DESC:TECHNICAL FIELD OF THE INVENTION
The present invention relates to a fluidized bed based coating process for preparation of modified release multiparticulate systems. In particular, the fluidized bed based coating process relates to coating of multiparticulate system with a coating composition comprising poorly conducting and insulating material and amorphous hydrated silica having high water adsorption capacity and high porosity. By adding an amorphous hydrated silica having high water adsorption capacity and high porosity to the coating composition, it is possible to eliminate or reduce the accumulation of electrostatic charge generated in the fluidized bed during the process. Further, the process facilitates the manufacture of uniformly coated modified release multiparticulate systems which do not exhibit burst release.

BACKGROUND OF THE INVENTION
Polymer film coating is often used in oral modified release systems. A modified release formulation may consist of a single unit, or of many modified-release units i.e. multiparticulate system e.g. pellets. Such composition may further require coating of the pellets. The quality of coated pellets may affect in-vitro release performance.

The quality of the coating process can be measured at a macroscopic level (coater performance) or at a microscopic level (coating quality). At the microscopic level, quality can be characterized as a function of different parameters, one of which is the coating mass uniformity. The coating mass uniformity refers to the variation in the amount of coating material each particle receives during a batch coating operation. The non-uniformity in coating level among different particles in a coated batch is due to two different aspects: 1) each particle receives a different amount of coating each time it passes through the spray zone, and 2) the number of times a particle passes though the spray zone varies from particle to particle. Significant variation in coating levels among particles may occur even when pellets of uniform size are used. It has been shown that the presence of dead/slow zone in the fluid bed where particles are retained has a negative effect on the coating uniformity. The situation becomes more complicated when particles having a wide size distribution are used.

It has been reported that the larger particles receive a larger portion of coating material compared to the smaller ones in the case of bottom spray fluid beds equipped with a Wurster insert. All this is further complicated by the buildup of electrostatic charges on the particles which arise during the operation of such multiphase systems of fluidized beds. Particularly, electrostatic charges are generated when the materials involved are dielectric in nature. The accumulation of electrostatic charges within the system can be an operational hazard.

The majority of polymers used in coating of modified release formulations are water insoluble or water swellable and hence a non-aqueous solvent composition is used very often to prepare the polymer dispersion for coating. Further, these release rate controlling polymers are generally poorly conducting or insulating in nature. In order to achieve the desired polymeric coating layer thickness, repeated exposure of the core pellet to the polymer dispersion spray is required inside the coating equipment and this leads to particle to particle and particle to wall attrition and tremendous triboelectric static charge generation. A most conventional and reliable equipment used for controlled release polymer coating is the Wurstor coating process in a fluid bed processor. But, accumulation of static charge during processing hinders the fluidization of pellets inside the fluid bed processor and makes it virtually impossible to coat the pellets. This also leads to the non-uniformity in coated pellets and resultant dose dumping, creating pellets with dissolution profile which cannot be reproduced in-vitro during repeated attempts.

In a study, Marucci M. et al (Chem. Biochem. Eng. Q. 26 (4) 379–384; 2012) suggests the solutions like control on pellet load & pellet size taken for coating, control on fluidizing air flow volume, and the use of humidified air for resolving the non-uniformity in pellet coating due to the electrostatic charge accumulation.

For multiparticulate systems, the release of the drug from a whole dose is the result of the combination of the release from each single unit. When the units are coated with a modified-release film, the drug release rate is mainly controlled by the film thickness and the film quality. The thinner the coating, the faster the release of drug from the unit occurs. The thickness and the uniformity of coating may play a crucial role in the manufacturing of modified release coated formulations. The non-uniformity of pellets coating thus affects the release of pellets payload and may give rise to initial burst in the drug release profile.

Therefore, when pellets are coated in a fluid bed coater it is fundamental to reduce the electrostatic charges generated on the pellets when materials with high insulating properties are used, in order to achieve better coating uniformity and, consequently, more favorable release profiles. But, relatively little work is performed on multiparticulate and multiphase systems with non-conductive liquids as the medium.

Mesalamine is an aminosalicylate anti-inflammatory agent for gastrointestinal use indicated for the treatment of patients with mild to moderately active ulcerative colitis. Mesalamine Controlled Release Capsule is marketed by Shire under the trade name Pentasa®.

