Tag: Medication

What is Neuropsychopharmacology?

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Introduction

Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (study of effects of drugs on the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behaviour.

It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of “how” and “why”, and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behaviour, and sleep behaviour.

Brief History

Drugs such as opium, alcohol, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually worked was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw psychology and psychiatry as largely phenomenological, in that behaviours or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the behavioural branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as “software” errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields – until several developments after World War II began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as MAO inhibitors, tricyclic antidepressants, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the prefrontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury.

The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.

Overview

An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neurochemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10-10 M such as found with extrastriatal D1 receptor for dopamine.

One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuropathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These “hyperselective-action” drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximising the efficacy (or technically the potency) of the drug within the clinical target and minimising adverse effects. However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is Vortioxetine, a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of relapse) and greatly reduced incidence of sexual dysfunction, without loss in antidepressant efficacy.

The groundwork is currently being paved for the next generation of pharmacological treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons – the study of which, in addition to neurotrophic factors, may hold hope for neurodegenerative diseases like Alzheimer’s, Parkinson’s, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.

Neurotransmission

So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device.

By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:

  • The synthesis and storage of neurotransmitter substances;
  • The transport of synaptic vesicles and subsequent release into the synapse;
  • Receptor activation and cascade function; and
  • Transport mechanisms (reuptake) and/or enzyme degradation.

The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterisation of a large number of very specific subtypes of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further “sub-subtypes” exist together with variants, totalling in the hundreds for just these 6 transmitters (refer to serotonin receptor, for example). It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.

It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl−. The concentration differences between the inside and outside of the cell determine the membrane voltage.

Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein coupled processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.

The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expression determines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.

Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.

Drugs

The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. “dirty drug”) and safe to consume. The 2005 Physicians’ Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with “selective serotonin reuptake inhibitors“, or SSRIs which exemplify modern pharmaceuticals. These SSRI antidepressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker anti-psychotics, and GABA agonist tranquilisers (benzodiazepines).

New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the antinarcoleptic action of the drug modafinil which was already being used only a year prior.

The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1 antagonists, and 5HT2c antagonists. Another is the proposal of new routes of exploration for antipsychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.

Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. Phencyclidine has been found to cause cell death in striatopallidal cells and abnormal vacuolisation in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons (Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself). As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.

Neural Circuits

It is a not-so-recent discovery that many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioural, and genetic correlates of receptor action, completing the knowledge of neural signalling (refer to Human Cognome Project). The signal paths of neurons are hyperorganised beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts.

Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviours with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signalling, even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviours as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation.

Significant progress has been made on central mechanisms of certain hallucinogenic drugs. It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the “classical psychedelics”, can be attributed largely to agonism of serotonin receptors. The 5HT2A receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT2C receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. 5HT2A activity has a net pro-dopaminergic effect, whereas 5HT2C receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory postsynaptic potentials, a process antagonised by serotonin itself through 5HT1 receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT1 receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT2A-mGlu2 heterodimer is also necessary for classical psychedelic activity. This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of “hallucination”.

Circadian rhythm, or sleep/wake cycling, is centred in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsin cells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABAergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibres. The output of the SCG, stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of melatonin which “entrains” the 24-hour cycle of SCN activity. The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.

Research

Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioural effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signalling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual’s specific reactions or degree of response to a drug or their tendency to develop addictions in the future. These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson’s disease and schizophrenia while still others are attempting to establish previously unknown neural correlates underlying certain phenomena.

Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes European Neuropsychopharmacology, and as part of the Reed Elsevier Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002, a recent comprehensive collected work of the ACNP, “Neuropsychopharmacology: The Fifth Generation of Progress” was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain.

Many other journals exist which contain relevant information such as Neuroscience. Some of them are listed at Brown University Library.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Neuropsychopharmacology >; 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.

Yes or No: Is there a Link Between Depression and Serotonin?

Published on by Andrew Marshall1 Comment

Every year many suffering with depression are prescribed antidepressants to manage their condition, with antidepressants being described – by a spokesperson for the Royal College of Psychiatrists – as “an effective evidence-based treatment” (The Pharmaceutical Journal, 2022).

