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 inhal ...
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, administ ...
(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 c ...
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, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delive ...
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 ...
s (pills) and capsules to dissolve 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 inhal ...
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
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 ...
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
Vaginal rings (also known as intravaginal rings, or V-Rings) are polymeric drug delivery devices designed to provide controlled release of drugs for intravaginal administration over extended periods of time. The ring is inserted into the vagina a ...
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
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medicati ...
.
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 mic ...
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 cellu ...
, 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 Dose dumping is a phenomenon of drug metabolism in which environmental factors can cause the premature and exaggerated release of a drug. This can greatly increase the concentration of a drug in the body and thereby produce adverse effects or even d ...
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.
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.[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.
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.