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Pharmaceutical Industry

Innovative molecules

Biolab completes development of two new drugs in hopes of expanding its presence in the international market

076_Biolab_238Pharmaceutical laboratory Biolab Farmacêutica completed 18 years of activity in 2015 with good reason to celebrate.  The 100% Brazilian company, owner of a portfolio of over 100 drugs and based in the city of São Paulo, submitted an application to the National Health Surveillance Agency (ANVISA) for registration of Zilt, a new treatment for fungal infections.  Its active compound is based on a new molecule, BL 123, entirely produced in Biolab’s laboratories.  In late 2014, before Zilt, Biolab had filed for registration of Nanorap, a topical nano-anesthetic developed in partnership with researchers from the Federal University of Rio Grande do Sul (UFRGS).

“Every step of the development process for BL 123, which was named dapaconazole, was performed by our scientists, including modeling and synthesis, until the antimycotic Zilt was achieved.  This is a first for Biolab,” says the laboratory’s chief scientist, Dante Alario Junior.  “This puts Brazil in a position to supply innovative molecules.”  The company is currently running tests on 38 new molecules and has 259 patent applications pending, not to mention 79 incremental innovation and five radical innovation projects.  According to ANVISA Board of Directors Resolution No. 37, issued in July 2014, incremental innovation “results in a new pharmaceutical form, new concentration, new method of administration or a new indication for a molecular entity already registered in Brazil.”  Radical innovation is described as “innovation resulting in a new molecule not registered in Brazil.”  According to Alario, “dapaconazole is a radical innovation because it is a new chemical entity, not yet described in the literature or patented in Brazil or anywhere else in the world.”

Zilt was formulated with the goal of putting a new antimycotic drug on the market.  Because this type of medication is commonly used on a frequent and continual basis, it gradually becomes ineffective at preventing or inhibiting fungal proliferation.  This happens because fungi develop a resistance to the drug over time.  “Dapaconazole will be used mainly in cases of resistance to miconazole, an antifungal agent that has been available on the market for many years,” highlights Gilberto De Nucci, a professor at the Biomedical Sciences Institute and the School of Medicine at the University of São Paulo (USP), responsible for conducting pre-clinical and clinical trials for the drug.

Biolab hopes that Zilt will be registered within a year.  Patent applications for the drug have been approved in the United States, Japan, Australia, South Africa, Singapore and Ukraine.  The application for Brazil is still undergoing analysis by the Brazilian Industrial Property Institute (INPI).  Research for the drug’s development began in 2007, and Zilt will initially be sold in topical cream and lotion forms.  Other formulations under development include a pill, spray, vaginal cream and vaginal ovules.  “We are also testing an injectable version, but I don’t know if we will pass the toxicity tests.  If we do, it will be a very sophisticated drug,” says De Nucci, adding that early-stage research on the compound has generated one doctoral thesis, two master’s dissertations and several scientific articles.

According to the researcher, dapaconazole is truly innovative, but would most accurately be described as a “me-too drug”, a term used by the pharmaceutical industry to define molecules that give rise to new products within an already existing class of drugs.  “Me-too molecules are not a break of paradigm, but they bring exceptional advantages.”  De Nucci was responsible for designing the lodenafil carbonate molecule, commercially sold as Helleva, for Brazilian laboratory Cristália, based in Itapira, a city in the interior of São Paulo State.  The drug, indicated for erectile dysfunction, is a me-too of Viagra (sildenafil citrate), which is owned by Pfizer.  According to Professor Bartira Rossi Bergmann from the Carlos Chagas Biophysics Institute at the Federal University of Rio de Janeiro (UFRJ), Zilt is a new molecule within a known class of antifungals called the imidazoles.  “But it is an important discovery and, from what I have read in articles published by the group, it seems to offer better results than miconazole, a well-established antifungal available on the market,” says Bergmann.

Encapsulated nano-anesthetic
Like Zilt, the nano-anesthetic Nanorap was also developed in partnership with academic researchers.  Pharmacists Sílvia Guterres, a professor at the UFRGS School of Pharmacy, and Adriana Pohlmann, from the Chemistry Institute at the same university, were responsible for developing the technology to encapsulate the active principles in the drug’s formulation, namely prilocaine and lidocaine.  The two compounds are well-known by the medical community.  “We designed and developed the nanocapsules, which are the means for transporting and delivering the active principles to the desired region of the body,” Guterres explains.  She adds that the nanocapsules are spherical, with an average diameter of 200 nanometers (one nanometer is one millionth of a millimeter).  For comparison’s sake, a human hair is approximately 50,000 nanometers thick.

Nanorap is a topical anesthetic cream designed to be applied to the skin of patients before they undergo minor dermatological interventions such as wart removal or laser treatments.  Patents have already been granted for it in the United States, Japan, Australia, Mexico and South Africa, among other countries.  In Brazil and Europe, the respective patent applications are still pending.  The main advantage of Nanorap in relation to similar topical anesthetics is its ultra-fast effect.  The cream starts to work within 10 minutes, one sixth of the time needed by conventional non-injectable products.  Nanorap’s quick action shortens the waiting time between applying the anesthetic and starting the intervention.