Within England, UK, “From 2021-22, there was a 5% rise in the number of adults receiving them – from 7.9 million in the previous 12 months to 8.3 million. [… with …] “An estimated 83.4 million antidepressant drug items were prescribed between 2021 and 2022, which marks a 5% increase from the previous year.” (BBC, 2022).

Within the US, Brody and Gu (2020) reported that “During 2015–2018, 13.2% of adults aged 18 and over used antidepressant medications in the past 30 days. [… and … ] In 2018, an estimated 7.2% of American adults had a major depressive episode in the past year. Carey and Geberloff reported in 2018 that “Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010.”

Now it is important to remember that:

  • Depression is associated with diminished quality of life and increased disability;
  • Antidepressants are one of the primary treatments for depression;
  • Antidepressants are among the most frequently used therapeutic medications in the UK and US; and
  • There is research to suggest antidepressants work, at least in some people.

However, a new major analysis (by Moncrief et al., 2022) reported in the New Scientist suggests there is no link between serotonin levels and depression, raising questions about antidepressants that focus on this brain-signalling molecule (Wild, 2022, p.20).

Although this analysis suggests antidepressants might not be as effective as previously stated, brain electrodes might be. Read our next post about brain electrodes and depression here.

References

BBC (British Broadcasting Corporation). (2022) Nearly Half a Million More Adults on Antidepressants in England. Available from World Wide Web: https://www.bbc.co.uk/news/health-62094744. [Accessed: 17 November, 2022].

Carey, B. & Gebeloff, R. (2018) Many People Taking Antidepressants Discover They Cannot Quit. Available from World Wide Web: https://www.nytimes.com/2018/04/07/health/antidepressants-withdrawal-prozac-cymbalta.html. [Accessed: 17 November, 2022].

Moncrief, J., Cooper, R.E., Stockman, T., Amendola, S., Hengartner, M.P. & Horowitz, M.A. (2022) The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence. Molecular Psychiatry. doi.org/gqh6nd.

The Pharmaceutical Journal. (2022) Antidepressant Prescribing Increases by 35% in Six Years. Available from World Wide Web: https://pharmaceutical-journal.com/article/news/antidepressant-prescribing-increases-by-35-in-six-years. [Accessed: 17 November, 2022].

Wild, S. (2022) No Link between Depression and Serotonin, Finds Major Analysis. New Scientist. 30 July 2022, pp.20.

What is Drug Delivery?

Published on by Andrew Marshall2 Comments

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 Liberation (in Pharmacology)?

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Introduction

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 ionised, as cell membranes are relatively impermeable to ionised molecules.

The characteristics of a medication’s excipient play a fundamental role in creating a suitable environment for the correct absorption of a drug. This can mean that the same dose of a drug in different forms can have different bioequivalence, as they yield different plasma concentrations and therefore have different therapeutic effects. Dosage forms with modified release (such as delayed or extended release) allow this difference to be usefully applied.

Dissolution

In a typical situation, a pill taken orally will pass through the oesophagus and into the stomach. As the stomach has an aqueous environment, it is the first place where the pill can dissolve. The rate of dissolution is a key element in controlling the duration of a drug’s effect. For this reason, different forms of the same medication can have the same active ingredients but different dissolution rates. If a drug is administered in a form that is not rapidly dissolved, the drug will be absorbed more gradually over time and its action will have a longer duration. A consequence of this is that patients will comply more closely to a prescribed course of treatment, if the medication does not have to be taken as frequently. In addition, a slow release system will maintain drug concentrations within a therapeutically acceptable range for longer than quicker releasing delivery systems as these result in more pronounced peaks in plasma concentration.

The dissolution rate is described by the Noyes-Whitney equation:

Where:

  • {\frac {dW}{dt}} is the dissolution rate.
  • A is the solid’s surface area.
  • C is the concentration of the solid in the bulk dissolution medium.
  • C8 is the concentration of the solid in the diffusion layer surrounding the solid.
  • D is the diffusion coefficient.
  • L is the thickness of the diffusion layer.

As the solution is already in a dissolved state, it does not have to go through a dissolution stage before absorption begins.

