FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)


INJECTABLE SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION
SUN PHARMA ADVANCED RESEARCH COMPANY LTD.

A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR OFFICE AT 17/B, MAHAL INDUSTRIAL ESTATE, OFF MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA, INDIA
The following specification describes the invention


The present invention relates to an injectable pharmaceutical composition comprising antipsychotic agents having basic groups.
BCKGROUND OF THE INVENTION
Psychotic disorders are difficult mental disorders to treat. Patients having such a disorder are often reluctant to seek the medical attention necessary to diagnose the disorder. Such reluctance is often related to the patient's fear of the stigma associated with seeking psychiatric help or to the patient's feelings of worthlessness associated with depression. Moreover, once patients seek competent psychiatric help, it is difficult to successfully treat the disorder through psychoanalytic approaches alone.
The treatment of psychotic conditions requires the patient to take the medicament daily for prolonged periods of time. Unfortunately, the conventional immediate release oral delivery systems for antipsychotics yield effective plasma levels during a limited time interval, often deliver inaccurate doses and require frequent dosing which makes the treatment patient non compliant. In addition, frequent dosing of immediate release formulations leads to peak and trough levels of antipsychotic agent causing undesirable side effects or inadequate efficacy. Thus, patient compliance is a significant issue which causes re-lapse (or under-treatment) in a large number of the afflicted patient population treated with the oral administration regimens.
Long-acting injectable antipsychotic dosage forms would be valuable in maintenance therapy and would enhance patient compliance. Currently available long-acting neuroleptics include viscous oily solutions of oil-soluble ester derivatives of the neuroleptic compounds. Viscous oily depots of flupentixol, fluphenazine, haloperidol, zuclopenthixol, and pipotiazine are administered by deep intra-muscular (IM) injection, repeated at intervals ranging from 14-35 days. Depending on to the volume of injection, they may cause the site of injection complications like, skin thickening, infection/erythema, nodules/lumps, bleeding, pain, tenderness and/or seepage of formulation form site of injection.
Other long acting antipsychotic compositions disclosed in the art comprise long-acting salts of antipsychotics such as risperidone pamoate and olanzapine pamoate. US patent Number US 5,612,346, US patent 5,723,467 discloses the process of preparing pamoate acid addition salt of risperidone and compositions comprising the same. But this pamoate salt being very hydrophobic is suspended in oil bases for preparing injectable. US20080096871 discloses invention related olanzapine pamoate dihydrate, pharmaceutical compositions thereof and use in treating certain mental disorders, such as schizophrenia.
US20070077304 describes an injectable depot formulation that includes a biocompatible polymer, an organic solvent combined with a biocompatible polymer to form a viscous gel and a small molecule drug incorporated in viscous gel for sustained release. Sustained release of risperidone is disclosed in the examples. These compositions are packed in prefilled syringes for storage and require heating using a circulator water bath to
' 1 5 APR 2009

