What is Drug Delivery?

Introduction

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 optimise 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.

Drug delivery is a concept heavily integrated with dosage form and route of administration, the latter sometimes being considered part of the definition. While route of administration is often used interchangeably with drug delivery, the two are separate concepts. Route of administration refers to the path a drug takes to enter the body, whereas drug delivery also encompasses the engineering of delivery systems and can include different dose forms and devices used to deliver a drug through the same route. Common routes of administration include oral, parenteral (injected), sublingual, topical, transdermal, inhaled, rectal, and vaginal, however drug delivery is not limited to these routes and there may be several ways to deliver medications through each route.

Since the approval of the first controlled-release formulation in the 1950s, research into new delivery systems has been progressing, as opposed to new drug development which has been declining. Several factors may be contributing to this shift in focus. One of the driving factors is the high cost of developing new drugs. A 2013 review found the cost of developing a delivery system was only 10% of the cost of developing a new pharmaceutical. A more recent study found the median cost of bringing a new drug to market was $985 million in 2020, but did not look at the cost of developing drug delivery systems. Other factors that have potentially influenced the increase in drug delivery system development may include the increasing prevalence of both chronic and infectious diseases, as well as a general increased understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of many drugs.

Current Efforts

Current efforts in drug delivery are vast and include topics such as:

Targeted Delivery

Targeted drug delivery is the delivery of a drug to its target site without having an effect on other tissues. Interest in targeted drug delivery has grown drastically due to its potential implications in the treatment of cancers and other chronic diseases. In order to achieve efficient targeted delivery, the designed system must avoid the host’s defence mechanisms and circulate to its intended site of action. A number of drug carriers have been studied to effectively target specific tissues, including liposomes, nanogels, and other nanotechnologies.

Controlled-release Formulations

Controlled or modified-release formulations alter the rate and timing at which a drug is liberated, in order to produce adequate or sustained drug concentrations. The first controlled-release (CR) formulation that was developed was Dexedrine in the 1950s. This period of time saw more drugs being formulated as CR, as well as the introduction of transdermal patches to allow drugs to slowly absorb through the skin. Since then, countless other CR products have been developed to account for the physiochemical properties of different drugs, such as depot injections for antipsychotics and sex hormones that require dosing once every few months.

Since the late 1990s, most of the research around CR formulations has been focused on implementing nanoparticles to decrease the rate of drug clearance.

Delivery of Biologic Drugs

Pharmaceutical preparations containing peptides, proteins, antibodies, genes, or other biologic components often face absorption issues due to their large sizes or electrostatic charges, and may be susceptible to enzymatic degradation once they have entered the body. For these reasons, recent efforts in drug delivery have been focused on methods to avoid these issues through the use of liposomes, nanoparticles, fusion proteins, protein-cage nanoparticles and many others. Intracellular delivery of macromolecules by chemical carriers is most advanced for RNA, as known from RNA-based COVID-19 vaccines, while proteins have also been delivered into cells in vivo and DNA is routinely delivered in vitro.

What is a Tablet (Pharmacy)?

Introduction

A tablet (also known as a pill) is a pharmaceutical oral dosage form (oral solid dosage, or OSD) or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose.

Tablets are prepared either by moulding or by compression. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet’s appearance. Medicinal tablets were originally made in the shape of a disk of whatever colour their components determined, but are now made in many shapes and colours to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimetres to about a centimetre.

The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions.

Brief History

Pills are thought to date back to around 1500 BC. Earlier medical recipes, such as those from 4000 BC, were for liquid preparations rather than solids. The first references to pills were found on papyruses in ancient Egypt, and contained bread dough, honey or grease. Medicinal ingredients, such as plant powders or spices, were mixed in and formed by hand to make little balls, or pills. In ancient Greece, such medicines were known as katapotia (“something to be swallowed”), and the Roman scholar Pliny, who lived from 23 to 79 AD, first gave a name to what we now call pills, calling them pilula.

Pills have always been difficult to swallow and efforts long have been made to make them go down easier. In medieval times, people coated pills with slippery plant substances. Another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. In the 1800s sugar-coating and gelatine-coating was invented, as were gelatine capsules.

