Investigation of Drug Degradation in Moisture Barrier Coated Non-Hygroscopic Tablets

October 30, 2021

^*Bricklane Innovations

St Johns Innovation Centre

Milton, Cambridge CB4 0WS

^**Department of Pharmaceutics

UCL School of Pharmacy, University of London

29-39 Brunswick Square

London WC1N 1AX

Abstract

This study investigated the moisture barrier performance of polymer film coatings on a low hygroscopic tablet formulation based on dibasic calcium phosphate dihydrate and aspirin. Tablets were prepared by direct compaction and coated with aqueous dispersions of Eudragit® L30 D-55, Eudragit® EPO, Opadry® AMB and Sepifilm® LP.

Moisture uptake was studied by dynamic vapour sorption at 0 and 75% RH (25 ^oC). Stability was studied at 75 %RH/25 ^oC for 120 days and HPLC assay used to determine aspirin content.

Uncoated tablet cores equilibrated rapidly and took up very little water (0.11±0.006 %), confirming their low hygroscopicity. The amounts for coated cores varied as follows: 0.19±0.001 (Eudragit L30 D-55), 0.35±0.005 (Opadry AMB), 0.49±0.006 (Sepifilm LP) and 0.75±0.008 (Eudragit EPO) indicating that coated cores had higher uptake.

There was a progressive decrease in the strength of aspirin in all the samples studied, with the coated cores showing more pronounced degradation of the active (mean % aspirin recovered after 4 months was 80.02±0.04 for uncoated cores compared with 78.75±0.30 for cores coated with Eudragit L30 D-55, 76.15±0.55 for Opadry AMB, 75.98±1.25 for Sepifilm LP and 66.45±1.13 for Eudragit EPO).

It is concluded that the benefits of using polymer films as moisture barrier coatings to increase drug stability in tablet formulations of low hygroscopicity are limited.

1 Introduction

Many physical and chemical properties of pharmaceutical substances are modified when they take up appreciable amounts of water (Dawoodbhai and Rhodes, 1989). During pre-manufacture processing, raw materials may come into contact with water, and some moisture may be retained as a result. Finished products can also become exposed to water vapour during manufacture, for instance while in temporary storage in the warehouse before packaging or even when in use by the patient. Water sorbed this way has the potential to alter functionality of the product, including key properties like disintegration and dissolution, and chemical and physical stability (Carstensen, 1988). For many drug products, especially those with moisture-sensitive ingredients, preventing water uptake is a key objective.

There are many ways of minimizing water uptake into dosage forms and/or preventing its interaction with active drug substances susceptible to hydrolysis. One approach involves the careful selection of excipients that are able to bind or repel water. When combined with a variety of technologies and packaging solutions, the deleterious effects of environmental water can be mitigated (Zografi and Kontny, 1986; Ahlneck and Zografi, 1990; Alvarez-Lorenzo et al, 2000).

A relatively recent innovation is the application of polymer film coatings with moisture barrier properties onto actual unit solid dosage forms (Mwesigwa et al., 2005). This approach is attractive since it provides a means of limiting moisture uptake into the product in addition to the usual benefits associated with application of polymer film coatings.

An ideal moisture barrier coating should exhibit low permeability to water vapour. Additionally, the coating should have a high moisture binding capacity so that any sorbed water can be prevented from reaching into the core.

In previous studies, the moisture uptake and permeability characteristics of polymer films commonly used as moisture barrier coatings were described (Eudragit L30 D-55, Eudragit EPO, Opadry AMB and Sepifilm LP).

These studies showed that polymer films exhibited complex moisture sorption behaviour with no discernable differentiation of permeability characteristics on the basis of hygroscopicity. Crucially for moisture barriers, there was no relationship between either sorption or permeability characteristics of cast films and functionality as protective coatings after application onto hygroscopic tablet cores. Our studies found that the levels of aspirin degradation were inexplicably higher in the coated cores than the uncoated cores despite coated samples achieving a net reduction in moisture uptake.

The purpose of the current study therefore was to investigate whether the same moisture barrier polymer films applied onto a non-hygroscopic tablet core might offer better protection and ensure the stability of a hydrolysable active drug substance.

2 Materials and Methods

2.1 Materials

Poly(methacrylic acid ethyl acrylate) copolymer (Eudragit L30 D-55, Evonik, Darmstadt, Germany), poly(butyl methacrylate (2-dimethylaminoethyl) methacrylate methyl methacrylate copolymer (Eudragit EPO, Evonik), a polyvinyl alcohol (PVA) – based coating system (Opadry AMB, Colorcon, Dartford, UK); and a hypromellose-based coating system (Sepifilm LP 014, Seppic, Paris, France) were free samples from the respective vendors.

Dibasic calcium phosphate dihydrate (Emcompress, JRS Pharma, Rosenberg, Germany) was purchased from JRS Pharma. Aspirin (USP Grade), triethyl citrate, talc, titanium dioxide, poly ethylene glycol (PEG) 6000, stearic acid, magnesium stearate, sodium lauryl sulphate, and carboxy methylcellulose sodium were all purchased from Sigma Aldrich (Dorset, UK).

2.2 Methods

2.2.1 Tablet Preparation and Coating

Tablet cores were obtained by direct compression and were based on aspirin (30%), dibasic calcium phosphate dihydrate (69.5%) and stearic acid (0.5%) using an eccentric tablet press (Manesty, Merseyside, UK). The tablet target weight was 200 mg and a breaking force strength of ≥ 70N.

Tablet core coating was undertaken in a laboratory-scale fluidized bed coater (Aeromatic-Fielder AG, Switzerland) at 40 ^oC. The coatings vendors’ recommended guidelines were followed to achieve theoretical dry weight gains of 1.8 % (Eudragit L30 D-55), 6.4% (Eudragit EPO), 4% (Opadry AMB), and 3 % (Sepifilm LP).

All coated and uncoated samples cores were thoroughly dried in a vacuum oven (for six hours at 40 ^oC) and stored in closed bottles over phosphorous pentoxide dessicant pending further tests.

The aspirin activity remaining in the tablet cores after coating application was compared with that of uncoated tablets. The degradation in coated samples was found to be less than 0.1 %.

2.2.2 Equilibrium Moisture Sorption-Desorption Studies

Moisture sorption characteristics of uncoated and coated tablet cores were studied in a dynamic vapour sorption apparatus (DVS 1, Surface Measurement Systems, London, UK).

Relative humidity (RH) was programmed to expose samples at 0% RH and then automatically switch to 75 %RH. The equilibration condition for each RH stage was set at a mass change rate of 0.001 %/min between two consecutive measurements.

All experiments were performed in triplicate at 25 ^oC. The results of water uptake are reported as the per cent dry basis (db) versus exposure time.

2.2.3 Aspirin Stability Studies

Stability studies were undertaken at 75% RH/25 ^oC in sealed glass desiccators, which were placed in a thermostatted incubator (Sanyo-Gallenkamp, Loughborough, UK). The RH condition was provided by a NaCl slurry. Sampling was undertaken periodically once a month for a total period of four months.

2.2.4 HPLC Assay

A previously validated HPLC method (Fogel et al, 1984) was used (with minor modification) with to assay the retained strength of aspirin with the tablets. The HPLC conditions were an integrated HP 1050 Series HPLC system, an Agilent Zorbax Exclipse XDB–C8 4.6×150 mm column and a water-acetonitrile system (75:25) acidified with orthophosphoric acid as the mobile phase.

3 Results and Discussion

The specific equilibrium moisture uptake data at the 0-90% RH/25C cycle for uncoated and coated tablet cores are shown in Fig. 1. We elected to use this cycle to illustrate the sorption patterns otherwise the rest of the data and analysis are based on the 0-75%/25C cycles.

The data show that uncoated cores equilibrated rapidly (within 50 min) and took up very little water (0.11 ±0.006 % dry basis). When contrasted with hygroscopic cores under the same studied (reported elsewhere Mwesigwa et al, 2008) showed that the uptake at 75% RH was 2.91 ± 0.011 % and equilibration time was 500 min. This therefore demonstrates that the sorptive properties of non-hygroscopic cores used in this study were limited, confirming the non-hygroscopicity of the excipients used in the formulation.

With respect to data for coated low-hygroscopic cores, it is clear that coated cores sorbed considerably more water than the uncoated samples and also took longer to equilibrate. There were further differences in sorption patterns of the different coatings. For example, Eudragit L30 D-55 and Sepifilm LP coated cores exhibited nearly similar uptake profiles (similar rates of mass change) but the total amounts of water sorbed were different. These differences are best illustrated in Figure 2, which shows the specific equilibrium mositure uptake at each time point.

The cores coated with Opadry AMB and Eudragit EPO exhibited slower rates of uptake. However, the Eudragit EPO coated core took longer to equilibrate and also sorbed the most amount of water (0.75 ± 0.008%). These results appear to suggest that application of the barrier coatings to non-hygroscopic cores did not slow the moisture uptake kinetics and may actually have “enhanced” uptake into the core. In effect, the moisture uptake characteristics obtained are from the applied films rather than the cores, the former being the more hygroscopic component.

This contrasts with the behaviour of hygroscopic cores previously reported, where it was observed that applied films resulted in a marked reduction in the water uptake and therefore thought to have contributed less to the sorption equilibrium of the cores.

Nevertheless, it should be noted that even with this apparent “enhancement”, the equilibrium total water uptake of coated non-hygroscopic cores was still only a fraction of that observed for the hygroscopic formulation (e.g., the equilibrium uptake at 75% RH for the hygroscopic core coated with Sepifilm LP was 2.18 ± 0.001 compared with 0.49 ± 0.060 for the non-hygroscopic core coated with the same polymer).

The distribution of water between the core and the applied film is an important performance characteristic of a barrier system. To determine the availability of sorbed moisture in the applied films and the tablet cores, it is necessary to recap the equilibrium moisture sorption and permeability data obtained with free standing cast films in our earlier report (Mwesigwa et al, 2008) together with the data in Fig. 1. The data showed that at 75% RH Eudragit EPO free film was the least hygroscopic with an equilibrium moisture uptake of 1.85 ± 0.255 %. The Eudragit L30 D-55 took up 2.59 ± 0.195 % db); followed by Opadry AMB (5.18 ± 1.169) and Sepifilm LP (9.64 ± 0.252 %).

