RESUMEN
The aim of this work was to stabilize doxycycline in mucoadhesive buccal films at room temperature (25 °C). Since doxycycline is susceptible to degradation such as oxidation and epimerization, tablets are currently the only formulation that can keep the drug fully stable at room temperature, while liquid formulations are limited to refrigerated conditions (4 °C). In this study, the aim was to make formulations containing subclinical (antibiotic) doxycycline concentration that can act as matrix metalloproteinase inhibitors (MMPI) and can be stored at temperatures such as 25 °C. Here, doxycycline was complexed with excipients using three techniques and entrapped into microparticles that were stored at 4 °C, 25 °C and 40 °C. Effect of addition of precomplexed doxycycline microparticles on films: stability mucoadhesion capacity, tensile strength, swelling index and in vitro release was studied. The complexation efficiency between drug-excipients, microparticles and films was studied using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Two of the films were found to be stable at 4 °C but the film containing microparticle composed of precomplexed doxycycline with ß-cyclodextrin, MgCl2, sodium thiosulfate, HPMC and Eudragit® RS 12.5 was found to be stable at 25 °C until 26 weeks. The addition of microparticles to the films was found to reduce the mucoadhesive capacity, peak detachment force, tensile strength and elasticity, but improved the stability at room temperature.
RESUMEN
BACKGROUND: The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound. METHODS: Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPßCD was studied using the DSC, FTIR and XRPD. RESULTS: The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures. CONCLUSION: In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.
Asunto(s)
Doxiciclina/administración & dosificación , Excipientes/química , Inhibidores de la Metaloproteinasa de la Matriz/administración & dosificación , Estomatitis Aftosa/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Adhesividad , Administración a través de la Mucosa , Química Farmacéutica , Doxiciclina/química , Doxiciclina/farmacocinética , Estabilidad de Medicamentos , Hidrogeles/química , Concentración de Iones de Hidrógeno , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacocinética , Metaloproteinasas de la Matriz/metabolismo , Mucosa Bucal/química , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/inmunología , Mucosa Bucal/metabolismo , Oxidación-Reducción , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Estomatitis Aftosa/inmunología , Estomatitis Aftosa/patología , Agua/químicaRESUMEN
The aim of this study was to develop a stable aqueous formulation containing a combination of doxycycline and monocaprin in clinically relevant concentrations. Increase in expression of Matrix metalloproteinases (MMPs) and microbial role in oral diseases is well established and the combination of above active ingredients could be potentially beneficial in treatment of oral mucosal conditions. The hydrogels containing different concentrations of doxycycline and monocaprin in the presence and absence of stabilizing excipients were developed and their stabilities were studied at 4 °C for up to 1 year. The drug-drug interaction was evaluated using Fourier-transform infrared spectroscopy (FTIR). The addition of monocaprin on doxycycline in situ hydrogel's mucoadhesiveness, texture properties and drug release mechanism was studied. The addition of monocaprin negatively affected the doxycycline stability and was concentration dependent, whereas monocaprin was stable up to 1 year. Doxycycline did not interfere with the anti-Candidal activity of monocaprin. Furthermore, the presence of monocaprin significantly affected the formulation hardness, compressibility and adhesiveness. Monocaprin and doxycycline release followed zero order kinetics and the release mechanism was, by anomalous (non-Fickian) diffusion. The addition of monocaprin increased the drug release time and altered the release mechanism. It is possible to stabilize doxycycline in the presence of monocaprin up to 1 year at 4 °C.
