Excipients in Polymeric Drug Delivery and Formulations

Excipients play an important role in polymeric drug delivery. They may be used to modulate the release of a drug, stabilize a drug, and faciliate localized delivery of a drug. In addition, the excipient itself may be a polymer that can add important functionality to a formulation. To gain a perspective of these issues, we asked several leading scientists to provide their input on noteworthy advances of polymer-based excipients. Participating in the roundtable are: John Doney, PhD and manager of research and development, and Jiao Yang, PhD and research chemical engineer, both with ISP Pharma Technologies (Columbia, MD); Hans Baer, senior scientist of the Pharma Polymers business line with Evonik Röhm GmbH(Darmstadt, Germany); and Elena Draganoiu, PhD and a senior research and development pharmacist in the Pharmaceutical Ingredients business with The Lubrizol Corporation (Wickliffe, OH).

Drug-polymer solid solutions and dispersions

Doney and Yang: Greater sophistication in drug discovery is leading to a growing number of potent new molecular entities (NMEs). These compounds present challenges to the formulator when they exhibit extreme water insolubility. Indeed, nearly 40% of the drugs on the market today and nearly 60% of drugs in development are poorly soluble. These formulation problems can be compounded as new disease states emerge. Pharmaceutical companies no longer enjoy the luxury of dropping these "brick-dust" candidates from development, yet conventional formulation strategies may not adequately deliver them. A need for nontraditional technologies, including drug-polymer solid solutions and solid dispersions, arises.

Despite a perceived newness, solid solutions and dispersions have been around for almost 50 years. Their pharmaceutical application to enhance oral bioavailability was first envisioned in 1961 (1). Since then, five commercial products use the solid solution/dispersion approach:

• A solid dispersion of crystalline griseofulvin in polyethylene glycols (gris-PEG) was marketed that cut the crystalline 500-mg dose in half while maintaining plasma concentrations (2)

• The antiemetic "Cesamet" (nabilone) (Valeant Pharmaceuticals, Costa Mesa, CA) contains a solid dispersion of nabilone in polyvinylpyrrolidone (3)

• Solid solutions of lopinavir and ritonavir in polyvinylpyrrolidone-vinyl acetate copolymer successfully enabled a reformulation of "Kaletra" (Abbott Laboratories, Abbott Park, IL). In addition to reducing the dosage burden from six softgel capsules to four tablets, tablets made with the solid solutions eliminate the need for refrigeration.

• "Sporanox" (Janssen Pharmaceutical, Titusville, NJ) is a solid dispersion of itraconazole in hypromellose that has been layered onto sugar spheres (4)

• The most recently approved product is the nonnucleoside reverse transcriptase inhibitor "Intelence" (Tibotec, Yardley, PA), an amorphous, spray-dried solid dispersion of etravirine, hypromellose, and microcrystalline cellulose (5, 6).

In addition, an ever-growing body of pharmacokinetic literature points to drug-polymer solid solutions/dispersions to enhance bioavailability. For example, three solid solutions of "R103757," (Johnson & Johnson, Beerse, Belgium), an inhibitor of microsomal triglyceride transfer protein, were formulated with hypromellose (and other adjuvants) using solvent evaporation and hot-melt methods. In a clinical trial, the three solid solutions provided greater plasma concentrations than the crystalline drug form, for which exposure was not detected. Of particular note, an amorphous solid solution made by a solvent evaporation method was estimated to be bioequivalent to a liquid solution of the drug complexed with hydroxypropyl-β-cyclodextrin (4).

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dispersed in an inert matrix (7). In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solution refers to the case in which drug-polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutically acceptable polymers are ideal to create this matrix, due to the wide range in functionalities attained with polymer chemistries and molecular weights. Commonly used polymers include polyvinylpyrrolidones, polyvinylpyrrolidone-vinyl acetate copolymer, and the family of cellulosics (such as hypromellose and hypromellose phthalate). Polymer selection is based on many factors, including physicochemical (e.g., drug-polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints.

Given the potential for formulation flexibility, pharmaceuticists are practicing multiple technologies to produce solid solution/dispersions. Many methods have been reported and reviewed in the literature, including: spray drying, hot-melt extrusion, melt congelation, spray freezing into liquid, and nanocrystal technology. These methods impose their own restrictions on polymer selection and formulation, resulting in different physical properties. Melt-extrusion methods can produce dense compositions. But, due to the requirement for polymer softening upon heating, the cooled extrudate may be tacky and difficult to pulverize (3). In contrast, solvent-based spray drying can yield powders of good flowability but of low-bulk density, although new technologies are addressing this limitation. Additionally, special facilities are required to process and dispose of solvents. Because the amorphous form eliminates the energy barrier inherent in the crystal lattice, amorphous drug-polymer compositions can enhance aqueous solubility by fifty-fold or more (8, 9). As a result, water-insoluble NMEs can be formulated and evaluated for enhanced absorption, and ultimately efficacy. Formulation and process development, however, are needed to optimize final product attributes.

