Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...

with a delay after its

administration Administration may refer to: Management of organizations * Management, the act of directing people towards accomplishing a goal ** Administrative Assistant, traditionally known as a Secretary, or also known as an administrative officer, admini ...

(delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a specific target in the body (targeted-release dosage).Pharmaceutics: Drug Delivery and Targeting
p. 7-13 Sustained-release dosage forms are

dosage form Dosage forms (also called unit doses) are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a ca ...

s designed to release (liberate) a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s. This can be achieved through a variety of formulations, including

liposome A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...

s and drug-polymer conjugates (an example being

hydrogel A hydrogel is a crosslinked hydrophilic polymer that does not dissolve in water. They are highly absorbent yet maintain well defined structures. These properties underpin several applications, especially in the biomedical area. Many hydrogels ar ...

s). Sustained release's definition is more akin to a "controlled release" rather than "sustained". Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage. SR maintains drug release over a sustained period but not at a constant rate. CR maintains drug release over a sustained period at a nearly constant rate. Sometimes these and other terms are treated as synonyms, but the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

has in fact defined most of these as different concepts. Sometimes the term "depot tablet" is used by non-native speakers, but this is not found in any English dictionaries and is a literal translation of the term used in Swedish and some other languages. Modified-release dosage and its variants are mechanisms used in

tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the ...

s (pills) and capsules to dissolve a

over time in order to be released slower and steadier into the bloodstream while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. For example,

extended-release morphine Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

enables people with chronic pain to only take one or two tablets per day. Most commonly it refers to time-dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that it not only prolongs action, but it attempts to maintain drug levels within the therapeutic window to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency. In addition to pills, the mechanism can also apply to capsules and injectable

drug carriers A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration. Drug carriers are primarily used to control the release of drugs into ...

(that often have an additional release function), forms of controlled release medicines include gels, implants and devices (e.g. the vaginal ring and

contraceptive implant A contraceptive implant is an implantable medical device used for the purpose of birth control. The implant may depend on the timed release of hormones to hinder ovulation or sperm development, the ability of copper to act as a natural spermici ...

) and transdermal patches. Examples for cosmetic, personal care, and food science applications often centre on odour or flavour release. The release technology scientific and industrial community is represented by the Controlled Release Society (CRS). The CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the ''

Journal of Controlled Release The ''Journal of Controlled Release'' is a biweekly peer-reviewed medical journal and the official journal of the Controlled Release Society. The journal covers research on the controlled release and delivery of drugs and other biologically active ...

'' and ''Drug Delivery and Translational Research'' scientific journals.

List of abbreviations

There is no industry standard for these abbreviations, and confusion and misreading have sometimes caused prescribing errors. Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable. A few other abbreviations are similar to these (in that they may serve as suffixes) but refer to dose rather than release rate. They include ''ES'' and ''XS'' (Extra Strength).

Methods

Today, most time-release drugs are formulated so that the

active ingredient An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. The ...

is embedded in a matrix of insoluble substance(s) (various: some acrylics, even

chitin Chitin ( C8 H13 O5 N)n ( ) is a long-chain polymer of ''N''-acetylglucosamine, an amide derivative of glucose. Chitin is probably the second most abundant polysaccharide in nature (behind only cellulose); an estimated 1 billion tons of chit ...

; these substances are often

patented A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...

) such that the dissolving drug must find its way out through the holes. In some SR formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface.

Micro-encapsulation Microencapsulation is a process in which tiny particles or droplets are surrounded by a coating to give small capsules, with useful properties. In general, it is used to incorporate food ingredients, enzymes, cells or other materials on a micro ...

is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere, one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients into any two piece gelatin capsule. There are certain considerations for the formation of sustained-release formulation: * If the pharmacological activity of the active compound is not related to its blood levels, time releasing has no purpose except in some cases, such as bupropion, to reduce possible side effects. * If the absorption of the active compound involves an

active transport In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...