Prior arts reveal an unmet need for a well defined composition and process executable at a lab scale and scalable to a production scale without the issue of non uniformity of coated pellets resulting from triboelectric static charge generation and accumulation. Hence it would be a valuable contribution to the art to develop a composition and process devoid of triboelectric static charge to manufacture uniformly coated pellets of controlled release mesalamine.

US Patent No. 4,880,794 describes sustained release granules of mesalamine coated with ethyl cellulose.

US Patent No. 5,910,319 discloses formulation of antidepressant drug, fluoxetine, in the form of enteric pellets wherein the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

PCT publication WO 201314417 A1 discloses controlled release formulation comprising mesalamine.

PCT publication WO 2009/114773 A2 discusses the difficulty in devising a modified release mesalamine dosage form that provides desirable in-vivo drug release.

Thus, there still exists an enduring need to provide a workable solution for the pharmaceutical based multiparticulate system comprising poorly conducting and insulating material to reduce or eliminate the accumulation of electrostatic charge during coating process in fluidized bed processor.

SUMMARY OF THE INVENTION
The present invention relates to fluidized bed based coating process for preparation of modified release multiparticulate systems. In particular, the fluidized bed based coating process relates to coating of multiparticulate system with a coating composition comprising poorly conducting and insulating material and amorphous hydrated silica having high water adsorption capacity and high porosity. Further, the process relates to eliminating or reducing the accumulation of triboelectric static charge by addition of amorphous hydrated silica having high water adsorption capacity and high porosity to the coating composition. Further, a composition and process is disclosed which do not necessitate the use of a humidification system in an attempt to dissipate the triboelectric static charge generated during drug loading and functional coating using poorly conducting and insulating polymers. Specific reference is made to the manufacture of mesalamine modified release capsules.

In one general aspect, there is provided an fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a multiparticulate system comprising one or more active pharmaceutical ingredients; and
(b) coating multiparticulate system of step (a) with a coating solution or dispersion comprising one or more poorly conducting and insulating material and a amorphous hydrated silica having high water adsorption capacity and high porosity.

In an embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a multiparticulate system comprising one or more active pharmaceutical ingredients; and
(b) coating multiparticulate system of step (a) with a coating solution or dispersion comprising one or more poorly conducting and insulating material and a amorphous hydrated silica having high water adsorption capacity and high porosity,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of modified release multiparticulate system.

In another general aspect, the amorphous hydrated silica is having moisture adsorption capacity of at least of 15 % by weight at 60% RH.

In another embodiment, the amorphous hydrated silica is having moisture adsorption capacity of at least of 20 % by weight at 60% RH, preferably at least 25 % by weight at 60% RH.

In another general aspect, the amorphous hydrated silica used in the coating composition is having moisture adsorption capacity of at least of 50 % by weight at 90% RH.

In another embodiment, the amorphous hydrated silica used in the coating composition is having moisture adsorption capacity of at least of 55 % by weight at 90% RH, preferably at least 60 % by weight at 90% RH.

In another general aspect, there is provided a coating composition comprising amorphous hydrated silica having average pore volume of at least about 0.5 ml/g.

In another embodiment, the coating composition comprises amorphous hydrated silica having average pore volume of about 1.5 ml/g.

In another general aspect, there is provided a coating composition comprising amorphous hydrated silica having average particle size of at least about 1.0 µm.

In another embodiment, the coating composition comprises amorphous hydrated silica having average particle size of at least 3.2 µm.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the amount of amorphous hydrated silica is in the range of about 0.01% to about 50% of weight of the composition.

In another embodiment, the amorphous hydrated silica is Syloid® 244 FP.

In another general aspect, there is provided a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(c) providing a multiparticulate system comprising one or more active pharmaceutical ingredients; and
(d) coating multiparticulate system of step (a) with a coating solution or dispersion comprising one or more poorly conducting and insulating material and a amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH and average pore volume of about 1.5 ml/g,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of modified release multiparticulate system.

In another embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the process produces uniformly coated modified release multiparticulate system.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the coated modified release multiparticulate system do not exhibit burst release.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the active pharmaceutical ingredient is mesalamine.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the poorly conducting and insulating material is a polymer.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the poorly conducting and insulating material comprises methyl cellulose, ethyl cellulose, hydroxypropyl cellulose hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose or combination thereof.

