DESC:TECHNICAL FIELD OF THE INVENTION
The invention relates to microparticles having improved flow characteristics. In particular, the invention relates to the pharmaceutical composition comprising microparticles having improved flow characteristics. There is provided a process of preparing such microparticles composition. By subjecting the emulsion to multiple steps including quenching, fine removal by decantation, washing, and de-watering in a single vessel followed by lyophilization that is performed during the preparation of the microparticles, good quality microparticles can be prepared. The composition comprising the microparticles according to the invention exhibits excellent flow characteristics, shape uniformity and lesser agglomeration tendency.

BACKGROUND OF THE INVENTION
The invention relates to pharmaceutical composition of microparticles containing one or more active pharmaceutical ingredients. More particularly, the invention relates to pharmaceutical composition comprising microparticles having improved flow characteristics.

There are several commercially available polymeric microparticles based products in the market including Risperdal Consta® and Vivitrol®. Risperidone was initially marketed as Risperdal® in the form of Tablet, Orally Disintegrating Tablet and Oral Solution. Currently marketed long-acting injectable risperidone formulation, Risperdal Consta®, is the first depot atypical antipsychotic drug in the market. It is an intramuscular risperidone-containing PLGA microparticles formulation and is intended to deliver therapeutic levels of risperidone by bi-weekly administrations.

There are several methods are known by which compounds can be encapuslated in the form of polymeric microparticles.

US 3,737,337 Patent discloses a conventional microencapsulation process wherein a solution of a wall or shell forming polymeric material in a partially water miscible solvent is prepared.

US 4,389,330 Patent describe the preparation of microparticles containing an active agent by using a two-step solvent removal process.

US 5,407,609 Patent disclose another conventional method of preparing drug containing microparticles.

US 5,650,173 Patent discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biologically active agent, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer.

US 5,654,008 Patent discloses a microencapsulation process that uses a static mixer. A first phase, comprising drug and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the drug.

US 5,945,126 Patent discloses a continuous process of making microparticles. The process involve step of continuously introducing the dispersed phase and continuous phase in to the reactor vessel under rapid mixing and continuously transporting the emulsion from the reactor vessel to a solvent removal vessel.

US 6,194,006 Patent discloses method for preparing microparticles, including performing a degree of substantial intermediate drying of the microparticles by subjecting the microparticles to multistep processes (e.g. de-watering, filtering, vacuum, drying and washing).

US 7,247,319 Patent discloses method for improving flowability of microparticles by subjecting the microparticles to conditioning or ageing at specific temperature over a specific period.

The PCT Application Number WO2015150942 discloses process for preparing microparticles exhibiting a selected release profile for release of drug contained in the microparticles.

Despite of the various known techniques, it still remains challenging to develop a pharmaceutical composition comprising microparticles having improved flow characteristics.

SUMMARY OF THE INVENTION
The inventors of the inventions have surprisingly found that by preparing a pharmaceutical composition comprising microparticles with the help of varying composition and process variables, it is possible to achieve the preferred flow characteristics without affecting the desired release profile of active agent/s. Furthermore such composition may provide stable pharmaceutical compositions for long period of time.

In one general aspect of the invention, there is provided a pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof, wherein the angle of repose of microparticles is less than about 35.

The present invention further relates to a pharmaceutical composition comprising microparticles, wherein the compressibility factor (Carr's Index) of microparticles is in the range of 1% to 25%.

The tapped density is obtained by compacting the bulk density with vibrational motion. The compressibility parameter depends on only bulk density and tapped density.
According to the invention, the dry powder microparticles composition having a good flowability can be prepared by adjusting the process variables in the manner that compressibility parameter of the formulation is in the range of 1% to 25%, preferably in the range of 15% to 25% during production.

In another general aspect of the invention, there is provided a pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
a) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
b) angle of repose less than about 35 and
c) compressibility index in the range of 1% to 25%,
wherein the composition is prepared by a process comprising steps of:
(a) preparing an emulsion; (b) quenching the emulsion to form microparticles suspension (c) lyophilizing the microparticles suspension (d) washing the microparticles (e) filtering the microparticles slurry (f) lyophilizing the microparticles.

