The Micawber approach to thyroid hormone doses

Charles Dickens, Micawber and thyroid dosing

Mr Micawber's famous, and oft-quoted, recipe for happiness:

"Annual income twenty pounds, annual expenditure nineteen [pounds] nineteen [shillings] and six [pence], result happiness. Annual income twenty pounds, annual expenditure twenty pounds ought and six, result misery."

If you take 100 micrograms of levothyroxine a day and your body expends 99 micrograms, result happiness. Take 100 micrograms of levothyroxine a day, body expends 101 micrograms, result misery.

Every extra day leaves you further behind, until eventually you reach a new but definitely suboptimal steady state. A tiny, tiny amount more than you need is of little or no consequence.

For example, if you were on 125 micrograms and needed a small dose reduction, say to 112, but you were actually reduced to 100, you would be falling behind by 12 micrograms a day. In one week, you are down by 84 micrograms. Only when your body reduces its "consumption" of levothyroxine to 100 can the new steady state occur - and you will be well down by then.

(Be careful not to interpret this as an invitation to take more and more levothyroxine, that is taking the analogy too far.)

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Private Prescription Charges

If you ever get issued with a private prescription, Stop! Consider how much it will cost to get the item dispensed

First, is the item actually prescription-only? If it is available over-the-counter, that will almost certainly be the cheapest option.

What is the actual price of the medicine?

The pharmacy will likely have a range of possible suppliers with a range of prices. Then discounts depending on all sorts of factors. That makes it very difficult to get the exact price. But you can often get an idea from the British National Formulary.

https://bnf.nice.org.uk/

NHS pay the pharmacy through an agreed reimbursement mechanism based on the NHS Drug Tariff.

NHS also pays a dispensing fee (something like 245.0 through 286.8 per item depending on prescription).

NHS Drug Tariff prices for amitriptyline range from 75 through 98 pence per 28 (depending on dosage). Actually very similar prices to most levothyroxine tablets.

A pharmacy might charge £9.65 might is simply a base price equal to NHS prescription charge.

For example:

For private prescriptions you've obtained from another GP, we have a minimum dispensing charge of £9.65 per item.
https://www.pharmacy2u.co.uk/prescriptions/

I've never seen anything that stops pharmacies charging whatever they want for private prescriptions. But maybe there is some sort of price control mechanism?

Find the cheapest private prescriptions 

While NHS prescription prices are fixed, pharmacies can set their own for private prescriptions. These are given when you want a drug not covered by the NHS in your region, such as Malarone to prevent malaria if you're travelling and some cancer drugs. 

It could be a drug for a lifestyle-enhancing purpose, such as sexual aid Viagra (although this can be on the NHS if your erectile dysfunction's caused by a medical problem, such as diabetes, prostate cancer or a kidney transplant) or anti-baldness drug Propecia. 

Non-NHS doctors can't give NHS prescriptions. So go to one for emergency weekend diagnosis, or because you're a member of a scheme, and you'll get a private prescription.

Always compare prices 

Unlike the world of NHS prescriptions, with private prescriptions it's an open marketplace and pharmacies can set their own prices, meaning costs vary hugely. 

The table below shows how prices can vary for just one item, but it can be an even bigger difference if you ask for the generic version.
https://www.moneysavingexpert.com/family/cheap-prescriptions/

Note: NHS prescription charges only apply in England and even then only if you do not qualify for exemption.

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helvella - Thyroid USP

The Standard

Thyroid USP is, first, a standard. The U.S. Pharmacopeia defines medicine standards for the USA. And some countries follow USP standards, especially when there are few, if any, other standards for something.

The Products

Secondly, Thyroid USP is the substance produced that conforms to the USP standard.

And on the Thyroid UK forum, we do try to use the terms Natural Desiccated Thyroid (NDT) and Desiccated Thyroid Extract (DTE) solely for products which conform to USP. Sometimes this results in admin action to ensure consistency of information.

Products which do not claim to be Thyroid USP tend to be called "thyroid glandulars" as we don't really have any other suitable term.

The current Thyroid USP standard is not readily accessible. Which makes it difficult to say anything definitive. Some of what follows is historic and might no longer be true.

Discussion

Nothing in USP demands that the animal source is porcine. It could be bovine (cattle) or ovine (sheep). But I am not aware of ANY Thyroid USP product which isn't porcine. Though there are at least a few bovine glandular products.

The USP standard was originally devised to try to ensure consistency of the product but the chemical assay techniques were nothing like as refined and capable as those now available. The standard checked the amount of iodine which was bound - and assumed that represented thyroid hormone.

More recently it has been revised to use techniques which specifically check levothyroxine and liothyronine content much more directly.

 Further, in general we rely on the manufacturer's claims. For USA products, we know the FDA is involved. Similarly the relevant agencies for Canada and any EU countries.

The current official Thyroid USP monograph is not readily accessible. The link below claims to be the version from 2007 but this cannot be verified.

http://pharmacopeia.cn/v29240/usp29nf24s0_m83400.html

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Transdermal Levothyroxine

The possibility of delivering levothyroxine avoiding the digestive system has many advantages. These include interference with food, drinks, other medicines, supplements, etc. Also the possible effects of levothyroxine on the gut ling and biome.