In 1843, the British painter and inventor William Brockedon was granted a patent for a machine capable of “Shaping Pills, Lozenges and Black Lead by Pressure in Dies”. The device was capable of compressing powder into a tablet without use of an adhesive.

Types

Pills

A pill was originally defined as a small, round, solid pharmaceutical oral dosage form of medication. The word’s etymology reflects the historical concepts of grinding the ingredients with a mortar and pestle and rolling the resultant paste or dough into lumps to be dried. Today, in its strict sense, the word pill still refers specifically to tablets (including caplets) rather than capsules (which were invented much later), but because a simple hypernym is needed to intuitively cover all such oral dosage forms, the broad sense of the word pill is also widely used and includes both tablets and capsules – colloquially, any solid oral form of medication falls into the “pill” category.

An early example of pills came from Ancient Rome. They were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes, and were found aboard a Roman ship that wrecked in 140 BC. However, these tablets were meant to be pressed on the eyes, not swallowed.

Caplets

A caplet is a smooth, coated, oval-shaped medicinal tablet in the general shape of a capsule. Many caplets have an indentation running down the middle so they may be split in half more easily. Since their inception, capsules have been viewed by consumers as the most efficient method of taking medication. For this reason, producers of drugs such as OTC analgesics wanting to emphasize the strength of their product developed the “caplet”, a portmanteau of capsule-shaped tablet, in order to tie this positive association to more efficiently produced tablet pills, as well as being an easier-to-swallow shape than the usual disk-shaped tablet.

Orally Disintegrating Tablets (ODT)

An orally disintegrating tablet or orodispersible tablet (ODT), is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications.

Film Coated Tablets (FCT)

A film coated tablet is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. The used films protect the drug substance against denaturation by stomach acid and/or support a delayed (modified) release of the drug substance (“retard effect”). Such tablets should not be damaged or broken.

Tabletting Formulations

In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity, but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet.

Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).

Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.

Tablet Properties

Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.

Tablet diameter and shape are determined by the machine tooling used to produce them – a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they do not break up in the bottle, yet friable enough that they disintegrate in the gastric tract.

Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of simple failure and erosion tests, and more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias‘ (USP/NF, EP, JP, etc.). The hardness of tablets is the principal measure of mechanical strength. Hardness is tested using a tablet hardness tester. The units for hardness have evolved since the 1930s, but are commonly measured in kilograms per square centimetre. Models of tester include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die.

Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatine capsules.

Manufacturing

Manufacture of the Tableting Blend

In the tablet pressing process, the appropriate amount of active ingredient must be in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression (“DC”). Direct Compression is desirable as it is quicker. There is less processing, equipment, labour, and energy consumption. However, DC is difficult when a formulation has a high content of poorly compressible active ingredient.

Wet Granulation

Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.

Procedure

  • The active ingredient and excipients are weighed and mixed.
  • The wet granulate is prepared by adding the liquid binder-adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of corn starch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatine, and povidone.
  • Screening the damp mass through a mesh to form pellets or granules.
  • Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.
  • After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.

Dry Granulation

Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a ‘dry binder’ may need to be added to the formulation to facilitate the formation of granules.

Hot Melt Extrusion

Hot melt extrusion is utilised in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and bioavailability. Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and ‘extrude’ them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The extruded particles can then be blended and compressed into tablets or filled into capsules.

Granule Lubrication

After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate or stearic acid.

Manufacture of the Tablets

Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500-50 mg per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is repeated for each tablet.

Common problems encountered during tablet manufacturing operations include:

  • Fluctuations in tablet weight, usually caused by uneven powder flow into the die due to poor powder flow properties.
  • Fluctuations in dosage of the Active Pharmaceutical Ingredient, caused by uneven distribution of the API in the tableting blend (either due to poor mixing or separation in process).
  • Sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, or a sticky powder formulation.
  • Capping, lamination or chipping. This is caused by air being compressed with the tablet formulation and then expanding when the punch is released: if this breaks the tablet apart, it can be due to incorrect machine settings, or due to incorrect formulation: either because the tablet formulation is too brittle or not adhesive enough, or because the powder being fed to the tablet press contains too much air (has too low bulk density).
  • Capping can also occur due to high moisture content.

