WO2008052294A1 - Préparation de composés de cyclodextrines et de dérivés de ces derniers avec des composés de bismuth - Google Patents

Préparation de composés de cyclodextrines et de dérivés de ces derniers avec des composés de bismuth Download PDF

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WO2008052294A1
WO2008052294A1 PCT/BR2006/000232 BR2006000232W WO2008052294A1 WO 2008052294 A1 WO2008052294 A1 WO 2008052294A1 BR 2006000232 W BR2006000232 W BR 2006000232W WO 2008052294 A1 WO2008052294 A1 WO 2008052294A1
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compounds
derivatives
bismuth
cyclodextrin
cyclodextrins
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PCT/BR2006/000232
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English (en)
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Ruben Dario Sinisterra Millan
Heloisa De Oliveira Beraldo
Angelo Marcio Leite Denadai
Izabela Mariane Pampolini Daniel
Maria Experenza Cortes Segura
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Universidade Federal De Minas Gerais
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • One of the characteristics of the present invention is the increase of the solubility of bismuth compounds in water after the formation of complexes with cyclodextrins of stoichiometry 1 :1 , these parameter being non-limiting of the invention.
  • This increase in solubility provides an increase in bioavailability and a reduction in its minimal inhibitory concentrations.
  • Another characteristic of the present invention is the use of bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof as antibacterial agents in the treatment of gastrointestinal disorders, halitosis, bacterial plaque, ocular treatment, periodontal disease, ear infections, dermal wounds and other bacterial infections, mixed with pharmaceutically acceptable excipients, in solution or in solid state.
  • the combination of bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof of the present invention are useful in pharmaceutical compositions with conventional carriers or vehicles for administration to humans or animals, in dosages in the form of tablets, chewing tablets, chewing gums, capsules, pills, powders, granules, sterile non-parenteral solutions or suspensions, oral solutions or suspensions, oil in water or water in oil suspensions, emulsions and the needed amount of the active principles.
  • nano- or microparticles or nano- or microcapsules containing or carrying compounds made of cyclodextrins and derivatives thereof and bismuth compounds and derivatives thereof, based on bucoadhesive polymers, gels, alginates or biodegradable polymers such as PLA, PLGA or mixtures thereof, for controlled release of bismuth compounds.
  • Those devices may be for local action, implantable or for systemic use.
  • Gastritis is a benign disease that affects the stomach and duodenum in certain individuals and in certain periods, and today it is considered as the second more prevalent infection in humans, only supplanted by dental caries [L. G. V. Coelho, Helicobacter pylori e Afecg ⁇ es Associadas IN: Mincis M. Gastroenterologia & Hepatologia. 3 a Ed. Sao Paulo; Lemos; 2002, p.331-358].
  • Gastritis and ulcer are multifactorial diseases, that is, they have several determining factors. Food patterns and emotional stress are the most important factors followed by hereditariness and racial habits.
  • Helicobacter pylori is a gram-negative rod that colonizes the mucus of the luminal surface of the gastric epithelium. Infection by H. pilory causes inflammatory gastritis and hypothetically contributes to peptic ulcer, gastric lymphoma and adenocarninoma [Goodman & Gilman, As Bases Farmacol ⁇ gicas da Terapeutica. Ed. Mc. Graw Hill, 9 a Edicao, 663-670]. Infection by H. pilory is very common, with a prevalence of about 20% in Caucasians with 30 years old, and higher in Hispanics and Blacks. The prevalence increases with age.
  • pylori is the cause of almost all peptic ulcers, about 80% of gastric ulcers and more than 90% of duodenal ulcers. That bacteria weakens the protecting mucous of the stomach and duodenum, thus enabling the contact of gastric acid with the mucosa. Both the acid and the bacteria irritate the gastroduodenal protector and cause ulcers. The bacteria is capable to survive in low pH ranges because it segregates enzymes that neutralize the acid. Infection occurs by direct contact among people and by means of infected food and water. In the related treatment, medicaments that temporarily block the natural production of stomach acid are employed, until the coating of the stomach is recovered. In some cases, the use of antibiotics, bismuth compounds or proton pump inhibitors is necessary to eradicate the bacteria.
