Concepts of Sustained Release Dosage Forms Full HTML

CONCEPTS OF SUSTAINED RELEASE DOSAGE FORMS

Ayush Garg*1 And Indrajeet Singhvi1

1Pacific College of Pharmacy, Udaipur – 313024, Rajasthan

Abstract

Sustained release drug delivery systems are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. There are several advantages of sustained release drug delivery over conventional dosage forms like improved patient compliance due to less frequent drug administration, maximum utilization of the drug, increased safety margin of potent drug, reduction of fluctuation in steady-state drug levels, reduction in healthcare costs through improved therapy and shorter treatment period. Wide varieties of polymers like Hydroxy Propyl Methyl Cellulose (HPMC), Carboxy Methyl Cellulose (CMC), Ethyl Cellulose (EC), Cellulose Acetate Phthalate, HPMC K100M, Xanthan gum, Carrageenan gum, Karaya gum, HPMC K15, Carbopol 971P and Carbopol 974P etc. are available for retarding the release rate of drugs hence sustains the action of drugs. This review article describes the basic information regarding sustained-release formulation, its advantages, disadvantages, selection of drug for sustain release, mechanism of release, different types, and factor involved in oral sustained-release dosage form design.

Keywords: Sustained-release, Conventional dosage form, Dissolution, Diffusion, Matrix.

 

INTRODUCTION

Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most drugs, conventional methods of drug administration are effective, but some drugs are unstable or toxic and have narrow therapeutic ranges. Some drugs also possess solubility problems. In such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma levels as shown in Figure 1.1.1

To overcome these problems, controlled drug delivery systems were introduced three decades ago. These delivery systems have a number of advantages over traditional systems such as improved efficiency, reduced toxicity and improved patient convenience. The main goal of controlled drug delivery systems is to improve the effectiveness of drug therapies.2

Sustained release drug system is “any drug or dosage form modification that prolongs the therapeutic activity of the drug”. 3

Ideally a sustained release oral dosage form is designed to release rapidly some pre determined fraction of the total dose in to GI tract. This fraction (loading dose) is an amount of drug, which will produce the desired pharmacological response as promptly as possible and the remaining fraction of the total dose (maintenance dose) is then release at a constant rate. The rate of the drug absorption from the entire maintenance dose into the body should equal to the rate of the drug removal from the body by all the processes over the time for which the desired intensity of pharmacological response is required.2, 3

 

Figure 1.1: A hypothetical plasma-concentration time profile from conventional multiple                    dosing and single doses of sustained and controlled delivery formulations

 

Ideally two main objectives exist for these systems: Spatial delivery, which is related to the control over the location of drug release and temporal drug delivery, in which the drug is delivered over an extended period of time during treatment.3, 4

 

Disadvantages of Conventional Drug Delivery System

  1. Inconvenient
  2. Difficult to monitor
  3. Careful calculation necessary to prevent overdosing
  4. Large amounts of drug can be “lost” when they don’t get to the target organ
  5. Drug goes to non-target cells and can cause damage
  6. Expensive (using more drug than necessary).5

 

Advantages of sustained release dosage forms

  1. Reduction in frequency of intakes.
  2. Reduce side effects.
  3. Uniform release of drug over time.
  4. Better patient compliance.5, 6

 

Disadvantages of sustained release drug delivery

  1. Increased cost.
  2. Toxicity due to dose dumping.
  3. Unpredictable and often poor in vitro-in vivo correlation.
  4. Risk of side effects or toxicity upon fast release of contained drug (mechanical failure, chewing or masticating, alcohol intake).
  5. Increased potential for first- pass clearance.
  6. Need for additional patient education and counseling.6, 7

1.2 RATIONALE OF SUSTAINED AND CONTROLLED DRUG DELIVERY

The basic rationale for controlled drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacological active moieties by using novel drug delivery system or by modifying the molecular structure and physiological parameters inherent in the selected route of administration. It is desirable that the duration of drug action becomes more a desiring property of a rate controlled dosage form and less or not at all a property of the drug molecules inherent kinetics properties. Thus optional design of controlled release systems necessitates a thorough understanding of the pharmacokinetics and pharmacodynamics of the drugs.