In terms of permeability, the best barrier films were Eudragit EPO and Opadry AMB (permeability coefficients at 75% RH were 0.58 x10^-6 and 0.69 x10^-6 cm³ (STP) cm/cm²s.cmHg, respectively). Eudragit L30 D55 and Sepifilm LP free films with permeability coefficients of 1.58×10^-6 and 1.92 x10^-6, respectively. The data for the equilibrium sorption (in Fig. 1) provides an interesting contrast; for instance, it can be seen that cores coated with Eudragit L30 D-55 were the least hygroscopic, followed by Opadry AMB, Sepifilm and Eudragit EPO.

This suggests that the barrier properties of the films were not being replicated on the cores. This pattern becomes more clear when the distribution of the sorbed water between the film and the core is considered.

Table 1 displays the amounts (in mg) of moisture in the applied coatings (calculated from the product of the total uptake in % of the cast film and the weight in mg of applied coating) and the total water uptake (in mg) of the coated sample (being the product of % total water uptake and the weight in mg of coated sample divided by 100), and from which the amount of water that potentially reached the core can be easily obtained (being the difference of the two quantities). It can be seen that the Eudragit EPO coated samples had the highest amount of water in the core despite the low hygroscopicity and permeability of the free film. Eudragit L30 D-55 and Opadry AMB coated samples had the least quantities of water sorbed in the cores.

The behaviour of Opadry AMB system is of interest: the free film exhibited comparable permeability to that of Eudragit EPO but had much higher hygrocopicity, on the core, this film showed lower levels of water ingress into the core, which were comparable to Eudragit L30 D-55. Therefore, as in our previous report, there appears to be no meaningful relationship that can be established between either water sorption or permeability characteristics of free films and the protective function of the coatings on non-hygroscopic tablet cores.

When a coated tablet is exposed to moisture stress, it is expected that the applied coating will either completely repel the moisture or hold a portion of the moisture and allow the excess into the underlying core depending on its permeability and the amount that the core can accommodate at the prevailing conditions. Equilibrium sorption sorption is achieved when the water activity of the sample equals that of the surroundings.

Given that the cores have lower water attracting propensity than the coatings, the sorption equilibrium is largely directed by the more hygroscopic films. Under these conditions, the cores easily reach their maximum water holding capacity and any extra sorption above this amount is taken up by the film to the point equilibration with the surrounding RH is achieved. We propose this is the reason for the observed failure of the coatings to achieve a net reduction in the total amount of water taken up over the uncoated cores. This also accounts for the observation that total sorption of low hygroscopic cores are nearly a simple sum-total of that taken up by the core and the film.

Do the above results have any bearing on stability given the relatively low water uptake in non-hygroscopic cores? Figure 3 shows the results of the stability studies of aspirin in uncoated and coated tablet cores.

Firstly, it is apparent, just like the data for hygroscopic cores, that there was a progressive decrease in the strength of aspirin upon exposure to moisture stress in all samples. By the end of study, uncoated cores exhibited the lowest levels of aspirin degradation. It is worthy emphasising at this stage that the degradation observed in the samples was solely attributed to moisture uptake post coating in the fluidised bed coater.

As it would normally be expected that samples exhibiting the highest water uptake also show the greater aspirin hydrolysis, the outcome of the stability studies does not appear paradoxical. However, when viewed in the context of the barrier characteristics of the films or the total amount of water taken in (and in comparison to the hygroscopic cores), it can be seen that despite the non-hygroscopic cores taking up only a fraction of the amount of water taken up by the hygroscopic cores, the extent of degradation was higher in these samples. Also, as no correlation between water sorption/permeability characteristics of free standing films, total water uptake of uncoated/coated cores with the extents of hydrolysis of aspirin in the cores to which the films have been applied can be established, it would suggest that the ability to prevent drug degradation in the non-hygroscopic tablet cores is not necessarily the result of preventing moisture uptake, per se.

It is already well known that excipients play an important role in the stability of moisture sensitive actives. For instance, the influence of the particle size and pore volume distribution of dibasic calcium phosphate dihydrate on the hydrolysis of aspirin has been reported (Landin et al, 1994).

Other factors, including hardness (Lee et al., 1966); excipient type and crystallinity (Maulding and Zoglio, 1969; Ahlneck and Alderborn, 1988, Du and Hoag, 2001) have been discussed. In this present study, we found that the low-hygroscopic formulation exhibited greater degradation despite the lower levels of water uptake. In this formulation, more of the sorbed moisture was available as free water, which was more available to interact with aspirin.

It is also apparent that while coated cores sorb more water than the uncoated cores, we are inclined to believe that considerably higher levels of degradation of coated non-hygroscopic cores are a result of a combination of other factors rather than water uptake alone. We have previously proposed that when coated tablets are exposed to moisture stress, the adhesion of the coating to the core is compromised and this augments the degradation of aspirin over and above the levels that would be observed through simple permeation into the core (Mwesigwa et al, 2008).

There is already a significant body of corroborating evidence to support our proposition (Okhamafe and York, 1985, Felton and McGinity, 1997). It is widely known that adhesion is of primary importance to barrier performance and its loss compromises the ability of the coating to provide mechanical protection to the substrate (Fung and Parrot, 1980, Klages et al 1996 and Barranco et al, 2004), who have reported the formation of a water layer at a paint film-substrate boundary and associated this phenomenon with a reduction in adhesion to the substrate and greater levels of corrosion in oxidation.

4 Conclusions

This study was undertaken to understand whether the stability of a moisture sensitive active could be improved through application of moisture barrier coatings on tablet cores exhibiting low hygroscopicity. The moisture barrier coatings applied to tablet cores did not achieve a net reduction in the amount of moisture sorbed when exposed to elevated RH. The uncoated cores exhibited lower overall levels of aspirin degradation compared with coated samples. The use of current moisture barrier coatings on tablet cores with minimal water uptake characteristics does not appear to prevent the degradation of moisture sensitive actives.

References

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Ahlneck, C., Zografi, G. 1990. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int. J. Pharm. 62, 87-95.

Alvarez-Lorenzo, C., Gomez-Amoza, L., Martinez-Pacheco, R., Sonto, C., Cocheiro, A. 2000. Interactions between hydroxypropyl celluloses and vapour/liquid water. Eur. J. Pharm. Biopharm. 50 (2000) 307-318.

Barranco, V. Carpentier, J. Grundmeier G. 2004. Correlation of morphology and barrier properties of thin microwave plasma polymer films on metal substrates. Electrochim Acta 49, 1999-2013.

Buckton, G., Darcy, P. 1996. Water mobility in amorphous lactose below and close to the glass transition temperature, Int. J. Pharm. 136, 141–146.

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Dawoodbhai, S., Rhodes, C.T., 1989. The effect of moisture on powder flow and on compaction and physical stability of tablets. Drug Dev. Ind. Pharm. 15, 1577-1600.

Du, J., Hoag, S.W. 2001. The influence of excipients on the stability of the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose, Pharm. Dev. Technol. 6, 59–66.

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Fogel, J., Epstein, P., Chen, P. 1984. Simultaneous high-performance liquid chromatography assay of acetylsalicylic acid and salicylic acid in film-coated aspirin tablets. J Chromatog A 327, 507-511.

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Klages, C.P., Dietz, A, Höing, T. Thyen, R., Webber, A, Willich, P. 1996. Deposition and properties of carbon-based amorphous protective coatings. Surf Coat Technol 80, 121-128.

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Beating Burnout: A Practical Guide for Pharmaceutical Scientists

October 30, 2021

Unrealistic pressures to perform and deliver results are creating burnout among many career scientists. If not adressed, work-related chronic reduces productivity, mental health deterioration.

At the last summer Olympics in Tokyo, Simone Biles, the four-time Olympic champion, stunned and also won applaud when she announced her withdrawal from the gymnastic team final and women’s individual finals to focus on her mental health.

For most of us engrossed in the world of chemicals and drug substances, the pommel horse is as far away as it gets, yet we can easily relate with the daily struggles of work, very much like Ms Biles. We may hate Mondays, find it hard to get motivated for even the smallest tasks, we often feel like we’ve lost skills, and the career that excited us and brought so much happiness is no more! Some of us have even contemplated leaving the field altogether, or even worse.

According to recent studies, these feelings are very common. It is just that among scientists, the rates of mental health are higher than those in the general public. In some reports, one in three PhDs is at risk of developing a mental-health disorder, including depression.

Many mental health problems are driven, in part, by the immense pressure on scientists to win funding, publish work in reputable periodicals, land jobs or create innovations in an unforgivingly competitive environment, where tolerance for failure is low. And COVID-19 has not helped matters.

To cap it all, studies have identified that scientists have poor mentorship, poor access to counselling services and those in their line management lack the training to manage wellbeing. This is why universities and employers are now being urged to improve mental health support services, revise leave-of-absence policies, and provide mentorship training all those in line management roles.

In this article, I describe burnout, a common cause of mental health deterioration among working professionals. I describe its causes and risk factors and how it can be prevented. Finally, I outline practical steps on how to recover if you have work-related stress.

What is burnout?

Burnout or chronic work-related stress, is a condition characterised by exhaustion. According the World Health Organisation, burnout is a syndrome arising from chronic workplace stress that has not been successfully managed. It is characterized by three dimensions:

feelings of energy depletion or exhaustion;
increased mental distance from one’s job, or feelings of negativism or cynicism related to one’s job; and
reduced professional efficacy.

Three of the world’s experts on burnout, Susan Jackson, Christina Maslach and Michael Leiter, all agree that burn-out is an occupational phenomenon, specifically defining as a psychological response to interpersonal stressors of work. It is different and apart from experiences in other areas of life.

It is important to mention that work-related stress is not an official medical condition in itself, it is usually only a symptom of other underlying issues, such as depression.

