INTRODUCTION:

Oral medication administration is the most common method, partly because it is the most convenient and partly because gastrointestinal physiology allows for greater design freedom in dose forms than most other routes. When referring to drug delivery systems intended to attain or prolong the therapeutic effect by continually releasing medication over a longer period of time following administration of a single dose, terms such as long-lasting release, extended release, modified release, extended release, or depot formulations are used (Shah SJ, 2015). Over the last thirty years, a multitude of oral delivery systems have been designed to serve as drug reservoir from which the active ingredient may be released at a regulated and predefined rate over a particular amount of time.

Drugs with a short half-life and easy absorption from the gastrointestinal tract (GIT) are more suited for oral controlled release formulations, which help them leave the bloodstream swiftly. Since these will allow the medication to enter the GIT gradually and keep the level of the medication in the plasma steady for a longer amount of time. (Kumar S, 2012).

The 1960s saw the introduction of extended-release medication formulations. With the help of these formulations, the medication is longer-lasting when taken orally. Through the use of a unit dosage form that releases the medicine gradually over a 24-hour period, an extended-release therapy can enhance the therapeutic impact and safety of a medication while also improving patient convenience and compliance. Low- and high concentration side effects are less likely with this formulation. Plasma concentrations should remain constant and the optimal drug delivery method should have a constant order zero releasing rate. (Reddy DV, 2015, Chourasiya J, 2013) For the purpose of developing novel drugs and addressing a number of unmet therapeutic requirements, prolonged-release formulation is a crucial programme. These dosage forms are appealing for a number of reasons, including increased drug bioavailability, decreased frequency of administration to extend the duration of therapeutic blood levels, decreased peak trough concentration fluctuations and adverse effects, and potential improvement of the drug's specific distribution. (Barzeh H, 2016, Khambat SB) A medicine delivered using an extended-release mechanism releases the medication gradually over a longer time or absorbs it over a longer length of time.Therapeutic drugs must be taken at regular intervals as part of conventional pharmacological therapy. The purpose of the formulation of these ingredients is to maximise their bioavailability, stability, and activity. Conventional drug delivery techniques are successful for the majority of medications; nevertheless, certain drugs have limited therapeutic ranges and are unstable or hazardous. ((Reddy DV, 2015) A patient's compliance will increase when fewer doses are required to maintain the therapeutic effect due to the longer duration that systemic drug levels remain within the therapeutic range when administered in expanded & sustained release dosage forms. When it comes to prolonged release applications, the most often utilised water insoluble polymers are the polyvinyl derivative polyvinyl acetate and the ammonium ethacrylate copolymers that cellulose derivatives of ethyl cellulose and cellulose acetate. (Khan GM, 2001).

Some Merits of Extended-Release Drug Delivery System (Shah SJ, 2015).

· To improve stability, shield the drug from gastrointestinal tract degradation processes like hydrolysis.

· The convenience and compliance of patients may be enhanced by extended-release formulations.

· Therapeutic concentrations could be maintained by the prolonged release formulations.

· The amount of administration of a drug dose is decreased by the extended-release formulations.

· Slow down the absorption of the drugs to lessen its toxicity.

· By using these formulations, elevated blood concentrations are prevented.

· Reduce the adverse effects, both systemic and local.

· Chronic dosing to reduce drug accumulation.

· Prolonging the duration of action for drugs with a short half-life.

· Enhancement of special effects capability.

Some Demerits of Extended-Release Drug Delivery System (Reddy DV, 2015).

· Long-release products' bigger size may make them harder to swallow or pass through the stomach.

· The rate of transit through the stomach and the kind of food has an impact on the release rates.

· Since the drug load in an extended-release formulation is larger, the dosage form's release properties may lose some of their integrity.

· Although they have been reduced by contemporary formulations, there are still some variations in the release rate between doses.

· Drug tolerance may develop on occasion by exposing the target tissue to a continuous dose of the medication for a lengthy period of time.

· High preparation cost

Features of the Drug that make it Appropriate for the Extended-Release Table (Priya VS, 2016, Ummadi S, 2013)

The following are the ideal pharmacokinetic and physicochemical properties of drugs that can be made into extended-release tablets:

· When the pH ranges from 1 to 7.8, the solubility in water should be in excess of 0.1 mg/ml.