It will take years of research for any products to reach market. Even then, most novel medicines, even if just a different route of delivery, cost considerably more than existing products. Therefore access will be limited by wealth of countries and, within countries, wealth of patients or other funding mechanisms

To this end, there have been a number of trials of possible ways of delivering levothyroxine transdermally.

I used the following search (which will return updated results each time it is run).

 https://europepmc.org/search?query=transdermal%20levothyroxine

The most obvious results of interest were:

Film-Forming Systems for Dermal Drug Delivery

 Film-forming formulations represent a novel form of sustained release dermatic products. They are applied to the skin as a liquid or semi-solid preparation. By evaporation of the volatile solvent on the skin, the polymer contained in the formulation forms a solid film. Various film-forming formulations were tested for their water and abrasion resistance and compared with conventional semi-solid formulations. Penetration and permeation studies of the formulations indicate a potential utility as transdermal therapeutic systems. They can be used as an alternative to patch systems to administer a variety of drugs in a topical way and may provide sustained release characteristics.

https://europepmc.org/article/MED/34201668

Levothyroxine sodium loaded dissolving microneedle arrays for transdermal delivery.

Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm2) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm2) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm2) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.

https://europepmc.org/article/MED/36131889

Levothyroxine: Conventional and Novel Drug Delivery Formulations.

Although levothyroxine is one of the most prescribed medications in the world, its bioavailability has been reported to be impaired by many factors, including interfering drugs or foods and concomitant diseases, and persistent hypothyroidism with a high dose of levothyroxine is thus elicited. Persistent hypothyroidism can also be induced by noninterchangeability between formulations and poor compliance. To address these issues some strategies have been developed. Novel formulations (liquid solutions and soft gel capsules) have been designed to eliminate malabsorption. Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing, such as thyroid emergencies and dysphagia. Moreover, nanomaterials have been used to develop delivery systems for the sustained release of levothyroxine to improve patient compliance and reduce costs. Some delivery systems encapsulating nanoparticles show promising release profiles. In this review, we first summarize the medical conditions that interfere with the bioavailability of oral levothyroxine and discuss the underlying mechanisms and treatments. The efficacy of liquid solutions and soft gel capsules are systematically evaluated. We further summarize the novel delivery routes for levothyroxine and their possible applications. Nanomaterials in the levothyroxine field are then discussed and compared based on their load and release profile. We hope the article provides novel insights into the drug delivery of levothyroxine.

https://europepmc.org/article/MED/36412275

Preparation and in vitro evaluation of injectable formulations of levothyroxine sodium using in situ forming hydrogel temperature-responsive systems based on PLA-PEG-PLA and PLGA-PEG-PLGA triblock copolymers.

Objectives

Recently, great attention has been paid to developing new drug delivery systems to manage the rate, time, and site of drug release. We aimed to design a novel drug delivery system to support targeted and gradual delivery of levothyroxine sodium.

Materials and methods

The triblock copolymers of PLA-PEG-PLA and PLGA-PEG-PLGA were constructed using the ring-opening copolymerization method and then purified and characterized by 1H-NMR, DSC, and GPC techniques. The phase transition temperature of the polymers was determined, and levothyroxine sodium stability was investigated in a phosphate-based buffer (pH 7.4). In vitro drug release into the PBS was measured at different concentrations of the triblocks for one month.

Results

The results of NMR and GPC showed successful fabrication of the copolymers with low molecular weight dispersion and Tg points of -8.19 °C and -5.19 °C for PLA-PEG-PLA and PLGA-PEG-PLGA, respectively. Stability tests showed that during one month, most of the triblocks' masses degraded at 37 °C while levothyroxine sodium remained stable. Initial burst release of the drug in both copolymers is inversely correlated with the concentration of the polymer. Evaluation of drug release for 35 days showed that PLA-PEG-PLA had a slower drug release rate than PLGA-PEG-PLGA.

Conclusion

Considering the low initial burst release, as well as continuous and long-term release kinetics of PLA-PEG-PLA and PLGA-PEG-PLGA copolymers, they can be used to gradually deliver levothyroxine sodium, obviating the need for frequent administrations and concerns over drug-food interactions.

https://europepmc.org/article/MED/35656181

Transdermal Delivery Systems for Biomolecules.

Purpose

The present review article focuses on highlighting the main technologies used as tools that improve the delivery of transdermal biomolecules, addressing them from the point of view of research in the development of transdermal systems that use physical and chemical permeation enhancers and nanocarrier systems or a combination of them.

Results

Transdermal drug delivery systems have increased in importance since the late 1970s when their use was approved by the Food and Drug Administration (FDA). They appeared to be an alternative resource for the administration of many potent drugs. The first transdermal drug delivery system used for biomolecules was for the treatment of hormonal disorders. Biomolecules have been used primarily in many treatments for cancer and diabetes, vaccines, hormonal disorders, and contraception.

Conclusions

The latest technologies that have used such transdermal biomolecule transporters include electrical methods (physical penetration enhancers), some chemical penetration enhancers and nanocarriers. All of them allow the maintenance of the physical and chemical properties of the main proteins and peptides through these clinical treatments, allowing their efficient storage, transport, and release and ensuring the achievement of their target and better results in the treatment of many diseases.

https://europepmc.org/article/MED/33425065

If any more interesting papers are published, I'll happily add them to this blog if you tell me about them.

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Red Yeast Rice

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