WO2012139190A1 - Films multicouches à libération contrôlée de substances volatiles adsorbées sur un support solide, et leur utilisation - Google Patents

Films multicouches à libération contrôlée de substances volatiles adsorbées sur un support solide, et leur utilisation Download PDF

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Publication number
WO2012139190A1
WO2012139190A1 PCT/BR2012/000111 BR2012000111W WO2012139190A1 WO 2012139190 A1 WO2012139190 A1 WO 2012139190A1 BR 2012000111 W BR2012000111 W BR 2012000111W WO 2012139190 A1 WO2012139190 A1 WO 2012139190A1
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WIPO (PCT)
Prior art keywords
films
chitosan
film
controlled release
item
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PCT/BR2012/000111
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English (en)
Portuguese (pt)
Inventor
André Augusto GOMES FARACO
Tatiana GOMES RIBEIRO
Rachel OLIVEIRA CASTILHO
Juçara RIBEIRO FRANCA
Eduardo Antonio Ferraz Coelho
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Universidade Federal De Minas Gerais - Ufmg
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Application filed by Universidade Federal De Minas Gerais - Ufmg filed Critical Universidade Federal De Minas Gerais - Ufmg
Publication of WO2012139190A1 publication Critical patent/WO2012139190A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Multilayer films consist of three layers of natural and biodegradable polymer (chitosan), the second layer containing volatile liquid substance adsorbed on a solid support (starch or talc). The films were tested against Leishmania amazonensis and showed antileishmanial activity.
  • Drug release at the site of action using appropriate delivery devices has an advantage over the conventional drug delivery system (orally). In recent years, it has been shown that drug release at the site of action increases treatment efficiency, as well as decreasing toxicity in the use of antineoplastic drugs, for example.
  • One of the ways of controlled release of drugs at the site of action is through the use of matrix systems.
  • Matrix systems are systems designed to prolong the release of a drug, dissolved or dispersed in a degradation-resistant support. They are considered monolithic devices, in which the drug is dispersed in a polymeric matrix and its release is controlled by diffusion from this matrix (PRISTA, LN; ALVES, AC; MORGADO, RMR. Pharmaceutical technique and galenic pharmacy. 3. ed., Portugal : Calouste Gulbenkian Foundation, 1990. v.3.).
  • a hydrophilic polymer matrix Upon contact with an aqueous medium, a hydrophilic polymer matrix gradually begins to hydrate from the periphery towards the center, forming a swollen gelatinous mass which controls the diffusion of drug molecules through the polymeric material toward the aqueous system.
  • the release of the active ingredient depends on its diffusion power through the gel network, the matrix's erosion capacity or the combination of both processes. Soluble drugs are released by diffusion through the gelatinous wall and also by exposure of the contents due to erosion. Insoluble drugs are released exclusively by content exposure due to matrix system erosion (CAVALCANTI, OA Modified drug delivery systems. Pharmacotechnics module of the postgraduate degree in pharmaceutical sciences. UNIVALI. Feb. 2001).
  • Polymer drug delivery devices are also used as rigid implants. This dosage form impairs the adaptation of the device to the different shapes of the body cavities where the implant is administered. Thus, the elaboration of these devices in the form of polymeric films has been used for drug release because it is more malleable and allows better adaptation to the administration sites.
  • Biodegradable polymers have been explored as a biomaterial in the drug delivery system area. Research on optimal biomaterials is still ongoing for drug delivery, which has their device properties dictated, for example, by biocompatibility, biodegradability, physicochemical properties, non-toxicity and others (LUDWIG, A., 2005. The use of mucoadhesive polymers in ocular drug delivery Adv.Drug Deliv Rev. 57, 1595-1639; FELT, O; FURRER, P.; MAYER, JM; PLAZONNET, B.; BURI, P .; GURNY, R. 1999. Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention. Int. J. Pharm., 180, 185-193).
  • Films that have natural polymers in their composition have been described in the literature, including solid system polymer blends and films whose matrix is composed of polymer and lipid material. However, these films differ in their composition, drug release times, and in the fact that they promote secondary reactions from lipid materials, such as oxidation. In addition, little has been said about the use of double (or double layer) films. In particular, powders of the films have difficulty attaching to the site of application and also retaining the drug therein for sustained controlled release of the drug. Consequently, alternatives such as polymeric film-based systems for sustained and controlled drug release have been investigated. Drug delivery systems including oil based materials and ceramic devices are known in the art.
  • chitosan is a polymer widely targeted by researchers in different fields. Examples of the versatility of this material can be seen from its application in fruit and food packaging systems, through its use in water and industrial waste treatment, to medical use, where both the fibers and the matrix systems of this material. polymer have attracted interest.
  • Chitosan is a natural polymer derived from chitin by an N-deacetylation process. Chitin is widely found in nature as the largest cell wall component of various insect and shellfish fungi and carapaces. In the last two decades, chitosan has been reported in the literature as a promising polymer due to its biodegradability properties, low immunogenicity and abundant availability.
  • chitosan has been used in a wide variety of biomedical applications (FELT, O .; FURRER, P.; MAYER, JM; PLAZONNET, B.; BURI, P .; GURNY, R. 1999. Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention. Int. J. Pharm., 180, 185-193.).
