Classification of CRDDS

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Chapter: Biopharmaceutics and Pharmacokinetics : Controlled Release Medication

CRDDS can be classified in various ways – 1. On the basis of technical sophistication 2. On the basis of route of administration.


CRDDS can be classified in various ways –

1. On the basis of technical sophistication

2. On the basis of route of administration.

On the basis of technical sophistication, CRDDS can be categorised into 4 major classes:

1. Rate-programmed DDS

2. Activation-controlled DDS

3. Feedback-controlled DDS

4. Site-targeted DDS

In the former three cases i.e. except site-targeted DDS, the formulation comprise of three basic components –

i. The drug

ii. The rate controlling element

iii. Energy source that activates the DDS.

1. Rate-Programmed DDS

These DDS are those from which the drug release has been programmed at specific rate profiles. They are further subdivided into following subclasses:

i.               Dissolution-controlled DDS

ii.               Diffusion-controlled DDS

iii.               Dissolution and diffusion-controlled DDS.

All the above systems can be designed in one of the following ways –

i.               Reservoir systems (membrane-controlled DDS)

ii.               Matrix systems (soluble/erodible/swellable/degradable)

iii.               Hybrid systems (i.e. membrane cum matrix systems)

1. Dissolution-Controlled DDS

These systems are those where the rate-limiting phenomenon responsible for imparting the controlled-release characteristics to the DDS is either of the two -

(a) Slow dissolution rate of the drug - the drug present in such a system may be one of the following two types:

i. Drug with inherently slow dissolution rate e.g. griseofulvin, digoxin and nifedipine. Such drugs act as natural prolonged-release products, or

ii. Drug that transforms into slow dissolving forms on contact with GI fluids e.g. ferrous sulphate.

(b) Slow dissolution rate of the reservoir membrane or matrix - the drug present in such a system may be the one having high aqueous solubility and dissolution rate e.g. pentoxifylline and metformin. The challenge in designing such systems lies in controlling the drug dissolution rate by employing either or combination of following techniques –

i. Embedment in slowly dissolving, degrading or erodible matrix. The matrix in addition may have low porosity or poor wettability.

ii. Encapsulation or coating with slow-dissolving, degrading or erodible substances. In this approach, the rate of dissolution fluid penetration and/or wettability of the reservoir system are controlled.

Slowly soluble and erodible materials commonly employed to achieve these objectives include hydrophobic substances such as ethyl cellulose (containing an added water-soluble release modifying agent such as PVP), polymethacrylates with pH independent solubility (e.g. Eudragit RS and RL 100) and waxes such as glyceryl monostearate, and hydrophilic materials like sodium CMC.

2. Diffusion-Controlled DDS

These systems are those where the rate-controlling step is not the dissolution rate of drug or release controlling element, but the diffusion of dissolved drug molecule through the rate-controlling element. The rate-controlling element in such a system is thus neither soluble, erodible nor degradable but is water-swellable or water-insoluble. Water-swellable materials include hydrophilic polymers and gums such as xanthan gum, guar gum, high viscosity grades of HPMC and HPC, alginates, etc. Water-insoluble polymers most commonly used in such systems are ethyl cellulose and polymethacrylates.

3. Dissolution and Diffusion-Controlled DDS

These systems are those where the rate of drug release is controlled by drug or polymer dissolution as well as drug diffusion i.e. the system is a combination of the two systems discussed above.

A summary of various approaches that are employed in the design of rate-programmed DDS is illustrated in figure 14.6.

Fig. 14.6 Approaches in the design of rate-programmed DDS

i. Reservoir systems (membrane-controlled DDS) (see also Modern Pharmaceutics for advantages and disadv) These systems are those where the drug is present as a core in a compartment of specific shape encased or encapsulated with a rate-controlling wall, film or membrane having a well-defined thickness. The drug in the core must dissociate themselves from the crystal lattice and dissolve in the surrounding medium, partition and diffuse through the membrane.

Depending upon the physical properties of the membrane, two types of reservoir systems are possible –

(a) Non-swelling reservoir systems are those where the polymer membrane do not swell or hydrate in aqueous medium. Ethyl cellulose and polymethacrylates are commonly used polymers in such systems. Such materials control drug release owing to their thickness, insolubility or slow dissolution or porosity. Reservoir system of this type is most common and includes coated drug particles, crystals, granules, pellets, minitablets and tablets.

