INTRODUCTION:

The important function of novel drug delivery systems, which increase the therapeutic efficacy of included medications by delivering controlled, sustained distribution or by directing the medication to the targeted location. The drug delivery system's goal is to deliver a therapeutic dose of the medication to the targeted bodily location in order to quickly reach and then sustain the appropriate drug concentration¹.

The pharmaceutical industry has long since realized the benefits of giving a single dose of a medicine that releases over an extended period of time instead of giving several doses. The goal of maintaining uniform and nearly constant blood drug levels frequently leads to better patient compliance and higher clinical efficacy of the medication for the intended application. It has placed more of an emphasis on the development of sustained or controlled drug release systems because of the difficulties and higher expenses involved in introducing new pharmacological entities to the market. For sustained release, the matrix system is employed. It's a drug delivery mechanism that spreads or dissolves a medication and controls its release over time².

Due in part to its convenience of use and the fact that gastrointestinal physiology allows for greater design flexibility in dosage form creation than most other routes, the oral route is the most often used method for drug administration³.

Advantages sustained Release Drug Delivery System:⁴

1. Reduced dosing frequency.

2. Dose reduction.

3. Improved patient compliance.

4. A constant drug concentration in the blood plasma.

5. Reduced overdose toxicity.

6. Reduces the fluctuating concentration of valley peaks.

Disadvantages Sustained Release Drug Delivery System:^5,6,7

1. Possible reduction in systemic availability.

2. Dose dumping: Dose dumping may occur with faulty formulation.

3. Cost is more than conventional dosage form.

4. Poor in vivo and in vitro correlations.

5. Reduced potential for dose adjustment.

6. Increase potential for first pass metabolism.

7. For proper medication patient education is necessary.

THE MATRIX SYSTEM:

Matrix tablets provide the most affordable option for sustained and controlled release solid dosage forms, they are a viable option for the introduction of extended-release medication therapy. Oral solid dosage forms called matrix tablets are those in which the drug or active component is uniformly distributed throughout the hydrophilic or hydrophobic matrices, acting as release rate retardants⁸.

The introduction of matrix tablets as sustained release (SR) has led to a new breakthrough for novel drug delivery systems (NDDS). Complex production processes like coating and pelletization during manufacture are not included, and the kind and amount of polymer employed in the preparations primarily controls the drug release rate from the dosage form. The hydrophilic polymer matrix is a commonly employed formula for SR dosage forms⁹.

These systems use diffusion- and dissolution-controlled methods to continuously release the medication. There are two distinct release mechanisms at work: dissolving of coated particles and zero-order erosion with decreasing surface area. However, the total tablet release profile, which combines the two mechanisms in order, is almost linear for the majority of the tablet's dosage¹⁰.

Fig 1: - Sustained Release Matrix System

MATRIX TYPES:

1. Hydrophobic Matrices (Plastic matrices): Inert or hydrophobic materials were initially proposed as matrix materials in 1959. The medication is combined with an inert or hydrophobic polymer and crushed into a tablet in this oral dosage form approach for prolonged release. The dissolving medication has diffused through a network of channels that exist between compressed polymer particles, resulting in sustained release. A few examples of substances that have been employed as hydrophobic or inert matrices are acrylate polymers and their copolymers, polyethylene, polyvinyl chloride, and ethyl cellulose. In these formulations, liquid penetration into the matrix serves as the rate-controlling step. Diffusion is one potential medication release mechanism in these kinds of tablets¹¹.

2. Lipid Matrices: These matrices were created using lipid waxes and associated substances. Such matrices allow for both pore diffusion and erosion-mediated drug release. Therefore, the nature of the digestive fluid has a greater influence on release properties than the polymer matrix, which is completely insoluble. For several prolonged release formulations, carnauba wax has been used as a retardant base in conjunction with stearyl alcohol or stearic acid¹².

3. Hydrophilic Matrices: Hydrophilic polymer matrix systems are extensively employed in oral controlled drug delivery due to their cost-effectiveness, wide regulatory acceptability, and flexibility in achieving a desired drug release profile. In the realm of controlled release, there is particular interest in the formulation of pharmaceuticals in gelatinous capsules or, more commonly, tablets, using hydrophilic polymers with high gelling capabilities as base excipients. A well-mixed combination of one or more pharmaceuticals and a gelling agent (hydrophilic polymer) is referred to as an infected matrix. Swellable controlled release systems are the name given to these systems. There are three main categories of polymers that are utilized to create hydrophilic matrices¹³.

A. Cellulose derivatives: The following are the concentrations of methylcellulose: 400 and 4000 cPs; hydroxy ethyl cellulose; 25, 100, 4000, and 15000 cPs; and sodium carboxy methyl cellulose.

