New Opportunities for Oral Sustained Release Formulations with Polyvinyl Alcohol
Achieving the appropriate release kinetics for an active pharmaceutical ingredient (API) is essential to ensure success of the therapeutic. For example, for sustained release formulations, a consistent API dose over a prolonged period ensures that levels in the blood plasma remain within the therapeutic window. This is important, as the API levels must be maintained higher than the minimum effective concentration and below the maximum tolerated dose. The combined effect is a safe and efficacious dosage form, which provides a therapeutic effect while avoiding toxic side effects. For certain medications, sustained release can allow a larger amount of API to be taken in a single dose, which can reduce the number of total daily doses required. Ultimately, sustained release can combine a more optimized and safe dosage regime with patient convenience, leading to increased adherence.
Strategies for Sustained Release
There are two primary formulation strategies that can be applied to produce sustained release kinetics – functional coatings and matrix systems (Figure 1). Functional coatings are used to create a membrane around the tablet which controls the rate of API release related to the rate of dissolution of the coating layer, through which the drug will diffuse and dissolve. Such sustained release systems are also often referred to as reservoir systems. Flexibility can be provided in this approach, as the coating type, thickness and pores can be adjusted to modify the sustained release profile. However, there are several drawbacks to this approach, as well. The tablet coating process is an additional labor-intensive step, which increases process costs and production times. Furthermore, any inconsistency in the layer thickness or pores will introduce inconsistency in the sustained release profiles between different tablets. An additional concern is dose-dumping which is defined as the “unintended, rapid release of the entire amount or a significant portion of the drug contained in a modified release form”.1 In the case of a single unit dosage form where the release rate is controlled by a coating layer, defects in the layer or splitting or chewing of the tablet by the patient may compromise the intended modified release profile. The resultant high levels of the drug in the bloodstream can cause serious adverse or toxic side effects. Dose dumping can also occur due to pH variability in the gastrointestinal tract, e.g. induced by food intake, or if the medication is taken with alcohol.2
In matrix-based sustained release formulations, the API is homogeneously dispersed within a polymer-based matrix. Depending on the rate-controlling polymer material properties, matrix systems are classified as hydrophilic and hydrophobic matrix systems, which show different release mechanisms. In hydrophilic matrix systems, the polymer hydrates and swells upon contact with gastrointestinal medium forming a gel layer on the surface of the system; the API is then released via diffusion through the viscous gel layer and by matrix erosion. Release kinetics can be adjusted with use of different polymer types, grades and quantity but are also dependent on API solubility. In contrast, hydrophobic matrix systems use polymers that are not water soluble and show no or only minimal swelling. The drug is dissolved by the outer liquid penetrating the matrix, with the porosity having a direct influence on the release kinetics.
With sustained release matrix systems, there is generally a reduced risk of dose dumping compared to coated formulations. 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 even allowing for division of the tablet in some cases. The main drawback of this approach is the identification of the right matrix-forming material as release kinetics may be influenced by the test conditions such as pH value as well as API properties and, in the case of hydrophobic matrices, API content.3
Several naturally derived and synthetic polymers are available for oral sustained release formulations. These 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 co- processed excipients based on hypromellose (HPMC) and a filler.
The most commonly used excipients for this application are cellulose-based polymers, with semi-synthetic, non-ionic HPMC being the main representative. Formulation with HPMC is relatively cost-effective and straightforward. However, the matrix system performance is dependent on polymer viscosity which in turn is directly related to the molecular weight of the material. Given that HPMC is a semi-natural polymer, batch-to-batch variations can lead to inconsistent performance of the final products. This inconsistency also poses a challenge to Quality by Design (QbD) implementation.
Advantages of Polyvinyl Alcohol for Sustained Release
Polyvinyl alcohol (PVA) is a synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer and is generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA). The polymer was first discovered in 19244 and has been used in approved drug products for decades. For example, PVA was listed as a suitable polymer for coatings of pharmaceutical drug products in a pharmaceutical reference handbook published in the 1950s.5 As a fully synthetic polymer, the physicochemical and functional characteristics of PVA can be tightly controlled, enabling robust and reproducible manufacturing processes and batch-to-batch consistency for reliable performance of the final products. Its suitability for sustained release formulations has been confirmed with formulations targeted at non-oral administration routes.6,7,8
The attached white paper describes the use of PVA-based Parteck® SRP 80, a functional excipient specifically developed for matrix-based sustained release oral solid dose formulations. With a mean particle size of 80 µm, Parteck® SRP 80 excipient is a PVA optimized for drug dissolution, easy handling, good flowability and good reproducibility with respect to both sustained API release and direct compression (DC) manufacturability (Table 1). Batch-to-batch consistency ensures consistent quality and enables use of QbD to further minimize risks in development and manufacture. Parteck® SRP 80 excipient is also compliant with Ph. Eur., USP, ChP and JPE monographs. Continue the full whitepaper text
Download the full whitepaper as a PDF here or click the picture
Authors: Daniel Joseph Price, Gudrun Birk