In another general aspect, there is provided a fluidized bed coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a multiparticulate system comprising mesalamine;
(b) coating multiparticulate system of step (a) with a coating solution or dispersion comprising ethylcellulose, hydroxypropyl methyl cellulose and amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH and average pore volume of about 1.5 ml/g,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of uniformly coated modified release multiparticulate system.

In another general embodiment, a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, wherein the composition exhibits a release profile such that:
(a) not less than about 10% and not more than about 45% of mesalamine released at 2 hours,
(b) not less than about 45% and not more than about 80% of mesalamine released at 4 hours, and
(c) not less than about 80% of mesalamine released at 8 hours,
when measured in USP Type II apparatus at 100 rpm in a 900 mL of pH 6.8 phosphate buffer.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 describes the interior view of Fluid Bed Processor bowl during coating process of Comparative Example A.
Figure 2 describes the interior view of Fluid Bed Processor bowl during coating process of Comparative Example B.
Figure 3 describes the interior view of Fluid Bed Processor bowl during coating process of Example 1.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.

The term “antistatic agent” is generally used to describe a substance that is added to a material to make that material static dissipative. Antistatic agents can function either by reducing the generation of charge, by increasing the rate of charge dissipation, or by both mechanisms. Most antistatic agents operate by increasing the rate of charge dissipation.

The term “triboelectric static charge” is a type of contact electrification in which certain materials become electrically charged after they come into frictive contact with a different material. Most everyday static electricity is triboelectric. The polarity and strength of the charges produced differ according to the materials, surface roughness, temperature, strain, and other properties. The two materials only need to come into contact and then separate for electrons to be exchanged. After coming into contact, a chemical bond is formed between parts of the two surfaces, called adhesion, and charges move from one material to the other to equalize their electrochemical potential. This is what creates the net charge imbalance between the objects.

As used herein, the term "average particle size" (or synonymously, "mean particle size") refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term "D50" or "d(0.5)". The average particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter's principle. Such average particle size can be determined by laser light scattering using e.g. a Malvern- Mastersizer Apparatus MS 2000, Malvern Instruments.

By virtue of their chemical constitution most polymers act as good electrical insulators. This property is the basis for the accumulation of static electricity which is not discharged fast enough due to their low surface conductivity. Increasing the moisture content of the surrounding atmosphere (humidification), by application of internal or external antistatic agents, or by chemically modifying the material, is a means of controlling static charges.

Humidity plays an important role in the area of static charge dissipation. Unfortunately the humidities required to avoid static problems (as high as 60 – 70%) are normally too high to be feasible from a production point of view. The self-dissipation of static is very much a surface effect and can be strongly influenced by absorbed moisture. With an increase in the relative humidity, a conductive layer of water is formed on the polymer surface which disperses the charge via ionic conduction.

Accumulation of static charge during processing hinders the fluidization of pellets inside the fluid bed processor and makes it virtually impossible to coat the pellets. This leads to non-uniformity in the drug loading and control release polymer coating which can result in dose dumping. Conventional excipients used as anti-adherents like talc, colloidal silicon dioxide, stearic acid, magnesium stearate, polyethylene glycols, and glyceryl monostearates were found not beneficial in dissipating the accumulated triboelectric static charge during the coating process involving highly insulating and poorly conduction material.

The said composition and process of present invention do not necessitate the use of a humidification system in an attempt to dissipate the triboelectric static charge generated during drug loading and functional coating comprising poorly conducting and insulating polymers. As the process eliminates the accumulation of triboelectric static charge generated during the drug loading and coating process it thereby avoids any probability of explosion hazards when using non-aqueous solvent as a major component in the coating dispersion composition.

The inventors of present invention have surprisingly found that the incorporation of amorphous hydrated silica characterized by high surface area and high moisture adsorption capacity produced uniformly coated pellets having desired in-vitro release characteristics i.e. no burst release.

