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Pharmaceutical industry

Weekly dose

Company acquires from UFMG the right to produce antihypertensive with technique for controlled release of the drug

The dream of every sufferer from high blood pressure – keeping the blood pressure under control with little medicine – is close to becoming a reality. The novelty is to swallow just one dose of antihypertensive medicine a week, to stay free of the ills of high blood pressure, a disease that causes serious functional deficiencies in the cardiovascular system and affects about 20% of the world population. The composition of the drug, developed at the Federal University of Minas Gerais (UFMG), is at the stage of preclinical tests that within six to eight months will give way to clinical tests, when hundreds of volunteers, under severe medical supervision, will test the new medicine. If approved, the drug will be transformed into a world-wide novelty. These good medical and commercial expectations lie on the route of the future manufacturer, Biolab-Sanus, a company with Brazilian capital that purchased the right to produce and market the medicine, under the protection of domestic and international patents, and is now funding the preclinical and clinical tests. For UFMG, this is the first contract to transfer technology to a pharmaceutical company, based on patents and royalties.

Both one of the coordinators of the project at UFMG, Professor Rubén Sinisterra, from the Chemistry Department, and the Technical-Scientific Director of Biolab-Sanus, Dante Alário Júnior, believe that the medicine will be on the drugstores shelves within three years. The swift approval time, usually longer in these cases, stems from the fact that the medicine does not contain a new active principle or unprecedented molecule, but rather that it uses modern technologies of molecular encapsulation. The novelty lies in the composition of the wrapping of the active ingredient, the latter an old friend of doctors and patients that cannot yet have its name revealed.

The formula for this new medicine was obtained by means of the technology of molecular encapsulation, a system for the controlled release of a drug into the organism, which, in the case of this antihypertensive, allows the same quantity as the daily dose of the traditional medicine to act on the organism for up to one week, reducing the intake to just one pill every seven days. For the sufferers of high blood pressure, besides the comfort of not taking the medicine on a daily basis, the lower quantity of drugs in the organism reduces the possible side effects.

The encapsulation of the drug is done with a substance made up of molecules of a glucose, called cyclodextrin, which have in the insides of them a hydrophobic cavity (which repels water) capable of containing the active ingredient. One of the possibilities of the researchers is to finish off the medicine with a microencapsulated inclusion compound (cyclodextrin plus the drug), in a support made up of biodegradable polymers of the latest generation, derived from glycolic and lactic acids, which are dissolved little by little in the organism. According to Sinisterra, encapsulation does not alterthe physicochemical and biological properties of the active principle, and it provides the protection necessary for maintaining the stability of the drug and allowing it to be absorbed slowly by the organism.

One of the functions of the cyclodextrins is to take the drug to the colon (the large intestine), where it interacts and little by little passes through the gastrointestinal membrane, to fall into the bloodstream afterwards. The difference between the new formulation and the traditional drugs lies in the slow and constant release while it passes through the intestines. Little absorption and rapid elimination is one of the main problems with conventional formulations. In the system of controlled release, much better use is made of the drug.The innovation was developed jointly by researchers Rubén Dario Sinisterra and his student, studying for a doctorate, Washington Xavier de Paula, from the Chemistry Department of the Exact Sciences Institute (ICEx), and Robson Augusto Souza dos Santos and Fredéric Frézard, professors from the Physiology Department of the Biological Sciences Institute.

For the university, the process for transferring technology was also innovative. According to Sinisterra, this contract is a landmark in the relations between the university and the Brazilian pharmaceutical industry. “In terms of negotiation, perhaps it is not the best or most advantageous, but it is the most important, because it was the first. It’s a novelty in Brazil”, explains the professor. Biolab-Sanus’s technical-scientific director, Dante Alário Júnior, said that he was “positively surprised” with the agility and maturity of UFMG in this negotiation. And, for him, this is something to be commemorated by the industry as well. “As far as I know, it will be the first time that a medicine with technology developed by a Brazilian university and produced by the domestic pharmaceutical industry will arrive on the foreign market as an innovation. “We have indeed exported, but we compete only on price, and never for any technological differential”, he reveals.

The university and the company are not disclosing the details of the technology developed and of the negotiation. Those involved avoid talking about amounts, because they believe that this helps to preserve the success of this pioneer contract. The research was financed by UFMG itself, by means of its Research Development Foundation (Fundep). Among other items, the contract with Biolab provides for the reimbursement of what has been spent by the university and the payment of royalties on the net sales proceeds of the medicine. The funds will be distributed in three equal parts, of which one for the institution, another split between the two units that took part in the research, ICB and Icex, and the third apportioned between the four researchers involved in the project. The agreement was handled by UFMG’s Technology Transfer and Innovation Coordinating Body.

