Collaborative research and development for additional indication for our pharmaceuticals

As mentioned in the section on drug re-positioning (DR), additional indications of pharmaceuticals clinically used will become more important under the current situation where it is hard to develop new pharmaceuticals using new compounds. We work positively for additional indications of our PC-SOD under development and our launched lipo-PGE1 or lipo-NSAID. Especially, these products are excellent in safety, and we believe that they can be applied to many kinds of diseases, the mechanism of action considered. The following shows more information about our products, such as PC-SOD, lipo-PGE1 or lipo-NSAID. Please contact us if you have interesting suggestions about additional indications for these products.

1. PC-SOD

(1) Background of development

Reactive oxygen species (ROS) generates at inflammatory sites with strong cytotoxicity and histotoxicity, and they are underlying causes of various diseases. Specifically, the lungs, which control the respiratory function, are the place where large amounts of ROS is produced at any time, and many lung-related diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS), and asthma are caused by ROS.
Proteins derived from living bodies that remove ROS have been the focus as pharmaceuticals for a long time. This is because living animals naturally have these proteins to protect themselves from ROS, and supplements of these proteins may be effective, while side effects seem unlikely to occur. Out of them, superoxide dismutase (SOD) removes superoxide anion, which is strong ROS, and had been particularly focused on from a long time ago, and many large pharmaceutical companies had tried to develop drugs using this protein. However, they found that SOD had low blood stability and tissue affinity, and all clinical trials failed. To solve this problem, DDS technology, which prolongs the half-life in the blood of SOD and enhances tissue affinity of the SOD, came to be required.
We made a hypothesis that binding phospholipids, which is a component of biological cell membranes, to SOD may improve tissue affinity. Based on the fact that low blood stability of SOD is caused by its excretion from the kidneys, we also expected that the increased molecular weight by binding of phospholipid to SOD and binding of phospholipid to serum albumin may control renal excretion and improve blood retention. We found that binding of two human SOD molecules to four phospholipid molecules (phosphatidylcholine, PC), which is PC-SOD, increased blood stability and tissue affinity to as many as 80 times and 50–100 times, respectively (paper 1). Although polyethylene glycol (PGE) modifier (for example, PEG-modified interferon) is well known for a DDS product that modifies proteins, we also recognize lecithinization as an important DDS technology that can be applied to other proteins.

(2) Development of PC-SOD intravenous injection

Ulcerative colitis (UC) is caused by invasion of gastrointestinal bacteria to tissues injured by ROS, leading to worsened inflammation and SOD is a promising therapeutic agent for this disease. First of all, we compared PC-SOD and non-modified SOD in UC affected animal models and found PC-SOD had significant suppression effects on intestinal inflammation under the condition that no effect of non-modified SOD was shown (paper 2). After the nonclinical trial and phase I clinical trial confirmed the high safety of PC-SOD intravenous injection, we conducted the phase II clinical trial (open-labeled trial) in UC patients. The trial results revealed that PC-SOD intravenous injection was significantly associated with improved symptoms (paper 3).
Idiopathic pulmonary fibrosis (IPF) is a serious disease that causes the lungs to gradually become fibrotic and leads to loss of respiratory functions, resulting in deaths in 80% or more of patients diagnosed within five years. (It has a poorer prognosis than lung cancer.) Recent research has revealed that IPF may be caused by abnormally increased responses to restore tissues injured by ROS. Then, we estimated that PC-SOD may also be effective in IPF. After the treatment effect was confirmed in animal models of IPF (papers 4 and 5), we conducted the phase II clinical trial of PC-SOD intravenous injection in IPF patients (randomized, multi-center, double-blinded trial). The trial results showed the forced vital capacity (FVC) improved in more patients receiving PC-SOD, compared to those receiving placebo and PC-SOD injection significantly improved the level s of IPF biomarkers such as SP-A or LDH (paper 6).

2. Lipo-PGE1, lipo-NSAID

(1) Background of development

Lipid microsphere is a lipid emulsion with an average diameter of 200–300 nm consisting of soybean oil and egg yolk lecithin. Nutritional supplements clinically used are made up of lipid microsphere-formed particles. We focused on easy accumulation of this particle on affected vascular sites or inflammatory tissues and considered the possibility of an effective DDS carrier. After efficacy was demonstrated by pioneering research, we achieved the first successful practical use of a lipid microsphere product (lipo product) in the world. DDS carriers can be used for various pharmaceuticals by replacing them encapsulated. We have been successful in actual use of lipo-steroids, lipo-PGE1, and lipo-NSAID (non-steroidal anti-inflammatory drug), in order of approval.

(2) Lipo-PGE1

Patients with chronic arterial occlusive disease have been steadily increasing because of aging, westernized lifestyles, and the rapid increase in patients with diabetes. However, they have a very low five-year survival rate of 40% and about a half of severe patients die of the disease within a year.
Although PGE1’s effects of vascular dilation, promotion of vascularization or platelet aggregation inhibition are effective in chronic arterial occlusive disease, PGE1 is immediately deactivated inside the body and any preparatory design with DDS was required. LTT achieved successful development and launching of Lipo-PGE1 intravenous injections (Liple, Palux), DDS products to reduce deactivation of PGE1 inside the body, and deliver it selectively to affected sites by encapsulation of PGE1 in lipid microsphere (paper 7). Lipo-PGE1 has a high effect on chronic arterial occlusive disease. This has achieved the sales at peak of over 50 billion yen in Japan and contributed considerably to improving healthcare.

(3) Lipo-NSAID

Non-steroidal anti-inflammatory drugs (NSAID) are very commonly used as a drug with excellent antipyretic, analgesic, and anti-inflammatory effects; however, most of them are taken orally or dermally, and injection-type drugs are rarely available. But, it is necessary to control pain quickly and strongly in clinical practice, and there is a need for injection-type drugs. Injection-type drugs have the advantages that may reduce gastrointestinal disorders and use NSAIDs in patients with difficulty in oral administration. We have achieved the successful development and launching of lipo-NSAID (Ropion), a lipo product encapsulating the prodrug of flurbiprofen in lipid microspheres. This is currently used for treatment of post-operative pains and various cancer pains. In China, this drug is also distributed by Beijing Tide Pharmaceutical.

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