Although solid dispersions are well known to enhance aqueous solubility and bioavailability, their stability must be monitored to ensure product invariability with time and storage conditions. Crystalline solid dispersions may undergo Ostwald ripening, a thermodynamically driven process that can occur when the crystalline drug exists with a wide particle-size distribution. To reach thermodynamic equilibrium, mass is spontaneously transferred from small to large drug crystals to minimize the high surface energy of the small crystals (10). Proper polymer selection is critical to impede diffusion and inhibit any tendency for nucleation and crystal growth. Pure drug in the amorphous state often displays a high likelihood to recrystallize (11). Likewise, amorphous drug-polymer dispersions also may exhibit this solid-state instability. However, drug-polymer solid solutions can offer unique stability options (1, 9, 12). Understandably, the choice of polymer can strongly influence drug-polymer molecular interactions and the resulting physicochemical properties. In every case, stability testing of solid solutions/dispersions, including long-term and accelerated conditions under the International Conference on Harmonization standards is a must for these formulations. A new, promising approach is to use recrystallization kinetics to model nucleation and crystal growth rates in order to better understand the effects of formulation and process conditions on stability (13).

The chemical structure and amount of polymer play an important role in drug-polymer solid solutions and solid dispersions, enabling efficacious drug delivery and stability. Appropriate dispersibility of the dosage form, drug release, and absorption can be achieved with proper polymer selection. Without doubt, solid solutions and dispersions will provide greater application and serve as an irreplaceable technology to deliver the ever-increasing number of water-insoluble NMEs.

John Doney, PhD, is a manager of research and development, and Jiao Yang, PhD, is a research chemical engineer, at ISP Pharma Technologies.

References

1. K. Sekiguchi and N. Obi, "Studies on Absorption of Eutectic Mixture: A Comparison of the Behavior of Eutectic Mixture of Sulphathiazole and that of Ordinary Sulfathiazole in Man," Chem. Pharm. Bull. 9 (11), 866–872 (1961).

2. S. Riegelman, and W.L. Chiou, "Increasing the Absorption Rate of Insoluble Drugs," US Patent 4151273, 1978.

3. W. Dong, "Multiparticulate Drug Delivery System for Lipophilic Drugs and Macomolecules," PhD dissertation in Chemistry, Freie Universität, Berlin, 2005.

4. G.Verrek et al., "The Use of Three Different Solid Dispersion Formulations-Melt Extrusion, Film-Coated Beads, and a Glass Thermoplastic System-To Improve the Bioavailability of a Novel Microsomal Triglyceride Transfer Protein Inhibitor," J. Pharma. Sci. 93 (5), 1217–1228 (2004).

5. R.J. Pomerantz, "Combining Biomedical Research within Academia and Industry in the 21st Century," presented as the keynote address, American Association of Pharmaceutical Scientists Annual Meeting, San Diego, CA, 2007.

6. Intelence, Full Prescribing Information, Tibotec, Inc., 2008.

7. W.L. Chiou and S. Riegelman, "Pharmaceutical Applications of Solid Dispersions," J. Pharm. Sci. 60 (9), 1281–1302 (1971).

8. N. Hirasawa, et al., "An Attempt to Stabilize Nilvadipine Solid Dispersion by the Use of Ternary Systems," Drug Devel. Ind. Pharm. 29 (9), 997–1004 (2003).

9. C. Leuner and J. Dressman, "Improving Drug Solubility for Oral Delivery Using Solid Dispersions," Eur. J. Pharm. Biopharm. 50 (1), 47–60 (2000).

10. J.Yang et al., "Distribution Kinetics of Polymer Crystallization and the Avrami Equation," J. Chem. Phys. 122 (6), 64901–64911 (2005).

11. M. Yoshioka et al., "Crystallization of Indomethacin from Amorphous State Below and Above Its Glass Transition Temperature," J. Pharm. Sci. 83 (12), 1700–1705 (1994).

12. M. Langer et al., "Investigations on the Predictability of the Formation of Glassy Solid Solutions of Drugs in Sugar Alcohols," Intl. J. Pharm. 252 (1–2), 67–179 (2002).

