Worldwide Pharmaceuticals

Cyclodextrin’s in Pharmaceutical Products Around the World:

Japanese pharmaceutical companies were the first to put Cyclodextrin containing pharmaceuticals on the market anywhere in the world. Ono, Teikoku, Shinogi, Fujinaga, Takeda, Nippon Kayaku, Kyushin, Meiji Seika have been selling pharmaceutical products containing Cyclodextrin’s in Japan since the early 80’s.

Ono was the first Japanese company to file patents that described pharmaceuticals using Cyclodextrin’s to improve the delivery of medication for humans. Almost all of Ono’s work involved prostaglandins, potent but highly insoluble compounds, that benefited greatly from the enhanced water solubility created by the Cyclodextrin complexes. Ono’s patents describing these prostaglandin (PG) “Clathrates” go back to the early 1970’s. Ono has at least 83 patents and filings describing Cyclodextrin containing inventions between 1971 and 1999.

Ono is the only company to get an injectable Cyclodextrin containing pharmaceutical product to market. Prostandin was an ACyclodextrin/PG complex given by arterial injection. Ono licensed this product to Schwarz Pharma in Germany and thereby this product found its way into Western European markets. Ono also produced sublingual and oral tablets of this pharmaceutical. Even with US patents issued to Ono in 1974 (3816393) describing these Cyclodextrin/PG inventions, products based on these inventions have yet to get to market in the US.

Ulgut®, an antiulcerant manufactured by Teikoku containing a complex of Benexate and BCyclodextrin was described in a 1981 Japanese patent application and was marketed in Japan in the late 1980’s.

Shionogi came out with a similar product based on Benexate/BCyclodextrin called Lonmiel® and marketed it in Japan in the early 90’s.

Takeda Chemical Co., a giant Japanese chemical and pharmaceutical manufacturer received Japanese patents as early as 1981 and even obtained a US patent (4480033) in 1984 describing its Cyclodextrin/PG inventions. Takeda had been marketing an antibiotic/ACyclodextrin preparation in Japan for many years; it is called Pansporin T, an oral tablet containing a cefotiam antibiotic.

As early as 1975 Nippon Kayaku received a Japanese patent describing a nitroglycerin formulation stabilized by BCyclodextrin. They marketed this product in Japan in the 80’s as the sublingual tablet, Nitropen®.

Kyushin patented an over-the-counter (OTC) iodine/BCyclodextrin mouthwash in Japan in 1983 and has been selling it since the early 80’s as Mena-gargle®.

Based on Japanese patents issued in 1989, Fujinaga has been marketing an ointment containing a dexamethasone/BCyclodextrin complex as Glymesason® ointment.

The first Cyclodextrin containing pharmaceutical marketed outside of Japan probably occurred in Germany in the mid 80’s. Ono pharmaceutical licensed its ACyclodextrin/prostaglandin product to Schwarz. Schwarz marketed this product, Prostavasin® with great success in western Europe generating annual sales in the millions of dollars. It is interesting to note that the patent describing this prostaglandin product had a Japanese priority date of 1970 and was issued as a German patent (DE 2128674) in 1971. Finally in 1974 US 3816393 was issued describing this pharmaceutical invention, but no effort was successful by either Ono or Schwarz to market the product in the US.

Chiesi Pharmaceutical of Italy was the first European company to successfully market a Cyclodextrin containing pharmaceutical product that it owned through filed patents. Chiesi filed patents for piroxicam formulations with BCyclodextrin with a priority date as early as 1984. Patents for these formulations were issued in Belgium (900836) in 1985 and the US (4603123) in July of 1986. It wasn’t until the early 90’s that Chiesi began marketing in Italy a product, Brexin®, based on those patented formulations. The 6-8 years between patent issuance and marketing the product is an unusually short time for new drugs and is a testament to the effort that Chiesi put behind this really excellent improvement to analgesia. Even by 1998, Brexin still was not marketed in the US, but could be found in Scandanavia, Belgium, Netherlands, Switzerland, Germany, and Brazil as a result of the licensing efforts of Chiesi.

