INTRODUCTION:

Controlled drug delivery systems can involve maintaining drug levels within a specified range, reducing the number of required administrations, maximizing the efficacy of the drug in question, and enhancing patient adherence. Although these benefits can be considerable, the possible drawbacks must not be overlooked.¹

These include the potential toxicity or non-biocompatibility of the materials used, unwanted by-products of degradation, any surgery necessary to implant or remove the system, the risk of patient discomfort from the delivery device, and the greater expense of controlled-release systems in comparison to traditional pharmaceuticals. The perfect drug delivery system ought to be inert and biocompatible, possess mechanical strength, ensure patient comfort, achieve a high drug loading capacity, prevent accidental release, and allow for straightforward administration and removal as well as easy fabrication and sterilization. Many of the initial controlled-release systems aimed to create a delivery profile that would maintain elevated blood levels of the drug for an extended duration. In traditional drug delivery systems, the drug concentration in the blood increases after each drug administration and subsequently decreases until the next dose. With conventional drug administration, the crucial factor is that the concentration of the substance in the bloodstream must be kept within two limits: an upper limit, which may indicate toxicity, and a lower limit, below which the drug ceases to work.²

Advantages and Limitations of Control Release Dosage Forms:

Clinical Advantages^2,6

· Less frequent drug administration

· Enhanced patient adherence

· Diminished variability of drug levels in blood

· Decrease in (local/systemic) medical toxicity

· Drug condition stabilization (due to more consistent drug levels)

· Enhanced bioavailability of certain medications due to spatial control

· Cost-effective for both healthcare providers and patients

Commercial/Industrial Advantages:

· Demonstration of innovative/technological leadership

· Extension of product life cycle

· Differentiation of product

· Market growth

· Extension of patent

Potential Limitations:

· Drug action may take longer to begin

· If the formulation strategy is inadequate, there is a chance of dose dumping

· Higher likelihood of first-pass metabolism

· GI residence time of dosage form has greater influence

· In certain situations, dose adjustments may be less precise

· Compared with traditional doses, the cost per unit dose is greater

· Not every drug can be effectively formulated as an ER dosage form

The choice of drug to be formulated into an extended-release dosage form is the crucial step. The following candidates are typically unsuitable for ER dosage forms

Characteristics That May Make A Drug Unsuitable for Control release Dosage Form

· Short elimination half-life

· Narrow therapeutic index

· Active absorption

· Extensive first pass effect

· Long elimination half-life

· Poor absorption

· Low or slow absorption

Mechanism of Controlled Drug Release Systems^7,8

1.Diffusion Controlled System^9,10

The diffusion process essentially illustrates the movement of drug molecules from an area of higher concentration to one of lower concentration. Fick’s law states that the flux of drug J (in amount/area–time) across a membrane is directed toward the area of lower concentration.

J= - D dc/dx

Where,

D = Diffusion coefficient in area/ time

dc/dx = change of concentration 'c' with distance 'x'

(a) Reservoir Type^11,12

In the system, a water insoluble polymeric material encloses a core of drug, which controls release rate. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media. The polymers commonly used in such devices are Ethyl cellulose and Poly-vinyl acetate.

Fig 1: Schematic Representation of Reservoir Diffusion Controlled Drug Delivery Device

The rate of drug released (dm/dt) can be calculated using the following equation

dm ∆C

-------- = ADK -------

dt ℓ

Where, A = Area,

D = Diffusion coefficient, ℓ = Diffusion pathlength

K = Partition coefficient of the drug between the drug core and the membrane,

∆C= Concentration difference across the membrane.

Advantage:

This system allows for zero order delivery and release rates that vary based on the type of polymer.

Disadvantage:

The system has to be taken out physically from the implant sites. High molecular weight compounds are challenging to deliver, typically leading to higher costs per dosage unit and potential toxicity in the event of system failure.

(b) Matrix Type^{13, 14}:

A solid drug is evenly distributed within an insoluble matrix, and the drug's release rate relies on the diffusion rate rather than the dissolution rate of the solid.

Fig 2: Schematic Representation of Monolithic (matrix) Diffusion Controlled Drug Delivery

Advantage:

Can deliver high molecular weight compounds and is easier to produce than reservoir or encapsulated devices.

Disadvantage:

Zero order release cannot be provided; it is necessary to remove the remaining matrix for the implanted system.

