Interview with one of the developers of “Nano Pulverizer” – Professor Naofumi Hashimoto of Setsunan University –

The following describes an interview with Professor Naofumi Hashimoto of Setsunan University, who is a codeveloper of Nano Pulverizer NP-100, which can make nanoparticles of a material in a short time, and is also a technical advisor of our company. The Nano Pulverizer was first developed for use in the field of medicine, but now it is also actively used in other industrial fields.

1. Please tell us about the first point of contact between yourself and our products.

I knew about THINKY MIXER since about 17 years ago and actually started using it about 12 years ago. At that time, I worked at Central Research Laboratory of Pfizer Japan Inc.
One of my tasks was to make a uniform suspension for safety testing, and I started using THINKY MIXER. In the safety test, suspended medicine is administered to animals and its side effects and toxicity are examined. If the suspension is not uniform, the amount of medicine to be administered will not be constant, causing fluctuations in data. Therefore, making a uniform suspension is most important.
Until then, a stirrer was used for mixing, but I started to use THINKY MIXER, which can produce a uniform suspension easily in a short time. Because it gave very satisfactory results in the laboratory in Japan, I recommended it to Pfizer laboratories in the UK and the USA and proposed a method of unified safety examination for Pfizer laboratories throughout the world. The proposal was approved and THINKY MIXER was included in the common operating procedure and installed also in laboratories in the UK and the USA.

2. What purpose was THINKY MIXER used for other than for preparing suspension?

One member in my group conducted experiments to make grains of medicine finer by agitating suspension with a stirrer. Looking at his experiments, I thought that the medicine in the container would be pulverized finely if THINKY MIXER were used. Therefore, I immediately tried pulverization using THINKY MIXER.
Then, particles with the size of several hundred micrometers were reduced to several micrometers. This experiment showed the possibility of pulverization using THINKY MIXER. In fact, it reduced the time of pulverization, which requires a whole day with a stirrer, to only several minutes.

3. This led to the development of Nano Pulverizer NP-100, didn’t it?

Yes. When the topic of nano-pulverization was being tossed around in Pfizer, the Central Research Laboratory was closed down. Then, I moved to the University and resumed my research. The development of the machine itself was conducted in collaboration with Thinky.
Meanwhile, “nanotechnology” had become a hot topic in various fields since around 2003 and its application started to attract attention also in the field of pharmaceuticals.

4. Please tell us the main merits of pulverizing medicine into nanoparticles.

By converting medicine to nanoparticles, the total surface area of the powder is significantly increased and at the same time, the solubility increases. As a result, its absorption through the gastrointestinal tract after oral administration (administration through the mouth) is improved.
In those days, many laboratories throughout the world were discovering a lot of compounds that were pharmacologically active (active as medicine) but water-insoluble. Medicine cannot be absorbed through the gastrointestinal tract unless it is soluble in water. Therefore, I realized that pulverizing medicine into nanoparticles would be a very effective way of improving absorbability.
Initially the conversion into nanoparticles was aimed at improving absorbability in the case of oral administration. However, when pulverized to particles with size of 200 nm or less, various administration routes such as instillation (applying medicinal solution in the eyes), transdermal administration (administration by absorption of medicine through the skin surface), intravenous administration, and intramuscular administration become possible.

5. Will nanomedicines become more popular in the future?

Yes, I think that their use will increase dramatically in the future. For example, consider medicine whose dissolution rate is slow because of its large particle size and suppose that only 10% of oral doses of 100 mg is absorbed from the gastrointestinal tract. It is likely that if the medicine is converted into nanoparticles, the dissolution rate will be much faster and the total dose will be absorbed, necessitating the administration of only 10 mg. In other words, it is possible to obtain the same medicinal efficacy as the conventional dose with just a small dosage.
Large doses may cause undesirable effects such as absorption fluctuations or side effects. While there are, of course, good aspects in medicine, there are also bad aspects. Administering excessive amounts of medicine will become unnecessary by converting it into nanoparticles. I believe, therefore, that nanopulverization will lead to the development of highly safe medicines.