B. Non cellulose natural or semi synthetic polymers: Agar-Agar; Carob gum; Alginates; Molasses; Polysaccharides of mannose and galactose, Chitosan and Modified starches.

C. Polymers of acrylic acid: Polymers which are used in acrylic acid category is Carbopol 934. Other hydrophilic materials used for preparation of matrix tablet are Alginic acid, Gelatin and Natural gums.

4. Biodegradable Matrices: They are composed of polymers with unstable backbone linkages made of monomers connected to one another via functional groups.Enzymes produced by the surrounding living cells break them down or erode them naturally. Alternatively, non-enzymatic processes convert them into oligomers and monomers that can be digested or eliminated. Examples include modified natural polymers, such proteins and polysaccharides, and synthetic polymers, like aliphatic poly (esters) and poly anhydrides¹⁴.

5. Mineral Matrices: These are made of polymers derived from several kinds of seaweed. Alginic acid, for instance, is a hydrophilic carbohydrate that may be made from brown seaweed species (Phaephyceae) by using diluted alkali^15\

METHODS OF PREPARATION:

1. Direct Compression: This process involves mixing or blending the first powder, then compressing the powder materials without changing the drug's chemical or physical characteristics¹⁶.

2. Wet granulation: This approach involves mixing a sufficient volume of granulating agent with a measured amount of medication and excipients. The wet weight is considered once adequate consolidation has been reached. After being tested on dry granules, the dried pellets are combined with lubricant and disintegrant to create compressed "liquid powder" tablets that can be compressed using a single pierceable tablet compressor¹⁷.

3. The Hot Extrusion Process: A mixture of processed materials, thermoplastic polymers, and active substances are fed into the extruder barrel through a hopper in the hot extrusion process. A spinning screw is used to move the materials into the heated tube. A cylinder end attachment is used to process the soluble materials and the high-temperature melt continuously. The nozzle cylinder's size determines the extruder's ability to create films¹⁸.

4. Melt granulation: A material that melts at low temperatures is used in this technique. By dissolving this material in the substrate and heating it above its melting point, it can be added. We tried several lipophilic binders with a granular solution¹⁹.

POLYMERS USED IN MATRIX TABLET⁴:

1. Hydrogels: Poly hydroxyl ethyl methylacrylate (PHEMA), Cross-linked polyvinyl alcohol (PVA), Cross-linked polyvinyl pyrrolidone (PVP), Polyethylene oxide (PEO), Poly acryl amide (PA).

2. Soluble polymers: Poly ethylene glycol (PEG), polyvinyl alcohol (PVA), Poly vinyl pyrrolidone (PVP), Hydroxy propyl methyl cellulose (HPMC).

3. Biodegradable polymers: Polylactic acid (PLA), Polyglycolic acid (PGA), Poly caprolactone (PCL), Poly anhydrides, Poly orthoesters.

4. Non-biodegradable polymers: Polyethylene vinyl acetate (PVA), Poly dimethylsiloxane (PDS), Polyether urethane (PEU), Polyvinyl chloride (PVC), Cellulose acetate (CA), Ethyl cellulose (EC).

5. Mucoadhesive polymers: Poly carbophil,Sodium carboxy methyl cellulose,Poly acrylic acid, Tragacanth, Methyl cellulose, Pectin.

6. Natural gums: Xanthan gum, Guar gum, Karaya gum, Locust bean gum.

BIOLOGICAL FACTORS AFFECTING DESIGN OF ORAL SUSTAINED RELEASE DOSAGE FORM^20,21

1. Biological half-life:

Drugs with a biological half-life of two to eight hours are thought to be good candidates for sustained release dosage forms since they can lower the frequency of administration. This is constrained, though, since medications with extremely brief biological half-lives could need excessively high dosage concentrations in order to sustain long-lasting effects, which would make the dosage form itself unnecessarily big. Generally speaking, drugs having half lives shorter than two hours make bad candidates for systems of continual release.

2. Therapeutic Index:

It is most frequently used to calculate a drug's margin of safety.TI is equal to TD50/ED50. The medicine is safer the longer its T.I. value. It is not a good idea to formulate drugs with very low Therapeutic Index values into products with prolonged release. If a drug's T.I. value is higher than 10, it is regarded as safe.