inject the gel. This patent application teaches to use a organic solvent such as benzyl alcohol or benzyl benzolate to dissolve the biodegradable polymer.
United States patent application number US20060I59721 describes an invention comprising implants of comprising a therapeutic drug and PLA and/or PGA. It also describes methods of maintaining drug levels and releasing therapeutic drug in substantially linear rate, and treating schizophrenia and other disorders. United States patent application number US20050240166, discloses an implantable device, formulation and method for anti-psychotic therapy using risperidone. The implantable device disclosed both these patent applications need to be used only with the help of surgery which may not be desirable always.
Controlled release compositions have also been developed by formulating a microparticle of risperidone in a polymeric matrix material. Such compositions include microencapsulation of risperidone in poly(lactide-co-glycolide) (PLG) polymer for delivery of the active agent to the patient for a period of at least 14 days. This composition is marketed under the trade name RISPERDAL® CONSTA® and is described in United States Patent No. 5688801, 5770231, 5792477, 5916598, 5965168, 6110921, 6194006, 6264987 and 6368632, among others. The drug release from these microsphere compositions may be by diffusion or by biodegradation of the matrix material or both. Risperdal Consta is administered by deep 1M gluteal injection every two (2) weeks. A particular limitation of the Risperdal Consta is that the accumulation of PLG in the body may occur due the high molecular weight (PLGA 75:25, approximately >100,000). The total degradation time for such a polymer does not match the time of action (14 d). This infers that the polymer may stay in the body even after the complete release of drug leading to polymer accumulation over a period of time. Product label states that there is a latent period of about week 3 after the injection before plasma active-moiety levels start to increase. The latent period necessitates supplementation with oral risperidone during the first 3-4 weeks after the first injection. Additionally, after dose titration to higher or a lower dose, the effect is seen after 3-4 weeks. Microparticies characteristics such as size and morphology demands soaking time suggesting poor wettability, suspendability. Thick and long needle, deep intragluteal injection suggests poor injectability, injection site reactions. The product is stable for not more than 7 days at 25°C.
United States patent number US 5,871,778 and United States Patent Number US 5,656,299 discloses a sustained release microsphere preparation which is produced by including a hydrophobic antipsychotic in the form of microcrystals having particle size of 0.5 microns to 5 microns into a base composed of a high molecular weight polymer having in vivo histocompatibility such as polylactic acid, poiy(lactic-coglycolic) acid or the like, and a process for the production thereof.
United States Patent Number 6,631,358 (hereinafter referred to as Patent '358) provides a biocompatible polymer particle for sustained release of a pharmaceutical substance, wherein said particle comprises a substantially amorphous biocompatible, polymer having a crystallinity of no more than 25 %, wherein the said pharmaceutical substance is combined with an amphiphilic material to form a hydrophobic ion paired complex;
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wherein said biocompatible polymer comprises at least one polymer selected from the group consisting of poly (L-lactic acid), poly (D-lactic) acid, polyglycolic acid, polyanhydride, polycarboxyphenoxyhexane, polybutyrate, and cellulose hwerein said amphophilic material is selected from the group consisting of sodium dodecyl sulfate, bis- (2-ethylhexyl) sodium sulfosuccinate, cholesterol sulfate and sodium laurate, wherein said particle comprises a substantially homogeneous mixture of said pharmaceutical substance and said amorphous biocompatible polymer, wherein the weight percentage of said hydrophobic ion paired complex to the total weight of said hydrophobic ion paired complex and said biocompatible polymer is in the range of about 15 % to 70 %. The patent '358 discloses a laundry list of pharmaceutical agents and discloses the sustained release composition for drugs like protein.
Another publication namely WO2006010939AI discloses a composition for oromucosal delivery of a biologically active agent, which composition releases the active agent within 5 minutes when applied to an oramucosa! surface in use, comprises a biologically active agent and a matrix-former. The biologically active agent may be present as an ion pair complex. However, the patent application teaches that for a basic drug, a lipophilic species according to the invention is, for I example, a fatty acid or another lipophilic species. For a basic drug, a lipophilic species according to the invention may, for example, be one or more of the following fatty acids, or long-chain alkyl sulfonic acids, or a long-chain alkyl sulfuric acids: caproic, caprylic, cupric. lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, Iinoleic, linolenic, licanic or arachidonic. Further, the patent application teaches that for acidic drugs a lipophilic species, for example, a fatty amine or another lipophilic species. For an acidic drug, a lipophilic species according to the invention is. for example, cetrimide, olearnidopropyl dimethylamine, didecyldimethyl ammonium chloride, quaternary surfactants, cetylpyridinium chloride, hexetidine, benzalkonium chloride, arginine and cholesterol esters, carbamates, carbonates and ketals and the following fatty amines and acid amides: caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, iinoleic, linolenic, licanic, arachidonic and/or clupanadonic may be suitable.
According to the present invention it was found that for antipsychotic agents having basic group, cholesteryl sulfate or its alkali metal salt was suitable for the formation of the ion pair complex. Surprisingly and unexpectedly, we found that the alkali metal salt of cholesteryl sulfate was capable of forming the ion pair complex that surprisingly provided a release of the antipsychotic agent for a long duration and the composition comprising such complex was also stable upon long term storage.
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OBJECTS OF THE INVENTION
It is the object of the present invention to provide an injectable sustained release composition of antipsychotic agents having basic groups.
It is another object of the present invention to provide an injectable controlled release composition of antipsychotic agents that do not have any sudden burst release.
It is yet another object of the present invention to provide an injectable controlled release composition of antipsychotic agents that is prepared by a process which contain very low amount of organic solvents such as ethyl acetate, acetone.
It is further object of the invention to avoid use of very high molecular weight biodegradable polymers.
SUMMARY OF THE INVENTION
The present invention may be summarized as follows:
A. An ion-pair complex of an antipsychotic agent with cholesteryl sulfate or its alkali metal salt.
B. An ion-pair complex of A wherein the antipsychotic agent is selected from the group consisting of
risperidone, olanzapine, clozapine, quetiapine, aripiprazole, paliperidone, asenapine, lioperidone,
zotepine, ziprasidone, sertindole, bifeprunox, meperone and Amisulpiride.
C. An ion-pair complex of A wherein the ratio of antipsychotic agent to the cholesterol sulfate ranges
from about 1:10 to about 10:1.
D. An injectable sustained release pharmaceutical composition comprising an ion-pair complex described
in A above and a biodegradable polymer.
E. An injectable sustained release pharmaceutical composition as described in A above wherein ion pair