In an embodiment, the stable pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
a) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
b) angle of repose less than about 35 and
c) compressibility index in the range of 1% to 25%,
wherein the stable pharmaceutical composition is prepared by a process comprising: (a) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising the drug, one or more polymers, and one or more solvents for the polymer; (b) quenching, extraction, washing and de-watering the emulsion in a vessel to form suspension of microparticles containing the drug; (c) filtering the microparticles to form microparticles suspension; (d) lyophilizing the microparticles suspension to form drug containing microparticles.(e) washing the microparticles; (f) filling the microparticles in vials; and (g) filling the headspace in the vials with inert gas.

In another general aspect of the invention, the emulsion comprises first phase comprising a risperidone, 9-hydroxyrisperidone or salts, one or more polymers, and one or more solvents and a second phase.

In another embodiment, the solvent in first phase of the emulsion comprises benzyl alcohol.

In another general aspect of the invention, the first phase is prepared by a process comprising the steps of: (a) separately preparing solution of a risperidone, 9-hydroxyrisperidone or salts and one or more polymers; (b) aseptically filtering the drug solution and polymer solution; and (c) mixing the filtered drug solution and polymer solution.

In another embodiment, the drug solution and polymer solution are aseptically filtered separately prior to preparation of first phase.

In another embodiment, both phases were subjected to sterile filtration in order to achieve the sterile product. The sterile phases can be then combined to form emulsion.

In another embodiment, sterile phases comprise first phase and second phase mixed using static mixers or in line homogenizers known in the art to form emulsion.

In another general aspect of the invention, the quenching step further followed by fine removal by decantation, washing and de-watering of the emulsion that is performed in a single vessel.

In another embodiment, the extraction, de-watering and washing in the vessel is performed at room temperature or 37°C ± 10°C. The temperature of the extraction medium allows the microparticles to be dispersed without agglomeration caused by elevated temperatures.

In another general aspect of the invention, the washing in step (d) is performed in a vessel having temperature in the range of 25° to 40°C.

In another embodiment, the quenching of the emulsion is done with a quench phase comprising ethyl acetate.

In another general aspect of the invention, the lyophilization step comprises freezing at temperature up to -45° C, primary drying at temperature in the range of -35°C to -3°C and secondary drying at temperature up to 45° C.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows microscopic image of the microparticles prepared as per the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term "microparticles" or "microspheres" as used herein refers to solid particles that contain a drug dispersed or dissolved within a polymer that serves as the matrix of the particle. The polymer is preferably biodegradable and biocompatible.

The term "biodegradable" as used herein refers to a material that should degrade by bodily processes to products readily disposable by the body and do not accumulate in the body. The products of the biodegradation should also be biocompatible with the body.

The term "biocompatible" is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues.

By "% w/w" is meant parts by weight per total weight of microparticles. For example, 10 % w/w drug would mean 10 parts drug by weight and 90 parts polymer by weight.

Because of the large number of various formulation variables and process variables that could potentially affect on the quality and performance of resulting microparticles in an attempt to optimize the quality, it is difficult to predict outcome of any particular adjustment.

For instance, altering process variables (conditions related to the manufacturing process of microparticles, such as temperature, mixing speed, flow rate and drying speed) may alter drug release pattern instead. Also several (intermediate or final) drying steps in the manufacturing process can result in irregular shaped microparticles.

The commercial scale production of microparticles, therefore, requires extensive optimization and in process controls. The process further demands several additional measures in order to prevent in process agglomeration and achieve desired degree of drying of the microparticles. The process complexity thus can make the commercial scale production of microparticles uneconomical and also can reduce the product yield.

However, in order to obtain good quality microparticles, it is significantly important to adjust basic characteristics accurately such as flow property, particle size, cohesiveness and hardness of the powder microparticles without compromising on selected release characteristics. In addition, when the basic characteristics are adjusted, the production and processing of a microparticles formulation is easily performed. The flowability characteristic is important particularly in the phases of the microparticles composition during large-scale processing when invariably these powders or microparticles must be moved from place to place and also at filling step specifically in automated equipment such as certain automated vial filling machine where material must flow from a hopper and it is further important in advancement of the production without any problems. The dry powder microparticles composition having good flowability characteristic provides easy filling into the vial and consequently provides measurement accuracy.

The flowability of the composition is considerably affected from the particle size distribution of the active pharmaceutical agent/s and the inactive pharmaceutical excipient/s comprised in the composition. The smaller the particle sizes are, the larger adhesion and cohesion forces among them occur. Increase in adhesion and cohesion forces causes the tendency of agglomeration of the particles to increase and therefore, the flowability of the formulation to worsen.

