Successful ophthalmic drug formulations rely on the selection of the correct polymer to ensure the desired characteristics such as retention in the eye cavity and solubility. One example of such an excipient is polyvinyl alcohol (PVA) which offers many advantages for ophthalmic drug formulations including eye drops, suspensions, and gels. It is a biocompatible synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer. PVA is recognized as safe (GRAS) by the US Food and Drug Administration (FDA) , does not have any immunogenic effects, and its long-term use has been demonstrated in many different formulations including oral, topical, and ophthalmic.
PVA offers many advantages for ophthalmic formations including eye drops and hydrogels. It is water soluble and has a narrow range of viscosity and a high degree of swelling, offering the precise viscosity needed for formulations to remain in the eye cavity. Scientific evidence and long-term use confirm the physiological compatibility and safety of PVA, while a variety of grades allows selection of the exact properties needed for specific formulations.
Its physicochemical properties make PVA especially well suitable for the application in ophthalmic drug delivery systems including:
As a synthetic polymer, PVA offers batch-to-batch consistency and is available in different grades defined by viscosity, hydrolysis and the microbial load (total aerobic bacteria, total yeast and total mold count), which should be specified by the manufacturer. These grades come with different physicochemical properties, making them suitable for different applications.
Lower viscosity grades of PVA can be used for lubricant activity, to enhance API solubility and as inhibitors of crystallization. If the formulation is a suspension or gel, a high viscosity grade PVA is more suitable and can be used as a thickener or viscosity enhancer. Different hydrolysis grades of PVA, which refer to the amount of residual, unhydrolyzed acetate groups within the polymer chain, also affect the polymer performance. Higher hydrolysis grades improve tensile strength of the hydrogel and provide a stronger gel scaffold through H-bonds while lower hydrolysis grades might be a better choice for drug delivery of poorly water-soluble APIs. However, since some pharmacopoeias restrict the hydrolysis grade variation, there is limited flexibility in this aspect.
Another important consideration when using PVA is the possible presence of crotonaldehyde, which is a strong eye irritant and a process impurity generated during synthesis. While there is no information in the pharmacopeia regarding the limit of this impurity, given its toxic nature, it is important that this impurity content is known and controlled. Due to stringent regulatory requirements in this segment, a multi-compendial product and regulatory and documentation support by the manufacturer is essential to facilitate regulatory submission. We specify low crotonaldehyde limits for PVAs.
Table 1 compares the preparation, appearance, and presence of foam and particles in solutions of three different polymers commonly used in ophthalmic preparations: PVA, and semi-synthetic options such as hydroxypropylmethylcellulose (HPMC) and carboxymethyl cellulose (CMC). While a higher temperature is recommended for PVA dissolution, the result will be a clear, particle free solution without foam. HPMC and CMC can be dissolved at room temperature, but it may be challenging to obtain particle-free solutions, and foaming was observed during HPMC solution preparation.
Different sterilization methods can be used with polymer solutions including steam and filtration, and each affects attributes of the polymer in different ways.
When PVA, HPMC, and CMC are sterilized at 121°C for 15 minutes at 15 PSI, only the PVA solution remains clear and transparent (Figure 1). The CMC solution becomes cloudy while a white colloidal appearance was observed with the HPMC solution turns white colloidal nature which became transparent once cooled to room temperature. PVA and HPMC solutions remain similar following sterilization times of 15, 20, and 25 minutes while the viscosity of CMC decreases significantly after the first 15 minutes of steam sterilization indicating that some degradation might be occurring.
Figure 1.Comparison of CMC, HPMC and PVA following steam sterilization.
Sterile filtration can also be used to achieve a sterile formulation as demonstrated by the results of a study comparing polymers. The study also found that scale-up is facilitated with use of PVA. Filtration of a PVA 4-88 solution was possible through both 0.2 µm polyvinylidene fluoride (PVDF) and polyethylsulfone (PES) membranes. Of these two options, the PES membrane provided better process economics with a higher Vmax and mean flux. The CMC solution could not be filtered using this method due to high viscosity. In the case of HPMC, filtration was feasible, but the filter size required to process this batch was much larger than for the PVA. Scale up and commercial production are thus more viable with PVA, without any challenge to sterile filtration, as compared to HPMC or CMC.
A final consideration when selecting an excipient is compatibility with other excipients and the API contained within the final ophthalmic formulation; other excipients may include preservatives, inorganic salts to maintain osmolarity, and buffers. Inorganic salts do not alter the viscosity of PVA, indicating compatibility. In contrast, when CMC comes into contact with the inorganic salts, the viscosity was drastically changed. There is also no change in the viscosity of a PVA solution across a pH range of 5.5 to 8.5 which is the typically preferred pH range for ophthalmic preparations. PVA does precipitate completely when used in ophthalmic formulations containing boric acid. This is one of the very few limitations of PVA.
PVA meets all the essential requirements to be used in ophthalmic preparations and offers important benefits compared to HPMC and CMC (Table 2).
As they are semi-synthetic in nature, HPMC and CMC have a relatively large range in viscosity compared to PVA and can be expected to have a higher microbial load. While PVA requires a higher temperature for solution preparation, foam and particles have been observed in HPMC and CMC solutions. PVA and HPMC can be sterilized using steam sterilization or sterile filtration with no changes in viscosity. Changes in pH do not affect the PVA solution and this polymer was shown to be compatible with a variety of inorganic salts.
In summary, while several polymers are available for use in ophthalmic formulations, PVA offers important advantages. It is best suited to overcome many formulation challenges and is a viable alternative to HPMC and CMC for ophthalmic formulations, which is why it is an important part of the formulator toolbox for ophthalmics.
To continue reading please sign in or create an account.Don't Have An Account?