  • Several chitosan-derived carriers have been developed as drug delivery systems, however, clinical applications remain under investigation (FELT, O .; FURRER, P.; MAYER, JM; PLAZONNET, B.; BURI, P .; GURNY, R. 1999. Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention. Int. J. Pharm., 180, 185-193-.).
  • erodible and non-erodable inserts are more logical systems of prolonged drug release in the frontal cavity of the eye.
  • LDWIG The use of mucoadhesive polymers in ocular drug delivery. Adv.Drug. Deliv. Rev., 57, 1595-1639.
  • These systems support and control drug release, thus avoiding the burst effect, characterized by transient overdose, then a relatively short acceptable dosing period, which is followed by another prolonged underdose
  • LUDWIG, A., 2005 The use of mucoadhesive polymers in ocular drug delivery (Adv.Drug. Deliv. Rev., 57, 1595-1639.).
  • a drug-containing chitosan carrier can be applied to the outbreak of a disease, drugs can be released gradually and improve therapeutic efficacy (FELT, O .; FURRER, P .; MAYER, JM; PLAZONNET, B .; BURI, P. GURNY, R. 1999.
  • US5300494 entitled “Delivery systems for quaternary and related compounds” describes the manufacture of drug delivery devices having a polymeric matrix consisting of chitosan derivatives and not natural polymer, which increases the number of steps for obtaining the drug. device, burdening the process.
  • US20070042045 entitled “Multilayer dosage form comprising a matrix that influences the release of a modulatory substance" describes the manufacture of multilayer drug release films using acrylic acid-derived polymers in one layer, followed by layers of the same polymer or of different composition. The constituent layers of the system are obtained by compression.
  • US20080026040 entitled “Active agent-releasing dosage forms” describes the production of polymeric films by process using an ink jet system of the polymeric solution as well as the solution with the drug. .
  • Organic solvents are used to obtain the system and heat seal the polymeric material.
  • the polymers used are of varying composition.
  • the document US patent does not clearly report prolongation of drug release.
  • Patent document WO2005089825A2 entitled “Medical articles having regions with polyelectrolyte multilayer coatings for regulating drug release”, describes drug delivery devices employing ceramic framework.
  • the disadvantage of this method is its constituents and function in the device, especially the non-biodegradability of the entire preparation.
  • Patent document WO2006102965 entitled “Multiparticulate pharmaceutical form comprising pellets with a matrix which influences the delivery of a modulatory substance”, describes the production of pellets using polymeric solutions. It is a rigid system that does not adapt to the most different body cavities.
  • Figure 1 Result of hydration of the formulations prepared in 1.5% acetic acid solution.
  • Figure 1 Result of hydration of formulations prepared in 50% acetic acid solution.
  • Figure 3 Extended release profile of TN 1, 5% film.
  • Figure 4 Extended release profile of 50% TN film.
  • Figure 5 TAN 10 mg prolonged release profile 1.5%.
  • Figure 6 TAN 10 mg prolonged release profile 50.
  • Figure 7 Extended release profile of TAN 20 mg film 1, 5.
  • Figure 8 TAN 20 mg prolonged release profile 50.
  • Figure 11 Result of antileishmanial activity of formulations without nerolidol.
  • Multilayer films consist of three layers of natural and biodegradable polymer (chitosan), the second layer containing volatile liquid substance adsorbed on a solid support (starch or talc). The films were tested against Leishmania amazonensis and showed antileishmanial activity.
  • the invention described herein utilizes chitosan as the sole constituent polymer of the layers. Having a single polymer leads to a more economical manufacturing process.
  • a system obtained by a dissolution / evaporation process is described.
  • it is a system that allows the device to be adapted to body cavities because it is a film.
  • the present device has made drug release time longer than conventional dosage forms by allowing greater water inclusion (film hydration capacity) through the formation of hydrogen bonds between water and polymer. These "extra” interactions coming from the water molecules act as a glue, joining the polymer layers, thus hindering the diffusion process of the drug.
  • MUCHA M .
  • PAWLAK A. 2005. Thermal analysis of chitosan and its blends. Thermochim. Acta, 427, 69-76; RODRIGUES, LB; MILK, HF; YOSHIDA, MI; SALIBA, JB; JUST JUNIOR, AS; FARACO, AAG In vitro release and characterization of chitosan films as dexamethasone, Int. J.
  • the incorporation of a third layer further extends this release profile as a further barrier to the release of the active ingredient is introduced.
  • the solid support on which the volatile substance is adsorbed before being incorporated into the polymer matrix contributes to the fixation of volatile substances in the formulation and to a longer release profile.
  • the addition of layers as well as the use of solid support act as fixatives of volatile substances in the formulation, preventing their volatilization and consequent loss. This fact, in industrial terms, is of immense importance, since there is a great economy of the active principle. Therefore, prepared films are potential carriers for the release of volatile drugs for weeks.
  • Acetic acid chitosan matrix films were developed with and without nerolidol adsorbed on a solid support (starch or talc). The degree of deacetylation of chitosan used was about 85%.
  • a solution of acetic acid in distilled water at a concentration of 1.5% to 25% v / v was prepared. Then, 2.0 g of chitosan was weighed. The acidic solution was gradually poured over the chitosan and the system was kept under magnetic stirring at room temperature for about 24 hours until complete dissolution of the polymer.