The angle of repose has been used in several branches of science to characterize the flow properties of solids. Angle of repose is a characteristic related to interparticulate friction or resistance to movement between particles. The angle of repose is the constant, three-dimensional angle (relative to the horizontal base) assumed by a cone-like pile of material formed by any of several different methods.

The angle of repose can be considered as the constant angle to the horizontal assumed by a cone-like pile of microparticles. The pile is built up by dropping the microparticles from a point above the horizontal, until a constant angle is measured.

The angle of repose was measured in the following manner. A standard 100 mm Nalgene funnel was positioned in a ring stand so that the funnel discharge was at a height of approximately three inches above a level horizontal surface. Approximately 100 g of microparticles were weighed out. The microparticles were placed in the funnel, which was fitted with a stopper to block discharge. The stopper was removed, and the microparticles were allowed to flow through the funnel until all material was discharged. The discharged microparticles formed a pile having an angle of repose characteristic of the microparticles forming the pile.

The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content, and cohesiveness of materials because all of these can influence the observed compressibility index. The compressibility index and the Hausner ratio are determined by measuring both the bulk volume and the tapped volume of a powder.

Hausner ratio is the unsettled volume divided by the tapped volume (that is the volume after tapping produces no further change in volume), or alternatively the tapped density divided by the bulk density.

The compressibility parameter is a value varying according to the ratio of bulk density to tapped density and it is calculated using the formula below:

C: Compressibility parameter (Carr's index) PB: Bulk density PT: Tapped density
Despite some variation in experimental methods, generally accepted scales of flow properties have been published (Table 1) for angle of repose, compressibility index and Hausner ratio (Carr, RL, Chern. Eng. 1965, 72:163-168).
Table 1: Scale of Flowability
Flow Characters Angle of Repose Compressibility index
(%) Hausner Ratio
Excellent 25-30 =10 1.00-1.11
Good 31-35 11-15 1.12-1.18
Fair 36-40 16-20 1.19-1.25
Passable 41-45 21-25 1.26-1.34
Poor 46-55 26-31 1.35-1.45
Very poor 56-65 32-37 1.46-1.59
Very, very poor =66 >38 >1.60

Therefore, there is a need in the art to develop a pharmaceutical composition comprising microparticles having improved flow characteristics such as angle of repose, compressibility index (Carr's Index), Hausner ratio, particle size distribution, flow rate through an orifice and shere cell. Further, there exists a need for a pharmaceutical composition comprising microparticles having improved flow characteristics and process of manufacturing the good quality microparticles which is simple, robust, requires relatively less control of processing parameters and also having a selected release profile for release of drug in the microparticles.

The invention relates to a pharmaceutical composition having improved flow characteristics. The microparticles having angle of repose less than about 35 can be prepared by employing specific process and optimized set of process sequence.

The invention relates to a pharmaceutical composition comprising microparticles wherein the angle of repose of microparticles is less than about 35. The inventors of the invention have surprisingly found that by employing specific process and optimized set of process sequence, the microparticles with angle of repose less than 35 can be obtained, thereby improving flowability that in turn overcome the above mentioned problems arising from flowability.

In an aspect, there is provided a pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
a) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
b) angle of repose less than about 35,
c) compressibility index in the range of 1% to 25% and
d) Hausner ratio below 1.34,
wherein the pharmaceutical composition is prepared by a process comprising step of (a) preparing an emulsion; (b) quenching the emulsion to form microparticles suspension (c) lyophilizing the microparticles suspension (d) washing the microparticles (e) filtering the microparticles slurry (f) lyophilizing the microparticles.

In another aspect, there is provided a pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof, obtained by the steps of:
(a) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising drug, one or more polymer, and one or more solvent for the polymer;
(b) quenching, extraction, washing and de-watering the emulsion to form suspension of microparticles containing the drug;
(c) filtering the microparticles to form microparticles suspension; and
(d) lyophilizing the microparticles suspension to form drug containing microparticles.

In another aspect, there is provided a pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof, wherein the Hausner ratio is less than about 1.34.

The resulting lyophilized microparticles may exhibit an initial lag phase and a substantially sigmoidal release profile.

The process for preparing such pharmaceutical composition may employ a vessel that is adapted to perform multiple operations such as quenching, de-watering, washing and optionally filtration resulting in simplification of the process. In its simplest configuration, the process may employ a single vessel embedded with a filter and several components to perform other operations.