complex of antipsychotic agents with alkali metal salt of cholesteryl sulphate provides release of the
antipsychotic agent for a period of days.
F. An injectable sustained release pharmaceutical composition described in E wherein composition further
comprises biodegradable polymers of molecular weight less than 100,000 Daltons, preferably less than
80, 000 Daltons in admixture with the ion pair complex.
G. An injectable sustained release pharmaceutical composition described in F wherein composition is in
the form of microparticies.
H. An injectable sustained release pharmaceutical composition as in F above, wherein the said
biocompatible and biodegradable polymer is poly (lactic-co-glycolic acid) or poly (lactic acid). I. An injectable sustained release pharmaceutical composition as in H above, wherein the molar ratio of
lactide to glycolide in poly(lactic-co-glycolic acid) ranges from about 50:50 to about 100:0. J. An injectable sustained release pharmaceutical composition as in F above wherein the ratio of an ion
pair complex of a antipsychotic agents with cholesteryl sulphate or its alkali metal salt to biodegradable
carrier ranges from about 95 : 5 to about 5 : 95.
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K. An injectable sustained release pharmaceutical composition as in G above, wherein the amount of
biodegradable and biocompatible carrier is present in amount ranging from 5 %w/w to about 80 %w/w
of the total weight of the microparticles. L. An injectable sustained release pharmaceutical composition as in G above, wherein the antipsychotic
agent - cholesterol sulfate complex is present in amount ranging from about 20 % w/w to about 95 %
w/w of the total weight of the microparticles. M. An injectable sustained release pharmaceutical composition as described in G above wherein the
microparticles are further coated with a biodegradable polymer. N. An injectable sustained release pharmaceutical composition as in M above, wherein the biodegradable
polymer used for coating is poly (lactic-co-glycolic acid) or poly(lactic acid). O. An injectable sustained release pharmaceutical composition as in N above, wherein the molecular
weight of poly (lactic-co-glycolic acid) ranges from about 10,000 Daltons to about 30,000 Daltons. P. An injectable sustained release pharmaceutical composition as in N above, wherein the molecular
weight of poly (lactic acid) ranges from about 10, 000 Daltons to about 20,000 Daltons. Q. An injectable sustained release pharmaceutical composition as in A to D above, wherein the
antipsychotic agent is released over a period of at least 1 day. R. An injectable sustained release pharmaceutical composition as in E and F above, wherein the
antipsychotic agent is released over a period of at least 7 days. S. An injectable sustained release pharmaceutical composition as in F above, wherein the antipsychotic
agent is released over a period of at least 14 days. T. An injectable sustained release pharmaceutical composition as in M above, wherein the antipsychotic
agent is released over a period up to 30 days.
DESCRIPTION OF THE DRAWINGS
Figure 1 indicates the release of risperidone from the composition prepared according to Example 1, Example I a, Example 1 b and Example 1 c. The data of Example 1 a indicates that the risperidone in the form of ion pair complex with the cholesteryl sulphate sodium salt showed a slow release. The data of Example lb indicates the effect of incorporation of this complex into the biodegradable polymer having 66,000 Daltons molecular weight. The data of example lc where the microparticles of example lb were coated with biodegradable polymer indicate a further slow release of risperidone from the microparticles.
Figure 2 indicates the release of risperidone from the composition prepared according to Example 2, Example 2a, Example 2b and Example 2c. The data of Example 2a indicates that the risperidone in the form of ion pair complex with the cholesteryl sulphate sodium salt showed a fast release similar to risperidone base alone (example 2). The data of Example 2b indicates the effect of incorporation of this complex into the biodegradable polymer having molecular weight of about 66,000 Daltons. The data of example 2c where the microparticles of example 2b when further coated with biodegradable polymer indicate a further slow release of risperidone from the microparticles.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an ion-pair complex of an antipsychotic agent having a basic group with alkali metal salt of cholesteryl sulphate.
The term "biocompatible carrier", as used herein means a carrier, the degradation products of which are non¬toxic, and which causes no significant deleterious or untoward effects, such as a significant immunological reaction at the injection site. The biocompatible carrier that may be used to incorporate the antipsychotic agent -cholesterol sulfate complex so as to provide sustained release of the antipsychotic agent can be biodegradable polymers or blends or copolymers thereof or lipids selected from cholesterol and steroid derivatives. The term "biodegradable", as defined herein, means the composition will degrade or erode in vivo to form smaller non¬toxic chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes.
As used in the present invention the term 'ion pair complex' refers to an ionic interaction that occurs between two opposite charged compounds. In the instant case, the two oppositely charged compounds are antipsychotic agent (s) having basic group and the cholesteryl sulfate having acidic group. The cholesteryl sulphate or its alkali metal salt interacts with the oppositely charged antipsychotic agents having basic group and an ion-pair complex is thus formed. The ion-pair complex of the cholesteryl sulphate or its alkali metal salt and the antipsychotic agent having basic group was surprisingly found to exhibit a retard effect on the release of the antipsychotic agent with or without incorporation into a biodegradable polymer.
Without wishing to be bound by any theory, the applicants wish to state that it may be the free alkali metal ion that remains in the ion pair complex when the complex is not either passed through cation-exchange resin, or not recrystallized from a solvent or mixture of solvents or any other method which results in removal of the free alkali metal ion, that causes retarding effect on the release of an antipsychotic agent from the complex. It was observed that when such an ion pair complex was processed to remove the free alkali metal ion, the hindrance effect on release of the antipsychotic agent was substantially reduced. Therefore, when a longer sustained release effect is desired, the ion pair complex comprising free alkali metal ions is found to be more suitable.
The present invention also provides an injectable, sustained release pharmaceutical composition comprising a antipsychotic agent having basic group in the form of an ion pair complex with cholesteryl sulfate or its alkali metal salt and pharmaceutically acceptable carrier comprising one or more biodegradable polymers having a molecular weight of less than 100,000 Daltons wherein the composition provides sustained release for a period of days.
The antipsychotic agents that are suitable for the compositions of the present invention include, and are not limited to risperidone, olanzapine, clozapine, quetiapine, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, ziprasidone, sertindole, bifeprunox, rneperone and Amisulpiride and their pharmaceutically acceptable salts. The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with
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1 5 APR 2009
suitable acids, such as those of inorganic acids, for example hydrochloric, hydrobromic. nitric, sulphuric or phosphoric acids or of organic acids, such as organic carboxylic acids, for example glycolic, maleic. hydroxymaleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonicacid and the like.