Ionisation

Cell membranes present a greater barrier to the movement of ionised molecules than non-ionised liposoluble substances. This is particularly important for substances that are weakly amphoteric. The stomach’s acidic pH and the subsequent alkalization in the intestine modifies the degree of ionisation of acids and weak bases depending on a substance’s pKa. The pKa is the pH at which a substance is present at an equilibrium between ionised and non-ionised molecules. The Henderson-Hasselbalch equation is used to calculate pKa.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Liberation_(pharmacology) >; 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.

What is a Medical Prescription?

Published on by Andrew Marshall3 Comments

Introduction

A prescription, often abbreviated ℞ or Rx, is a formal communication from a physician or other registered health-care professional to a pharmacist, authorising them to dispense a specific prescription drug for a specific patient.

Historically, it was a physician’s instruction to an apothecary listing the materials to be compounded into a treatment – the symbol ℞ (a capital letter R, crossed to indicate abbreviation) comes from the first word of a medieval prescription, Latin: Recipere (“Take thou”), that gave the list of the materials to be compounded.

Brief History

The idea of prescriptions dates back to the beginning of history. So long as there were medications and a writing system to capture directions for preparation and usage, there were prescriptions.

Modern prescriptions are actually extemporaneous prescriptions (from the Latin ex tempore, “at/from the time”), meaning that the prescription is written on the spot for a specific patient with a specific ailment. This is distinguished from a non-extemporaneous prescription that is a generic recipe for a general ailment. Modern prescriptions evolved with the separation of the role of the pharmacists from that of the physician. Today the term extemporaneous prescriptions is reserved for compound prescriptions that requires the pharmacist to mix or compound the medication in the pharmacy for the specific needs of the patient.

Predating modern legal definitions of a prescription, a prescription traditionally is composed of four parts: a superscription, inscription, subscription, and signature.

The superscription section contains the date of the prescription and patient information (name, address, age, etc.). The symbol “℞” separates the superscription from the inscriptions sections. In this arrangement of the prescription, the “℞” is a symbol for recipe or literally the imperative “take!” This is an exhortation to the pharmacist by the medical practitioner, “I want the patient to have the following medication” – in other words, “take the following components and compound this medication for the patient.”

The inscription section defines what is the medication. The inscription section is further composed of one or more of:

  • A basis or chief ingredient intended to cure (curare).
  • An adjuvant to assist its action and make it cure quickly (cito).
  • A corrective to prevent or lessen any undesirable effect (tuto).
  • A vehicle or excipient to make it suitable for administration and pleasant to the patient (jucunde).

The subscription section contains dispensing directions to the pharmacist. This may be compounding instructions or quantities.

The signature section contains directions to the patient and is often abbreviated “Sig.” or “Signa.” It also obviously contains the signature of the prescribing medical practitioner though the word signature has two distinct meanings here and the abbreviations are sometimes used to avoid confusion.

Thus sample prescriptions in modern textbooks are often presented as:

  • Rx: medication.
  • Disp.: dispensing instructions.
  • Sig.: patient instructions.

Format and Definition

For a communication to be accepted as a legal medical prescription, it needs to be filed by a qualified dentist, advanced practice nurse, physician or veterinarian, for whom the medication prescribed is within their scope of practice to prescribe. This is regardless of whether the prescription includes prescription drugs, controlled substances or over-the-counter treatments.

Prescriptions may be entered into an electronic medical record system and transmitted electronically to a pharmacy. Alternatively, a prescription may be handwritten on pre-printed prescription forms that have been assembled into pads, or printed onto similar forms using a computer printer or even on plain paper according to the circumstance. In some cases, a prescription may be transmitted from the physician to the pharmacist orally by telephone. The content of a prescription includes the name and address of the prescribing provider and any other legal requirement such as a registration number (e.g. DEA Number in the United States). Unique for each prescription is the name of the patient. In the United Kingdom and Ireland the patient’s name and address must also be recorded. Each prescription is dated and some jurisdictions may place a time limit on the prescription. In the past, prescriptions contained instructions for the pharmacist to use for compounding the pharmaceutical product but most prescriptions now specify pharmaceutical products that were manufactured and require little or no preparation by the pharmacist. Prescriptions also contain directions for the patient to follow when taking the drug. These directions are printed on the label of the pharmaceutical product.