2. Dissolution Controlled Systems^15,16

Drugs with high aqueous solubility and dissolution rate pose challenges for controlling their dissolution rate. A slower dissolution rate of a drug in the GI medium can achieve dissolution-controlled release by incorporating the drug within an insoluble polymer and coating drug particles or granules with polymeric materials of different thicknesses. The step that limits the rate of drug dissolution is the diffusion across the aqueous boundary layer. The drug's solubility is the source of energy for its release, which is opposed by the stagnant-fluid diffusional boundary layer. The dissolution rate (dm/dt) can be approximated by

dm/dt=ADS/h

Where, S = Aqueous solubility of the drug, A = Surface area of the dissolving particle or tablet,

D = Diffusivity of the drug, and h = Thickness of the boundary layer.

(a) Encapsulation Dissolution Systems¹⁷:

The drug particles are enveloped or coated using microencapsulation methods with materials that dissolve slowly, such as cellulose, polyethyleneglycols, polymethacrylates, waxes, and others. The rate at which the coat dissolves is determined by the coating's solubility and thickness. The initial dose will be provided by those that have the thinnest layers. Drug levels will be maintained at later times using those with a thicker coating.

Fig 3: Encapsulation Dissolution Controlled Systems

(b) Matrix Dissolution Controlled Systems¹⁸:

In matrix systems, the drug is uniformly distributed within a medium that controls the rate. They use waxes like beeswax, carnauba wax, and hydrogenated castor oil to manage drug dissolution by regulating the rate at which the dissolution fluid penetrates the matrix. This is achieved by modifying the tablet's porosity, reducing its wettability, or dissolving at a slower pace. From such matrices, the drug release is often characterized as first order. The drug embedded in wax is usually made by dispersing the drug in liquid wax, then solidifying and granulating it.

3. Dissolution and Diffusion Controlled Release Systems^19-21:

A membrane that has partial solubility surrounds the core of the drug. Pores are formed as a result of the dissolution of membrane components, allowing an aqueous medium to enter the core and facilitating drug dissolution and the diffusion of the dissolved drug from the system. A way to achieve such a coating is by using a blend of ethyl cellulose with polyvinyl pyrrolidone or methylcellulose.

Fig 4: Dissolution and Diffusion Controlled Release System

4. Water Penetration Controlled Systems²²

In controlled delivery systems that manage water penetration, the rate is regulated by how water enters the system. They exist

(a) Swelling Controlled Systems:²³

Controlled release systems that swell are initially dry; upon being placed in the body, they absorb water or other bodily fluids and expand. The swelling increases the content of aqueous solvent in the formulation and the size of the polymer mesh, allowing the drug to diffuse through the swollen network into the external environment.

(b) Osmotically Controlled Release Systems:^24,25

These systems are created by enclosing an osmotic drug core that holds an osmotically active drug (or a mix of an osmotically inactive drug and an osmotically active salt such as NaCl) within a semi-permeable membrane crafted from a biocompatible polymer, such as cellulose acetate. They create a gradient of osmotic pressure, which continuously pumps drug solutes out of the tablet through a small delivery orifice in the tablet coating over an extended period. This kind of drug system provides continuous dispensing of drug solutes at a zero order rate. The release of the drug does not depend on the system's environment.

Fig 5: Osmotically Controlled Release System

5. Methods using lon Exchange^26-28:

This system aims to ensure the controlled release of a drug that is ionic or can become ionic. The preparation involves several steps: first, an ionized drug (e.g., codeine base) is absorbed onto ion-exchange resin granules like Amberlite. After filtration from the alcoholic medium, the drug-resin complex granules are coated with a water-permeable polymer, such as a modified copolymer of polyacrylic and methacrylic ester. Finally, the coated granules are spray-dried to produce the polymer-coated drug resin preparation. The drug is liberated through ion exchange with appropriately charged ions in the GIT. The drug then diffuses out of the resin.

Resin+ - drug- + X- resin+ - X- + drug-

Where

X- are ions in the GI tract

The rate of diffusion is controlled by the diffusion area, length of the diffusion path, and rigidity of the resin. As a result, the drug's release is affected by ionic conditions (like pH and electrolyte concentration) and the properties of the resin.

Advantage:

For those substances that are particularly vulnerable to breakdown through enzymatic processes, as it provides a safeguard by temporarily modifying the substrate.

