Polyvinyl alcohol: Revival of a long lost polymer

Figure 9: Comparative dissolution of itraconazole extrudates with different polymers as carrier, as well as a marketed, solid-dispersion based product of itraconazole

Introduction

With target-oriented drug discovery and an increasing focus on specialized medicines, the manufacturing of final drug products is becoming more and more complex. The processing and formulation of active pharmaceutical ingredients (APIs) designed with a specific target and functionality in mind may present challenges during the development and manufacture of the final formulation. Aspects such as bioavailability of the API in the body, API stability, and low dosage formulations are frequent hurdles to be overcome when bringing a drug to the market.

It has been observed that approximately 60% of new chemical entities (NCEs) have solubility issues, compared to 39% of marketed APIs.[1] Sufficient solubility of the API is an important factor for the absorption of the API into the body and thus the API’s therapeutic effect in vivo. Solubility may be increased by using specific solubility enhancing techniques and excipients in pharmaceutical formulation. Controlled release of the API continues to be another area of major interest in the pharmaceutical sector, as it allows the performance of the final formulation to be adapted to the therapeutic need. Sustained release as a specific controlled-release drug delivery model makes it possible to address issues highly relevant to long-term therapy, such as dosingregime, convenience, and patient compliance, as well as the efficacy-to-safety ratio.[2]

While novel solutions, excipients, and innovative technologies can open up new pathways to improved formulations, it is important to note that they may also induce hurdles to regulatory approval. Novel excipients require in-vitro and in vivo safety assessments, as well as in-depth regulatory review. These additional assessments can result in unplanned costs and delays, and add a further dimension to the risk evaluations of taking the final drug product to market. However, new does not always mean novel. Using familiar materials in innovative ways can result in new solutions that offer the peace of mind and safety of tried and trusted excipients.

One of these familiar excipients, which shows great and not yet fully exploited potential for new formulation approaches, is polyvinyl alcohol (PVA; sometimes also referred to as PVOH in other sources). It is a synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer.

PVA is currently used very commonly in pharmaceutical products across the different classes of marketed new molecular entities, new formulations and new indications (Fig. 1). While PVA is predominantly applied in oral formulations, typically in tablet coatings, other marketed drug products that utilize the distinct features of the various commercially available PVA grades can also be found in ophthalmic, transdermal, and topical dosage forms, for instance (Fig. 2). This publication will focus on additional applications of PVA for sustained release and solubility enhancement that address the aforementioned challenges in pharmaceutical formulations.

PVA Grade – Points to Consider

There are many points to consider when choosing the correct PVA grade. Typically, PVAs are classified according to their viscosity and degree of hydrolysis. The typical twofigure nomenclature for the different grades
is thus made up of the viscosity of a 4% solution at 20°C (first figure) and the degree of hydrolysis of the polymer (saponification level; second figure). For example, PVA 5–88 indicates a PVA grade with a viscosity of 5 mPa• s that is 88% hydrolyzed. Both parameters have a substantial effect on the polymer’s performance. For example, as hydrolysis increases, so do crystallinity,
melting temperature, and mechanical strength, due to the high level of hydrogen bonding between chains. A lower hydrolysis grade has higher solubility in water and may show better compatibility with other excipients. Viscosity, determined by the polymer chain length, also has a great influence on the performance of a formulation. As the chain length rises and with it the molecular weight (MW), the viscosity in solution also increases. However, while all PVAs are water-soluble, the dissolution time and the

maximum amount in solution are strongly dependent
on the PVA’s MW. With increasing MW, the time required for dissolution increases while the maximum soluble amount decreases (Table 1). Viscosity is not only influenced by internal intrinsic factors but also by external conditions in the formulation, such as pH. For example, PVA solutions show a pH-induced viscosity shift in the presence of boric acid: up to a specific pH value, the viscosity of the PVA solution remains constant, but upon a further increase of the pH, the viscosity of the PVA solution begins to increase. As the molecular weight of the PVA rises, the viscosity shift occurs at lower pH values. The viscosity shift is also more distinct at higher concentrations of the PVA solution. For high-MW PVA grades, this shift tends to occur at lower pH than for low-MW grades (Fig. 3). Temperature can also have an effect
on the viscosity of the PVA solution. As such, formulators can fine-tune formulations not only by selecting different PVAs for different applications, but also through the formulation conditions and additional excipients.

Another point to consider when choosing the PVA grade is the requirement of the pharmacopeias. When comparing the Ph. Eur. and JPE to the USP, the Ph. Eur. and JPE are more liberal, as the hydrolysis grade is stated as >72.2% or 78–96% and >97% respectively, compared to the USP’s relatively narrow range of 85–89%. Of the PVA grades discussed above, only those with a hydrolysis grade of 85-89% fulfill the requirements of all three major pharmacopoeias.