6. Did you have any difficulties in the development process?

Initially, increasing the rotation speed caused the problem of temperature rise. Because heat is a very detrimental factor for medicine, I focused on how to reduce heat generation and how to finish pulverization in a short time. It was very difficult to find the best conditions considering various factors such as the number of rotations, the shape of the container, the influence of the concentration, and the volume of the suspension.
After Nano Pulverizer NP-100 was commercialized, I investigated the scaling factor of a large mixer capable of processing up to 20 l/20 kg, THINKY MIXER ARV-10kTWIN. I succeeded in making pulverized material with ARV-10kTWIN, and obtained the same data as for NP-100. Now, the pulverization with ARV-10kTWIN by applying the data obtained with NP-100 can produce suspension with the same particle-size distribution as that obtained with NP-100.
The scaling factor, although casually mentioned above, is very important. In fact, it will affect not only the scaling-up of the machine but also the manufacturing cost. By investigating the pulverization into nanoparticles of only a few tens of mg of very expensive medicine using NP-100 at the laboratory level, we can predict the pulverization conditions at the production level. Without this scaling factor, tens of kg of expensive medicine would have to be used at the production level using ARV-10kTWIN. Good pulverization conditions cannot be determined with just a single attempt. Then, medicine amounting to tens or hundreds of millions of yen would have to be used just for the determination of the appropriate conditions. Therefore, the scaling factor realizes huge savings in terms of cost.

7. Currently, your laboratory is conducting research using Nano Pulverizer NP-100. What are the main subjects?

A poorly water-soluble medicine pulverized into nanoparticles exists in suspension in water. In order to process such pulverized products into pharmaceutical tablets or capsules, they must be made into powder (solid). We can obtain such powder by draining (drying) the suspension of nanoparticles. One typical method is freeze-drying.
In freeze-drying, however, a considerable number of nanoparticles exhibit the tendency to form aggregates. Nanoparticles tend to have higher electrostatic activity on their surface and agglomerate to form something like a lump of flour. These lumps do not easily dissolve even after oral administration. Therefore, it is important to prevent the lump formation for the purpose of increasing the absorbability through the gastrointestinal tract. We are performing research in which water is drained from the suspension to make powder and then the same suspension is reformed by introducing water again. We are getting promising results.
Another subject is ointment instillation (eye ointment). It is very painful when dust enters the eye while wearing contact lenses. This pain is caused by irritation caused by dust with the size of a few hundred micrometers. There is no irritation at all when it becomes nanosized.
In addition, patients feel strong fear when administering eye ointment by themselves. In particular, elderly people feel that rubbing ointment on the eye is frightening because their hands tremble. Eye drops in aqueous solution are possible if the medicine dissolves well in water. If water-insoluble medicine is converted into nanoparticles, it can be administered as ordinary eye drops in the form of suspension, which causes no foreign-body feeling and provides the same effect. These are the two main researches I am currently working on.

8. Currently, “NP-100” is used by customers in various industrial fields beyond the field of medicine. How do you feel about this as one of the developers?

I was surprised at the spin-off effect. Initially, I did not imagine that it would be applied in a wider range of chemical and industrial fields besides the pharmaceutical field. I am very pleased to hear that there are many inquiries concerning the machine.

Remarks after the interview

Nano Pulverizer NP-100 is highly appreciated because it can efficiently pulverize small amounts of particles into nanoparticles. Currently, the development of midsize and large-size machines that can process more quantities is under way. Look forward to future developments of Thinky’s Nano Pulverizer.

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Professor Naofumi Hashimoto
Brief biography

March 1977	Completed Master’s Course, School of Pharmaceutical Sciences, Graduate School of Natural Science & Technology, Kanazawa University
April 1977	Pharmaceutical Production Division, Central Research Laboratory, Shionogi & Co. Ltd.
January 1999	General Manager, Medicine, Analysis, and CMC Laboratory; Senior Fellow, Pharmacokinetics and Metabolism Research Department; Senior Fellow, Pharmaceutical Science Laboratory Central research Laboratory, Pfizer Japan Inc.
January 2007	Professor, Faculty of Pharmaceutical Sciences, Setsunan University Pharmaceutical Physicochemistry Laboratory