Limitation:

The rate of release is directly related to the concentration of ions located near the site of administration. The release rate of the drug is influenced by dietary variation, water consumption, and intestinal contents.

There are primarily two varieties: cation exchange and anion exchange resin.

· Cationic Drugs:

An anionic ion exchange resin, such as one having a SO3-group, combines with a cationic medication to generate a complex. The hydronium ion (H+) in the gastrointestinal fluid enters the GI tract and causes the drug resin complex to release a cationic medication.

H+ + Resin – SO₃ - Drug + H+ --à Drug+ Resin – SO₃ –

· Anionic Drugs:

A cationic ion exchange resin, such as one containing a [N (CH₃)₃+] group, and an anionic medicament combine to produce a complex. An anionic drug is released from the drug resin complex in the GI tract when the chloride ion (Cl-) in the gastrointestinal fluid enters the system.

Cl^- + Resin – [N (CH₃)₃ ⁺] – Drug àResin –[N (CH₃)₃ ⁺] - Cl^- + Drug^-

6. Resin Chemically Controlled Release Systems²⁹

Systems with chemically controlled release alter their chemical makeup in response to biological fluid exposure. Biodegradable polymers are primarily made to break down into increasingly smaller, physiologically safe moieties through hydrolysis of the polymer chains. Erodible systems and pendent chain systems are its two categories.

Erodible Systems:

The process by which drugs are released in erodible systems is erosion.

There are two forms of erosion, and they are

Bulk Erosion Degradation of process polymers can happen by bulk hydrolysis.

· Hydrolysis takes place when the polymer is exposed to water.

· Large polymers are broken down by hydrolysis into smaller, biocompatible molecules.

· e.g., poly lactide, polyglycolic acid

Surface Erosion procedure The release rate of polymers, such as polyorthoesters and polyanhydrides, is proportional to the surface area of the delivery system because degradation only takes place at the polymer's surface.

· Hydrolysis takes place when the polymer is exposed to water.

· Large polymers are broken down by hydrolysis into smaller, biocompatible molecules.

· e.g polyanhydrides

Fig 6: Bulk Erosion and Surface Erosion

Pendent Chain System:

The medication is affixed to the backbone chains of linear homo or copolymers that make up dependent chain systems. By hydrolyzing or enzymatically breaking down the bonds, the medication is liberated from the polymer. The drug's cleavage is the rate-controlling mechanism, and zero order can be achieved. As an illustration, consider the polymers n-(2- hydroxy propyl) methacrylamide and others that are employed in pendent chain systems.

7. pH– Independent Formulations:^30,31

The gastrointestinal tract has some unique characteristics for the oral route of drug administration, including a relatively short transit time that limits the length of prolongation and a chemical environment that limits the design of dosage forms along the entire length of the gastrointestinal tract. The release from sustained release formulations depends on pH because the majority of medications are weak acids or weak bases.
To help maintain a consistent pH and enable pH-independent drug release, buffers such citric acid, phthalic acid, phosphoric acid, tartaric acid, or salts of amino acids can be added to the formulation. A basic or acidic medication is combined with one or more buffering agents to create a buffered controlled release formulation. Then, the drug is granulated with the proper pharmaceutical excipients, gastrointestinal fluid, and permeable film-forming polymer.

8. Hydrogels:^32,33

Hydrogels are three-dimensional formations that swell with water and are mostly made of hydrophilic polymers. Physical or chemical cross-links make them insoluble. Crystallites, entanglements, or weak relationships like hydrogen bonds or van der Waals forces are examples of physical cross-links. The network's structure and physical integrity are provided by these cross-links. Hydrogels offer desired protection for proteins, peptides, and labile medications.

9. Altered Density Formulations^34,35

Numerous strategies, such as the high density and low-density techniques, have been developed to extend the drug delivery system's residence time in the gastrointestinal tract.

Biopharmaceutic and Pharmacokinetic Aspects in The Design of Controlled Release Per Oral Drug Delivery Systems:

Systems for controlled release medication delivery ³⁶ are dosage forms that release the medication at a predefined rate based on the pharmacokinetic properties of the drug and a desired therapeutic concentration.

Biological half-life (t ½):

The difference between the maximum steady state concentration and the maximum steady state concentration after repeated dosage will be greater for drugs with shorter t ½. Therefore, it is necessary to administer the medication product more regularly.