RESUMEN
BACKGROUND: Current treatment of herpes labialis is usually with topical antiviral drugs and early drug administration is required for effectiveness. Monocaprin, a 1-monoglyceride of capric acid, has high microbicidal activity in vitro and efficiently inactivates herpes simplex virus. Tetracyclines are inhibitors of matrix metalloproteinases that are part of the inflammatory response and contribute to the breakdown of tissue in ulcers. The study objective was to investigate the antiviral and wound-healing effect of a hydrogel containing either monocaprin or a combination of monocaprin and a low dose of doxycycline in vivo against herpes labialis. METHODS: Subjects were divided into two groups: (i) with prodromal symptoms of herpes labialis; (ii) with a vesicle. Both groups applied the hydrogel five times a day for five days. Test formulations were: (i) hydrogel containing monocaprin and doxycycline (MCD), (ii) hydrogel containing only monocaprin and (iii) placebo hydrogel. Formulations were distributed randomly to subjects within each group. Subjects recorded treatment results in a 6-day diary and a 7-day follow-up diary. RESULTS: For the MCD group the mean time to healing was 5.5 days (prodromal) and 5.3 days (vesicles/ulceration) or significantly shorter than for the placebo groups (7.25 and 7.5 days respectively; P < 0.05). Pain relief was significantly more with MCD (combining both the prodromal and vesicle groups) than with the monocaprin and placebo groups (P = 0.0114). CONCLUSION: Combining monocaprin with low-dose doxycycline offers an effective treatment for herpes labialiss, significantly reducing time to healing and pain compared with the placebo and monocaprin alone.
Asunto(s)
Antivirales/uso terapéutico , Doxiciclina/uso terapéutico , Glicéridos/uso terapéutico , Herpes Labial/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antivirales/administración & dosificación , Vesícula/tratamiento farmacológico , Método Doble Ciego , Doxiciclina/administración & dosificación , Portadores de Fármacos , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Glicéridos/administración & dosificación , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato , Masculino , Inhibidores de la Metaloproteinasa de la Matriz , Registros Médicos , Persona de Mediana Edad , Dimensión del Dolor , Placebos , Simplexvirus/efectos de los fármacos , Estomatitis Aftosa/tratamiento farmacológico , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacos , Adulto JovenRESUMEN
OBJECTIVE: Aphthous ulceration is a common form of recurrent ulceration of the oral mucosa. Numerous treatments have been tried as a means of relieving pain, disinfecting the ulcer base, and reducing inflammation, but with limited success. Tetracycline and its derivatives have been shown to be inhibitors of matrix metalloproteinases (MMPs), which are part of the inflammatory response and contribute to the breakdown of tissue in the ulcer. Of the commercially available tetracyclines, doxycycline has shown the best inhibition of the MMPs. The aim of this study was to test clinically whether the inhibitory effect of a low-dose doxycycline in a hydrogel on MMPs would speed the recovery of oral ulceration. MATERIAL AND METHODS: Forty-nine patients participated in a randomized, double-blind, placebo-controlled trial. RESULTS: Sixty-eight percent of ulcers had healed by the third day of treatment with the doxycycline gel, whereas only 25% of the patients receiving the placebo reported healing of their ulcers within 3 days. Patients treated with the docycline gel recounted faster reduction in pain during the treatment period than the placebo group did. CONCLUSIONS: Incorporation of low-dose doxycycline in a muco-adhesive gel has been demonstrated to have potential in the treatment of recurrent oral ulceration. It is concluded that MMP enzymes can be inhibited by low doses of doxycycline below levels likely to disrupt the oral flora.
