Compositions and methods for preparing polymeric films loaded with uniformly distributed drug particles
Inventors
Dave, Rajesh N. • Zhang, Lu • Buyukgoz, Guluzar Gorkem • Cetindag, Eylul
Assignees
New Jersey Institute of Technology
Publication Number
US-10918602-B2
Publication Date
2021-02-16
Expiration Date
2038-10-03
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Abstract
The present disclosure provides improved film based pharmaceutical products containing uniformly distributed drug or active agent particles (e.g., to achieve improved/excellent dissolution control including enhancing dissolution and bioavailability and/or product uniformity). More particularly, the present disclosure provides improved systems/methods for fabricating film based pharmaceutical products by utilizing higher surface modified micronized drug or active agent powders and film forming precursors and drying methods that accomplish improved/efficient drying and provide improved/excellent content uniformity of active pharmaceutical agents in the fabricated film based pharmaceutical products. In exemplary embodiments, the present disclosure provides for an easier means of directly incorporating dry micronized poorly water-soluble drugs or active agent particles (e.g., fenofibrate (“FNB”)) into films. The present disclosure demonstrates some advantages of direct incorporation of surface modified-micronized poorly water-soluble drug or active agent powders in film manufacturing.
Core Innovation
The invention provides improved film-based pharmaceutical products containing uniformly distributed drug or active agent particles, particularly focused on achieving excellent dissolution control, enhanced dissolution and bioavailability, and improved product uniformity. The core development enables the fabrication of these films by utilizing higher levels of surface-modified micronized drug or active agent powders, film-forming precursors, and specific drying methods to promote efficient drying while retaining the form and size of the active agents.
The problem addressed is that conventional approaches such as solvent casting and hot melt extrusion have notable limitations, especially for poorly water-soluble drugs. Solvent casting can cause drug recrystallization and residual solvents, while hot melt extrusion presents drug loading and high-temperature restrictions and cannot produce sufficiently thin films. Additionally, previously used methods like media milling require high energy and costly surfactants and additives, which come with toxicity risks and complications in achieving all desired film quality attributes.
In response, the disclosed systems and methods allow for the direct incorporation of dry, micronized, and surface-modified poorly water-soluble drug powders (such as fenofibrate) into films. Surface modification, for example with hydrophilic silica via a fluid energy mill, promotes improved dispersion, minimizes agglomeration, and thus enhances critical quality attributes such as content uniformity, mechanical strength, and dissolution performance of the film products. The process avoids the need for surfactants in the product and is applicable to high drug loading and various poorly water-soluble drugs.
Claims Coverage
The patent contains several independent claims that establish methods for fabricating film-based pharmaceutical products featuring specific steps and features.
Method using dry micronized and surface-modified poorly water-soluble drug particles without surfactant
A method for fabricating a film-based pharmaceutical product comprises: 1. Providing dry active agent poorly water-soluble particles. 2. Micronizing and surface modifying these particles with a dry coating agent via dry milling, without adding a surfactant, to obtain micronized active agent particles surface coated with the coating agent, in dry powder form. 3. Mixing the micronized surface-coated particles in dry powder form with at least one film-forming precursor to form a mixture. 4. Drying and fabricating the mixture to form a film. *The entire mixing and drying process is carried out without addition of surfactant so the final film is fabricated without any surfactant.*
Simultaneous micronization and surface modification of the poorly water-soluble particles via fluid energy mill
The method includes: - Simultaneously micronizing and surface modifying poorly water-soluble active agent particles with a dry coating agent via dry milling, specifically employing a fluid energy mill. - This process is performed without the addition of surfactant. - The particles may include BCS Class II or IV poorly water-soluble drugs.
Direct mixing of surface-modified drug particles with film-forming precursor solution
The micronized active agent particles surface coated with a dry coating agent are directly mixed with a film-forming precursor (such as a polymer solution), optionally using mixers such as a planetary mixer, impeller mixer, high-intensity vibratory mixer, or twin screw extruder, to form a uniform mixture.
Use of specific coating agents and particle sizes
The dry coating agent used for surface modification is chosen from hydrophilic silica, silica, a lipid, lecithin, a wetting agent, or combinations thereof, and is dry coated onto the micronized active agent particles. The resulting particles have sizes of about 3 µm or greater or about 4.2 µm.
Fabrication of films with defined properties and optional redispersion test
The resulting film possesses properties such as tensile strength in the range of about 21.7 to 35.8 MPa and thickness of 500–2,000 µm or 1,000–2,000 µm. An optional step allows redispersion of the film in a medium, with the D50 particle size distribution of the redispersed drug varying less than about 10% compared to the pre-mixing value.
Continuous and batch mixing process compatibility
The method is compatible with both batch (e.g., impeller or planetary mixer) and continuous mixing (e.g., twin screw extruder), accommodating direct mixing of dry powder drug into polymer solutions.
The inventive features collectively claim a method for producing films containing uniformly distributed, micronized, and surface-modified poorly water-soluble drug particles, fabricated without surfactants, using selective dry coating, direct mixing, and drying to create pharmaceutical films with improved content uniformity, mechanical strength, and dissolution properties.
Stated Advantages
Enables improved and efficient drug content uniformity of active pharmaceutical agents in film-based pharmaceutical products.
Allows for films with enhanced or excellent dissolution control, including faster and more complete drug release.
Provides enhanced mechanical properties, such as increased tensile strength and elongation, due to uniform distribution of drug particles.
Facilitates easy and more uniform dispersion of surface-modified micronized drug particles directly into film-forming mixtures without surfactants.
Avoids limitations and disadvantages of traditional solvent casting and hot melt extrusion, such as drug recrystallization, instability, residual solvents, and high temperature restrictions.
Eliminates the need for surfactants or high-energy, high-cost nanomilling; reducing risks of toxicity and product contamination.
Method supports high drug loading and preserves particle size upon redispersion from the film.
Drying methods keep moisture content in films low, providing improved stability and handling.
Enables scalability and flexibility via both batch and continuous processing (e.g., twin screw extrusion).
Documented Applications
Fabrication of film-based pharmaceutical dosage forms containing poorly water-soluble drugs, such as fenofibrate or griseofulvin.
Preparation of orodispersible polymeric films suitable for pediatric, geriatric, or dysphagic patients requiring ease of handling and precise dosing.
Construction of thin or thick polymer films capable of immediate or zero-order sustained release depending on film thickness.
Continuous film manufacturing with twin screw extruders or batch processing for the incorporation of surface-modified active agents.
Production of feedstock or films suitable for 3D printing in pharmaceutical applications.
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