The sinister thing about burnout is that it may even go unnoticed and sufferers may not even be aware that the source of burn-out is their job!

Suffice to say burn-out, whether formally diagnosed or not, has the ability to impact both mental and physical health. And for this reason, it is important that burnout is recognised early and a plan put in place to help one recover from it.

How to tell if you have work-related stress

According to psychologist Susan Maslach, burnout manifests in the form of three symptoms, namely exhaustion, cynicism and inefficacy due to chronic stressors at work.

Exhaustion is the main symptom of burnout. It encompasses deep emotional exhaustion, physically, cognitively and emotionally, leading to an individual’s inability to function.

Cynicism or depersonalisation refers to a loss of connection and engagement with one’s work. Essentially, the sufferer of chronic burnout feels mentally removed from work, including colleagues, customers or assignments.

Inefficacy refers to feelings of failure and a lack of sense of accomplishment or productivity. Individuals who experience inefficacy feel their skills are eroding and may worry that they will not be successful in other areas of work.

The signs or symptoms can be physical, psychological and behavioural:

Physical symptoms include:

Fatigue
Muscular tension
Headaches
Heart palpitations
Sleeping difficulties, such as insomnia
Gastrointestinal upsets, such as diarrhoea or constipation
Dermatological disorders.

Psychological symptoms include:

Depression
Anxiety
Discouragement
Irritability
Pessimism
Feelings of being overwhelmed and unable to cope
Cognitive difficulties, such as a reduced ability to concentrate or make decisions.

Behavioural symptoms include:

An increase in sick days or absenteeism
Aggression
Diminished creativity and initiative
A drop in work performance
Problems with interpersonal relationships
Mood swings and irritability
Lower tolerance of frustration and impatience
Disinterest
Isolation.

Questions to ask yourself:

Do you constantly feel like you do not have energy for anything?
Is your sleep interrupted? For instance, do you sleep during the whole day or have problems falling or staying asleep?
Do you feel like you have to force yourself to go into work? Do you struggle to get started with work tasks?
Do you notice that you are easily irritated or impatient with work colleagues, clients or customers?
Have you become particularly critical or cynical about your work or others at work?
Do you feel you’re not as productive as you were in the past? Are you struggling to focus on your work?
Do you feel you no longer take interest in your achievements? Has your passion for the job gone?
Are you increasingly binge-eating to feel better? Are you using alcohol or drug to improve your mood?
Do you frequently suffer from headaches, unexplained stomach problems or any other unexplained pains or twitches?

Note that the mere fact that you answered yes to any of these questions, it does not necessarily mean you have work-related stress. Equally, you shouldn’t have to live with any of these feelings. Seeking help from professionals will help you deal with it early enough so that you can regain your mojo back and start living life to its fullness.

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Common causes of burnout

Chronic work-related stress is a growing concern in the workplace around the world. Health experts attribute the rise in burnout to increase in work demands and lack of awareness on practical ways to manage it.

All the following issues have been identified as potential stressors at workplaces. A risk management approach will identify which ones exist in your own workplace and what causes them. They include:

Organisation culture
Bad management practices
Job content and demands
Physical work environment
Relationships at work
Change management
Lack of support
Role conflict

If a job saps a lot of energy and exposes you constantly to stress, for instance the pressure to meet very tight deadlines, absence of social and supportive network or if the job is chaotic or monotonous, the chances of experiencing burnout are much higher.

Some of the factors that commonly cause burnout include:

Long hours
Heavy workload
Changes within the organisation
Tight deadlines
Changes to duties
Job insecurity
Lack of autonomy
Boring work
Insufficient skills for the job
Over-supervision
Inadequate working environment
Lack of proper resources
Lack of equipment
Few promotional opportunities
Harassment
Discrimination
Poor relationships with colleagues or bosses
Crisis incidents, such as an workplace death
Unclear expectations

How to prevent or handle early stages of burnout

Thanks to ongoing research by psychologists and health professionals, our understanding of causes and solutions for burnout is much improved. We have a better understanding of what to do once the symptoms of burnout are picked up.

So here are some strategies that have been successful across the board:

Focus on self-care and wellbeing

It’s crucial to refill your physical and emotional energy, as well as your ability to focus by prioritising sleep hygiene, nutrition, exercise, social networks, and practices that promote mental calmness, such as meditation, journaling and nature appreciation.

If for one reason or another you find it difficult to squeeze in these activities in your schedule, take a week to examine how you spend your time.

You can then take a look at each block of time in your day and record how you spend time, i.e., what you do, the people you spend the time with and how you feel. Then score each activity in terms of how valuable it is or how it leaves you (1 = drained, 10 = energised).

This can enable you find breaks and opportunities to reduce exposure to situations that do not build you, and this way, find breaks for rejuvenating moments away from work.

Shift your outlook

Although relaxation, resting and rejuvenation can help alleviate exhaustion, address cynicism and improve productivity, they do little as far as mollifying the underlying causes of burnout.

Back at work, you may still have to contend with the same unmanageable workload, conflicts or lack of resources. It is therefore important to take a look at your expectations with respect to work:

Which aspects of work can be changed? It helps to ask yourself what tasks can be delegated to free up energy for other meaningful tasks. Perhaps some aspects of your work could be changed to allow you regain some level of control over your workday.

And if it is cynicism, look into ways of sheltering yourself from parts of the workplace that antagonise or frustrate you and instead re-engage with those aspects of the job that are most meaningful.

It also greatly helps if you can find supportive relationships and networks that can help counteract those that drain you.

Eliminate or reduce exposure to stressors

Reduction of job stressors requires you to recognize those particular activities and relationships that trigger unhealthy stress. This might require a reset of expectations from colleagues, clients and even family members regarding what and how much you are willing to take on as well as the ground rules for walking together.

You may, of course, experience resistance as you go about this; the most important thing, however, is to assure yourself that the changes you’re making will improve your long-term productivity as well as protecting your wellbeing.

Invest in connectivity

It has been found that one of the most effective remedies for burnout, especially when its driven by cynicism and inefficacy, are finding and making rewarding interpersonal connections and seeking professional growth. Reaching out to and engaging in coaching and with suitable mentors that can help identify opportunities for growth can be highly rewarding.

Another issue is finding opportunities to volunteer in your community or to help others in similar situations can be a very powerful way to break out of a negative cycle of cynicism and lack of motivation.

Finally, given the role of the situational dimension to burnout, chances are that others in your organisation have burnout, too. So finding and identifying with others in a similar predicament will help identify organisation-wide problems and lasting ways to address them.

Nip burnout in the bud

Getting aware of the problem is the first step to addressing burnout. However, this is often the most difficult simply because we tend not to accept ‘weakness’ or reassess aspects of our behaviour.

If you hear family or colleagues express any concerns about your work, its important to take heed. Granted, accepting that you are heading into a crisis will be hard to take, however, and at the end of the day, your wellbeing is what counts.

Get support

It is crucial to find someone who is willing to challenge your assumptions and give you a different take on things. This may be a trusty friend, a coach, family member or therapist. This is because burnout has the potential to cloud your thinking and decision making. Hence, if you can be helped with finding and mapping out work-life boundaries, it will be easier to to find that happy medium.

Take time to recharge even if you love your job very much

It’s common to get exhausted from time to time, particularly on those occasions when the job is all consuming. This is not full burnout. Still, it is important not to let things slip, so here are some quick ways to recharge:

Take breaks during the day. In order to perform at your best consistently, you need to find opportunities to restock your mental energy. Taking regular breaks allows to step away and clear your headspace.

Put away digital devices for a moment. Today, we find ourselves carrying our offices wherever we go with no downtime at all. It is a good practice to place your work phone away when you arrive home so that you’re not tempted to check work emails during out of office hours.

Take weekend breaks. Short breaks have been shown to help reduce stress, aid with maintain peak performance while also reducing the need for long lay-offs. Make sure that while you’re away, you completely switch off from work.

How to recover if you already have burnout

The first step to take in order to recover from burnout is to regain your perception of control of your situation first. During the state of burnout, people often feel as if their circumstances are out of their grasp, a few others may even feel the rest of the world is working against their interests. This mentality creates a virtuous cycle and block them from dealing with their circumstances.

But what is resilience? Simply it is an individual’s ability to positively respond to stress, pressure, risk and adversity.

To fully appreciate resilience, we need to borrow from the British Army’s highly acclaimed mental resilience programme for its soldiers. This programme recognises soldiers do not only need physical strength but also mental toughness if they are to effectively face the many challenges of their careers. It comprises the following principles:

SELF-BELIEF – confidence in your own abilities and judgement

POSITIVE AFFECT – the ability to interact with life in a positive way

EMOTIONAL CONTROL – the ability to understand and express your emotions

MENTAL CONTROL – the ability to control thinking, attention, concentration, focus, self-awareness, reflexivity, problem-solving

SENSE OF PURPOSE – the motivation that drives you forward

COPING – adaptability, natural coping strategies you have learnt through coping in previous stressful situation

SOCIAL SUPPORT – the social network you have and the ways you use it.

Here are some of the things you can do to build mental toughness:

1. Develop a positive mindset

To increase your resilience, the first thing that one has to do is refocus on building a strong, positive mindset in everyday life.

2. Know your why

Another aspect of building resilience is constantly being aware of your “why” when it comes to your short and long-term goals. If you’re going to achieve a big goal knowing why you need to do it in the first place cushions you against discouragements and disengagements as soon as you experience your first setback.

3. Find strength in others

Developing resilience is much about your inner fortitude as much as embracing the idea that you’re not in it alone. Even the most successful people among us rely and count on others for support, mentorship, guidance and encouragement when times are difficult. So you should have the confidence to do the same.

4. Learn to pick yourself up

Finally, it is worth remembering that building resilience isn’t easy! Anyone who’s ever achieved massive success knows that obstacles, setbacks, and failure are inevitable, and you’re no different.

As you work on your goals, you’re going to face many ups and downs, but this doesn’t mean that you don’t have mental toughness, willpower, or discipline.