Minimum effective concentration (MEC):

If a minimum effective concentration (MEC) is needed, either a controlled release preparation or frequent dosage of a traditional medication product may be selected.

Dose size and Extent of duration:

The delivery mechanism must have a bigger cumulative dose per unit the longer the period. As a result, the quantity of medication that can be realistically added to such a system is limited.

Relatively long t1/2 or fluctuation desired at steady state:

Some people think that for medications with a half-life of 12 hours or longer, neither an SR nor a CRDDS are necessary or helpful. This is untrue because a 12 or 24 CRDDS appears to be recommended in two situations:

1. Every two to three days, a medication with a t ½ between 12 and 72 hours may be created for a CRDDS allowing application. The drug's t ½ will determine how the blood level time curve declines after the drug is released from the system. Naturally, there may be a significant variation between Css max and Css min; in other words, this adds a delayed release to the slow elimination process.

2. states because the therapeutic spectrum is limited or to provide a specific therapeutic effect.

Desired Biopharmaceutic Characteristics of Drug to Qualify For Crdds:

Molecular weight or size:

Convective transport is one way that small molecules can move across a membrane's pores. This holds true for both medication transport over a biologic membrane and drug release from the dosage form. The limit for biological membranes could be 150 molecular weights for spherical molecules and 400 molecular weights for chain-like substances.

Solubility:

The drug must be present at the absorption site in the form of a solution for all absorption mechanisms to work. The solubility of the medicine at different pH values must be ascertained during the preformulation investigation. In an acidic solution, a solubility of less than 0.1μg/ml may indicate fluctuating and decreased bioavailability. Absorption and availability are probably going to become dissolution limited if the solubility is less than 0.01μg/ml. Therefore, the driving force behind diffusion could not be sufficient.

If at least 0.1 to 1% of the medication is in non-ionized form, it appears that medications are well absorbed by passive diffusion from the small intestine when taken orally.

Apparent partition coefficient (APC):

Drugs that are absorbed passively need to have a minimum APC. For many medicines, the flow across a membrane increases with increasing APC in an n-octanol/buffer environment. It is necessary to calculate the APC for the whole pH range in the GI tract. Additionally, the medicine must be partitioned between the biological fluid and CRDDS using the APC.

General absorption mechanism:

A drug must be absorbed by diffusion across the whole GI tract in order to qualify as a variable candidate for oral CRDDS. The two pathways of absorption—partitioning into the lipid membrane (across the cells) or moving through water-filled channels (between the cells)—are referred to as diffusion in this context.
It's also critical that absorption happens from every GI tract segment, which may be influenced by the drug's pKa, the segment's pH, the drug's mucus binding, blood flow rate, etc. The GI lumen's hydrodynamics appear to have a significant influence on the absorption process.

Although extremely effective drug delivery systems can be achieved with first order and square root of time release, zero order release profile is generally accepted as the ideal.

Pharmacokinetic Parameters:

Elimination half life (t ½):

CRDDS is best suited for medications with a t ½ of 8 hours. The dose amount needed to be included in a dosage form with a 12- or 24hour duration may be too large if the t½ is less than an hour. A CRDDS is typically not required if the t½ is particularly long, unless its sole purpose is to lessen the variability of steady state blood levels.

Total clearance (CL):

CL is a metric that quantifies the amount of drug distribution cleared in a certain amount of time. It is the crucial factor in determining the steady state concentration and the necessary dose rate for CRDDS.

Terminal disposition rate constant (Ke or λz):

The t½ can be used to determine the terminal disposition rate constant, also known as the elimination rate constant, which is necessary to forecast a blood level time profile.

Apparent volume of distribution (Vz):

The Vz is the approximate volume that a drug would take up if it were dissolved at the same concentration as blood. It is the proportionality constant between the drug's measured concentration in the blood and its quantity in the body.

Absolute bioavailability (F):

The proportion of the medicine that enters the systemic circulation after extravascular injection is known as the absolute bioavailability. A drug's F value should be near 100% in order for it to be approved for CRDDS.

Intrinsic absorption rate constant (Ka):

The drug administered orally in the form of a solution should have a high intrinsic absorption rate constant, typically an order of magnitude higher than the drug's desired release rate constant from the dosage form, to ensure that the release process is the rate-controlling step.

