MXPA00004793A - Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters - Google Patents

Abstract

The present invention is concerned with a pharmaceutical composition suitableas 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 pharmaceuticall 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.

Description

AQUEOUS SUSPENSIONS OF 9-HIDROXYRISPERIDONE FATTY ACID ESTERS IN THE FORM OF SUBMICRON The present invention relates to 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 an ester or a 9-hydroxy fatty acid salt -risperidone, or a stereoisomer or stereoisomeric mixture thereof in the form of submicrons and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein; and to a process for preparing such composition. The invention further involves such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, schizophrenia, non-schizophrenic psychosis, behavioral alterations associated with neurodegenerative disorders, for example, in dementia, behavioral alterations in the delay mental and autism, Tourette syndrome, bipolar mania, depression, anxiety. Risperidone is the generic name for 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2 -met.l-4H-pyrido [1, 2- a] pyrimidin-4-one. The preparation and pharmacological activity thereof are described in EP-0,196,132 (corresponding to the patent E.U.A. 4,804,663). Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions, and injectable solutions are exemplified in said dosages. In practice, risperidone is usually administered as the base in a tablet or in an intramuscular, oral or pH-regulated solution. Particular solutions for oral or intramuscular administration are described in WO 96/01652. Risperidone is an extremely potent drug that has a relatively narrow therapeutic index. It can produce undesirable side effects with overdoses, most notably extra pyramidal syndrome (EPS) and to a lesser degree 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 relief of behavioral disturbances associated with neurodegenerative disorders, the total daily dose is generally lower and typically ranges from about 0.5 to about 2 mg. The differences between individuals and co-medication may require titration of doses in patients. It is known that risperidone is metabolized to 9-hydroxyrisperidone which has a pharmacological profile and potency comparable to that of the main drug risperidone, but which has a half-life for longer elimination. Risperidone is distributed and eliminated from brain tissues more rapidly than its metabolite 9-hydroxy-risperidone. The 9-hydroxyrisperidone, its enantiomeric forms and the C2-20 alkanoic acid esters are described in EP-0,368,288 (corresponding to US patent 5,254,556 and US patent 5,254,556). Such 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) formulation that is effective over a prolonged period, preferably of about 3 weeks or more, in particular about 1 month. WO 94/254460 (corresponding to EP-0,697,019) relates to a first such depot formulations and refers to the pamoate salt of risperidone, a risperidone salt form very poorly soluble in water, which can be suspended in a pharmaceutically acceptable vehicle, such as water or oil, and can be administered subcutaneously or intramuscularly. However, this salt has pharmacokinetic properties that 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 inadequate average duration of action, both characteristics which should be improved in a truly effective depot formulation. WO 95/13814 relates to sustained release formulations for parenteral administration in which risperidone is microencapsulated in a biodegradable, biocompatible, wall-forming material (e.g., a polymer such as dl- (polylactide-co-glycolide)) . Microencapsulated formulations have adequate pharmacokinetic properties, but require sophisticated preparation procedures in a plant constructed for that purpose. PCT / EP97 / 02504 discloses aqueous suspensions of fatty acid esters of 9-hydroxyrisperidone in water in which the prodrug of the active ingredient is in micronized form. Unexpectedly, these formulations proved too long-lasting in humans to be therapeutically useful. Accordingly, there is still a need to obtain an easily available and effective depot formulation of risperidone or a compound of the risperidone type. The nonaparticles 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 at the surface of the particles so that the effective average particle size is less than about 400 nm. It is also known that said particles are particularly useful for formulating active ingredients that are poorly soluble in water. The present invention is the result of investigations into the development of an efficient, well tolerated, sustained release or delayed (deposit) formulation of an alkanoic acid ester of 9-hydroxyrisperidone that is therapeutically effective for at least three weeks or more, in particular about 1 month. By the term "effective for at least three weeks or more", it is meant that the plasma level of the active ingredient, 9-hydroxyrisperidone (free alcohol released by hydrolysis from the alkanoic acid ester), should be above about 10. ng / ml. On the other hand, said plasma level should remain below a threshold value of approximately 100 ng / ml all the time in order to call the formulation "efficient". The threshold value is the average level in plasma over a considerable period, for example, for more than 15 minutes, above which patients may experience undesirable side effects, or conversely, the value of the plasma level below which the Systematic tolerance of the