· The ideal molecular size is less than 1000 Daltons.

· The overall absorbability from the release of all GI segments should be controlled by diffusion rather than by pH or enzymes.

· Drugs shouldn't be metabolized in order to reduce their bioavailability before absorption.

· There should be a high partition coefficient.

· A suitable elimination half-life is two to eight hours.

· The constant of absorption rate (Ka) ought to be greater than the rate of release.

· Dosage shouldn't affect total clearance.

· Drug shouldn't be metabolized before to absorption as this reduces its bioavailability.

· At least 75% should be the absolute bioavailability.

· Therapeutic concentrations (Css) should be minimal and low (Vd), and clearance constants for rates are required for design.

· A high apparent volume of distribution, also known as Vd, is desirable.

Rationale of Extended Drug Delivery System (Wang S, 2020, Ummadi S, 2013).

Increase the time intervals between dosages. This results in a decrease in the overall quantity of dosages needed each day. Reduced drug blood level volatility around the mean. A dose form with controlled release reduces the variation in the drug's concentration by

· Lowering the blood levels (C max) may lessen the negative effects of the dosage and

· If a certain threshold concentration is needed, raising the required minimum concentration in the blood (C min) will boost effectiveness. The "therapeutic occupancy time" refers to the duration of time that the plasma concentration remains within the therapeutic range.

Fig 1.1 A Typical Plasma Concentration Time Profile Showing

Factors Influencing the Extended-Release Drug Delivery System:

I. Physiochemical Properties:

a. Aqueous Solubility:

Drugs with poor aqueous solubility usually present with oral bioavailability issues because of their restricted solubility at the absorption site and reduced gastrointestinal (GI) transit time of undissolved medication, which occurs because the drug must be present in a solution state before absorption. (Shah SJ, 2015)

Therefore, drugs of this kind are not desired. Strongly aqueous-soluble drugs are not recommended for ER usage because the release of the medication from the dose form is too unpredictable. Because it will result in variations in the rate of dissolution, physiological pH dependent solubility, or variations in solubility at various GI pH, is undesirable (aspirin, for example, is less soluble in the stomach but more soluble in the intestine). An oral novel drug delivery system should ideally have a medication with strong water solubility and pH independence. (Bhowmik D, 2018, Chourasiya J,2013)

b. Partitions Coefficient:

The partition coefficient of a medicine has a significant impact on its bioavailability since biological membranes are lipophilic, which means that drugs must filter through them. It is not ideal for an oral ER system for drug delivery to use drugs with lower partition coefficient values than the optimal activity, as these drugs will have very little lipid solubility and will be localized at the first phase of water involving the drug. Because more lipid-soluble drugs will not partition out through the lipid membranes once they are within, drugs with partition coefficient values higher than the optimal activity are unsuitable for oral ER drug delivery systems. (Patel K, 2012, Wang S, 2020)

c. Binding of proteins:

Drugs are partially or completely attached to plasma and/or tissues proteins, and this affects the pharmacological action of the drug. This is different from the overall concentration of the drug. The therapeutic effect of a drug is largely determined by its ability to bind to proteins. This is true irrespective of the dosage form; for example, drugs with extensive binding to the plasma have a longer biological half-life and will release their contents over longer periods of time, negating the need for the development of extended-release drug delivery systems. (Ansari S).

d. Drug Stability:

Drugs should be stable in the GI environment since the majority of ER drug delivery systems are designed to distribute the drugs along the length of the GIT. Therefore, because to an issue with bioavailability, the unstable drugs cannot be produced as an orally ER drug delivery system. (Shah SJ, 2015, wang S. 2020).

e. Mechanism and Absorption Site:

Drugs absorbed through apertures or by carrier-mediated transport are not good candidates for oral ER drug delivery systems. Oral ER systems for drug administration can effectively administer drugs that are absorbed by pore transport, passive diffusion, and throughout the GIT. (Shah SJ, 2015, Chourasiya J, 2013)

f. Quantity of Dose:

A product is a poor fit for an ER drug administration system if its dosage size is more than 0.5 g because a larger drug bulk results in a larger product volume. As a result, the medication dose should be the minimum in order for it to be a good candidate for a prolonged-release drug delivery system. (Wen H.,2011)

II. Characteristics Biological:

a. Absorption:

The rate of drug absorption (ka) in an oral ER delivery system for drugs should be greater than the rate of drug dissolution (kr) from the form of administration (i.e., kr < ka). Drugs with a variable absorption rate or those that absorb slowly are poor candidates for oral ER drug delivery systems. limited water solubility, a small partition coefficient, acid hydrolysis, metabolism, or the location of absorption are a few potential causes of limited absorption. (Wen H,2011, Kallam R, 2011)

b. Distribution:

Drugs like chloroquine that have a large apparent amount of distribution, which affects how quickly the drug is eliminated, are not good candidates for oral ER delivery systems for drugs. (Wen H., 2011, Gorle AP, 2023).

c. Metabolism:

A drug that undergoes substantial metabolism is unsuitable for the ER drug delivery system. A drug such as levodopa or nitroglycerine that can stimulate metabolism, inhibit metabolism, or process at the site of absorption of first-pass action is not a good choice for ER administration since it may be difficult to maintain a steady blood level. (Wen H., 2011, Nalini G, 2010).

d. Half-life of drug:

A drug that has a biological half-life of two to eight hours is most appropriate for an oral ER drug distribution system. For drugs with a biological half-life of more than eight hours, formulation into an oral ER drug delivery system is not essential, since the system will need an excessively high rate and big dosage to sustain the study condition if the biological half-life is less than two hours. (Barzeh H, 2016).

e. Margin of safety:

As we know, the higher the therapeutic index number, the safer the drug. Typically, drugs with a lower therapeutic index are poor candidates for oral ER drug delivery systems. (Wen H., 2011, Ramrao CT, 2022).

f. Relationship of Plasma Concentration Response:

Generally, rather than dosage and size, a medication's pharmacological response is determined by its plasma drug concentration. Unfortunately, some drugs have pharmacological action that is not reliant on plasma concentrations, making them poor choices for oral ER drug delivery systems. For instance, Reserpine(Wen H., 2011).

Approaches for establishing Extended-Release Drugs:

The goal of creating an ER dosage form is to produce a dependable formulation that lacks dose dumping while possessing all the benefits of an instant release dosage form. Multiple approaches have been utilized during the manufacturing of ER products. In general, the method of drug release may be used to classify prolonged formulations into different categories. (Priya VS, 2016)

1. Dissolution Controlled Release

2. Diffusion Controlled Release

3. Ion Exchange Resins Controlled Release

4. Swelling Controlled Release.

1. Dissolution Controlled Release:

Drug molecules are released from the surface within the solid structure and diffuse into the surrounding liquid interface, which is followed by their absorption into the bulk liquid medium. This kind of controlled release is achieved by these two processes. The Noyes-Whitney equation, which links the characteristics of the solid and the dissolving medium to the rate of dissolution of solids, may be used to determine the quantity dissolved per unit of time and the rate of dissolution from this system. (Wang S, 2012, Priya VS, 2016)

dW/dtL = DA (Cs-C)

dW/dt is the rate of dissolution

A is the solidification's surface area.

C is the solid's concentration in the bulk dissolving media.

Cs is the solid concentration in the solid's surrounding diffusion layer.

D represents the diffusion coefficient, and

L is the diffusion layer thickness.

2. Diffusion Controlled Release:

In this system, the diffusion of the dissolved drugs over a polymeric barrier controls the rate rather than the rate of dissolution. The matrix structure and reservoir devices are two distinct types of diffusion-controlled systems. (Shah SJ, 2015)

a. The Matrix System:

In order to develop tablets with prolonged release, this review article places more focus on matrix-controlled release. An active and inactive component is combined and distributed uniformly throughout the dosage form to generate a matrix system. The popularity of matrix systems may be ascribed to several variables, and it is the oral extended-release technique that is most frequently employed. Fick's first law of diffusion governs the release from the matrix type formulations. (Kumar S, 2012)

b. The Reservoir system:

In reservoir systems, derivatives of cellulose are frequently utilized. The coated membranes (the diffusion barrier) and the core (the reservoir) make up this structure. Via the coated membrane, the active component diffuses out of the reservoir. (Kumar S, 2012)

Drug release over the polymeric hydrogel membrane surrounding the drug deposit in a reservoir system may be explained by Fick's first rule of diffusion.