1.2.1 Types of Non-immediate release drug delivery system

The conventional dosage forms are immediate release type. Non-immediate release delivery systems may be divided conveniently into three categories:  8, 9, 10

Delayed release drug delivery systems:

Repeat action DDS

Timed release DDS

Sustained release drug delivery systems:

Controlled release DDS

Prolonged release DDS

 

Site specific and receptor release drug delivery systems:

Organ targeting DDS

Cellular targeting DDS

Sub cellular targeting DDS

 

  1. Delayed Release system

These systems are those systems that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release system include repeat action tablets and capsules, as shown in Figure 1.2. A delayed release dosage form does not produce or maintain uniform drug blood levels within the therapeutic range.

Figure 1.2: Drug levels in the blood with Repeat action drug delivery systems

  1. Sustained Release system

It includes any drug delivery system that achieves slow release of drug over an extended period of time.

 

  1. Controlled Release system

If the system is successful at maintaining constant drug level in the blood or target tissues, it is considered as a controlled release system. Drug delivery systems from which therapeutic agents may be automatically delivered at predefined rates over a long period of time are called as controlled drug delivery systems.

 

  1. Prolonged Release system

If without maintaining constant level, the duration of action is extended over that achieved by conventional delivery; it is considered as a prolonged release system. This is illustrated in Figure 1.3.

Figure 1.3: Drug levels in the blood with prolonged release drug delivery systems

  1. Site-Specific and Receptor Release

It refers to targeting of a drug directly to a certain biological location. In the case of site-specific release, the target is a certain organ or tissue, while for receptor release; the target is the particular receptor for a drug within an organ or tissue. Both of these systems satisfy the spatial aspects of drug delivery.

 

1.2.2 Principle of sustained release drug delivery

The conventional dosage forms release their active ingredients into an absorption pool immediately. This is illustrated in the following simple kinetic scheme.

The absorption pool represents a solution of the drug at the site of absorption, and the term Kr, Ka and Ke are first order rate-constant for drug release, absorption and overall elimination respectively. Immediate drug release from a conventional dosage form implies that Kr>>>>Ka. Alternatively speaking the absorption of drug across a biological membrane is the rate-limiting step. For non immediate release dosage forms, Kr<<<Ka i.e. the release of drug from the dosage form is the rate limiting step. This causes the above Kinetic scheme to reduce to the following.

The main objective in designing a sustained release delivery system is to deliver drug at a rate necessary to achieve and maintain a constant drug blood level. This implies that the rate of delivery must be independent of the amount of drug remaining in the dosage form and constant over time. It means that the drug release from the dosage form should follows zero-order kinetics, as shown by the following equation:

 

Kr° = Rate In = Rate Out = Ke Cd Vd                …………. (1.1) 

Where,

Kr°       : Zero-order rate constant for drug release-Amount/time

Ke        : First-order rate constant for overall drug elimination

Cd        : Desired drug level in the body – Amount/volume, and

Vd        : Volume space in which the drug is distributed

Sustained-release systems include any drug-delivery system that achieves slow release of drug over an extended period of time. If the systems can provide some control, whether this being of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered a controlled-release system.11

1.2.3 Classification of sustained/controlled release systems

(A) Monolithic Systems (Matrix System)