formulation in question is still acceptable. The threshold value does not accept high transient plasma levels for a short period, for example for less than 15 minutes, which is due, for example, to the unexpected sudden release of the active ingredient. Both mentioned characteristics - plasma levels above a minimum therapeutic concentration but below a threshold value that produces side effects - are considered basic requirements that a contemporary deposit formulation should meet in order to be acceptable to the intended patients. Limiting the number of administrations of the drug and the appearance of undesirable side effects after each administration will undoubtedly improve the patient's compliance with the therapy. However, beyond these basic requirements, a number of wishes can be identified that would further improve patient complianceyou. ; the two most notable being good local tolerance and ease of administration. Good local tolerance means minimal irritation and inflammation at the injection site; ease of administration refers to the size of the needle and the time necessary to administer a dose of a particular pharmacological formulation. Additionally, deposit formulations must be stable and must have a shelf life of at least two years under normal conditions. Investigations into the development of an efficient, well-tolerated, sustained release or delayed (deposit) formulation of an alkanoic acid ester of 9-hydroxyrisperidone that meets the aforementioned requirements led to the discovery that a suitable pharmaceutical composition as a The reservoir formulation for administration by intramuscular or subcutaneous injection should comprise: a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula: or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C9-19 alkyl radical; having a surfactant absorbed to the surface thereof in an amount effective to maintain a specific surface area > 4 m2 / g (corresponds to an effective average particle size less than 2,000 nm), in a pharmaceutically acceptable vehicle comprising water. Surprisingly, it appears that the aqueous suspensions of the micronised 9α-C-2 0-2o alkanoic acid esters of 9-hydroxyrisperidone (wherein R represents a C 9-19 straight alkyl radical) have an exceptionally long-lasting effect on humans, but not in test animals, particularly dogs. This is quite unexpected because the pharmacokinetics of drugs in humans and in dogs is often comparable. The pharmacokinetic properties in humans of the aqueous suspensions of the alkanoic acid esters of 9-hydroxyrisperidone depend on the particle size to a greater extent than previously thought possible. C10-20 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 ecosanoico It was found that the ester having a C15 chain (pentadecyl) and the corresponding active ingredient being the palmitate ester of 9-hydroxyrisperidone is the higher ester from a pharmacokinetic point of view, as well as from a tolerance point of view. 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 m2 / g (ie, corresponding to an average particle size less than 2,000 nm), preferably the specific surface area > 6 m2 / g, and in particular it is in the range of 10 to 16 m2 / g. It is believed that useful surface modifiers include those that physically adhere to the surface of the active agent but do not chemically bind 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. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, for example, macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, for example, commercially available Tweens ™, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminosilicate, triethanolamine, polyvinyl alcohol (PVA), poloxamers, tyloxapol and polyvinylpyrrolidone ( PVP). The majority of these dossiers 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. 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. Particularly preferred surface modifiers include polyvinylpyrrolidone; Tyloxapol; poloxamers, such as Pluronic ™ F68, F108 and F127 which are block copolymers of ethylene oxide and propylene oxide available from BASF; poloxamines, such as Tetronic ™ 908 (T908) which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine available from BASF; dextran; lecithin; Aerosol OT ™ (AOT) which is a dioctyl ester of sodium sulfosuccinic acid available from Cytec Industries; Duponol ™ P which is a sodium lauryl sulfate available from DuPont; Triton ™ X200 which is an alkylaryl polyethersulfonate available from Rohm and Hass; Tweens ™ 20, 40, 60 and 80 which are esters of polyoxyethylene sorbitan fatty acids available from ICI Specialty Chemicals; Span ™ 20, 40, 60 and 80 which are sorbitan esters of fatty acids; Arlacel ™ 20, 40, 60 and 80 which are sorbitan esters of fatty acids available from Hercules, Inc .; Carbowax ™ 3550 and 934 which are polyethylene glycols available from Union Carbide; Crodesta ™ F110 which is a mixture of sucrose stearate and sucrose distearate available from Croda Inc; Crodesta ™ SL-40 that is available at Croda, Inc; Hexyldecyltrimethylammonium chloride (CTAC); bovine serum albumin and SA90HCO which is c? 8H17CH2 (CON (CH3) CH2 (CHOH) 4 CH2OH) 2. Surface modifiers that have been found to be particularly useful include tyloxapol and a poloxamer, preferably, Pluronic ™ F108 and Pluronic ™ F68. Pluronic ™ F108 corresponds to poloxamer 338 and is the polyoxyethylene, polyoxypropylene block copolymer which is generally formed to the formula HO [CH2CH2?] X [CH (CH3) CH2?] V [CH2CH2O) zH in which the average values of x, y and z are respectively 128, 54 and 128.