In summary, you can build resilience through learning to recognize negative tendencies and taking action to correct them early on with healthy habits. Developing resilience is not about eliminating weakness, but learning how to deal with it and overcome it.

Final Thoughts on Burnout

The never-ending pressures to deliver new knowledge and products and be on top of things have undesirable consequences for scientists’ wellbeing. Burnout, the term that is sometimes used for all sorts of work-related stresses, is, in realty a serious red-flag that things are not going well. Unmanaged, chronic burnout leads to low productivity, negative emotions and mental ill-health. Recognising burnout early and taking steps to deal with its causes is important. But equally, all stakeholders, from line managers, to the boardroom, need to understand and recognise burnout and institute processes to address it so that workplaces are supportive and more productive.

Reference

Diane Wood. Corporate burnout affecting the mental health of 20% of top performers in uk businesses. Personnel today, may 3, 2017.
Christina Maslach and Susan E Jackson. The Measurement of Experienced Burnout. Journal of Occupational Behaviour 2 (1981): 99-113.

Opinion | What Does the Recent Pig-to-Human Kidney Transplant Mean for Tissue Therapeutics?

October 29, 2021

In a pioneering procedure, a team of surgeons at New York University Langone Health Grossman School of Medicine in New York City managed to attach a pig kidney to a human patient. The kidney functioned normally for 54 hours.

Last week, a team of surgeons in New York City were to able to successfully attach a pig kidney to a human patient and watch the organ function normally for a whole 54 hours. While procedures of this kind are not new in nonhuman primates, it is the first time that a pig kidney has been transplanted into humans and not been immediately rejected.

The process of transplanting living cells, tissues or organs from one species into another is what scientists call xenotransplantation. However, owing to genetic differences between species, past xenotransplantation efforts have not been successful, leading to immediate organ rejection by the human immune system.

The breakthrough procedure, which was announced at a news conference and widely reported in the media on October 21, represents a giant step towards the aim of increasing availability of life-saving organs for transplantation. Waiting list for donated organs around the world are in the millions, and demand is not expected to drop anytime soon despite a rise in organ donation registrations.

Speaking on condition of anonymity, a nephrologist at Abbott Northwestern Hospital, Minneapolis, MN said the fact that transplant survived three days with full function and no signs of rejection was an “incredible achievement,” and gives fresh confidence that “patients will have access to additional sources of organ for transplantation in the near future”.

However, several years of more of research, clinical trials and regulatory scrutiny are required before we can start to see pig kidneys on surgical tables.

In a press release, Robert Montgomery, MD and chair of the department of surgery at NYU Langone and director of the NYU Langone Transplant Institute, noted that the future of this work is not limited to kidneys.

“Transplanting hearts from a genetically engineered pig may be the next big milestone,” he said. “This is an extraordinary moment that should be celebrated — not as the end of the road, but the beginning. There is more work to do to make xenotransplantation an everyday reality.”

Why pigs?

In the quest to address the chronic shortage of organs, scientists have long sought the use animal organs. Pigs have emerged as an interesting choice because their organs are anatomically similar to those of humans, and they can be easily bred in a highly controlled manner.

However, it is more that ease of breeding. In the mid-20th century, xenotransplantation scientists noticed that transplanted animal organs quickly turned black, a phenomenon known as hyperacute rejection.

As knowledge has improved, scientists have been able to use genetic engineering to overcome some of these challenges. For example, it was found that aggressive immune responses seen after a pig xenotransplant was due to antibodies detecting alpha-gal, a sugar moiety found on porcine vasculature.

Disabling the gene that codes for alpha-gal was key to addressing hyperacute rejection of pig organs. Until now, a test of this sort of transplant hadn’t been done successfully in humans.

So what did the New York University Langone Health team do?

In order to overcome the many ethical hurdles of performing such an operations in humans the surgical team approached the family of a woman with brain stem death kept alive on a ventilator. Although the woman was an organ donor, her organs were not suitable for donation.

Over a period of several hours, the surgical team worked to attach the pig kidney, which had been genetically engineered to remove the alpha-gal sugar to blood vessels, in the upper leg of the patient. The kidney was kept outside of the body so the team could assess its function in real time.

In order to improve chances of acceptance, the team also transplanted the animal’s thymus gland, which aids the education of the immune system to recognize the kidney as part of the body. The patient was also given specific drugs that suppress the immune system.

Within minutes, the kidney started producing large amounts of urine and showed other signs of normal functioning. The pig kidney functioned just like a human kidney transplant. The research team stopped monitoring at 54 hours in line with IRB ethical guidance.

The patient was taken off life support after the procedure.

What’s next for these sort of transplants?

To survive 54 hours represents a significant development but to become mainstream, animal kidneys will need to survive for years not days. For this to happen, researchers will need to show that these organs can withstand immune system attacks for years in the human body.

A key aspect of this journal is to show that transplants are safe in the long-term and obtain approval from health authorities, including the U.S. FDA and the European Medicines Agency.

Are there any ethical concerns about breeding pigs for organ harvesting?

Using any animal for the sole benefit of humans raises important ethical questions. Advocates for xenotransplantation argue the potential benefits of expanding the organ supply are worth any potential harm done to animals.

The jury is still out on how acceptable the idea of breeding millions of pigs in order to harvest organs for human transplantation is.

PETA (People for the Ethical Treatment of Animals), a campaigning organisation against the use of animals in research, contests the whole idea that we should consign animals as sources of spare parts for humans (see their statement through this link).

Questions or comments on this article? E-mail us at editor@pharmacentral.com.

Sources

NYU Langone Health. Progress in xenotransplantation opens door to new supply of critically needed organs. Published online October 21, 2021.

What does COP26 mean for the pharmaceutical sector?

October 29, 2021

The stakes for this year’s UN Climate Change Conference couldn’t be higher. But what can we expect from the talks in Glasgow? And how will the summit impact industry?

From the 31st of October to the 12th November 2021, the United Kingdom and Italy will jointly host the 26th UN Conference of the Parties on Climate Change (COP26) in Glasgow. Heads of state, climate scientists and other stakeholders will gather to flesh out and agree on joint steps to combat climate change.

What is a COP?

‘COP’ simply means ‘Conference of the Parties’. In the world of climate change, ‘the Parties’ are the governments that have signed the UN Framework Convention of Climate Change (UNFCCC).

The COP brings these signatory governments together once a year to discuss how to jointly address climate change crisis.

COP conferences are attended by world leaders, ministers, and negotiators but also by representatives from civil society, business, international organizations, and the media.

The COP is hosted by a different country each year and the first such meeting – ‘COP1’ – took place in Berlin, Germany in 1995.

COP26 is the 26th climate change COP. It is being co-hosted by the UK and Italy. COP26 was originally scheduled to take place in November 2020 in Glasgow, UK but it was postponed by one year due to the COVID-19 pandemic. It is now due to take place 31 October-12 November 2021.

The ‘pre-COP’ (a preparatory meeting) took place in Milan, Italy, from 30 September-2 October.

COP26 builds on the Paris Agreement, an international treaty signed by almost all countries in the world at COP21 in Paris in 2015. This landmark treat aimed to keep the rise in the global average temperature to ‘well below’ 2 degrees above pre-industrial levels, strengthen the ability to adapt to climate change and build resilience; and align all finance flows with ‘a pathway towards low greenhouse gas emissions and climate-resilient development’.

The Paris Agreement has a ‘bottom-up’ approach, namely, each signatory country was to decide by how much it would reduce emissions by a certain year. These countries communicate these targets to the UNFCCC in the form of ‘nationally determined contributions’, or ‘NDCs’.

Goals of COP26

COP26 arrives at an important time in the global climate action debate. If the world is to have a chance of limiting warming to 1.5 degrees, emissions must halve by 2030 and reach ‘net-zero’ by 2050. Unprecedented action is needed if this goal is to be achieved.

It has long been argued that the NDCs submitted in 2015 were not ambitious enough to limit global warming to ‘well below’ 2 degrees, never mind 1.5 degrees. The signatories of the Paris Agreement are, however, expected to submit new – and more ambitious – NDCs every five years, known as the ‘ratchet mechanism’.

COP26 is the first test of this ambition-raising function. One of the main ‘benchmarks for success’ in Glasgow is that as many governments as possible submit new NDCs and, when put together, these are ambitious enough to put the world on track for ‘well below’ 2 degrees, preferably 1.5.

As of September 2021, 86 countries and the EU27 have submitted new or updated NDCs to the UNFCCC.

A few governments, like China and Japan, have pledged new 2030 targets but are yet to submit them officially.

The UK has, for instance, pledged to reduce emissions by 68 per cent by 2030 compared to 1990 levels, and 78 per cent by 2035. The European Union (EU) is aiming for a reduction of at least 55 per cent by 2030 relative to 1990 levels, and the US target is ‘a reduction of 50-52 per cent’ compared to 2005 levels.

However, the NDC updates only narrow the gap to 1.5 degrees by 15 per cent at most.

Around 70 countries are yet to communicate new or updates targets. And several – Australia, Brazil, Indonesia, Mexico, New Zealand, Russia, Singapore, Switzerland and Vietnam – have submitted without raising ambition.

A successful outcome in COP26 is for developed countries to honour a 2009 pledge of mobilising $100 billion per year by 2020 to support climate action in developing countries. This goal has not been met to date.

The recent announcement by President Joe Biden to double US climate finance has been welcomed but more will need to be done to restore credibility and strengthen trust between developing and developed nations.

No doubt discussions at COP26 will focus on mobilizing finance but other issues will be touched upon, especially how best to operationalise the Paris Agreement’s.

Against this background, here below are COP26 main goals:

Securing net-zero by the middle of the 21st century in a bid to keep global temperature increases below the critical 1.5C threshold.
Making progress on climate adaptation measures to protect lives, ecosystems and economies from the impact of global warming.
Mobilising private finance to address the climate challenge.
Fostering international collaboration to accelerate progress on climate goals.

Ways your pharmaceutical business can get involved

The World Economic Forum has identified environmental degradation, climate and environmental disruptions (like extreme weather, droughts, wild fires and resource depletion) as the greatest dangers to businesses going forward.