Monolithic (matrix) devices are possibly the most common of the devices for controlling the release of drugs. This is possibly because they are relatively easy to fabricate, compared to reservoir devices, and there is not the danger of an accidental high dosage that could result from the rupture of the membrane of a reservoir device. In such a device the active agent is present as dispersion within the polymer matrix, and they are typically formed by the compression of a polymer/drug mixture or by dissolution or melting. The dosage release properties of monolithic devices may be dependent upon the solubility of the drug in the polymer matrix or, in the case of porous matrixes, the solubility in the sink solution within the particle’s pore network, and also the tortuosity of the network (to a greater extent than the permeability of the film), dependent on whether the drug is dispersed in the polymer or dissolved in the polymer. For low loadings of drug, (0 to 5% w/v) the drug will be released by a solution-diffusion mechanism (in the absence of pores). At higher loadings (5 to 10% w/v), the release mechanism will be complicated by the presence of cavities formed near the surface of the device as the drug is lost: such cavities fill with fluid from the environment increasing the rate of release of the drug.12

It is common to add a plasticizer (e.g., poly ethylene glycol), or surfactant, or adjuvant (i.e., an ingredient which increases effectiveness), to matrix devices (and reservoir devices) as a means to enhance the permeability (although, in contrast, plasticizer may be fugitive, and simply serve to aid film formation and, hence, decrease permeability – a property normally more desirable in polymer paint coatings). It was noted by that the leaching of PEG acted to increase the permeability of (ethyl cellulose) films linearly as a function of PEG loading by increasing the porosity; however, the films retained their barrier properties, not permitting the transport of electrolyte.13, 14

It was deduced that the enhancement of their permeability was as a result of the effective decrease in thickness caused by the PEG leaching. This was evinced from plots of the cumulative permeant flux per unit area as a function of time and film reciprocal thickness at a PEG loading of 50% w/w: plots showing a linear relationship between the rate of permeation and reciprocal film thickness, as expected for a (Fickian) solution-diffusion type transport mechanism in a homogeneous membrane. Extrapolation of the linear regions of the graphs to the time axis gave positive intercepts on the time axis: the magnitude of which decreased towards zero with decreasing film thickness. These changing lag times were attributed to the occurrence of two diffusion flows during the early stages of the experiment (the flow of the ‘drug’ and also the flow of the PEG), and also to the more usual lag time during which the concentration of permeant in the film is building-up. Caffeine, when used as a permeant, showed negative lag times. No explanation of this was forthcoming, but Donbrow noted that caffeine exhibited a low partition coefficient in the system, and that this was also a feature of aniline permeation through polyethylene films which showed a similar negative time lag.15

………………… (1.2)

Where,

J = flux of the drug across a membrane in the direction of decreasing concentration,

D = Diffusion coefficient of the drug, and

dCm /dx = Change in the concentration of the drug in the membrane.

Figure 1.4: Rate Control: Matrix System 15

(B) Reservoir Systems

A typical approach to controlled release is to encapsulate or contain the drug entirely (e.g., as a core within a polymer film or coat (i.e., microcapsules or spray/pan coated cores). Kala H., et al has reviewed the Film coating (with particular reference to polymers and their additives), whilst Arshady et al., has reviewed microencapsulation.16, 17, 18

 

When the device contains dissolved active agent, the rate of release decreases exponentially with time as the concentration (activity) of the agent (i.e., the driving force for release) within the device decreases (i.e., first order release). If, however, the active agent is in a saturated suspension, then the driving force for release is kept constant (zero order) until the device is no longer saturated. Alternatively the release-rate kinetics may be desorption controlled, and a function of the square root of time.19

 

The research workers investigated the effect of deionised water on salt containing tablets coated in poly (ethylene glycol) (PEG)-containing silicone elastomer, and also the effects of water on free films. The release of salt from the tablets was found to be a mixture of diffusion through water filled pores, formed by hydration of the coating, and osmotic pumping. KCl transport through films containing just 10% PEG was negligible, despite extensive swelling observed in similar free films, indicating that porosity was necessary for the release of the KCl which then occurred by ‘trans-pore diffusion.’ Coated salt tablets, shaped as disks, were found to swell in de ionized water and change shape to an oblate spheroid as a result of the build-up of internal hydrostatic pressure: the change in shape providing a means to measure the ‘force’ generated. As might be expected, the osmotic force decreased with increasing levels of PEG content. The lower PEG levels allowed water to be imbibed through the hydrated polymer; whilst the porosity resulting from the coating dissolving at higher levels of PEG content (20 to 40%) allowed the pressure to be relieved by the flow of KCl.20