Other trade names of poloxamer 338 are Hodag Nonionic ™ 1108-F available from Hodag and Synperonic ™ PE / F108 available from ICI America. The optimum relative amount of the antipsychotic agent and the surface modifier depends on various parameters. The optimum amount of the surface modifier may depend, for example, on the particular antipsychotic agent and the selected surface modifier, the critical micelle concentration of the surface modifier in case of micelles, the surface area of the antipsychotic agent, etc. The specific surface modifier is preferably 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 an antipsychotic agent and Pluronic ™ F108 as a surface modifier, a relative amount (w / w) of both ingredients of about 6: 1 is preferred. As used in the present invention, 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 conventional techniques known in the art, such as fractionation of sedimentation field flow, 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 an effective average particle size smaller than the effective average particle size, by example 2,000 nm. More preferably, essentially all of the particles have a size below 2,000 nm. The particles of the present 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 people to a size of average effective particle 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 friction. A general procedure for preparing the particles of the present 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 a mechanical medium in the presence of a grinding medium to reduce the effective average particle size. The antipsychotic agent selected in micronized form is obtained commercially or is prepared using techniques known in the art. i It is preferred that the particle size of the micronized antipsychotic agent is less than approximately 100 μm as determined by analysis by sieve. If the particle size of the micronized antipsychotic agent is greater of approximately 100 μm, it is then preferred that the particles of the antipsychotic agent be reduced in size to less than 100 μm. 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-for-weight percentage) can vary widely and depends on the selected antipsychotic agent, the selected surface modifier and other factors. Suitable concentrations of the antipsychotic agent in the compositions vary between 0.1 and 60%, preferably 0.5 to 30%, and more preferably, is about 7% (w / v). A more preferred method involves the addition of a surface modifier to the premix prior to its subjection to the mechanical means to reduce the effective average particle size. The concentration of the surface modifier (percentage weight in weight) can vary from 0.1% to 90%, preferably from 0.5% to 80%, and more preferably, is about 7% (w / v). The premix can be used directly by subjecting it to the 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 friction. Alternatively, the antipsychotic agent and, optionally, the surface modifier, may 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 can conveniently take the form of a dispersion mill. Suitable dispersion mills include a ball mill, a rub mill, a vibratory mill, a planetary mill, media mills such as a sand mill and a pearl mill. A media mill is preferred due to the relatively shorter grinding time required to provide the desired reduction in particle size. For the media mill, the apparent viscosity of the premix is preferably between 0.1 and 1 Pa.s. For the ball mill, the apparent viscosity of the premix is preferably between 1 and 100 mPa.ss. The grinding media for the particle size reduction step may be selected from rigid media preferably of spherical or particulate form having an average size of less than 3 mm and more preferred, less than 1 mm. Such means can conveniently provide the particles of the invention with shorter process times and can impart less wear to the grinding equipment. It is believed that the selection of the material for the grinding media is not important. However, al95% ZrO stabilized with magnesia, zirconium silicate and glass grinding media, provide particles having levels of contamination that are considered acceptable for the preparation of pharmaceutical compositions. Additionally, other media, such as polymer beads, stainless steel, titanium dioxide, alumina and 95% ZrO stabilized with trio are used. Preferred milling media have a density greater than 2.5 g / cm.sup.3 and include 95% ZrO stabilizing with magnesia and the polymer beads. The friction time can vary widely and depends mainly on the particular mechanical means and the selected processing conditions. For roller mills, process times of up to two days or more may be required. The particles should be reduced in size at a temperature that does not significantly degrade the antipsychotic agent. Processing temperatures of less than 30 to 40 ° C are commonly preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under ambient temperature conditions and at processing pressures that are safe and effective for the milling process. The surface modifier, if not present in the premix, should be added to the dispersion after the friction in an amount as described for the previous premix. The dispersion can then be mixed by, for example, stirring vigorously. Optionally, the dispersion can be subjected to a sonication step using, for example, an ultrasonic energy supply. The aqueous compositions according to the present invention further comprise, conveniently, a suspending agent and a regulator, and optionally one more of a preservative and an isotonizing agent. The particular ingredients can function as two or more of these agents simultaneously, for example, they can behave as a conservative and a regulator, or behave as a regulator and an isotonizing agent. Suitable suspending agents for use in the aqueous suspensions according to the present invention are cellulose derivatives, for example methylcellulose, carboxymethylcellulose and sodium hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene and polyoxyethylene. propylene ethers. Preferably, sodium carboxymethylcellulose is used in a concentration of 0.5 to 2%, more preferably 1% (w / v). Wetting agents suitable for use in aqueous suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, for example polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene and polyoxypropylene, sodium deoxycholate. Preferably, polysorbate 20 is used in a concentration of 0.5 to 3%, more preferred 0.5 to 2%, even more preferred 1.1% (w / v). Suitable regulating agents are the salt of weak acids and should be used in an amount sufficient to convert the dispersion from 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 disodium phosphate (anhydrous) mixture (typically about 0.9% (w / v)) and monosodium phosphate monohydrate (typically about 0.6% (w / v)). This regulator also makes the dispersion more sotonic and, in addition, less prone to the flocculation of the ester suspended in it. The preservatives are antimicrobials and antioxidants which may be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutyl, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl chloride, ? -picolinium, phenylmercuric acetate and thimerosal. In particular it is the benzyl alcohol which can be used in a concentration of up to 2% (w / v), preferably up to 1.5% (w / v). The isotonizing agents are, for example, sodium chloride, dextrose, mamitol, sorbitol, lactose, sodium sulfate. The suspensions conveniently comprise between 0 and 10% (w / v) of isotonizing agent. Mannitol can be used in a concentration of 0 to 7%. However, more preferably, between about 1 and about 3% (w / v), especially between about 1.5 and about 2% (w / v) of one or more electrolytes is used to render the suspension sotonic, apparently due to that the ions help to avoid the flocculation of the suspended ester. In particular, the regulator electrolytes serve as an isotonizing agent. A particularly desirable feature for an injectable depot formulation relates to the ease with which it can be administered. In particular, an injection as such should be possible using a needle as thin as possible in as short a time as possible.