This is because of the ability of these factors to reduce the availability of raw materials, disrupt supply chains, wither demands for goods and services, and change resource availability while increasing costs.

The New York Times referenced a study which asked companies to calculate how climate change could affect their business financially. After analyzing submissions for 215 of the world’s 500 biggest corporations, it was potentially put at $1 trillion in costs related to climate change.

But it’s not just the Fortune 500 firms that face substantial losses, because when the environment loses, the whole world loses. According to a report by insurance giant Swiss Re, the world’s global domestic product (GDP) could drop up to 18%, or $23 trillion, by 2050 if no action is taken.

Experts agree the poorest nations would be most adversely affected by climate change, although even the major economies would suffer irreparable harm. The U.S. GDP could dip as much as 10.5% by 2100.

This is not just an issue for companies that rely on oil, natural gas, or other natural resources. Any business that uses petroleum-based plastics (over 99% of plastic is produced using fossil fuels) along its supply chain or generates greenhouses gases has a part to play. The pharmaceutical industry is not immune – the vast number of precursors used in synthesis are petroleum derived, not to mention the energy used as well as other inputs need to make pharmaceutics.

This is why every company, irrespective of size, influence, or availability of resources, can and should make a collective effort to address climate change.

So here’s how pharmaceutical businesses can join the climate action plan and do their bit:

Set science-based and net-zero targets

Setting a net-zero target in line with a 1.5°C future is necessary for businesses to make a dent in limiting the worst impacts of climate change. Join the Business Ambition for 1.5°C, which is an urgent call to action from a global coalition of UN agencies, business and industry leaders, in partnership with the Race to Zero.

Take the lead by going 100% renewable

While many companies are already reducing their carbon emissions, they could go further and commit to using 100% renewable power and resources.

Switch to electric transportation

Keeping global average warming below the 1.5°C thresholds requires a large shift in the way companies operate. Making the switch to electric vehicles is something that many companies should immediately consider, if they have not yet done so.

Reassess supply chain choices

All good charity starts at home, and while companies can concentrate on their own internal practices, greater change can be achieved if businesses reach out across their value chains, and probe the environmental commitments of suppliers and partners to ensure they are aligned with their own environmental goals

Prepare to be held accountable

All around the world, people want companies to lead on climate change instead of waiting for governments. They expect CEOs to speak out and champion change and not just talk the talk. But expectations come with accountability, and businesses can soon expect the public to start demanding answers.

Final thoughts

Pharmaceutical businesses can play a pivotal role in achieving new climate targets, and also integrating needed changes. Climate changes creates risks to all businesses regardless of the exact outcome of the conference, with changes needed within corporate strategy, governance, finance and operations.

We hope that COP26 acts as a catalyst for businesses to set the new standards on climate stewardship, with a specific focus on practices and encourage them to step up to the challenge, tackling climate risk head-on.

Resources:

UN Climate Change Conference (COP26) at the SEC Glasgow 2021 (https://ukcop26.org/uk-presidency/what-is-a-cop)

How Large is the Excipients Market Size? We Compared 3 Market Reports

October 17, 2021

There is no shortage of market reports online that purport to estimate the global excipients market (currently estimated between 7.5 – 8.5 $ billion – 2021).

The question is how representative are these figures? Is the pharmaceutical flavour market really worth $400m?

We appraised 3 market reports, compared reported estimates with first hand primary data for specific products that we know very well.

The results are summarised in this post.

Excipients Value Chain

Excipients are specialty raw materials included in formulations of medicines, medical devices, some cosmetic products or nutraceutical food supplements. They are used to perform specific purposes, such as:

stabilisation
bulking
aids to processing

As a sub-sector of the wider chemicals industry, the excipients sector plays an important role in the medicines value chain, making a real contribution to the world economy and human welfare.

Below is a simplified value chain:

You can read more about the excipients sector by downloading a Fact Sheet. about the global excipients sector through this link.

End-users of Excipients

Excipients are utilised mainly in the manufacture of bio-pharmaceutical products, which accounts for the lion share of utilisation. However, other industries also use excipients, namely:

Personal & Home Care
Animal & Human Health
Specialty Agriculture/Horticulture
Topical & OEM Medical Devices
Upstream applications (intermediates, fermentation, etc)
Nutraceuticals/Dietary Supplements
Industrial (e.g paper making, yes, paper making)

Comment

Over the years, we have found that market reports tend to ignore several excipient categories and materials, such as:

starter materials and intermediates in other excipients.
active pharmaceutical ingredient synthesis
materials used in upstream biological manufacturing
nutraceutical, medical devices and some food products
industrial goods

Uptake into other sectors is also ignored. As an example, hyromellose and acacia can be used on their own or incorporated /co-processed into other excipients.

Leading Manufacturers

These are the top 10 excipient manufacturers (by product focus):

Ashland
BASF
Cargill
Colorcon
Dow/Dupont/IFF
Evonik
JRS Pharma
Roquette Freres
ShinEtsu
Tereos

Other companies that are significant but often missed out in analyses:

Angus
IOI Oleochemicals
Cargill
Ingredion
Merck KGaA
Samsung
K+S Group
CP Kelco

Comment

The failure by some researcher to companies such as Colorcon Inc. in the top tier of excipient manufacturers is a mistake.

This company commands a market share in excess of 80% for film coatings and has annual sales in excess of $800 million (both from sales of coatings & distribution

On the other hand, companies such as ADM and Lubrizol are always counted in – ADM may well be a large food ingredients producer – but their excipient portfolio are relatively small.

Sector Outlook

The three market reports we appraised (BCC Publishing, Markets & Markets, and Transparency Market Research) estimated the global excipients to be between $ 6.9 – 8.3 billion in 2021 rising to $ between $10.0 -10.7 billion.

The CAGR is quoted as being 5 – 5.8% for the study period (compare these to an earlier study period (2013-2018):

Markets & Markets and Transparency Market Research projected growth from $5.0 and $5.7 billion to 7.4 and 7.5 billion.

In terms of regional market share, we do not agree with their projections. Europe is pitched as the largest (approx. 32% share).

North America at 31%. Asia Pacific, including Japan, is estimated at 25%, while the rest of the world is put at 12 – 13%.
With respect to specific product or categories, the following are the estimated market sizes (2019 estimates):

Microcrystalline cellulose: $300 million
Povidone: $400 million
Artificial sweeteners: $36 million
Flavours: $400 million
Film coatings: $800 million

Comment

We found a number of inconsistencies in projections the three market research companies presented.

First, the largest regional market is not Europe but North America. The excipient market closely tracks the wider pharmaceutical market, and currently, the North American region is the largest.

That said, there are some specific segments where Europe clearly leads, for instance, in inorganic salts and oxides, and sugars.

Secondly, when one takes a deep dive into particular products where we have very accurate results, the inconsistencies are even more glaring:

For instance, the total worldwide market for microcrystalline cellulose is $1billion (add $200 million if food use is included). China is the largest producer, closely followed by North America and finally, Europe.

The largest single producer is IFF (formerly, Dupont/FMC – Avicel®).

Other discrepancies, based on primary market data (actual producer data) are shown below (in 2021):

Thirdly, market researchers ignore an up-and-coming product category, which is elastomers, rubbers and silicones, which are increasingly used in transdermal drug delivery and topical medical devices.

Fourthly, there are further inconsistencies with respect to country data for individual product market size.

A case in point is that the total flavour market (it is just not possible to put this at $400m), we would say it is more like $100 million – and possibly half that (50 – 70 million, at best).

We established that generally, market research companies underestimate the total excipient market by around 15%. The more accurate figure should be in the region of $9 to 10 billion in 2021.

Market Drivers

The major growth drivers are rightly identified as growth in demand for drugs across the world, which drives the demand for functional materials.

All the three reports identify growing demand for co-processed, full-formulated excipient systems and technologies that enhance patient convenience, such as orally disintegrating products, film coatings and modified release.

The role of biologicals, which have consistently accounted for up to 40% of new drug approvals, is mentioned, as are patent expirations and entry of generics. Both factors create new markets for raw materials.

Biological products have been the fastest growing segment for the last two decades, and this trend shows no signs of slowing down.

Market constraints are identified as increasing regulations, a rise in pharmaceutical product R&D costs, a lack of innovation and increasing requirement for supply chain transparency.

The long development cycles and high attrition rates, and particularly, very costly late-stage failures that are emblematic of pharmaceutical R&D, are major dampeners of excipient market growth. It takes on average 4 years, from the point a pharmaceutical company takes a sample for assessment, to make a commercial sale for an excipient!

A lack of innovation is also rightly identified. Innovation is what traditionally drives market growth, and with nearly two decades since the last brand new excipient was introduced, it is not difficult to see why growth in the sector has remained lacklustre for a while.

Comment

While it is the case that the sector has increasingly demanded supply chain transparency, the reasons were not due to outsourcing to low cost countries, but rather, the Falsified Medicines Directive.

We think that the contribution of biologicals to market growth is over played. This is because biologicals generally require relatively simple salts (buffers, and occasionally, cryoprotectants) to formulate, meaning that, from an excipient perfective, they are not significant.

Finally, the role of IPEC and EXCiPACT GMP to market growth is also over played in the analyses since, as per current regulations, GMPs are not mandatory for excipients.

Final thoughts

In our judgement, the current excipient market size of between 7.5 – 8.5 $ billion (2021) underestimates the size of sector by 15%, and the true figure should be between $9.5 and 10.5 billion.

We have also identified a number of omissions and errors in presented figures for individual products and country data, which do not tally with primary market information from excipient manufacturers (for example, MCC, silica, flavours, povidone, sugars and film coatings).

In our judgement, BCC Research excels in their strategic assessments, and their total market estimates also tended to be more in line with primary data that we have access to.

On the other hand, Transparency Research had more accurate data on regional market-shares, data on film coatings as well as xxx. However, data on specific product categories were less accurate.

