Patent Description:
Paliperidone palmitate is an atypical antipsychotic agent belonging to the chemical class of benzisoxazole derivatives. The chemical name for paliperidone palmitate is <NUM>-(<NUM>-(<NUM>-(<NUM>-fluoro-3a,7a-dihydrobenzo[d]isoxazol-<NUM>-yl)piperidin-<NUM>-yl)ethyl)-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-a]pyrimidin-<NUM>-yl palmitate and is represented by the following formula:
<CHM>.

Currently, paliperidone palmitate is approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of schizophrenia or a schizoaffective disorder. Additionally, paliperidone palmitate can be used to treat mania and at lower doses as maintenance for bipolar disorders.

Paliperidone palmitate can be formulated for parenteral administration. It was previously discovered that the particle size distribution of paliperidone palmitate determines the extended release kinetics of the formulations. Currently, paliperidone palmitate is micronized using air-jet mills or a multi-step wet milling process. Generally, sterile air-jet milling is carried out in isolators or by using a restricted access barrier system.

Paliperidone palmitate has been previously formulated for an extended-release suspension for intramuscular injection. The extended-release formulation is the result of the suspension having a range of paliperidone palmitate particle sizes. The range of paliperidone palmitate particle sizes is due to a multi-step wet milling process. The multi-step wet milling process requires the use of at least two different sized milling media, wherein a filtration or separation step is required to remove the first milling media before addition of the second milling media.

<CIT> discloses a process for micronizing paliperidone palmitate by wet milling utilizing two types of milling beads sequentially. In comparative examples a single milling step is used.

Thus, there is a need to develop a manufacturing process that is more controlled than prior methods.

The present disclosure provides a one step process for preparing a micronized paliperidone ester, the process comprising wet milling for <NUM> minutes ±<NUM>% to <NUM> minutes ±<NUM>% a suspension comprising a solid paliperidone ester having an average particle size from <NUM> ±<NUM>% to <NUM> ±<NUM>%, at least one suspending agent, and at least one wetting agent in the presence of a plurality of polymeric beads to form the micronized paliperidone ester, wherein the plurality of polymeric beads has an average diameter from <NUM> ±<NUM>% to <NUM> ±<NUM>%, the micronized paliperidone ester has a particle size distribution from <NUM> ±<NUM>% to <NUM> ±<NUM>%, and wherein the at least one suspending agent is polyethylene glycol, polypropylene glycol, or combinations thereof.

Other aspects and iterations of the disclosure are described in more detail below.

The present disclosure provides injectable pharmaceutical compositions that provide controlled release of an active pharmaceutical ingredient. Also provided are methods of making the controlled release pharmaceutical composition. The methods comprise a one-step wet milling process to provide a particle size distribution of the active pharmaceutical ingredient to obtain a controlled release formulation. The pharmaceutical compositions disclosed herein comprise at least one wetting agent, at least one suspending agent, and at least one active pharmaceutical ingredient. The pharmaceutical composition may further comprise at least one buffer and at least one pH modifier. Applicants of the present invention discovered that the milling of the active pharmaceutical ingredient with the other components, specifically, a wetting agent and a suspending agent, provides better control of the milling process which in turn provides better control of particle size distribution of the active pharmaceutical ingredient and prevents the generation of fine particles. The pharmaceutical compositions disclosed herein are milled in a one step process using polymeric beads. The resulting pharmaceutical composition provides better control of the controlled release profile.

One aspect of the disclosure encompasses a process for preparing micronized paliperidone ester. The process is defined in the claims.

The first step of the process comprises forming a suspension comprising a solid paliperidone ester, at least one suspending agent, and at least one wetting agent. The suspending agent is polyethylene glycol, polypropylene glycol, or combinations thereof. The process for forming the suspension generally takes place under aseptic conditions. Such methods are generally known in the art.

The suspension comprises a paliperidone ester. In further embodiments, the paliperidone ester is paliperidone palmitate.

The API may be in any of its crystalline, semi-crystalline, amorphous, or polymorphous forms. In an exemplary embodiment, the API may be in a crystalline form.

