Polymer Strip Films for Delivery of Poorly Water-Soluble Drugs

• New Jersey Institute of Technology

Abstract

While polymer strip films have garnered significant attention for their patient compliance and cost-effective scale-up, recent studies have shown that they are also an ideal platform for poorly water-soluble drug delivery. This article offers a review of the advances in delivery of poorly water-soluble drugs via strip films including formulation, processing, and performance advantages over more traditional solid dosage forms, as well as recent developments in strip film applications.

Introduction

Polymer films have emerged as a promising platform for delivery of pharmaceutical products in recent years. These films, generally used for oral delivery, are roughly the size of a postage stamp and can be placed on the tongue for immediate release as well as under the tongue (sublingual) or on the inside of the cheek (buccal) for sustained release. Strip films offer several distinct advantages over more traditional solid dosage forms, including larger available surface area, which allows for rapid disintegration and dissolution in the oral cavity.¹ This makes films easy to swallow without the need for water, leading to improved acceptance and compliance among pediatric, geriatric, and dysphagic patients. Films are also more flexible and durable than other solid dosage forms, which leads to simpler processing, transportation, handling, and storage. In addition, the film manufacture process is inherently continuous, allowing for cost-effective production and realtime process monitoring. Thin films also present the ability to bypass the first-pass metabolism via buccal delivery.²

The majority of pharmaceutical films available on the market are orodispersible, meaning they disintegrate and dissolve quickly in the mouth. These films have included drugs such as ondansetron for nausea and vomiting caused by radiation therapy, simethicone for pain or discomfort caused by excessive gas, donezepil for treatment of dementia caused by Alzheimer’s disease, and dextromethorphan/menthol as cough suppressant.¹ One thing that all of these films have in common is their use of water-soluble drugs, which are easiest to formulate for fast dissolution and homogeneous drug distribution. Despite the growing number of poorly water-soluble drug candidates in the pharmaceutical industry in recent years,³ they have yet to appear on the market in the strip film format due to their limited dissolution and bioavailability. However, this review will demonstrate that the strip film format can be ideal for the delivery of poorly water-soluble drugs, as well.

Manufacture and Processing

Most of the studies mentioned in this review employ an aqueous slurry casting technique for strip film manufacture. This is in contrast to the more prevalent solvent casting technique which involves dissolving poorly water-soluble drugs in organic solvent to be removed upon drying. Solvent casting imposes a potential limit on the drug loading in the resulting film, as exceeding this limit may lead to uncontrollable precipitation of drug particles upon removal of organic solvent during drying. To avoid this issue, the slurry casting technique preserves the drug particles in the crystalline state, suspended in an aqueous solution prior to film manufacture.^4,5 This process involves mixing a viscous polymer solution, typically with a plasticizer for improved film mechanical properties, with the drug in the form of an aqueous suspension or powder. The resulting mixture is then cast at a specified thickness using a doctor blade or pressurized die and gently dried using a combination of conduction and convection.

Film manufacture also offers the distinct advantages of continuous processing and real-time monitoring, as presented in Figure 1. The film drying process is inherently continuous, which allows for multi-stage drying where different drying regimes and temperatures can be employed at each stage. This provides the manufacturer with the freedom to easily customize the drying process to suit the specific application. Humidity control can also be implemented to influence the residual water content in the film. In addition, the continuous drying process permits easy incorporation of process analytical technology (PAT) tools for real-time, in-line monitoring of the film. For example, Raman spectroscopy may be used to quantify drug concentration and film thickness during drying.⁶ Integration of non-destructive real-time monitoring with process control will allow for quick, on-the-fly adjustment of process parameters to ensure the film product meets specification, and may facilitate real-time release.

Figure 1. Diagram of the continuous pharmaceutical strip film manufacture process with real-time in-line monitoring. Reprinted from Ref. 6, with permission from Elsevier.

