Advancing controlled release: from polymers to inorganics

Advanced drug delivery systems that provide improved control over active ingredient release have become a focus for research. Aia Malik and Mark Cresswell, from Lucideon, explore the use of polymers and inorganic materials for advanced controlled release systems

Organic polymers have had a significant impact on the market for the controlled delivery of therapeutic compounds, but recent developments in inorganic materials research have demonstrated great potential for their use as controlled drug delivery systems. Inorganic materials are providing improved alternatives to conventional controlled release formulations, while also providing solutions to unmet formulation challenges.

Active pharmaceutical ingredients (APIs) generally require inclusion within a drug delivery system consisting of various excipients and additives, such as preservatives or lubricants. A key component of the formulation is a controlled release agent, referred to as a controlled release technology (CRT), that can deliver sustained release. CRT is employed to enable a more efficacious delivery of the API, such that the rate of its release or absorption across biological membranes is improved, elimination is reduced or specific sites of action can be targeted.

The benefits of controlled release include the improvement of patient compliance (through dose number reduction and improved efficacy), an increase in safety (through slower, more accurate release) and the prevention of abuse (through tightly controlled release of the active), among other features.

The materials and mechanisms for achieving controlled release vary and have developed greatly in the last half century.

Polymers and inorganics

The different categories for sustained delivery systems can be loosely grouped as either chemical barriers or physical barriers. Chemically activated release systems are controlled by the nature of the chemical bond between the active and the carrier and its rate of cleavage in vivo. Physically controlled release systems are dependent on the rate of active diffusion from the carrier system.1 Pharmaceutical products rely on these systems, whether for immediate release systems or smart systems for sustained delivery. It can be argued that Lipowski’s work on coated pellets for prolonged release in 1938 was the earliest sustained release research.2

Within polymeric systems, controlled release carriers can be further grouped into three mechanisms of release: diffusion controlled systems – porous membrane or porous particles; swelling controlled systems; and dissolution controlled systems – polymer degradation/erosion.

A range of polymers, employing various mechanisms, are extensively used in drug delivery today

A range of polymers, employing various mechanisms, are extensively used in drug delivery today. These include vinyl polymers, cellulose ethers, polysaccharides and silicones, among others. The use of polymers for the controlled release of APIs was first systematically investigated in the 1970s and these materials were subsequently found to be safer and have improved delivery profiles over existing traditional drug carriers.3 In later years, biodegradable polymers, unlike the non-biodegradable polymer matrix3 predecessors, offered the advantage of biocompatibility.

There is now a range of new smart polymers that can be used to give very specific pH-triggered release of encapsulated actives depending on the desired release rate and site of release. Polymers have indeed dominated the market and advanced the delivery of drugs vastly; however, some fundamental problems associated with their use remain.

The use of organic polymers is well studied and, due to the diverse nature of the active molecules approved for therapeutic use, it remains an active area of research in both academia and industry. However, these materials do not provide effective solutions for all APIs and dosage forms.

Certain classes of polymers, while having favourable formulation properties, are known to cause inflammation of local tissues due to their degradation products

There are a number of reasons for this, including the presence of undesirable ‘burst’ effects (the sudden release of a large quantity of API without control), the challenges associated with providing sustained release of both highly water-soluble and water-insoluble compounds, and the fact that drug-polymer interactions often result in complex release mechanisms, which makes the prediction and transfer of existing formulation technologies to new actives difficult and time-consuming. Additional barriers to the development of robust, generic controlled release drug delivery systems include: abuse and compliance issues, food effects, side-effects, and excipient artefacts (e.g. caused during preparation).

Another drawback is that certain classes of polymers, while having favourable formulation properties, are known to cause inflammation of local tissues due to their degradation products (enzymatic or hydrolytic). Biocompatibility issues arising from debris are also a big problem for polymeric materials, as are processing limitations, which in some cases can be severe. Therefore, the fate of the delivery system and any additives and plasticisers must be considered, as well as associated cost and processing limitations.

Research into alternative materials and formulation approaches has gained significant momentum in recent times

All of these issues present challenges for advanced polymeric drug delivery systems. Development of new polymer families with unique physicochemical properties and improvements in advanced polymer processing techniques are key to resolving these issues and improving the efficacy of pharmaceuticals.

In the face of a lack of materials solutions to formulation issues, stricter regulatory requirements and the desire to differentiate products on the market, research into alternative materials and formulation approaches has gained significant momentum in recent times.