The word “prescription”, from “pre-” (“before”) and “script” (“writing, written”), refers to the fact that the prescription is an order that must be written down before a drug can be dispensed. Those within the industry will often call prescriptions simply “scripts”.

Contents

Every prescription contains who prescribed the prescription, who the prescription is valid for, and what is prescribed. Some jurisdictions, drug types or patient groups require additional information as explained below.

Drug Equivalence and Non-Substitution

Many brand name drugs have cheaper generic drug substitutes that are therapeutically and biochemically equivalent. Prescriptions will also contain instructions on whether the prescriber will allow the pharmacist to substitute a generic version of the drug. This instruction is communicated in a number of ways. In some jurisdictions, the pre-printed prescription contains two signature lines: one line has “dispense as written” printed underneath; the other line has “substitution permitted” underneath. Some have a pre-printed box “dispense as written” for the prescriber to check off (but this is easily checked off by anyone with access to the prescription). In other jurisdictions, the protocol is for the prescriber to handwrite one of the following phrases: “dispense as written”, “DAW”, “brand necessary”, “do not substitute”, “no substitution”, “medically necessary”, “do not interchange”. In Britain’s National Health Service, doctors are reminded that money spent on branded rather than generic drugs is consequently not available for more deserving cases.

Prescriptions for Children

In some jurisdictions, it may be a legal requirement to include the age of child on the prescription. For paediatric prescriptions some advise the inclusion of the age of the child if the patient is less than twelve and the age and months if less than five. In general, including the age on the prescription is helpful, and adding the weight of the child is also helpful.

Label and Instructions

Prescriptions in the USA often have a “label” box. When checked, the pharmacist is instructed to label the medication and provide information about the prescription itself is given in addition to instructions on taking the medication. Otherwise, the patient is simply given the instructions. Some prescribers further inform the patient and pharmacist by providing the indication for the medication; i.e. what is being treated. This assists the pharmacist in checking for errors as many common medications can be used for multiple medical conditions. Some prescriptions will specify whether and how many “repeats” or “refills” are allowed; that is whether the patient may obtain more of the same medication without getting a new prescription from the medical practitioner. Regulations may restrict some types of drugs from being refilled.

Writing Prescriptions

Legal Capacity to Write Prescriptions

National or local (i.e. US state or Canadian provincial) legislation governs who can write a prescription. In the United States, physicians (either M.D., D.O. or D.P.M.) have the broadest prescriptive authority. All 50 US states and the District of Columbia allow licensed certified Physician Assistants (PAs) prescription authority (with some states, limitations exist to controlled substances). All 50 US states and the District of Columbia, Puerto Rico and Guam allow registered certified nurse practitioners and other advanced practice registered nurses (such as certified nurse-midwives) prescription power (with some states including limitations to controlled substances). Many other healthcare professions also have prescriptive authority related to their area of practice. Veterinarians and dentists have prescribing power in all 50 US states and the District of Columbia. Clinical pharmacists are allowed to prescribe in some US states through the use of a drug formulary or collaboration agreements. Florida pharmacists can write prescriptions for a limited set of drugs. In all US states, optometrists prescribe medications to treat certain eye diseases, and also issue spectacle and contact lens prescriptions for corrective eyewear. Several US states have passed RxP legislation, allowing clinical psychologists who are registered as medical psychologists and have also undergone specialised training in script-writing, to prescribe drugs to treat emotional and mental disorders.

In August 2013, legislative changes in the UK allowed physiotherapists and podiatrists to have independent prescribing rights for licensed medicines that are used to treat conditions within their own area of expertise and competence. In 2018 this was extended to paramedics.

Standing Orders

Some jurisdictions allow certain physicians (sometimes a government official like the state Secretary of Health, sometimes physicians in local clinics or pharmacies) to write “standing orders” that act like a prescription for everyone in the general public. These orders also provide a standard procedure for determining if administration is necessary and details of how it is to be performed safely. These are typically used to authorise certain people to perform preventive, low-risk, or emergency care that would be otherwise logistically cumbersome to authorise for individual patients, including vaccinations, prevention of cavities, birth control, treatment of infectious diseases, and reversal of drug overdoses.

