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 [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage).[1]
Sustained-release dosage forms are dosage forms 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 effects. This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates (an example being hydrogels). 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.[1]
Modified-release dosage and its variants are mechanisms used in tablets (pills) 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 (IR) formulations of the same drug. For example, orally administered extended-release morphine can enable certain chronic pain patients to take only 1–2 tablets per day, rather than needing to redose every 4–6hours 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 (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 (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) 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 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.[2] Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable.
Abbreviation
Meaning
Notes
CD
Controlled Delivery
CR
Controlled Release
CC
Continuous Control, Constant Control
DR
Delayed Release
ER
Extended Release
IR
Immediate Release
ID
Initial Depot
LA
Long-Acting
LAR
Long-Acting Release
MR
Modified Release
PR
Prolonged Release
SA
Sustained Action
Ambiguous, can sometimes mean Short-Acting
SR
Sustained Release
TR
Timed Release
XL
Extra Long
XR
Extended/Extra Release
XT
Extended/Extra Time
LS
Lesser/Lower Strength
DS
Double Strength
DA
Double Action
ES
Extra Strength
XS
Extra Strength
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).
Today, most time-release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance(s) (various: some acrylics, even chitin; these substances are often patented) 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 (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.[3] 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.[4][5]
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.[6] For a drug that is made to be released over time, the objective is to stay within the therapeutic range as long as needed.[3]
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.[3]
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.[3] 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.[7][8]
Matrix devices forms a matrix (drug(s) mixed with a gelling agent)[9] where the drug is dissolved/dispersed.[8] 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.[7] 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.[6]
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.[3] It is used for drug compounds with high solubility in water.[6] 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.[3] Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices.[6]
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.[6]
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.[6]
A 54mg tablet of Concerta, which uses OROS technology.
Osmotic controlled-release oral delivery systems (OROS) 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(s) in the tablet. OROS is a trademarked name owned by ALZA Corporation, which pioneered the use of osmotic pumps for oral drug delivery.[10][11][12]
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.[10][13][14][15][16][17][18]
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.[3][6] 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.[6]
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 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.[3] Many types of forms of drugs use this method such as powders, capsules, and tablets.[19]
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.[3]
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.[3]
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.[3]
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.[3] 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.[20]
A lipid matrix uses wax or similar materials. Drug release happens via diffusion through, and erosion of, the wax and tends to be sensitive to digestive fluids.[3]
Biodegradable matrices are made with unstable, linked monomers that will erode by biological compounds such as enzymes and proteins.[3]
A mineral matrix which generally means the polymers used are obtained in seaweed.[3]
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,[21] and electronic control of MEMS[22] and NEMS.[23]
Spherical hydrogels, in micro-size (50-600μm 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.[24]
Pill splitting
Empty half-shell of a split bupropion XL 150mg manufactured by Anchen Pharmaceuticals that was soaked in water overnight and then shaken.
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.[25][26]
Among the health information technology (HIT) that pharmacists use are medication safety tools to help manage this problem. For example, the ISMP "do not crush" list[27] 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.[7] 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 in which the active compound is formulated. Enteric coating and other encapsulation technologies can further modify release profiles.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Lilesh Khalane, Atulal Kunte, and Arunadevi Blrajdar. Sustained Release Drug Delivery System: A Concise Review. Pharmatutor: pharmacy infopedia. 2016. Accessed: May 30, 2016.
↑ Sampath Kumar, Debjit Bhowmik, Shweta Srivastava, Shravan Paswan, and A. Dutta. Sustained. Release Drug Delivery System Potential. The Pharma Innovation. 2012. Accessed: May 30, 2016.
↑ Kapil Patil, Prashant Patil , Javesh Patil , and Sunil Pawar. A Basic Approach on Sustained Release Drug Delivery System. American Journal of PharmTech Research. 2011. Accessed: May 30, 2016.
1 2 3 4 5 6 7 8 Ratnaparkhi P. and Gupta P. Sustained Release Oral Drug Delivery System – An Overview. International Journal of Pharma Research & Review. 2013. Accessed: May 30, 2016.
1 2 3 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.
1 2 Perrie, Y., & Rades, T. Pharmaceutics: Drug delivery and targeting. London: Pharmaceutical Press. Accessed: May 30, 2016.
↑ Tarun Parashar, Soniya, Vishal Singh, Gaurav Singh, Satyanand Tyagi, Chirag Patel, and Anil Gupta. International Journal of Research and Development in Pharmacy and Life Sciences. Novel Oral Sustained Release Technology: A Concise Review. 2013. Accessed: May 30, 2016.
1 2 Malaterre, V; Ogorka, J; Loggia, N; Gurny, R (November 2009). "Oral osmotically driven systems: 30 years of development and clinical use". European Journal of Pharmaceutics and Biopharmaceutics. 73 (3): 311–23. doi:10.1016/j.ejpb.2009.07.002. PMID19602438.
