U.S. patent application number 10/383118 was filed with the patent office on 2003-08-21 for aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters.
Invention is credited to Basstanie, Esther Dina Guido, Dries, Willy Maria Albert Carlo, Francois, Marc Karel Jozef.
Application Number | 20030157180 10/383118 |
Document ID | / |
Family ID | 8228929 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030157180 |
Kind Code |
A1 |
Francois, Marc Karel Jozef ;
et al. |
August 21, 2003 |
Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid
esters
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-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 composition for
use as a medicament in the treatment of 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.
Inventors: |
Francois, Marc Karel Jozef;
(Kapellen, BE) ; Dries, Willy Maria Albert Carlo;
(Merksplas, BE) ; Basstanie, Esther Dina Guido;
(Zandhoven, BE) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
8228929 |
Appl. No.: |
10/383118 |
Filed: |
March 6, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10383118 |
Mar 6, 2003 |
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09530687 |
May 2, 2000 |
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6555544 |
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09530687 |
May 2, 2000 |
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PCT/EP98/07321 |
Nov 10, 1998 |
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Current U.S.
Class: |
424/489 ;
514/259.41 |
Current CPC
Class: |
A61P 25/28 20180101;
Y10S 977/775 20130101; Y10S 977/926 20130101; A61K 9/146 20130101;
A61P 25/24 20180101; A61K 9/0019 20130101; A61P 25/18 20180101;
A61P 25/22 20180101; Y10S 977/915 20130101; A61P 25/00 20180101;
A61K 9/145 20130101 |
Class at
Publication: |
424/489 ;
514/259.41 |
International
Class: |
A61K 031/519; A61K
009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 17, 1997 |
EP |
97.203.568.7 |
Claims
1. A pharmaceutical composition suitable as a depot formulation for
administration by intramuscular or subcutaneous injection,
comprising a dispersion of particles consisting essentially of a
therapeutically effective amount of a crystalline
9-hydroxyrisperidone fatty acid ester having the formula 2or a
salt, or a stereoisomer or a stereoisomeric mixture thereof,
wherein R represents a straight C.sub.9-19alkyl radical; having a
surfactant adsorbed to the surface thereof in an amount effective
in maintaining a specific surface area>4 m.sup.2/g
(corresponding to an effective average particle size of less than
2,000 nm) in a pharmaceutically acceptable carrier comprising
water.
2. A composition according to claim 1 wherein R represents a
straight C.sub.15 (penta-decyl) 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 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 surfactant is polysorbate
20.
5. A composition according to claim 4 wherein the preservative is
benzyl alcohol and the isotonizing agent is mannitol or a phosphate
buffer.
6. A composition according to claim 1 having a viscosity of less
than 75 mPa.s.
7. A composition according to claim 1 comprising 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 (up to 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%.
8. A pharmaceutical composition as claimed in any one of claims 1
to 7 for use as a medicament in the treatment of 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.
9. The use of a composition as claimed in any one of claims 1 to 7
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.
Description
[0001] The present invention is concerned with a pharmaceutical
composition suitable as a depot formulation for administration via
intramuscular or subcutaneous injection, comprising:
[0002] (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
[0003] (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.
[0004] 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 associated with
neurodegenerative disorders, e.g. in dementia, behavioural
disturbances in mental retardation and autism, Tourette's syndrome,
bipolar mania, depression, anxiety.
[0005] 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 U.S. Pat. No.
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
WO-96/01652.
[0006] 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 typically ranges from about 0.5 to about 2 mg.
Inter-individual differences and co-medication may necessitate dose
titrating in patients.
[0007] 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 C.sub.2-20 alkanoic acid esters
thereof are described in EP-0,368,388 (corresponding to U.S. Pat.
No. 5,158,952 and U.S. Pat. No. 5,254,556). Said esters are
considered to be potentially valuable prodrugs of the active
metabolite of risperidone for use in depot formulations.
[0008] 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, preferably
about 3 weeks or more, in particular about 1 month.
[0009] 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 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
truly effective depot formulation.
[0010] 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 suitable pharmacokinetic
properties, but require sophisticated processes of preparation in a
purpose-built plant.
[0011] PCT/EP97/02504 discloses aqueous suspensions of
9-hydroxyrisperidone fatty acid esters in water wherein the prodrug
of the active ingredient is in micronized form. Unexpectedly, these
formulations prove to be far too longlasting in humans to be
therapeutically useful.
[0012] Consequently, there is still a need for an effective and
readily available depot formulation of risperidone or a
risperidone-like compound.
[0013] 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.
[0014] 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, 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 liberated 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.
[0015] 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 patients3 compliance; the two most
notable being good local tolerance and ease of administration.
[0016] 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.
[0017] 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:
[0018] a dispersion of particles consisting essentially of a
therapeutically effective amount of a crystalline
9-hydroxyrisperidone fatty acid ester having the formula 1
[0019] or a salt, or a stereoisomer or a stereoisomeric mixture
thereof, wherein R represents a straight C.sub.9-9alkyl radical;
having a surfactant absorbed to the surface thereof in an amount
effective in maintaining a specific surface area >4 m.sup.2/g
(corresponding to an effective average particle size of less than
2,000 nm), in a pharmaceutically acceptable carrier comprising
water.
