The Design Of Drug Delivery Systems

IAN W.KELLAWAY

CONTENTS

2.1 INTRODUCTION 29

2.2 FORMULATION AIMS 31

2.3 PHYSICO-CHEMICAL FACTORS INFLUENCING DRUG BIOAVAILABILITY 31

2.3.1 Rate of solution 32

2.3.2 Complexation 34

2.3.3 Drug stability 34

2.4 INFLUENCE OF ROUTE OF ADMINISTRATION AND TYPE OF DOSAGE

FORM 35

2.5 FORMULATION FACTORS 35

2.5.1 Solutions 36

2.5.2 Emulsions 36

2.5.3 Soft gelatin capsules 37

2.5.4 Suspensions 37

2.5.5 Hard gelatin capsules 37

2.5.6 Tablets 38

2.5.7 Coated tablets 38

2.6 DRUG DELIVERY TO THE LUNG 38

2.6.1 Therapeutic aerosol generation and particle fate 39

2.6.2 Metered dose inhalers (MDIs) 40

2.6.3 Nebulizers 41

2.6.4 Dry powder inhalers (DPIs) 41

2.6.5 Pulmonary drug selectivity and prolongation of therapeutic effects 42

2.6.5.1 Prodrugs 42

2.6.5.2 Polyamine active transport system 42

2.6.5.3 Rate control achievable by employing colloidal drug carriers 42

2.6.6 Delivery of drugs to the systemic circulation by the pulmonary route 43

2.7 SUSTAINED AND CONTROLLED RELEASE DOSAGE FORMS 44

2.7.1 Potential advantages of sustained controlled release products 45

2.7.2 Therapeutic concentration ranges and ratios 45

2.7.3 Dosage interval concentration ratio and rate of elimination 46

2.7.4 Mechanisms of achieving sustained release by the oral route 46

2.7.4.1 Hydrophilic gel tablets or capsules 46

2.7.4.2 Matrix tablets 46

2.7.4.3 Capsules containing pellets with disintegrating coatings 46

2.7.4.4 Pellets or tablets coated with diffusion controlling membranes 47

2.7.5 Positional controlled release 47

2.7.6 Gastrointestinal transit of sustained release dosage formulations 47

2.8 SITE-SPECIFIC DRUG DELIVERY 48

2.8.1 Carrier systems 48

2.8.2 Fate of site-specific delivery systems 49

2.9 BIOEQUIVALENCE 50

FURTHER READING 50

2.1 INTRODUCTION

Drugs are rarely, if ever, administered to patients in an unformulated state. The vast majority of the available medicinal compounds which are potent at the milligram or microgram levels could not be presented in a form providing an accurate and reproducible dosage unless mixed with a variety of excipients and converted by controlled technological processes into medicines. Indeed, the primary skills of the pharmacist lie in the design, production and evaluation of a wide range of dosage forms, each providing an optimized delivery of drug by the selected route of administration. The aims of this chapter, therefore, are to outline mechanisms by which the onset, duration and magnitude of the therapeutic responses can be controlled bv the designer of the drug delivery system.

It has been appreciated for a considerable time that dosage forms possessing the same amount of an active compound (chemically equivalent) do not necessarily elicit the same therapeutic response. The rate at which the drug is liberated from the dosage form and the subsequent absorption, distribution, metabolism and excretion kinetics will determine the availability of the active species at the receptor site.

The majority of systemically acting drugs are administered by the oral route and therefore must traverse certain physiological barriers including one or more cell membranes. Pro-drugs may alter this part of the overall rate process (see Chapter 7) although generally, control of plasma levels is achieved by modulation of the drug liberation process from the dosage form. The critical drug activity at the receptor site is usually related to blood and other distribution fluid levels, as well as elimination rates. Other factors affecting activity include deposition sites, biotransformation processes, protein binding and the rate of appearance in the blood. Hence in order to obtain the desired response, the drug must be absorbed both in sufficient quantity and at a sufficient rate.

The term bioavailability is used to express the rate and extent of absorption from a drug delivery system into the systemic circulation. The crucial influence of rate as well as extent of absorption in considerations of bioavailability can be seen in Figure 2.1.

The plasma levels are illustrated following a single oral administration of three chemically equivalent delivery systems (A, B and C) but with different drug liberation rates (A>B>C). Formulation A has a shorter duration of activity but results in a more rapid onset of activity compared with formulation B. The magnitude of the therapeutic response is also greater for A than B. Formulation C is therapeutically inactive, as the minimum effective plasma concentration (MEC) is not achieved. Therefore, unless a multiple dosing regimen is to be considered, C has no clinical value.

It should also be noted that the plasma concentrations from A exceed the maximum safe concentration (MSC) and some toxic side-effects will be observed. Unless rapidity of action is of paramount importance and the toxic effects can be tolerated, B therefore becomes the formulation of choice. Generally, however, a rapid and complete absorption profile is required to eliminate variation in response due to physiological variables which include gastric emptying rate and gut motility. Bioavailability can also therefore be influenced by physiological and pathological factors, although in this chapter only the pharmaceutical or formulation aspects will be considered.

Bioavailability may be assessed by the determination of the induced clinical response which, because it often involves an element of subjective assessment, makes quantitation

Minimum Safe Concentration

Figure 2.1 The influence of drug release rate on the blood level—time profile following the oral administration of three chemically equivalent formulations. MSC=maximum safe concentration; MEC= minimum effective concentration.

Figure 2.1 The influence of drug release rate on the blood level—time profile following the oral administration of three chemically equivalent formulations. MSC=maximum safe concentration; MEC= minimum effective concentration.

difficult. Measurement of drug concentrations at the receptor site is not feasible; therefore, the usual approach is the determination of plasma or blood levels as a function of time making the implicit assumption that these concentrations correlate directly with the clinical response. Areas under the concentration—time profiles give the amount of drug absorbed and hence (if related to those of an intravenous solution of the same drug) permit an absolute bioavailability to be determined, whilst if related to a 'standard' formulation (often the original or formula of the patent holder) then the term 'relative bioavailability' is employed.