Amorphous hydrated silica is a highly porous micronized silica powder. The high surface area and internal porosity of such silica is capable of adsorbing considerable amount of moisture via a hydrogen bonding and the internal porosity retains the physically adsorbed water. It has polar functional groups in the surface and displays molecular interactions like dipole-dipole, Van der Waals forces and it also exhibits capillary forces. The amorphous hydrated silica used in the present invention has moisture adsorption capacity of about 40% by weight at 60% relative humidity (RH). Preferably, amorphous hydrated silica used in the present invention has moisture adsorption capacity of at least of 60% by weight at 90% RH. The amorphous hydrated silica used in the invention has average pore volume of at least 1.0 ml/g, preferably, the average pore volume is about1.5 ml/g. The amorphous hydrated silica used in the present invention has average particle size of at least 1.0 µm, preferably the particle size is about 3.2 µm. The amorphous hydrated silica with such characteristics is available commercially from Grace Material Technologies by the trade name of Syloid® 244 FP.

Without binding to the theory inventors of present invention propose that the presence of polar functional groups in the surface and molecular interactions (dipole dipole, van der waals) among particles of such amorphous hydrated silica are responsible for dissipation of electrostatic charge generated during the coating process of multiparticulate system comprising insulating material in fluidized bed processor. The incorporation of such amorphous hydrated silica into the coating dispersion helps to retain moisture on the surface of the particles to be coated inside the fluid bed coater thereby increasing the conductivity and dissipating the accumulated triboelectric static charge.

In one general aspect, there is provided a fluidized bed based coating process for the preparation of modified release multiparticulate system comprising one or more active pharmaceutical ingredients; wherein the process eliminates the accumulation of triboelectric static charge during coating by incorporating amorphous hydrated silica having high moisture adsorption and high porosity in the coating composition.

In an embodiment, a process of coating multiparticulate system; wherein the modified release coated multiparticulate system exhibits desired in-vitro release characteristics.

In another embodiment, a process of coating multiparticulate system wherein the modified release coated multiparticulate system do not exhibit burst release.

In another embodiment, a modified release coating composition, wherein the poorly conducting and insulating material is a polymer.

In another embodiment, a coating composition for multiparticulate system, wherein the coating composition either in the form of solution or dispersion, comprises a polymeric material and amorphous hydrated silica having high water adsorption capacity and high porosity.

In another general aspect, the modified release pharmaceutical composition comprising:
a) a core multiparticulate system comprising mesalamine, and
b) a coating composition comprising one or more poorly conducting and insulating material and amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH,
wherein the coating composition of step (b) is coated on core multiparticulate system comprising mesalamine of step (a).

In another general aspect, there is provided a fluidized bed based coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a multiparticulate system comprising one or more active pharmaceutical ingredients; and
(b) coating multiparticulate system of step (a) with a coating solution or dispersion comprising one or more poorly conducting and insulating material and amorphous hydrated silica having high water adsorption capacity and high porosity,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of modified release multiparticulate system.
In another general aspect, the amorphous hydrated silica is having moisture adsorption capacity of at least of 15 % by weight at 60% RH.

In another embodiment, the amorphous hydrated silica is having moisture adsorption capacity of at least about 20 % by weight at 60% RH. Preferably, the amorphous hydrated silica is having moisture adsorption capacity of about 25 %, %, about 30%, about 35%, about 40%, about 45% or about 50% by weight at 60% RH.

In another general aspect, the amorphous hydrated silica used in the coating composition is having moisture adsorption capacity of at least about 40 % by weight at 90% RH. Preferably the amorphous hydrated silica is having moisture adsorption capacity of about 42 %, about 44%, about 46%, about 48%, about 50% or about 52% by weight at 90% RH

In another embodiment, the amorphous hydrated silica used in the coating composition is having moisture adsorption capacity of at least of 55 % by weight at 90% RH, preferably at least 60 % by weight at 90% RH.

In another general aspect, there is provided a coating composition comprising amorphous hydrated silica having average pore volume of at least about 0.5 ml/g. Preferably, the average pore volume of about 0.7 ml/g, about 0.9 ml/g, about 1.1 ml/g, about 1.3 ml/g, about 1.5 ml/g, about 1.7 ml/g, or about 1.9 ml/g.