↑ Conley, R; Gupta, SK; Sathyan, G (October 2006). "Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form". Current Medical Research and Opinion. 22 (10): 1879–92. doi:10.1185/030079906x132613. PMID17022845. S2CID42490425.
↑ Verma, RK; Mishra, B; Garg, S (July 2000). "Osmotically controlled oral drug delivery". Drug Development and Industrial Pharmacy. 26 (7): 695–708. doi:10.1081/ddc-100101287. PMID10872087. S2CID35670161.
↑ van den Berg, G; van Steveninck, F; Gubbens-Stibbe, JM; Schoemaker, HC; de Boer, AG; Cohen, AF (1990). "Influence of food on the bioavailability of metoprolol from an OROS system; a study in healthy volunteers". European Journal of Clinical Pharmacology. 39 (3): 315–6. doi:10.1007/bf00315121. PMID2257873. S2CID1838636.
↑ Bass, DM; Prevo, M; Waxman, DS (2002). "Gastrointestinal safety of an extended-release, nondeformable, oral dosage form (OROS: a retrospective study". Drug Safety. 25 (14): 1021–33. doi:10.2165/00002018-200225140-00004. PMID12408733. S2CID35424637.
↑ Auiler, JF; Liu, K; Lynch, JM; Gelotte, CK (2002). "Effect of food on early drug exposure from extended-release stimulants: results from the Concerta, Adderall XR Food Evaluation (CAFE) Study". Current Medical Research and Opinion. 18 (5): 311–6. doi:10.1185/030079902125000840. PMID12240794. S2CID25994524.
↑ 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.
↑ Jaimini Manish and Kothari Abhay. Sustained Release Matrix Type Drug Delivery System: A Review. Journal of Drug Delivery & Therapeutics. 2012. Accessed: May 30, 2016.
A tablet is a pharmaceutical oral dosage form or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.
A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".
Excipient is a substance formulated alongside the active ingredient of a medication. Excipients serve various purposes, including long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts, or enhancing the therapeutic properties of the active ingredient in the final dosage form. They can facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients can also aid in the manufacturing process by improving the handling of active substances, facilitating powder flowability, or preventing denaturation and aggregation during the expected shelf life. The selection of excipients depends on factors such as the route of administration, dosage form, and active ingredient.
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 metric scale. Microencapsulation can also be used to enclose solids, liquids, or gases inside a micrometric wall made of hard or soft soluble film, in order to reduce dosing frequency and prevent the degradation of pharmaceuticals.
Zydis is a technology used to manufacture orally disintegrating tablets developed by R.P. Scherer Corporation. Zydis tablets dissolve in the mouth within 3 seconds.
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 effects of the drug, or to release the drug after the stomach. Some drugs are unstable at the pH of gastric acid and need to be protected from degradation. Enteric coating is also an effective method to obtain drug targeting. Other drugs such as some anthelmintics may need to reach a high concentration in a specific part of the intestine. Enteric coating may also be used during studies as a research tool to determine drug absorption. Enteric-coated medications pertain to the "delayed action" dosage form category. Tablets, mini-tablets, pellets and granules are the most common enteric-coated dosage forms.
Absorption is the journey of a drug travelling from the site of administration to the site of action.
Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.
The osmotic-controlled release oral delivery system (OROS) is an advanced controlled release oral drug delivery system in 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 laser drilled opening(s) in the tablet and into the gastrointestinal tract. OROS is a trademarked name owned by ALZA Corporation, which pioneered the use of osmotic pumps for oral drug delivery.
An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. The ODT serves as an alternative dosage form for patients who experience dysphagia or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population and 18-22% of all patients in long-term care facilities ODTs may have a faster onset of effect than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.
Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.
Thin-film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth and/or via the small intestines (enterically). A film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.
Pharmaceutical engineering is a branch of engineering focused on discovering, formulating, and manufacturing medication, analytical and quality control processes, and on designing, building, and improving manufacturing sites that produce drugs. It utilizes the fields of chemical engineering, biomedical engineering, pharmaceutical sciences, and industrial engineering.
Mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. Bioadhesion is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of polymers can be evaluated via rheological synergism studies with freshly isolated mucus, tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans.
Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, granulation, coating, tablet pressing, and others.
Glyceryl behenate is a fat used in cosmetics, foods, and oral pharmaceutical formulations. In cosmetics, it is mainly used as a viscosity-increasing agent in emulsions.
Buccal administration is a topical route of administration by which drugs held or applied in the buccal area diffuse through the oral mucosa and enter directly into the bloodstream. Buccal administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication does not pass through the digestive system and thereby avoids first pass metabolism. Drug forms for buccal administration include tablets and thin films.
Liberation is the first step in the process by which medication enters the body and liberates the active ingredient that has been administered. The pharmaceutical drug must separate from the vehicle or the excipient that it was mixed with during manufacture. Some authors split the process of liberation into three steps: disintegration, disaggregation and dissolution. A limiting factor in the adsorption of pharmaceutical drugs is the degree to which they are ionized, as cell membranes are relatively impermeable to ionized molecules.
Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture.
Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.
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