 

Li developed methods and equations, which by monitoring (independently) the release of two different salts (e.g. KCl and NaCl) allowed the calculation of the relative magnitudes that both osmotic pumping and trans-pore diffusion contributed to the release of salt from the tablet. At low PEG levels, osmotic flow was increased to a greater extent than was trans-pore diffusion due to the generation of only a low pore number density: at a loading of 20%, both mechanisms contributed approximately equally to the release. The build-up of hydrostatic pressure, however, decreased the osmotic inflow, and osmotic pumping. At higher loadings of PEG, the hydrated film was more porous and less resistant to outflow of salt. Hence, although the osmotic pumping increased (compared to the lower loading), trans-pore diffusion was the dominant release mechanism. An osmotic release mechanism has also been reported for microcapsules containing a water soluble core.21, 22

 

Figure 1.5: Microbeads & Microtubes

(C) Chemically Controlled System

  • Bioerosion control
  • Drug attached to a polymer backbone
  • Drug in a biodegradable core
  • Drug dispersed in a bioerodible matrix
    • Diffusion controlled
    • Erosion controlled
  • Regulated Systems
    • Release varies with environment
    • Externally regulated
  • Ultrasound
  • Heat
  • Magnetic
  • Pumps
    • Self regulated
  • pH changes
  • Bonding to specific lectins
  • Triggered devices

Figure 1.6: Rate control: Chemical Reaction

(D) Other Systems

(a) Variations on the theme of microspheres.

Kawashima has described methods for the preparation of hollow microspheres (‘micro balloons’) with the drug dispersed in the sphere’s shell, and also highly porous matrix-type microspheres (‘micro sponges’). The micro sponges were prepared by dissolving the drug and polymer in ethanol. On addition to water, the ethanol diffused from the emulsion droplets to leave a highly porous particle. Variation of the ratios of drug and polymer in the ethanol solution gave control over the porosity of the particle, and the drug release properties were fitted to the Higuchi model.23, 24

The hollow microspheres were formed by preparing a solution of ethanol/dichloro-methane containing the drug and polymer. On pouring into water, this formed an emulsion containing the dispersed polymer/drug/solvent particles, by a coacervation-type process, from which the ethanol (a good solvent for the polymer) rapidly diffused precipitating polymer at the surface of the droplet to give a hard-shelled particle enclosing the drug, dissolved in the dichloromethane. At this point, a gas phase of dichloromethane was generated within the particle which, after diffusing through the shell, was observed to bubble to the surface of the aqueous phase. The hollow sphere, at reduced pressure, then filled with water, which could be removed by a period of drying. (No drug was found in the water.) A suggested use of the microspheres was as floating drug delivery devices for use in the stomach.25, 26

 

(b) Osmotically Controlled System

The osmotic pump is similar to a reservoir device but contains an osmotic agent (e.g., the active agent in salt form) which acts to imbibe water from the surrounding medium via a semi-permeable membrane. Such a device, called the ‘elementary osmotic pump, has been described by Theeuwes. Pressure is generated within the device which forces the active agent out of the device via an orifice (of a size designed to minimize solute diffusion, whilst preventing the build-up of a hydrostatic pressure head which has the effect of decreasing the osmotic pressure and changing the dimensions {volume} of the device). Whilst the internal volume of the device remains constant, and there is an excess of solid (saturated solution) in the device, then the release rate remains constant delivering a volume equal to the volume of solvent uptake.27