(b) Swelling-controlled reservoir systems are those where the polymer membrane swell or hydrate on contact with aqueous medium. In such systems drug release is delayed for the time period required for hydration of barrier and after attainment of barrier hydration, drug release proceeds at a constant rate. HPMC polymers are commonly employed in such systems.

ii. Matrix systems (monolithic DDS) (see also Modern Pharmaceutics for advantages and disadv) These systems are those where the drug is uniformly dissolved or dispersed in release-retarding material. Such devices can be formulated as conventional matrix, or bi-or tri-layered matrix systems.

Depending upon the physical properties of the membrane, two types of matrix devices are possible –

(a) Hydrophilic matrix is the one where the release retarding material is a water swellable or swellable cum erodible hydrocolloid such as high molecular weight HPMCs, HPC, HEC, xanthan gum, sodium alginate, guar gum, locust bean gum, PEO (polyethylene oxide) and cross linked polymers of acrylic acid. Hydrophilic matrices are porous systems.

Depending upon the swelling behaviour of hydrophilic polymer, two types of matrices are possible –

·            Free-swelling matrix is the one in which swelling is unhindered.

·            Restricted-swelling matrix is the one in which the surface of the device is partially coated with an impermeable polymer film that restricts the hydration of swellable matrix material.

(b) Hydrophobic matrix is the one where the release retarding material is either

·            Slowly soluble, erodible or digestible, for e.g. waxes such as glyceryl monostearate, cetyl alcohol, hydrogenated vegetable oils, beeswax, carnauba wax, etc.

·            Insoluble or non-digestible, for e.g. ethyl cellulose, polymethacrylates, etc.

Depending upon the manner of incorporation of drug in the matrix, hydrophobic matrices can be further classified as –

a. Porous (heterogeneous) matrix is the one where the drug and release-retarding matrix microparticles are simply mixed with each other and compressed into a tablet or the drug is dispersed in the polymer solution followed by evaporation of the solvent.

b. Nonporous (homogeneous) matrix – is the one in which the release-retarding matrix material is first melted and the drug is then incorporated in it by thorough mixing followed by congealing the mass while stirring. Two types of nonporous matrix systems are possible –

·           Dissolved drug nonporous system is the one where the drug is dissolved in the molten release-retarding matrix material.

·           Dispersed drug nonporous system is the one where the quantity of drug is greater than its solubility in molten matrix polymer.

iii. Hybrid systems (membrane cum matrix DDS) (see also Modern Pharmaceutics for advantages and disadv) These systems are those where the drug in matrix of release-retarding material is further coated with a release-controlling polymer membrane. Such a device thus combines the constant release kinetics of reservoir system with the mechanical robustness of matrix system.

2. Activation-Controlled DDS

In this group of CRDDSs, the release of drug molecules from the delivery systems is activated by some physical, chemical, or biochemical processes and/or facilitated by an energy supplied externally (Fig. 2 Chien article). The rate of drug release is then controlled by regulating the process applied or energy input. Based on the nature of the process applied or the type of energy used, these activation-controlled DDSs can be classified into following categories:


A. Activation by Physical Processes

1. Osmotic pressure-activated DDS

2. Hydrodynamic pressure-activated DDS

3. Vapour pressure-activated DDS

4. Mechanical force-activated DDS

5. Magnetically-activated DDS

6. Sonophoresis-activated DDS

7. Iontophoresis-activated DDS

B. Activation by Chemical Processes

1. pH-activated DDS

2. Ion-activated DDS

3. Hydrolysis-activated DDS

C. Activation by Biochemical Processes

1. Enzyme-activated DDS


A. Physical Process-Activated DDS

1. Osmotic Pressure-Activated DDS

Osmotic systems release drug at a predetermined, typically zero-order rate, based on the principle of osmosis. Osmosis is natural movement of a solvent through a semipermeable membrane into a solution of higher solute concentration, leading to equal concentration of the solute on either sides of the membrane. Osmotic systems imbibe water from the body through a semipermeable membrane into an osmotic material which dissolves in it and increase in volume and generate osmotic pressure that results in slow and even delivery of drug through an orifice.

A semipermeable membrane (e.g. cellulose acetate) is the one that is permeable to a solvent (e.g. water) but impermeable to ionic (e.g. sodium chloride) and high molecular weight compounds.