This can be achieved with the aqueous suspensions of the present invention maintaining the viscosity below about 75 mPa.s., preferably below 60 mPa.s. Aqueous suspensions of such viscosity or lower can both be easily taken in a syringe and injected through a fine needle (for example, a needle of 21 G 1 1/2, 22 G 2 or 22 G 1 1/4. , the aqueous suspensions according to the present invention will comprise as much prodrug as can be tolerated so that the volume injected is kept to a minimum, and as little of the other ingredients as possible.In particular, such composition will comprise by weight taking as base 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 regulatory agents of pH sufficient to turn the composition from neutral to very slightly basic (pH 8.5), (d) from 0.5 to 2% (w / v) of suspending agent, (e) up to 2% (w / v) of preservatives and (f) water cbp 100% In view of the usefulness of 9-hydroxyrisperidone in the treatment of a quantity of disorders, the present invention also relates to a pharmaceutical composition as described hereinabove for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral alterations associated with neurodegenerative disorders, for example in dementia, alterations in behavior in mental retardation and autism, Tourette syndrome, bipolar mania, depression, anxiety. Additionally, the present invention relates to the use of a composition as described above in the present invention for the preparation of a medicament for the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral alterations associated with neurodegenerative disorders, for example in dementia, alterations in behavior in mental retardation and autism Tourett syndrome, bipolar mania, depression, anxiety. The present invention also relates to a method of treating warm-blooded animals, in particular humans suffering from psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral alterations associated with neurodegenerative disorders, for example in dementia, alterations in behavior in mental retardation and autism, Tourett syndrome, bipolar mania, depression, anxiety, said method comprising administering a therapeutically effective amount of an aqueous suspension as described above in the present invention. Typically, said formulation will be administered approximately every three weeks or even at longer intervals when possible. The dosage should vary from about 2 to 4 mg / kg / body weight The following examples are for the purpose of illustrating the present invention.