In the mid 90’s other BCyclodextrin based pharmaceutical products were marketed in Europe and the UK by Stada of Germany and other Italian companies such as Roussel-Maestrelli, LPB Institute, Synthelab, and Novartis Farma.

Even South America had a BCyclodextrin formulation containing chlordiazepoxide (Trinxillium®) marketed by the Argentina company, Gador.

Note that all of the pharmaceutical products marketed up until about 1996 contained only the natural cyclodextrins, alpha or beta Cyclodextrin and none of these were approved for marketing in the US. Only as a result of a conscientious (financial and human resource expenditure) effort by Janssen Pharmaceutical of Beerse, Belgium did a product containing a chemically modified Cyclodextrin and the anti-fungal, itraconazole, finally get to market in the US.

As we look back on Janssen’s efforts to monopolize the ownership of pharmaceutical inventions containing chemically modified Cyclodextrin’s (especially hydroxypropyl BCyclodextrin) it becomes obvious that they planned to create many new drug offerings containing HPBCyclodextrin. Despite their sometimes unreasonable pursuit of this monopolizing position, great credit must be given them for tackling the often provincial regulatory attitudes of Europe and the UK; however, for taking on the US FDA, the medal for courage above and beyond reason must be awarded. In 1997 Janssen received approval to market an oral antifungal product containing 40% HPB (Sporanox®) in the US. Remember, Janssen had priority dates to HPB containing pharmaceuticals as early as 12/21/83. Millions of dollars in legal fees and patent related costs had to be added to the tens of millions of dollars it costs to prove a drug is suitable for human use. Kudos to Janssen for doing that very important ground-work. Janssen deserves to have great financial success with its latest patented inventions (US 5814330 & 5904929) using Cyclodextrin’s to improve transmucosal delivery in drugs.

While Janssen owned rights to derivatives of GCyclodextrin through early inappropriate composition of matter patents issued in 1985, it seems that they have either –

(a) Decided to avoid similar (to the HPB experience) expenses of solidifying weak GCyclodextrin patents

(b) Decided that GCyclodextrin derivatives will not present great pharmaceutical benefits over BCyclodextrin derivatives

It is also well known that Wacker Chemie has put great effort and many dollars into securing a strong manufacturing position in gamma Cyclodextrin’s around the world.

It becomes pretty clear from the preceding that two different business mindsets have inadvertently conspired to prevent the incorporation of Cyclodextrin’s into pharmaceutical products. Again the people who lost out are those who could have benefited from the improved delivery characteristics and concomitant efficacy of drugs that would further improve their quality of life.

Japanese pharmacopoeial and regulatory organizations are very much in tune with “natural” remedies; therefore, products (Cyclodextrin’s) originating from starch presented little risk of toxicity. Formulations containing these new, but natural materials were not held up by undue regulatory considerations. Many products quickly evolved because the benefits were so conclusive.

However, the Japanese pharmaceutical business in the 70’s and 80’s was very much isolated as a result of culture and politics from the rest of the world, especially from the large manufacturers and marketing machines in Western Europe and the US. Hence, the new Cyclodextrin containing pharmaceutical products being marketed in Japan remained unknown in other parts of the world.

At the same time, the globally extroverted marketing giants in the US were put off from developing pharmaceutical products based on these wonderful enhancers of aqueous delivery called cyclodextrins by a highly protective and bureaucratic regulatory system that still had fresh in its mind a thalidomide travesty. Such reticence on the part of the US regulatory community translated into perceived, greatly increased costs for getting new formulations containing these cyclodextrins approved for use in humans. Add a mindset that requires minute chemical detail describing even natural products, and does not accept scientific work done by non-US facilities. You’ve now got a barrier to entry that even the most aggressive pharmaceutical manufacturer and/or marketer will back away from until someone else “does it first”.

The country that made the early decision to promote and develop Cyclodextrin applications had voluntarily isolated itself from the global pharmaceutical community; the country that could provide the market stimulus to the rest of the world had voluntarily isolated itself into a state of impossible technical demands and “got-to-do-it-myself” mentality.

These are the independent and inadvertently conspiring mind-sets that delayed the introduction of Cyclodextrin improved pharmaceuticals by at least twenty years.