Polymers for Controlled Release Formulation Follows FunctionMaribel Rios

Once considered mainly an afterthought in a company's lifecycle-management strategy, controlled-release dosage forms are now positioned at the forefront of many formulation strategies. In contrast to drug discovery, formulation work focuses not only on the intricacies of the active pharmaceutical ingredient (API), but also on fine-tuning the excipients, the release profile, and the delivery mechanism to provide optimal therapeutic benefit. Because of their wide range of applications and functionalities, especially in controlled-release therapies, polymers are among the most widely used excipients.

First steps

Polymers, and all other excipients, are selected on the basis of the controlled-release formulation as well as the delivery mechanism (e.g., enteric or parenteral dosage form). Because their business depends heavily on keeping current on demands and trends within the pharmaceutical industry, polymer makers are keenly aware of the factors that drive their clients' decisions.

First, and most important, the physicochemical properties of the API and how it can be most effectively absorbed by the body are taken into account. Those particular properties will naturally lend themselves to one or two technologies. Formulators are particularly interested in determining whether the API displays instability, where in the body it has maximum stability, and whether a targeted delivery will be possible. In some cases, a controlled-release formulation is the only solution.

The strength of the pharmaceutical company's expertise and capabilities also is a key decision point. Some companies have internal expert teams and dedicated equipment for tablet coating, for example. Each company is equipped to do what has worked for it in the past and what capabilities it performs the best, and most firms prefer to stay within their areas of expertise.

Some actives get shelved because the dosing regimen is not convenient, so patient compliance must be taken into account. In addition, patient demographics and the targeted disease contribute to the type of controlled-release that will be necessary. For example, arthritic patients often experience pain in the early morning hours. For bed-time dosing, they may require a formulation that has no release for a period of time and then 100% release for 30–45 minutes, thereby necessitating a pulsed release.

In some cases, a company's marketing department may still have a lot of say in the type of drug-release to be formulated to meet lifecycle-management needs. "That mindset is shifting," says Tim Cabelka, senior product research specialist at Dow's WSP Pharmaceutical Excipients R&D (Midland, MI). "Perhaps 15 to 20 years ago, a controlled-release dosage form may have been almost a second thought. Now the industry is taking a much more rational approach by looking at the pharmacokinetics of the drug, the dose level, where the drug is absorbed in the gastrointestinal tract, and the half-life in the body, and so on—all in addition to their lifecycle management concerns. There is a lot more scrutiny today. There has to be a pharmacological benefit for putting it into a controlled-release dosage form."

Formulation requirements

A polymer's unique characteristics can help realize such pharmacological benefits. "When formulators choose a polymer, they are looking for the functionality and the physical and chemical properties of that polymer. The basis for that is going to be the chemistry of the polymer," says Nasser Nyamweya, PhD, technical services manager, Degussa Röhm Pharma Polymers (Piscataway, NJ). Although the choice is determined mainly on a case-by-case basis for each API, "very rarely will you find a drug that is not compatible with a general class of polymers," says Ketan Mehta, PhD, business manager, Degussa. Two criteria are that the chemistry of the polymer must not compromise the therapeutic action of the active ingredient and that the physical properties of the polymer must be consistent and reproducible from batch to batch. After these criteria have been met, formulators focus on the polymer's specific properties.

Polymer properties. A polymer's chemical and physical characteristics are determined mainly by its average molecular weight and chemical structure (i.e., the functional groups attached to its backbone). Smaller sized polymers are suitable for formulation coatings and as co-solvents. Higher molecular weight polymers are covalently attached to pharmaceutical actives (e.g., polymers for pegylation). In addition, polymers can have various architectures, shapes, and linkers. The architecture can be one-dimensional (threads), two-dimensional (sheets), or three-dimensional (networks). The shape of a three-dimensional configuration can vary as well. For example, poly(ethylene glycols) (PEGs) used for biopharmaceuticals can be straight chains, branched, or forked. Some types of drugs work better with certain classes of polymers. Fragmented antibodies, for example, work well with forked PEGs.

