Modified-release dosage


Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.
Sustained-release dosage forms are dosage forms designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects. This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates. Sustained release's definition is more akin to a "controlled release" rather than "sustained".
Extended-release dosage consists of either sustained-release or controlled-release 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 has in fact defined most of these as different concepts. Sometimes the term "depot tablet" is used, by analogy to the term for an injection formulation of a drug which releases slowly over time, but this term is not medically or pharmaceutically standard for oral medication.
Modified-release dosage and its variants are mechanisms used in tablets and capsules to dissolve a drug over time in order to be released more slowly and steadily into the bloodstream, while having the advantage of being taken at less frequent intervals than immediate-release formulations of the same drug. For example, orally administered extended-release morphine can enable certain chronic pain patients to take only tablets per day, rather than needing to redose every as is typical with standard-release morphine tablets.
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 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, forms of controlled release medicines include gels, implants and devices 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. 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 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.
AbbreviationMeaningNotes
CDControlled Delivery
CRControlled Release
CCContinuous Control, Constant Control
DRDelayed Release
ERExtended Release
IRImmediate Release
IDInitial Depot
LALong-Acting
LARLong-Acting Release
MRModified Release
PRProlonged Release
SASustained ActionAmbiguous, can sometimes mean Short-Acting
SRSustained Release
TRTimed Release
XLExtra Long
XRExtended/Extra Release
XTExtended/Extra Time
LSLesser/Lower Strength
DSDouble Strength
DADouble Action
ESExtra Strength
XSExtra Strength

A few other abbreviations are similar to these but refer to dose rather than release rate. They include ES and XS.

Methods

Today, most time-release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance 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 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, the development of a time-release product may be problematic.
The biological half-life 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, 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. Appropriate half-lives used to apply sustained methods are typically 3–4 hours and a drug dose greater than 0.5 grams is too high.
The therapeutic index 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. 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.
  • Matrix devices forms a matrix 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 have the form of a rigid tablet 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 via osmosis, and the resulting osmotic pressure is used to push the active drug through the opening in the tablet. OROS is a trademarked name owned by ALZA Corporation, 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. 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.