The constraints of space dictate the limitation of both discussion and examples to the oral route, which is the most widely used route for systemically active agents, and the pulmonary route for which there is an interdependence between the device and the formulation in order to optimise drug efficiency. However, there are alternative routes to be considered including nasal, ocular, transdermal, buccal, vaginal and rectal— details are available from specialist textbooks (see Further Reading).

2.2 FORMULATION AIMS

Formulation aims, in the light of bioavailability considerations, are to produce a drug delivery system such that:

(a) A unit dose contains the intended quantity of drug. This is achieved by homogeneity during the manufacturing process and a suitable choice of excipients, stabilizers and manufacturing conditions to ensure both drug and product stability over the expected shelf-life.

(b) The drug is usually totally released but always in a controlled manner, in order to achieve the required onset, intensity and duration of clinical response as previously outlined. Most dosage forms can be designed to give a rapid response: if, however, a long duration of response is required then it is easier to achieve sustained release using solid rather than liquid formulations.

2.3 PHYSICO-CHEMICAL FACTORS INFLUENCING DRUG BIOAVAILABILITY

Drug concentrations in the blood are controlled either by the rate of drug liberation from the dosage form or by the rate of absorption. In many cases it is the drug dissolution rate that is the rate-determining step in the process. Dissolution is encountered in all solid dosage forms, i.e. tablets and hard gelatin capsules as well as suspensions, whether intended for oral use or administration via the intramuscular or subcutaneous routes. If absorption is rapid, then it is almost inevitable that drug dissolution will be the rate-determining step in the overall process and hence any factor which affects the solution process will result in changes in the plasma—time profile. Hence the pharmacist has the opportunity of controlling the onset, duration and intensity of the clinical response by controlling the dissolution process.

2.3.1 Rate of solution

Dissolution of a drug from a primary particle in a non-reacting solvent can be described by the Noyes-Whitney equation

where dwldt is the rate of increase of the amount of drug dissolved; k is the rate constant of dissolution; cs the saturation solubility of the drug in the dissolution media; c the concentration of drug at time t; A is the surface area of drug undergoing dissolution; D the diffusion coefficient of the dissolved drug molecules and h, the thickness of the diffusion layer. Hence it can be readily appreciated that the dissolution rate is dependent on the diffusion of molecules through the diffusion layer of thickness h. Closer examination of this equation will demonstrate some of the mechanisms for controlling solution rate.

(1) dwldt A. Reduction in the particle size of the primary particle will result in an increase in surface area and hence more rapid dissolution will be achieved. A change in the shape of the plasma—time profile will result and it is possible also to increase the area under this curve, which of course means an increase in bioavailability. It is therefore possible to achieve a reduction in the time necessary for the attainment of maximum plasma levels, an increase in the intensity of the response and an increase in the percentage of the dose absorbed. Griseofulvin is one of the most widely studied drugs in relation to bioavailability, as this poorly water-soluble, antifungal drug exhibits a striking example of dissolution rate-limited absorption. Plasma levels have been shown to increase linearly with an increase in specific surface area and thus, despite the cost of micronization, griseofulvin is marketed as a preparation in this form because identical blood levels can be achieved by using half the amount of drug present in the unmicronized formulation. Micronization, however, is not the only solution to the griseofulvin bioavailability problem. For example, microcrystalline dispersions have been formed in a water-soluble solid matrix in which the dispersion state is determined by the preparative procedures, some of which result in true solid solutions. The two most widely accepted approaches are (a) crystallization of a melt, resulting from fusing of drug and carrier and (b) co-precipitation of drug and carrier from a common organic solvent. In the latter case a griseofulvin— polyvinylpyrrolidone dispersion resulted in a ten-fold increase in solution rate, compared with a micronized preparation. It should be emphasized, however, that griseofulvin is at the extreme end of the bioavailability spectrum! For drugs exhibiting good aqueous solubility, little is to be gained by reducing the particle size of the drug, as plasma levels are unlikely to be dissolution rate-limited. Indeed, if enzymatic or acid degradation of the drug occurs in the stomach, then increasing dissolution rates by reducing particle size can result in reduced bioavailability.

(2) dwldt cs. Many drugs are weak acids or bases and hence exhibit pH-dependent solubility. It is therefore possible to increase cs in the diffusion layer by adjustment of pH in either (a) the whole dissolution medium or (b) the microenvironment of the dissolving particle. The pH of the whole medium can be changed by the co-administration of an antacid. This raises the pH of the gastric juices and hence enhances the dissolution rate of a weak acid. However, this is rarely a practical proposition and therefore most pH adjustments are made within the very localized environment of the dissolving drug particles. Solid basic substances may be added to a weakly acidic drug, which raises the pH of the microenvironment. Probably the best known example is that of buffered aspirin products which use the basic substances sodium bicarbonate, sodium citrate or magnesium carbonate. Rather than employ another agent to alter the pH, a highly water-soluble salt of the drug can be equally, if not more, effective. The dissolving salt raises the pH of the gastric fluids immediately surrounding the dissolving particle. On mixing with the bulk of the gastric fluids the free acid form of the drug will be precipitated, but in a microdispersed state with a large surface area to volume ratio which will rapidly redissolve. The process is represented diagrammatically in Figure 2.2.

Many examples exist to illustrate the importance of salt formation on bioavailability. One such example is provided by the antibiotic novobiocin, where the bioavailability was found to decrease in the order, sodium salt>calcium salt>free acid. The dissolution rate of weak bases can be similarly changed by salt formation: however, dissolution rate-limited absorption is less important for bases than acids. This is because little absorption occurs in the stomach where the bases are ionized: most of the drug being absorbed post gastric emptying and this delay compensates any benefits accruing from more rapid solution rates. However, basic drugs are often administered as salts, e.g. phenothiazines and tetracyclines, to ensure that gastric emptying, and not dissolution, will be the rate-limiting factor in the absorption process.