  • the bilayer films were obtained from the monolayer film by the addition of a second layer of chitosan dispersion in acetic acid between 1.5% to 50% over the previously formed film, followed by the same drying process as was done. made for the monolayer film.
  • Trilayer films were obtained by the addition of a first layer using 5 ml of the chitosan dispersion in 1.5% to 50% acetic acid whose solvent was evaporated at room temperature until a thin film film was produced. Subsequently, the carrier layer prepared in the portion of the above-mentioned form containing nerolidol and the excipient in different proportions was added. In the next step, another layer of chitosan, using 5 ml of the dispersion, was added in 1.5% to 50% acetic acid whose solvent was evaporated at room temperature until a thin film was produced.
  • White films were prepared in the same manner as described above, but without the addition of nerolidol.
  • MTN 20 1, 5% - Nerolidol starch monolayer film produced with 5% acetic acid solution and 20 mg of talc.
  • TTN 10 50% - Trilayer film nerolidol starch produced with 50% acetic acid solution and 10 mg of talc.
  • TTN 20 1, 5% - Nerolidol starch layer film produced with 1, 5% acetic acid solution and 20 mg of talc.
  • the water absorption properties of the films were evaluated by determining the hydration percentage. This test is important to characterize the system as hydrophilic and also to check the water absorption capacity of the device. The greater the absorption capacity, the larger the size of the system after application at the action site may make its application unfeasible.
  • the hydration capacity of chitosan film formulations was determined by weighing the film before and after the addition of pH 7.4 phosphate buffer solution. The films were cut into circumferences of approximately 5 mm in diameter, weighed and placed in buffer for predetermined periods of time (5, 10, 20, 40, 60 and 90 min) as described by ⁇ ner and collaborators ( ⁇ ner, L ; Eroglu, H.; Sargon, MF; 2007.
  • Chitosan formulations for steroid delivery Effect of formulation variables on in vitro characteristics (Drug. Dev. Ind. Pharm., 33, 265-271). After immersion, the films were removed from the medium and weighed after removing excess surface water using filter paper. Hydration percentages were calculated. The experiment was performed in triplicate.
  • the nerolidol loaded films with constant exposed area were soaked in an appropriate volume in glass vials, as specified below, on a five replicate horizontal laboratory shaker. These glass vials were incubated at 37 ⁇ 0.5 ° C under shaking at 50 rpm. At appropriate time intervals all solution was withdrawn from the glass vial and the amount of nerolidol released from the loaded films was evaluated by the method developed by Ribeiro et al. (RIBEIRO, TG; FARACO, AAG; CASTILHO, RO. Development and validation of the method). Spectrometric analysis for quantification of nerolidol in a prolonged release polymeric device Quim Nova, 2010 (article submitted for publication)). Then an equal volume of the same solution was added to maintain a constant volume. The solution used for controlled release studies were typical solutions with pH 7.4 (10mM NaH 2 PO 4 / Na 2 HPO 4 - buffer solution).
  • Chitosan films produced sustained release in mono and multilayer formulations.
  • the release rate of films with chitosan-volatile substance layer and 20 mg of solid support was the longest, as can be seen in figures 3 to 8.
  • the chitosan films produced were able to fix the volatile active principle in different proportions, which can be seen in Figures 9 and 10.
  • the fixation of the volatile active principle was higher in the chitosan-volatile substance trichrome films and 20 mg of the solid support. .
  • Films loaded with essential oil or nerolidol were suitably cut into 1 cm 2 area pieces. A liquid nitrogen fracture was made to view the side of the film. The films were bonded with a double-sided carbon tape on an appropriate support and placed in an electron microscopy device to scan their surface. The results obtained are presented in Figure 11.
  • Leishmania amazonensis (IFLA / BR / 1967 / PH-8) were used in this test. Parasites were grown at 24 ° C in Schneider culture medium (Sigma, St. Louis, MO, USA) supplemented with 20% heat-inactivated fetal bovine serum (FBS, Sigma), 20 mM L-glutamine, 200 U / mL penicillin and 100 pg / ml streptomycin at pH 7.4.
  • Inhibition of growing cells was tested in vitro by cultivating L. amazonensis promastigotes in the presence of formulations without the volatile substance (nerolidol) at the concentration at which each formulation released within 1 week of the extended release test. in vitro in 96-well microplates (Corning Life Sciences, Corning, NY) for 48 h at 24 ° C. The viability of the parasites was evaluated using a colorimetric assay based on the breakdown of tetrazolium 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl bromide (MTT) to observe metabolic activity.
  • MTT tetrazolium 3-
  • MTT break was measured by a multiscan spectrophotometer (LABTRADE, model 660) at a wavelength of 570 nm. Measurements were made in triplicate and the results expressed as the percentage measurement of parasite reduction compared to the untreated control by at least two independent experiments. The amphotericin drug was used as a positive control.
  • the results of antileishmanial activity of chitosan films are shown in Table 2 and Figure 11.
  • chitosan has leishmanicidal activity. Leishmanicidal activity was higher the higher the amount of. chitosan used: for monolayer films a death rate of about 20% was achieved, whereas that for trilayer films a death rate of about 40% was obtained. Thus, chitosan can be used either as a single active ingredient or in combination with other active substances, resulting in a synergistic effect.
  • Table 2 Result of antileishmanial activity of chitosan films.
  • Amphotericin B (50 ⁇ g / ml) 0.131 0.155 0.1 82.63175 79.4978 86.7418 82.94111 3.647099