One area of focus is the use of inorganic materials as novel controlled drug delivery systems. Inorganic materials, which are well known in the production of drug formulations, form a number of the FDA GRAS (generally regarded as safe) and IID (Inactive Ingredients Database) listed materials. Silicate- and aluminate-based materials have long been used in drug delivery as excipients performing various roles. Originally, such excipients were considered inert by default, i.e. not having a therapeutic effect. However, they have subsequently been found to affect uptake of compounds thus affecting bioavailability.4,5

Inorganics for controlled release

The understanding of inorganic materials in the context of controlled release materials has developed rapidly. In 1965, the use of attapulgite, an aluminosilicate mineral, in antidiarrhoea mixtures was found to affect the rate and extent of promazine absorption.4,5 Following this, amorphous silica was used as an insoluble excipient to improve the dissolution rates of poorly water-soluble compounds. Adsorption of these compounds onto the silica surface resulted in a significantly enhanced available surface area, thereby increasing the drug dissolution rate.6

The most relevant materials researched with applications in drug delivery include mesoporous silicas, non-ordered silicates and calcium phosphates (common to bone cement research and ceramics). For the delivery of ions, bioactive glasses have been used for several applications including dental treatment. These systems can additionally boast bioactivity, where appropriate.

Figure 1: Two approaches to technology. Depending on the drug’s characteristics, an additional selectively-soluble coating may be applied to the porous carrier (left), or not (right)

These inorganic materials have a number of advantages, including improved structural stability under conditions of extreme pH, lower risk of burst effects by virtue of the materials being non-swelling, and the ultimate formation of degradation products with reduced toxicity that are largely ubiquitous to the body.

A platform technology called iCRT has been developed by Lucideon for the controlled release of APIs and is based on the use of ceramics and/or glasses (GRAS materials). By controlling the material synthesis process, actives can be incorporated and then released with controlled rates tailored to the desired application.

By being able to control the chemical and physical properties of the carrier material, such as the composition, whether it is inert or degradable, the surface functionality, and the extent of porosity (total porosity and pore size), the properties of the delivery system can be tightly controlled – both release rates and the triggering or inhibition of drug release by different stimuli (e.g. pH, shear, moisture, temperature, etc.). Having full control of the carrier material enables Lucideon to produce a drug delivery system that not only releases its active at a specified rate but can also contain additional desirable functionality such as bioactivity, controlled degradation or abuse deterrence.

Abuse deterrent formulations are attracting attention due to a marked rise in fatalities resulting from the intentional or accidental overdosing of prescription painkillers

Abuse deterrent formulations are attracting attention at the moment due to a marked rise in fatalities resulting from the intentional or accidental overdosing of prescription painkillers. iCRT-deter, Lucideon’s oral drug delivery platform technology, has been developed so that its formulations retain their controlled release properties following conventional tampering methods such as chewing, crushing and heating.7 Unlike traditional polymer systems, the extremely hard silica structure used is very hard to crush without specialist equipment and therefore very difficult to inject.

Much research is being carried out into the next generation of controlled release platforms. As the market demands enhanced properties, such as bioactivity, abuse deterrence and controlled degradation, it seems that a shift to the use of inorganic materials may be imminent. A thorough knowledge and understanding of the properties of such materials is paramount if formulations are to be optimised to deliver superior controlled release. Furthermore, such platforms need to be rapidly adaptable from lab to manufacturing, and commercially viable.

References

1. E.J. Ariens et al. (1980). Drug Design: Medicinal Chemistry: A Series of Monographs. Vol. 10

2. Mandhar, P. and Joshi, G. (2015) Asian Pac. J. Health Sci. 2(1): 179–185

3. Langer R, Folkman J. Nature. 1976;263:797–800

4. Sorby DL, J Pharm Sci, 55, 5, 504–510, 1966

5. Sorby DL, J Pharm Sci, 54, 5, 673–683, 1965

6. Monkhouse, D. C., Lach, J. L., Int. J. of Pharm Sci. 1972; 61:1430–1435

7. Budd G and Malik A., Abuse Deterrence for the Pharmaceutical Market, a white paper, www.lucideon.com

The authors

Aia Malik is Healthcare Product Manager and Mark Cresswell is Senior Development Scientist, both at Lucideon.

Companies