INTRODUCTION:

Oral route is the most oldest and convenient route for the administration of therapeutic agents because of low cost of therapy and ease of administration leads to higher level of patient compliance.¹ Approximately 50% of the drug delivery systems available in the market are oral drug delivery systems and historically too, oral drug administration has been the predominant route for drug delivery.^2,3 It does not pose the sterility problem and minimal risk of damage at the site of administration.⁴

During the past three decades, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate.⁵The oral controlled release formulation have been developed for those drug that are easily absorbed from the gastrointestinal tract (git) and have a short half-life are eliminated quickly from the blood circulation.⁶ As these will release the drug slowly into the git and maintain a constant drug concentration in the plasma for a longer period of time.⁷

The sustained release, sustained action, prolonged action, controlled release, extended action, timed release, depot and respiratory dosage forms are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.⁸

Extended release formulation is an important program for new drug research and development to meet several unmet clinical needs. There are several reasons for attractiveness of these dosage forms viz. provides increase bioavailability of drug product, reduction in the frequency of administration to prolong duration of effective blood levels, Reduces the fluctuation of peak trough concentration and side effects and possibly improves the specific distribution of the drug.⁹

Extended release drug delivery system achieves a slow release of the drug over an extended period of time or the drug is absorbed over a longer period of time. Extended release dosage form initially releases an adequate amount of drug to bring about the necessary blood concentration (loading dose, D_L) for the desired therapeutic response and therefore, further amount of drug is released at a controlled rate (maintenance dose, D_M) to maintain the said blood levels for some desirable period of time.^10,11

Objectives of Extended Release Drug Delivery System:

Every noval drug delivery system had a rationale for developing the dosage form likewise, ERDDS also having some objectives that are discussed below:

Suitable Drug Candidate for Extended Release Drug Delivery System^{12, 13:}

The drugs that have to be formulated as a ERDDS should meet following parameters.

· It should be orally effective and stable in GIT medium.

· Drugs that have short half-life, ideally a drug with half life in the range of 2 – 4 hrs makes a good candidate for formulation into ER dosage forms eg. Captopril, Salbutamol sulphate.

· The dose of the drug should be less than 0.5g as the oral route is suitable for drugs given in dose as high as 1.0g eg. Metronidazole.

· Therapeutic range of the drug must be high. A drug for ERDDS should have therapeutic range wide enough such that variations in the release do not result in concentration beyond the minimum toxic levels¹⁴

Merits of Extended Release Drug Delivery System:

· The extended release formulations may maintain therapeutic concentrations over prolonged periods.

· The use of extended release formulations avoids the high blood concentration.

· Reduce the toxicity by slowing drug absorption.

· Minimize the local and systemic side effects.

· Improvement in treatment efficacy.

· Minimize drug accumulation with chronic dosing.

· Improvement of the ability to provide special effects.

· Enhancement of activity duration for short half life drugs.

Demerits Extended Release Drug Delivery System:

Despite of several merits, extended release dosage forms are not devoid of certain demerits explained following:

· In case of acute toxicity, prompt termination of therapy is not possible.

· Less flexibility in adjusting doses and dosage regimens.

· Risk of dose dumping upon fast release of contained drug.

· High cost of preparation.

· The release rates are affected by various factors such as, food and the rate transit through the gut.

· The larger size of extended release products may cause difficulties in ingestion or transit through gut.^15-17

Factors Affecting the Extended Release Drug Delivery System:

Physiochemical Properties:

Aqueous Solubility:

Certain drug substance having low solubility is reported to be 0.1 mg/mL. As the drug must be in solution form before absorption, drug having low aqueous solubility usually suffers oral bioavailability problem due to limited GI transit time of undissolved drug and limited solubility at absorption site. So these types of drug are undesirable to be formulated as extended release drug delivery system. Drug having extreme aqueous solubility are undesirable for extended release because, it is too difficult to control release of drug from the dosage form.

Partition Co-efficient:

As biological membrane is lipophilic in nature through which the drug has to pass, so partition co-efficient of drug influence the bioavailability of drug very much. Drug having lower partition co-efficient values less than the optimum activity are undesirable for oral ER drug delivery system, as it will have very less lipid solubility and the drug will be localized at the first aqueous phase it come in contact. Drug having higher partition co-efficient value greater than the optimum activity are undesirable for oral ER drug delivery system because more lipid soluble drug will not partition out of the lipid membrane once it gets in the membrane.