The filtration of the microparticles is performed in the vessel itself; however, single or multiple filters can be externally connected to the vessel to facilitate the filtration process.

In another general aspect of the invention, process for preparing microparticles comprises separate aseptic filtration of the drug solution and polymer solution prior to preparation of first phase of the emulsion.

In another general aspect of the invention, the process comprises steps of, after the lyophilization step followed by washing of microparticles which is followed by final lyophilization of the microparticles.

In another general aspect of the invention, the process utilizes two lyophilization steps.

In another general aspect of the invention, the pharmaceutical composition prepared by the process comprises washing of microparticles, optionally followed by filtering of the microparticles suspension, and final filling of the microparticles suspension in vials, preferably under stirring.

In another general aspect of the invention, the washing step is carried out by: introducing the microparticles into a vessel containing an extraction medium; agitating the vessel contents to disperse the microparticles in the extraction medium.

In another general aspect of the invention, the washing step comprises:
a) introducing the microparticles into a vessel containing an extraction medium;
b) agitating the vessel contents to disperse the microparticles in the extraction medium; and
c) transferring the microparticles in the form of suspension or slurry from the vessel to a lyophilizer.

It is desirable for a pharmaceutical composition to be stable during shelf life and before its ultimate use by the person in need thereof. In this regard, it is advantageous for the composition to be stable at standard conditions, in particular the standard condition means a temperature ranging for 20°C to 40°C and a relative humidity ranging for 50% to 75%.

In the description of this invention, the term "stable" means that the quantitative composition does not significantly change over the time, during the entire shelf-life of the composition for at least 3 months, advantageously for at least 6 months, more advantageously for at least 12 months, even more advantageously for at least 36 months, under standard conditions.

In another aspect, the pharmaceutical composition of drug containing microparticles remains stable at least 6 months under standard condition.

In the present invention, the composition is advantageously stable during 6 months at a temperature of 40°C and a relative humidity of 75%.

In another aspect, the adjusting step to the lyophilization comprises: performing washing of the microparticles; and optionally, further performing final lyophilization of the microparticles.

In another aspect, the adjusting step to the lyophilization comprises: performing washing of the microparticles; further performing filtration of the microparticles; followed by vials filling of the microparticles; and final lyophilization of the microparticles. The resulting microparticles may exhibit in an initial lag in release of the drug and a substantially sigmoidal release of the drug.

In another aspect, there is provided a stable pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
a) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
b) angle of repose less than about 35
c) compressibility index in the range of 1% to 25%,
wherein the stable pharmaceutical composition is prepared by steps of:
(a) preparing an emulsion (b) quenching, extraction, washing and de-watering the emulsion (c) filtering; (d) lyophilizing (e) washing (f) filling the microparticles into vial and (g) filling the headspace in the vials with inert gas.

The pharmaceutical composition can be used to provide, inter alia, a biodegradable, biocompatible system that can be injected into a patient, the ability to mix microparticles containing different drugs, and the ability to program release by preparing microparticles with selected release profiles and with multiphasic release patterns to give faster or slower rates of drug release as needed.

A large volume of the solvent is removed in the vessel by decantation resulting in simplification (reduction in total number of steps) of the process. Further, due to absence of vibration mechanism in the vessel, the possibility of wear and tear of the vibrator and vessel may be avoided.

The pharmaceutical composition provided in the form of microparticles suspension or slurry, obviates the difficulties with dry microparticles filling in vials and poor flow properties through syringe needle.

The products prepared by the process of the invention may exhibit durations of action ranging from several days to more than 200 days can be obtained, depending upon the type of microparticles desired and release profile selected.

The invention relates to a pharmaceutical composition comprising microparticles that possess better shape, which in turn is likely to enable improved flowability during manufacturing, vial filling and passage through needle during administration. The invention further provides microparticles that exhibit controlled release of an effective amount of a drug over an extended period of time.

The process of the invention is simple, robust, cost effective and requires relatively less control of processing parameters to produce microparticles with improved flow characteristics.

The pharmaceutical composition comprising microparticles according to invention is prepared by mixing a first phase and second phase to form an emulsion. One of the two phases is discontinuous, and the other of the two phases is continuous. The first phase preferably comprises a drug, a polymer, and one or more solvents for the polymer.