A large number of drugs exhibit polymorphism, that is, they exist in more than one crystalline form. Polymorphs exhibit different physical properties including solubility, although only one polymorph will be stable at any given temperature and pressure. Others may exist in a metastable condition, reverting to the stable form at rates which may permit their use in drug delivery systems. The most desirable property of the metastable forms is their inherently higher solubility rates which arise from the lower crystal lattice energies.

Amorphous or non-crystalline drugs are always more soluble than the corresponding crystalline form because of the lower energy requirements in transference of a molecule from the solid to the solution phase. Crystalline novobiocin dissolves slowly in vitro

Figure 2.2 The dissolution of a highly water-soluble salt of a weak acid in the stomach.

Figure 2.2 The dissolution of a highly water-soluble salt of a weak acid in the stomach.

compared with the amorphous form, kinetics which correlate well with bioavailability data. Amorphous chloramphenicol stearate is hydrolysed in the gastrointestinal tract to yield the absorbable acid, whilst the crystalline form is of such low solubility that insufficient is hydrolysed to give effective plasma levels.

Solvates are formed by some drugs: when the solvent is water, the hydrates dissolve more slowly in aqueous solutions than the anhydrous forms, e.g. caffeine and glutethimide. For ampicillin, greater bioavailability has been shown for the higher energy form anhydrate than the trihydrate, which illustrates the dependence of solubility and dissolution rates on the free energy of the molecules within the crystal lattice. Conversely, organic solvates such as alkanoates dissolve more rapidly in aqueous solvents than the desolvated forms.

2.3.2 Complexation

Increased solubility or protection against degradation may be achieved by complex formation between the drug and a suitable agent. Complexes may also arise unintentionally as a result of drug interaction with an excipient or with substances occurring in the body. Complex formation is a reversible process and the effect on bioavailability is often dependent on the magnitude of the association constant. As most complexes are non-absorbable, dissociation must therefore precede absorption.

The formation of lipid-soluble ion-pairs between a drug ion and an organic ion of opposite charge would result in greater drug bioavailability. Rarely have such results been achieved, presumably due to the dissociating influence of the mucosa and the poor membrane partitioning of the bulky ion-pair.

Surfactants are used in a wide range of dosage forms often to increase particle wetting, control the stability of dispersed particles, and to increase both solution rates and the equilibrium solubility by the process of solubilization. Bioavailability may, however, be enhanced or retarded and often exhibits surfactant concentration dependent effects. Below the critical micelle concentration (CMC), enhanced absorption may be encountered due to partition of the surfactant into the membrane, which results in increased membrane permeability. At post-CMC levels, the dominant effect is the 'partitioning' of the drug into the micelle, a lower drug thermodynamic activity results and absorption is reduced. Micellar solubilization of membrane components with a loss of membrane integrity can also occur. Thus it is not easy to predict the effect of surfactants on bioavailability for, although dissolution rates will be increased by high concentrations of surfactant, the effect on the absorption phase may be complex.

2.3.3 Drug stability

Drug stability, in addition to being of paramount importance to product shelf-life, can also affect bioavailability. Some therapeutic substances are degraded by the acid conditions of the stomach or by enzymes encountered in the gastrointestinal tract. Reduced or zero therapeutic effectiveness will result. Penicillin G is an example of a drug rapidly degraded in the stomach and for which enteric coating is not a solution to the problem, as the drug is poorly absorbed from the small intestine. The semisynthetic penicillins such as ampicillin and amoxacillin show much greater acid stability. Improved bioavailability of acid-labile drugs can sometimes be achieved by reducing the rate of drug release from the dosage form.

2.4 INFLUENCE OF ROUTE OF ADMINISTRATION AND TYPE OF DOSAGE FORM

Although many routes exist for the administration of a systemically acting drug (including parenteral, rectal, vaginal, pulmonal, nasal, transdermal, etc.) by far the most popular is the oral route. Bioavailability, in addition to being dependent on the route of administration, will also be influenced by the dosage form selected. Although it is not possible to generalize completely regarding the relative drug release rates and hence bioavailabilities from different dosage forms. Table 2.1 attempts to provide guidelines. It is however possible, for example, to produce a tablet with bioavailability equivalent to an aqueous solution!

Aqueous solutions are rarely used due to solubility, stability, taste and non-unit dosing problems. The use of oils as drug carriers either as an emulsion, in which homogeneity and flavour masking are important, or in a soft gelatin capsule, provides efficient oral dosage forms. The release of the oil from the soft gelatin capsule shell is rapid but the surface area of the oil/water interface is lower than in an emulsion and hence partitioning of the drug is slower. Suspensions are suited to drugs of low solubility and high stability. Although a large surface area is provided, a dissolution stage nevertheless exists. On proceeding along the sequence from powders to hard gelatin capsules to tablets (see Table 2.1), the particles become more compacted and hence the deaggregation/dissolution phase becomes longer (see Figure 2.3).

2.5 FORMULATION FACTORS

It should by now be appreciated that, by design, it is possible to formulate a potent, well-absorbed drug in such a manner that it is essentially non-absorbable. Hence the pharmacist with his unique skills in designing drug delivery systems can significantly influence the therapeutic efficacy of a drug. In most cases, the formulator can only influence bioavailability if the drug release phase is the rate-controlling step in the overall process.

Table 2.1 The ranking of dosage forms for oral administration with respect to the rate of drug release.

Aqueous solutions Emulsions Soft gelatin capsules Suspensions Powders Granules

Hard gelatin capsules Tablets Coated tablets

Increasing release rates and bioavailability

Figure 2.3 Summary of the processes following oral administration of dosage forms. Processes (a) dissolution; (b) deaggregation; (c) disintegration; (d) partitioning; (e) dispersion; (f) precipitation; (g) absorption.