Therapeutic concentration (Css):

The target or desired steady state minimal concentrations (Css min), the mean steady state concentration (Css avg), and the desired or target steady state peak concentrations (Css max) are the therapeutic concentrations. The fluctuation is the difference between CSS max and CSS min. The more precisely the dose form performs, the lower the intended fluctuation must be.

The longer t ½, the higher F, the smaller Vz, the lower Css, and the less medication that must be added to a CRDDS.

Modelling And Comparison of Dissolution Profile:

The drug release characteristics of immediate release and modified release dosage forms were described by a number of theories and kinetic models 10, 11, 12, and 13. These were based on dissolution data and quantitative interpretation of values obtained in dissolution assay, if made possible by the use of the generic equation dosage form, which mathematically translates the dissolution curve in function of certain parameters related to pharmaceutical dosage form. The mechanism of drug release of extended release was studied in the current work using a few analytical models, which include the following models:

1. Zero order

The following formula can be used to depict medication dissolution from pharmaceutical dosage forms that don't disintegrate and release the drug gradually.

Q_t= Q₀ +K₀ t

Where, Qt =amount of drug released in time t,

Q0= initial amount of drug in solution, K0 =zero order release constant

Application:

The drug dissolution of various modified release dosage forms, such as transdermal systems, matrix tablets with limited drug solubility, coated forms, osmotic systems, etc., can be described by this connection. This profile of pharmaceutical dosage forms releases the same quantity of drug per unit of time, making it the best way to release drugs for a pharmacologically extended action.

2. First order model:

Gibaldi and Feldman (1967) were the first to propose applying this concept to medicine dissolution research, and Wagner (1969) followed suit. The decimal logarithm between the quantity left and the time will be linear in this scenario. It uses the following equation to express first-order release.

log Qt=logQe+(Ki.t/2.303)

where,

Qt = amount of drug released in time t,

Qe = initial amount f drug in solution, Ki = first order release constant

3. Higuchi model:

The release of water-soluble and low-soluble drugs incorporated in solid matrices was studied by Higuchi in 1961 and 1963. He developed a number of theoretical models to describe the drug release characteristics as a diffusion process based on Fick's law related with square root of time dependent, and he obtained mathematical expressions for drug particles dispersed in a uniform matrix acting as diffusion media.

Qt=KH√t

Where

Qt = amount of drug released in time t, KH=Higuchi Constant,

√t =dependent square root of time

Application:

The drug dissolution of various modified release dosage forms, such as transdermal systems and matrix tablets with poor drug solubility, can be explained by the Higuchi model.

4. Korsmayer’s and Peppa’s model:

In 1983, Korsmayer and Peppa created a straightforward empirical model that used "n" numbers to describe a number of release mechanisms by exponentially linking the drug release to the amount of time that had passed. In certain experimental scenarios, the release mechanism exhibits aberrant behavior that deviates from Fick's equations; in these situations, it should be represented by the following equation.

Log(m_t/m_f) =logK+n.logt

Where,

mt=amount of drug released at time t, mf=amount of drug released at infinite time t

K=release rate constant, n= diffusion expression (drug release mechanism)

Application:

When the release mechanism is unclear or there may be multiple types of release mechanisms at play, this model is typically employed to assess the release of pharmaceutical polymeric dosage forms.

5. Hixson-Crowell model:

Hixson-Crowell (1931) developed an equation that can be explained as follows after realizing that a particle's regular area is proportional to the cubic root of its volume:

W₀^1/3_W_t^1/3K_st

Where

W0 is the initial amount of drug in the pharmaceutical dosage form

Wt is the remaining amount of drug pharmaceutical dosage form at time t

Ks is the constant incorporating the surface volume relation.

CONCLUSION:

Modern technologies, such as the target idea, have surfaced in recent years for effective oral controlled delivery. Oral controlled release products offer benefits over traditional dosage forms by optimizing the drug's biopharmaceutics, pharmacokinetics, and pharmacodynamics properties to minimize the frequency of dosing until a single daily dose is adequate for therapeutic management through uniform plasma concentration, maximizing the drug's usefulness. Based on the information above, it can be inferred that the oral controlled release drug delivery system is the most widely used and practical drug administration method.

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Received on 26.02.2025 Revised on 21.03.2025

Accepted on 04.04.2025 Published on 23.04.2025

Available online from April 26, 2025

Asian J. Pharm. Tech. 2025; 15(2):197-204.

DOI: 10.52711/2231-5713.2025.00031

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