In an embodiment, the stable pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
a) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
b) angle of repose less than about 35 and
c) compressibility index in the range of 1% to 25%,
wherein the stable pharmaceutical composition is prepared by a process comprising: (a) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising the drug, one or more polymers, and one or more solvents for the polymer; (b) quenching, extraction, washing and de-watering the emulsion in a vessel to form microparticles containing the drug; (c) filtering the microparticles to form microparticles suspension; (d) lyophilizing the microparticles suspension to form drug containing microparticles; (e) washing the microparticles; (f) filling the microparticles in vials; and (g) filling the headspace in the vials with inert gas.

In another embodiment, the angle of repose of microparticles composition is less than about 35, preferably less than about 33, more preferably about 32.

In another embodiment, there is provided a pharmaceutical composition comprising microparticles having a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.

In another embodiment, there is provided a pharmaceutical composition comprising microparticles having a particle size distribution defined as follows:
- D (v,0.1) is between about 45 and about 70 micrometers,
- D (v,0.5) is between about 85 and about 115 micrometers,
- D (v,0.9) is between about 145 and about 175 micrometers.

In another embodiment, there is provided a pharmaceutical composition comprising microparticles having a particle size distribution defined as follows:
- D (v,0.1) is between about 50 and about 60 micrometers,
- D (v,0.5) is between about 90 and about 105 micrometers,
- D (v,0.9) is between about 150 and about 170 micrometers.

In another embodiment, there is provided a pharmaceutical composition comprising microparticles having a particle size distribution defined as follows:
- D (v,0.1) is about 55 micrometers,
- D (v,0.5) is about 100 micrometers,
- D (v,0.9) is about 165 micrometers.

The sizes of the microparticles can be determined using conventional methods of measuring and expressing particle size like Malvern particle size analysis, sieving, light scattering optical microscopy, image analysis, sedimentation and such other methods known to one skilled in the art.

Particle size distribution information can be obtained from the values D10, D50, and D90, such as can be generated from a Malvern particle size determination. D90 as used herein is defined as the size for which 90 volume percent of the particles are smaller than that size given, and D50 as used herein is defined as the diameter where 50% of the distribution is above and 50% is below.. Likewise, D10 as used herein is defined as the size for which 10 volume percent of the particles are smaller than that size given. The term D10, D50, D90 and D(v,0.1), D(v,0.5), D(v,0.9) used interchangeably.

The microparticles according to the present invention may be of any shape including spherical, oblong and ellipsoidal and the like. In one embodiment of the present invention, the microparticles are substantially spherical in nature. Figure 1 shows the SEM (scanning electron microscope) images of the microparticles prepared according to various embodiments of the present invention.

In another embodiment, without wishing to be bound by any theory, the inventors believe that because of the substantially uniform, porous spherical nature of the particles, the flowability and release of the drug from the microparticles incorporated in a suitable vehicle will be more uniform. Further the release of the drug from such compositions may be controlled by changing the size of the microparticles and its surface area. The specific surface area may be determined by any suitable method, for example, Malvern light scattering particle size measurement, BET and such other methods known to one skilled in the art.

In another embodiment, the Hausner ratio of microparticles composition is less than about 1.34. Alternatively, the Hausner ratio of microparticles composition is less than about 1.32, or less than about 1.30, or less than about 1.28, or about 1.26.

In another embodiment, the compressibility Index of microparticles composition is about 23. Alternatively, the compressibility Index of microparticles composition is about 22, or about 21, or about 20.

In another embodiment, the solvent in first phase of the emulsion comprises benzyl alcohol.

In another embodiment, the drug solution and polymer solution are aseptically filtered separately prior to preparation of first phase.

In another embodiment, both phases were subjected sterile filtration in order to achieve the sterile product. The sterile phases can be then combined to form emulsion.

In another embodiment, sterile phases comprises first phase and second phase mixed using static mixers or in line homogenizers known in the art to form emulsion.

Preferred drugs according to the present invention include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles. The most preferred drugs of this kind for treatment by the process of the present invention are 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ("risperidone") and 3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetra hydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ("9-hydroxyrisperidone") and the pharmaceutically acceptable salts thereof. Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred.