2.5.1 Solutions

As the drug is in a form readily available for absorption, few problems should exist. However, if the drug is a weak acid or a cosolvent is employed, then precipitation of the drug in the stomach may take place. Rapid redissolution of these 'micro-precipitates' normally occurs. Aqueous solutions will require the addition of a suitable selection of colours and flavours to minimize patient non-compliance, and preservatives and perhaps buffers to optimize stability. Such factors would be elucidated in preformulation studies.

2.5.2 Emulsions

The use of oral emulsions is on the decline. Most oils are unpalatable and an emulsion is an inherently unstable system. The choice of carrier oil dictates the extent and rate of drug partitioning between the oil and water. Emulsifying agents are either a mixture of surfactants or a polymer. Polymers may also be present to control the rheological properties of the emulsion and achieve an acceptable rate of creaming. The effect of surfactants on bioavailability has been previously discussed. Polymers can form non-absorbable complexes with drugs and an increase in viscosity brought about by 'thickening agents' can delay gastric emptying which in turn may affect absorption. Viscosity effects, however, are not likely to be encountered with small dose volumes (5-10 ml).

2.5.3 Soft gelatin capsules

After rupture of the glycero-gelatin shell, a crude emulsion is formed when the oil containing the drug is dispersed in the aqueous contents of the gastrointestinal tract. Oils are not always used to fill soft gelatin capsules; indeed occasionally water-miscible compounds such as polyethylene glycol 400 are used as vehicles. Soft gelatin capsules are a convenient unit dosage form generally exhibiting good bioavailability.

2.5.4 Suspensions

A high surface area of the dispersed particles ensures that the dissolution process begins immediately the administered dose is diluted with the fluids of the gastrointestinal tract. Most pharmaceutical suspensions mav be described as coarse, that is they have particles in the size range 1-50 pm. Colloidal dispersions are expensive to produce and the theoretically faster solution rates arising from increased surface area are often offset by the spontaneous aggregation of the particles due to the possession of high surface energy. Particles>50 pm result in poor suspensions with rapid sedimentation, slower solution rates and poor reproducibility of the unit dose. In order to achieve desirable settling rates and ease of redispersion of the resulting sediments, controlled flocculation of the suspension is necessary. This is normally achieved by the use of surfactant or polymers, both of which may significantly influence drug bioavailability for reasons previously discussed. Polymers are also used, as with emulsions, as thickening agents to achieve the desired bulk rheological properties. On storage, the particle size distribution of suspensions may change with the growth of large particles at the expense of small. Hence solution properties and bioavailability may well be altered on storage.

2.5.5 Hard gelatin capsules

It might be assumed that powders distributed into loosely packed beds within a rapidly dissolving hard gelatin capsule would not provide bioavailability problems. However, in practice, this is not true. One of the classic bioavailability cases in the pharmaceutical literature arose when the primary excipient in phenytoin capsules, calcium sulphate dihydrate, was substituted (by the manufacturing company in Australia) by lactose. Minor adjustments were also made to the magnesium silicate and magnesium stearate levels. The overall effect was that previously stabilized epileptic patients suddenly developed the symptoms associated with phenytoin overdose. It is now generally accepted that the calcium ions form a poorly absorbable complex with phenytoin.

Another study demonstrated the reduced bioavailability of tetracycline from capsules in which calcium sulphate and dicalcium phosphate were used as fillers. The calcium—tetracycline complex formed in such formulations is poorly absorbed from the gastrointestinal tract.

The choice and quantity of lubricant employed can greatly influence bioavailability. Even with a water-soluble drug it is possible to vary the drug release patterns from rapid and complete to slow and incomplete. With hydrophobic drugs, the problems can be even more acute. Hence, hydrophilic diluents should be employed to aid the permeation of aqueous fluids throughout the powder mass, reduce particle clumping and hence increase solution rates.

2.5.6 Tablets

For economic reasons as well as for the convenience of the patient, the compressed tablet is the most widely used dosage form. However, by virtue of the relatively high compression forces used in tablet manufacture, together with the inevitable need of a range of excipients (including fillers, disintegrants, lubricants, glidants and binders), tabletting of drugs can give rise to serious bioavailability problems. As was seen in Figure 2.3, the active ingredient is released from the tablet by the processes of disintegration, deaggregation and dissolution: the latter occurring, however, at all stages in the overall liberation process. The rate-limiting step is normally dissolution, although by the use of insufficient or an inappropriate type of disintegrant, disintegration may become the all-important rate-limiting step. Division of the disintegrant between the granule interior and the intragranular void spaces can accelerate the disintegration process. Several interdependent factors determine disintegration rates, including concentration and type of drug, the nature of diluent, binder and disintegrant as well as the compaction force. High compression forces will often result in the retardation of disintegration due to reduced fluid penetration and extensive interparticulate bonding. Soluble drugs and excipients may lead to a decrease in disintegration due to the local formation of viscous solutions.

The effect of hydrophobic lubricants is similar to that observed for capsules. The method by which the lubricant is incorporated, as well as the efficiency of mixing, have also been shown to influence drug dissolution rate from tablets.

When the excipient-drug ratio is increased, thus increasing tablet size, solution rates of poorly water-soluble drugs also increase.

2.5.7 Coated tablets

The application of an outer coat to a tablet presents a further barrier between the fluids of the gastrointestinal tract and the drug particles and one which is the first to be dissolved or ruptured prior to the fluid penetration of the tablet mass. Film coats are usually thin and readily soluble and hence would be expected to have but a negligible effect on bioavailability. The more traditional sugar coat is similarly water soluble.