[0020] Surprisingly, it appears that aqueous suspensions of
micronized 9-hydroxyrisperidone C.sub.10-20 alkanoic acid esters
(wherein R represents a straight C.sub.9-19 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.
[0021] C.sub.10-20 alkanoic 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. The ester having a C.sub.15 (pentadecyl) chain and
the active ingredient corresponding thereto being the
9-hydroxyrisperidone palmitate ester was found to be the superior
ester from a pharnacokinetic, as well as from a tolerance point of
view.
[0022] The nanoparticles of the present invention have a surfactant
or surface modifier adsorbed on the surface thereof in an amount
sufficient to maintain a specific surface area >4 m.sup.2/g
(i.e. corresponding to an average particle size of less than 2,000
nm), preferably the specific surface area >6 m.sup.2/g, and in
particular is in the range from 10 to 16 m.sup.2/g. Useful surface
modifiers are believed to include those which physically adhere to
the surface of the active agent but do not chemically bond
thereto.
[0023] 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. Preferred surface
modifiers include nonionic and anionic surfactants. 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,
polyoxyethylene allcyl ethers, e.g., macrogol ethers such as
cetomacrogol 1000, polyoxyethylene castor oil derivatives,
polyoxyethylene sorbitan fatty acid esters, e.g., the commercially
available Tweens.TM., polyethylene glycols, polyoxyethylene
stearates, colloidal silicon dioxide, phosphates, sodium
dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminate silicate, triethanolamine, polyvinyl alcohol
(PVA), poloxamers, tyloxapol and polyvinylpyrrolidone (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 available and/or can be prepared by techniques known
in the art. Two or more surface modifiers can be used in
combination.
[0024] Particularly preferred surface modifiers include
polyvinylpyrrolidone; tyloxapol; poloxamers, such as Pluronic.TM.
F68, F108 and F127 which are block copolymers of ethylene oxide and
propylene oxide available from BASF; poloxamines, such as
Tetronic.TM. 908 (T908) which is a tetrafunctional block copolymer
derived from sequential addition of ethylene oxide and propylene
oxide to ethylenediamine available from BASF; dextran; lecithin;
Aerosol OT.TM. (AOT) which is a dioctyl ester of sodium
sulfosuccinic acid available from Cytec Industries; Duponol.TM. P
which is a sodium lauryl sulfate available from DuPont; Triton.TM.
X-200 which is an alkyl aryl polyether sulfonate available from
Rohm and Haas; Tweens.TM. 20, 40, 60 and 80 which are
polyoxyethylene sorbitan fatty acid esters available from ICI
Speciality Chemicals; Span.TM. 20, 40, 60 and 80 which are sorbitan
esters of fatty acids; Arlacel.TM. 20, 40, 60 and 80 which are
sorbitan esters of fatty acids available from Hercules, Inc.;
Carbowax.TM. 3550 and 934 which are polyethylene glycols available
from Union Carbide; Crodesta.TM. F110 which is a mixture of sucrose
stearate and sucrose distearate available from Croda Inc.;
Crodesta.TM. SL-40 which is available from Croda, Inc.; hexyldecyl
trimethyl ammonium chloride (CTAC); bovine serum albumin and
SA90HCO which is C.sub.18H.sub.17CH.sub.2
(CON(CH.sub.3)CH.sub.2(CHOH).su- b.4CH.sub.2OH).sub.2. The surface
modifiers which have been found to be particularly useful include
tyloxapol and a poloxamer, preferably, Pluronic.TM. F108 and
Pluronic.TM. F68.
[0025] Pluronic.TM. F108 corresponds to poloxamer 338 and is the
polyoxyethylene, polyoxypropylene block copolymer that conforms
generally to the formula
HO[CH.sub.2CH.sub.2O].sub.x[CH(CH.sub.3)CH.sub.20].sub.y[C-
H.sub.2CH.sub.2O).sub.zH in which the average values of x, y and z
are respectively 128, 54 and 128. Other commercial names of
poloxamer 338 are Hodag Nonionic.TM. 1108-F available from Hodag,
and Synperonic.TM. PE/F108 available from ICI Americas.
[0026] 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 preferably is present in an amount of 0.1
to 1 mg per square meter surface area of the antipsychotic agent.
In case 9-hydroxyrisperidone palmitate is used as antipsychotic
agent and Pluronic.TM. F108 as a surface modifier, a relative
amount (w/w) of both ingredients of approximately 6:1 is
preferred.
[0027] 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 particle
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.
[0028] 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 mechanical 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.
[0029] A general procedure for preparing the particles of this
invention includes
[0030] (a) obtaining an antipsychotic agent in micronized form;
[0031] (b) adding the micronized antipsychotic agent to a liquid
medium to form a premix; and
[0032] (c) subjecting the premix to mechanical means in the
presence of a grinding medium to reduce the effective average
particle size.