13. J. Yang et al., "An Improved Kinetics Model to Describe Drug Amorphous Stability," poster presented at the American Association of Pharmaceutical Scientists Annual Meeting, San Diego, CA, 2007.

Flexible pharmaceutical polymers

Baer: In solid-dosage forms, the chemical character of the active ingredient and its sensitivity to the conditions in the digestive tract often call for ingenious formulations, especially if the drug is to be set free at a specific site within the gastrointestinal (GI) tract (1). Multi-unit dosage forms have a low risk of dose dumping and a higher chance of therapeutic success. Multi-unit dosage forms release the active ingredient from a high number of subunits (e.g., coated granules or pellets.) The compression of coated subunits to multiparticulate tablets or coated capsules is a big challenge. The flexibility of the applied enteric layer is a major factor for the compression of coated pellets as well as for the pellet size and layer thickness. Known enteric polymers for oral applications are normally hard, brittle and less flexible (2).

Figure 1: Volatility of propylene glycol (PG) from anionic coatings. R.H. is relative humidity. DS is dry substance. (FIGURES ARE COURTESY OF EVONIK RÖHM GMBH.)

For compression of coated pellets or particles, an elongation of at least 100% is necessary. Pure polymers are not able to fulfill this requirement. Instead, a certain amount of plasticizer or a mixture with very flexible sustained-release polymers (e.g., "Eudragit (R) NE 30 D" [poly(ethyl acrylate-co-methyl methacrylate 2:1, 800,000], Evonik, Essen, Germany]) is necessary to increase flexibility. With the use of "Eudragit (R) FS 30 D" [poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, 220,000, Evonik] or the addition of propylene glycol as a plasticizer, the elongation at break can be increased over 100%. Propylene glycol is a lightly volatile and low-boiling plasticizer. It will decrease the intermolecular forces of the film formers on the one side, and on the other side, it could lead to less storage stability. Therefore, a study was performed to identify the volatile tendency of propylene glycol (3).

Soft-gelatin capsules were coated with a polymer weight gain of 10 mg/cm² of "Eudragit (R) L 30 D-55 [poly(methacrylic acid-co-ethyl acrylate) 1:1, 250,000, Evonik]. Glycerolmonostearate was used as a glidant, and polysorbate 80 as an emulsifier. The plasticizer content was adjusted with four different values: 10, 15, 20, and 25% propylene glycol. After six-month storage, more than 80% of the theoretical amount of propylene glycol was evaporated (see Figure 1). The applied coating became brittle, and cracks were formed. Other well-known plasticizers such as triethyl citrate or polyethlyene glycol types were comparatively stable as observed in Figure 2. The results of this plasticizer study show that propylene glycol is not the best choice of a plasticizer for compression of coated subunits.

Figure 2: Volatility of triethyl citrate (TEC) or polyethylene glycol (PEG) from anionic coatings. R.H. is relative humidity. DS is dry substance. (FIGURES ARE COURTESY OF EVONIK RÖHM GMBH.)

Other factors for a successful compression process are the particle size and the applied-layer thickness. The type of polymer used and the layer thickness will have a significant influence on a successful multiparticulate formulation. Increased layer thickness leads to a more slowly active release. For evaluation of the coating performance, 25-μm and 50-μm layers were applied. The studies showed that coatings on small pellets were damaged more extensively than those on large pellets, independent of film thickness. Increased layer thickness leads to a slower release of the active ingredient (5).

Multi-unit dosage forms with a colon-targeting functionality have advantages for active ingredients redesigned for local treatment in the large intestine (such as Colitis ulcerosa, Crohn's disease, and colon cancer). Colon-targeting also makes sense or is required for several systemic substances. The colon is a preferred region for the absorption of peptidic drugs (peptides and proteins, including peptide hormones and antibodies) as they cannot be absorbed via the mucosa of the stomach or small intestine. The enzymes (proteases) there break down peptides and proteins. The colon, on the other hand, has physiological properties that enable absorption of both peptides and proteins. These properties include an approximately neutral pH, a long residence time, special absorption mechanisms for peptides, and a microflora that produces hardly any peptide-hydrolyzing enzymes (2).

To minimize systemic effects, the subunits need to release the active ingredient as close as possible to the affected colonic sites. Colon-delivery systems with Eudragit (R) FS 30 D have advantages with regard to compression flexibility and targeted drug release in the colon. To ensure the functionality of the dosage form, it is essential to select suitable polymers and/or ingredients that provide the required flexibility and storage stability.