Enteric coatings can give rise to considerable variations in drug plasma levels due primarily to variation in stomach residence times, which, for non-disintegrating tablets, can vary between 1-5 and 6 hours. As a single enteric coated tablet or capsule empties from the stomach in an all or none manner, better control of the plasma concentration—time profile is obtained by the use of individually enteric-coated granules either packed into a capsule or compressed into a rapidly disintegrating tablet.

2.6 DRUG DELIVERY TO THE LUNG

Drug delivery to or via the respiratory tree has been a long-standing pharmaceutical objective. For locally acting agents it is desirable to confine the action of the drug to the lung in order to eliminate unintended side effects which might result following absorption and distribution to other extravascular sites. Oral inhalation is often the preferred route in order that such effects be minimised. The large surface area for absorption provided by the alveolar region, together with reduced extracellular enzyme levels compared with the gastrointestinal tract, ensures that pulmonary administration is a potentially attractive route for the delivery of systemically active agents including the new generation of biotechnology molecules.

2.6.1 Therapeutic aerosol generation and particle fate

There are three principal types of aerosol generators currently used in inhalation therapy, viz. the pressurized pack (metered-dose) inhaler (MDI), the nebulizer for continuous administration and the unit-dose dry powder inhaler (DPI). The pharmaceutical formulator is not only concerned with the drug formulation but also the selection of the appropriate device as it is the intimate relationship between device and formulation that leads to optimal drug deposition within the lower respiratory tract. The latter consists of the bronchial and pulmonary regions and in order to deliver drug to these regions, the polydispersed therapeutic aerosol containing particles/droplets of the drug should ideally be in the size range of 2-5 pm in diameter.

The influence of particle diameter in determining deposition site is illustrated in Figure 2.4, where the fraction deposited in the alveolar and tracheo-bronchial regions of the lung is shown as a function of aerodynamic particle diameter. Tracheobrochial deposition may occur by various mechanisms but inertial impaction, sedimentation and Brownian diffusion predominate. Mouth breathing—the normal route of pulmonary delivery of medicinal agents—bypasses the nasal removal of large particles, which are

Figure 2.4 Particle diameter dependence of alveolar and tracheobronchial deposition for mouth breathing. Tidal volume 1 1, breathing frequency 7.5/min, mean flow rate 250 cm3/s, inspiration/expiration times 4 s each. (Reproduced from Routes of Drug Administration. Eds. A.T.Florence and E.G.Salole (1990), p. 53. London: Wright.

Figure 2.4 Particle diameter dependence of alveolar and tracheobronchial deposition for mouth breathing. Tidal volume 1 1, breathing frequency 7.5/min, mean flow rate 250 cm3/s, inspiration/expiration times 4 s each. (Reproduced from Routes of Drug Administration. Eds. A.T.Florence and E.G.Salole (1990), p. 53. London: Wright.

therefore deposited in the throat and part of the tracheobronchial region. In the bronchioles, ciliated cells are dominant and in conjunction with mucus secreted by goblet cells and submucosal glands, constitutes the 'mucociliary escalator' which ensures rapid (within hours) removal of insoluble or slowly soluble deposited particles by transport to the mouth for subsequent swallowing. Soluble particles, in contrast, dissolve and may enter the bloodstream. Particles penetrating to the pulmonary compartment may be retained on the pulmonary surfaces as a result of settling, diffusion and interception processes. Several mechanisms ensure clearance, including dissolution with absorption, phagocytosis of particles by macrophages with translocation to the ciliated airways, and lymphatic uptake. Aerosol characteristics will therefore determine the depth of penetration within the airways and hence particle fate.

2.6.2 Metered Dose Inhalers (MDls)

This is a sprayable product in which the propellant force is a liquified or compressed gas (Figure 2.5). They are currently the major device used by domiciliary patients and consist of a container hermetically sealed by a metering valve and composed of aluminium or glass protected with a plastic outer casing. As most drugs are of low propellant solubility, they are frequently formulated as micronised suspensions. Stability is achieved by the addition of surfactants such as lecithin, oleic acid or sorbitan esters which also serve as a lubricant of the metering valve assembly. Solution formulations may be achieved by addition of a cosolvent such as ethanol or by solubilization in the added surfactant. Chlorofluorocarbons (CFC's) are currently the propellant of choice, blended to achieve a vapour pressure of 350-450 kPa although the Montreal Protocol on Substances that Deplete the Ozone Layer calls for the phasing out of CFC's by the year 2000. Replacement propellants are being investigated with the hydrofluorocarbons HFA-134A and HFA-227 being the most likely substitutes. In 1995 a number of products were marketed using hydrofluorocarbon propellants.

Maiering v;

Container

Actuate

Maiering v;

Container

Actuate

Oral tube

■ Actuatqr orifice Aciuaior seat

Figure 2.5 Diagram of a metered dose inhaler.

Oral tube

■ Actuatqr orifice Aciuaior seat

Figure 2.5 Diagram of a metered dose inhaler.

Within the container is the drug formulation which typically comprises micronised drug suspended in the propellant and stabilized by a surfactant. (Reproduced from Morén, F. (1981). Pressurized aerosols for oral inhalation. Int. J. Pharm. 8, 1-10).

2.6.3 Nebulizers

Nebulizers are devices for converting aqueous solutions or micronised suspensions of drug into an aerosol. This is effected by two principal mechanisms, either high velocity airstream dispersion (the air-jet nebulizers) or by ultrasonic energy dispersion (the ultrasonic nebulizers). The former require a source of compressed gas (cylinder or air compressors) and hence tend to be more frequently encountered in hospitals than the domiciliary environment. Ultrasonic nebulizers are, in contrast, easily portable but, although producing a dense aerosol plume, often the population of droplets have a higher mass median aerodynamic diameter compared with the air jet nebulizers.