Disclaimer

The information in this post idoes not constitute any offer, recommendation or solicitation to any person to enter into any transaction or adopt any hedging, trading or investment strategy, nor does it constitute any prediction of likely future value.

Pharmacentral is not an investment adviser, and is not purporting to provide you with investment, legal or tax advice. We accept no liability and will not be liable for any loss or damage arising directly or indirectly from your use of this information

You should seek your own advice regarding the appropriateness of investing in any securities, financial instruments or investment strategies referred to on this post.

Statements regarding future prospects may not be realised.

The sensory performance of masking flavours in bitter drug cocktails

October 4, 2021

By Cecile Guillon and Philippe Lepinay

Quest Pharma

Abstract

The effectiveness of two commercial masking flavours to conceal bitterness of a drug cocktail made of paracetamol, caffeine, and quinine was investigated. Using a panel of 20 trained panellists it was found that masked solutions achieved a 28% reduction in bitterness perception using an Aspartame – Acesulfame potassium masking system flavoured with lemon and strawberry flavours. When the same solutions were masked with a sucralose-based masking system, the reduction in bitterness intensity was 47% for lemon flavour and 38% for strawberry flavour. This study demonstrates the effectiveness of using masking technologies in reducing bitterness intensity, however care must be taken to select a complimentary flavour for even higher effectiveness.

Introduction

Among the five basic tastes, bitterness is perceived by humans as the most unpleasant, and is therefore of commercial and clinical importance for pharmaceutical products⁽¹⁾. Creating palatable products, in which aversive sensory attributes have been reduced, is of utmost importance.

The traditional approach to countering bitter tastes is through the use of sweeteners, flavours and other excipients carefully selected and combined in a manner which permits each ingredient to contribute complimentary attributes to the formulation. The goal is to achieve a neutral base taste, which can then be appropriately flavoured.

Sweeteners are used since being very soluble, they quickly dissolve in saliva and coat the taste buds, thwarting the interaction of bitter active substance with taste buds. However, there is a limit to the use of sweeteners. For instance, for overwhelmingly bitter actives, it is not always feasible to use large quantities of sweeteners to overwhelm such intensely bitter actives.

There is also the often overlooked issue of bitterness perception kinetics. Sweeteners such as sucrose have a fairly rapid onset of action and quickly fade away whereas most bitter chemicals linger on for a while in the mouth. Thus, even formulations containing sucrose may require the addition of specific flavour chemicals interacting with bitter receptors with a long temporal profile.

A different approach is to use compounds that compete with the bitter drug for binding with the bitter receptor on the tongue. When carefully formulated, these materials may have the effect of decreasing the perception of bitterness.

The aim of this study was to assess the effectiveness of two commercial masking flavour technologies to reduce the perception of bitterness (bitterness intensity) of drug cocktail made of paracetamol, caffeine, and quinine. To minimise grittiness and mouthfeel effects, the drug solution was suspended in a 0.05% w/w Gellan gum fluid gel.

Materials and Methods

Drug cocktail preparation

A simple cocktail of well-known bitter active pharmaceutical ingredients (quinine hydrochloride, paracetamol and caffeine) was prepared using commercially-available lemon or strawberry flavours. The drug cocktails were then masked with either an Acesulfame/Aspartame K-based masking flavour system or a sucralose-based masking flavour system in accordance with the manufacturer’s recommendations (Table 1).

Fluid gel preparation

The fluid gel was prepared following the bill of quantities shown in Table II.

The required quantities of Gellan gum was added to water and heated to 85 ^oC with moderate stirring. Once fully hydrated, sodium citrate was added and stirring continued. The mixture was then allowed to cool to 56 ^oC to form a gel. Anhydrous citric acid was added and the mixture gently sheared form a fluid gel.

The fluid gels were further characterised rheologically with the aid of a commercial theometer (Anton Paar MCR 300, Anton Paar, Graz, Austraia) using a concentric cylinder geometry. Steady state shear flow tests were used to measure viscosity and shear stress. The results are shown in Figure 2.

Sensory protocol for masking evaluation

Twenty trained panellists ranked the bitter intensity of the four solutions on a 0-10 linear scale. Each series were evaluated on separate days. Within each series, a blind balanced presentation order was used to avoid order effect. Acquisition and statistical analysis of the sensory results were performed using Fizz v.2.0 (F-Biosystemes) software.

Results and Discussion

Sensory performance of masking flavours

The traditional approach for masking bitterness uses a flavour associated with bitterness (e.g. lemon or grapefruit) in order to trick the brain to dissociate the bitterness from the taste of the base to that of the flavour. However, using red fruit flavours (e.g strawberry) which are associated with sweetness, makes consumer to link the bitterness with the base and not with the fruit flavour, which reduces the overall acceptability of the final product. This is the reason the performance of the masking flavours were assessed using two opposite flavour tonalities that exhibit opposite bitterness tolerances: lemon and strawberry.

Sucralose based masking flavors

The bitterness perceptions by 20 trained panellists of the two solutions (control, masked) are indicated in Figure 3.

The profiles of both samples were not modified by the addition of the masking flavours. Results clearly indicate a 47% and 38% reduction in bitterness perception for the lemon and strawberry flavoured samples with a high level of statistical significance.

Aspartame/Acesulfame K based masking flavours

The bitterness perceptions by 20 trained panellists of the two solutions (reference and masked) are indicated in Figure 4.

Results clearly indicate a 28% reduction in bitterness perception with a high level of statistical significance. The profile of the lemon was not modified by the addition of the masking flavour.

The panel described the sample as milder and sweeter than the reference. Similar benefits were observed in the strawberry flavoured product, where results indicate a 30% reduction in bitterness perception. The profile of the strawberry was only slightly modified by the addition of the masking flavour (sweeter, more caramelic).

Conclusion

Masking flavours can efficiently reduce bitterness intensity in very bitter drug cocktails made of paracetamol, caffeine, and quinine.

References

Walsh J, Cram A, Woertz K, Breitkreutz J, Winzenburg G, Turner R, Tuleu C; European Formulation Initiative. Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Adv Drug Deliv Rev. 2014 Jun;73:14-33. doi: 10.1016/j.addr.2014.02.012. Epub 2014 Mar 12. PMID: 24614069.

CITATION:

When referring to this article, please cite as: C. Guillon and P. Lepinay, The sensory performance of masking flavours in bitter drug cocktails. Pharmacentral Science and Technology Bulletin 01 (09) 2021.

Merck’s new Covid drug, Molnupiravir is a game changer, early trial results show

October 4, 2021

An antiviral drug originally developed to treat influenza has been shown to reduce hospitalisation and death from Covid-19 by as much as 50 per cent in patients recently infected with the virus, early trial results suggest.

It is now hoped the drug, administered in oral form, will be play a key role in treating people who test positive for Covid-19 and prevent their infection from culminating in severe disease.

Molnupiravir (development codes MK-4482 or EIDD-2801) was developed at Emory University before being acquired by Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop and commercialise the molecule further.

It is thought molnupiravir works by interfering with an enzyme that the virus needs to replicate, thereby preventing it from further spreading throughout the body.

If authorised for use as planeed, molnupiravir will be the first oral antiviral medication for Covid-19. There are currently two approved ways of treating the disease: using steroids, such as dexamethasone, or by administering monocloncal antibodies intravenously.

Preliminary data from Merck’s trial is based on around 800 adult patients with mild to moderate Covid-19 judged to be at greater risk of serious disease owing to underlying comorbidities such as obesity, diabetes or heart disease.

Among the half of patients taking molnupiravir twice a day, 7.3 per cent were admitted to hospital over the course of 30 days. This compared with 14.1 per cent of the second group of patients who were given a placebo.

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The drug also appeared to lower the risk of mortality by 50 percent, though the numbers are small and experts have cautioned against over-interpreting the data. There were no deaths among the molnupiravir group, while eight of those who received the placebo died from Covid-19.

Upon reviewing the data, the US FDA recommended stopping the phase three trial early to begin the process of applying for emergency authorisation.

A course of molnupiravir is expected to cost around £500 or $650. An official at Merck said the company will only be able to make 10 million doses before the end of the year, 1.7 million of which are reserved for the US.

EMA evaluating booster doses of COVID-19 vaccines

October 4, 2021

Evaluation of data on booster doses of Comirnaty and Spikevax are now underway at the European Medicines Agency (EMA), according to a recent press release.

Comirnaty, the name for Biotech – Pfizer mRNA vaccine, is authorised for use in people aged 12 and older. EMA’s Committee on Human Medicines (CHMP started evaluating an application for the use of a booster dose of Comirnaty to be given 6 months after the second dose in people aged 16 years and older as a way to boost protection after it has waned.

Spikevax (formerly COVID-19 Vaccine Moderna) is also to be given after six months of the second dose in people aged 12 years and older.

CHMP plans to carry out an accelerated assessment of data submitted by the two companies, including data from ongoing clinical trials. Depending on the strength of evidence, CHMP will recommend whether updates to the product information are required.

Both EMA and the European Centre for Disease Prevention and Control (ECDC) have already made clear what their positions are on booster doses, which was that booster doses were not necessarily critical in fully vaccinated people, unless they were immunocompromised.

EMA has already reviewed evidence on vaccine effectiveness and duration of protection, and verified the highly protective effects of all authorised vaccines against COVID-19-related hospitalisation, severe disease and death.

However, with around 30% of all adults in the EU yet to be inoculated, EMA believes the urgency should be to vaccinate all those eligible individuals who still have to complete vaccination courses.

National immunisation technical advisory groups of individual member states still retain prerogative on how vaccinations are to be given remains. EMA’s role is simply to assess relevant data, and member States are free to consider contingency plans for booster doses and additional doses.

Comirnaty and Spikevax received conditional marketing authorisation across the EU, respectively on 21 December 2020 and 6 January 2021.

These 5 technologies were supposed to change the pharmaceutical industry. They haven’t (and probably will never)

October 4, 2021

By Dr. Enosh Mwesigwa, Pharmacentral Guest Writer

Innovation in the pharmaceutical industry can have far reaching impact on society. Just think about antibiotics, vaccines or recombinant DNA (rDNA). Vaccines have enabled humanity to eradicate diseases like polio and smallpox in a single generation. The impact of rDNA technology spans medicine, agricultural and law and order.

