-
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 004
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 004
`
`

`

`US 6,555,544 B2
`
`7
`lose is used in a concentration of 0.5 to 2%, most preferably
`1% (w/v). Suitable wetting agents for use in the aqueous
`suspensions according to the present invention are polyoxy-
`ethylene derivatives of sorbitan esters, e.g. polysorbate 20
`and polysorbate 80, lecithin, polyoxyethylene- and polyox-
`ypropylene ethers, sodium deoxycholate. Preferably
`polysorbate 20 is used in a concentration of 0.5 to 3%, more
`preferably 0.5 to 2%, most preferably 1.1% (w/v).
`Suitable buffering agents are salt of weak acids and should
`be used in amount sufficient to render the dispersion neutral
`to very slightly basic (up to pH 8.5), preferably in the pH
`range of 7 to 7.5. Particularly preferred is the use of a
`mixture of disodium hydrogen phosphate (anhydrous)
`(typically about 0.9% (w/v)) and sodium dihydrogen phos-
`phate monohydrate (typically about 0.6% (w/v)). This buffer
`also renders the dispersion isotonic and, in addition, less
`prone to flocculation of the ester suspended therein.
`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 0 to 10% (w/v)
`isotonizing agent. Mannitol may be used in a concentration
`from 0 to 7% More preferably, however, from about 1 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 floccula-
`tion of the suspended ester. In particular electrolytes of the
`buffer serve as isotonizing agent.
`A particularly desirable feature for an injectable depot
`formulation relates to the ease with which it can be admin-
`istered. In particular such an injection should be feasible
`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 11/2, 22 G 2 or 22 G 1%
`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 0.5 to 2% (w/v) of a wetting agent;
`(c) one or more buffering agents sufficient to render the
`composition neutral to very slightly basic (pH 8.5);
`(d) from 0.5 to 2% (w/v) of a suspending agent;
`(e) up to 2% (w/v) preservatives; and
`(f) water q.s. ad 100%.
`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
`psychosis, schizophrenia, schizoaffective disorders, non-
`schizophrenic psychoses, behavioural disturbances associ-
`ated with neurodegenerative disorders, e.g.
`in dementia,
`behavioural disturbances in mental retardation and autism,
`Tourette’s syndrome, bipolar mania, depression, anxiety.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`In addition, the present invention concerns the use of a
`composition as described hereinbefore for the preparation of
`a medicament
`for
`treating psychosis, schizophrenia,
`schizoaffective disorders, non-schizophrenic psychoses,
`behavioural disturbances associated with neurodegenerative
`disorders, e.g.
`in dementia, behavioural disturbances in
`mental retardation and autism, Tourette’s syndrome, bipolar
`mania, depression, anxiety.
`The present invention further concerns a method of treat-
`ing warm-blooded animals, in particular humans suffering
`from psychosis, schizophrenia, schizoaffective disorders,
`non-schizophrenic psychoses, behavioural disturbances
`associated with neurodegenerative disorders, e.g.
`in
`dementia, behavioural disturbances in mental retardation
`and autism, Tourette’s syndrome, 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 (MgSO4), 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 palmi-
`tate ester (2.67 g; 80.4%).
`
`B. Composition Examples
`
`The formulations hereunder were prepared according to
`the following general recipe: The surfactant, suspending
`agent and buffer were dissolved by stirring in water at room
`temperature and the solution was sterilized by heating
`during 30 minutes at 121° C. The active ingredient
`(micronized) was sterilized by gamma irradiation at 25 kGY
`and suspended in the previously prepared solution under
`sterile conditions. Appropriate glass vials were filled to
`about 30% of their total volume with the suspension and
`with the grinding medium, and then rolled at about 50 rpm
`for several hours. The submicron formulations were then
`sieved to remove the grinding medium and stored under
`sterile conditions. Formulation A (micronized) was rolled
`for 0 hours, B for 4 hours, C for 7 hours and D for 38 hours.
`
`Formulation (w/v)
`
`9-hydroxyrisperidone palmitate
`
`polysorbate 20
`sodium carboxymethyl cellulose 30 mPa.s
`benzyl alcohol parenteral
`disodium hydrogen phosphate anhydrous
`
`7.02% (4.5%
`9-hydroxyrisperidone)
`1.1%
`1%
`1.5%
`0.9%
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 005
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1005 p. 005
`
`

`

`US 6,555,544 B2
`
`9
`
`-c0ntinued
`
`Formulation (w/v)
`
`sodium dihydrogen phosphate monohydrate
`water q.s. ad
`
`0.6%
`100%
`
`Viscosity and pH values for each of the thus obtained
`submicron dispersion A—D were as follows:
`
`10
`
`Formulation
`A
`B
`C
`D
`
`pH
`8.19
`7.9
`8.02
`7.98
`
`viscosity
`:7 mPa.s
`:8 mPa.s
`:9 mPa.s
`:10 mPa.s
`
`Particle size distribution was measured using a Master-
`sizer X and specific surface area using a Mastersizer S. The
`following values were obtained for formulations A—D
`
`Particle size gm
`
`Formulation
`A
`B
`C
`D
`
`10%
`2.51
`0.62
`0.52
`0.43
`
`50%
`6.03
`1.38
`0.74
`0.52
`
`90% specific surface area (mZ/g)
`7.64
`1.3
`6.83
`6.5
`1.15
`13.5
`0.65
`>15
`
`15
`
`25
`
`30
`
`Formulations C and D were put on a three month stability
`test and the following values were obtained for the stored
`formulations C and D:
`
`35
`
`Particle size gm
`
`Formulation
`C
`D
`
`10%
`0.27
`0.52
`
`50%
`0.40
`0.75
`
`90% specific surface area (mz/g)
`0.62
`13.5
`1.18
`not determined
`
`40
`
`10
`taneous injection, comprising a dispersion of particles con-
`sisting essentially of a therapeutically effective amount of a
`crystalline 9-hydr0xyrisperidone fatty acid ester having the
`formula
`
`or a salt, or a stereoisomer or a stereoisomeric mixture
`thereof, wherein R represents a straight C15 (pentadecyl)
`chain and the active ingredient
`is 9-hydr0xyrisperidone
`palmitate ester; having a surfactant adsorbed to the surface
`thereof in an amount effe