3. Absorption:

When considering about how to formulate a medication into an extended release system, the rate, degree, and homogeneity of absorption are crucial considerations. Kr<Ka is the most crucial when administered orally. Maximum absorption half-life should be 3–4hours, assuming that the medication transits through the gastrointestinal tract's absorptive region in 9–12hours. This translates to a minimal absorption rate constant Ka value of 0.17–0.23/hr required for about 80–95% absorption during a transit period of 9–12 hours. When the first order release rate constant (Kr) is less than 0.17/hr for medications with a very slow rate of absorption (Ka<<0.17/hr), many patients experience unacceptablely low bioavailability. Hence, it will be challenging to construct slowly absorbed drugs into prolonged release systems where the Kr<\<Ka requirement must be satisfied. Drugs that are only transported to a certain area of the GIT or that are absorbed by active transport are not good candidates for sustained release systems.

4. Metabolism:

An active drug component is either inactivated or an inactive drug molecule is activated as a result of metabolism. The liver is where most medication metabolism takes place. Drug elimination constants and metabolite appearances are indicators of metabolism. If the rate and degree of metabolism are predictable, these factors can be appropriately taken into account when designing products. However, complex metabolic patterns can complicate this process, especially when a metabolite is responsible for biological activity. A medicine that causes or displays enzyme production over long-term treatment is not a good fit for a sustained release product since it will be difficult to maintain a consistent blood level.

FACTORS AFFECTING DRUG RELEASE FROM MATRIX TABLETS^4,22:

1. Molecular Size and Diffusivity:

Over the length of the drug's presence in the body, it must diffuse through a number of biological membranes in order to be absorbed. In many controlled-release systems, medications not only need to diffuse through these biological membranes, but also through a rate-controlling polymeric membrane or matrix. Medications with molecular weights between 150 and 400 make ideal candidates for dosage formulations with prolonged release. Diffusion coefficients for medications with molecular weights larger than 500 Da are often so tiny in many polymers that they are challenging to measure.

2. Size of dosage:

The usual range for dose sizes in conventional dosage forms is 500–1000 mg, and this range also applies to sustained release dosage forms.

3. Aqueous Solubility:

The amount of drug in the G.I. tract solution, or the drug's intrinsic permeability, determines the fraction of the drug that is absorbed into the blood. A medication needs to dissolve in the aqueous phase around the delivery site and partition into the absorbing membrane in order to be absorbed. As a result, a drug's aqueous solubility can be used to estimate its rate of dissolution in water. Medication that is poorly soluble in water typically dissolves slowly and has issues with oral bioavailability. The drug's lowest limit of solubility for a sustained release method is 0.1 mg/ml. Medications that are well soluble in water make excellent candidates for formulations with prolonged release.

4. Coefficient of partition (K):

Medications with incredibly high K values are oil-soluble, easily partition into membranes, and remain localized in the body for extended periods of time. When K values are higher than optimal, the drug's solubility in water is reduced, but its solubility in lipids is increased, and once it is inside the lipid barrier, it cannot leave. In n-octanol/water, the value of K at which optimal activity is observed is roughly 1000/1. Generally speaking, medications that have partition coefficients that are either greater or lower than ideal are not good candidates for formulation into extended release dosage forms.

5. Stability of Drugs:

A regulating unit that releases its contents exclusively in the intestine would be the most suitable for medications that are unstable in the stomach. The most suitable regulating drug in this situation would be one that releases its contents solely in the stomach. This is especially true for medications that are unstable in the intestinal environment. Therefore, medications having notable stability issues in any specific GIT region are less appropriate for formulation into controlled release systems that distribute the contents evenly across the GIT.

EVALUATIONS OF SUSTAINED-RELEASE MATRIX TABLETS:

1. Weight Variation: All of the twenty tablets was weighed separately, and the average weight of the tablets was then determined²².

2. Hardness: Using a Monsanto hardness tester, tablets from each batch were subjected to a hardness test, and average values were determined²³.

3. Friability: Tablets are tested for friability using Roche friability controller run at 25 rpm for four minutes²³.

4. Thickness: The thickness of the tablets are determined using micrometre gauge²³.

5. Content Uniformity: Using UV-visible spectrophotometer, the amount of drug was determined using standard curve method²³

CONCLUSION:

Pharmaceutical innovation that is important for enhancing patient compliance, optimizing medication therapy, and cutting healthcare expenses is sustain-release matrix tablets. Important factors in their development are their composition, design, and release mechanisms. Despite certain obstacles, their use is growing in a variety of therapeutic domains and is advantageous to patients as well as healthcare professionals.

In result, sustain-release matrix tablets provide a potentially useful pharmaceutical formulation that enhances patient outcomes by providing a regulated, extended release of medication. A complete understanding of drug characteristics, matrix materials, and release processes is necessary for their development. Sustain-release matrix tablets will probably continue to be a crucial instrument in medication delivery as long as pharmaceutical science progresses.