Preferred examples of polymer matrix materials include poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), copolymers of the foregoing, and the like. Various commercially available poly(lactide-co-glycolide) materials (PLGA) may be used in the method of the present invention. For example, poly (d,l-lactic-co-glycolic acid) is commercially available from Alkermes, Inc. (Blue Ash, Ohio). A suitable product commercially available from Alkermes, Inc. is a 50:50 poly(d,l-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolide. Other suitable commercially available products are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,l-lactic acid) (100 DL). Poly(lactide-co-glycolides) are also commercially available from Boehringer Ingelheim (Germany) under its Resomer® mark, e.g., PLGA 50:50 (Resomer® RG 502), PLGA 75:25 (Resomer® RG 752) and d,l-PLA (Resomer® RG 206), and from Birmingham Polymers (Birmingham, Ala.). These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid.

The most preferred polymer for use in the practice of the invention is the copolymer, poly(d,l-lactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 85:15 to about 50:50.

The molecular weight of the polymeric matrix material may be detrimental in the quality and release profile of the microparticles. The molecular weight should be high enough to permit the formation of satisfactory polymer coatings, i.e., the polymer should be a good film former. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons. However, since the properties of the film are also partially dependent on the particular polymeric matrix material being used, it is very difficult to specify an appropriate molecular weight range for all polymers. The molecular weight of the polymer is also important from the point of view of its influence upon the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade. The drug can also be released from the microparticles as the polymeric excipient bioerodes. By an appropriate selection of polymeric materials a microparticles formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according multiphasic release patterns.

The formulation prepared by the process of the invention contains a drug dispersed in the microparticles polymeric matrix material. The amount of such drug incorporated in the microparticles usually ranges from about 1 % w/w to about 90 % w/w, preferably 30 to 50 % w/w, more preferably 35 to 45 % w/w.

A first phase is provided. First phase is preferably the discontinuous phase, comprising a polymer dissolved in one or more solvents, and a drug. The drug can be dissolved or dispersed in the same or a different solvent than the solvent(s) in which the polymer is dissolved. A second phase is preferably the continuous phase, preferably comprising water as the continuous processing medium. Preferably, an emulsifying agent such as a surfactant or a hydrophilic colloid may be added to the continuous phase to prevent the microdroplets from agglomerating and to control the size of the microdroplets in the emulsion.
Examples of compounds that can be used as surfactants or hydrophilic colloids include, but are not limited to, poly(vinyl alcohol) (PVA), carboxymethyl cellulose, gelatin, poly(vinyl pyrrolidone), Tween 80, Tween 20, and the like. The concentration of surfactant or hydrophilic colloid in the continuous phase will be from about 0.1% to about 10% by weight based on the continuous processing medium, depending upon the surfactant, hydrophilic colloid, the discontinuous phase, and the continuous processing medium used. A preferred continuous phase is 0.1 to 10 % w/w, more preferably 0.5 to 2 % w/w, solution of PVA in water. Although not absolutely necessary, it is preferred to saturate the continuous phase with at least one of the solvents forming the discontinuous phase. This provides a stable emulsion, preventing transport of solvent out of the microparticles prior to quench step.
First phase and second phase are combined under the influence of mixing means to form an emulsion. A preferred type of mixing means is a static mixer or inline homogenizer (commercially available as, e.g. Silverson inline homogenizer). Other mixing means suitable for use with the present invention include, but are not limited to, devices for mechanically agitating the first and second phases, such as homogenizers, propellers, impellers, stirrers, and the like.
Preferably, the discontinuous and continuous phases are pumped through mixing means to form an emulsion, and into a large volume of quench liquid, to obtain microparticles containing the drug encapsulated in the polymeric matrix material.
In an embodiment, the discontinuous and continuous phases are pumped through a membrane filter for sterilization. The membrane filter is in fluid communication with the mixing means.
The emulsion is transferred into a vessel for performing multiple operations (quenching, extraction, de-watering, washing and optionally, filtration). The vessel contains quench liquid for the quench or primary extraction step. The primary purpose of the quench step is to extract or remove residual solvent from the microparticles that are formed. In a preferred embodiment of the present invention, quench step is followed by a de-watering step, primary extraction step and multiple washing steps.

The objective of de-watering step is to concentrate the microparticles from the dilute suspension that is formed during extraction step to a concentrated slurry prior to subsequent lyophilization of the microparticles. The vessel is provided with ports for removal of waste. Preferably, the ports are provided at particular height for removal of the waste such as supernatant containing fines. The vessel is also provided with multiple inlets and outlets for quench, extraction solvents and water in order to recycle in the vessel.