A straight-chain molecule can have the active group on one end or both ends, and those active groups can be the same or different. Polymers used as excipients or in biodegradable implants may contain ionic groups, in which case the polymer may be pH dependent. Biodegradable polymers (e.g., polylactides, polyglycolides, and poly(lactide-co-glycolides) [PLGAs]) are commonly used for controlled release from microspheres (for parenteral routes), from polymeric micelles, and implantable drug-device systems.

Depending on the release mechanism, a polymer's pH also may be an important property. When drug is to be delivered at a particular pH to allow targeted release (e.g., in the gastrointestinal tract or in the colon), nonionic polymers can't be used because they are pH independent. For some coated tablets, the pH is neutral to prevent interaction between the polymer and the drug. In other applications, the release takes advantage of the natural pH changes of the body to deposit the drug in a general area of the gastrointestinal tract.

Oral dosage forms. In general, drug release occurs by erosion, diffusion through a membrane, or diffusion after matrix swelling. In many cases, the drug must partition into a polymeric membrane and then diffuse through the membrane to reach the dissolution media. The coating polymer may be water insoluble, and the solubility of drug in the membrane gives rise to the driving force of diffusion. The material may also be either partially soluble in water or a mixture of water-soluble and water-insoluble polymers. The water-soluble polymer then dissolves out of the film, creating small channels through which the drug can diffuse.

Figure 1: Example of a coated sustained-release drug delivery system (DDS).

Most often, controlled release from tablets is achieved by coating tablets or beads or by configuring drug–polymer matrix coated tablets (see Figures 1 and 2). The traditional type of coating for modifying drug release is an enteric, pH-dependent coating that delays the release until reaching the appropriate pH environment. For coated tablets, important polymer characteristics include elasticity, stability, and the ability to control moisture penetration of the tablet.

Figure 2: Example of a matrix tablet.

Bilayered coating (i.e., one coating on top of another) also can be used to achieve sustained or controlled release. Depending on the active ingredient, if the thickness of the polymer membrane is constant, then the release is constant under ideal conditions. A topcoat of a water-soluble polymer such as hydroxypropyl methylcellulose can be used to produce smoother tablet surfaces and harder tablets without compromising dissolution times (1).

One polymer-coating agent requires little or no plasticizer (Kollicoat SR 30D, BASF, Ledgewood, NJ) because of the high flexibility of the polymer (see Figure 3). Povidone is incorporated into the coating dispersion as a stabilizer. Povidone is highly soluble in water, and when the tablet comes into contact with the dissolution media, it dissolves and acts as a pore-forming agent. The drug dissolves and diffuses out through the pores at a controlled rate, leaving an empty polymer shell.

Figure 3: SEM of a broken tablet, compaction of pellets (Kollicoat SR 30D).

A hydrophilic, swellable polymer matrix releases the drug through a polymeric hydrogel pathway, thereby enabling sustained release of the drug. In contrast, hydrophobic polymeric matrices do not swell, therefore the modified release is by Fickian diffusion. In turn, when Fickian diffusion controls the release, the drug's solubility affects the release (highly soluble drugs release at a faster rate).

Of increasing interest in pharmaceutical formulations is sustained release through osmotic systems (2). The coating in this case is a semipermeable membrane that allows water (but not the drug) to penetrate the membrane to dissolve the contents in the dosage form. The dissolved drug plus diluents establish an osmotic pressure, forcing the dissolved drug to be "pumped" out of a hole in the tablet coating.

Parenteral innovations. Polymer excipients for parenteral use are well documented (3). Drugs delivered by inhalation, as injectables, or in topical creams may need to be modified on a smaller scale for sustained release from microspheres, nanosized micelles, or molecularly engineered compounds. At these scales, the properties of the polymer are especially important because the polymers act not only as rate-determining agents, but also as delivery vehicles (e.g., as polymeric encapsulations of a concentrated core of the API). A polymer's biodegradability and its ability to reduce immunogenicity, toxicity, and yield loss are of special concern.