, the development of a time-release product may be problematic. The

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of the drug refers to the drug's elimination from the bloodstream which can be caused by metabolism, urine, and other forms of excretion. If the active compound has a long half-life (over 6 hours), it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended.Lilesh Khalane, Atulal Kunte, and Arunadevi Blrajdar. Sustained Release Drug Delivery System: A Concise Review. Pharmatutor: pharmacy infopedia. 2016. Accessed: May 30, 2016. Appropriate half-lives used to apply sustained methods are typically 3–4 hours and a drug greater than 0.5 grams is too big. The

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...

also factors whether a drug can be used as a time release drug. A drug with a thin therapeutic range, or small therapeutic index, will be determined unfit for a sustained release mechanism in partial fear of dose dumping which can prove fatal at the conditions mentioned.Ratnaparkhi P. and Gupta P. Sustained Release Oral Drug Delivery System – An Overview. International Journal of Pharma Research & Review. 2013. Accessed: May 30, 2016. For a drug that is made to be released over time, the objective is to stay within the therapeutic range as long as needed. There are many different methods used to obtain a sustained release.

Diffusion systems

Diffusion systems' rate release is dependent on the rate at which the drug dissolves through a barrier which is usually a type of polymer. Diffusion systems can be broken into two subcategories, reservoir devices and matrix devices. *Reservoir devices coat the drug with polymers and in order for the reservoir devices to have sustained-release effects, the polymer must not dissolve and let the drug be released through diffusion. The rate of reservoir devices can be altered by changing the polymer and is possible be made to have zero-order release; however, drugs with higher molecular weight have difficulty diffusing through the membrane.Perrie, Y., & Rades, T. Pharmaceutics: Drug delivery and targeting. London: Pharmaceutical Press. Accessed: May 30, 2016. *Matrix devices forms a matrix (drug(s) mixed with a gelling agent) where the drug is dissolved/dispersed. The drug is usually dispersed within a polymer and then released by undergoing diffusion. However, to make the drug SR in this device, the rate of dissolution of the drug within the matrix needs to be higher than the rate at which it is released. The matrix device cannot achieve a zero-order release but higher molecular weight molecules can be used. The diffusion matrix device also tends to be easier to produce and protect from changing in the gastrointestinal tract, but factors such as food can affect the release rate.

Dissolution systems

Dissolution systems must have the system dissolved slowly in order for the drug to have sustained release properties which can be achieved by using appropriate salts and/or derivatives as well as coating the drug with a dissolving material. It is used for drug compounds with high solubility in water. When the drug is covered with some slow dissolving coat, it will eventually release the drug. Instead of diffusion, the drug release depends on the solubility and thickness of the coating. Because of this mechanism, the dissolution will be the rate limiting factor for drug release. Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices. *The reservoir device coats the drug with an appropriate material which will dissolve slowly. It can also be used to administer beads as a group with varying thickness, making the drug release in multiple times creating a SR. *The matrix device has the drug in a matrix and the matrix is dissolved instead of a coating. It can come either as drug-impregnated spheres or drug-impregnated tablets.

Osmotic systems

Osmotic controlled-release oral delivery systems (OROS) have the form of a rigid

with a semi-permeable outer membrane and one or more small laser drilled holes in it. As the tablet passes through the body, water is absorbed through the

semipermeable membrane Semipermeable membrane is a type of biological or synthetic, polymeric membrane that will allow certain molecules or ions to pass through it by osmosis. The rate of passage depends on the pressure, concentration, and temperature of the molecul ...

via

osmosis Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of low water potential (region ...

, and the resulting

osmotic pressure Osmotic pressure is the minimum pressure which needs to be applied to a solution to prevent the inward flow of its pure solvent across a semipermeable membrane. It is also defined as the measure of the tendency of a solution to take in a pure ...

is used to push the active

through the opening(s) in the tablet. OROS is a trademarked name owned by

ALZA Corporation Alza Corporation was a pharmaceutical and medical systems company. Background Founded in 1968 by Dr. Alejandro Zaffaroni; the company's name is a portmanteau of his name. Alza was a major pioneer in the field of drug delivery systems, bringing ...

, which pioneered the use of osmotic pumps for oral drug delivery. Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as pH, food intake, GI motility, and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

. However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet.

Ion-exchange resin

In the ion-exchange method, the resins are cross-linked water-insoluble polymers that contain ionisable functional groups that form a repeating pattern of polymers, creating a polymer chain. The drug is attached to the resin and is released when an appropriate interaction of ions and ion exchange groups occur. The area and length of the drug release and number of cross-link polymers dictate the rate at which the drug is released, determining the SR effect.