Figure 1.7: Osmotic drug delivery system

(c) Pendent devices

Scholsky and Fitch developed a means of attaching a range of drugs such as analgesics and antidepressants, etc., by means of an ester linkage to poly (acrylate) ester latex particles prepared by aqueous emulsion polymerization. These lattices when passed through an ion exchange resin such that the polymer end groups were converted to their strong acid form could ‘self-catalyze’ the release of the drug by hydrolysis of the ester link.28

 

Chafi present a number of papers where drugs have been attached to polymers and also where monomers have been synthesized with a pendent drug attached. The research groups have also prepared their own dosage forms in which the drug is bound to a biocompatible polymer by a labile chemical bond. e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used to form a matrix with a second polymer (Eudragit® RL) which released the drug on hydrolysis in gastric fluid. Chafi has also described the use of polymeric Schiff bases suitable for use as carriers of pharmaceutical amines.29, 30

 

(d) Electrically stimulated release devices

Yuk et al, Prepared monolithic devices using polyelectrolyte gels which swelled when, for example, an external electrical stimulus was applied, cause a change in pH. The release could be modulated, by the current, giving a pulsatile release profile.31

 

(e) Hydrogels

Hydrogels find a use in a number of biomedical applications, in addition to their use in drug matrices. E.g. soft contact lenses, and various ‘soft’ implants, etc.32, 33

 

1.2.4 Mechanisms of drug release from matrix systems

The  release  of  drug  from  controlled  devices  is  via  dissolution  or  diffusion  or  a combination of the two mechanisms.

  1. Dissolution controlled systems

A drug with slow dissolution rate will demonstrate sustaining properties, since the release of the drug will be limited by the rate of dissolution. In principle, it would seem   possible   to   prepare   extended   release   products   by   decreasing   the dissolution rate of drugs that are highly water-soluble.34

This can be done by:

  • Preparing an appropriate salt or derivative
  • Coating the drug with a slowly dissolving material – encapsulation dissolution control
  • Incorporating the drug into a tablet with a slowly dissolving carrier – matrix dissolution control  (a  major  disadvantage  is  that  the  drug  release  rate continuously decreases with time).

The dissolution process can be considered diffusion-layer-controlled, where the rate of diffusion from the solid surface to the bulk solution through an unstirred liquid film is the rate-determining step. The dissolution process at steady-state is described by the Noyes-Whitney equation:

 ………………….. (1.3)

Where,

dC / dt = dissolution rate

D = the dissolution rate constant (equivalent to the diffusion coefficient    divided by the thickness of the diffusion layer D/h)

Co = saturation solubility of the solid

C = concentration of solute in the bulk solution

A = Surface area

h = Diffusion layer thickness

Equation predicts that the rate of release can be constant only if the following parameters are held constant:

  • Surface area
  • Diffusion coefficient
  • Diffusion layer thickness
  • Concentration

These  parameters,  however,  are  not  easily  maintained  constant,  especially surface  area,  and  this  is  the  case  for  combination  diffusion  and  dissolution systems.34

  1. Diffusion controlled systems

Diffusion   systems   are   characterized   by   the   release   rate   of   a   drug   being dependent on its diffusion through an inert membrane barrier. Usually, this barrier is an insoluble polymer. In general, two types or subclasses of  diffusional  systems  are  recognized:  reservoir  devices  and  matrix  devices.34  It  is  very  common  for  the  diffusion-controlled devices to exhibit a non-zero order release rate due to an increase in diffusional resistance  and  a  decrease  in  effective  diffusion  area  as  the  release  proceeds.35

 

       Diffusion in matrix devices

In  this  model,  drug  in  the  outside  layer  exposed  to  the  bathing  solution  is dissolved first and then diffuses out of the matrix. This process continues with the interface  between  the  bathing  solution  and  the  solid  drug  moving  toward  the interior. It follows obviously that for this system to be diffusion controlled, the rate of  dissolution  of  drug  particles  within  the  matrix  must  be  much  faster  than  the diffusion rate of dissolved drug leaving the matrix. Derivation  of  the  mathematical  model  to  describe  this  system  involves  the following assumptions:

 

  1. A pseudo-steady state is maintained during drug release;
  2. The diameter of the drug particles is less than the average distance of drug diffusion through the matrix;
  3. The diffusion  coefficient  of  drug  in  the  matrix  remains  constant  (no  change occurs  in  the  characteristics  of  the  polymer  34  
  4. The bathing solution provides sink conditions at all times;
  5. No interaction occurs between the drug and the matrix;
  6. The total amount of drug present per unit volume in the matrix is substantially greater than the saturation solubility of the drug per unit volume in the matrix(Excess solute is present)36
  7. Only the diffusion process 37

 

In  a  hydrophilic  matrix,  there  are  two  competing  mechanisms  involved  in  the drug release: Fickian diffusional release and relaxation release. Diffusion is not the only pathway by which a drug is released from the matrix; the erosion of the matrix following polymer relaxation contributes to the overall release. The relative contribution of each component to the total release is primarily dependent on the properties of a given drug.38

 

For  example,  the  release  of  a  sparingly  soluble  drug  from  hydrophilic  matrices involves  the  simultaneous  absorption  of  water  and  desorption  of  drug  via  a swelling-controlled  diffusion  mechanism.  As  water  penetrates  into  a  glassy polymeric  matrix,  the  polymer  swells  and  its  glass  transition  temperature  is lowered.  At  the  same  time,  the  dissolved  drug  diffuses  through  this  swollen rubbery region into the external releasing medium.39

This type of diffusion and swelling does not generally follow a Fickian diffusion mechanism. The semi-empirical equation to describe drug release behavior from hydrophilic matrix systems: 39

Where,

Q = fraction of drug released in time t,

k = rate constant incorporating characteristics of the macromolecular network system and the drug

n = the diffusional exponent.  It has been shown that the value of n is indicative of the drug release mechanism.

For n=0.5, drug release follows a Fickian diffusion mechanism that is driven by a chemical potential gradient. For n=1 drug release occurs via the relaxational transport that is associated with stresses and phase transition in hydrated polymers. For   0.5<n<1   non-Fickian   diffusion   is   often   observed   as   a   result   of   the contributions from diffusion and polymer erosion.37

 

Advantages of hydrophilic matrix tablets

With proper control of manufacturing process, reproducible release profiles are possible. They variability associated with them is slightly less than that characterizing coated release forms. Their capacity to incorporate active principles is large, which suits them to delivery of large doses.

 

Disadvantages of hydrophilic matrix tablet

For a hydrophilic sustained release matrix tablet, in which the release is mainly controlled by erosion of the swollen polymer gel barrier at the tablet surface, the presence of food may block the pores of the matrix and inhibit the drug release rate.

The hydrophilic polymers can be arranged into three broad categories:

(A) Non-cellulose natural or semi synthetic polymer

These are products of vegetable origin and are generally used as such. Agar, alginate, guar gum, chitosan, modified starches, are commonly used polymer.

(B) Polymers of acrylic acid

These are arranged in carbomer group and commercialized under the name of carbopol. The major disadvantage of this type of polymer is its pH dependent gelling characteristics.

(C) Cellulose ether

This group of semi-synthetic cellulose derivatives is the most widely used group of polymer. Non-ionic such as Hydroxypropylmethylcellulose (HPMC) of different viscosity grades are widely used group of polymers. Non-ionic such as HPMC of different viscosity grades is widely used.

Figure 1.8: Drug release from hydrophilic matrix tablet

  1. Bioerodible and combination of diffusion and dissolution systems

Strictly speaking, therapeutic systems will never be dependent on dissolution or diffusion only. In practice, the dominant mechanism for release will overshadow other processes enough to allow classification as either dissolution rate-limited or diffusion-controlled release.34

As a further complication these systems can combine diffusion and dissolution of both the drug and the matrix material.  Drugs  not  only  can  diffuse  out  of  the dosage  form,  as  with  some  previously  described  matrix  systems,  but  also  the matrix  itself  undergoes  a  dissolution  process.  The complexity of the system arises from the fact that as the polymer dissolves the diffusion path length for the drug may change. This usually results in a moving boundary diffusion system. Zero-order release is possible only if surface erosion occurs and surface area does not change with time.