Sodium salt of cholesteryl sulfate
Cholesterol sulfate is used in the form of its pharmaceutical ly acceptable form. The suitable salts of cholesterol sulfate for preparation of the complex includes alkali metal salts of cholesterol sulfate like cholesterol sulfate sodium, cholesterol sulfate potassium, lithium cholesterol sulfate, and the like. Preferably, the alkali metal sail of cholesterol sulfate used in the compositions of present invention is cholesterol sulfate sodium. In one embodiment, the antipsychotic agents used in the present invention include risperidone or olanzapine, and the molar ratio of risperidone or olanzapine to cholesterol sulfate salt in the complex, varies from about 1:0.1 to about 1:10, more preferably about 1:0.5-1:2.
The antipsychotic agent-cholesterol sulfate complex of the present invention contains antipsychotic agent having basic group and cholesterol sulfate. In one embodiment, the antipsychotic agent used \s risperidone or its pharmaceutical^ acceptable salt and is present as a complex with sodium salt of cholesteryl sulfate. In an embodiment, the therapeutically antipsychotic agent is olanzapine and the complex is formed with sodium salt of cholesterol sulfate. In yet another embodiment, the therapeutically antipsychotic agent is aripiprazole and the ion pair complex is formed by cholesterol sulfate sodium. The risperidone and sodium salt of cholesterol sulfate present as risperidone-cholesterol sulfate complex, are formed by dissolving the two in a suitable solvent, for example, glacial acetic acid. In one embodiment, the molar ratio of risperidone to cholesterol sulfate salt in the complex, varies from about 1:0.1 to about 1:10, more preferably about 1:0.5-1: 2.
In an embodiment the antipsychotic agent-cholesterol sulfate complex of the present invention provides a sustained release of antipsychotic agent for at least about 24 h, more preferably for about 7 days and most preferable about 14 days.
We have found that for antipsychotic agent having basic group, alkali metal salt of cholesteryl sulfate were particularly suitable for the formation of the ion pair complex. Surprisingly and unexpectedly, we found that only cholesteryl sulfate in the form of alkali metal salt were capable of forming the ion pair complex that provided the release of the antipsychotic agent for a long duration i.e in days. This surprising effect on solubility provides the feasibility to choose a biodegradable polymer of even lower molecular weight less than 100, 000 Daltons when a sustained release of the antipsychotic agent for long duration i.e as many as 30 days is desired. It is the antipsychotic agent in the form of an ion pair complex that provides a sustained release composition of the antipsychotic agent that is suitable for release from few days to as long as release for a month or more. The lower molecular weight of the biodegradable polymers such as PLGA are generally
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desirable because its microparticles results in lesser loading in the body due to faster degradation rate (i.e.
* degradation time of 3 to 4 weeks) in the body and less chances of granuloma formation on multiple dosing
compared to compositions containing PLGA having higher molecular weight, which results higher loading in
the body, slower degradation time (i.e. degradation time of about 4 to about 5 months) and greater probability of
granuloma formation.
In one aspect of the present invention, the sustained release composition is in the form of microspheres or microparticles. Suitable biocompatible and biodegradable polymer like poly(lactic acid), a poly(glycolic acid), a poly(lactic-co-glycolic acid), or a poly(lactide-co-glycolide) and lipids selected from cholesterol and its derivatives can be used to further prolong the release of antipsychotic agent from the cholesterol sulfate complex. The amount of the polymers or lipids used in the microspheres of the present invention can be varied in any convenient amounts depending on the type antipsychotic agent, the amount of control of release required. The weight ratio of the polymer or lipids in the microspheres of the present invention can also be varied in such a manner in addition to the amount of cholesterol sulfate used in the complex formation so as to provide a controlled delivery of the antipsychotic agent to the patient. Poly (lactic-co-glycolic acid) is used to prolong the duration of release of antipsychotic agent from antipsychotic agent having basic group -cholesterol sulfate complex. The poly (lactic-co-glycolic acid) is a copolymer of poly(glycolic acid) and poly-D,L-lactic acid. The molar ratio of lactide to glycolide in such copolymers may be present in the range from about 50:50 to about 100:0, preferably about 50:50. The molecular weight of poly(lactic-co-glycolic acid) has a significant influence on the biodegradation rate of poly(lactic-co-glycolic acid). For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microspheres and then degrade. The drug can also be released from the microspheres as the polymer excipient bioerodes. The drug can be made to be released from the microspheres by both diffusional as well as biodegradation by selection of appropriate amount and the polymer and its molecular weight. In a preferred embodiment, the poly(lactic-co-glycolic acid) that can be used in the composition of the present invention has a molecular weight lesser than about 100,000 Daltons. Poly(lactic acid) or d,l-Po!y(lactic acid) is used to prolong the duration of release of antipsychotic agent from the antipsychotic agent -cholesterol sulfate complex. The molecular weight of Poly(lactic acid) that can be used in the compositions of the present invention ranges from about 1000 Daltons to about 75000 Daltons, preferably from about 50,000 Daltons to a about 70,000 Daltons.
In an embodiment of the present invention, the ratio of the ion pair complex to biocompatible and biodegradable carrier in the injectable sustained release pharmaceutical composition of the invention, varies from about 95:5 to about 20:80 preferably from about 95:5 to about 50:50, more preferably from about 80:20 to about 60:40. In another embodiment of the invention, the ion pair complex may be present in the injectable sustained release pharmaceutical composition, in amounts ranging from about 20 %w/w to about 95 %w/w, preferably from about 50 % w/w to about 90 % w/w, more preferably from about 60% w/w to about 85 % w/w, of the total weight of the composition. In another embodiment, the biocompatible and biodegradable carrier may be present in the injectable sustained release pharmaceutical composition, in amounts ranging from about 5%w/w to about
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80%w/w, preferably from about 5% w/w to about 50% w/w, more preferably from about 20%w/w to about 40%w/w of the total weight of the composition.
The inventors surprisingly found that when the antipsychotic agent having a basic group for example, risperidone was converted into the choiesteryl sulphate complex and incorporated into the biodegradable polymer the degradation effect of risperidone base on the polymer is nullified. It is known in the art that risperdione base has a detrimental effect of biodegradable polymer when either stored or processed at higher or lower temperatures in presence of risperidone base. Surprisingly, no degradation of the biodegradable polymer was seen when the risperidone base was incorporated in the form of an ion pair complex.
The ion pair complex of the antipsychotic agent having basic group and cholesterol sulfate complex may be prepared by any suitable method. In one embodiment, the complex is prepared by initially suspending the antipsychotic agent having basic group in an organic solvent and dissolving by adding glacial acetic acid gradually. Cholesterol sulfate or its pharmaceutically acceptable salt is dissolved in an organic solvent by sonication. The antipsychotic agent and cholesterol sulfate solutions are mixed. The organic solvent is evaporated by means of rotavapor to obtain a precipitate. The precipitate may be used as such or used after a suitable treatment. For example it may be washed with water followed by either lyophilization or vacuum drying or it may be recrystallized to obtain purified ion-pair complex, if required. The antipsychotic agent -cholesterol sulfate complex so obtained is suitably dried, stored in a suitable container at room temperature or at 2-8 °C.
