VIPDESIGNUSA/DREAMSTIME.COM
Innovations in the design of oral formulations are driven by the need to target the site and monitor the time required for drug release, enhance the bioavailability of poorly soluble drugs, minimise dose dumping and prevent intentional or accidental misuse by patients. Oral dosage forms, such as tablets and capsules, can result in poor patient compliance among paediatric and geriatric patients owing to their difficulty in swallowing.1 The need to formulate age adapted and misuse-adapted formulations is one of the priorities in the design of oral dosage forms. Such formulation approaches are described in this second of two articles.
Liquid formulations
Liquid oral formulations are easier to administer to the elderly and to the young and therefore tend to exhibit greater patient compliance than solid oral dosage forms. Liquid oral formulations also allow an easier dose adjustment to a patient’s age and weight. On the downside, many drugs are not stable in liquid and the formulation has to be palatable in order to retain patient acceptability. In addition, the modified release technologies used in tablets and capsules are not applicable to liquid formulations.
To meet these challenges, sophisticated oral liquid formulations have been developed. Delsym and Phentuss syrups have been formulated using the Pennkinetic technology, a drug-polymer ionic complex where the polymer is an ion exchange resin, allowing controlled release of the drug depending on the pH and ionic strength of the delivery site. In these systems, ion-exchange resin systems allow sustained drug release, prevent dose dumping and are also abuse-resistant.2
LiquiTime platform, from Flamel Technologies, involves a suspension of proprietary film-coated microparticles. The active component is encapsulated in the core of the microparticles, allowing effective masking of taste. The microparticles have a homogeneous size distribution of below 200μm, resulting in a smooth feel of the suspension on the palate. The technology can be tailored to a wide range of drugs and release kinetics, from immediate to extended release. LiquiTime formulations also exhibit long-term physical stability and reproducible performance lasting over two years of storage.3
Micropump platform, again, from Flamel Technologies, involves microparticles with the ability to target the site of drug release and can be adapted to the formulation of oral suspensions. It is a useful technology for drugs that can only be absorbed in the small intestine and, similar to the LiquiTime platform, can be used for a combination of drugs with different release kinetics.
Liquid-filled formulations
The use of liquid-filled formulations (eg, liquid-filled hard and soft capsules) is on the increase. They can improve the bioavailability of the active ingredient by presenting it in a liquid or semisolid form. For example, self emulsifying drug delivery systems and self-microemulsifying drug delivery systems form emulsions or microemulsions on contact with the aqueous gastrointestinal fluids, therefore enhancing the solubility of the active ingredient.
Another advantage of liquid-filled formulations is that they can enhance the chemical stability of active compounds that are sensitive to light, moisture and oxygen. Such compounds are usually dissolved in a non-aqueous liquid vehicle that is compatible with the capsule shell material. Neoral soft gelatin capsules from Novartis is an example of an improved formulation of ciclosporin.
Neoral capsules contain a concentrated solution of ciclosporin in an oily vehicle that undergoes spontaneous microemulsification with GI fluids. The benefits of Neoral compared with the previous ciclosporin formulation Sandimmun, which forms an oilin-water emulsion rather than microemulsion on contact with the GI fluids, are that Neoral allows predictable and consistent absorption profile for ciclosporin that is unaffected by the presence of food and bile in the GI tract.4
Liquid-filled formulations are also becoming increasingly popular for highly potent (less than 10mg) drugs because they can ensure homogeneous distribution of the active drug in the liquid vehicle thus avoiding the low content uniformity issues of powder fills. In addition, the formulation of anticancer agents in liquid-filled products is advantageous due to processing simplicity, safer handling and avoidance of product cross-contamination.
Solid dispersions
A number of drugs have low aqueous solubility that subsequently compromises their oral bioavailability. One of the techniques used to tackle this problem is the combination of these lipophilic compounds with polymers at specific ratios to form solid dispersions or solid solutions. In the latter case, the drug is molecularly dispersed in the polymer matrix. These drug-polymer complexes enable the drug to convert to its amorphous form, which is easier to dissolve than the crystalline form.
Solumer technology is an example of a solid dispersion technology. On contact of the solid dispersion powder with the GI fluids, a colloidal suspension is formed that enables an enhanced dissolution rate of the drug.
SUBA technology from Mayne Pharma involves solid dispersions of active ingredients with suitable polymers. SUBA technology has been used for the reformulation of itraconazole to a product (SUBAItraconazole) with improved bioavailability.
Combination technologies
Combination or multi-phase products incorporating different formulations and active drugs represent another reformulation strategy that has been exploited in recent years to meet the market need for increased patient compliance. DuoCap by Encap Drug Delivery is a capsule-in-capsule technology that allows the incorporation of different drugs in one formulation. The inner and outer capsules usually contain different types of formulation (eg, the inner part may contain liquid, pellets or semisolids, whereas the outer capsule may contain liquid or semisolids). The site of drug release along the GI tract and release kinetics of the inner and outer capsules can also be different by incorporating appropriate coatings.