  • the treatment using only bismuth compounds does not require the use of proton pump inhibitors since those compounds are active even in acid media.
  • the usual treatment includes a combination of all the above mentioned medicaments.
  • the treatment that proved to be the most effective lasts two weeks and is called triple therapy.
  • the treatment comprises the use of two antibiotics against the bacteria and an acid suppressor or gastric epithelium protector.
  • Therapy of the infections by H. pilory with single agents has proved to be relatively ineffective in vitro and has led to the appearance of new H. pilory cell lines that are drug-resistant, especially resistant to metronidazole and tinidazole (due to activity of a mutant nitroreductase). Both amoxylin and claritromicyn are effective in some patients.
  • Patent US6902738 "Topical Oral Dosage Forms Containing Bismuth Compounds" [Gubler; Scott A., 2005]: Oral dosages containing bismuth compounds were prepared, among them the cyclodextrin sulfate complex, (a cyclodextrin salt with bismuth), which are useful for combating Helicobacter pylori and other bacterial infections that cause halitosis, gastrointestinal disorders, as well as for the treatment of ocular and dermal wounds.
  • WO2003097011-A; AU2003241464-A1 "Treatment of Gastroesophageal Reflux Disease, Symptomatic Gastroesophageal Reflux Disease and Symptomatic Duodenal Ulcer Disease Involves Administering at Least one Proton Pump Inhibitor" [Barth J, leni J., 2004].
  • New pharmaceutical formulations were prepared for the treatment of gastroesophageal reflux or symptomatic duodenal ulcer disease, which involves the administration of bismuth compounds and at least one protonic pump inhibitor.
  • One of the formulations involves two proton pump inhibitors, a histamine antagonist, an antacid, a bismuth compound, sulcralfat, cisapride, misoprostole, a nonsteroidal anti-inflammatory drug, an anti-viral agent, an anti-fungal agent and cyclodextrin.
  • the prior art discloses formulations of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, bismuth aluminate, bismuth polysulfates, bismuth polyhydroxy compounds, bismuth subascorbate and cyclodextrin sulfate with bismuth.
  • a pharmaceutical may be chemically modified to change its properties such as biodistribution, pharmacokinetics and solubility.
  • Several methods have been used to increase solubility and stability of drugs, among them the use of organic solvents, emulsions, liposomes, pH adjustment, chemical changes and complex formation with a suitable encapsulating agent such as cyclodextrins.
  • Cyclodextrins are compounds of the cyclic oligosaccharide family that include six, seven or eight units of glucopyranose. Due to space interactions, cyclodextrins form cyclic structures in a truncated cone shape with an apolar internal cavity. These are chemically stable compounds that may be modified in a regioselective manner.
  • the cyclodextrins (hosts) form complexes with several hydrophobic molecules (guests) including said molecules in the cavity in whole or in part.
  • cyclodextrins have been used for solubilization and encapsulation of drugs, perfumes and aromatizers as described in the literature [Szejtli, J., Chemical Reviews, 98, 1743 1998; Szejtli, J., J. Mater. Chem., 7, 575 (1997)]. According to detailed studies of toxicity, mutagenicity, teratogenicity and carcinogenicity of cyclodextrins, they normally have low toxicity [Rajewski, R.A.; Stella, V.; J. Pharmaceutical Sciences, 85, 1142 1996], especially hydroxypropyl- ⁇ -cyclodextrin [Szejtli, J. Cyclodextrins: Properties and Applications.
  • the structure of the cyclodextrin molecule is similar to that of a truncated cone, of approximately C n symmetry.
  • the primary hydroxyls are located on the narrowest side of the cone and the secondary hydroxyls on the widest side.
  • it is flexible enough to enable a considerable deviation from the regular shape.