In comparison to DDS based on diffusion and erosion, osmotic systems are more complex in design but provide better zero-order drug delivery.

2. Hydration/Hydrodynamic Pressure-Activated DDS

These systems are identical to osmotic systems that release drug at a zero-order rate. It however differs from osmotic system in that hydrodynamic pressure generating agent which is typically a water swellable hydrocolloid such as HPMC is contained in one compartment and the drug solution/dispersion in another collapsible reservoir. Both these compartments are housed in a rigid, shape retaining but water permeable housing. The hydrocolloid imbibes water and swells to generate hydrodynamic pressure that pushes the drug reservoir compartment and thus force the drug through an orifice at a slow and uniform rate.

3. Vapour Pressure-Activated DDS

These systems are identical to hydrodynamic systems in that the pumping compartment and the drug solution/dispersion compartment are separated by a freely movable partition and the whole system is enclosed in a rigid housing. The pumping compartment contains a liquefied compressed gas that vaporises at body temperature and creates vapour pressure that moves the partition to force the drug out of the device through a series of flow regulator and delivery cannula into the blood circulation at a constant rate. A typical example is the development infusion pump of heparin in anticoagulant therapy, of insulin in the control of diabetes and of morphine for patients suffering from the intensive pain of a terminal cancer.

4. Mechanical Force-Activated DDS

In these systems the drug reservoir is a solution in a container equipped with a mechanically activated pumping system. A metered dose of drug formulation can be reproducibly delivered into a body cavity, such as the nose, through the spray head upon manual activation of the drug-delivery pumping system. The volume of solution delivered is fixed and is independent of the force and duration of activation. A typical example of this type of drug-delivery system is the development of a metered-dose nebuliser for the intranasal administration of a precision dose of luteinizing hormone-releasing hormone (LHRH) and its synthetic analogues, such as buserelin.

5. Magnetically-Activated DDS

In these systems a tiny doughnut-shaped magnet is positioned in the centre of a hemispherical shaped drug-dispersing biocompatible polymer matrix and then coating the external surface of the medicated polymer matrix, with the exception of one cavity at the centre of the flat surface of the hemisphere, with a pure polymer, for instance, ethylene– vinyl acetate copolymer or silicone elastomers. This uncoated cavity is designed for allowing a peptide drug to release. When the magnet is activated, to vibrate by an external electromagnetic field, it releases the drug at a zero-order rate by diffusion process. (fig in Chien)

6. Sonophoresis-Activated DDS

This type of activation-controlled drug delivery system utilizes ultrasonic energy to activate or trigger the delivery of drugs from a polymeric drug delivery device. The system can be fabricated from either a non-degradable polymer, such as ethylene–vinyl acetate copolymer, or a bioerodible polymer, such as poly(lactide–glycolide) copolymer.

7. Iontophoresis-Activated DDS

This type of CRDDS uses electrical current to activate and modulate the diffusion of a charged drug molecule across a biological membrane, such as the skin, in a manner similar to passive diffusion under a concentration gradient but at a much faster rate. It is a painless procedure. Since like charges repel each other, application of a positive current drives positively charged drug molecules away from the electrode and into the tissues; and vice versa. (see fig. In book rev, what is iontophoresis, absorption of drug folder)

A typical example of this type of activation-controlled system is percutaneous penetration of anti-inflammatory drugs such as dexamethasone to surface tissues.


B. Chemical Process-Activated DDS

1. pH-Activated DDS

These systems are designed for acid-labile drugs or drugs irritating to gastric mucosa and target their delivery to the intestinal tract. It is fabricated by coating a core tablet of such a drug with a combination of intestinal fluid-insoluble polymer, like ethyl cellulose, and intestinal fluid-soluble polymer, like HPMCP. In the stomach, the coating membrane resists dissolution in pH 1-3. After gastric emptying, the system travels to the small intestine, and the intestinal fluid-soluble component in the coating membrane is dissolved in at pH above 5 thereby producing a microporous membrane that controls the release of drug from the core tablet. An example of such a system is oral controlled delivery of potassium chloride, which is highly irritating to gastric epithelium. (fig. Chien)