Combodart from GlaxoSmithKline is an example of a commercial combination formulation containing a soft capsule incorporated into a hard capsule. The hard capsule contains tamsulosin hydrochloride as modified release pellets and the soft capsule contains dutasteride. (It is indicated for the treatment of benign prostatic hyperplasia.)
Vimovo, from Pozen and AstraZeneca, is a modified release tablet formulation containing enteric-coated naproxen for the treatment of arthritis and spondylitis, and film-coated esomeprazole, which can protect the patient against naproxen-induced GI ulceration.5–6
Abuse-resistant mechanisms
As part of the “Risk evaluation and mitigation strategies” used by the US Food and Drug Administration, all manufacturers of opioid containing dosage forms are required to take measures to reduce the risk of serious harm from the use or misuse of such medicines.7 The development of abuse-resistant formulations in conjunction with patient education on the appropriate use of opioid medicines and the risks by their misuse are approaches that have been used to achieve this goal.8–9 Abuse-resistant formulations are delivery systems for scheduled drugs (eg, opioid analgesics and narcotics) that deter consumers from extracting the active drug or experiencing euphoria by inappropriate use.9
Gel-Cap technology, by Pain Therapeutics and King Pharmaceuticals, uses gelatin capsules filled with a highly viscous, adhesive, water-insoluble material called sucrose acetate isobutyrate (SAIB). On oral administration, the gelatine capsule dissolves and the drug is released in a controlled manner from the SAIB matrix. The low aqueous solubility of SAIB prevents extraction of the active drug out of the capsule whereas its high viscosity and adhesivity prevent crushing and snorting of the formulation. Dosage forms using the Gel-Cap technology are currently under clinical trials.
Trigger Lock from Flamel Technologies is a specially designed formulation containing micropump particles that are crush-resistant thus preventing extraction of the active drug.
Abusolve by Encap Drug Delivery uses liquid-fill hard-shell capsule technology where the fill material can consist of waxy or thickening agents. It has a high melting point and unpleasant-tasting excipients or taste modifiers that prevent methods of abuse such as extraction, snorting and injection of the active drug.
Abuse Resistant Technology (ART) by Elite Laboratories contains a mixture of micropellets of the opioid oxycodone and of the opioid antagonist naltrexone. The proprietary coating of the micropellets allows release of the antagonist only if the formulation is crushed with the aim of extracting the active drug. Formulations of oxycodone using ART are currently in development.
Orodispersible tablets
Rapidly dissolving tablets and thin films for systemic drug delivery have been gaining popularity among patients and caregivers due to their ease of administration, especially among patients with difficulty in swallowing solid dosage forms. These formulations disintegrate or dissolve as soon as they are placed in the mouth without the need for chewing or water intake. The dissolved tablet is then swallowed with saliva. Orodispersible systems are also commonly known as fast melt and fast disintegrating tablets. Such tablets can be formulated via direct compression using super-disintegrants such as croscarmellose sodium and crospovidone.
Other preparation methods involve patented technologies (eg, the Zydis freeze-drying fastdissolve technology by Catalent has been used in the formulation of more than 20 commercial products, including loperamide hydrochloride, eg Imodium Instants, for the treatment of acute diarrhoea).
Conclusion
A plethora of technologies has been used in the development of novel oral dosage forms, which have enhanced therapeutic outcomes and improved patient compliance. The pharmacist’s role in patient education is vital in order to ensure the appropriate use of such sophisticated formulations.
References
1 Kelly J, D’Cruz G, Wright D. A qualitative study of the problems surrounding medicines administration to patients with dysphagia. Dysphagia 2009;24:49–56.
2 Patel RR, Patel JK. Novel technologies of oral controlled release drug delivery systems. Systemic Reviews in Pharmacy 2010;1:128–32.
3 LiquiTime oral liquid controlled release drug delivery platform. Available at: www.ondrug delivery.com (accessed 8 May 2012).
4 Neoral soft gelatin capsules. Available at: www.medicines.org.uk/emc/ (accessed 8 May 2012). 5 Combodart hard capsules. Available at: www.medicines.org.uk/emc/ (accessed 8 May 2012).
6 Vimovo modified release tablets. Available at: www.medicines.org.uk/emc/ (accessed 8 May 2012).
7 Opioid drugs and risk evaluation and mitigation strategies (REMS). Available at: www.fda.gov (accessed 8 May 2012).
8 Woodcock J. A difficult balance — pain management, drug safety and the FDA. New England Journal of Medicine 2009;361:2105–7.
9 Murri N. Abuse-deterrent dosage formulation. Available at: www.medscape.com (accessed 8 May 2012).