  • Cyclodextrins are moderately soluble in water, methanol and ethanol, and promptly soluble in aprotic polar solvents, such as dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetamide and pyridine.
  • aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetamide and pyridine.
  • the present invention refers to the obtainment of bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof, non-limiting examples of which are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ - cyclodextrin ( ⁇ -CD) and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and derivatives thereof, which, when tested in gram-positive bacteria, have enabled a reduction in the minimal inhibitory concentration (MIC) from 32 ⁇ g/mL for bismuth citrate to 16 ⁇ g/mL, when compounds of bismuth citrate and hydroxypropyl- ⁇ -cyclodextrin are used, which may mean an increase in the bioavailability of the compounds in the biological systems.
  • MIC minimal inhibitory concentration
  • the present invention is also characterized by the obtainment of bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof, non-limiting examples of which are ⁇ -cyclodextrin ( ⁇ -CD), 5 ⁇ -cyclodextrin ( ⁇ -CD) and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and derivatives thereof, which, when tested in gram-positive bacteria cultures, have shown bismuth citrate/ ⁇ -cyclodextrin activity similar to the activity of the free bismuth citrate in 64 ⁇ g/mL.
  • ⁇ -CD ⁇ -cyclodextrin
  • ⁇ -CD ⁇ -cyclodextrin
  • ⁇ -CD 5 ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • I O bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof non-limiting examples of which are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and hydroxypropyl- ⁇ - cyclodextrin (HP- ⁇ -CD) and derivatives thereof, which, when tested in gram-negative bacteria, have enabled a reduction in the minimal inhibitory concentration (MIC) from 64
  • the present invention is characterized by the obtainment of bismuth compounds and derivatives thereof with cyclodextrins and 0 derivatives thereof, non-limiting examples of which are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and derivatives thereof with specificity of compounds of bismuth citrate/hydroxypropyl- ⁇ -cyclodextrin against gram-positive bacteria and specificity of compounds of bismuth citrate/ ⁇ -cyclodextrin and bismuth 5 citrate/ ⁇ -cyclodextrin against gram-negative bacteria.
  • ⁇ -CD ⁇ -cyclodextrin
  • ⁇ -CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • the present invention is further characterized by an increase in the efficacy of new antibacterial agents comprised of bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof, non- limiting examples of which are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) 0 and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and derivatives thereof in the treatment of gastrointestinal disorders (esophagitis, enteritis, diarrhea, pancreatitis), middle ear infection, halitosis, ocular infections and dermal wounds, and bismuth compounds and derivatives thereof with cyclodextrins and derivatives thereof, when compared to the free components.
  • ⁇ -CD ⁇ -cyclodextrin
  • ⁇ -CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • Example 1 Preparation of a complex between hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and bismuth citrate (CiBi).
  • HP- ⁇ -CD/CiBi compound was obtained from the reaction between hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and bismuth citrate (CiBi) in aqueous solutions at equimolar ratios.
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • CiBi bismuth citrate
  • the mixture was kept under agitation for 28 hours and then it was frozen in liquid nitrogen and submitted to the lyophilization process.
  • the solid obtained was submitted to physicochemical characterization.
  • MM mechanical mixture
  • MM was prepared at the same molar ratio, through mechanical agitation, without addition of water.
  • Table 1 CD mass m used in stock solution in 25mL MiIIi-Q water.
  • Hp- ⁇ -CD seems to be the most efficient to solubilize bismuth citrate, because it was the one with the highest angular coefficient as well as maximum solubility for the complex formed in the solubility curves. This solubility difference may be due to a higher tendency of Hp- ⁇ -CD to accommodate the bismuth citrate since it is more flexible in relation to ⁇ -CD and ⁇ -CD.