It is of particular importance that multiple operations (quenching, washing and optionally extraction and de-watering) are carried out in the vessel which makes the overall process simple and robust.

In another embodiment, the quenching of the emulsion is done with a quench phase comprising polyvinyl alcohol and ethyl acetate.

In another embodiment, the extraction, de-watering and washing in the vessel is performed at room temperature or 37°C ± 10°C. The temperature of the extraction medium allows the microparticles to be dispersed without agglomeration caused by elevated temperatures.

The vessel may also comprise of filter. Preferably, the filter is placed before the ports in the vessel in order to retain microparticles in the vessel. The filtration causes smaller microparticles of desired fines and liquid to pass through the screen, while larger particles are retained. The smaller particles and liquid that drop through the screen are removed as waste. Size of the filter may range from about 25 microns to about 200 microns. Preferred size of the filter is 75 microns.

In another embodiment, the filter may not be the integral component of vessel, but fitted in fluid connection with vessel.

The filtered microparticles are in the form of suspension or slurry. The microparticles slurry is then subjected to lyophilization using suitable lyophilizer. The lyophilizer is in fluid communication with the filter.
It is significant to maintain microsphere temperature substantially below 10° C during and/or after lyophilization to prepare good quality, smooth and free flowing microspheres. Due to non-aggregation property, such microspheres can be advantageously filled in vials or ready to use for processing on the formulation development line.

The microparticles are, optionally, washed in suitable washing solvent (preferably, organic solvent, e.g. ethanol) to remove or extract any further residual solvent. The microparticles then filtered through a filter to remove smaller particles and liquid that drop through the screen that is removed as waste. The filtration may be performed by employing inline sieving as the microparticles pass through the process tubings.

In another embodiment, solvent removal after washing of the microparticles is performed by decantation.

The microparticles formed in the form of slurry of suspension can be filled in vials, preferably under stirring using suitable vial filling assembly and lyophilized to form solid microparticles. The moisture content of the microparticles is maintained, preferably less than about 1%, more preferably approximately equal to about 0.2%. The residual solvents level can be controlled accurately by optimizing pressure and temperature during further lyophilization.

Alternatively, after the lyophilization, the microparticles can be collected directly without washing, and filled in vials.

Suitable carriers may be added to the microparticles suspension prior to lyophilization in order to reduce sticking of the microparticles. The preferred carrier is mannitol.

In another embodiment, the process of preparing the microparticles according to the invention may be partially or completely aseptic. Alternatively, the end product prepared through such process can be subjected to terminal sterilization using various sterilization methods known in the art.

In another embodiment, the stable pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
i) a particle size distribution defined as follows:
- D (v,0.1) is about 50 and about 60 micrometers,
- D (v,0.5) is between about 95 and about 105 micrometers,
- D (v,0.9) is between about 160 and about 170 micrometers.
ii) angle of repose less than about 33
iii) compressibility index in the range of 20% to 25%,
wherein the stable pharmaceutical composition is prepared by steps of:
(a) preparing an emulsion by mixing dispersed phase and continuous phase, wherein the dispersed phase comprises about 20-26% w/w risperidone, 9-hydroxyrisperidone or salts thereof in benzyl alcohol and 10-20 % w/w polymer in ethyl acetate and continuous phase comprises about 0.2-2 % w/w polyvinyl alcohol and 2-8 % w/w ethyl acetate (b) quenching the emulsion by quenching phase comprises water containing 1-5 % w/w of ethyl acetate at temperature about 5° C to 10° C to form microparticles suspension, (c) extraction, washing and de-watering the microparticles suspension (d) filtering; (e) lyophilizing (f) washing (g) filling the microparticles into vial and (h) filling the headspace in the vials with inert gas.

In a further embodiment, the end product is subjected to terminal sterilization when process of preparing the microparticles is partially or completely non-aseptic.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example
Example 1: Preparation of microparticles comprising risperidone
A dispersed phase containing 20-26% w/w drug in benzyl alcohol and 10-20 % w/w polymer in ethyl acetate was prepared by mixing drug and polymer solutions. The solutions were filtered through a filter (0.2µ) and mixed or the two solutions were filtered through a filter (0.2µ) after mixing. A continuous phase containing 0.2-2 % w/w polyvinyl alcohol and 2-8 % w/w ethyl acetate was prepared by mixing both the solvents. Emulsion of the dispersed and continuous phases in weight ratio ranging from 1:2 to 1:20 was prepared by using static mixer or homogenizer or inline homogenizer.