The ion pair complex so prepared may be incorporated into the micro particles by any process known n the art. For example, the microspheres of poly (lactic-co-glycolic acid) or d,l-Poly(lactic acid) may be prepared by either solvent evaporation, pulverization and spray drying, that effectively entraps the complex and provides for sustained release of the antipsychotic agent. The inventors surprisingly found that when the antipsychotic agent having a basic group for example, risperidone was converted into the choiesteryl sulphate complex and incorporated into the biodegradable polymer which was otherwise known to be susceptible to degradation at higher or lower temperatures in presence of risperidone base, either during manufacturing or upon storage, was found to stable. No degradation of the biodegradable polymer was seen when the risperidone was incorporated in the form of an ion pair complex. Without wishing bound by any theory, the inventors believe that the risperidone base when converted as ion pair complex, the properties of the risperidone are changed such that it provides a sustained release of the risperidone either with choiesteryl sulphate or with alkali metal salt of choiesteryl sulphate along with providing no harmful effect to the biodegradable polymer.
Organic solvents may be used in the preparation of antipsychotic agent-cholesterol sulfate complex or the microspheres comprising antipsychotic agent -cholesterol sulfate complex in a biocompatible and biodegradable carrier, of the present invention. The solvents that may be suitable include, but are not limited to, monohydric alcohols (methanol, ethanol,; ethers (tetrahydrofuran (THF); amides (n-methyl pyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO); dimethylacetamide, esters (ethyl acetate);
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chlorocarbons (CH2CI2). Preferably, methanol or ethanol or glacial acetic acid or their mixtures are used as solvents for the preparation of antipsychotic agent -cholesterol sulfate complex and solvents like methanol or methylene chloride or chloroform or DMSO or their mixtures are used in the preparation of microspheres comprising antipsychotic agent -cholesterol sulfate complex in a biocompatible and biodegradable carrier.
The microspheres of poly(lactic-co-glycolic acid) or d,l-Poly(lactic acid) are prepared by the solvent evaporation procedure that effectively entraps the complex. The entrapment procedure consists of emulsifying an organic solution of poly(lactic-co-glycolic acid) or d,l-Poly(lactic acid), antipsychotic agent -cholesterol sulfate complex and an aqueous surfactant solution, evaporation of solvent, separation, washing and drying to produce microparticles of desired size.
In an embodiment, the microspheres of poly (lactic-co-glycolic acid) or d,l-Poly(lactic acid) are prepared by following the process of pulverization. The process of microsphere formation by pulverization includes steps of dissolving or dispersing antipsychotic agent -cholesterol sulfate complex and poly(lactic-co-glycolic acid) or d,l-Poly(lactic acid) in an organic solvent to obtain a uniform dispersion, drying and sieving to produce microparticles of uniform size. In another embodiment, the microspheres of poly (lactic-co-glycolic acid) or d,l-Poly(lactic acid) are prepared by the process of spray drying. The process of microspheres formation by spray drying includes the steps of, dissolving or dispersing antipsychotic agent -cholesterol sulfate complex and poly(lactic-co-glycolic acid) or d,l-Poly(lactic acid) in an organic solvent and spray drying to produce the microparticles of desired size. The process of emulsification may be carried out by processes known to those skilled in the art, which include but are not limited to, static mixer, blender, magnetic bar agitation, over head stirrer, in-line homogenizer and the like. The microspheres may be collected by isolating the microspheres on a standard mesh sieves, washed with water or other appropriate medium, and air dried. Other collection and drying methods and pharmaceutically acceptable equipment conventional in the pharmaceutical art may also be used.
In another embodiment of the present invention, microparticles of the first biocompatible and biodegradable polymer containing the complex of antipsychotic agent and cholesteryl sulfate or alkali metal salt can be further coated with second biocompatible and biodegradable polymer to control the initial release of the active ingredient. In the preferred embodiment of the present invention, the second biocompatible and biodegradable polymer is selected from poly(lactic-co-glycolic acid) or d.I-Poly(lactic acid). In the preferred embodiment of the present invention, the molar ratio of the second poly(lactic-co-glycoIic acid) polymer may be present in the range from about 100:0-to about 50:50, preferably form about 100:0 to about 85:15, more preferably 100:0.In the preferred embodiment of the present invention, the molecular weight of the second poly(lactic-co-glycolic acid) polymer ranges from about 1000 Daltons to about 30,000 Daltons, preferably from about 5000 Daltons to about 20.000 Daltons. In the preferred embodiment of the present invention, the first poly(lactic-co-glycolic acid) polymer has a different molecular weight than the second poly(lactic-co-glycolic acid). In the preferred embodiment of the present invention, the first poly (lactic-co-glycolic acid) polymer has greater molecular
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weight than the second poly (tactic-co-glycolic acid). In the preferred embodiment of the present invention, the first po!y(lactic-co-g!ycolic acid) polymer has molecular weight of about 10000 Daltons to 75000 Daltons and the second poly(lactic-co-glycolic acid) polymer has a molecular weight of 5000 Daltons to 30000 Daltons. In the preferred embodiment of the present invention, the first poly(lactic-co-glycolic acid) polymer has different molar ratio of lactic acid to glycolic acid than the second poly(lactic-co-glycolic acid). In the preferred embodiment of the present invention, the first poly(lactic-co-glycolic acid) polymer has 50:50 to 100:0 molar ratio of lactic acid to glycolic acid and the second poly(lactic-co-glycolic acid) polymer has 100:0 to 50:50 molar ratio of lactic acid to glycolic acid. In an embodiment, the ratio of the microparticles to coating polymer ranges from about 95:5 to about 25:75, preferably from about 80:20 to about 60:40. In another embodiment of the invention, the microparticles may be present in amounts ranging from about 95% w/w to about 25% w/w, preferably from about 80% w/w to about 60% w/w, of the total weight of the composition. In another embodiment, the coating polymer may be present in the injectable sustained release pharmaceutical composition, in amounts ranging from about 5% w/w to about 75% w/w. preferably from about 20% w/w to about 40% w/w of the total weight of the composition. In one embodiment, the coating may be done by any suitable manner for e.g. coacervation phase separation, spray coating, and solvent evaporation or like. In a preferred embodiment coating is done using an in-water solvent evaporation method.
In one embodiment, the antipsychotic agent -cholesterol sulfate microspheres are in the form of powder, which can be stably stored, reconstituted with a vehicle immediately before use, and administered by injection. In such a case, the formulation and vehicle may be provided or packaged in the form of a kit. The vehicles that may be used for dispersing or suspending the microparticles or microspheres of antipsychotic agent-cholesterol sulfate, before injection, include aqueous and non-aqueous vehicles known in the art. Examples of aqueous vehicles include physiological saline solutions, solutions of sugars such as dextrose or mannitol, and pharmaceutically acceptable buffered solutions. The vehicles may further include antibacterial preservatives, antioxidants, tonicity agents, buffers, stabilizers and pharmaceutically acceptable excipients.
The antipsychotic agent -cholesterol sulfate complex was subjected to in vitro and in vivo studies in rats. The studies indicated that antipsychotic agent release from the antipsychotic agent -cholesterol sulfate complex was sustained for a period of at least 7 days. The release of risperidone was sustained further by incorporating the complex in a suitable biocompatible and biodegradable carrier, i.e. by incorporating in a poly(lactic acid) or poly(lactic-co-giy colic acid) micro spheres. Preferably, the formulation comprising antipsychotic agent -cholesterol sulfate complex in a polyflactic acid) or polyflactic-co-glycolic acid) sustains the release for a period of at least 7 days, more preferably at least 14 days, and most preferably up to 30 days. The burst of risperidone was decreased by an additional coating of poly(lactic acid) or poly(Iactic-co-glycolic acid) over the microspheres.
It will be understood by those of skill in the art that numerous modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the following examples are illustrative only and should not to be construed to limit the scope of the present invention.
1 5 APR 2009