2. Ion-Activated DDS

Based on the principle that the GIT has a relatively constant level of ions, this type of system has been developed for controlling the delivery of an ionic or an ionisable drug at a constant rate. Such a CRDDS is prepared by first complexing an ionisable drug with an ion-exchange resin. A cationic drug is complexed with a resin containing SO3 group or an anionic drug with a resin containing N(CH3)3+ group. The granules of the drug–resin complex are further treated with an impregnating agent, like polyethylene glycol 4000, for reducing the rate of swelling upon contact with an aqueous medium. They are then coated by an air-suspension coating technique with a water-insoluble but water-permeable polymeric membrane, such as ethyl cellulose. This membrane serves as a rate-controlling barrier to modulate the release of drug from the CRDDS. In the GI tract, hydronium and chloride ions diffuse into the CRDDS and interact with the drug–resin complex to trigger the dissociation and release of ionic drug

Acidic drug release

Basic drug release

An example of such a formulation is liquid-oral with sustained release of a combination of hydrocodone and chlorpheniramine. (Fig. Chien).

3. Hydrolysis-Activated DDS

This type of CRDDS depends on the hydrolysis process to activate the release of drug molecules. In this system, the drug reservoir is either encapsulated in microcapsules or homogeneously dispersed in microspheres or nanoparticles prepared from bioerodible or biodegradable polymers such as polylactide, poly(lactide–glycolide) copolymer, poly(orthoester) or poly(anhydride). The release of a drug from the polymer matrix is activated by the hydrolysis-induced degradation of polymer chains, and the rate of drug delivery is controlled by polymer degradation rate. A typical example is injectable microspheres for the subcutaneous controlled delivery of luprolide, a potent biosynthetic analogue of gonadotropin-releasing hormone (GnRH) for the treatment of gonadotropin-dependent cancers, such as prostate carcinoma in men and endometriosis in the females, for up to 4 months. (Fig. Chien).


C. Biochemical Process-Activated DDS

1. Enzyme-Activated DDS

In this type of CRDDS, the drug reservoir is either physically entrapped in microspheres or chemically bound to polymer chains fabricated from biopolymers, such as albumins or polypeptides. The release of drugs is made possible by the enzymatic hydrolysis of biopolymers by a specific enzyme in the target tissue. A typical example is the development of albumin microspheres, which release 5-fluorouracil, in a controlled manner, by protease-activated biodegradation.


3. Feedback-Controlled DDS

In this group of CRDDSs, the release of drug molecules is activated by a triggering agent, such as a biochemical substance, in the body via some feedback mechanisms. The rate of drug release is regulated by the concentration of a triggering agent detected by a sensor built into the CRDDS. (fig chien)

1. Bioerosion-Activated DDS

This CRDDS consists of drug dispersed in a bioerodible matrix made of poly(vinyl methyl ether) half-ester, which is coated with a layer of immobilized urease. In a solution at neutral pH, the polymer erodes slowly. In the presence of urea, urease at the surface of the drug delivery system metabolizes urea to form ammonia. This causes the pH to increase which activates a rapid degradation of polymer matrix and subsequently release of drug molecules.

2. Bioresponsive DDS

In this CRDDS, the drug reservoir is contained in a device enclosed by a bioresponsive polymeric membrane whose permeability to drug molecules is controlled by the concentration of a biochemical agent in the tissue where the CRDDS is located. A typical example of this is the development of a glucose-triggered insulin delivery system, in which the insulin reservoir is encapsulated within a hydrogel membrane containing pendant NR2 groups. In an alkaline solution, the NR2 groups exist at neutral state and the membrane is not swollen and thus impermeable to insulin. As glucose penetrates into the membrane, it is oxidized enzymatically by the glucose oxidase entrapped in the membrane to form gluconic acid. This process triggers the protonation of NR2 groups to form NR2H+, and the hydrogel membrane becomes swollen and permeable to insulin molecules. The amount of insulin delivered is bioresponsive to the concentration of glucose penetrating into the CRDDS. (fig chien)

3. Self-Regulating DDS

This type of feedback-controlled DDS depends on a reversible and competitive binding mechanism to activate and to regulate the release of drug. The drug reservoir is a drug complex encapsulated within a semipermeable polymeric membrane. The release of drug from the CRDDS is activated by the membrane permeation of a biochemical agent from the tissue where the CRDDS is located. An example of this is development of self-regulating insulin delivery system that utilizes complex of glycosylated insulin– concanavalin A, which is encapsulated inside a polymer membrane. As glucose penetrates into the system, it activates the release of glycosylated insulin from the complex for a controlled release from the system. The amount of insulin released is thus self-regulated by the concentration of glucose that has penetrated into the insulin delivery system.