 

Swelling-controlled matrices exhibit a combination of both diffusion and dissolution mechanisms. Here the drug is dispersed in the polymer, but instead of  an  insoluble  or  non-erodible  polymer,  swelling  of  the  polymer  occurs.  This allows  for  the  entrance  of  water,  which  causes  dissolution  of  the  drug  and diffusion  out  of  the  swollen  matrix.  In these systems the release rate is highly dependent on the polymer-swelling rate and drug solubility. This system usually minimizes  burst  effects,  as  rapid  polymer  swelling  occurs  before  drug  release.

With regards to swellable matrix systems, different models have been proposed to describe the diffusion, swelling and dissolution processes involved in the drug release mechanism.  However  the  key  element  of  the  drug  release  mechanism  is  the forming   of   a   gel   layer   around   the   matrix,   capable   of   preventing   matrix disintegration and further rapid water penetration.40, 41

 

The gel strength is important in the matrix performance and is controlled by the concentration, viscosity and chemical structure of the rubbery polymer.  This restricts  the  suitability  of  the  hydrophilic  polymers  for  preparation  of  swellable matrices. Polymers such as carboxymethyl cellulose, hydroxypropyl cellulose or tragacanth gum, do not form the gel layer quickly.  Consequently, they are not recommended as excipients to be used alone in swellable matrices.40, 43

The swelling behavior of heterogeneous swellable matrices is described by front positions,  where  ‘front’  indicates  the  position  in  the  matrix  where  the  physical conditions sharply change. Three fronts are present, as shown in Figure 1.9.40

 

  • The ‘swelling front’ clearly separates the rubbery region (with enough water to lower the  Tg   below  the  experimental  temperature)  from  the  glassy  region (Where the polymer exhibits a Tg that is above the experimental temperature).
  • The ‘erosion front’, separates the matrix from the solvent. The gel-layer thickness as a function of time is determined by the relative position of the swelling and erosion moving
  • The ‘diffusion  front’  located  between  the  swelling  and  erosion  fronts,  and constituting the boundary that separates solid from dissolved drug, has been identified.
  • During drug release, the diffusion front position in the gel phase is dependent on drug solubility and The diffusion front movement is also related to drug dissolution rate in the gel.44

 

Figure 1.9: The fronts in a swellable HPMC matrix 44

Factors Influencing the Drug Release from Matrix:

  • Choice of matrix material.
  • Amount of drug incorporated in the matrix.
  • Viscosity of the hydrophilic material in aqueous system at a fixed concentration.
  • Drug: matrix ratio.
  • Tablet hardness, porosity, and density variation.
  • Entrapped air in tablet.
  • Tablet shape and size.
  • Drug particle size.
  • Solubility of drug in aqueous phase.
  • Surfactants and other additives.

Factors Influencing Design of Sustained Drug Delivery Systems

  1. Biological factors

 

  1. A) Biological half-life:

Therapeutic compounds with short half-lives are excellent candidates for sustained-release preparations, since this can reduce dosing frequency.45, 46

 

  1. B) Absorption:

The absorption rate constant is an apparent rate constant, and should, in actuality, be the release rate constant of the drug from the dosage form. If a drug is absorbed by active transport, or transport is limited to a specific region of the intestine, sustained-release preparations may be disadvantageous to absorptions.45, 46

 

  1. C) Metabolism:

Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period, allowing more complete conversion of the drug to its metabolite.45, 46

 

  1. D) Dosage form Index:

It is defined as the ratio of Css, max. to Css, min. Since the goal of controlled release formulation is to improve therapy by reducing the dosage form index while maintaining the plasma drug levels within the therapeutic window, ideally its value should be as close to one as possible.46

 

  1. 2. Physicochemical factors
  2. A) Dose Size:

In general, single dose of 0.5 – 1.0 g is considered maximal for a conventional dosage form. This also holds true for sustained-release dosage forms. Another consideration is the margin of safety involved in administration of large amounts of drug with a narrow therapeutic range.