The crystalline, semi-crystalline, amorphous, or polymorphous forms may have a particle size of about <NUM> to about <NUM>. In some embodiments, the crystalline, semi-crystalline, amorphous, or polymorphous forms may have a particle size of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

The amount of API in the suspension can and will vary depending upon the active agent. In certain embodiments, the API in the suspension is paliperidone palmitate. In certain embodiments, the amount of paliperidone palmitate before milling may range from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, or from about <NUM>% to about <NUM>% w/v of the suspension. In certain embodiments, the amount of paliperidone palmitate in the suspension may be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% w/v of the suspension.

The suspension comprises at least one suspending agent. In general, the at least one suspending agent provides long-term stabilization, facilitate drug adsorption, alter viscosity, or enhance solubility.

The suspending agent is polyethylene glycol, polypropylene glycol, or combinations thereof (e.g., PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>, PEG <NUM>,<NUM>, PEG <NUM>,<NUM>, PEG <NUM>, PEG <NUM>,<NUM>, etc.). In an exemplary embodiment, the suspending agent may be polyethylene glycol <NUM> (PEG <NUM>).

The amount of the at least one suspending agent present in the suspension can and will vary depending upon the identity of the suspending agent as well as the identity and/or amount of the other components in the suspension. In general, the amount of the at least one suspending agent in the suspension may range from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, or from about <NUM>% to about <NUM>% w/v of the suspension. In some embodiments, the amount of the at least one suspending agent in the suspension may be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% w/v of the suspension.

The suspension also comprises at least one wetting agent. The at least one wetting agent can comprise amphiphilic compounds that contain polar, hydrophilic moieties as well as non-polar hydrophobic moieties. The wetting agent can be an anionic, cationic, a zwitterionic, or a non-ionic wetting agent.

Suitable wetting agents include, without limit, polyethylene glycol fatty acid monoesters (e.g., polyethylene glycol laurate or stearate, etc.); polyethylene glycol fatty acid diesters (e.g., polyethylene glycol dilaurate, disterate, dipalmitate, or dioleate, etc.); polyethylene glycol glycerol fatty acid esters (e.g., polyethylene glycol glycerol laurate, glycerol stearate, glycerol oleate, etc.); polyglycerized fatty acids (e.g., polyglyceryl laurate, oleate, or stearate; polyglyceryl mono and dioleate; etc.); sterol derivatives (e.g., polyethylene glycol cholesterol ether, polyethylene glycol cholestanol, polyethylene glycol phyto sterol, etc.); and polyethylene glycol sorbitan fatty acid esters (e.g., polysorbate <NUM>, polysorbate <NUM>, PEG-<NUM> sorbitan laurate, PEG-<NUM> sorbitan monolaurate, sorbitan tristearate, etc.). In an exemplary embodiment, the wetting agent may be polysorbate <NUM>.

The amount of the at least one wetting agent present in the suspension can and will vary depending upon the identity of the wetting agent as well as the identity and/or amount of the other components utilized in the suspension. In general, the amount of the at least one wetting agent in the suspension may range from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, or from about <NUM>% to about <NUM>% w/v of the suspension. In some embodiments, the amount of the at least one wetting agent in the suspension may be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% w/v of the suspension.

The suspension may comprise at least one buffer. The identity of the buffer can and will vary depending on the pH of the suspension. Non-limiting examples of the buffer include the sodium or potassium salt of phthalate, phosphate, borate, and acetate. In an exemplary embodiment, the buffer may comprise sodium dihydrogen phosphate and/or disodium hydrogen phosphate.

In general, the amount of the at least one buffer in the suspension may range from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, or from about <NUM>% to about <NUM>% w/v of the suspension. In certain embodiments, the amount of buffer in the suspension may be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% w/v of the suspension.

The suspension may comprise at least one pH modifier to adjust the pH of the suspension. Non-limiting examples of a pH modifier include organic or inorganic acids and bases, for example, acetic acid, citric acid, benzoic acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, phosphoric acid, sorbic acid, sulfuric acid, tartaric acid, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide. In certain embodiment, the pH modifier may comprise sodium hydroxide and citric acid. In a specific embodiment the pH modifier may be citric acid.