Integrating Engineered Drug Particles into Strip Films

The greatest challenge to formulating for the delivery of poorly water-soluble drugs is their inherently limited dissolution and bioavailability. This can be combatted in multiple ways, such as particle size reduction and surface modification. However, these techniques also introduce the new challenge of incorporating and stabilizing the engineered drug particles in a solid dosage form from which they can be recovered upon delivery while maintaining their enhanced dissolution during manufacture and release. Recent studies have shown that polymer strip films are ideal for the stabilization and delivery of poorly watersoluble drugs prepared by several standard particle engineering techniques employed to enhance their dissolution rate.^4,5,7,8

Particle size reduction, for instance, can be used to improve the dissolution rate of poorly water-soluble compounds by increasing the surface area-to-volume ratio of the particles.⁹ One of the most common techniques for particle size reduction is wet stirred media milling (WSMM), a top-down approach in which an aqueous suspension of drug particles and dissolved stabilizers (typically polymer and/or surfactant) are stirred at high speed along with hard beads.¹⁰ However, as with many of the particle engineering techniques mentioned in this review, preservation of particle size within the dosage form and upon delivery of the drug is crucial, as particles tend to agglomerate due to their increased surface area and surface energy.¹¹ Such drug particle agglomeration leads to a decrease in surface area and, hence, an undesirable decrease in dissolution rate. While the right combination of stabilizers can significantly reduce agglomeration in WSMM suspension, this stabilization is not guaranteed when the nanoparticles are transferred into the final dosage form.^12,13

The possibility for incorporation of poorly water-soluble drug nanoparticles into polymer films for enhanced dissolution was first investigated for WSMM suspensions of griseofulvin (GF), fenofibrate (FNB), and naproxen (NPX).⁵ These drug suspensions were each shear mixed with a polymer solution of hydroxypropyl methylcellulose (HPMC) along with glycerin as plasticizer and manually cast to form polymer films loaded with poorly water-soluble drug nanoparticles. Drug nanoparticles were successfully recovered from films upon redispersion in water, although slight agglomeration was observed in redispersed NPX particles. Perhaps most importantly, a drastic improvement in dissolution rate was observed from films containing drug nanoparticles over films containing drug microparticles, a physical mixture, and compact, shown in Figure 2. The formulations and drying techniques used were further optimized in a subsequent study involving films with GF nanoparticles from WSMM, along with the development of dosage-scale content uniformity assessment.⁸ It was established that the film-forming solution cast required sufficient viscosity to ensure the formation of a uniform, good-quality film. This led to the investigation of viscosity enhancing agents in strip films. Not only were superdisintegrants found to successfully enhance the viscosity of the film-forming solution, improving the content uniformity of the films, but they also increased the rate of drug release from films, as opposed to traditional viscosity enhancers which drastically reduced the dissolution rate of the film, such as natural gums.⁴

Figure 2. Dissolution behavior of fenofibrate films containing (a) nanoparticles as compared to a physical mixture, compact, and (b) film containing microparticles. Reprinted from Ref. 5, with permission from Elsevier.

Following these process and formulation optimizations, as well as the establishment of particle-laden strip film characterization techniques,^6,14 the robustness of the strip film platform for the delivery of several different poorly water-soluble drugs was investigated. In order of increasing solubility in water, model BCS Class II drugs included FNB, GF, NPX, phenylbutazone (PB), and azodicarbonamide (AZD), with FNB being 50 times less soluble in water than AZD. Aqueous WSMM nanosuspensions were prepared for each drug and incorporated into HPMC strip films. Despite the differences in various properties and solubility of these drugs, nanoparticles similar in size to those in the suspensions from which they were taken were successfully recovered from strip films of each drug upon redispersion in water, as shown in Figure 3. This demonstrates the ability of the strip film format to physically stabilize the embedded drug nanoparticles. In addition, all five drugs exhibited similar dissolution rates from strip films regardless of their differences in water solubility, as shown in Figure 4. This emphasizes the consistency with which poorly watersoluble drug nanoparticles are released from strip films.

Figure 3. Particle size distribution of drug in WSMM suspension prior to shear mixing with polymer solution (dark green) and drug redispersed from dry films (light green). dXX represents the particle size below which XX% of the particle size distribution falls. Bars in each set of 3 indicate d10, d50, and d90 from left to right.

Figure 4. Dissolution behavior of strip films containing a variety of BCS Class II drugs in a USP IV flow-through cell dissolution apparatus with 5.4 mg/mL sodium dodecyl sulfate dissolution media.