Floating systems

A floating system is a system where it floats on gastric fluids due to low density. The density of the gastric fluids is about 1 g/mL; thus, the drug/tablet administered must have a smaller density. The

buoyancy Buoyancy (), or upthrust, is an upward force exerted by a fluid that opposes the weight of a partially or fully immersed object. In a column of fluid, pressure increases with depth as a result of the weight of the overlying fluid. Thus the ...

will allow the system to float to the top of the stomach and release at a slower rate without worry of excreting it. This system requires that there are enough gastric fluids present as well as food. Many types of forms of drugs use this method such as powders, capsules, and tablets.Dusane Ratilal, Gaikwad D., Banker H., and Pawar P. A Review On: Sustained Release Technology. International Journal of Research in Ayurveda and Pharmacy. 2011. Accessed: May 30, 2016.

Bio-adhesive systems

Bio-adhesive systems generally are meant to stick to mucus and can be favorable for mouth based interactions due to high mucus levels in the general area but not as simple for other areas. Magnetic materials can be added to the drug so another magnet can hold it from outside the body to assist in holding the system in place. However, there is low patient compliance with this system.

Matrix systems

The matrix system is the mixture of materials with the drug, which will cause the drug to slow down. However, this system has several subcategories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, and mineral matrices. *A hydrophobic matrix is a drug mixed with a hydrophobic polymer. This causes SR because the drug, after being dissolved, will have to be released by going through channels made by the hydrophilic polymer. *A hydrophilic matrix will go back to the matrix as discussed before where a matrix is a mixture of a drug or drugs with a gelling agent. This system is well liked because of its cost and broad regulatory acceptance. The polymers used can be broken down into categories: cellulose derivatives, non-cellulose natural, and polymers of acrylic acid. *A lipid matrix uses wax or similar materials. Drug release happens through diffusion through, and erosion of, the wax and tends to be sensitive to digestive fluids. *Biodegradable matrices are made with unstable, linked monomers that will erode by biological compounds such as enzymes and proteins. *A mineral matrix which generally means the polymers used are obtained in seaweed.

Stimuli inducing release

Examples of stimuli that may be used to bring about release include pH, enzymes, light, magnetic fields, temperature, ultrasonics, osmosis, cellular traction forces, and electronic control of

MEMS Microelectromechanical systems (MEMS), also written as micro-electro-mechanical systems (or microelectronic and microelectromechanical systems) and the related micromechatronics and microsystems constitute the technology of microscopic devices, ...

and NEMS. Spherical hydrogels, in micro-size (50-600 µm diameter) with 3-dimensional cross-linked polymer, can be used as drug carrier to control the release of the drug. These hydrogels are called microgels. They may possess a negative charge as example DC-beads. By ion-exchange mechanism, a large amount of oppositely charged amphiphilic drugs can be loaded inside these microgels. Then, the release of these drugs can be controlled by a specific triggering factor like pH, ionic strength or temperature.

Pill splitting

Some time release formulations do not work properly if split, such as controlled-release tablet coatings, while other formulations such as micro-encapsulation still work if the microcapsules inside are swallowed whole. Among the

health information technology Health information technology (HIT) is health technology, particularly information technology, applied to health and health care. It supports health information management across computerized systems and the secure exchange of health informa ...

(HIT) that pharmacists use are medication safety tools to help manage this problem. For example, the ISMP "do not crush" list can be entered into the system so that warning stickers can be printed at the point of dispensing, to be stuck on the pill bottle. Pharmaceutical companies that do not supply a range of half-dose and quarter-dose versions of time-release tablets can make it difficult for patients to be slowly tapered off their drugs.

History

The earliest SR drugs are associated with a patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles.Navin Dixit, Sheo Dutt Maurya, and Bhanu Sagar. Sustained Release Drug Delivery System. Indian Journal of Research in Pharmacy and Biotechnology. 2013. Accessed: May 30, 2016. The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s, and controlled release fertilizer in the 1970s where sustained and controlled delivery of nutrients was achieved following a single application to the soil. Delivery is usually effected by dissolution, degradation, or disintegration of an

excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...

in which the active compound is formulated.

Enteric coating An enteric coating is a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment. This helps by either protecting drugs from the acidity of the stomach, the stomach from the detrimental ef ...

and other encapsulation technologies can further modify release profiles.

Footnotes

External links

Controlled Release Society

United Kingdom & Ireland Controlled Release Society

5-day short course at MIT with Professor Robert Langer. {{DEFAULTSORT:Sustained Release Dosage Forms Dosage forms Routes of administration Drug delivery devices Pharmacokinetics