In general, the amount of the at least one pH modifier in the suspension may range from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, from about <NUM>% to about <NUM>% w/v, or from about <NUM>% to about <NUM>% w/v of the suspension. In certain embodiments, the amount of pH modifier in the suspension may be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% w/v of the suspension.

The pH of the suspension may range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. In certain embodiment, the pH of the suspension may be about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

In an embodiment, forming the suspension is carried in a batch or continuous process. In an exemplary embodiment, forming the suspension is carried out in a continuous process.

The process further comprises milling the suspension to form micronized paliperidone ester. The process comprises milling the suspension to reduce particle size and generate a size distribution of micronized paliperidone ester particles. The milling process can be accomplished by techniques generally known in the art. Further, the milling process generally takes place under aseptic conditions.

The milling process generally utilizes milling media. The milling media comprise polymeric beads. Non-limiting examples of polymeric beads include polystyrene, polyamide, polycarbonate, acrylic, crosslinked polystyrene, crosslinked polyamide, or crosslinked polycarbonate. In an exemplary embodiment, the milling media is polystyrene beads crosslinked with divinylbenzene.

The size of the polymeric beads may vary depending upon the desired particle distribution. In some embodiments, the size of the polymeric beads may range from about <NUM> to about <NUM>. In various embodiments, the size of the polymeric beads may range from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The milling process reduces the size of the paliperidone ester to the desired particle size distribution. The milling process is preferably accomplished so that the particle size distribution provides satisfactory dosage content uniformity, dissolution profiles, and a controlled release profile. The particle size distribution ranges from about <NUM> to about <NUM> or from about <NUM> to about <NUM>. In some embodiments, the d10 is from about <NUM> to about <NUM>, d50 is from about <NUM> to about <NUM>, and d90 is from about <NUM> to about <NUM>.

The time of the milling step can and will vary depending upon the components of the suspension. Additionally, the milling time may vary depending on the total amount of suspension prepared in Section (I)(a). The milling step proceeds for about <NUM> minutes to about <NUM> minutes, or from about <NUM> minutes to about <NUM> minutes.

The temperature of the milling step may also vary depending upon the identity of the API. In general, the milling step may occur at a temperature ranging from about <NUM> to about <NUM>. In specific embodiments, the milling step may occur at room temperature or about <NUM>-<NUM>.

The tip speed of the milling step can and will vary depending upon the mill utilized, media milling size, and final particle size distribution. In general, the milling speed may occur at from about <NUM>/s to about <NUM>/s. In further embodiments, the milling speed may occur at from about <NUM>/s to about <NUM>/s.

Following the milling process, the milling media is removed by standard techniques known in the art, and the micronized paliperidone ester suspension is diluted to the desired API concentration.

In an embodiment, the milling process is carried in a batch or continuous process. In an exemplary embodiment, the milling process is carried out in a continuous process.

The process of preparing a micronized palmitate ester can be conducted at a bench top (e.g., <NUM> to <NUM>) to commercial scale (e.g., <NUM> to <NUM>).

One aspect of the present disclosure provides a pharmaceutical composition that can be formulated to provide a controlled release of a micronized palmitate ester. Detailed below are the components and dosage forms of the pharmaceutical composition.

The pharmaceutical composition disclosed herein comprises at least one wetting agent, at least one suspending agent, at least one buffer, at least one pH modifier, and at least one active pharmaceutical ingredient. The order of component addition and the one-step milling process provide the desired API particle distribution which creates a controlled release formulation.

In an exemplary embodiment, the pharmaceutical composition comprises paliperidone palmitate, polysorbate <NUM>, polyethylene glycol <NUM>, citric acid monohydrate, sodium dihydrogen phosphate, sodium hydroxide, and water for injection. In further exemplary embodiment, the pharmaceutical composition comprises paliperidone palmitate in an amount from about <NUM>% to about <NUM>% by weight of the composition, polyethylene glycol <NUM> in an amount from about <NUM>% to about <NUM>% by weight of the composition, polysorbate <NUM> in an amount from about <NUM>% to about <NUM>% by weight of the composition, citric acid in an amount from about <NUM>% to about <NUM>% by weight of the composition, sodium dihydrogen phosphate in an amount from about <NUM>% to about <NUM>% by weight of the composition, sodium hydroxide in an amount from about <NUM>% to about <NUM>% by weight of the composition, and has a pH of about <NUM> to about <NUM>.