[0033] 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 .mu.m as determined by
sieve analysis. If the particle size of the micronized
antipsychotic agent is greater than about 100 .mu.m, then it is
preferred that the particles of the antipsychotic agent be reduced
in size to less than 100 .mu.m.
[0034] 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 concentrations 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).
[0035] 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).
[0036] The premix can be used directly by subjecting it to
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.
[0037] 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 Pa.s. For ball milling, the apparant viscosity of the
premix preferably is anywhere between 1 and 100 mPa.s.
[0038] The grinding media for the particle size reduction step can
be selected from rigid media preferably spherical or particulate 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 pharmaceutical
compositions. Further, other media, such as polymeric beads,
stainless steel, titania, alumina and 95% ZrO stabilized with
yttrium, are useful. Preferred grinding media have a density
greater than 2.5 g/cm.sup.3 and include 95% ZrO stabilized with
magnesia and polymeric beads.
[0039] The attrition time can vary widely and depends primarily
upon the particular mechanical means and processing conditions
selected. For rolling mills, processing times of up to two days or
longer may be required.
[0040] 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.degree. 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.
[0041] 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.
[0042] 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.
[0043] 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 1% (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
polyoxy-propylene 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).
[0044] 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 phosphate 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.
[0045] 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-.gamma.-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).
[0046] 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 flocculation of the suspended ester. In particular
electrolytes of the buffer serve as isotonizing agent.
[0047] 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 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
1/222 G 2 or 22 G 1 1/4 needle).
[0048] 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:
[0049] (a) from 3 to 20% (w/v) of the prodrug;
[0050] (b) from 0.5 to 2% (w/v) of a wetting agent;
[0051] (c) one or more buffering agents sufficient to render the
composition neutral to very slightly basic (pH 8.5);
[0052] (d) from 0.5 to 2% (w/v) of a suspending agent;
[0053] (e) up to 2% (w/v) preservatives; and
[0054] (f) water q. s. ad 100%.
[0055] 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 associated with neurodegenerative disorders, e.g. in
dementia, behavioural disturbances in mental retardation and
autism, Tourette's syndrome, bipolar mania, depression,
anxiety.
[0056] 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.
[0057] The present invention further concerns a method of treating
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.
[0058] The following examples are intended to illustrate the
present invention.
[0059] Experimental Part
[0060] A. Preparation of 9-hydroxyrisperidone Palmitate Ester.
[0061] N,N-Dicyclohexylcarbodiimide (1.39 g; 6.8 mmol) was added to
a solution of hexa-decanoic 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 (MgSO.sub.4), 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 (2.67 g; 80.4%).
[0062] B. Composition Examples.
[0063] 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.degree. 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.
1 Formulation (w/v) 9-hydroxyrisperidone palmitate 7.02% (4.5%
9-hydroxyrisperidone) polysorbate 20 1.1% sodium carboxymethyl
cellulose 1% 30 mPa .multidot. s benzyl alcohol parenteral 1.5 %
disodium hydrogen phosphate 0.9 % anhydrous sodium dihydrogen
phosphate 0.6 % monohydrate water q.s. ad 100%
[0064] Viscosity and pH values for each of the thus obtained
submicron dispersion A-D were as follows:
2 Formulation pH viscosity A 8.19 .+-.7 mPa .multidot. s B 7.9
.+-.8 mPa .multidot. s C 8.02 .+-.9 mPa .multidot. s D 7.98 .+-.10
mPa .multidot. s
[0065] Particle size distribution was measured using a Mastersizer
X and specific surface area using a Mastersizer S. The following
values were obtained for formulations A-D:
3 Particle size (.mu.m) Formulation 10% 50% 90% specific surface
area (m.sup.2/g) A 2.51 6.03 7.64 1.3 B 0.62 1.38 6.83 6.5 C 0.52
0.74 1.15 13.5 D 0.43 0.52 0.65 >15
[0066] 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:
4 Particle size (.mu.m) Formulation 10% 50% 90% specific surface
area (m.sup.2/g) C 0.27 0.40 0.62 13.5 D 0.52 0.75 1.18 not
determined
[0067] C. Pharmacological Examples.
[0068] C. 1. Pharmacological Testing of F1 and Analogous Oil
Formulations.
[0069] Each of the four formulations A-D were administered to four
beagle dogs intramuscularly in the m. biceps femuris of the left
hind paw at 2.5 mg/kg bodyweight using a 21 G 1 1/2 BD Microlance
needle; syringability posed no problem. Blood samples were
withdrawn during 2 months in order to determine 9-hydroxy
risperidone plasma levels. The following pharmacokinetic parameters
were calculated from the experimental data (mean .+-.S.D.):
5 formulation C.sub.max (ng/ml) T.sub.max (days) AUC.sub.0-t
(ng.h/ml) A 41.1 (.+-.22.1) 12 (.+-.5) 19487 (.+-.7697) B 86.4
(.+-.30.5) 7 (.+-.3) 25769 (.+-.9782) C 139 (.+-.33) 1.8 (.+-.1.5)
28603 (.+-.4305) D 132 (.+-.60) 6.3 (.+-.1.5) 34852 (.+-.14055)
* * * * *