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Doxiciclina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz , Estomatitis Aftosa/tratamiento farmacológico , Administración Tópica , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Estomatitis Aftosa/enzimología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Antivirales/química , Materiales Biocompatibles/química , Química Farmacéutica/métodos , Emulsiones/química , Glicéridos/administración & dosificación , Glicéridos/química , Pomadas/química , Administración Tópica , Antivirales/análisis , Materiales Biocompatibles/análisis , Evaluación Preclínica de Medicamentos , Elasticidad , Emulsiones/análisis , Glicéridos/análisis , Humanos , Ensayo de Materiales , Pomadas/análisis , Enfermedades Virales de Transmisión Sexual/tratamiento farmacológico , Estadística como Asunto , ViscosidadRESUMEN
Monocaprin is a 1-monoglyceride of capric acid that has antimicrobial activity against enveloped viruses, certain bacteria, and the yeast Candida albicans. Solutions containing monocaprin were formulated and tested in vitro against a number of micro-organisms, including species found in the oral cavity and common pathogenic species. The antimicrobial activity of monocaprin was tested with strains growing on a surface as well as in the planktonic phase. Micro-organisms tested were: Streptococcus mutans, Candida albicans, Lactobacillus sp., Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Two sets of dilutions were prepared for each test strain; one to be inoculated with the micro-organism growing in the planktonic phase and the other with the same strain growing on a filter paper disk. Control solutions were also prepared to find out if any of the excipients were affecting the microbicidal effect of monocaprin. Test strains growing on the filter paper surface were less sensitive to monocaprin than the same strain growing in its planktonic phase. C. albicans was the micro-organism that was most sensitive to monocaprin, but S. mutans also showed appreciable sensitivity. The indication that monocaprin may have potential as a topical agent against Candida was tested in an open study of denture disinfection in 32 patients attending a geriatric daycare centre. A significant, but short-term, reduction in counts of Candida on the fitting surface of full dentures was observed.
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Candida albicans/efectos de los fármacos , Limpiadores de Dentadura/farmacología , Dentadura Completa/microbiología , Glicéridos/farmacología , Anciano , Antiinfecciosos Locales/farmacología , Antiinfecciosos Locales/uso terapéutico , Biopelículas/efectos de los fármacos , Recuento de Colonia Microbiana , Desinfectantes Dentales/farmacología , Desinfectantes Dentales/uso terapéutico , Limpiadores de Dentadura/uso terapéutico , Dentadura Completa/efectos adversos , Escherichia coli/efectos de los fármacos , Glicéridos/uso terapéutico , Humanos , Lactobacillus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Estomatitis Subprotética/tratamiento farmacológico , Estomatitis Subprotética/etiología , Streptococcus mutans/efectos de los fármacosRESUMEN
The depside atranorin and depsidone fumarprotocetraric acid, isolated from the lichens Stereocaulon alpinum and Cetraria islandica, respectively, were chosen as prototypes for poorly soluble natural compounds in an effort to facilitate testing in pharmacological models. Solubilizing agents previously identified as being non-toxic towards a malignant leukemic (K-562) cell line and suitable for testing of anti-proliferative activity of the dibenzofuran lichen metabolite (+)-usnic acid were used in solubilization studies of the depside and depsidone. Cyclodextrin derivatives were found to be most suitable for solubilizing the lichen compounds, the greatest rise in solubility being witnessed for fumarprotocetraric acid, increasing almost 300-fold from 0.03 mg/ml in water to 8.98 mg/ml in 10% 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). Subsequently, the lichen compounds, including (+)-usnic acid, were solubilized in 10% HPbetaCD and tested for effects on three malignant human cell lines; T-47D (breast), Panc-1 (pancreas) and PC-3 (prostate) in a standard proliferation assay. Atranorin and fumarprotocetraric acid did not exhibit anti-proliferative effects but usnic acid was active against all test cell lines with EC50 values of 4.3-8.2 microg/ml. The non-toxic solubilizing agents used in this study could prove useful for pharmacological testing of other poorly soluble natural products.