Drug formulations for use in nebulizers are, wherever possible, aqueous solutions. Selection of appropriate salts and pH adjustment will usually permit the desired concentration to be achieved. If this is not feasible, then the use of cosolvents such as ethanol and/or propylene glycol can be considered. However, such solvents change both the surface tension and viscosity of the solvent system which, in turn, influence aerosol output and droplet size. Water insoluble drugs can be formulated by either micellar solubilization or by forming a micronised suspension.

Nebulizer solutions are often presented as concentrated solutions from which aliquots are withdrawn for dilution before administration. Such solutions require the addition of preservatives, e.g. benzalkonium chloride and antioxidants (e.g. sulphites). Both excipient types have been implicated with paradoxical bronchospasm and hence the current tendency to use small unit-dose solutions that are isotonic and free from preservatives and antioxidants.

Nebulizers of different design produce aerosols of different output and particle size of droplets. For maximum efficacy, the drug-loaded droplets need to be less than 5 pm. In the treatment of prophylaxis of Pneumocystis carinii pneumonia with nebulized pentamidine and where the target is the alveolar space, it is desirable to use nebulizers capable of generating droplets of less than 2 pm. During the nebulization from air jet nebulizers, cooling of the reservoir solution occurs which, together with vapour loss, results in concentration of the drug solution. This can lead to drug recrystallisation with subsequent blockage within the device or variation in aerosol droplet size. In contrast, ultrasonic nebulization results in a rise in solution temperature and a decrease in aerosol size.

Although aerosol size distributions are a critical determinant of effective pulmonary drug delivery, it is also desirable to consider output in selection of a nebulizer. For most applications drug administration should occur over a maximum of 10-15 minutes to optimise patient compliance.

2.6.4 Dry Powder Inhalers (DPls)

These breath activated devices aerosolise a set dose of micronised drug on an airstream. The earliest devices consisted of the micronised drug contained within a single-dose capsule which often contained lactose as an inert drug carrier and diluent. On rapid inhalation, mechanical deaggregation of the powder occurs but the high inertia ensures a significant deposition of the powder on the back of the throat. DPls tend to be even less efficient than MDIs but because of the higher doses employed, an equivalent therapeutic effect can be achieved. Multidose systems are now available, e.g. Diskhaler® and Turbuhaler®, the latter functioning at low inspiratory flow rates with the capability of delivering, for example, 200x1 mg doses of terbutaline sulphate.

2.6.5 Pulmonary drug selectivity and prolongation of therapeutic effects

2.6.5.1 Prodrugs

In addition to improved selectivity of action in the lung relative to other organs, it is possible to obtain prolongation of therapeutic effects and enhancement of pulmonary activity by the design of appropriate prodrugs. Lung accumulation from the blood pool is achieved by many drugs which are both highly lipophilic and strongly basic amines. Such drugs exhibit very slowly effluxable lung pools.

Lung tissue exhibits high nonspecific esterase activity which is species dependent and capable of cleaving carboxylate or carbonate ester linkages. In vivo prodrug conversion to active drug moiety can be controlled by use of different aliphatic or aromatic coupling agents, together with stereochemical modifications.

Terbutaline (2.1) is an example of a bronchodilator drug for which a number of prodrugs exist. Terbutaline exhibits little affinity for lung tissue being rapidly absorbed following inhalation with peak plasma concentrations occurring within 0.5 h. The diisobutyryl ester (ibuterol) (2.2) results in an increased bioavailability of 1.6 fold over terbutaline following oral administration. However, it is 3 times as effective as terbutaline post-inhalation in inhibiting bronchospasm. Enhanced effects are attributable to more rapid absorption and better tissue penetration. Bambuterol (2.3) is the bis-AA-dimethylcarbonate of terbutaline and as such is well absorbed from the gastrointestinal tract and is relatively resistant to hydrolysis leading to a sustained release oral product. However, it is not readily metabolised in the lung which precludes its administration by the pulmonary route.

2.6.5.2 Polyamine active transport system

The cell types which accumulate polyamines such as endogenous putrescine, spermidine and spermine, together with compounds such as paraquat, are the Clara cells and the alveolar Type I and Type II cells.

2.6.5.3 Rate control achievable by employing colloidal drug carriers

Control of the duration of local drug activity and of the plasma levels of systemically active agents may be achievable by employing a colloidal carrier possessing appropriate drug release characteristics. Tracheobronchial deposition of such carriers may not be

desirable as their clearance will occur in a relatively short time period on the mucociliary escalator. Pulmonary deposition will, in contrast, result in extended clearance times which may be dependent upon the composition of the colloid. The mechanism by which clearance is effected will also vary, but will involve alveolar macrophage uptake, with subsequent metabolism or deposition on to the mucus blanket in the ciliated regions or lymphatic uptake. Colloidal carriers, of which liposomes are an example, can therefore control both drug delivery rates and availability. Technological problems, however, exist such as the design of delivery devices to ensure deposition in the appropriate regions of the lung without degradation or loss of entrapped drug. Toxicological considerations, foremost amongst which is the processing of the colloid, also require to be addressed.

2.6.6 Delivery of drugs to the systemic circulation by the pulmonary route

The large surface area, thin epithelial membrane provided by Type I cells and a rich blood supply, ensures that many compounds are readily transported from the airways into the systemic circulation. Gaseous anaesthesia and oxygen therapy are examples of efficient clinical utilisation of the pulmonary absorption process. Compounds are absorbed by different processes including active transport and passive diffusion through both aqueous pores and lipophilic regions of the epithelial membranes. Absorption can be both rapid and efficient; for example, sodium cromoglycate is well absorbed from the lung whereas less than 5% is absorbed from the gastrointestinal tract.

Small lipophilic molecules, such as the gaseous anaesthetics, are absorbed by a nonsaturable passive diffusion process. Hydrophilic compounds are absorbed more slowly and generally by a paracellular route. Aqueous pores are, by virtue of their size, capable of controlling the rate and extent of hydrophilic compound absorption. Sodium cromoglycate is absorbed by both active and passive (paracellular) mechanisms. The rates of absorption by the paracellular route decreases as the molecular weight of the compound increases.