Protein Binding:

The Pharmacological response of drug depends on unbound drug concentration rather than total concentration and all drugs bound to some extent to plasma and/or tissue proteins. Proteins binding of drug play a significant role in its therapeutic effect regardless the type of dosage form as extensive binding to plasma, increase biological half life and thus, such type of drug will release upto extended period of time then there is no need to develop extended release drug delivery for this type of drug.

Drug Stability:

As most of ER Drug delivery system is designing to release drug over the length of the GIT, hence drug should be stable in GI environment. So drug, which is unstable, can’t be formulated as oral ER drug delivery system, because of bioavailability problem.

Mechanism and Site of Absorption:

Drug absorption by carrier mediated transport and those absorbed through a window are poor candidate for oral ER drug delivery system. Drugs absorbed by passive diffusion, pore transport and through over the entire length of GIT are suitable candidates for oral ER drug delivery system.

Dose Size:

If a product has dose size >0.5g it is a poor candidate for ER drug delivery system, because increase in bulk of the drug, thus increases the volume of the product. Thus dose of drug should small to make a good drug candidate for extended release drug delivery system.

Biological Properties:

Absorption:

The absorption behaviour of a drug can affect its suitability as an extended release product. The aim of formulating an extended release product is to place a control on the delivery system. It is essential that the rate of release is much slower than the rate of absorption. If we assume the transit time of most drugs and devices in the absorptive areas of GI tract is about 8-12 hours, the maximum half-life for absorption should be approximately 3-4 hours. Otherwise the device will pass out of absorptive regions before drug release is complete. Therefore the compounds with lower absorption rate constants are poor candidates for extended release systems. Some possible reasons for a low extent of absorption are poor water solubility, small partition co-efficient, acid hydrolysis, and metabolism or its site of absorption.

Distribution:

The distribution of drugs in tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending on time course of drug disposition. Drugs with high apparent volume of distribution, which influence the rate of elimination of the drug, are poor candidate for oral ER drug delivery system e.g. Chloroquine. For design of extended release products, one must have information on disposition of the drug.

Metabolism:

Drug, which extensively metabolized is not suitable for ER drug delivery system. A drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site of absorption or first-pass effect is poor candidate for ER delivery, since it could be difficult to maintain constant blood level e.g. levodopa, nitroglycerine. Drugs that are metabolised before absorption, either in lumen or the tissues of the intestine, can show decreased bioavailability from the extended releasing systems. Most intestinal walls are saturated with enzymes. As drug is released at a slow rate to these regions, lesser drug is available in the enzyme system. Hence the systems should be devised so that the drug remains in that environment to allow more complete conversion of the drug to its metabolite.

Half-life of Drug:

A drug having biological half-life between 2 to 8 hours is best suited for oral ER drug delivery system. As if biological half-life < 2hrs the system will require unacceptably large rate and large dose and biological half-life > 8hrs formulation of such drug into ER drug delivery system is unnecessary.^16,18-20

Mechanistic Aspects of Oral Extended Release System

Continuous Releases:

Diffusion Controlled Drug Release:

In this system the rate controlling step is not the dissolution rate but the diffusion of dissolved drug through a polymeric barrier. The two types of diffusion controlled system are – Matrix System and Reservoir Devices. The drug is dispersed in an insoluble matrix of rigid non swellable hydrophobic matrials is called as matrix system. Materials used for rigid matrix are insoluble plastics such as PVC and fatty materials like stearic acid, beewax etc. With plastic materials the drug is generally kneaded with the solution of PVC in an organic solvent and granulated. It is a hollow system containing an inner drug core surrounded in water insoluble membrane is called as reservoir devices. Polymer can be applied by coating or microencapsulation. The rate controlling mechanism partitioning into membrane with subsequent release into surrounding fluid by diffusion and commonly used polymers are HPC, EC and PVA.