Poorly water-soluble drug nanoparticles produced via bottom-up approach have also been incorporated into strip films. One such technique is liquid antisolvent precipitation (LASP) in which crystals are precipitated out of a mixture of solvent and antisolvent.¹⁵ This mixture creates an environment for supersaturation, nucleation, and particle growth. Adequate control of particle size and morphology can be achieved with the appropriate combination of stabilizers and process parameters. However, as with nanoparticles produced via WSMM, these precipitated nanoparticles also exhibit a tendency to agglomerate, and polymer strip films have been shown to offer a platform for their stability and fast dissolution.⁷ The combination of HPMC and Pluronic F-127 added prior to precipitation produced GF nanoparticles with the best control of particle size and agglomeration, which led to significantly faster dissolution from polymer films than improperly stabilized GF particles, as seen in Figure 5. Other means of dissolution rate enhancement via incorporation of engineered drug particles into strip films are also being investigated, including surface modification via dry coating and drug nanoparticles prepared via melt emulsification.

Figure 5. Dissolution behavior of films containing GF as-received micronized powder, unprocessed with stabilizers, and produced via LASP in (a) 0.54% sodium dodecyl sulfate solution and (b) water. Reprinted from Ref. 7, with permission from Elsevier.

Advantages

As evidenced by the examples outlined above, strip films for poorly water-soluble drug delivery offer many significant advantages over more traditional solid dosage forms. Films have demonstrated the ability to retain the dissolution rate enhancement imparted to poorly water-soluble drugs by multiple particle engineering techniques including WSMM and LASP after incorporation into the film, accentuating the robustness of the film platform. The film format also boasts excellent content uniformity, especially for well stabilized systems with sufficient viscosity when cast.⁸ Good content uniformity also goes hand-in-hand with another major advantage of strip films: personalized dosing. Since strip films can be easily sized and cut based on the need of the patient, they are ideal for adjustable dosages. Along with inherently continuous manufacture and real-time in-line process monitoring, the strip film format offers a uniquely versatile and controllable manufacturing process.

Opportunities

While the current market for strip films is centralized on orodispersible films for immediate drug release, several other applications have emerged in recent years. Buccal delivery, for instance, involves placing the film on the inside of the cheek where it adheres to the buccal mucosa and the drug permeates through the membrane into systemic circulation. As a result, it has become the preferred method of delivery for drugs that are prone to degradation in the gastrointestinal tract.¹ Buccal delivery also offers the advantage of sustained release over durations as long as 4–6 hours. Film encapsulation has become increasingly popular among emerging applications as well, which involves enclosing the drug-loaded film in a protective barrier, such as a capsule, to ensure targeted release. This is particularly useful for gastro-retention where the delivery target is the upper gastrointestinal tract. One such application seals a folded film within a capsule such that it opens and unfolds in the stomach, where it is retained for up to 10.5 hours.¹⁶ Multilayer films are also being pursued for several different applications, including extended release and multiple drug formulations.¹⁷

Final Thoughts

Polymer strip films offer a uniquely robust and versatile platform for the delivery of poorly water-soluble drug particles engineered for dissolution rate enhancement. Strip films are able to successfully stabilize the drug particles such that their enhanced dissolution is maintained upon release. In addition, film production is both continuous and cost-effective, with opportunities for in-line real-time monitoring and process control. While orodispersible films dominate the current market, emerging applications have demonstrated new and innovative uses for drug-loaded strip films.

Acknowledgement

The authors are grateful for financial support from NSF in part through the ERC (EEC-0540855) award.

Author Biographies

Scott Krull is a PhD candidate in Chemical Engineering at NJIT. He serves as the project coordinator for Film Formation in the NSF Engineering Research Center for Structured Organic Particulate Systems. His research focuses on delivery of poorly water-soluble drugs via incorporation of nano-size drug particles into polymer strip films.

Meng Li is a PhD candidate in Chemical Engineering at NJIT. Her research field is drug nanoparticles and nanocomposites. She serves as the project coordinator for Project A1-Stable Suspensions of Crystalline and Amorphous Active Particles within the NSF Engineering Research Center for Structured Organic Particulate Systems.

Ecevit Bilgili is an associate professor of Chemical, Biological, and Pharmaceutical Engineering at NJIT. His research areas center on particle engineering and pharmaceutical nanotechnology. He is a leader of Project A1-Stable Suspensions of Crystalline and Amorphous Active Particles within the NSF Engineering Research Center for Structured Organic Particulate Systems.