Sustaining the release of an injectable API may require modifying the drug at the molecular level. Pegylation, which involves attaching PEG chains to the original active compound to increase its circulation time, is one approach. Although the technology has existed since the 1970s, improvements in the past 10 years have made it possible to use for developing commercial products (Nektar Therapeutics, Huntsville, AL). Currently, Nektar scientists are working on cleavable reagents, which can achieve sustained release even when attachment of a PEG deactivates the drug molecule. The time the PEG molecules are cleaved from the drug molecule can be "dialed in" according to the reagent. The reagents can have various half-lives for release of the PEG from the conjugate. The technology is suited for most proteins and peptides.

Polymeric micelles are a relatively new technology (since about the 1990s). Micelles enclose individual drug molecules (because their size is in the nanometer range) and take advantage of the biodegradable cycles of copolymers such as PLGAs. Drug release through a block copolymer gel (Pluronic gel) also is the basis for a novel depot-type mechanism for topically administered drugs (ProGelz, RxKinetix, Louisville, CO), including a sustained-release formulation of GCSF, currently in preclinical studies, and RK0202 for oral mucositis, currently in late Phase II studies. Unique to the technology is its ability to control the release characteristics by varying the composition and concentration of the gel, without changing the original form of the drug compound. Advantages of the technology reportedly include low toxicity, higher efficiency compared with competing technologies, lower yield loss, and ease of manufacture.

If you build it, will they come?

Knowledge of physicochemical properties reveals only half of the needed information about the polymer. As Philip Pilnik, commercial director, Dow's WSP Pharmaceutical Excipients, observes, "Within the past seven to eight years, the pharmaceutical industry as a whole has been demanding more than products from the excipients industry—they are demanding solutions." Those solutions encompass data about the polymer's properties, how it is processed to fulfill the need for material reproducibility and consistency, and how it performs in a manufacturing setting to assist formulators in scale-up and tech transfer. "It's part of fulfilling the responsibility of selling specialty polymers or ingredients to the industry," says Paul Sheskey, Dow's WSP Pharmaceutical Excipients development leader.

While formulators study the effects of a polymer's physical and chemical properties on a release profile, manufacturers evaluate how these properties affect the manufacture and quality of the final product. A majority of experimental work involving polymers is in evaluating their performance in typical manufacturing processes (e.g., roller compaction, direct compression, milling, granulation, mixing, and blending). The type of polymer, the amount that is used (drug:polymer ratio), and process equipment settings all affect tablet friability, strength, content uniformity, agglomeration, hardness, and so forth. Studies may involve several experimental variables, even if only one polymer is investigated. For example, if the polymer is to be used as a coating, it may be a dispersion in an aqueous solvent. If the same polymer is used in a matrix system, it would be granulated, the water would be evaporated, and the substance would be dried. Each study has its own set of process conditions. Although an overview of current research into evaluating the effect of these process conditions on polymer-containing controlled-release dosage forms is beyond the scope of this article, there are some areas of research especially worth noting.

Various polymers can perform essentially the same function, but the key to developing products that will reach market acceptability is to prove a considerable processing advantage. For example, in developing its polyvinyl acetate (PVA)-based materials, Kollidon SR (PVA/PVP matrix) and Kollicoat SR 30D (30% aqueous dispersion of polyvinyl acetate stabilized with polyvinyl pyrrolidone) (see Figure 4), BASF knew it had to deliver new performance characteristics to distinguish it from existing, well-accepted agents. Says Anisul Quadir, PhD, technical development manager, Pharma Solutions Business, BASF, "We had to come up with a polymer that has an advantage compared with other existing polymers in terms of chemistry, in terms of application, in terms of production, and in terms of processing. Polymer research is going on the needs and trends of the pharmaceutical industry."