In another general aspect, there is provided a coating composition comprising amorphous hydrated silica having average particle size of at least about 1.0 µm. Preferably, having average particle size of about 1.2 µm, about 1.4 µm, about 1.6 µm, about 1.8 µm, about 2.0 µm, about 2.2 µm, about 2.4 µm, about 2.6 µm, about 2.8 µm, about 3.0 µm, about 3.2 µm, about 3.4 µm, about 3.6 µm, about 3.8 µm, or about 4.0 µm.

In another embodiment, the amorphous hydrated silica used in the coating composition is having moisture adsorption capacity of about 40 % by weight at 60% RH, having average particle size of about 3.2 µm, and having average pore volume of about 1.5 ml/g.

In another general aspect, there is provided a fluidized bed processor based coating process of multiparticulate system, wherein the amount of amorphous hydrated silica is in the range of 0.01% to 50% by weight of the composition.

In another general aspect, there is provided a fluidized bed processor based coating process of multiparticulate system, wherein the amount of amorphous hydrated silica is in the range of 20% to 40% by weight of the coating composition.

In another embodiment, the amount of amorphous hydrated silica is 29% by weight of the coating composition.

In another embodiment, the amorphous hydrated silica is Syloid® 244 FP.

In another general aspect, there is provided a fluidized bed processor based coating process of multiparticulate system, wherein the amount of a poorly conducting and insulating material is in the range of 0.01% to 50% by weight of the composition.

In another embodiment, the amount of a poorly conducting and insulating material is in the range of 55% to 85% by weight of the coating composition.

In another embodiment, the amount of a poorly conducting and insulating material is in the range of 68.84 by weight of the coating composition.

In another general aspect, the multiparticulate system is in the form of pellets.
In another general aspect, there is provided a composition comprising pellets filled in the hard gelatin capsule.

In another general aspect, there is provided a multiparticulate composition comprising mesalamine.

In another general aspect, there is provided a modified release pharmaceutical composition comprising multiparticulate system comprising mesalamine and a coating composition comprising ethyl cellulose, hydroxypropyl methyl cellulose, castor oil and amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH.

In another general aspect, there is provided a modified release coating solution or dispersion comprising amorphous hydrated silica having moisture adsorption capacity of about 40 % by weight at 60% RH and a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, methylene chloride and mixture thereof.

In another general aspect, the modified release composition of mesalamine, wherein the weight ratio of poorly conducting and insulating material to amorphous hydrated silica is in the range of about 1: 0.1 to about 1: 10.

In another embodiment, the weight ratio of poorly conducting and insulating material to amorphous hydrated silica is in the range of about 1: 0.4 to about 1: 0.8.

In another embodiment, the weight ratio of poorly conducting and insulating material to amorphous hydrated silica is 1: 0.433.

In another general aspect, the poorly conducting and insulating materials in the coating composition comprises ethyl cellulose and hydroxypropyl methylcellulose in a weight ratio of 1: 0.61

In another general aspect, the modified release composition comprises by weight of the total composition:
(a) about 90% of mesalamine loaded central core pellets,
(b) about 6% of poorly conducting and insulating material,
(c) about 3% of amorphous hydrated silica having amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH, and
(d) about 1% of pharmaceutically acceptable excipient.

In another general aspect, the modified release composition comprises by weight of the total composition:
(a) about 90% of mesalamine loaded central core pellets,
(b) about 6% of ethyl cellulose and hydroxypropyl methylcellulose,
(c) about 3% of amorphous hydrated silica having amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH, and
(d) about 1% of talc and castor oil.

In another general aspect, the modified release composition comprises by weight of the total composition:
(a) 90.27% of mesalamine loaded central core pellets,
(b) 3.97% of ethyl cellulose,
(c) 2.43% of hydroxypropyl methylcellulose
(d) 2.78% of amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH,
(e) 0.40% of castor oil,
(f) 0.1% of talc, and
(g) 0.05% of colloidal silicon dioxide.

In another general aspect, the coating composition comprises:
a) 66.85% by weight of ethyl cellulose and hydroxypropyl methylcellulose,
b) 29.01% by weight of amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH, and
c) 0.5% by weight of talc and castor oil,
wherein the coating composition of step (b) is coated on multiparticulate system comprising mesalamine of step (a) in a fluidized bed coater.