  • Bismuth citrate is thermodynamically stable up to approximately 25O 0 C and shows two mass losses in the analyzed range (25 to 800 0 C), the first one being the loss of 35.9%, in the range of 300.3 0 C to 359,7°C, with maximum decomposition at 327.4 0 C, and the second of 6.6%, in the range of 359.7°C to 449.O 0 C, with maximum decomposition at 411.79°C. Consequently, 42.511 % of mass was reduced, leaving 57.5%, which may correspond to metallic bismuth.
  • HP- ⁇ -CD shows three mass losses in the temperature range analyzed (25 0 C to 800 0 C). The first loss of 10.0% occurs in the temperature range of 31.6 0 C to 138.8 0 C, and may correspond to the loss of water molecules. A thermal stability level is observed up to 25O 0 C. The second loss of 71.9%, observed after the stability event, is associated with the complete thermodecomposition of HP- ⁇ -CD. Finally, a residue of 5.2% is observed.
  • the compound formed between bismuth citrate and HP- ⁇ -CD shows three mass losses in the temperature range analyzed (25 to 800 0 C). The first one, of 8.5%, in the range of 26.5°C to 60.0 0 C, with maximum temperature peak at 35.6 0 C, may correspond to the loss of water molecules. Then, a thermal stability level is observed up to 250°C, also indicating a strong interaction between cyclodextrin and bismuth citrate.
  • the TG curve of the mechanical mixture is very similar to the complex curve, indicating that even in the solid state there are interactions between the species.
  • the DSC curve corresponding to bismuth citrate shows an endothermic physicochemical phenomenon at 301.99 0 C, associated to the decomposition of the compound.
  • the DSC curve for HP- ⁇ -CD initially shows a behavior of low thermal stability, only one large endothermic event in the temperature range between 290-350 0 C, associated with the thermodecomposition process thereof being observed.
  • the DSC curve of the Hp- ⁇ -CD/CiBi compound corroborates data offered by the respective TG curve, wherein an increase in thermal stability of the complex is observed.
  • Three very discrete endothermic events are observed at approximately 39.O 0 C, 288.7 0 C and 334.3 0 C, different from those discussed for cyclodextrin and free bismuth citrate.
  • the complex with cyclodextrin ( ⁇ -CD/CiBi) was obtained through the reaction between ⁇ -cyclodextrin ( ⁇ -CD) and bismuth citrate in milli-Q water at equimolar ratios. The mixture was maintained under agitation during
  • Bismuth citrate is thermodynamically stable up to approximately 250°C and shows two mass losses in the analyzed range (25 to 80O 0 C) 1 the first one being the loss of 35.9%, in the range of 300.3°C to 359.7°C, with maximum decomposition at 327.4°C and the second of 6.6%, in the range of 359.7°C to 449.0 0 C, with maximum decomposition at 411.79°C. Consequently, 42.511 % of mass was reduced, leaving 57.5%, which may correspond to metallic bismuth.
  • ⁇ -CD shows two mass losses in the analyzed temperature range (25 0 C to 800 0 C).
  • the first loss occurs in the temperature range of 33 0 C to 120 0 C, and may correspond to the loss of water molecules.
  • a thermal stability level is observed between 12O 0 C and 300 0 C 1 after which a mass loss of 83.9% is observed associated with the complete thermodecomposition of cyclodextrin. Finally, a residue of 4.1% was obtained.
  • the compound formed between bismuth citrate and ⁇ -CD has three mass losses in the analyzed temperature range (25 to 800 0 C).
  • a stability level is observed up to 320°C, suggesting a higher thermal stability of the compound after the interaction between bismuth and ⁇ -cyclodextrin.
  • the second mass loss of 63.2% is in the range of 320°C to 367.9°C, with peak temperature at 332.2°C.
  • the third loss of 13.1% occurs in the temperature range of 367.9°C to 475.3°C, with maximum temperature peak at 450.3 0 C.
  • a residue of 23,7% is observed.
  • the TG curve of the mechanical mixture is very similar to the complex curve, suggesting that even in the solid state there is intramolecular interaction.
  • the DSC curve corresponding to bismuth citrate has an endothermic physicochemical phenomenon at 301.99 0 C associated to the decomposition of the compound.