Figure 4: Broken tablet (a) before and (b) after dissolution comprising Kollidon SR and caffeine.

One innovation is a novel wet granulation technology involving the delivery of foamed polymeric binders (see Figure 5). Suitable for immediate- and controlled-release dosage forms requiring a granulation step, the foamed binder was designed as an improvement to spraying or pouring in binders onto a moving powder bed.

Figure 5: Rapid batch addition of foam to granulate. (a) Initial foam charge. (b) After 1 minute of mixing. (c) After 2 minutes of mixing.

Polymer researchers are experimenting with formulations made with polymer combinations, which provide properties that two individual polymers do not have by themselves. "By working with both of those polymers together, you can come up with a totally different release profile that can give you whatever your intended application is," says Nyamweya. Making coprocess blends of two well-known, safe materials is of special interest. For example, researchers at Noveon (Cleveland, OH) introduced a new material after working with it under roller compaction. The team was careful not to add material so that the end product conforms to the same monograph as the starting material, thus avoiding regulatory hassles. Without changing the material's chemistry, the particle shape and size were changed such that the product had less dust and improved flowability compared with the traditional carbomer powders for direct compression processes. Other uses of coprocess blends in solid dosage forms have been reported in the literature (3).

Other studies have focused on how stress conditions such as variations in compression force and dissolution tester paddle speeds can affect the drug release of some polymer-containing tablets. For example, in one study, researchers evaluated the release of tablets formulated with a new polyvinyl acetate-based polymer (Kollidon SR, BASF). The studies demonstrated that the tablets had the same release profile under various compressional forces and under variations in paddle speeds from 50 to 110 rpm during dissolution tests. "In vivo, this means that if the patient has a different gastric motility rate, then the release rate of the drug in the gastrointestinal tract is not affected," says BASF's Quadir.

Regulatory and industry challenges

Incremental improvements to existing polymers may eventually lead to new polymers. The pharmaceutical industry, however, approaches a new ingredient or technology with scrutiny. Even the most veteran excipient companies admit to launching a new product only every five years or so. "It's not that the pharmaceutical industry is unwilling to look at new polymers, it's just that it takes very long for a new polymer to work its way through the development and regulatory process," says Cabelka. In addition, the development expenses and the costs of addressing safety concerns and regulatory issues are extremely high. "The pharmaceutical industry is not simply interested in innovation for innovations sake. A new polymer that is 10% better than an existing polymer is of virtually no interest, but one that is 80% better, for example, will gain attention."

This attention is vital for an excipients company to stay in business. Just as the pharmaceutical industry relies on the capabilities of the excipients industry to deliver a desired drug-release profile, excipient suppliers, to a great extent, depend on collaborations with the pharmaceutical industry to gain market acceptability.

Need for guidance. Obtaining a USP monograph for a new excipient would facilitate its acceptance by the pharmaceutical industry, but the process takes at least three to four years, which has led excipient companies to seek better guidance. "What is unavailable at the moment is guidance about what sends the right message to customers, or the industry primarily, that says you can use a certain polymer at a certain level freely because FDA is willing to accept it," says Mehta.

Frustration over the lack of guidance is not exclusive to polymer excipients. According to the International Pharmaceutical Excipients Council (IPEC), there are only three FDA-approved ways that any excipient can be qualified for use in pharmaceutical products, because "under US law, an excipient, unlike an active drug substance, has no regulatory status." These mechanisms are:

• FDA has determined that the substance is generally recognized as safe (GRAS) according to 21 CFR Parts 182, 184, or 186.

• Approval of a food additive petition as set forth in 21 CFR 171.

• The excipient is referenced in, and part of, an NDA for a particular function in that specific drug product.