In another aspect, there is provided a modified release composition of mesalamine which exhibits a release profile such that:
(a) not less than about 10% and not more than about 45% of mesalamine released at 2 hours,
(b) not less than about 45% and not more than about 80% of mesalamine released at 4 hours, and
(c) not less than about 80% of mesalamine released at 8 hours,
when measured in USP Type II apparatus at 100 rpm in a 900 mL of pH 6.8 phosphate buffer.

In another aspect, there is provided a fluidized bed coating process for the preparation of a modified release pharmaceutical composition, the process comprising:
(a) providing a multiparticulate system comprising mesalamine;
(b) coating multiparticulate system of step (a) with a coating solution or dispersion comprising ethylcellulose, hydroxypropyl methyl cellulose and amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of uniformly coated modified release multiparticulate system.

The multiparticulate system comprising mesalamine is in the form of the mesalamine loaded central core pellets and prepared as described in the method of manufacture in the present invention. A modified release polymeric coating which envelopes or substantially envelopes such central core was applied as per compositions.

The pharmaceutical composition comprises pellets comprising a central core and a polymeric coating which envelopes or substantially envelopes the central core. The central core may be prepared by any well known techniques in the art. Typically, the active pharmaceutical ingredient in dispersion form is bound to an inert carrier with any conventional binding agent using a fluid bed processor. The inert carrier selected can preferably be sugar spheres selected within a diameter range of 12-80 mesh depending on the amount of active pharmaceutical ingredient to be bound on the inert carrier.

A dispersion of the active pharmaceutical ingredient blend is prepared in a binding agent solution. The binding agent solution comprises of a polymer (e.g. ethyl cellulose, hydroxypropyl methyl cellulose), a plasticizer (e.g. castor oil, acetylated monoglycerides), and suitable anti-adherents known in the art, dissolved or dispersed in a pharmaceutically acceptable solvent like purified water, methanol,isopropyl alcohol, or mixture thereof. The mesalamine dispersion thus formed is bound to the inert carrier in a fluid bed processor by conventional means known in the art. The drug loaded central core pellets thus formed is polymer coated to impart modified release characteristics to the coated pellets. The quantity and composition of the polymeric materials used for modified release coating will determine the release characteristics of the coated pellets.

The polymeric materials preferred for the modified release coating are ethyl cellulose and hydroxypropyl methyl cellulose, alone or in combination in a suitable ratio. The polymer coating may optionally contain a sufficient quantity of a suitable plasticizer (e.g. castor oil, acetylated monoglycerides). The coating composition further comprises amorphous hydrated silica having moisture adsorption capacity of at about 40% by weight at 60% RH. This is commercially available from Grace Materials Technologies under the trade name Syloid® 244 FP Silica. Suitable antiadherants and glidants like stearic acid and talc can be incorporated optionally.

The modified release coating solution or dispersion is prepared by mixing the individual components of the coating composition into a pharmaceutically acceptable solvent such as purified water, methylene dichloride, methanol, isopropyl alcohol, acetone, or mixture thereof. The preferred solvents are methylene chloride and methanol. It is also preferred to incorporate a minor quantity of water into the solvent composition while preparing the coating dispersion.

The quantity of polymer coating to be given on the central core to obtain the desired dissolution release profile can be easily determined by one skilled in the art based on the target dissolution profile to be achieved. After the polymer coating has been applied to the central core, the active pharmaceutical ingredient modified release pellets are dried inside the fluid bed processor for suitable time. The dried pellets are further blended with conventional glidants and lubricants and filled into hard gelatin capsules. Alternatively the dried pellets can be blended with conventional diluents, binders and lubricants which can further be compressed into tablets.

The present invention provides a composition and process which eliminates the accumulation of triboelectric static charge generated during the drug loading and coating process and facilitates in the manufacture of uniform functional coated multiparticulate systems. The said composition and process disclosed do not necessitate the use of a humidification system in an attempt to dissipate the triboelectric static charge generated during drug loading and functional coating using poorly conducting and insulating polymers.

In another embodiment, the modified release coating solution or dispersion comprises amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH and a solvent selected from the group of water, methanol, ethanol, isopropyl alcohol and methylene chloride.

In another embodiment, the modified release composition of mesalamine, wherein the ethyl cellulose is present in an amount ranging from about 0.1% toabout 50% of the total weight of the composition.