Hans Baer is a senior scientist of the Pharma Polymer business line with Evonik Röhm GmbH.

References

1. Evonik Röhm GmbH, "Colon Targeting," Pharma Polymer News 7, 1 (2000).

2. M. Rudolph, "Entwicklung und in vitro Charakterisierung von per oralen multipartikulären Arzneiformen zur Optimierung der Therapie der Colitis ulcerosa und Morbus Crohn," PhD dissertation, J.W Goethe University Frankfurt, Institute of Pharmaceutical Technology, Frankfurt, 2002.

3. H. Baer et al., Effect of Different Plasticizers on the Storage Stability of Enteric Coated Soft Gelatine Capsules," poster presented at the 5th International Symposium on Solid Dosage Forms, Stockholm, 2007.

4. T. Beckert, "Verpressen von magensaftresistent überzogenen Pellets zu zerfallenden Tabletten," PhD dissertation, University of Tübingen, Institute of Pharmaceutical Technology, Tübingen, Germany, 1995.

5. Evonik Röhm GmbH, "Larger Pellets, Less Damages to Films," Pharma Polymer News, 6, 2 (1999).

Carbomer combinations in controlled-release matrix tablets

Draganoiu: Carbomers are highly efficient gel-matrix formers for controlling drug release in tablets, capsules, and multiparticulate systems. In many cases carbomers have demonstrated slower drug-release rates at lower concentrations than other commercially available excipients, enabling overall formulation cost savings and smaller tablet sizes. Additionally, tablet formulations using carbomers have demonstrated excellent hardness and low friability over a wide range of compression forces. Carbomers can enable scientists to develop patentable technologies that offer the benefits of product differentiation and/or life-cycle extension.

Carbomers are widely compatible with commonly used tablet ingredients and can be used alone or in combination with other extended-release excipients (e.g. hypromellose, hydroxypropyl cellulose, sodium alginate) to achieve a desired release profile. Select carbomers are available in both powder and granular forms; therefore, they can be used in all types of tablet-manufacturing processes. A free-flowing granular product is available for use in direct-compression processes.

A new concept in controlled release is the use of carbomer combinations that allow formulators to include the polymer both intra- and extra-granularly. This approach provides flexibility in achieving target release profiles. An example is the use of a combination of powder-grade ("Carbopol" 971P NF, Lubrizol, Wickliffe, Ohio) and granular-grade ("Carbopol" 71G NF) carbomer homopolymers in a metoprolol extended-release formulation.

The powder-grade polymer and active drug were incorporated by wet granulation and the resulting granules blended with the granular-grade polymer. Use of carbomers both intra- and extra-granularly enables inclusion of a higher total polymer level compared with the amount of carbomer that can be used in wet granulation without affecting the processability of the wet mass.

Intra-granular addition of the powder-grade polymer allows more efficient drug release at lower polymer levels than direct compression with the granular-grade polymer alone (lower cost; smaller tablets). The difference in hydrogel formation and controlled-release performance is a result of the larger surface area of the powder-grade carbomer compared with the granular-grade carbomer. This approach allows for formulation flexibility by varying total polymer level and the intra-versus extra-granular ratio.

By combining both types of carbomers, it is possible to achieve a desirable balance with regard to processing (generally easier at lower polymer levels) and controlling drug release (more efficient at higher polymer levels).

Metoprolol extended-release tablets were successfully formulated using a combination of carbomers. Various inclusion levels of the powder-grade and granular-grade polymers for two formulations were used. One formulation (Formulation A) contained an intra-granular addition of 6% weight/weight (w/w) of the powder-grade carbomer homopolymer (Carbopol 971P NF) and an extra-granular addition of 24% w/w of the granular-grade carbomer homopolymer (Carbopol 71G NF). The second formulation (Formulation B) contained an intra-granular addition of 8% w/w of the powder-grade carbomer homopolymer (Carbopol 971P NF) and an extra-granular addition of 24% w/w of the granular-grade carbomer homopolymer (Carbopol 71G NF). 

The active drug, powder-grade polymer, and filler were mixed and granulated with deionized water. The resulting granules were blended with granular-grade polymer then with the glidant and the lubricant, and compressed at target weight and hardness.

Formulations A and B met US pharmacopeial requirements and matched the release profile of the reference commercial product. The carbomer combination in these formulations provided easier handling during the wet-granulation process and enabled less complex processing compared to other extended-release technologies.

Elena Draganoiu, PhD, is a senior research and development pharmacist in the Pharmaceutical Ingredients business of The Lubrizol Corporation.