Legibility of Handwritten Prescriptions

Doctors’ handwriting is a reference to the stereotypically illegible handwriting of some medical practitioners, which sometimes causes errors in dispensing. In the US, illegible handwriting has been indirectly responsible for at least 7,000 deaths annually.

There are several theories about the causes of this phenomenon. Some sources say the extreme amount of writing doctors employ during training and at work leads to bad handwriting, whereas others claim that doctors neglect proper handwriting due to medical documents being intended to be read solely by medical professionals, not patients. Others simply classify the handwriting of doctors as a handwriting style. The issue may also have a historical origin, as physicians from Europe-influenced schools have historically used Latin words and abbreviations to convey prescriptions; many of the abbreviations are still widely used in the modern day and could be a source of confusion.

Some jurisdictions have legislatively required prescriptions to be legible – Florida, US specifies “legibly printed or typed” – and the Institute for Safe Medication Practices advocated the elimination of handwritten prescriptions altogether. There have been numerous devices designed to electronically read the handwriting of doctors, including electronic character recognition, keyword spotters, and “postprocessing approaches,” though the gradual shift to electronic health records and electronic prescriptions may alleviate the need for handwritten prescriptions altogether. In Britain’s NHS, remaining paper prescriptions are almost invariably computer printed and electronic (rather than paper) communication between surgery and pharmacy is increasingly the norm.

Conventions for Avoiding Ambiguity

Over the years, prescribers have developed many conventions for prescription-writing, with the goal of avoiding ambiguities or misinterpretation. These include:

  • Careful use of decimal points to avoid ambiguity:
    • Avoiding unnecessary decimal points and trailing zeros, e.g. 5 mL rather than 5.0 mL, 0.5 rather than .50 or 0.50, to avoid possible misinterpretation as 50.
    • Always using leading zeros on decimal numbers less than 1: e.g. 0.5 rather than .5 to avoid misinterpretation as 5.
  • Directions written out in full in English (although some common Latin abbreviations are listed below).
  • Quantities given directly or implied by the frequency and duration of the directions.
  • Where the directions are “as needed”, the quantity should always be specified.
  • Where possible, usage directions should specify times (7 am, 3 pm, 11 pm) rather than simply frequency (three times a day) and especially relationship to meals for orally consumed medication.
  • The use of permanent ink.
  • Avoiding units such as “teaspoons” or “tablespoons”.
  • Writing out numbers as words and numerals (“dispense #30 (thirty)”) as in a bank draft or cheque.
  • The use of the apothecaries’ system or avoirdupois units and symbols of measure – pints (O), ounces (℥), drams (ℨ), scruples (℈), grains (gr), and minims (♏︎) – is discouraged given the potential for confusion. For example, the abbreviation for a grain (“gr”) can be confused with the gram, abbreviated g, and the symbol for minims (♏︎), which looks almost identical to an ‘m’, can be confused with micrograms or metres. Also, the symbols for ounce (℥) and dram (ℨ) can easily be confused with the numeral ‘3’, and the symbol for pint (O) can be easily read as a ‘0’. Given the potential for errors, metric equivalents should always be used.
  • The degree symbol (°), which is commonly used as an abbreviation for hours (e.g., “q 2-4°” for every 2-4 hours), should not be used, since it can be confused with a ‘0’ (zero). Further, the use of the degree symbol for primary, secondary, and tertiary (1°, 2°, and 3°) is discouraged, since the former could be confused with quantities (i.e. 10, 20 and 30, respectively).
  • Micrograms are abbreviated mcg rather than µg (which, if handwritten, could easily be mistaken for mg (milligrams). Even so, pharmacists must be on the alert for inadvertent over- or under-prescribing through a momentary lapse of concentration.

Abbreviations

Many abbreviations are derived from Latin phrases. Hospital pharmacies have more abbreviations, some specific to the hospital. Different jurisdictions follow different conventions on what is abbreviated or not. Prescriptions that do not follow area conventions may be flagged as possible forgeries.

Some abbreviations that are ambiguous, or that in their written form might be confused with something else, are not recommended and should be avoided. These are flagged in the table in the main article. However, all abbreviations carry an increased risk for confusion and misinterpretation and should be used cautiously.