  • the DSC curve of ⁇ -CD has two endothermic events. The first one, at 86.7 0 C, and the second one at 315 0 C, referring to dehydration and melting with decomposition, respectively.
  • the DSC curve corresponding to the ⁇ -CD/CiBi complex has a quite different thermal behavior than that of cyclodextrin and bismuth citrate, respectively, since the cyclodextrin melting peak disappears at 260 0 C, and a new endothermic peak appears at 33O 0 C, strengthening the hypothesis of the thermal stabilization process of the complex after the hostguest interaction.
  • the respective DSC curve of the physical mixture also reveals the stabilization process of the starting components, as seen in the TG curve.
  • Example 3 Preparation of a complex between ⁇ -cyclodextrin ( ⁇ -CD) and bismuth citrate (CiBi)
  • the ct-CD/CiBi compound was obtained through the reaction in between ⁇ -cyclodextrin ( ⁇ -CD) and bismuth citrate (CiBi) milli-Q water at equimolar ratios.
  • ⁇ -CD ⁇ -cyclodextrin
  • CiBi bismuth citrate
  • the mixture was kept under agitation for 28 hours and was then frozen in liquid nitrogen and submitted to the lyophilization process, which caused the sublimation of water.
  • the solid obtained was submitted to physicochemical characterization.
  • a mechanical mixture was prepared (MM ⁇ -CD/CiBi), at the same molar ratio, by means of mechanical agitation, without addition of water.
  • Bismuth citrate is thermodynamically stable up to approximately 250°C and shows two mass losses in the analyzed range (25 to 80O 0 C) 1 the first one being the loss of 35.9%, in the range of 300.3°C to 359.7 0 C, with maximum decomposition at 327.4°C and the second of 6.6%, in the range of 359.7°C to 449.0°C, with maximum decomposition at 411.79°C. Consequently, 42.511% of mass was reduced, leaving 57.5%, which may correspond to metallic bismuth.
  • the ⁇ -cyclodextrin shows two mass losses in the analyzed temperature range (25 0 C to 800 0 C).
  • the first loss which corresponds to the loss of water molecules, occurs in the temperature range of 25 0 C to 100 0 C.
  • a thermal stability level is then observed at approximately 32O 0 C.
  • a second thermodecomposition event of 99.7% is observed, with a temperature peak at 350°, associated with the complete thermodecomposition of cyclodextrin.
  • the compound formed between bismuth citrate and ⁇ -CD shows three mass losses in the analyzed temperature range (25 to 800 0 C).
  • the first one, of 7.7%, in the range of 27.8°C to 90.0 0 C, with maximum temperature peak at 33.9 0 C, may correspond to the loss of water molecules. Then, a thermal stability level is observed up to approximately 300 0 C, indicating a strong interaction between cyclodextrin and bismuth citrate. The second mass loss of 76.2%, in the range of 300 0 C to 535.6 0 C, with peak temperature at 332.2°C, is associated with the complex thermodecomposition. The third loss of 0.3% with a maximum temperature peak at 451.6 0 C. A residue of 15,8% is observed.
  • the TG curve of the mechanical mixture when compared to the curve of the complex and the free species, suggests that, even in the solid state, there is interaction through hydrogen bonds between the species.
  • the DSC curve corresponding to bismuth citrate has an endothermic physicochemical phenomenon, at 301.99 0 C, associated with the decomposition of the compound.
  • the DSC curve of ⁇ -CD has four thermal phenomena. The first two ones at 54.O 0 C and 84.6 0 C are associated with the loss of two types of water molecules: one of hydration and other of water present in the cavity.
  • the third endothermic event at 139.7 0 C may be attributed to a phase transition of cyclodextrin. After that, the peak is observed at 313.7 0 C due to the melting process together with thermodecomposition.