The emulsion was then transferred to a vessel and subjected to quenching by adding and stirring for about 1 to 12 hours in 0.1-2 L/gm of quenching phase of water containing 1-5 % w/w of ethyl acetate. The temperature of the quenching phase was maintained 5° C to 10° C to form microparticles suspension. The microparticles suspension was then subjected to decantation for about 5-60 minutes to concentrate the microparticle suspension to approximately 1/10 of the original volume by discarding about 90% supernatant containing fines as waste. The decantation port screen of size selected from the range of about 50-150 micron was used.

Microparticles suspension was further subjected to quenching by adding the quench media in the vessel and stirring for about 15-120 minutes at room temperature. The additional quench media contain water (about 90% of the quench volume). The resulting microparticles suspension in the vessel was again subjected to decantation for about 5-60 minutes to concentrate the microparticles suspension to approximately 1/10 of the original volume.

An additional quench media containing water (about 90% of the quench volume) having temperature of about 37° C was added to the microparticles suspension in the vessel and the mixture was then stirred for 15-120 minutes. The mixture of the microparticles suspension and quench media in the vessel was again decanted for about 5-60 minutes to concentrate the microparticles suspension to approximately 1/10 of the original volume followed by sieving the microparticles suspension through about 150 micron sieve to remove oversized particles.

The microparticles were then introduced to a lyophilizer and effectively lyophilized under cold condition (temperature less than about 10° C).

The solid microparticles prepared after lyophilization were dispersed in about 10-40 % w/w of ethanol (with temperature of 5-10ºC in 2-10% of the initial quench volume) followed by addition of another 10-40 % w/w of ethanol (with temperature of 25-40ºC. Final wash volume was in the range of 0.025 to 0.5L/gm. The microparticles suspension was then decanted for about 5-60 minutes to concentrate the microparticles suspension to approximately 1/10 of the original volume by discarding about 90% supernatant containing a portion of ethanol as waste.

The resulting microparticles were then filtered, dried and filled aseptically into vials or alternatively, the resulting microparticles were sieved through a filter of 100-200 micron size and transferred to vial filling line, filled in the vials under stirring, and finally lyophilizing the microparticle filled vials by optimized control of temperature and pressure to control residual solvents.
,CLAIMS:1. A pharmaceutical composition comprising microparticles of risperidone, 9-hydroxyrisperidone or salts thereof characterized by
i) a particle size distribution defined as follows:
- D (v,0.1) is between about 40 and about 75 micrometers,
- D (v,0.5) is between about 80 and about 120 micrometers,
- D (v,0.9) is between about 140 and about 180 micrometers.
ii) angle of repose less than about 35 and
iii) compressibility index in the range of 1% to 25%,
wherein the composition is prepared by a process comprising steps of:
(a) preparing an emulsion; (b) quenching the emulsion to form microparticles suspension (c) lyophilizing the microparticles suspension (d) washing the microparticles (e) filtering the microparticle slurry (f) lyophilizing the microparticles.

2. The pharmaceutical composition of claim 1, wherein the emulsion comprises first phase comprising a risperidone, 9-hydroxyrisperidone or salts, one or more polymers, and one or more solvents and a second phase.

3. The pharmaceutical composition of claim 2, wherein the first phase is prepared by a process comprising the steps of:
(1) separately preparing solution of a risperidone, 9-hydroxyrisperidone or salts and one or more polymers;
(2) aseptically filtering the drug solution and polymer solution; and
(3) mixing the filtered drug solution and polymer solution.

4. The pharmaceutical composition of claim 1, wherein the quenching step further followed by fine removal by decantation, washing and de-watering of the emulsion that is performed in a single vessel.

5. The pharmaceutical composition of claim 1, wherein the washing in step (d) is performed in a vessel having temperature in the range of 25° to 40°C.

6. The pharmaceutical composition of claim 1, wherein quenching of the emulsion is done with a quench phase comprising polyvinyl alcohol and ethyl acetate.

7. The pharmaceutical composition of claim 2, wherein the solvent in first phase of the emulsion comprises benzyl alcohol.

8. The pharmaceutical composition of claim 1, wherein the lyophilization step comprises freezing at temperature up to -45° C, primary drying at temperature in the range of -35°C to -3°C and secondary drying at temperature up to 45° C.