4. Site-Targeted DDS

Most conventional dosage forms deliver drug into the body that eventually reaches the site of action by multiple steps of diffusion and partitioning. In addition to the target site, the drug also distributes to non-target tissues that may result in toxicity or adverse reactions. Selective and targeted drug therapy could result in not just optimum and more effective therapy but also a significant reduction in drug dose and cost.

Targeted- or site-specific DDS refer to systems that place the drug at or near the receptor site or site of action.

Site-targeted DDS can be classified into three broad categories –

1. First-order targeting refers to DDS that delivers the drug to the capillary bed or the active site

2. Second-order targeting refers to DDS that delivers the drug to a special cell type such as the tumour cells and not to the normal cells

3. Third-order targeting refers to DDS that delivers the drug intracellularly.

Site-targeted DDSs have also been characterized as –

Passive targeting refers to natural or passive disposition of a drug carrier based on the physicochemical characteristics of the system in relation to the body.

Active targeting refers to alterations of the natural disposition of the drug carrier, directing it to specific cells, tissues or organs; for e.g. use of ligands or monoclonal antibodies which can target specific sites.

Drug targeting often requires carriers for selective delivery and can serve following purposes –

·           Protect the drug from degradation after administration;

·           Improve transport or delivery of drug to cells;

·           Decrease clearance of drug; or

·           Combination of the above.

Carriers for drug targeting are of two types –

·           Carriers covalently bonded to drug where the drug release is required for pharmacological activity.

·           Carriers not covalently bonded to drug where simple uncoating of the drug is required for pharmacological activity; e.g. liposomes. The various carriers used for drug targeting are –

a. Polymeric carriers

b. Albumin

c. Lipoproteins

d. Liposomes.

1. Polymeric Carrier Systems for Drug Targeting

The basic components of a polymeric targeted DDS are –

1. A polymeric backbone which is non-immunogenic and biodegradable that contains following three attachments;

2. A homing device, also called as site-specific targeting moiety, which is capable of leading the drug delivery system to the vicinity of a target tissue (or cell);

3. A solubiliser, which enables the drug delivery system to be transported to and preferentially taken up by the target tissue; and

4. A drug, which is covalently bonded to the polymeric backbone, through a spacer, and contains a linkage that is cleavable only by a specific enzyme(s) at the target tissue (fig. 14. 7).

Fig. 14.7. Polymeric carrier system for drug targeting

Polymers used for drug targeting include polyethylenediamine, polylysine, chitosan, dextran and PEG for macromolecular drugs such as gene therapy. The homing device is a monoclonal antibody, a recognised sugar moiety or a small cell-specific ligand. At present, most site-specific DDS are limited to parenteral administration and primarily utilise soluble polymers.

Besides their use as regular carriers, polymers may also be formulated as microparticles or nanoparticles, wherein the drug is encapsulated in a biodegradable colloidal polymer. The small size of nanospheres allows good tissue penetration while providing protection or sustained release.

The disposition of micro- or nano-sphere depends upon their size –

·           Particles > 12 μ are lodged in the capillary bed at the site of injection

·           Particles from 2 – 12 μ are retained in lung, liver or spleen

·           Particles < 0.5 μ (500 nm) deposit in spleen and bone marrow.

2. Albumin as Carrier for Drug Targeting

Although distribution of albumin is not site-specific, it has been conjugated with drugs such as methotrexate to increase duration of drug action and deliver drug to liver.

3. Lipoproteins as Carrier for Drug Targeting

Low-density lipoproteins enter cell by endocytosis and thus have the potential for transporting drugs into the cell in which lipoprotein-drug complex can be hydrolysed by lysosomal enzymes.

4. Liposomes as Carrier for Drug Targeting

Liposomes in the size range 0.5 – 100 have been used to reduce side effects and efficacy of drugs such as doxorubicin, amphotericin B, etc. The site-specificity to liposomes can be conferred by the type of lipid or by inclusion of a targeting agent such as monoclonal antibody into the liposomal bilayer.

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