Tablet Compaction Simulator

Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.

Tablet Presses

Tablet presses, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerised, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density/hardness can each be controlled. This is achieved using a series of cams, rollers, or tracks that act on the tablet tooling (punches). Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression. Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products. There are two main standards of tablet tooling used in pharmaceutical industry: American standard TSM and European standard EU. TSM and EU configurations are similar to each other but cannot be interchanged.

Modern tablet presses reach output volumes of up to 1,700,000 tablets per hour. These huge volumes require frequent in-process quality control for the tablet weight, thickness and hardness. Due to reduce rejects rates and machine down-time, automated tablet testing devices are used on-line with the tablet press or off-line in the IPC-labs.

Tablet Coating

Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings are polymer and polysaccharide based, with plasticizers and pigments included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition.

If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an enteric coating can be used, which is resistant to stomach acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the small intestine, where they are absorbed. Coatings are often chosen to control the rate of dissolution of the drug in the gastrointestinal tract. Some drugs are absorbed better in certain parts of the digestive system. If this part is the stomach, a coating is selected that dissolves quickly and easily in acid. If the rate of absorption is best in the large intestine or colon, a coating is used that is acid resistant and dissolves slowly to ensure that the tablet reaches that point before dispersing. To measure the disintegration time of the tablet coating and the tablet core, automatic disintegration testers are used which are able to determine the complete disintegration process of a tablet by measuring the rest height of the thickness with every upward stroke of the disintegration tester basket.

There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. Coating pans are used mostly to sugar coat pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with a remote control panel, a dehumidifier, and dust collectors. An explosion-proof design is required for applying coatings that contain alcohol.

Pill-Splitters

It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill-splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this exposes the tablet core to the digestive juices, circumventing the intended delayed-release effect.

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What is Modified-Release Dosage?

Introduction

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).

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.

Sometimes these and other terms are treated as synonyms, but the United States Food and Drug Administration (FDA) 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 tablets (pills) and capsules to dissolve a drug 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 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 maximise 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. Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable.

  • CD: Controlled Delivery.
  • CR: Controlled Release.
  • DR: Delayed Release.
  • ER: Extended Release.
  • IR: Immediate Release.
  • 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: Extended Release.
  • XR: Extended Release.
  • XT: Extended Release.
  • LS: Lesser/Lower Strength.
  • DS: Double Strength.
  • 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).

Brief 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.

Methods

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. 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 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 (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 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.

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.

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 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.

Bio-Adhesive Systems

Bio-adhesive systems generally are meant to stick to mucus and can be favourable 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 and NEMS.

Spherical hydrogels, in micro-size (50-600 ┬Ám 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

Refer to 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 (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.

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What is Pill Splitting?

Introduction

Pill-splitting refers to the practice of splitting a tablet or pill to provide a lower dose of the active ingredient, or to obtain multiple smaller doses, either to reduce cost or because the pills available provide a larger dose than required. Many pills that are suitable for splitting (aspirin tablets for instance) come pre-scored so that they may easily be halved.

It is unsafe to split some prescription medications.

Refer to Inverse Benefit Law.

Pill Splitters

A pill-splitter is a simple and inexpensive device to split medicinal pills or tablets, comprising some means of holding the tablet in place, a blade, and usually a compartment in which to store the unused part. The tablet is positioned, and the blade pressed down to split it. With care it is often possible to cut a tablet into quarters. Also available as consumer items are multiple pill splitters, which cut numerous round or oblong pills in one operation.

Pill Scoring

A drug manufacturer may score pills with a groove to both indicate that a pill may be split and to aid the practice of splitting pills. When manufacturers do create grooves in pills, the groove must be consistent for consumers to be able to use them effectively. Many manufacturers choose to not use grooves. The United States government Centre for Drug Evaluation and Research makes the following recommendations for manufacturers when scoring pills with grooves:

  1. Pills should only have grooves if the split dosage is at least the minimum therapeutic dosage of the medication.
  2. The split pill should not create a toxicity hazard.
  3. Drugs which should not be split should not be scored with a groove.
  4. The split pill should be stable for the expected temperature and humidity.
  5. The split pill should have an equivalent effect to a full pill at an equivalent dose.

