Some notes on Mannitol

[helvella]

There has been much discussion about Teva levothyroxine in the UK and Levothyrox (formerly Euthyrox) in France and other countries - where it appears that the mannitol ingredient could be the cause of issues.

I found a few papers about mannitol and thought that they could be of some interest. There could well be more available as I collected these some time ago.

Looks to me as if they point at some possible reasons some find it unacceptable. And why they want to use mannitol.

Probably always a good thing to remember how many people have criticised lactose (vegans, those with lactose intolerance, etc.). A great pity that mannitol seems to carry its own set of issues.

Anaesth Intensive Care. 2015 Nov;43(6):779-81.

Anaphylaxis following intravenous paracetamol: the problem is the solution.

Jain SS1, Green S1, Rose M1.

Author information

1 Anaesthetic Allergy Clinic, Department of Anaesthesia and Pain Management, Royal North Shore Hospital, St Leonards, New South Wales.

Abstract

Paracetamol is a ubiquitous analgesic and antipyretic that is widely administered, including by anaesthetists. Immediate hypersensitivity reactions to intravenous paracetamol are particularly rare. We report two cases involving four separate episodes of anaphylaxis to intravenous paracetamol in different perioperative settings without a past history of intolerance to the oral form. The allergological investigations are described, during which it became evident that both patients were allergic to an excipient (mannitol) present in the formulation and that neither was allergic to the principal agent (paracetamol). The importance of referral and investigation of perioperative drug reactions is underscored by these two cases.

KEYWORDS: acetaminophen [paracetamol]; anaphylaxis; excipient; mannitol; pharmaceutical solutions

PMID: 26603804

ncbi.nlm.nih.gov/pubmed/266...

Home > March 1999 - Volume 28 - Issue 3 > Altered Intestinal Permeability to Mannitol in Diabetes Mell...

Altered Intestinal Permeability to Mannitol in Diabetes Mellitus Type I

Carratù, Romano; Secondulfo, Mario; de Magistris, Laura; Iafusco, Dario*; Urio, Anna*; Carbone, Maria Grazia*; Pontoni, Gabriele†; Cartenì, Marilena†; Prisco, Francesco*

Journal of Pediatric Gastroenterology & Nutrition: March 1999 - Volume 28 - Issue 3 - p 264-269

• Abstract

Background: Intestinal permeability has seldom been investigated in diabetes mellitus, even though patients frequently report gastrointestinal symptoms, and it has recently been shown that the prevalence of celiac disease associated with diabetes mellitus is higher than expected.

Methods: Intestinal permeability to cellobiose and mannitol was investigated in 31 patients affected by type I uncomplicated diabetes mellitus. Values were compared with those obtained in 32 normal subjects.

Results: The percentage of mannitol recovery was far higher than normal in two thirds of the investigated patients and correlated with the length of disease, even though the probes' ratio (cellobiose/mannitol) was in the normal range.

Conclusions: A not previously reported increase of intestinal permeability to mannitol, clear-cut and not associated with that of the larger probe, is found in type I uncomplicated diabetes mellitus. These results may describe a primary feature of type I diabetes mellitus and the initial steps of evolution of celiac disease.

journals.lww.com/jpgn/Fullt...

March 1995, Volume 12, Issue 3, pp 393–396

The Effect of Different Concentrations of Mannitol in Solution on Small Intestinal Transit: Implications for Drug Absorption

1. Department of Pharmaceutical Sciences University of Nottingham University Park United Kingdom

2. Pharmaceutical Profiles Limited United Kingdom

3. Department of Human Morphology Queens Medical Centre United Kingdom

4. Glaxo Research and Development Limited United Kingdom

Abstract

The aim of the present study was to investigate the effect that different concentrations of mannitol have on small intestinal transit, and whether any observed effect was concentration dependent. Eight, healthy male subjects each received 200ml of radiolabelled purified water, or a 200ml solution of mannitol at three different concentrations; 0.755g/200ml, 1.509g/200ml and 2.264g/200ml, in a randomised, four way cross-over study. Transit of the radiolabelled solutions was followed by gamma scintigraphy. The study demonstrated no significant differences between the gastric emptying times of the four solutions. Rapid gastric emptying was observed in most cases. The mean small intestinal transit times for the 0.755g/200ml, 1.509g/200ml and 2.264g/200ml mannitol solutions was reduced by 11%, 23% and 34% respectively, when compared to the control solution. The intestinal transit data of the four solutions demonstrate that mannitol has a concentration dependent effect on small intestinal transit. Small concentrations of mannitol included in a pharmaceutical formulation could therefore lead to reduced uptake with any drug exclusively absorbed from the small intestine.

link.springer.com/article/1...

Review Article

Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms?

H. Leonhard Ohrem, Eva Schornick, Adela Kalivoda & Roberto Ognibene

Pages 257-262 | Received 10 Sep 2012, Accepted 21 Jan 2013, Published online: 26 Mar 2013

• doi.org/10.3109/10837450.20...

Abstract

Various fillers/binders which are applied for the formulation of solid oral dosage forms are assessed for their benefits and drawbacks, including lactose, sorbitol, mannitol, microcrystalline cellulose and calcium hydrogen phosphate dihydrate. A focus of this work was to evaluate the application of mannitol in comparison to other common fillers/binders as it was observed that this excipient is gaining more and more attention in pharmaceutical formulation development and production. While one of the main advantages of conventional fillers/binders such as lactose, microcrystalline cellulose and calcium hydrogen phosphate dihydrate is their low price level, mannitol excels regarding its physicochemical characteristics such as a low hygroscopicity, a strong inertness towards both the API and the patient’s body, its good compactibility and the ability to produce extremely robust tablets. Additionally, the suitability of mannitol for the emerging formulation technology of orally disintegrating tablets is pointed out. In summary, it is emphasized that the selection of the filler/binder is highly individual, depending, for example, on the preferred characteristics of the final solid dosage form, the applied API and the available budget. However, mannitol exhibits many strong advantages which can be expected to result in a more widespread application in the near future.

Keywords: binder, direct compression, excipients, filler, incompatibility, mannitol, solid oral dosage forms, stability, tablet

tandfonline.com/doi/abs/10....

[jgelliss]

Thank you Helvella for bringing up another very great and valuable topic/ information . Many of us just don't do well with many fillers that are used in our thyroid meds. Having thyroid in deficiencies is enough and sets us up for many sensitivities towards fillers/ dyes in the thyroid meds / gluten/lactose . It would be most appreciated for our well-being if manufactures of our thyroid meds would take into account our sensitivities.

[Hidden]

Interesting article, thanks for posting!

Don´t forget Euthyrox, available in many countries, which has also been reformulated to include mannitol.

[helvella Administrator Thyroid UK in reply to Hidden]

That was what I meant by referring to France but, I agree with you, it was not clear. So have adjusted the wording a little.

[Hidden in reply to helvella]

Apparently, the reformulated drug in France is called Lévothyrox by Merck. After hundreds of thousands of patients protested, Merck had to bring back the old formula...and it´s called Euthyrox...! So, Euthyrox in France does not contain mannitol whereas Lévothyrox does, while Euthyrox in all other countries contains mannitol...really confusing.