In another embodiment, the modified release composition of mesalamine, wherein the hydroxypropyl methyl cellulose is present in an amount ranging from about 0.1% to about 50% of the total weight of the composition.

In another embodiment, the coating composition for multiparticulate system comprises:
(a) about 0.1 to about 50% of poorly conducting and insulating material and
(b) about 0.1 to about 50% of an amorphous hydrated silica having high water adsorption capacity and high porosity.

In another embodiment, the coating composition for multiparticulate system comprises:
(a) about 0.1 to about 50% of ethyl cellulose and hydroxypropyl methyl cellulose and
(b) about 0.1 to about 50% of amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH.

In another embodiment, the modified release composition of mesalamine, wherein the weight ratio of ethyl cellulose to amorphous hydrated silica is in the range of about 1: 0.1 to about 1: 10.

In another embodiment, the modified release composition of mesalamine, wherein the weight ratio of ethyl cellulose to amorphous hydrated silica is 1:0.70.

In another embodiment, the modified release composition of mesalamine, wherein the weight ratio of hydroxypropyl methyl cellulose to amorphous hydrated silica is in the range of about 1: 0.1 to about 1: 10.

In another embodiment, the modified release composition of mesalamine, wherein the weight ratio of hydroxypropyl methyl cellulose to amorphous hydrated silica is 1: 1.14.

In another embodiment, the modified release composition of mesalamine exhibits a release profile such that:
(a) not less than about 10% and not more than about 25% of mesalamine released at 2 hours,
(b) not less than about 25% and not more than about 40% of mesalamine released at 4 hours, and
(c) not less than about 45% of mesalamine released at 8 hours,
when measured in USP Type II apparatus at 100 rpm in a 900 mL of pH 4.5 acetate buffer.

The following examples are provided to further illustrate the invention, but it should not be construed as limiting the invention in any manner.

EXAMPLES
Comparative Example A and B: Pharmaceutical compositions comprising mesalamine.
The mesalamine loaded central core pellets containing 500mg mesalamine were prepared as described in the method of manufacture. A modified release polymeric coating which envelopes or substantially envelopes the central core was applied as per compositions of comparative example A and B mentioned in table 1.

Table 1
Ingredients Comparative Example A
Qty (mg/cap) Comparative Example B
Qty (mg/cap)
Modified Release Polymer Coating
Mesalamine loaded central core pellets 595.60 595.60
Ethyl Cellulose 26.20 26.20
Hydroxypropyl Methyl Cellulose 16.06 16.06
Castor oil 2.62 2.62
Talc 6.55 6.55
Stearic Acid -- 3.93
Methanol qs qs
Purified Water -- qs
Methylene Dichloride qs qs
Total 647.03 650.96
Lubrication
Talc 0.65 0.65
Colloidal Silicon Dioxide 0.35 0.35
Total (Fill weight in Capsule) 648.03 651.96

Manufacturing procedure: Mesalamine was blended with conventional glidants and anticaking agents to improve its flow and dispersability and a dispersion of the mesalamine blend was prepared in a binding agent solution. The mesalamine dispersion thus formed was bound to the inert carrier in a fluid bed processor by conventional means known in the art to prepare mesalamine loaded central core pellets.

The modified release coating composition was prepared comprising ethyl cellulose, hydroxypropyl methyl cellulose, castor oil, and talc (and stearic acid only for comparative example B) in a mixture of methanol, methylene dichloride and purified water. The mesalamine loaded central core pellets were coated with the modified release polymer coating composition to impart modified release characteristics to the coated pellets.

Example 1: Pharmaceutical composition comprising mesalamine.
The Mesalamine loaded central core pellets containing 500mg mesalamine were prepared as described in the method of manufacture. A modified release polymeric coating which envelopes or substantially envelopes the central core was applied as per composition mentioned in table 2.
Table 2
Ingredients Qty (mg/cap)
Modified Release Polymer Coating
Mesalamine loaded central core pellets 595.60
Coating composition
Ethyl Cellulose 26.20
Hydroxypropyl Methyl Cellulose 16.06
Castor oil 2.62
Syloid® 244 FP Silica 18.34
Methanol qs
Purified Water qs
Methylene Dichloride qs
Total of coating composition 63.22
Total (coating composition + mesalamine loaded central core pellets) 658.81
Lubrication
Talc 0.65
Colloidal Silicon Dioxide 0.35
Total (Fill weight in Capsule) 659.81

Manufacturing procedure: Mesalamine was blended with conventional glidants and anticaking agents to improve its flow and dispersability and a dispersion of the mesalamine blend was prepared in a binding agent solution. The mesalamine dispersion thus formed was bound to the inert carrier in a fluid bed processor by conventional means known in the art to prepare mesalamine loaded central core pellets.