Example la
Preparation of risperidone cholesteryl sulfate (CS) complex

Ingredients Quantity
Risperidone 456.7 mg
Methanol 2.0 ml
Glacial acetic acid q.s. (*66.752 ul)
Cholesteryl sulfate (CS) sodium 543.5 mg
Methanol q.s. (*28.2 ml)
The drug was dissolved in methanol by adding the glacial acetic acid. Cholesteryl sulfate sodium was separately dissolved in methanol by gentle sonication. Both the solutions were mixed in a round bottom flask and stirred to get a clear solution at 40°C for 4 h. The methanol was evaporated on a Rotavapor to obtain a precipitate. The precipitate was washed with water using centrifugation and the sediment was dried overnight in vacuum desiccators at room temperature to evaporate the residual solvent almost completely.
The microparticles were subjected to stability studies. The results are tabulated as follows:

Time point and condition Assay (% LC)
Initial 96.32
2-8°C
1 M 101.62
3M 99.27
30°C / 65 RH
1 M 101.26
3M 97.80
40°C / 75 RH
1 M 100.50
3M 98.00
Example lb
Preparation of PLGA microparticles of risperidone cholesteryl sulfate (CS) complex

Ingredients Quantity
Risperidone 350.00 mg
Cholesteryl sulfate 416.69 mg
Acetic acid 51.20 mg
Dimethyl sulfoxide (DMSO) 4.25 g
PLGA (50:50, 66 kDa) 54.63 mg
Methylene dichloride (MDC) 2.00 2
Water for injection 150 ml
Risperidone, cholesteryl sulfate sodium and acetic acid was dispersed in DMSO. PLGA (50:50. 66 kDa) was separately dissolved in MDC by vortexing. The two solutions were mixed and heated to make a clear solution. The solution was delivered into water at 40°C using silverson homogenizer. The resultant suspension was kept on stirring for 1 h. The microparticles were separated by decantation and washing followed by centrifugation. Separated microparticles were lyophilized. Microparticles were sieved, weighed and filled in glass vials.
1 5 APR 2009

Example lc
Coating of PLGA microparticles of risperidone cholesteryl sulfate (CS) complex by PLA