Dissolution Controlled Drug Release:

In these products, the rate dissolution of the drug (and thereby availability for absorption) is controlled by slowly soluble polymer or by microencapsulation. Once the coating is dissolved, the drug becomes available for dissolution. By varying the thicknesses of the coat and its composition, the release rate of drug can be controlled. These systems are easiest to design. With inherently slow dissolution rate. Such drugs act as a natural prolonged release products. That produces slow dissolving forms when it comes in contact with GI fluids and having high aqueous solubility and dissolution rate.

Osmotically Controlled Drug Release:

The rate of release of drug in these products is determined by the constant in flow of water across a semi permeable membrane into a reservoir which contains an osmotic agent called as osmogens. The rate of release is constant and can be controlled within tight limits yielding relatively constant blood concentration. The advantage of this type of product is that the constant release is unaltered by the environment of the gastrointestinal tract and relies simply on the passage of water into the dosage form. The rate of release can be modified by altering the osmotic agent and the size of the hole.

Swelling Controlled Drug Release System:

It is useful for sustaining the release of highly soluble drug. The materials for such matrices are hydrophilic gums and natural origin (guar gum, tragacanth), semi-synthetic (HPMC, CMC, Xanthan gum) or synthetic (Polyacrylamides). The drug and gum are granulated together with solvent such as alcohol and compressed into tablets. The release of drug from initially dehydrated hydro gels involves adsorption of water and desorption of drug from a swelling controlled diffusion system. As the gum swell and the drug diffuses out of it.

Chemically Controlled Drug Release:

In this system the drug is chemically bound to a matrix (which is not necessarily biodegradable), coated solid dosage forms from which drug release occurs only upon crack formation within the surrounding membrane, and microchip-based drug delivery systems. If the drug is covalently bound to an insoluble matrix former via hydrolysable bondings, the latter are more or less rapidly cleaved upon water penetration into the device.

Dissolution and Diffusion Controlled Release System:

In this system the drug core is encased in a partially soluble membrane. Pores are thus created due to dissolution of parts of membrane which permits entry of aqueous medium into the drug core and hence drug dissolution allows diffusion of dissolved drug out of the system. An example of obtaining such a coating is using a mixture of ethyl cellulose with PVP or methyl cellulose; the latter dissolves in water and creates pores in the insoluble ethyl cellulose membrane.

Hydrodynamic Pressure Controlled Release System:

A hydrodynamic pressure-activated drug delivery system can be fabricated by enclosing a collapsible, impermeable container, which contains a liquid drug formulation to form a dug reservoir compartment, inside rigid shape retaining housing. A composite laminate of an absorbent layer and swellable, hydrophilic polymer layer is sandwiched between the drug reservoir compartment and the housing. In the GI tract the laminate absorb the gastrointestinal fluid through the annular opening at the lower end of the housing and become increasingly swollen, which generates hydrodynamic pressure in the system. The hydrodynamic pressure thus created forces the drug reservoir compartment to reduce in volume and causes the liquid drug formulation to release through the delivery orifice at the specific rate²¹. Such systems are also called as push-pull osmotic pumps.

pH-Independent Formulation:

Such system are designed to eliminate the influence of changing the gastrointestinal pH on dissolution and absorption of drugs by formulating them with sufficient amount of buffering agents (salts of phosphoric, citric or tartaric acids) that adjust the pH to the desired value as the dosage form passes along the GIT and permit drug dissolution and release at a constant rate independent of gastrointestinal pH. The dosage form containing drug and buffer is coated with a permeable substance that allows entry of aqueous medium but prevents dispersion of tablets.

Delayed Transit and Continuous Release System:

These systems are designed to prolong their residence in the GIT along with their release. Often, the dosage form is fabricated to detain in the stomach and hence the drug present therein should be stable to gastric pH. Systems included in this category are as follows:

Altered Density System:

The transit time of GI contents is usually less than 24 hours. This is the major limiting factor in the design of oral controlled release formulation which can reduce the frequency of dosing to a time period little more than the residence time of drug. If the residence time of drug in the stomach or intestine is prolonged in some way the frequency of dosing can be reduced. There are 3 ways by which this can be achieved such as altering the density of drug particles use of mucoadhesive polymer and altering the size of the dosage form.