PVA Safety

First discovered in 1924 by Herrmann and Haehnel [4, 5], PVA has been used in approved drug products for decades. As early as 1951, PVA was listed as a suitable polymer for coatings of pharmaceutical drug products in a pharmaceutical reference handbook.[6] PVA also has a long history of use in other applications such as the food and cosmetic industries. It is generally recognized as
safe (GRAS) by the US Food and Drug Administration (FDA) – a GRAS notice has been filed on the application of PVA in the solid oral coatings sector – and evaluations of PVA toxicity and safety by different authorities

are available, as well as scientific publications on this topic. The acceptable daily intake (ADI) for humans is 50 mg/kg body weight as identified by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2003. To summarize, there is well-founded scientific evidence for the safety of PVA. [7–13] With regard to the application, additional parameter specifications should be
considered to improve the safety profile—for instance, limiting the content of by-products such as residual solvents and crotonaldehyde, an irritant.

New Applications of PVA

PVA-based excipients have been characterized and introduced into the market for oral sustained release and solubility enhancement. These compendial grade PVAs surpass the requirements of all three major pharmacopeias (USP, Ph. Eur., and JPE)

by having additional specified parameters relevant for their respective application. The following sections present experimental work that makes it possible to assess the potential of these compendial grade PVAs in their main applications.

PVA in Sustained Release

Sustained release technologies have been used in pharmaceutical formulations for many years. In fact, coatings as a first approach to modified release were presented to a scientific audience as early as the 19th century. In the 1950s and 1960s, matrix-controlled release systems were the topic of several scientific publications.[6] Today, a wide variety of approaches are available, all with the aim of altering the rate of release and/ or place of liberation of the active ingredient compared to a conventional immediaterelease formulation.[14] Typical release profiles are delayed, sustained, multiphasic/ programmed, site-specific/targeted and triggered drug release. By modifying the drug release characteristics, significant therapeutic benefits can be achieved, such as improved efficacy of the therapeutic agent, reduced adverse effects, optimization of the dosing scheme and an overall improvement in patient compliance.

It is important to keep in mind that there is no one-size-fits-all solution for modified release formulations. When choosing the right approach, one must consider the API’s properties, the required dose, needs regarding the release profile, clinical and market needs, the size of the dosage form, development time and cost, and the available equipment, in addition to other factors. In the past few decades, many advances have been made in the area of formulationtechniques, applicable materials, and especially in the understanding of the rational design and development of modified release formulations, including the API properties, pharmacokinetic profile and clinical needs. One major area of continued interest and research is the pharmacokinetic modeling of drug release profiles to predict the formulation’s performance. While great progress has been made, there are still numerous challenges remaining in the modified release sector, such as finding a suitable material and/or technique to reliably achieve the desired release profile, prevent dose-dumping, and to facilitate the formulation of high-dose and low-solubility compounds.

Of the various possible modified release profiles, sustained release plays a major role in the pharmaceutical sector. Due to their simplicity, matrix systems— particularly monolithic matrix systems—are used extensively for sustained releaseformulations. The working principle of a hydrophilic matrix system is such that the API is homogeneously dispersed in a polymerbased matrix, where the polymer hydrates and swells upon contact with gastrointestinal medium. A gel layer is formed on the surface of the system and the API is then released via diffusion through the viscous gel layer and by matrix erosion. Another approach is the use of hydrophobic matrices, where the surrounding medium penetrates the dosage form, resulting in drug dissolution and diffusion through pores.

The difference in the drug release processes of the two matrix systems results in a different applicability: While the hydrophilic matrices can typically be applied to both insoluble and soluble APIs, the hydrophobic matrices are generally limited to soluble APIs, as the concentration gradient is too low for complete drug release of an insoluble API within the relevant timeframe.[2]

With sustained release matrix systems, there is generally a reduced risk of dose dumping compared to coated formulations: in the case of a single-unit dosage form where the only release rate-controlling material is present as a film coating on its surface, defects in the coating layer or the division of the tablet by the patient may compromise the intended modified release profile and result in an immediate release of the full amount of the active ingredient. Known as dose dumping, this can potentially result in serious adverse or toxic effects. With monolithic matrix systems, the active ingredient is homogeneously mixed with the release rate-controlling material, making the release profile less sensitive to surface damage of the dosage form and sometimes even allowing for division of the tablet.

Several natural polymer and synthetic polymer excipients are available on the market for the sustained release application. The performance of the system can be fine-tuned by using different polymers or a combination of polymers as the matrix material. A few fixed combinations of excipients are available on the market, but the type and ratio of the excipients are typically determined on a case-by-case basis by the formulator, allowing for full flexibility depending on the active ingredient’s properties and intended release profile. Common excipients for an oral sustained release formulation include cellulose ethers, polyethylene oxide, water-soluble natural gums of polysaccharides such as alginate, acrylic acid derivatives, and methacrylates. Fixed combinations available on the market include a blend of polyvinyl acetate and povidone, as well as a co-processed hypromellose (HPMC) and lactose excipient.

Following excipients are mentioned in the study besides other: PVA 4-88, PVA 5-88, PVA 8-88, PVA 18-88, PVA 26-88, PVA 40-88, PVA 28-99

See the white paper on “Polyvinyl alcohol: Revival of a long lost polymer” here

(click the picture to download the white paper)

Source: Merck white paper “Polyvinyl alcohol: Revival of a long lost polymer”