The modified release coating composition was prepared comprising ethyl cellulose, hydroxypropyl methyl cellulose, castor oil and Syloid® 244 FP Silica in a mixture of methanol, methylene dichloride and purified water. The mesalamine loaded central core pellets were coated with the modified release polymer coating composition to impart modified release characteristics to the coated pellets.
Dissolution studies: Table numbers 3, 4 and 5 shows in vitro dissolution studies carried out for capsules of Example 1 in certain dissolution medium at specified conditions.
Table 3
In-vitro Dissolution Study - 0.1N HCL, 900 mL USP Type II, 100 rpm
Time (hr) Drug release (%) for Example 1
0.5 31
1 49
2 82
3 100
4 101

Table 4
In-vitro Dissolution Study - pH 4.5 acetate buffer, 900 mL; USP Type II, 100 rpm
Time (hr) Drug release (%) for Example 1
0.5 6
1 11
2 21
3 28
4 33
5 38
6 43
8 51
10 59
12 67

Table 5
In-vitro Dissolution Study - pH 6.8 phosphate buffer, 900 mL; USP Type II, 100 rpm
Time (hr) Drug release (%) for Example 1
0.5 11
1 23
2 38
3 49
4 60
5 71
6 82
8 97
10 98
12 100

,CLAIMS:1. A fluidized bed coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a core multiparticulate system comprising mesalamine; and
(b) coating the core multiparticulate system of step (a) with a coating composition comprising one or more poorly conducting and insulating material and amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of modified release multiparticulate system.

2. The process of claim 1, wherein the amorphous hydrated silica have average particle size of about 3.2 µm and average pore volume of about 1.5 ml/g.

3. The process of claim 1, wherein the amount of amorphous hydrated silica is present in an amount of 29% by weight of the coating composition.

4. The process of claim 1, wherein the weight ratio of poorly conducting and insulating material to amorphous hydrated silica is 1: 0.433.

5. The process of claim 1, wherein the poorly conducting and insulating materials in the coating composition comprises ethyl cellulose and hydroxypropyl methylcellulose in a ethyl cellulose to hydroxypropyl methylcellulose weight ratio of 1: 0.61.

6. The process of claim 1, wherein the coating composition comprises ethyl cellulose, hydroxypropyl cellulose, amorphous hydrated silica, talc, colloidal silicon dioxide and castor oil.

7. A fluidized bed coating process for the preparation of a modified release pharmaceutical composition, the process comprising steps of:
(a) providing a multiparticulate system comprising mesalamine;
(b) coating multiparticulate system of step (a) with a coating composition comprising:
i. 66.85% of ethyl cellulose and hydroxypropyl methylcellulose,
ii. 29.01% of Syloid® 244 FP, and
iii. 0.5% of talc and castor oil,
wherein the process reduces or eliminates the accumulation of triboelectric static charge during manufacturing of uniformly coated modified release multiparticulate system.

8. The process of claim 1, wherein the composition comprises by weight of the total composition:
i. 90.27% of mesalamine loaded central core pellets,
ii. 3.97% of ethyl cellulose,
iii. 2.43% of hydroxypropyl methylcellulose
iv. 2.78% of amorphous hydrated silica having moisture adsorption capacity of about 40% by weight at 60% RH,
v. 0.40% of castor oil,
vi. 0.1% of talc, and
vii. 0.05% of colloidal silicon dioxide.

9. The modified release composition prepared by a process of claim 1 or 7, wherein the composition exhibits a release profile such that:
(a) not less than 10% and not more than 45% of mesalamine released at 2 hours,
(b) not less than 45% and not more than 80% of mesalamine released at 4 hours, and
(c) not less than 80% of mesalamine released at 8 hours,
when measured in USP Type II apparatus at 100 rpm in a 900 mL of pH 6.8 phosphate buffer.