Ingredients Quantity
PLGA microparticles of risperidone CS complex (Example lb) 830 mg
equivalent to risperidone *250 mg
d,l-PLA(15kDa) 170 mg
Ethyl acetate (EA) 3-5 g
Polyvenyl alcohol 0.05 g
Water for injection 100 ml
Delivery, solvent evaporation, separation, and drying
D.L-PLA (15 kDa) was dissolved in ethyl acetate to make a clear solution. PLGA microparticles of risperidone CS complex (Example lb) were added to the D,L -PLA solution. The resultant suspension was vortexed/ homogenized to make a uniform suspension. The dispersion was delivered to the aqueous PVA solution using Silverson type homogenizer at 30°C. The resultant suspension was kept on stirring for 3 h. The microparticles were separated using decantation washing. The microparticles were separated on a sieve and dried by hot nitrogen at 60CC for 2-3 h. Microparticles were sieved, weighed and filled in siliconized glass vials.
Example 2a
Preparation of risperidone cholesteryl sulfate (CS) complex

Ingredients Quantity
Cholesteryl sulfate (CS) sodium 543.5 mg
Methanol q.s. (~28.2 ml)
Indion 225H (cation) ion exchange resin -(q.s.)
Risperidone 456.7 mg
Methanol 2.0 ml
Cholesteryl sulfate sodium was dissolved in methanol by gentle sonication. The methanolic solution of cholesteryl sulfate sodium was passed through a column of indion 225H ion exchange resin to obtain cholesteryl sulfate acid. The risperidone was separately dissolved in methanol and added to the cholesteryl sulfate solution. The methanol was evaporated on a rotavapor to obtain a precipitate. The precipitate was dried overnight in vacuum dessicator at room temperature to evaporate the solvent almost completely. The complex precipitate was again dissolved in methanol and crystallized. The crystals were stored in a glass vials.
Example 2b
Preparation of PLGA microparticles of risperidone cholesteryl sulfate (CS) complex

Ingredients Quantity
Risperidone cholesteryl sulfate complex (Method - II) 625 mg
equivalent to risperidone *300 mg
PLGA (50:50, 66 kDa) 375 mg
Methylene dichloride (MDC) 4,00 g
Polyvinyl alcohol 1.0 g
Water for injection 100 ml
1 5 APR 2009

PLGA was dissolved in MDC to make a clear solution. Risperidone-cholesteryl sulfate complex (Example 2a) was added to PLGA solution and dissolved. This solution was delivered to the aqueous PVA solution using homogenization (Silverson type homogenizer). The resultant suspension was kept on stirring for 3 h with gradual temperature rise to 40°C. The microparticles were separated using decantation/centrifugation. Separated microparticles were dried by hot nitrogen at 60°C for 2-3 h. Microparticles were filled in a glass vials.
Example 2c
Coating of PLGA microparticles of risperidone cholesteryl sulfate (CS) complex by PLA

Ingredients Quantity
PLGA microparticles of risperidone CS complex [Example 2b) 800 mg
equivalent to risperidone ~I25 mg
d,l-PLA(15kDa) 200 mg
Ethyl acetate (EA) 2.3 g
Polyvinyl alcohol 0.05 g
Water for injection 100 ml
DX-PLA (15 kDa) was dissolved ethyl acetate to make a clear solution. PLGA microparticles (Example 2b) was added to the D,L PLA solution. The resultant suspension was mixed well using homogenizer to make a uniform suspension. PVA was weighed and dissolved in water for injection at room temperature. The organic solution was delivered to the aqueous solution using homogenization (Silverson type homogenizer). The resultant suspension was kept on stirring for 3 h with gradual temperature rise to 40°C. The microparticles were separated using centrifuge / decantation. Separated microparticles were dried by hot nitrogen at 60°C for 2-3 h. Microparticles were weighed and filled in a suitable labeled container.
Example 3
The microparticles prepared according to Example la, lb, 2a and 2b equivalent to « 3 mg risperidone were weighed and placed in a dissolution tube (50 ml). 30 ml dissolution media (0.05 M tris buffer pH 7.4 with 5% ethanol) was added to the dissolution tubes and microparticles were suspended. The tubes were rotated at 50 rpm and 37°C in air bath using tube rotating air bath apparatus. The tubes were removed on every day and microparticles were allowed to settle. The entire content was then centrifuged, the clear supernatant was withdrawn and the risperidone content was determined. The sedimented microparticles were re-suspended in the fresh dissolution medium to continue the dissolution study. The in-vitro release profile of the example la, lb and lc is presented in Figure 1 and the in-vitro release profile of the example 2a, 2b and 2c is presented in Figure 2.
15 APR 2009

EXAMPLE 4

Ingredients Quantity
Risperidone cholesteryl sulfate complex 625 mg
equivalent to risperidone *250 mg
d,l-PLA(0015, 15kDa) 375 mg
Methanol -
Dimethyl sulfoxide (DMSO) 3.00 g
Methylene dichloride (MDC) 6.00 g
Polyvinyl alcohol 2g
Water for injection 400 ml
Risperidone cholesteryl sulfate complex (Example la) was dispersed in DMSO with heating. PLA was separately dissolved in MDC to make a clear solution. PLA solution was added to DMSO phase and heated to make a clear solution. The solution was delivered to the aqueous PVA solution with homogenization (Silverson). The temperature of the suspension was raised slowly to 40°C for 1 h. The microspheres were washed by centrifligation and were separated on a sieve. The separated microparticles wee dried by hot nitrogen at 60°C for 2-3 h. The microparticles were weighed and filled in glass vials.
STABILITY DATA FOR EXAMPLE (RISPERIDONE CS COMPLEX IN PLA)