  1. B) Ionization, pKa and aqueous solubility:

Most drugs are weak acids or bases. Since the unchanged form of a drug preferentially permeates across lipid membranes, it is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. For dissolution or diffusion sustaining forms, much of the drug will arrive in the small intestine in solid form, meaning that the solubility of the drug may change several orders of magnitude during its release. The lower limit for the solubility of a drug to be formulated in a sustained release system has been reported to be 0.1 mg/ml.

  1. C) Partition coefficient:

Compounds with a relatively high partition coefficient are predominantly lipid-soluble and, consequently, have very low aqueous solubility. Furthermore these compounds can usually persist in the body for long periods, because they can localize in the lipid membranes of cells.

  1. D) Stability:

Orally administered drugs can be subjected to both acid-base hydrolysis and enzymatic degradation. For drugs that are unstable in the stomach, systems that prolong delivery over the entire course of transit in the GI tract are beneficial. Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered from a sustaining dosage form. 45, 46

  1. E) Molecular Weight of the Drug:

The lower the molecular weight, the faster and more complete the absorption. The upper limit of drug molecular size for passive diffusion is 600 Daltons. Drugs with large molecular size are poor candidates for oral controlled release systems e.g. peptides and proteins.

  1. F) Mechanism and Site of Absorption:

Drugs absorbed by carrier mediated transport processes and those absorbed through a window are poor candidates for controlled release systems e.g. several B vitamins.

  1. G) Biopharmaceutic Aspects of Route of Administration:

Oral and parenteral (i.m.) routes are most popular followed by transdermal application.

 

  1. Pharmacodynamic Characteristics of the Drug

 

  1. A) Therapeutic Range:

A candidate drug for controlled delivery system should have a therapeutic range wide enough such that variations in the release rate do not result in a concentration beyond this level.

  1. B) Therapeutic Index (TI):

The release rate of a drug with narrow therapeutic index should be such that the plasma concentration attained is within the therapeutically safe and effective range.

  1. C) Plasma Concentration-Response Relationship:

Drugs such as reserpine whose pharmacologic activity is independent of its concentration are poor candidates for controlled release systems.

 

Drug selection for oral sustained release drug delivery systems

The biopharmaceutical evaluation of a drug for potential use in controlled release drug delivery system requires knowledge on the absorption mechanism of the drug form the G. I. tract, the general absorbability, the drug’s molecular weight, solubility at different pH and apparent partition coefficient. 45, 46

Table 1.1: Physicochemical Parameters for drug selection

Parameter

Preferred value

Molecular weight/ size < 1000 Daltons
Solubility > 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition coefficient High
Absorption mechanism Diffusion
General absorbability From all GI segments
Release Should not be influenced by pH and enzymes

 

The pharmacokinetic evaluation requires knowledge on a drug’s elimination half- life, total clearance, absolute bioavailability, possible first- pass effect, and the desired steady concentrations for peak and trough.11, 45

 

Table 1.2: Pharmacokinetic parameters for drug selection

Parameter
Comment
Elimination half life Preferably between 0.5 and 8 h
Total clearance Should not be dose dependent
Elimination rate constant Required for design
Apparent volume of distribution Vd The larger Vd and MEC, the larger will be the required dose size.
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate
Therapeutic concentration Css, av The lower Css, av and smaller Vd, the loss among of drug required
Toxic concentration Apart the values of MTC and MEC, safer the dosage form. Also suitable for drugs with very short half-life.