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Extended Release Drug Delivery Technology

Extended Release Drug Delivery Technology

DRUG DELIVERY & FORMULATION Extended release delivery technology By providing smooth plasma levels of drug over longer periods of time, extended release technology can minimise side effects, improve effi cacy and – by enabling once-daily dosing – maximise patient compliance.

Peter Fyhr and Ken Downie, Amarin Development AB

xtended release oral drug formulations have methylcellulose (HPMC) and hydroxypropyl cellu- Ebeen used since the 1960s to enhance perform- lose (HPC), and then formed as a tablet by conven- ance and increase patient compliance. By incorpo- tional compression. Release from these tablets takes rating the dose for 24 hours into one tablet from place by a combination of physical phenomena. which the drug is slowly released, peaks of high Water diffuses into the tablet, swells the plasma concentration and troughs of low plasma and dissolves the drug, whereupon the drug may concentration can be prevented. This helps avoid diffuse out to be absorbed. If the drug diffuses out the side effects associated with high concentrations faster than the polymer dissolves, the release rate and the lack of activity associated with low concen- declines with time. Water penetration also depends trations – giving better overall therapy. In addition, on factors such as tablet porosity, and this makes in the treatment of diseases that are asymptomatic matrix tablets inherently variable and diffi cult to – such as hypertension – patients generally remem- formulate. If the is taken with food, ber morning and evening medication, but tend the increased mechanical stress leads to an increased to forget doses in between. Once- or twice-daily release rate and a higher risk of dose-dumping. In dosing thus improves therapy through the constant addition, these systems require a large amount of Early drug delivery presence of the drug. , and drug loading is consequently com- systems (DDS) Early drug delivery systems (DDS) tended to paratively low. tended to give non- give non-constant release rates, although this was Another method of obtaining controlled release constant release still a large improvement over immediate release is to employ diffusion-controlling membranes. rates... The ideal formulations. The ideal DDS should show a con- Here, a core that may be pure drug is coated with DDS should show stant zero-order release rate, as this has the potential a permeable polymeric membrane (see Figure 1). a constant zero- to create constant plasma concentrations. Water diffuses through the membrane and dis- order release rate, solves the drug which then diffuses through the as this has the A range of technologies membrane at a rate determined by the porosity and potential to create Many current oral extended release systems are of thickness of the membrane, the solubility of the constant plasma the matrix type, based on hydrophilic . drug and the membrane area. Available membrane concentrations With these technologies, drug and polymers – such as ethylcellulose – have relatively are mixed with polymers such as hydroxypropyl low permeability and, consequently, this technique

80 Innovations in Pharmaceutical Technology DRUG DELIVERY & FORMULATION

Figure 1. Diffusion controlling membrane. polymers that are either dissolved in an organic solvent or used as aqueous dispersions. A water- soluble pore former is suspended in the polymer /dispersion, and this coating mix is then spray-coated onto drug-containing cores by con- ventional coating techniques. This process cre- ates a macroporous membrane that controls the diffusion of the drug (see Figure 3). Compared with the osmotic pump, the membrane contains about one million holes. These are created by a stochastic process during coating, and con- sequently dose-dumping cannot take place by osmotic rupture of the membrane. Furthermore, the drug is released over the entire membrane Figure 2. Osmotic pump. surface, as compared with a single spot with the osmotic pump. This reduces the risk of side effects due to high drug concentrations close to gastric and intestinal mucosa.

Mathematical models The release of drug from the DCV system is described by a well-established mathematical model. The processes that may control the release include:

• Dissolution of the drug at the surface of the depot, • Mixing of the drug into the dissolved phase Amongst the is mainly used on small pellets to increase the total inside the membrane, stable of patented membrane area. • Diffusion of the drug through the membrane, oral DDS is the A special version is the so-called osmotic and diffusion controlled pump. Here, the membrane is semi-permeable • Mixing of the drug into the fl uid outside the vesicle (DCV) – water can diffuse in through the membrane but membrane. platform which the drug cannot diffuse out. However, by drilling uses impenetrable a hole in the membrane, dissolved drug may fl ow It can be assumed that the fi rst two processes water-insoluble out (see Figure 2). Drilling the hole is, however, and the last process are much faster than diffu- polymers that are an expensive step; furthermore, the existence of sion through the membrane. Consequently, the either dissolved in the hole must be assured since the system may release rate is given by Fick’s fi rst equation of an organic solvent otherwise explode – leading to complete dose- diffusion: or used as aqueous dumping. Amongst the stable of patented oral DDS dispersions dcd is the diffusion controlled vesicle (DCV) plat- J=-Dd form which uses impenetrable water-insoluble dx Where J is the rate of mass transport (mg/time), Figure 3. Macroporous membrane that controls drug Dd is the diffusion coeffi cient of the drug, and diffusion. dcd/dx is the diffusion gradient. The gradient can be approximated with the concentration dif- ference (Cs) across the membrane and the thick- ness of the membrane (h). The tortuous porous membrane reduces diffusion of the drug and Dd is replaced by Dd(P), the diffusion coeffi cient as a function of membrane porosity. Finally, we have to multiply with the membrane area A, which gives the release rate: dQ C = A D (P) s dt d h