Conditions Assay (% LC) Particle size (fim)

d(0.1) d (0.5) d (0.9)
Initial
Initial 101.12 3.607 27.876 61.467
2-8°C
I M 98.33 - - -
3M 100.57 - - -
6M 98.74 2.988 26.055 53.525
25°C / 60 RH
1 M 98.44 - - -
3M 100.39 - - -
6M 97.10 1.958 27.459 55.082
30°C / 65 RH
1 M 99.29 - - -
3 M 99.70 - - -
6M 95.91 2.73 24.804 53.065
40°C / 75 RH
1 M 97.70 - - -
3 M 100.80 - - -
6M 96.01 2.633 24.076 50.668
15 APR 2009

EXAMPLE 5
Table 6: Olanzapine-cholesteryl sulphate sodium complex

Ingredients Quantity % w/w
Olanzapine 39
Ethanol q.s
Glacial acetic acid q.s
Cholesterol sulfate sodium 61
Ethanol q.s
Olanzapine was suspended in ethanol and was dissolved by adding glacial acetic acid. Cholesterol sulfate was dissolved in ethanol in a separate container. Olanzapine and cholesterol sulfate solutions were mixed together in a round bottom flask. Ethanol was evaporated completely by means of a rotavapor till a precipitate was obtained. The precipitate was washed with water for injection, centrifuged and the supernatant liquid was discarded. The Olanzapine-cholesterol sulfate sodium complex obtained was dried overnight in a vacuum desiccators at room temperature to evaporate the residual solvent. In-vitro release was slow.

Days % Release of Olanzapine
1 26.80
3 51.56
5 50.93
7 59.61
The in-vivo release study of olanzapine-cholesterol sulfate complex was carried out on Sprague-Dawiey (SD) rats. Ten rats were weighed and were administered a single, intramuscular (IM) dose of olanzapine-cholesterol sulfate complex dispersion prepared in water for injection, at a dose of 10 mg/kg. The blood samples were collected at time points of 1, 2, 4, 8, 12, 24, 72 and 168 hours following administration. The detectable levels were obtained for 7 days i.e for 168 hours.
15 APR 2009
18

The present invention may be summarized as follows:
A. An ion-pair complex of an antipsychotic agent with cholesteryl sulfate or its alkali metal salt.
B. An ion-pair complex of A wherein the antipsychotic agent is selected from the group consisting of
risperidone, olanzapine, clozapine, quetiapine, aripiprazole, paliperidone, asenapine, lloperidone, zotepine,
ziprasidone, sertindole, bifeprunox, meperone and Amisulpiride.
C. An ion-pair complex of A wherein the ratio of antipsychotic agent to the cholesterol sulfate ranges from
about 1:10 to about 10:1.
D. An injectable sustained release pharmaceutical composition comprising an ion-pair complex described in A
above and a biodegradable polymer.
E. An injectable sustained release pharmaceutical composition as described in D above wherein ion pair
complex of antipsychotic agents with alkali metal salt of cholesteryl sulphate provides release of the
antipsychotic agent for a period of days.
F. An injectable sustained release pharmaceutical composition described in E wherein composition further
comprises biodegradable polymers of molecular weight less than 100,000 Daltons, preferably less than 80.000
Daltons in admixture with the ion pair complex.
G. An injectable sustained release pharmaceutical composition described in F wherein composition is in the
form of microparticles.
H. An injectable sustained release pharmaceutical composition as in F above, wherein the said biocompatible
and biodegradable polymer is poly (lactic-co-glycolic acid) or poly (lactic acid).
I. An injectable sustained release pharmaceutical composition as in H above, wherein the molar ratio of lactide
to glycolide in poly(lactic-co-glycolic acid) ranges from about 50:50 to about 100:0.
G. An injectable sustained release pharmaceutical composition as in F above wherein the ratio of an ion pair
complex of a antipsychotic agents with cholesteryl sulphate or its alkali metal salt to biodegradable carrier
ranges from about 95 : 5 to about 5 : 95.
H. An injectable sustained release pharmaceutical composition as in G above, wherein the amount of
biodegradable and biocompatible carrier is present in amount ranging from 5 %w/w to about 80 %w/w of the
total weight of the microparticles.
I. An injectable sustained release pharmaceutical composition as in G above, wherein the antipsychotic agent -
cholesterol sulfate complex is present in amount ranging from about 20 % w/w to about 95 % w/w of the total
weight of the microparticles.
J. An injectable sustained release pharmaceutical composition as described in G above wherein the
microparticles are further coated with a biodegradable polymer to prevent the burst of the active agent.
K. An injectable sustained release pharmaceutical composition as in M above, wherein the biodegradable
polymer used for coating is poly (lactic-co-glycolic acid) or poly(lactic acid).
L. An injectable sustained release pharmaceutical composition as in N above, wherein the molecular weight of
poly (lactic-co-glycolic acid) ranges from about 10,000 Daltons to about 30,000 Daltons.
M. An injectable sustained release pharmaceutical composition as in N above, wherein the molecular weight of
poly (lactic acid) ranges from about 10,000 Daltons to about 20,000 Daltons.
1 5 APR 2009

N. An injectable sustained release pharmaceutical composition as in A to D above, wherein the antipsychotic
agent is released over a period of at least I day.
O. An injectable sustained release pharmaceutical composition as in E and F above, wherein the antipsychotic
agent is released over a period of at least 7 days.
P. An injectable sustained release pharmaceutical composition as in F above, wherein the antipsychotic agent is
released over a period of at least 14 days.
Q. An injectable sustained release pharmaceutical composition as in M above, wherein the antipsychotic agent is
released over a period up to 30 days.