The efficiency of absorption from the lung is species dependent. For example, insulin is absorbed from the human lung but less efficiently than in the rat or rabbit. Human growth hormone (molecular weight 22 kDa) is absorbed from the lungs of hypophysectomised rats with an estimated bio-equivalence of 40% relative to the subcutaneous route and an absolute bioavailability of 10%, sufficient to induce growth. A nonapeptide (leuoprolide acetate) has been shown to have an absolute bioavailability following aerosolization to healthy male volunteers of between 4 and 18% which, when corrected for respirable fraction, corresponds to 35-55%.

Protein absorption, however, is postulated to occur through the extremely thin Type I cells by the vesicular process of transcytosis. The passage from lung to blood of proteins in the rat has recently been shown to increase during inflammatory conditions with the observed transport correlating to the severity of the lung injury. The pulmonary route therefore warrants further investigation for the systemic delivery of peptides and proteins.

2.7 SUSTAINED AND CONTROLLED RELEASE DOSAGE

FORMS

Figure 2.6 illustrates the differences between three distinct drug release profiles achieved by the use of (A) the usual single dose preparation, (B) a sustained release preparation and (C) a prolonged release preparation. Sustained release products are rarely achieved in practice although in many respects they represent an ideal delivery system. Initially a loading dose is rapidly released from the sustained action delivery system to provide the necessary blood levels to elicit the desired pharmacological response. The remaining fraction of the dose (maintenance dose) is then released from the preparation at rates which ensure the maintenance of a constant blood level. Prolonged action delivery systems merely extend the duration of the pharmacological response compared with the usual single dose preparation. Not all drugs are suitable candidates for prolonged action medication as (a) the drug must be absorbed efficiently over a substantial portion of the gastrointestinal tract, (b) the drug must possess a reasonably short biological half-life (<12 hours), (c) the size of the prolonged dosage form must not be too large for ease of swallowing, i.e. the drug must be effective at a 'reasonable' dose level and (d) the pharmacological activity of the drug should be clinically desirable. In some instances, the latter has been questioned if tolerance to the drug may result.

It should be noted that various terms have been employed to describe oral dosage forms which provide long-term therapeutic action. These include 'sustained', 'prolonged', 'slow', 'gradual', 'timed', 'extended', and 'controlled'. Often such terms are used interchangeably, although 'controlled' should be reserved for drug delivery systems

Time

Figure 2.6 The difference between sustained and prolonged release dosage forms as illustrated by the blood concentration— time profiles.

Time

Figure 2.6 The difference between sustained and prolonged release dosage forms as illustrated by the blood concentration— time profiles.

where the rate of drug release is determined solely by the device and is therefore independent of any anatomical or physiological constraints.

2.7.1 Potential advantages of sustained controlled release products

Prolonged drug absorption and reduced peak blood concentrations are two obvious advantages of effectively designed sustained release products. As a consequence of the prolonged absorption phase, therapeutic effects should also be extended and a more regular and even pattern established. It has been claimed that a reduction in dosing frequency to once daily will lead to improved compliance and a concomitant reduction in unwanted side-effects from high peak blood levels. Irritant drugs such as nonsteroidal anti-inflammatory agents, which are slowly released within the gut, should result in reduced inflammatory responses in the gastric mucosa.

2.7.2 Therapeutic concentration ranges and ratios

Rapid diffusion of the drug across capillary walls will result in equilibrium drug concentrations at the target site equivalent to the free serum concentration. Under these conditions, concentration-effect relationships can be established. Often it is difficult to define both MSCs and MECs due to variability in reported values (Figure 2.4). Therapeutic ranges are often related to patient age, disease state and concomitant therapy. The presence of active metabolites and intersubject variation in plasmaprotein binding often complicates both the highest tolerable and the minimum therapeutic concentrations; the ratio of which is the therapeutic concentration ratio (TCR). For drugs exhibiting a low TCR, it is critical to minimize variations in peak and trough plasma concentrations. Hence, a controlled release dosage form becomes highly desirable because, in addition, minimization of variations in serum concentration between doses will achieve both increased therapeutic effectiveness and safety.

2.7.3 Dosage interval concentration ratio and rate of elimination

The dosage interval concentration (DICR) is the ratio of the peak to the minimum plasma concentration achieved during a single dosing interval. It is dependent on and will increase with dosing frequency and absorption and elimination rates (see Chapter 1). Elimination rate is an intrinsic property of the drug molecule and therefore, unlike absorption rate, cannot be controlled by formulation factors. Minimization of the DICR for rapidly cleared drugs can be achieved by frequent administration, resulting in patient inconvenience and hence poor compliance, or by the more pragmatic approach, the design of sustained release formulations in order to prolong the absorption phase.

2.7.4 Mechanisms of achieving sustained release by the oral route

Oral sustained release products have been produced employing various drug release mechanisms. Unfortunately, no single approach is universally acceptable and selection is inevitably related to drug properties. For bona fide controlled release, in vitro release profiles are superimposable on those achieved in vivo. If drug release is pH

dependent, then greater variability in in vivo performance is to be expected. Excluding molecular modification in order to change drug solubility (prodrug, salt or complex formation) and the use of the limited applicability of ion exchange resins, the design of sustained release products is often accompanied by employing one or more of the following approaches.

2.7.4.1 Hydmphilic gel tablets or capsules

Hydrophilic gums are used to form a gel layer surrounding the tablet upon introduction to an aqueous medium. Diffusion across this layer constitutes the rate-determining release step. Nitroglycerin (glyceryl trinitrate) dispersed in hydroxypropylmethylcellulose for buccal administration permits sustained release for over 4 hours. Capsules, the contents of which swell within the stomach to produce a plug which is buoyant on the gastric contents, provide a further example of this type of technology.