Robson Santos, the coordinator of the ICB’s Hypertension Laboratory, speaks enthusiastically about the experience. “It was a very happy union,” he says. In the Inclusion Compounds and Biomaterials Chemistry Laboratory, coordinated by Professor Sinisterra, the system for the controlled release of the drug was developed, and in the Hypertension Laboratory, where the neural and hormonal mechanisms involved in the development and maintenance of raised blood pressure were studies, the preclinical tests were carried out (on rats), using telemetry. This control system is carried out by means of a catheter implanted in the rat, for transferring signals on the blood pressure to a computer, without the animal being handled and becoming stressed as a result.

“Until then, we didn’t even know each other”, says the doctor in physiology. Santos is the president of the Brazilian Physiology Society, a vice-president of the Brazilian Hypertension Society and a member of the editorial staff of the American Heart Association’s magazine, Hypertension.Rubén Dario Sinisterra is a Colombian who arrived in Brazil in 1989, to take a doctorate at USP’s Chemistry Institute. Afterwards, he was transferred to Belo Horizonte and has been a professor at the university in Minas Gerais since 1993.

Drawing the researchers from UFMG close to the company took place with the intermediation of the Applied Toxinology Center (CAT), one of the ten Research, Innovation and Diffusion Centers (Cepids) funded by FAPESP. The presentation of the microencapsulation system was made last year at a seminar organized by the CAT in São Paulo. “We laid down a bridge between the colleagues from Minas and the company that we already knew”, explains Professor Antônio Carlos Martins de Camargo, from the Butantan Institute and the CAT’s coordinator. Biolab, together with another company from the same group, União Química, and Biosintética, which make up the National Pharmaceutical Consortium (Coinfar), are financing the development of another hypertensive, also with the participation of researchers from UFMG, that has as its active principle a substance called Evasin, extracted from the venom of the jararaca and identified by the CAT. “This is a new molecule that calls for a larger number of tests before it is transformed into a medicine. We will be beginning the clinical tests in the middle of this year with good prospects, because all the experiments done up until now have been very positive.”

In the work carried out by the researchers at UFMG, the new medicine was tested on hypertensive rats, conventional and transgenic. Researcher Robson explains that it is important to test the two models, because the disease has different mechanisms in naturally hypertensive rats and in the transgenic ones developed for studying cardiovascular diseases. All the actions of the drug on the organism were tested and demonstrated, with good results.

The preclinical tests on a laboratory scale concluded that in the organism of rats the new formulation of the medicine remained for between three and seven days. The telemetric system makes it possible to monitor the cardiovascular parameters (blood pressure and heartbeats) for periods of up to six months, continuously. These tests have corroborated the concept, that is to say, the effectiveness of the compound. “But the National Health Surveillance Agency Anvisa) requires a lot more, to license, certify and authorize the marketing of a medicine”, explains Dante Alário, from Biolab. He said that the company will still do supplementary preclinical tests, for toxicity and others, and on a larger scale, for about eight months. Only then will the clinical tests begin on humans, and they should last for some two and a half years, when the time the drug remains in the organism will be known for sure.

Good price
Although a few stages are still missing for the medicine to be produced on an industrial scale, Dante Alário guarantees that Biolab will manage to ally quality to a good price. “Since it is without precedent, we are obliged to have more funds at our disposal until the product is ready. Even with the need for amortizing these costs, I believe that we shall manage to put onto the market a medicine that will be pharmacologically, therapeutically, and economically interesting for the consumer.”

In all the world, the routine of those with high blood pressure who know they have the disease includes a daily dose of medicine, to keep their blood pressure at normal levels. The disease is “democratic”, silent, and it affects people from all the continents, races and social classes, particularly after the age of 55. In at least 90% of the cases, the causes, for not being identifiable, are regarded as multifactorial, and for this reason it is the symptom that is treated. The consequences, though, are very clear. High blood pressure is often only perceived when the victim is surprised by a serious coronary disease or a cerebrovascular accident, which cause death or transform the lives of millions of persons negatively, often because of negligence with the treatment.

The Project
Molecular Encapsulation of antihypertensive drugs; Coordinators
Rubén Dario Sinisterra, Robson Augusto Souza dos Santos and Fréderic Frezard – UFMG; Investment Not disclosed

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