3. Ion Exchange Resins Controlled Release:

Ionizable functional groups are present in cross-linked, water-insoluble polymers that make up ion exchange resins. The resins are mostly utilized for controlled release systems and taste masking in therapeutic uses. Ionic exchange resins have been utilized as a disintegrant in tablet formulations due to their capacity to swell. With extended drug exposure to the resin, it forms an irreversible combination with ionizable drugs. In the presence of ion-exchanged groups, the proper ions cause the removal of a resin-bound medication. The rate of drug release is controlled by the area and length of the diffusion channel as well as the quantity of cross-linked polymers in the resin moiety. (Patel K, 2012, Wen H., 2011)

4. Swelling Controlled Release.

The basis of swelling-controlled systems is the swelling of ER polymers. Anomalous penetrate transport may be seen because to the viscoelastic characteristics of the polymers, which are strengthened by the cross-linked network. Pure Fickian diffusion & case II transportation constrain this behaviour. Thus, there are just three primary factors that drive transportation.

The polymer network results in the penetration concentration gradient, concentration of polymers gradient, and osmotic force behaviour that are seen. By slowing the release of the implanted medication, an appropriate polymer can counteract typical Fickian diffusion. This could result in zero-order release or a prolonged drug delivery duration. (Ansari S, Choudhari P, 2018)

The release of drugs from swellable matrix tablets can be influenced by a number of formulation factors, including polymer level and type, drug to polymer ratios, solubility of the drug, drug and polymers particle sizes, compaction pressure, and the presence of additives or excipients in the final formulation. The glassy-rubbery transition of the polymer is caused by water penetrating into the matrix and is thought that it is the primary factor for release control. (Wen H., 2011, Ramarao CT, 2022)

Benefits of the Matrix System:

Products that utilize matrix design, as opposed to reservoirs and osmotic systems, may be produced with standard tools and procedures. Furthermore, it is commonly accepted that the development time and cost of the matrix system are variables, and no further capital expenditure is necessary. Finally, a matrix system may accept active components with a variety of chemical and physical properties as well as low and high drug loading. (Shah SJ, 2015)

Limitations using the Matrix System:

Matrix systems have various restrictions, much as every other technology. First, as indicated by the results of clinical studies, matrix systems are not flexible enough to adapt to continuously changing dose amounts. greater often than not, a new formulation and thus greater resources are anticipated when a new dose strength is determined to be required. More intricate matrix-based technologies, including multilayer tablets, are also necessary for some items that need certain release patterns (dual delivery or delayed + prolonged release). (Shah SJ, 2015, Khambat SB)

CONCLUSION:

From the discussion above, we were capable of come to the conclusion that extended-release formulations are particularly beneficial in improving patient compliance by reducing the frequency of doses and also improving the effectiveness of drugs having short half-life. Many alternative oral extended-release dose forms are now accessible for a wide range of drugs.

However, the only ones that are likely to enhance treatment outcomes are those that lead to a significant decrease in the frequency of doses as well as a reduction in toxicity from high concentrations in the blood as well as gastrointestinal tract. A drug must dissolve in gastrointestinal fluids, be released from the dosage form during a predetermined rate, have enough gastrointestinal residence time, and be absorbed at a rate that will replace the total amount of drug that is being metabolized and excreted in order for an extended-release product to be successful. (Kumar S, 2012, Patel K. 2012)

ACKNOWLEDGEMENT:

We are grateful to the Teacher’s and Principal of Loknete Dr J. D. Pawar College of Pharmacy, Manur, and Tal. Kalwan for their helpful guidance.

CONFLICT OF INTEREST:

The author’s state that has no conflicts of interest.

REFERENCE:

1. Shah SJ, Shah PB, Patel MS, Patel MR, Samir Shah AJ. A review on extended release drug delivery system and multiparticulate system. World J. Pharm. Res. 2015 May 20;4(8):724-47.