  • the DSC curve of ⁇ -CD/CiBi is also completely different from the starting materials and the respective mechanical mixture, showing an increase in the thermal stability of the complex. No endothermic peaks related to the loss of water molecules are observed in the temperature range of 25-8O 0 C, nor is the phase transition peak of cyclodextrin at around 139 0 C, those events being clearly observed in the physical mixture. Those results strongly suggest the interaction between bismuth citrate and cyclodextrin.
  • Example 4 The present non-limiting example shows an improvement in the antimicrobial activity of the formulations of bismuth citrate with different cyclodextrins.
  • Sensitivity tests were performed according to the NCCLS standards. Previously unfroze strains of gram-positive bacteria isolated from patients of the Dentistry College Clinic of the Federal University of Minas Gerais (Approval No. 482/2003 by the Research Ethics Committee of the Federal University of Minas Gerais) and gram-negative bacteria, such as Actinobacillus actynomicetemcomitans (A.a) (Y4-FDC), were inoculated in Brain Heart Infusion (BHI) broth and incubated in micro-aerophilic conditions at 37 0 C for 18 to 24 hours.
  • BHI Brain Heart Infusion
  • Antimicrobial effectiveness was determined by successive dilution in tubes containing 5mL BHI, which were inoculated with 100 ⁇ l_ of culture with turbidity corresponding to 0.5 in the McFarland scale, at the concentrations of 64, 32, 16, 8, 4, 2, 1 , 0,5 and 0,25 ⁇ g/mL of the tested substances: CiBi and its complexes with cyclodextrins ⁇ -CD/CiBi, ⁇ -CD/CiBi and HP- ⁇ -CD/CiBi.
  • As negative controls isolated bacteria and ammonium hydroxide employed as solvent were used. The tests were made twice. After 15 hours of incubation in micro-aerophilic conditions in an incubator at 37 0 C, inhibition analyzes were carried out in spectrophotometer adjusted at 600 nanometers and the antimicrobial activity of the concentrations of the pharmaceutical was determined.
  • MIC Minimal Inhibitory Concentration
  • MBC Minimal Bactericidal Concentration
  • CiBi/HP ⁇ CD was the most effective compound in inhibiting gram- positive bacteria at concentrations ⁇ 16 ⁇ g/mL (MIC), showing bactericidal action in 64 ⁇ g/mL
  • pure bismuth citrate (CiBi) had MIC of 32 ⁇ g/mL
  • the CiBk ⁇ CD compounds presented MIC > 64 ⁇ g/mL.
  • the value of MIC for CiBi/HP ⁇ CD is half the value of MIC for the free bismuth citrate.
  • the CiBi: ⁇ CD compound presented activity similar to that of free bismuth citrate.
  • the CiBk ⁇ CD compound did not show significant activity in the bacterial growth of patient's colonies.
  • the CiBi:HP ⁇ CD compound was shown to be highly effective, and may become a new candidate for a pharmaceutical.
  • the CiBi/ ⁇ CD compound showed the best antimicrobial activity at concentrations > 32 ⁇ g/mL (MIC).
  • the CiBi/ ⁇ CD compound also had bacteriostatic activity at the concentration of 32 ⁇ g/ML, but this activity was lower than the one presented by CiBi/ ⁇ CD.
  • both compounds with cyclodextrins were more active when compared to pure bismuth citrate at the same concentration.
  • the CiBkHP ⁇ CD compound was inactive against these bacteria.
  • CiBi:HP ⁇ CD shows specificity against the gram-positive bacteria while CiBi/ ⁇ CD and CiBi/ ⁇ CD are specific against A.a. (Gram-negative).
  • Table 2 Percentage of inhibition of Bismuth Citrate and its inclusion compounds in alpha-cyclodextrins (CiBLaCD), beta-cyclodextrins (CiBi: ⁇ CD) and hydroxypropyl- ⁇ -cyclodextrin (CiBi: HP- ⁇ CD) in gram-positive bacterial growth in patients and Actinobacillus actynomicetemcomitans (Y4FDC), gram-negative.