But innovation is inherently risky. Numbers vary by firm but generally up to 90% of new product and service innovations fail to deliver expected results. When it comes to technology innovations, it could be even higher. By technological innovation, I mean improved or new processes that aim to provide significantly superior characteristics than before. These innovations are particularly important as they permit the creation of new productivity frontiers and new competitive positions as incumbents’ sources of advantage decline.

The high failure rates of new technology innovations correlate with a pervasive disconnect between what new technologies promise and the willingness by the industry to exploit them. Reasons for the gap (between technological potential and willingness to adopt that lead to so many genuinely promising technologies to remain unexploited) are complex, and explored elsewhere.

Here though, is my list of five highly anticipated technology innovations that have failed to scale and will likely never deliver new, cheaper medicines. It is not that they lack scientific fundamentals, for one reason or another, the distance between potential and wide-scale deployment has not narrowed and will probably never narrow for society to experience their full benefits.

Supercritical Fluid Technology

In the early 1990s, scientists started to explore how principles of green chemistry could be used to address excessive production of toxic solvent waste. Among the technologies considered was supercritical fluid technology (SCF), which was envisaged as an option for extractive and processing pharmaceutical processes. In drug delivery design, SCF promised to permit encapsulation of drug substances in polymeric systems at low temperature and in dry state, opening up additional manufacturing advantages. Money was liberally poured into SCF followed by a flurry of patents. However, despite its attractiveness SCS failed to become mainstream, perhaps due to the complex commercialisation landscape, which hamstrung efforts to adopt and exploit it.

Pharmaceutical 3D Printing

The wide-scale introduction of 3D printing technologies into the pharmaceutical industry started in the late 2000s as scientists imagined its prospects in pharmaceutical R&D. It was widely speculated 3D printing would enable scientists to produce small batches of badly needed medicines, each with personalized dosages, shapes, sizes, and release characteristics. Eventually, on-demand printing of personalised medicines would be possible in pharmacies, surgeries, vending machines and difficult-to-reach places underserved by traditional supply chains.

It is 2021 and the quest is, are we there yet? No. Are we likely to reach there? Probably not. As we have discovered, there are still many technical challenges in terms of cheaper raw materials, plus (and more importantly) a lack of scalability in the pharmaceutical industry, meaning that it will be sometime before we see 3D printing dominating the pharmaceutical manufacturing scene anytime soon. Instead, it will likely remain a fringe tool, useful in very limited instances, such as very early prototyping and academic institutions.

Artificial Neural Networks

Artificial Neural Networks (ANN) is a subfield of machine learning (ML) and artificial intelligence within the broader field of computer science. The underpinning idea in ANN is how past actions, observations and decisions can be used to make predictions or improve future decision, much the same way the human brain works. So by integrating AAN into drug discovery and development programmes it can permit automation of some important but repetitive tasks, and with soaring costs and tottering productivity, boost drug pipelines, reduce costs and speed up R&D. Thus, in the early 2000s, ANNs were widely trumpeted. In pharmaceutical development, however, it was soon found that ANN algorithms did not have meaningful statistical inference components to allow scientists to understand the accuracy of results or how they were derived. Another key limitation was the uneven and non-representative nature of data in drug discovery and development. These and many other factors have limited the usability of ANN, and instead, focus has shifted to ML and AI.

Bioinformatics

The field bioinformatics emerged to meet the huge data generated from the human genome project. Scientist envisaged bioinformatics as a bridge between experimentation and computation—enabling scientists to manage the huge volumes of data generated so that they could make sense of what lay behind it. From drug discovery view point, bioinformatics nirvana was the identification of a section of DNA that denoted a novel drug target for treating a disease, say Cancer, migraine or diabetes. As the years rolled on, data handled within bioinformatics become more complex, going beyond DNA strings to protein function and structure and cell signalling pathways. The euphoria around what bioinformatics could provide quickly begun to fade when it became apparent that that nirvana could not be delivered within the development timelines that were being expected. As a result, bioinformatics remains just that, a tool and service in support of experimentally driven research.

The Human Genome Project and Druggable Targets.

It has been two decades since the human genome was unveiled. During these twenty years or so, scientists have made enormous progress in applying genome information to diagnosing and treating diseases such as cancer, as well as identifying drug targets. In this sense, the value of genomics to disease genes is unquestioned, exactly how useful it is as a pointer to novel drugs remains to be seen. Indeed, many years after their identification, the genes involved in single-gene disorders such as muscular dystrophy and thalassaemia have proved to be not easily druggable as initially hoped. It is the same case for important diseases such as diabetes, high blood pressure and hyperlipidaemia, where successful identification of disease-linked genes is yet to pay dividends.

A comparative appraisal of the utility of broad-spectrum biocides

October 4, 2021

Dr. Enosh Mwesigwa, Pharmacentral Guest Columnist

This article reviews several antimicrobial actives widely used for antisepsis and disinfection. The focus is on the performance attributes of the most important broad-spectrum biocides and their use in homes and institutional settings.

Introduction

It is a plain fact that our ability to effectively control microbial proliferation is an innovation of the same standing as electricity and the internet in facilitating our modern ways of living.

Biocides supplement chemotherapeutics and underpin management of pathogen proliferation in food production, healthcare settings and many other environments where critical activities take place. Put simply, without biocides life would not be very different.

But first, what is a biocide? Generally the term biocide describes chemical agents that inactivate microorganisms (bacteria, fungi and protozoa), as well as viruses. Owing to its general applicability, other more specific terms, such as bactericide or fungicide, etc are often used. For more information on terminologies used, click here.

There are currently many different biocides available for use in antiseptic and disinfectant products, many of these have been in use for several years. They require careful selection since their indiscriminate and/or incorrect application can lead to sub-optimal results, and in the worst case scenarios, the development of resistant strains with catastrophic consequences for human welfare.

The purpose of this article is to review the properties and advantages of a selection of broad spectrum biocides with respect to their use in antisepsis, preservation and/or disinfection in the home or institutional settings.

Criteria used to select biocide

Antimicrobial activity is affected by many different factors, including formulation, presence of organic load, synergies, temperature, and concentration. With the emergence of resistant organisms the importance of using the most appropriate biocide products has become especially important.

Thankfully, there are guidelines from health protection agencies, such as the World Health Organisation and the Centre for Disease Control that we can use when evaluating a biocide product or chemistry:

Speed of action

Antimicrobial agents do not exert their actions immediately upon contact with microorganisms. Each product has a minimum “contact time” that’s needed in order for the biocide to exert antimicrobial effects.

In the case of disinfectants, contact time must be adhered to in order to achieve terminal disinfection. For instance, if a product were to dry out from the surface before its contact time has elapsed complete disinfection may not be achieved.

The ideal biocide is one that offers rapid and practical contact time, unaffected by formulation excipients, organic load or other external conditions.

Spectrum and Efficacy

In the microbial underworld, no single microorganism has a monopoly over the ability to cause us harm. And unfortunately for us, it is not possible to detect beforehand which microorganism is present on a given surface at a given time.

For this reason, having the option to select broad-spectrum biocides, including action on bacteria, spores, fungi and all viruses is highly beneficial. Thus, the ideal biocide has broad antimicrobial effectiveness, with the ability able to stop the proliferation of a broad range of microorganisms, including resistant strains.

Cleaning Capacity

A biocide’s cleaning properties are often overlooked, with emphasis instead being placed on spectrum or killing speed. However, cleaning efficacy is equally important because dirt and organic matter can create a barrier or protective reservoirs for pathogens.

Thus, a biocide that is also an effective cleaning agent can help eliminate the requirement for a secondary cleaning product. Biocides with concurrent surface active properties or products that include surfactants exhibit enhanced cleaning efficacy while ensuring complete and even coverage of surfaces with the biocide.

Compatibility

The optimum biocide is one that is compatible with and suitable for use on all surfaces. At the moment, there is no single material that exhibits 100 percent compatibility with all surfaces. A number of biocides do show excellent material compatibility profiles for their intended uses, but also fail miserably for particular applications or substrates.

For this reason, understanding and taking into account the likely uses of a biocide when formulating a product is necessary. Failure to do this can predispose users to reduced protection and greater harm.

User Health and Safety

As society modernises and ages the needs for infection control also grow, not just within traditional settings such as hospitals, but in the community and industrial settings as well. The resulting increase in exposure to biocides requires safer chemistries to be available. Thus, when selecting a biocide, chemistries that are non-toxic, non-irritating and non-sensitizing are highly desirable.

Environmental Profile

Increased introduction of biocide chemicals into the environment intensifies the need for chemistries that are sympathetic to the environment. It should not be forgotten that biocides are by their nature killing machines for microbes, both good and bad. Products that are non-selective, especially for aquatic life, are not sustainable in the long-run.

Properties and benefits of broad-spectrum biocides

Alcohols

In the context of biocides, ‘alcohols’ refer to a select number of compounds having the OH functional group and exhibiting antimicrobial properties. In this regard, ethyl alcohol, isopropyl alcohol and n-propanol are the most relevant.

The biocidal effect of alcohols is achieved through denaturation of proteins. Alcohols show rapid broad-spectrum activity against vegetative bacteria, mycobacteria, viruses and fungi. They inhibit sporulation but they are not sporicidal. Isopropyl alcohol is more effective against bacteria while ethyl alcohol is more potent against viruses.

Usage and Applications

Alcohols are mainly used as skin antiseptics in a variety of consumer products. Antimicrobial activity is optimal in the 60 to 90% concentration range. Lower concentrations can be used as preservatives and to potentiate other biocides e.g chlorhexidine.

However, due to their lack of sporicidal effects and inability to penetrate protein-rich materials, alcohols are not used as a sterilants for medical and surgical devices except for small implements, such as thermometers, pagers, scissors and stethoscopes but not for hard surfaces.