REFERENCE:

1. Kumar A., Raj V., Riyaz Md., Singh S., Review on sustained release matrix formulations. International Journal of Pharmacy and Integrated Life Sciences. 2013; 1(3):1-14.

2. Rao NG, Raj K, Nayak BS. Review on Matrix Tablet as Sustained Release. International Journal of Pharmaceutical Research & Allied Sciences. 2013 Jul 1; 2(3).

3. Gupta PK and Robinson JR. Oral controlled release delivery. Treatise on Controlled Drug Delivery. 1992; 93(2): 545-555.

4. Navrang D, Joshi D, Mahajan SC, Jain V, Sharma A. A Concise Review on “Sustained Release Drug Delivery System”.

5. Pundir S., Badola A., Sharma D., Sustained release matrix technology and recent advance in matrix drug delivery system : a review. International Journal of Drug Research and Technology. 2013; 3(1):12-20.

6. Brahmankar D. M., Jaiswal S B. Biopharmaceutics and Pharmacokinetics: Pharmacokinetics, 2nd Edn, published by Vallabh Prakashan, Delhi. 2009: 399-401

7. Lieberman. H.A., Lachman. L., and Kanig J L., The Theory and Practice of Industrial Pharmacy, 3rd Edn, Published by: Varghese Publishing House: 430-456

8. Salsa T, Veiga F And Pina M.E, Drug Develop. Ind. Pharm., 1997, 23, 931

9. Altaf AS, Friend DR, MASRx and COSRx Sustained-Release Technology in Rathbone MJ, Hadgraft J, Robert MS, Modified Release Drug Delivery Technology, Marcell Dekker Inc., New York, 2003. JPSBR. 2011; 1(3): 143-151 Patel H. 151 493-501.

10. Leon S, Susanna W, Andrew BC. Applied Biopharmaceutics and Pharmacokinetics. 5^th edition McGraw-Hill’s Access Pharmacy, 2004: 17.1-17.9.

11. Sayed I. Abdel-Rahman, Gamal MM, El-Badry M, Preparation and comparative evaluation of sustained release metoclopramide hydrochloride matrix tablets, Saudi Pharmaceutical Journal. 2009; 17: 283-288.

12. Chandran S, Laila FA and Mantha N, Design and evaluation of Ethyl Cellulose Based Matrix Tablets of Ibuprofen with pH Modulated Release Kinetics, Indian Journal of Pharmaceutical Sciences. 2008.

13. Gothi GD, Parinh BN, Patel TD, Prajapati ST, Patel DM, Patel CN, Journal of Global Pharma Technology. 2010; 2(2): 69-74.

14. Aulton Michael E, The Design and Manufacture of Medicines, Church Hill Living Stone. 2007; 3: 483-494.

15. Misal R, Atish W, Aqueel S. Matrix tablet: A Promising Technique for Controlled drug delivery. Indo American Journal of Pharmaceutical Research. 2013; 3: 3791-805.

16. Tonde N. Gaikwad A. Raykar M. A review on sustained release matrix tablet. International Journal of Creative Research Thoughts. 2022.

17. Shah N, Oza C, Trivedi S, Shah N, Shah S. Review on sustained release matrix tablets: An approach to prolong the release of drug. J Pharm Sci Bio Sci Res. 2015; 5(3): 315-21.

18. Shargel L, Yu ABC. Modified release drugproducts. In: Applied Biopharmaceutics and Pharmacokinetics. 4th edition, 1999: 169-171.

19. Thomas Wai-Yip Lee, Joseph R Robinson, „controlled-release drug delivery system, Chapter-47 in Remington: “The Science and Practice of Pharmacy”, 20th edition, Vol-1, p.907-910.

20. Hadi A, Rao AS, Vineeth P. Formulation and Evaluation of Once Daily Sustained Release Matrix Tablets of Terbutaline Sulphate for the Treatment of Nocturnal Asthma. Research Journal of Pharmaceutical Dosage Forms and Technology. 2013; 5(1): 27-32.

21. Madgulkar Ashwini R, Bhalekar Mangesh R, Warghade Nikhil S, Chavan Nilesh S. Preparation and evaluation of sustained release matrix tablet of Nateglinide: effect of variables. Inventi Rapid: NDDS. 2011 Mar 23.

22. Reddy AM, Karthikeyan R, Vejandla RS, Divya G, Srinivasa P. International Journal of Allied Medical Sciences and Clinical Research (IJAMSCR).

23. Zalte HD, Saudagar RB. Review on sustained release matrix tablet. International Journal of Pharmacy and Biological Sciences. 2013 Oct; 3(4): 17-29.

Received on 23.02.2024 Modified on 19.03.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(2):189-193.

DOI: 10.52711/0975-4377.2024.00030