Pharmacist Sílvia Guterres explains that Nanorap acts so quickly due to its nano-architecture, which ensures faster absorption by the skin.  “The drug has a pre-determined speed and reach.  So its effect is faster and lasts longer, making it more effective in comparison to conventional drugs,” says Guterres.  The nanocapsules are made from a biodegradable polymer.  They penetrate the corneous layer of the epidermis – the outermost layer of the skin – and stay there for a pre-set period of time, continually releasing the drug.  Then, the nanocapsules are biodegraded or simply removed in the shower or by simple localized friction.  “This new formulation confers new properties on the active principles, making them more effective.  It is a high-tech approach.  Its developers at UFRGS are at the cutting edge of the field of nano-encapsulation.  They are well ahead of any other research group in Brazil or abroad when it comes to mastering the production of these nanocapsules,” says Bergmann from UFRJ.

The partnership between Biolab and UFRGS for drug design using nanotechnology started in 2005 and resulted in the release, four years later, of the first Brazilian sunscreen using nanotechnological solutions, sold under the name Photoprot (see Pesquisa FAPESP Issue nº 167).  The cosmetic, which has an SPF of 100, was prepared by applying nano-encapsulation technology to organic chemical sunscreens.  Like Nanorap, Photoprot was made with a 100% biodegradable polymer.  Its formula contains the sunscreens avobenzone and octocrylene, which absorb UVA and UVB radiation, plus buriti oil, an important antioxidant agent.

International market
Biolab is among Brazil’s 10 leading pharmaceutical companies and is betting on the success of its two new drugs to increase market share at home and expand sales abroad.  In Brazil, it leads the segment of drugs for cardiological treatments, holding 17% of the market, and is in fourth place in the dermatology sector.  Its Research, Development and Innovation Center (P&D&I) in the city of Itapecerica da Serra, 33 kilometers from São Paulo, employs a team of 120 people.  Between 7% and 10% of Biolab’s annual revenue is earmarked for innovation projects.  In 2015, the company reported gross earnings of R$1.35 billion, a 16% year-over-year rise.  The pharmaceutical sector as a whole grew 8% that year, which means that Biolab successfully expanded its market share.

The Brazilian market for Nanorap and for the antifungal drug Zilt is estimated at $60 million and $450 million, respectively.  In the United States, which account for 45% of global demand for pharmaceuticals, the commercial potential for the two drugs is six times greater.  This explains the company’s efforts to enlarge its international footprint and reach American consumers.  Currently, Biolab only exports to countries in the Middle East and Africa, which represent less than 5% of the company’s revenue.  In 2015, Biolab opened an office in Miami, focusing on expanding its partnerships with multinationals.  In August of 2015, it launched a Research, Development and Innovation (R&D&I) facility in Toronto, Canada.  The expected investment over the coming two years is $40 million.

“We will not shut down our research in Brazil, but rather reinforce it with the facility in Canada.  The two units will work in a complementary manner,” explains Dante Alario Junior, highlighting that the Canadian laboratory will initially have an essential role in adapting Zilt and Nanorap to the North American market.  The facility will better enable Biolab to prepare the hefty dossiers required by regulators in the United States, Canada and Europe for new drugs.  The research center in Toronto, built in Canada’s biggest innovation hub, will occupy an area of a thousand square meters and will be the first Brazilian pharmaceutical company to set up shop in the country, according to Biolab.  Operation start-up is scheduled for early 2016.

A third production facility is being built in Estiva, a city in the interior of Minas Gerais State, to support the laboratory’s plans for global expansion.  Two facilities currently in operation are located in Jandira and Taboão da Serra, both in the São Paulo Metropolitan Area.  The plant in Minas Gerais will receive R$350 million in investments.  “The facility is being designed to meet global demand.  It will have a high production capacity and comply with international standards right from the outset.  We expect it to be ready in 2018, the same year that our two new drugs, Zilt and Nanorap, should enter the market,” concludes Biolab’s chief scientist.  “Biolab’s two new pharmaceutical innovations are important.  It is in Brazil’s best interest to offer high-tech, high-quality drugs.  They can help break down the paradigm that Brazilian pharmaceuticals are inferior to imported ones.  I imagine that the next great challenge for Biolab, after it obtains registration from ANVISA, will have to do with marketing.  They need to place the two products on the market and show consumers that they are innovative, good and affordable,” says Bergmann.

Scientific articles
Moraes, F. C. et al. Quantification of dapaconazole in human plasma using high-performance liquid chromatography coupled to tandem mass spectrometry: Application to a phase I studyJournal of Chromatography B. V. 258, pp. 102-7.  May 2014.
Gagliano-Jucá, T. et al. Pharmacokinetic and pharmacodynamic evaluation of a nanotechnological topical formulation of lidocaine/prilocaine (Nanorap) in healthy volunteersTherapeutic Drug Monitoring.  V. 37, No. 3, pp. 362-8.  June 2015.
Gobbato, A. A. et alA randomized double-blind, non-inferiority Phase II trial, comparing dapaconazole tosylate 2% cream with ketoconazole 2% cream in the treatment of Pityriasis versicolorExpert Opinion on Investigational Drugs.  V. 24, No. 11, pp. 1399-407.  Nov. 2015.