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Benzofuranos/química , Fumaratos/química , Hidroxibenzoatos/química , Líquenes/metabolismo , Benzofuranos/farmacología , Línea Celular , Fumaratos/farmacología , Hidroxibenzoatos/farmacología , Solubilidad , Timidina/metabolismoRESUMEN
Previous studies have shown that certain lipids and fatty alcohols have microbicidal activities against a number of pathogens. In this study, virucidal activities of fatty alcohols and lipids were tested against HSV types 1 and 2 at various concentrations, times, and pH levels. The aim was first, to determine which compounds are most virucidal against HSV and could possibly be used as active ingredients in topical drug formulations and second, to attempt to throw light on the mode of action of virucidal lipids. Good agreement was found between the activities for HSV-1 and HSV-2. The activity of a compound depends on the concentration and time of contact and most of the compounds are more active at pH 4.2 than at pH 7. This information may be helpful in the formulation of pharmaceutical dosage forms for treatment of herpes lesions in skin and mucosa. The difference between the polar groups of alcohols and fatty acids, i.e. hydroxyl group versus carboxyl group, and the corresponding difference in their hydrophile-lipophile balance (HLB) may explain their different virucidal activities against HSV. However, in most cases HLB numbers cannot explain the different virucidal activities of fatty alcohols and lipids, particularly not their increased activity at low pH. It is more likely that the acidic environment makes HSV more sensitive, possibly by ionic changes in the envelope proteins.
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Antivirales/farmacología , Ácidos Grasos/farmacología , Alcoholes Grasos/farmacología , Glicéridos/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Animales , Chlorocebus aethiops , Dodecanol/farmacología , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Células VeroRESUMEN
The purpose of this study was to characterize the rheological and structural properties of a pharmaceutical multicomponent hydrogel formulation. This formulation consists of a hydrogel-forming poly(acrylic acid) polymer (Carbopol 974P), microbicide (monocaprin), non-ionic surfactant (Tween 20 or Tween 40), and preservatives. The effects of surfactant addition, monocaprin concentration, and pH on the formulation are investigated with the aid of various rheological methods and small angle neutron scattering (SANS). A change of pH from 4 (reduced electrostatic interactions) to higher pH values (prominent electrostatic forces) resulted in a marked impact on both the structural and rheological characteristics, with higher values of the dynamic moduli. At pH 4, the rheological features were strongly influenced by the addition of surfactant and monocaprin concentration, whereas at higher values of pH the effect of additives was modest. The picture that emerges from SANS and rheology is that enhanced association structures evolve at pH 4, while at higher pH the tendency to form associations is inhibited. At all the conditions, the rheological results suggest a viscoelastic solid behavior, which is typical for many gels.
Asunto(s)
Glicéridos/química , Hidrogeles/química , Elasticidad , Neutrones , Preparaciones Farmacéuticas/química , Reología , Dispersión de Radiación , ViscosidadRESUMEN
The pharmacological testing of natural products can often be hampered by the poor solubility of such compounds in non-toxic solvents. There is thus a need for a suitable agent for solubilization of natural substances to allow testing on a variety of cell lines in-vitro. Such an agent should ideally have no direct effects on any of the commonly used cell lines from a variety of tissues and mammalian species to allow proper comparison. In this study, the lichen metabolite (+)-usnic acid, a dibenzofuran derivative, was used as a prototype for an insoluble natural product with the aim of finding a solvent that was both capable of solubilizing usnic acid and was free of direct activity against a test cell line. Solubilization was measured at different pH values in various concentrations of co-solvents (glycofurol 75, propylene glycol, polyethylene glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing agent 2-hydroxypropyl-beta-cyclodextrin. The solubility achieved in a 20% aqueous solution was 0.11 mg mL(-1) for propylene glycol, 0.19 for PEG 400, 0.27 for glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2-hydroxypropyl-beta-cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various solvent systems were tested on the human leukaemia cell line K-562 in a standard proliferation assay. Most of the solvents proved toxic with the exception of propylene glycol, PEG 400 and 2-hydroxypropyl-beta-cyclodextrin. Anti-proliferative activity of usnic acid could be demonstrated with an ED50 (amount of substance required to reduce thymidine uptake to 50% of uptake by untreated control culture) of 4.7 microg mL(-1) using PEG 400 and 2-hydroxypropyl-beta-cyclodextrin but only the latter gave satisfactory solubility. 2-Hydroxypropyl-beta-cyclodextrin was thus identified as a solubilizing agent that fulfilled both set criteria of solubility and lack of toxicity against the test cells.