In an additional exemplary embodiment, the pharmaceutical composition comprises paliperidone palmitate in an amount of about <NUM>/mL, polysorbate <NUM> in an amount of about <NUM>/mL, polyethylene glycol <NUM> in an amount of about <NUM>/mL, citric acid in an amount of about <NUM>/mL, sodium dihydrogen phosphate in an amount of about <NUM>/mL, sodium hydroxide in an amount <NUM>/mL, and has a pH of about <NUM> to about <NUM>.

The physical form of the pharmaceutical composition disclosed herein can and will vary. In general, the pharmaceutical composition can be prepared for parenteral administration.

Preparations for parenteral administration may be in a suspension. For parenteral administration (including subcutaneous, intradermal, intramuscular, and intraperitoneal), the preparation may be an aqueous or an oil-based suspension. Aqueous suspensions may include a sterile diluent such as water, saline solution, a pharmaceutically acceptable polyol such as glycerol, propylene glycol, or other synthetic solvents; an antibacterial and/or antifungal agent such as benzyl alcohol, methyl paraben, chlorobutanol, phenol, thimerosal, and the like; an antioxidant such as ascorbic acid or sodium bisulfite citrate; a chelating agent such as etheylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and/or an agent for the adjustment of tonicity such as sodium chloride, dextrose, or a polyalcohol such as mannitol or sorbitol. Oil-based suspensions may further comprise sesame, peanut, olive oil, or mineral oil. In an exemplary embodiment, the pharmaceutical composition is formulated as an injectable suspension.

Compounds useful in the compositions and methods include those described herein including diastereomers and enantiomers, as well as racemic mixtures and pure isomers of the compounds described herein, where applicable.

When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term "about," particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent.

The term "aseptic," as used herein, refers to aseptic processing or manufacturing that complies with Good Manufacturing Practice (GMP) industry guidelines such as those associated with Guidance for Industry-Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice, U. Department of Health and Human Services Food and Drug Administration.

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the invention.

Polysorbate <NUM> (<NUM>), PEG <NUM> (<NUM>), citric acid monohydrate (<NUM>), sodium dihydrogen phosphate (<NUM>), and sodium hydroxide (<NUM>) were weighed and transferred to a volumetric flask. Water (<NUM>) for injection was added to the excipient mixture in a volumetric flask, mixed until completely dissolved, and then filtered.

Paliperidone palmitate (<NUM>) was weighed and transferred to a glass bottle. The filtered excipient solution was added to the paliperidone palmitate and mixed to create a suspension at the targeted milling concentration (<NUM>-<NUM> w/v%). The mixture was stirred for an hour to thoroughly wet paliperidone palmitate to produce a homogenous suspension.

The suspension from Example <NUM> (<NUM>-<NUM> w/v%) was milled in a NETZSCH MINICER bead mill using <NUM> micron polystyrene grinding media (<NUM>-<NUM>% media load). The mixture was milled at a speed of <NUM>-<NUM>/s at <NUM>-<NUM> for <NUM> minutes.

Following milling, particle size was measured, in deionized water, using a MALVERN MASTERSIZER <NUM> particle size analyzer. The mean milled paliperidone palmitate particle size distribution of the suspension was D90 less than <NUM> micron, D50 less than <NUM> micron, and a D10 less than <NUM> micron (<FIG>).

Claim 1:
A one step process for preparing a micronized paliperidone ester, the process comprising wet milling for <NUM> minutes ±<NUM>% to <NUM> minutes ±<NUM>% a suspension comprising a solid paliperidone ester having an average particle size from <NUM> ±<NUM>% to <NUM> ±<NUM>%, at least one suspending agent, and at least one wetting agent in the presence of a plurality of polymeric beads to form the micronized paliperidone ester, wherein the plurality of polymeric beads has an average diameter from <NUM> ±<NUM>% to <NUM> ±<NUM>%, the micronized paliperidone ester has a particle size distribution from <NUM> ±<NUM>% to <NUM> ±<NUM>%, and wherein the at least one suspending agent is polyethylene glycol, polypropylene glycol, or combinations thereof.