Non-Prescription Drug Prescriptions

Over-the-counter medications and non-controlled medical supplies such as dressings, which do not require a prescription, may also be prescribed. Depending upon a jurisdiction’s medical system, non-prescription drugs may be prescribed because drug benefit plans may reimburse the patient only if the over-the-counter medication is taken at the direction of a qualified medical practitioner. In the countries of the UK, National Health Service (NHS) prescriptions are either free or have a fixed price per item; a prescription may be issued so the patient does not have to purchase the item at commercial price.

Some medical software requires a prescription.

Legislation may define certain equipment as “prescription devices”. Such prescription devices can only be used under the supervision of authorised personnel and such authorisation is typically documented using a prescription. Examples of prescription devices include dental cement (for affixing braces to tooth surfaces), various prostheses, gut sutures, sickle cell tests, cervical cap and ultrasound monitor.

In some jurisdictions, hypodermic syringes are in a special class of their own, regulated as illicit drug use accessories separate from regular medical legislation. Such legislation often allows syringes to be dispensed only with a prescription.

Use of Technology

As a prescription is nothing more than information among a prescriber, pharmacist and patient, information technology can be applied to it. Existing information technology is adequate to print out prescriptions. Hospital information systems in some hospitals do away with prescriptions within the hospital. There are proposals to securely transmit the prescription from the prescriber to the pharmacist using smartcard or the internet. In the UK a project called the Electronic Transfer of Prescriptions (ETP) within the National Programme for IT (NPfIT) is currently piloting such a scheme between prescribers and pharmacies.

Within computerised pharmacies, the information on paper prescriptions is recorded into a database. Afterwards, the paper prescription is archived for storage and legal reasons.

A pharmacy chain is often linked together through corporate headquarters with computer networking. A person who has a prescription filled at one branch can get a refill of that prescription at any other store in the chain, as well as have their information available for new prescriptions at any branch.

Some online pharmacies also offer services to customers over the internet, allowing users to specify the store that they will pick up the medicine from.

Many pharmacies now offer services to ship prescription refills right to the patient’s home. They also offer mail service where you can mail in a new, original prescription and a signed document, and they will ship the filled prescription back to you.

Pharmacy information systems are a potential source of valuable information for pharmaceutical companies as it contains information about the prescriber’s prescribing habits. Prescription data mining of such data is a developing, specialised field.

Many prescribers lack the digitised information systems that reduce prescribing errors. To reduce these errors, some investigators have developed modified prescription forms that prompt the prescriber to provide all the desired elements of a good prescription. The modified forms also contain predefined choices such as common quantities, units and frequencies that the prescriber may circle rather than write out. Such forms are thought to reduce errors, especially omission and handwriting errors and are actively under evaluation.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Medical_prescription >; 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.

What is a Tablet (Pharmacy)?

Published on by Andrew Marshall1 Comment

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.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Tablet_(pharmacy) >; 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.

What is Modified-Release Dosage?

Published on by Andrew Marshall3 Comments

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

Pill Splitting

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.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Modified-release_dosage >; 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.

What is the Inverse Benefit Law?

Published on by Andrew Marshall1 Comment

Introduction

The inverse benefit law states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively a drug is marketed. Two Americans, Howard Brody and Donald Light, have defined the inverse benefit law, inspired by Tudor Hart’s inverse care law.

A drug effective for a serious disorder is less and less effective as it is promoted for milder cases and for other conditions for which the drug was not approved. Although effectiveness becomes more diluted, the risks of harmful side effects persist, and thus the benefit-harm ratio worsens as a drug is marketed more widely. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.

State of Affairs

The law is manifested through 6 basic marketing strategies:

  • Reducing thresholds for diagnosing disease;
  • Relying on surrogate endpoints;
  • Exaggerating safety claims;
  • Exaggerating efficacy claims;
  • Creating new diseases; and
  • Encouraging unapproved uses.

Impact

This is the reason why organisations like “Worst Pill, Best Pill” recommend not to use/prescribe new medications before being in the market for at least ten years (except in the case of important new drugs that treat previously unsolved problems).

