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Smaller and more efficient

New formulation of drug against AIDS may facilitate treatment for children and the elderly

Maria Helena Andrade Santana/UNICAMPGranules formed by clumps of microspheres of chitosan containing the drug, didanosineMaria Helena Andrade Santana/UNICAMP

Instead of a large, difficult-to-swallow pill, some much smaller granules containing the same drug encapsulated in microspheres; this was the technological solution that a group of researchers from the School of Chemical Engineering (FEQ) at the State University of Campinas (Unicamp) came up with. The solution may make the treatment of AIDS in Brazil more efficient, particularly among elderly patients and children. This is a completely new pharmaceutical formulation of the drug didanosine (DDI), which is widely used in fighting the disease.

The new product, which is still in the experimental stage, is formed from small 1-millimeter (mm) diameter balls, with the capacity to stick to the intestinal mucus membrane. They consist of a mass of hundreds of microspheres of chitosan, a natural polymer obtained from the skeleton of crustaceans, such as the shrimp, crab and lobster. The antiretroviral drug didanosine is encapsulated within these microspheres. The new pharmaceutical form and its production process have already provided the group of researchers with a patent request, which was deposited in 2007 with the National Institute of Industrial Property (INPI), and which is valid abroad via the Patent Cooperation Treaty (PCT). According to chemical engineer Maria Helena Andrade Santana, the professor who coordinated the work, in the next stage of the study tests are likely to be carried out on humans, the last stage before the product is ready for marketing. Didanosine, a drug made by national pharmaceutical laboratories, is part of the antiretroviral cocktail given to patients when they are at an advanced stage of infection by the human immunodeficiency virus (HIV). Its function is to inhibit the replication of the HIV. Taken orally, as pills distributed by the Single Health System (SUS), the medication suffers from the inconvenient fact that it is very large, around one centimeter in diameter, which makes it difficult for children and the elderly to take, thus jeopardizing their treatment. In order to prevent it degrading when exposed to the acidic pH of the stomach, the drug is administered in buffered pills that contain substances such as magnesium hydroxide, which provides them with this protection.

The use of the buffer increases its size too much, making it difficult to swallow. Breaking the pill up may, in turn, render the drug ineffective, because it has to reach the intestine in one piece, where it will be absorbed by the organism.The main advantages of the product developed in the Biotechnological Process Development Laboratory at FEQ-Unicamp are the reduction in size of the medication, that fact that it adheres to the wall of the intestine and the gradual release of the drug. “The medication our group developed is a granule that, instead of comprising the free molecules of the ingredients, contains micrometric (two micrometers) spheres of chitosan embedded in its matrix, with the didanosine encapsulated inside”, explains Maria Helena. “Our product is easy to swallow and for the patient to adjust the dose, instead of breaking it up, all they have to do is count the number of granules to be taken. This makes the therapy easy for children and the elderly”. According to Maria Helena, a didanosine-based antiretroviral drug coated with a gastro-resistant polymer that ensures the active principle is protected already exists. However, it cannot be divided up – for example, to reduce the dose of the medicine – because when this happens the edges are left unprotected. “These granules are expensive and imported and their distribution is restricted to the public health network for patients with HIV-AIDS”. An additional advantage of the new formulation, whose research formed part of the PhD of chemical engineer Classius Ferreira da Silva, and the Master’s degree of pharmacist Patrícia Severino, both from FEQ, is the gradual and controlled release of didanosine, which increases the efficiency of the absorption of the drug by the mucous membrane in the intestine and makes the treatment more effective. “Our granules are capable of encapsulating and releasing the medication’s active compound in a slower and more controlled way”, says Maria Helena. Experimental results from trials on dogs have shown that the release of the didanosine occurred over a long period of 36 hours, and that the quantity of the drug absorbed by the organism in this time was double that of conventional pills and commercially-available granules. The authors of the study also emphasize that the granules of chitosan can be coated with gastro-resistant polymers, in such a way as to protect the activity of the active compounds that are sensitive to the stomach’s pH. Another distinguishing feature of the patent is the formulation’s manufacturing process. During the laboratory studies, production advanced in terms of the operational variables, making it possible to scale up and make on an industrial scale. The process involves both the production of the microparticles that encapsulate the drug, and the mucous-adhesive granules. Initially, the active compound is encapsulated in microparticles of chitosan, in a water dispersion. Then, these particles are separated by spinning and the water is removed. The damp particles are dried and chitosan is added to produce the granules. Gradual release – These granules were the subject of a pharmokinetic study – which is the time the drug remains in the blood stream – of the Master’s degree research of Patrícia Severino, with the support of Professor Teresa Dalla Costa, from the Pharmacy School of the Federal University of Rio Grande do Sul (UFRGS), which showed the superiority of the granules when compared to the commercially-available coated pill. “As a result it will be possible to reduce the frequency with which the drug is administered, and probably the dose”, says Maria Helena. According to the researcher, because of the association of these three properties – protection of the drug, or the active ingredient, its gradual release and specifically targeting the intestinal mucus membrane – these granules will be able to be used for other applications in the pharmaceutical, medical and veterinary areas, in addition to being employed in the production of the antiretroviral medication.

The final stage in the development of the new medication, which is essential for it to be made available commercially, depends on establishing a partnership with a pharmaceutical industry that will undertake to carry out the clinical trials on humans, which are both complex and above all expensive to do within the university environment. “It’s our idea to pass on the technology to an interested company, but we have no negotiations underway yet”, says Maria Helena.

The Project
Characterization of the polymeric and pharmacokinetic coating in vivo of granules containing microparticles of chitosan, incorporating didanosine (nº 06/06018-5); Modality Regular Research Awards; Coordinator Maria Helena Andrade Santana – Unicamp; Investment R$ 57,632.50 (FAPESP)

Scientific article
DA SILVA, C. F. et al. The intestinal permeation of didanosine from granules containing microspheres using the everted gut sac model. Journal of Microencapsulation. V. 26, p. 523-28. 2009.