2. Bhowmik D, Bhanot R, Kumar KP. Extended Release Drug Delivery-An Effective Way of Novel Drug Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018; 10(4): 233-44.

3. Kumar S, Kumar A, Gupta V, Malodia K, Rakha P. Oral extended release drug delivery system: A promising approach. Asian Journal of Pharmacy and Technology. 2012; 2(2): 38-43.

4. Reddy DV, Rao AS. A review on oral extended release technology. Research Journal of Pharmacy and Technology. 2015; 8(10): 1454-62.

5. Chourasiya J, Keshavrao Kamble R, Singh Tanwar Y. Novel approaches in extended release drug delivery systems. International Journal of Pharmaceutical Sciences Review and Researchers. 2013; 20(1): 218-22.

6. Wang S, Liu R, Fu Y, Kao WJ. Release mechanisms and applications of drug delivery systems for extended-release. Expert Opinion on Drug Delivery. 2020 Sep 1; 17(9): 1289-304.

7. Patel K, Patel U, Bhimani B, Patel G. Extended release oral drug delivery system. The International Journal of Pharmaceutical Research and Bio-Science. 2012; 1(3).

8. Barzeh H, Sogali BS, Shadvar S. A review on extended release matrix tablet. Journal of Pharmaceutical Research. 2016 Dec 1; 15(4): 147-52.

9. Khambat SB, Kale SA. A Review Extended Release Oral Drug Delivery System and Multiparticulate Drug Delivery Systems (MDDS).

10. Ansari S. Design and Fabrication of Extended Release Formulation.

11. Priya VS, Roy HK, Jyothi N, Prasanthi NL. Polymers in drug delivery technology, types of polymers and applications. Sch. Acad. J. Pharm. 2016; 5: 305-8.

12. Wen H, Park K, editors. Oral controlled release formulation design and drug delivery: theory to practice. John Wiley & Sons; 2011 Jan 14.

13. Khan GM. Controlled release oral dosage forms: Some recent advances in matrix type drug delivery systems. The sciences. 2001 Sep; 1(5): 350-4.

14. Ummadi S, Shravani B, Rao NR, Reddy MS, Sanjeev B. Overview on controlled release dosage form. System. 2013; 7(8): 51-60.

15. Kumar A, Goyal N. Design, Development and Evaluation of Extended Release Tablets of Anti-asthmatic Agents using various Polymers. International Journal of Research and Development in Pharmacy & Life Sciences. 2018 Aug 15; 7(4): 3050-4.

16. Ramarao CT, Madhuri S. In-vitro Design and Formulation of Levitiracetam Extended Release Tablets. Research Journal of Pharmacy and Technology. 2022; 15(8): 3681-4.

17. Somireddy M, Rao CH. In-vitro Design and Formulation of Levitiracetam Extended Release Tablets. Research J. Pharm and Tech. 2022; 15(8): 3681-4.

18. Gorle AP, Oza PN, Shende RS, Mahirrao JA. Formulation, development and evaluation of extended-release tablets of carbamazepine. Research Journal of Pharmacy and Technology. 2023; 16(6): 2808-12.

19. Kallam R, Sree KP, Arutla S, Bari MA. Formulation and Evaluation of Extended Release Matrix Formulation of Metoprolol Succinate. Research Journal of Pharmacy and Technology. 2011; 4(1): 160-4.

20. Kumar P, Tiwari R, Chaurasia B, Sahu RR, Tripathi FM, Bhardhwaj A. Multi Particulate Extended Release Formulation for Propranolol Hydrochloride. Research Journal of Pharmacy and Technology. 2010; 3(3): 835-9.

21. Nalini G, Kishore VS. Formulation and Evaluation of Extended Release Tablets of Alfuzosin Hydrochloride. Research Journal of Pharmaceutical Dosage Forms and Technology. 2010; 2(6): 384-7.

22. Choudhari P. Formulation and Evaluation of Prolong Release Tablet of Anti-hypertensive Drug. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018; 10(2): 55-9.

Received on 03.04.2024 Modified on 23.04.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(2):183-188.

DOI: 10.52711/0975-4377.2024.00029