2.7.4.2 Matrix tablets

The eroding variety of matrix tablets are generally slowly disintegrating tablets, although similar release systems can be achieved by using semi-solid lipophilic materials in hard gelatin capsules. This approach generally leads to poorer control of in vivo performance. Drugs dispersed in inert matrices can also be employed for sustained release tablets, and better in vivo reproducibility generally results, as drug release rates are not dependent on enzyme levels or gastric intestinal transit rates. Zero-order release kinetics are not obtained from these tablets; cumulative drug release is often proportional to the square root of time.

2.7.4.3 Capsules containing pellets with disintegrating coatings

By employing differentially coated pellets, i.e. pellets with varying thickness of a slowly dissolving or eroding polymer, it is possible to provide an extended dissolution profile of a drug. Such a coating may be pH sensitive or insensitive, the former to provide positional release (e.g. classic enteric coatings), the latter to achieve drug release rates independent of transit profiles within the gastrointestinal tract.

2.7.4.4 Pellets or tablets coated with diffusion conrolling membranes

Pellets or a compressed tablet may be coated with a rate-controlling membrane (non-disintegrating) across which the drug may diffuse. Pellets are normally presented in hard gelatin capsules. By encapsulating drugs in excess of their solubility, a constant concentration gradient will be maintained as long as the saturation state exists and zero-order kinetics will prevail.

The OROS® elementary osmotic pump comprises a central core of a salt to provide an osmotic gradient together with drug particles. Surrounding this core is a semipermeable membrane. Fluid is drawn into the core at a rate controlled by both the membrane characteristics and the osmotic gradient. Saturated drug solution is then forced from the device through a small orifice into the surrounding membrane at a constant rate.

2.7.5 Positional controlled release

Considerable benefits may ensue from drug delivery to a specific region of the gastrointestinal tract. An example of buccal absorption to eliminate first-pass metabolism has previously been described (2.7.4.1). Gastric retention of the drug delivery system may be required to achieve localized drug concentrations or to delay passage of the dosage form past the absorbing membranes of the small intestine, which may lead to improved bioavailability. Prolonged gastric retention may be achieved by the use of gel rafts which 'float' on the gastric contents (as with the hydrodynamically balanced capsule™) or by employing mucoadhesive delivery systems, although the latter are in early stages of development.

It is often necessary to prevent drug release in the stomach to avoid gastric degradation, reduce gastric side-effects such as inflammatory responses, or provide localized drug concentrations in the small intestine or colon. Enteric coating of both tablets and capsules provides the most widely used approach to avoid drug release in the stomach and is achieved by the use of film-forming ionizing polymers of suitable pKa and degree of substitution.

Alternative, more sophisticated, technologies exist to achieve colon specific drug delivery. For example, the Pulsincap® utilizes a novel hydrogel plug fitted into the neck of a water insoluble capsule. A water soluble cap fits over the capsule body and dissolves within the gastric juice to expose the underlying plug. The hydrogel swells at a controlled rate and ejects when it can no longer be contained, thus giving rise to pulsed delivery of the capsule contents within the colon approximately 5 hours after administration. Applications include treatment of local disorders, e.g. irritable bowel disease, and peptide delivery for absorption at what is the preferred gastro intestinal site.

2.7.6 Gastrointestinal transit of sustained release dosage formulations

Transit profiles are greatly influenced by diet. Comparison of gastric emptying of a single unit with a multiple or pelleted dosage form resulted in similar residence times when dosing followed a light breakfast. However, when a heavy breakfast was substituted for the light meal, an increase in residence time was noted for the pellets but the delay was considerably shorter than for the single dose unit (residence time approximately 10 hours).

Less intersubject variability in plasma concentrations would therefore be expected from pelleted formulations compared with single unit dosage forms, especially where there is no attempt to regulate diet and where the dosage forms show pH-dependent drug release profiles.

2.8 SITE-SPECIFIC DRUG DELIVERY

Having briefly reviewed the principal approaches to the temporal control of drug release from the dosage form, it is pertinent now to examine the subject of site-specific drug delivery or drug targeting. Originally driven out of a desire to therapeutically optimise the delivery of cytotoxic agents, the interest in site specific delivery has expanded rapidly as molecular biology advances have led to a better understanding of a number of disease states and the identification of potential target sites (receptors) for drugs. We are currently witnessing a revolution in availability of biotechnic drug products (e.g. genes, peptidergic mediators, antisense oligonucleotides), the successful clinical utilization of which requires significant application of drug delivery science. In essence, site specific drug delivery attempts to optimise drug activity by insuring exclusive availability to the specific receptors, i.e. differential accessibility and in so doing provide protection to both drug and body.

Target selectivity by differential sensitivity (drug distributed throughout the body but acting exclusively on target) is virtually impossible to achieve. Therefore, in order to selectively deliver drugs it is necessary to utilize a drug carrier system (Table 2.2). Such a site-specific carrier is required, in addition, to being a guiding device, to protect against drug excretion or inactivation, prevent drugs from eliciting adverse immune reactions, provide for site recognition and being retained at that site to achieve drug release over an appropriate timescale, and finally to be degraded/excreted.

Table 2.2 Classification of drug carriers.

Macromolecular carriers Microparticulate carriers_

Proteinaceous carriers Cellular carriers

(e.g. antibodies, albumin, (e.g. erythrocytes, leucocytes, lymphoid glycoproteins, lipoproteins, cells, fibroblasts)

gelatin, polypeptides)

Lectins Vesicular carriers

2.8.1 Carrier systems

(e.g. liposomes, niosomes)

Hormones Polysaccharides (e.g. dextran)

Lipid carriers

(e.g. emulsions, waxes, lipoproteins, chylomicrons) Microspheres/Nanoparticles (e.g. albumin, starch, dextran, polyalkylcyano-acrylate, polyamide, polyanhydrides, poly(lactic glycolic) acid)

Deoxyribonucleic acid

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