Mucoadhesive System:

A bioadhesive polymer such as cross-linked polyacrylic acid, when incorporated in a tablet, allows it to adhere to the gastric mucosa or epithelium. Such a system continuously releases a fraction of drug into the intestine over prolonged periods of time.

Size-Based System:

Gastric emptying of a dosage form can be delayed in the fed state if its size is greater than 2 mm. Dosage form of size 2.5 cm or larger is often required to delay emptying long enough to allow once daily dosing. Such forms are however to swallow.

Delayed Release System:

Intestinal Release System:

A drug may be enteric coated for intestinal release for several known reasons such as to prevent gastric irritation, prevent destabilization in gastric pH, etc. Certain drugs are delivered to the distal end of small intestine for absorption via peyer’s patches or lymphatic system. Peyer’s patches are mucosal lymphoid tissues that are known to absorb macromolecules like proteins and peptides and antigens by endocytosis. Selective release of such agents to peyer’s patch region prevents them from getting destroyed/digested by the intestinal enzymes. Such a site can be utilized for oral delivery of insulin.

Colonic Release System:

Drugs are poorly absorbed through colon but may be delivered to such a site for two reasons – Local actions as in the treatment of ulcerative colitis with mesalamine and systemic absorption of protein and peptide drugs like insulin and vasopressin. The advantage is taken of the fact that pH sensitive bioerodible polymers like polymethacrylates release the medicament only at the alkaline pH of colon or use of divinylbenzene cross-linked polymer that can be cleaved only by the azoreductase of colonic bacteria to release free drug for local effect or systemic absorption.^21,22

Polymers Used in Preparations of CRDDS:

Hydrogels:

· Polyhydroxyethylmethylacrylate (PHEMA)

· Cross-linked polyvinyl alcohol (PVA)

· Cross-linked polyvinylpyrrolidone (PVP)

· Polyethyleneoxide (PEO)

· Polyacrylamide (PA)

Soluble Polymers:

· Polyethyleneglycol (PEG)

· Polyvinyl alcohol (PVA)

· Polyvinylpyrrolidone (PVP)

· Hydroxypropylmethylcellulose (HPMC)

Biodegradeble Polymers:

· Polylactic acid (PLA)

· Polyglycolic acid (PGA)

· Polycaprolactone (PLA)

· Polyanhydrides

· Polyorthoesters

Non Biodegradeble Polymers:

· Polyethylene vinyl acetate (PVA)

· Polydimethylsiloxane (PDS)

· Polyetherurethane (PEU)

· Polyvinyl chloride (PVC)

· Cellulose acetate (CA)

Mucoadhesive Polymers:

· Polycarbophil

· Sodium carboxymethyl cellulose

· Polyacrilic acid

· Tragacanth

· Methyl cellulose

· Pectin

· Natural gums

· Xanthan gum

· Guar gum

· Karaya gum²³

Table 1: Extended Release Tablets Available in National and International Market:

Brand Name	Active Ingredient(s)	Manufacturer
Metapure-XL Tab	Metoprolol Succinate	Emcure, Mumbai
Etomax – ER Tab	Etodolac	Ipca, Mumbai
Betacap –TR Cap	Propranolol HCl	Sun Pharma, J and K
Metaride Tab	Glimipiride and Metformin HCl	Unichem, Mumbai
Augmentin – XR Tab	Amixicillin and Potassium Clavulanate	Glaxosmithkline, Mumbai
Wellbutrin - XL Tab	Buproprion HCl	Glaxosmithkline, Mumbai
Revelol – XL Tab	Metoprolol Succinate	Ipca, Mumbai
Dayo – OD Tab	Divolproex Sodium	Lupin, Baddi(HP)
Sentosa – ER Tab	Venlafaxine	Nicholas Piramal, Baddi(HP)
Zanocin – OD Tab	Ofloxacin	Ranbaxy, Ponta Sahib.
Glizid – MR Tab	Gliclazide	Panacea Biotech, Lalru(CHD).
Metzok Tab	Metoprolol Succinate	USV, Mumbai
Tegritol - CR Tab	Carbemezapine	Novartis, Goa
Glimestar PM Tab	Glimipride,Pioglitazone and metformin	Discovery Mankind, Ponta Sahib
Supermet – XL Tab	Metoprolol Succinate	Piramal Healthcare, Baddi(HP)
Gabaneuron – SR Tab	Gabapentin and Methylcobalamin	Aristo, Baddi(HP)
Cefoclox – XL Tab	Cefpodoxime Dicloxacillin and Lactic acid bacillus	Khandelwal
Zen Retard Tab	Carbemezapine	Intas, Ahemdabad
Tolol AM Tab	Metoprolol Succinate	Unichem, Mumbai
Exermet GM 502 Tab	Glimepiride and Metformin HCl	Cipla, Baddi(HP)
Mahacef – XL Tab	Cefpodoxime Dicloxacillin and Lactic acid bacillus	Discovery Mankind, Ponta Sahib
Gluconorm PG Tab	Glimepiride, Pioglitazone and Metformin HCl	Lupin, Baddi (HP)
Minipress –XL Tab	Parazocin HCl	Pfizer, Goa
Pomed – EX Tab	Pantaprozol and domperidone	Panjon
Riomet – Trio 2 Tab	Metformin HCl	Ranbaxy, Ponta Sahib
Divaa – OD Tab	Divalproex Sodium	Intas, Ahemdabad
Metocontin Tab	Metoclopramide HCl	Modi-Mundi Pharma, Meerut
Fecontin – F Tab	Ferrous Glycine Sulphate and Folic acid	Modi-Mundi Pharma, Meerut
Diucontin – K 20/250 Tab	Frusemide	Modi-Mundi Pharma, Meerut
Unicontin – E Tab	Theophyllin	Modi-Mundi Pharma, Meerut
Licab – XL Tab	Lithium Carbonate	Torrent, Ahemdabad
Embeta – XR Tab	Metoprolol Succinate	Intas, Ahemdabad
Glycomet – 1 GM Tab	Metformin HCl	USV, Mumbai
Venlor – XR Tab	Venlafexine HCl	Cipla Protec, Baddi(HP)
Altiva – D Tab	Fexofenadine HCl and Pseudoephidrine sulphate	Sidmak
Sporidex – AF Tab	Cefalaxin	Ranbaxy, Ponta Sahib
Vasovin- XL Tab	Nitroglycerin	Torrent, Ahemdabad
Lithosun SR Tab	Lithium Carbonate	Sun Pharma, J and K
Etura Tab	Etodolac	Dr’ Reddy, Hydrabad
Intalith CR	Lithium Carbonate	Intas, Ahemdabad
Pari – SR Tab	Proxitine HCl	Ipca, Mumbai
Reolol – AM 25/5 Tab	Metoprolol Succinate	Ipca, Mumbai
Valprol – CR Tab	Metoprolol Succinate and Amlodipine	Intas, Ahemdabad
Perinorm – CD Cap	Sodium Valproate and Valproic Acid	Ipca, Mumbai
Gluconorm G Tab	Metformin HCl	Lupin, Baddi(HP)
Zetpol CR Tab	Carbemezapine	Sun Pharma, J and K
Epsolin ER Cap	Phenytoin Sodium	Zydus, Ahemdabad
Gluconorm – SR Tab	Metformin HCl	Lupin, Baddi(HP)
Carvidon – MR Tab	Trimetazidine HCl	Microlab, Banglore

Extended Release Tablets Available in National and International Markets:

There are so many ER Tablets of different drug molecule by different manufacturers are available in the market. Some of their names are depicted in table 1.

CONCLUSION:

We concluded from the above discussion that extended release formulations are very much helpful in increasing the effectiveness of the drugs with short half life and also improve patient compliance by decreasing the dosing frequency. Now, a wide range of drugs are formulated in a variety of different oral extended release dosage forms. However, only those which result in a significant reduction in dose frequency and a reduction in toxicity resulting from high concentration in the blood or gastrointestinal tract are likely to improve therapeutic outcomes. To be a successful extended release product, the drug must be released from the dosage form at a predetermined rate, dissolve in the gastrointestinal fluids, maintain sufficient gastrointestinal residence time, and may be absorbed at a rate and will replace the amount of drug being metabolized and excreted.

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Received on 29.05.2012 Accepted on 10.07.2012

Asian J. Res. Pharm. Sci. 2(3): July-Sept. 2012; Page 101-106