Alcohol wipes are used to disinfect small surfaces such as rubber stoppers of multi-dose vials or vaccine bottles or external surfaces of equipment.

Biguanides

Biguanides are organic compounds with the biguanide [-HN(C(NH)NH₂)₂-] functional group. Chlorhexidine is the most widely used biguanide within the biopharmaceutical field but other biguanides are also available, including polyhexanide and alexidine.

Chlorhexidine

Chlorhexidine is a cationic bisbiguanide that has been used in the UK over several decades. Depending on concentration, it exhibits both bacteriostatic and bactericidal action, mediated via its ability to disrupt microbial cell membranes and precipitation of cell contents.

Chlorhexidine is known for being highly effective against Gram-positive organisms as well as against Gram-negative bacteria (at high concentrations). It is effective against fungi, yeasts and enveloped viruses, such as SARS COV 2 and HIV. Chlorhexidine has a much quicker kill rate than many other antimicrobial agents. Activity against mycobacteria and spores is, however, limited.

Usage and Applications

Chlorhexidine is used in consumer topical products as an antiseptic. Typical usage levels are 2-4% in topical products.

It is also used as catheter lubricant (intra-urethral), as well as a component of medicated mouthwashes (0.12%). A number of medical devices, such as implanted surgical mesh, intravenous catheters and topical dressings incorporate chlorhexidine.

Within hospitals chlorhexidine is used as a disinfectant to prevent spread of antimicrobial-resistant organisms. In this respect, it is often referred to as the gold standard for infection reduction.

Iodine and iodophors

Iodine’s biocidal effects have long been known. However, owing to its skin staining and irritating effects, iodine is largely superseded by iodophors as the active ingredient in these antiseptics.

Iodophors consist of elemental iodine, iodide or triiodide, bound to a polymer carrier (complexing agent) of high molecular weight, such as povidone or poloxamer. Complexation of iodine with a polymer increases the solubility of iodine, promotes sustained-release of iodine and reduces skin irritation.

The biocidal mechanism of action is via the formation of complexes with amino acids and unsaturated fatty acids in the cystol of microorganisms, impairing protein synthesis.

Usage and Applications

Iodine is potently bactericidal against Gram-positive, Gram-negative and some spore-forming bacteria. It is also active against mycobacteria, viruses and fungi. Povidone-iodine is a safe and effective antiseptic. Most preparations used for hand hygiene contain 7.5–10% povidone-iodine.

An important property of iodophors is their “available Iodine” which refers to the total amount of iodine that can be titrated with sodium thiosulfate. Typical 10% povidone-iodine formulations contain 1% available iodine and yield free iodine concentrations of 1 ppm.

The downsides to iodine compounds is that antimicrobial activity can be affected by pH, temperature, exposure time, concentration of total available iodine and the amount and type of organic and inorganic compounds present (e.g. alcohols and detergents).

Silver Compounds

Silver is a transitional metal element. It may exist as a pure element, as an alloy in combination with other elementals, as a mineral or as an organo-metallic compound. Silver and silver compounds have a long history of use as antimicrobial agents. Some of the well-known derivatives include silver sulfadiazine, silver nitrate and nano or colloidal silver.

Silver and silver compounds have a long history of use as antimicrobial agents. Some of the well-known derivatives include silver sulfadiazine, silver nitrate and nano or colloidal silver. Silver’s antimicrobial action is thought to be through:

Pore formation and puncturing of the bacterial cell wall when silver ions react with peptidoglycan components
Entry of silver ions into the bacterial cell, inhibiting respiration and other metabolic pathways, and
Disruption of DNA replication.

Usage and Applications

Silver has a broad spectrum of microbial activity. It is active against bacteria, fungi and viruses. Activity is more pronounced against Gram negative bacteria than Gram positive bacteria. Colloidal silver nanoparticles are advantageous due to their lower toxicity and higher antimicrobial activity due to their ability to penetrate bacterial cells more easily.

At present, the main use of silver compounds is in the area of topical chemoprophylaxis of burns. In this sense, silver-impregnated dressings and antimicrobial coatings are commercially available for use in infection management and stimulation of wound healing as well as in dental amalgam.

Silver is also impregnated into medical devices, such as heart valves. Silver nitrate and Silver sulfadiazine are used as topical antibacterials for the treatment of skin infections, including acne.

Quaternary Ammonium Compounds

Quaternary ammonium compounds are a group of related compounds composed of a nitrogen atom linked directly to four alkyl groups of varying structural complexity.

In the biopharmaceutical industry, commonly used quaternary ammonium compounds are benzalkonium chloride, cetrimide, cetylpyridium chloride and cetrimonium bromide (cetyltrimethylammonium bromide (CTAB)).

While primarily bacteriostatic and fungistatic, quaternary ammonium compounds can be virucidal, too, particularly at high concentration. Biocidal action is initiated through adsorption of the alkylammonium cation on the cell surface, diffusion through the cell wall and disruption of cytoplasmatic membrane, which releases potassium ions and other constituents, leading to the death of the cell.

Benzalkonium chloride, one of the most common QUAT, is actually a mixture of closely related QUATS (mainly benzyl (dodecyl) dimethyl ammonium chloride, benzyl (tetradecyl) dimethyl ammonium chloride). It is a cationic surfactant with broad-spectrum antimicrobial activity, making it suitable for use as a preservative, antiseptic, disinfectant, solubilising and wetting agent.

Cetrimide mainly consists of trimethyltetradecylammonium bromide and smaller amounts of dodeyl trimethylammonium bromide. It exhibits good bactericidal activity, particularly against Gram positive species but is less so active against Gram negative species. Pseudomonas aeruginosa, may exhibit resistance. Antifungal activity is variable and it is inactive against bacterial spores and viruses.

Usage and Applications

Benzalkonium chloride is widely used in cosmetics, wet wipes, hand and surface sanitisers. It has also been used as a spermicide.

Benzalkonium chloride has also been formulated into lozenges for use in the treatment of common mouth and throat infections. It remains one of the most commonly used preservatives in ophthalmic and nasal preparations.

Cetrimide, on the other hand, functions as an antimicrobial preservative in cosmetics and pharmaceutical eye drops and topical formulations as well as an antiseptic in topical creams, sprays and medicated shampoos.

The other uses are as a cationic surfactant, cleanser and disinfectant for hard contact lenses.

Bispyridines

Octenidine dihydrochloride is a cationic antiseptic that belongs to the bispyridine class of chemical substances. A relatively new biocide, Octenidine was developed just over two decades ago. It exhibits broad antimicrobial activity and is effective against biofilm-forming organisms, including MRSA, plaque-forming bacteria such as Actinomyces and Streptococcus, Chlamydia and Mycoplasma and also binds to negatively charged surfaces.

Usage and Applications

Octenidine dihydrochloride is a versatile biocide intended for use in human and all animal species for skin and mucosal disinfection. It works well as short-term supportive antiseptic in wound treatment as a 0.1% aqueous solution for cutaneous use as well as for long-term antisepsis.

In addition, octenidine is used for sterilization of IV catheters, and in dental medicine, it is used as mouth rinse, gutta-percha disinfectant, for biofilm inhibition on restorative materials, and as an irrigant in root canal procedures. It has been utilised in mouth rinses to prevent plaque and gingivitis, as well as whole body wash for methicillin-resistant S. aureus decolonization and for skin disinfection of premature new-born infants.

Conclusions

The true test of a biocide is to demonstrate that the product has reduced surface bioburden, prevented proliferation or killed microorganisms. Given the variety of factors at play, the selection of an appropriate biocidal agent can be a complex and challenging process.

Finally, the selection of biocides should not be considered as a one-off decision; it must remain part of the on-going quality review process of the formulator and institutional user.

References

McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999 Jan;12(1):147-79. doi: 10.1128/CMR.12.1.147. Erratum in: Clin Microbiol Rev 2001 Jan;14(1):227. PMID: 9880479; PMCID: PMC88911.

Bloomfield, S. F. Resistance of bacterial spores to chemical agents. In A. D. Russell, W. B. Hugo, and G. A. J. Ayliffe (ed.), Principles and practice of disinfection, preservation and sterilization, 3rd ed., 2013. Blackwell Science, Oxford, England.

CITATION

When referring to this article, please cite as: E. Mwesigwa, A comparative appraisal of the utility of broad-spectrum biocides. Pharmacentral Science and Technology Bulletin 01 (09) 2021

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Abstract

1 Introduction

2 Materials and Methods

2.1 Materials

2.2 Methods

2.2.1 Tablet Preparation and Coating

2.2.2 Equilibrium Moisture Sorption-Desorption Studies

2.2.3 Aspirin Stability Studies

2.2.4 HPLC Assay

3 Results and Discussion

4 Conclusions

What is burnout?

How to tell if you have work-related stress

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Common causes of burnout

How to prevent or handle early stages of burnout

How to recover if you already have burnout

1. Develop a positive mindset

2. Know your why

3. Find strength in others

4. Learn to pick yourself up

Final Thoughts on Burnout

Reference

Why pigs?

So what did the New York University Langone Health team do?

What’s next for these sort of transplants?

Are there any ethical concerns about breeding pigs for organ harvesting?

Sources

What is a COP?

Goals of COP26

Excipients Value Chain

End-users of Excipients

Leading Manufacturers

Sector Outlook

Market Drivers

Final thoughts

Dr. Enosh Mwesigwa, Pharmacentral Guest Columnist

Introduction

Criteria used to select biocide

Speed of action

Spectrum and Efficacy

Cleaning Capacity

Compatibility

User Health and Safety

Environmental Profile

Properties and benefits of broad-spectrum biocides

Alcohols

Usage and Applications

Biguanides

Chlorhexidine

Usage and Applications

Iodine and iodophors

Usage and Applications

Silver Compounds

Usage and Applications

Quaternary Ammonium Compounds

Usage and Applications

Bispyridines

Usage and Applications

Conclusions

When referring to this article, please cite as: E. Mwesigwa, A comparative appraisal of the utility of broad-spectrum biocides. Pharmacentral Science and Technology Bulletin 01 (09) 2021

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