The agency revamped its Inactive Ingredient Guide in late 2002 to an online Inactive Ingredient Database, which contains information about inactive ingredients present in FDA-approved drug products (accessible at: www.accessdata.fda.gov/scripts/cder/iig/index.cfm). IPEC and FDA are currently working on making this database more user friendly.

Compliance with global regulatory requirements may also affect the way scientists carry out the polymerization process. Reducing the level of residual monomers continues to be a challenge, for example. Monomers are generally toxic, but polymers can't be made without them. In addition, if a company is to market a product outside of the United States, it must meet international requirements on the formulation and ingredients, which may differ from US regulations. For example, notes William Wilber, manager of R&D and technical services, Noveon, Europe restricts ingredients containing more than 2 ppm benzene (which has been linked to leukemia). When the restriction came into effect in the United States, it did not apply to older benzene-containing products. In contrast, when Europe's restriction did not grandfather-in older formulations, several drugs had to be reformulated.

Improvements wanted. Even when not developing new products, polymer suppliers keep busy by continuously improving their products to meet their clients' increasing demands for cleaner materials with more-precise specifications and increased functionality (i.e., broadening a polymer's applicability). Such demands can be met thanks to the emergence of better analytics not available even five years ago. "We're able to measure properties more precisely and formulate better than we were before. As we do, the quality of the excipients improve," says Dow's Pilnik.

Improvements are not always easy to make. For example, in contrast to APIs and other excipients, which are defined in a chemical sense, polymers are identified by their average molecular weight. Requests for narrower molecular weight distributions are increasing. Says Noveon's Wilber, "there is a general theory that the tighter you control everything, the more uniform your output will be. It is very important to have compositional uniformity of the active within the dosage form or, if it's a designed dosage form, to have it distributed the way it is supposed to be. Tighter regulation of the raw materials, reduces the source of variability in your manufacture."

Technically exotic processes (e.g., step growth polymerization or proprietary purification techniques) can be used to accomplish this uniformity, but practically and economically, it is too expensive to carry out. In addition, absolute uniformity is not practical because of the size of the molecules. "It is very difficult to get all spaghetti of exactly 12.00 inches long. So you're going to have some low molecular weight materials and some higher molecular weight materials in an average."

"From a CMC perspective, you want to have a high-purity reproducible material when you are manufacturing your drug molecules. It is important to have a narrow molecular-weight distribution and have reproducible purity and reproducible reactivity to the drug molecule so that every time that drug molecule is made with a PEG attached to it, you end up with the same composition of PEGylated drug," says Jennifer Filbey, PhD, vice-president, business development, Nektar Therapeutics.

Formulating for controlled release involves a wide range of possible routes of administration, release profiles, excipient types, and process conditions. "Formulators will continue to be creative and look out for new ways to use polymers," predicts Nyamweya. Experience, hard work, and talent all are essential in developing a successful product; still, an extra kick of good fortune can't hurt. Says Harry Ross, MD, chairman and CEO, RxKinetix, "So far, we've beaten all the odds by being able to deliver essentially just what we thought we'd be able to. A lot of companies work just as hard as us and through bad luck, or perhaps the technology just doesn't pan out, don't make it. We seem to be delivering what people want and have gotten a little bit lucky along the way."

References

1. J. Yuan, N.M. Clipse, and S.H. Wu, "The Effects of Alternating Combinations of an Enteric Coating and HPMC as Inner and Outer Coatings on the Performance of Coated Aspirin Tablets," Pharm. Technol. 27 (11), 70–82 (2003).

2. A.M. Kaushal and S. Garg, "An Update on Osmotic Drug Delivery Patents," Pharm. Technol. 27 (8), 38–44, 97 (2003)

3. S. Apte and S.O. Ugwu, "A Review and Classification of Emerging Excipients in Parenteral Medications," Pharm. Technol. 27 (3), 46–60 (2003).

4. S.K. Nachaegari and A.K. Bansal, "Coprocessed Excipients for Solid Dosage Forms," Pharm. Technol. 28 (1), 52–64 (2004).