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

La présente invention concerne des dispositifs multicouches à libération contrôlée de substances liquides volatiles, et leur obtention. Les films multicouches sont constitués par trois couches de polymère naturel et biodégradable (chitosane), la deuxième couche contenant une substance liquide volatile adsorbée sur un support solide (amidon ou talc). Les films ont été testés contre Leishmania amazonensis et présentent une activité antileishmanienne.
PCT/BR2012/000111 2011-04-15 2012-04-13 Films multicouches à libération contrôlée de substances volatiles adsorbées sur un support solide, et leur utilisation WO2012139190A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
BRPI1101627-2 2011-04-15
BRPI1101627-2A BRPI1101627A2 (pt) 2011-04-15 2011-04-15 Filmes multicamadas de liberação controlada de substâncias voláteis adsorvidas em um suporte sólido e uso
BR014120000761 2012-04-12

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WO2012139190A1 true WO2012139190A1 (fr) 2012-10-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105144A1 (fr) * 2006-12-21 2009-09-30 Aicello Chemical Co., Ltd. Solution de chitosan et préparation médicale avec un enrobage de chitosan formé à partir de la solution

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105144A1 (fr) * 2006-12-21 2009-09-30 Aicello Chemical Co., Ltd. Solution de chitosan et préparation médicale avec un enrobage de chitosan formé à partir de la solution

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JONES, D.S. ET AL.: "Casting solvent controlled release of chlorhexidine from ethylcellulose films prepared by solvent evaporation.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 114, 1995, pages 257 - 261, XP000561368, DOI: doi:10.1016/0378-5173(94)00240-6 *
PENHA, A. R. S.: "Estudo da potencialidade de lignana langambina e da quitosana no tratamento de Leshmaniose experimental em camundongos suíços.", DISSERTAÇÃO DE MESTRADO, 3 October 2010 (2010-10-03), UNIVERSIDADE FEDERAL DA PARAIBA, FACULDADE DE CIêNCIAS FARMACêUTICAS, pages 67 - 68 *
REDESCHI, M. C. M.: "Preparação e caracterização de filmes a base de xiloglucana extraida de sementes de Hymenaea courbaril (Jatobd).", DISSERTAÇÃO DE MESTRADO, 8 November 2006 (2006-11-08), FACULDADE DE CIENCIAS FARMACEUTICAS - UNIVERSIDADE ESTADUAL PAULISTA JúLIO DE MESQUITA FILHO *
RODRIGUES, L. B. ET AL.: "In vitro release and characterization of chitosan films as dexamethasone carrier.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 368, 2009, pages 1 - 6, XP025928974, DOI: doi:10.1016/j.ijpharm.2008.09.047 *

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BR102012008550A2 (pt) 2013-11-26
BR102012008550B1 (pt) 2022-04-19
BRPI1101627A2 (pt) 2018-07-31

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