Dosage Uniformity

In the US “uniformity of dosage units” is defined by the United States Pharmacopeia (USP), which describes itself as “the official public standards-setting authority for all prescription and over-the-counter medicines, dietary supplements, and other healthcare products manufactured and sold in the United States.” More than 140 countries develop or rely upon US pharmaceutical standards according to the USP.

The USP standard for dosage uniformity expresses statistical criteria in the complex language of sampling protocols. The pharmaceutical dosage literature sometimes boils this down as requiring a standard deviation in dosage weight of less than 6%, which roughly corresponds to the weaker rule-of-thumb offered for public consumption that the vast majority of dosage units should be within 15% of the dosage target. “Dosage unit” is a technical term which covers oral medications (tablets, pills, capsules), as well as non-oral delivery methods.

A 2002 study of pill-splitting as conducted in four American long-term care facilities determined that 15 of the 22 dispensed prescriptions evaluated (68%) had fragment weight variance in excess of USP standards.

Cost Savings

Pill-splitting can be used to save money on pharmaceutical costs, as many prescription pharmaceuticals are sold at prices less than proportional to the dose. For example, a 10 mg tablet of a drug might be sold for the same or nearly the same price as a 5 mg tablet. Splitting 10 mg tablets allows the patient to purchase half the number of tablets at a lower price than the same weight of 5 mg tablets.

Both specialist and generalist physicians are not sufficiently aware of and do not communicate with patients about the cost to them of medication.

Some Potentially Suitable Medications

Randall Stafford of the Stanford School of Medicine published a study in 2002 of common prescription medications in the United States in which he evaluates pill splitting for “potential cost savings and clinical appropriateness”. The study identifies eleven prescription medications that satisfied the study criteria, based on the American pharmaceutical cost structure, pill formulation, and dosages of the time. Most of the medications listed in the table from the psychiatric drug class are antidepressants.

Uniformity of Split

Not all tablets split equally well. In a 2002 study, Paxil, Zestril and Zoloft split cleanly with 0% rejects. Glucophage was described as a hard tablet, requiring significant force, causing tablet halves to fly. Glyburide exhibited very poor splitting with many splitting into multiple pieces. Hydrodiuril and Oretic crumbled. Lipitor did not split cleanly, and the coating peeled. The diamond shaped Viagra tablets made location of the midline difficult. The worst result reported was Oretic 25 mg in which 60% of tablets failed to split to within 15% of target weight.

Alternative Purpose

Some drugs have a few different uses, and are usually sold in different packages and different doses for different applications. The price for some applications may be very different from that for other purposes. One example is Minoxidil, which is well known as a hair-growth stimulant; the same drug under the name Loniten is used for blood pressure control in much larger doses at a much lower price per unit weight.

Risks

The US Food and Drug Administration (FDA) has called pill splitting “risky”. At the same time, the FDA approves the manufacture of pills which are intended to be split.

Splitting pills may result in uneven splitting and creating pieces which will not deliver accurate dosage. Pills which are split might not be correctly halved, making the cut pieces unequal in size. Some pills are difficult to split. Some pills (particularly some time release drugs) are unsafe to split, and there could be mistakes in identifying when pills should not be split.

Lawsuits

In a California court filing dated April 2001, Trial Lawyers for Public Justice (TLPJ) brought a class-action lawsuit against Kaiser Permanente (Timmis v. Kaiser Permanente) on the grounds that “Kaiser’s mandatory pill-splitting policy endangers patients’ health solely to enhance the HMO’s profits” in violation of the California Unfair Competition Law (UCL) and the California Consumer Legal Remedies Act (CLRA). In December 2004, the California Court of Appeal affirmed the trial court ruling that Kaiser’s policy did not violate UCL or CLRA, noting the suit had failed to present evidence that the policy was unsafe.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Pill_splitting >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.