82 Innovations in Pharmaceutical Technology DRUG DELIVERY & FORMULATION

After integration, we obtain the cumulated release: acidic to the neutral intestinal environment. In the DCV system, this can be easily adjusted for by A D (P) C the addition of suitable buffers to the formulation. Q(t)= d s t Constant pH is thus maintained inside the mem- h brane and a constant release rate is attained along the entire gastrointestinal canal (GIC). Given that the While there is a solid depot of the drug present absorption, distribution, metabolism and elimina- inside the membrane, all parameters are constant tion (ADME) of the drug is known, it is possible to and, thus, the release rate is constant. The release predict the pharmacokinetics of the DCV formula- rate declines exponentially when the depot is tion. The drug is released and absorbed with con- depleted: stant rate along the entire GIC, giving steady plasma profi les over 24 hours. Figure 5 shows a diltiazem A D (P) DCV once-daily formulation, showing that absorp- dQ = A D (P) C - d t d s e Vh tion takes place even at times longer than 24 hours. dt h By using a technique called Wagner-Nelson analysis, it is possible to fi nd the absorption rate The model accurately predicts drug release from of the DCV compared with the solution. Figure 6 the system, and the formulation is consequently shows that there is a linear relation between in vitro constructed by computer simulation using the fol- release and in vivo absorption. This means that lowing parameters: the in vivo is entirely predictable given that the in vitro release is pH–independent. This is demon- • Drug dose, strated by formulating a super-generic, which is a product that is bioequivalent to another extended Drug solubility often • Drug solubility, release product. The appropriate DCV in vivo depends on pH; this • Drug size (diffusion coeffi cient), release profi les were obtained by fi tting the linked being the case, drug • Tablet size, membrane area, DCV pharmacokinetic model for the drug to the release rates in vivo • Membrane thickness, and from most drug • Membrane porosity. plasma profi le obtained with the original product. delivery systems Two such formulations were then compared with change as the tablet Figure 4 shows a comparison between a simu- the original in a pharmacokinetic study; Figure 7 transits from the lated release profi le and the release profi le of a for- shows a close match of both formulations which acidic stomach to mulation manufactured according to the simulation were bioequivalent to the original product. the neutral intestinal specifi cation. Recently, there has been a new development that environment Drug solubility often depends on pH; this being allows for the delivery of nanoparticles through the the case, drug release rates in vivo from most drug membrane; this will expand the applicable range to delivery systems change as the tablet transits from the all bioavailable .

Figure 4. DCV mathematical modelling and experimental profi le. Figure 5. Diltiazem DCV once-daily formulation.

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Peter Fyhr is R&D Director at Amarin Development AB. Dr Fyhr has worked in drug delivery for 25 years and has been with Amarin Development since 1996. His extensive experience includes parenterals, and oral formula- tions, and his current research focuses on methods for Figure 6. Absorption rate of the DCV compared with controlled release of very insoluble compounds. Dr the solution. Fyhr can be contacted at [email protected] Conclusion It is clear that oral drug delivery has come a long way since the 1960s and, with it, major advances Ken Downie is in the technology employed. By providing smooth Director of Business plasma levels of drug over extended periods of time, Development at side effects are minimised and effi cacy improved. Amarin Development In an ageing In an ageing population, it is also evident that AB. Mr Downie has population, it is also patient compliance is seen as a signifi cant factor worked in the phar- evident that patient in managing a disease or condition, and extended maceutical industry compliance is seen release and once-daily dosing has been shown to for 25 years with as a signifi cant maximise this. the last six spent in factor in managing a Today, it is estimated that around 80 per cent international business disease or condition, of all utilise the oral route, and tab- development. He has and extended lets, capsules and granules will remain the form of extensive experience in marketing and strategy, and release and once- choice. It is therefore not only important that oral in his current position specialises in pharmaceutical daily dosing has drug delivery technology continues to advance, but product development and licensing. Mr Downie been shown to as the ever-demanding patient population becomes can be contacted at [email protected] maximise this more informed, it is in fact essential for the future drug treatment of disease.

Figure 7. Formulation comparison.

86 Innovations in Pharmaceutical Technology