Rajesh N. Davé is a Distinguished Professor of Chemical Engineering at NJIT. He is also the Site-Leader, and a Thrust Leader, NSF ERC on Structured Organic Particulate Systems. His research contributions include 130 journal papers and seven patents. He has granted 26 PhDs, six of those are in US academia.

References

1. Dixit RP, Puthli SP. Oral Strip Technology: Overview and Future Potential. J Controlled Release. 2009;139(2):94–107.
2. Averineni RK, Sunderajan SG, Mutalik S, et al. Development of Mucoadhesive Buccal Films for the Treatment of Oral Sub-mucous Fibrosis: A Preliminary Study. Pharm Dev Technol. 2009;14(2):199–207.
3. Lipinski CA. Poor Aqueous Solubility—An Industry Wide Problem in ADME Screening. Amer Pharm Rev. 2002;5:82–85.
4. Davé RN, Susarla R, Bilgili E, et al. Inventors. System and Method for Fabrication of Uniform Polymer Films Containing Nano and Micro Particles Via Continuous Drying Process. PCT Application No. PCT/US14/30506. Filed March 17, 2014.
5. Sievens-Figueroa L, Bhakay A, Jerez-Rozo JI, et al. Preparation and Characterization of Hydroxypropyl Methyl Cellulose Films Containing Stable BCS Class II Drug Nanoparticles for Pharmaceutical Applications. Int Pharm. 2012;423(2):496–508.
6. Zhang J, Ying Y, Pielecha-Safira B, et al. Raman Spectroscopy for In-line and Off-line Quantification of Poorly Soluble Drugs in Strip Films. Int Pharm. 2014;475(1–2):428–437.
7. Beck C, Sievens-Figueroa L, Gärtner K, et al. Effects of Stabilizers on Particle Redispersion and Dissolution from Polymer Strip Films Containing Liquid Antisolvent Precipitated Griseofulvin Particles. Powder Technol. 2013;236:37–51.
8. Susarla R, Sievens-Figueroa L, Bhakay A, et al. Fast Drying of Biocompatible Polymer Films Loaded with Poorly Water-soluble Drug Nano-particles via Low Temperature Forced Convection. Int Pharm. 2013;455(1–2):93–103.
9. Hu J, Johnston KP, Williams III RO. Nanoparticle Engineering Processes for Enhancing the Dissolution Rates of Poorly Water Soluble Drugs. Drug Dev Pharm. 2004;30(3):233–245.
10. Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a Formulation Approach for Poorly-water-soluble Compounds. Eur Pharm. Sci. 2003;18(2):113–120.
11. Bilgili E, Afolabi A. A Combined Microhydrodynamics-polymer Adsorption Analysis for Elucidation of the Roles of Stabilizers in Wet Stirred Media Milling. Int Pharm. 2012;439(1– 2):193–206.
12. Bhakay A, Azad M, Bilgili E, Dave R. Redispersible Fast Dissolving Nanocomposite Microparticles of Poorly Water-soluble Drugs. Int Pharm. 2014;461(1–2):367–379.
13. Bhakay A, Davé R, Bilgili E. Recovery of BCS Class II Drugs During Aqueous Redispersion of Core–shell Type Nanocomposite Particles Produced via Fluidized Bed Coating. Powder Technol. 2013;236:221–234.
14. Sievens-Figueroa L, Pandya N, Bhakay A, et al. Using USP I and USP IV for Discriminating Dissolution Rates of Nano- and Microparticle-Loaded Pharmaceutical Strip-Films. AAPS PharmSciTech. 2012;13(4):1473-1482.
15. Thorat AA, Dalvi SV. Liquid Antisolvent Precipitation and Stabilization of Nanoparticles of Poorly Water Soluble Drugs in Aqueous Suspensions: Recent Developments and Future Perspective. Chem. Eng. J. 2012;181–182:1–34.
16. Kagan L, Lapidot N, Afargan M, et al. Gastroretentive Accordion Pill: Enhancement of Riboflavin Bioavailability in Humans. J Controlled Release. 2006;113(3):208–215.
17. Trout BL, Hatton TA, Chang E, et al. Inventors. Layer Processing for Pharmaceuticals. United States Patent Application No. 13/458222. Filed April 27, 2012.