  • Example 5 This non-limiting example describes the preparation and use of nano- or microparticles or nano- or microcapsules containing or carrying compounds of cyclodextrins and derivatives thereof with bismuth compounds and derivatives thereof in PLGA and its sustained release.
  • Polymeric particles were prepared from lactic and glycolic acid co-polymers (PLGA 50:50) by the W/O/W multiple emulsion method with later evaporation of the solvent [Jeffery et al. Int. J. Pharm. 77:169-175 (1991 )]. This method was employed for encapsulating compounds of cyclodextrins and derivatives thereof with the bismuth compounds and derivatives thereof according to the following steps.
  • the mixture was submitted to sonication (5000 rotations/minute) during approximately 1 minute.
  • a second emulsion water/oil/water (W/O/W) is formed.
  • the emulsion was kept under constant agitation for 2 hours at room temperature to evaporate the dichloromethane.
  • microspheres or nanospheres formed were submitted to 3 cycles of centrifugation/washing with deionized water.
  • the microspheres were then lyophilized and stored at -2O 0 C.
  • Precipitation and spray-dryer methods can also be used to obtain the nano- or micro particles or capsules, the industrial scale of the latter being easy to increase.

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Abstract

Préparation de composés de cyclodextrines et de dérivés de ces derniers avec des composés de bismuth et des dérivés de ceux-ci; de compositions pharmaceutiques; de produits comprenant ces compositions; et utilisation de ceux-ci en tant qu'agents antibactériens. La présente invention concerne la préparation de composés formés de cyclodextrines et des dérivés de celles-ci et de composés de bismuth et de dérivés de ceux-ci; des compositions pharmaceutiques; des produits contenant ces compositions; et l'utilisation de ceux-ci en tant qu'agents antibactériens. Une autre caractéristique de la présente invention concerne l'utilisation de composés de bismuth et de dérivés de ceux-ci avec des cyclodextrines et des dérivés de celles-ci ainsi que de produits obtenus à partir de ce procédé, dans le traitement d'une maladie parodontale, d'ulcères, d'une gastrite, d'infections cutanées, d'infections oculaires, de troubles gastro-intestinaux, d'une halitose, de la plaque dentaire, d'infections de l'oreille et d'autres infections bactériennes.
PCT/BR2006/000232 2006-10-30 2006-10-30 Préparation de composés de cyclodextrines et de dérivés de ces derniers avec des composés de bismuth WO2008052294A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2173400A (en) * 1985-04-01 1986-10-15 Chinoin Gyogyszer Es Vegyeszet Dusting powders
WO1992001457A1 (fr) * 1990-07-20 1992-02-06 Slagel, David Produits et procedes de traitement des voies alimentaires
WO1997007757A1 (fr) * 1995-08-24 1997-03-06 Josman Laboratories, Inc. Composes renfermant du bismuth sous forme de doses a application locale
US6110306A (en) * 1999-11-18 2000-08-29 The United States Of America As Represented By The Secretary Of The Navy Complexed liquid fuel compositions
US20060120967A1 (en) * 2004-12-07 2006-06-08 Qpharma, Llc Solution forms of cyclodextrins for nasal or throat delivery of essential oils

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2173400A (en) * 1985-04-01 1986-10-15 Chinoin Gyogyszer Es Vegyeszet Dusting powders
WO1992001457A1 (fr) * 1990-07-20 1992-02-06 Slagel, David Produits et procedes de traitement des voies alimentaires
WO1997007757A1 (fr) * 1995-08-24 1997-03-06 Josman Laboratories, Inc. Composes renfermant du bismuth sous forme de doses a application locale
US6110306A (en) * 1999-11-18 2000-08-29 The United States Of America As Represented By The Secretary Of The Navy Complexed liquid fuel compositions
US20060120967A1 (en) * 2004-12-07 2006-06-08 Qpharma, Llc Solution forms of cyclodextrins for nasal or throat delivery of essential oils

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