EXPERIMENTAL PART A. Preparation of the palmitate ester of 9-hydroxyrisperidone 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 (MgSO), filtered and evaporated. The mixture was triturated in diisopropyl ether (100 ml), filtered and recrystallized from isopropanol (60 ml). The crystals were separated by filtration and dried to give the palmitate ester of 9-hydroxyrisperidone (2.67 g, 80.4%).

B Composition Examples The following formulations were prepared according to the following general recipe: The surfactant, the suspending agent and the regulator were dissolved by stirring in water at room temperature and the solution was sterilized by heating for 30 minutes at 121 ° C. C.

The active ingredient (micronized) was sterilized by gamma irradiation at 25 kGY and suspended in the previously prepared solution under sterile conditions. The appropriate glass jars were loaded to approximately 30% of their total volume with the suspension and with the grinding medium, and then rolled at approximately 50 rpm for several hours. The submicron formulations were then sieved to remove the milling media and stored under sterile conditions. Formula A (micronized) was rolled for 0 hours, B 4 hours, C for 7 hours and D for 38 hours.

Formulation (w / v) 9-hydroxyrisperidone palmitate 7.02% (4.5% of 9-hydroxyrisperidone) Poisorbate 20 1.1% Sodium carboxymethylcellulose 30 mPa.s 1% Parenteral benzyl alcohol 1.5% Anhydrous disodium phosphate 0.9% Monosodium phosphate monohydrate 0.6% Water cbp 100% The viscosity and pH values for each of the submicron dispersions A-D thus obtained were as follows: Formulation PH viscosity A 8.19 ± 7 mPa.s B 7.9 ± 8 mPa.s C 8.02 + 9 mPa.s D 7.98 ± 10 mPa.s The particle size distribution was measured using a Mastersizer X and the specific surface area using a Mastersizer S. The following values were obtained for the A-D formulations: Formulation Particle Size (μm) surface area 10% 50% 90% specific (m2 / g) A 2.51 6.03 7.94 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 > fifteen Formulas C and D were placed in a stability test for three months and the following values were obtained for stored formulations C and D.

Formulation Particle Size (μm) surface area 10% 50% 90% specific (m2 / g) C 0.27 0.40 0.62 13.5 D 0.52 0.75 1.18 not determined C. Pharmacological examples C.1. Pharmacological test of F1 and analogous oily formulations Each of the four A-D formulations was administered to four beagle dogs intramuscularly in m. biceps femuris of the left hind paw at 2.5 mg / kg of body weight using a BD Microlance needle of 21 G 1/2; there was no problem with the syringe capacity. Blood samples were taken for 2 months in order to determine the plasma levels of 9-hydroxyrisperidone. The following pharmacokinetic parameters were calculated from the experimental data (mean ± Est. Dev.):

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a particle dispersion consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C9-19 alkyl radical; having a surfactant adsorbed to the surface thereof in an amount effective to maintain a specific surface area > 4 m2 / g (corresponding to an effective average particle size less than 2,000 nm), in a pharmaceutically acceptable vehicle comprising water.

2. - A composition according to claim 1, further characterized in that R represents a straight C15 (pentadecyl) chain and the active ingredient is the palmitate ester of 9-hydroxyrisperidone.

3. A composition according to claim 1, further characterized in that the composition also comprises a suspending agent, and optionally one or more of a preservative, a regulator and an isotonizing agent.

4. A composition according to claim 3, further characterized in that the suspending agent is sodium carboxymethylcellulose and the surfactant is polysorbate 20.

5. A composition according to claim 4, further characterized in that the preservative is alcohol benzyl and the isotonizing agent is mannitol or a phosphate regulator.

6. A composition according to claim 1, having a viscosity lower 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 pH regulating agents sufficient to render the composition from 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) of preservatives; and (f) water c.b.p. 100%

8. A pharmaceutical composition according to any of claims 1 to 7 for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral alterations associated with neurodegenerative disorders, for example, in the dementia, behavioral disturbances in mental retardation and autism, Tourette syndrome, bipolar mania, depression, anxiety.

9. The use of a composition according to any of claims 1 to 7 for the preparation of a medicament for the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, alterations in behavior associated with neurodegenerative disorders, for example , in dementia, behavioral alterations in mental retardation and autism, Tourette syndrome, bipolar mania, depression, anxiety.