Agencies of drugs, committee of ethics and organisations of patients’ safety should consider:

  • Requiring that clinical trials run long enough to pick up evidence of side effects and record all adverse reactions, including in subjects who drop out.
  • Paying companies more for new drugs in proportion to how much better they are for patients than existing drugs, and marketing according to the value of the new drugs (ratio of benefits to harms and marketing).
  • Considering that market could be a force against the best use of medications.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Inverse_benefit_law >; 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.

What is Pill Splitting?

Published on by Andrew Marshall2 Comments

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.

What is the British National Formulary for Children?

Published on by Andrew Marshall1 Comment

Introduction

The British National Formulary for Children (BNFC) is the standard UK paediatric reference for prescribing and pharmacology.

It contains a wide range of information and advice on prescribing for children – from newborn to adolescence. The entries are classified by group of drug, giving cautions for use, side effects, licensed use, indications and dose of most of the drugs available for children in the UK National Health Service. Though published in and for the United Kingdom, the vast bulk of the clinical information will apply in any country.

Authorship and Publication

The BNFC is jointly published annually by the British Medical Association, the Royal Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health, and the Neonatal and Paediatric Pharmacists Group.

The principal contributors are acknowledged in the front pages.

It is overseen by the BNFC Paediatric Formulary Committee and edited by an international team of pharmacists.

Brief History

The BNFC developed from the British National Formulary (BNF), which prior to 2005 had provided information on the treatment of children, with the doses largely determined by calculations based on the body weight of the child. The guidance was provided by pharmacists and doctors whose expertise was in the care of adults.

This was an anomaly, as in relation to responses to medicines, the difference between a newborn and a sixteen year old is greater than the difference between a sixteen year old and a sixty year old.

Starting in 2002, Professor Martin Kendall, then chairman of the BNF Joint Formulary Committee worked to get things changed.

The UK Department of Health (now the DHSC) agreed to fund the BNFC, as it does the BNF, to ensure that NHS clinicians can have up to date information in their pockets.

The first edition was published in 2005, with George Rylance chairing the Paediatric Formulary Committee and Dinesh Mehta as the first executive editor. Anne, the Princess Royal attended the launch on 14 July.

Editions

The BNFC is published annually, but electronic updates are produced frequently, as needed.

Availability

Though not aimed at the general public, the BNFC, like the BNF is available for purchase. It is provided to NHS staff – usually through their employer, but may be obtained through Medicines Complete.

The app is available through the usual app stores.

For general advice on Medicines for Children the website of that name may be a better source of information than the BNFC. It is published by two of the publishers of the BNFC (RCPCH & NPPG) and the charity WellChild so can reasonably be judged to be authoritative (Though as the site notes, it is not a substitute for contact with an appropriate clinician or pharmacist).

Contents

Table of Contents

  • How BNF publications are constructed.
  • How to use BNF Publications in print.
  • Changes.
  • Guidance on Prescribing.
  • Prescription writing.
  • Supply of medicines.
  • Emergency supply of medicines.
  • Controlled drugs and drug dependence.
  • Adverse reactions to drugs.
  • Guidance on intravenous infusions.
  • Prescribing in hepatic impairment.
  • Prescribing in renal impairment.
  • Prescribing in pregnancy.
  • Prescribing in breast-feeding.
  • Prescribing in palliative care.
  • Drugs and sport.
  • Medicines optimisation.
  • Antimicrobial stewardship.
  • Prescribing in dental practice.

Notes on Drugs and Preparations

  • Gastro-intestinal system.
  • Cardiovascular system.
  • Respiratory system.
  • Nervous system.
  • Infection.
  • Endocrine system.
  • Genito-urinary system.
  • Immune system and malignant disease.
  • Blood and nutrition.
  • Musculoskeletal system.
  • Eye.
  • Ear, nose and oropharynx.
  • Skin.
  • Vaccines.
  • Anaesthesia.
  • Emergency treatment of poisoning.

Appendices and Indices

  • Interactions.
  • Borderline substances.
  • Cautionary and advisory labels for dispensed medicines.
  • Dental Practitioners’ Formulary.
  • Nurse Prescribers’ Formulary.
  • Non-medical prescribing.
  • Index of manufacturers.
  • Special-order Manufacturers.
  • Index.
  • Medical emergencies in the community.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/British_National_Formulary_for_Children >; 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.