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Acta Farm. Bonaerense 22 (1): 11-5 (2003)
Recibido el 8 de septiembre de 2002Aceptado el 18 de octubre de 2002 Physicochemical Properties and Anti-Inflammatory Activity Ruy C.R. BECK 1*, Sílvia S. GUTERRES 2, Rodrigo J. FREDDO 1, Cecília B. MICHALOWSKI 2, Isadora BARCELLOS 1 & José A.B. FUNCK 1 1 PPG em Ciência e Tecnologia Farmacêuticas, Departamento de Farmácia Industrial, CCS, Universidade Federal de Santa Maria, Camobi, CEP 97119-900, Santa Maria, RS, Brazil. 2 PPG em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av Ipiranga, 2752 CEP 90610-000, Porto Alegre, RS, Brazil SUMMARY. The purpose of this study was to develop and characterize formulations of nanoparticles
containing dexamethasone and to evaluate their anti-inflammatory activity in rats. Nanoparticles were
prepared according to the procedure of nanoprecipitation, using poly (DL-lactide) and poly (
ε-caprolac-
tone) and dexamethasone, both in its base form and as acetate ester. The anti-inflammatory activity of the
formulations was evaluated using two in vivo
methodologies: inhibition of pellet cotton granuloma forma-
tion and of acute edema produced by injection of carragenin. The drug entrapment efficiency was about
80% and the formulations containing dexamethasone acetate was unstable. The association of this drug
with nanoparticles improve its pharmacological activity in comparison to a commercial formulation.
RESUMO. “Nanopartículas contendo dexametasona: propriedades físico-químicas e atividade antiinflamatória”.
O principal objetivo deste trabalho foi desenvolver e caracterizar formulações de nanopartículas contendo dexa-
metasona e avaliar a atividade antiinflamatória em ratos. As nanopartículas foram preparadas pelo método da na-
noprecipitação, utilizando o poli(ácido lático) e a poli(ε-caprolactona) como polímeros, e a dexametasona, como
fármaco modelo, tanto na sua forma livre, quanto de éster acetato. A atividade antiinflamatória das formulações
foi avaliada através de duas metodologias: a inibição da formação do granuloma e a inibição do edema de pata de
rato induzido por carragenina. A eficiência de incorporação foi em torno de 80% e as formulações contendo ace-
tato de dexametasona apresentaram-se instáveis. A associação do fármaco às nanopartículas melhorou a sua ati-
vidade farmacológica em relação a formulação comercial.
INTRODUCTION
the entrapment of dexamethasone in nanoparti- relevant clinical use mainly due to its anti-in- Seijo et al. 3 reported a dexamethasone en- flammatory and immunosuppressive effects.
trapment efficiency of 75% in PIBCA nano- However, the great number of side effects, such spheres prepared by the in situ polymerization as: hypertension, hydroelectrolytic disorders, hy- procedure and Song et al. 4 presented a drug perglycemia, peptic ulcers and glucosuria re- entrapment of 79.6 % in PLGA nanospheres ob- stricts the use of dexamethasone in prolonged tained using an emulsification/solvent evapora- tion technique. In addition, Fessi et al. 5 using In the last years much interest has been fo- nanodispersion of the preformed poly(DL-lac- cused on nanoparticles, as a drug delivery sys- tems, due to their possibilities of increasing drug nanocapsules. Nevertheless, these works used efficacy, reducing toxicity and controlling drug dexamethasone as a lipophilic drug model and release 2. However, few data are available about the only parameters evaluated were the entrap- KEY WORDS: Anti-inflammatory activity; Dexamethasone; Nanoparticles.
PALAVRAS-CHAVE: Atividade antiinflamatória; Dexametasona; Nanopartículas.
Author to whom correspondence should be addressed:R. Dr. Sebastião Leão, 136/301 - Porto Alegre, RS, Brazil, CEP 90050-090 (e-mail: ruybeck@bol.com.br) Beck, R.C.R, S.S. Guterres, R.J. Freddo, C.B. Michalowski, I. Barcellos & J.A.B. Funck ment efficiency, the particle size 3-5 and in vitro Determination of Entrapment Efficiency
Free drug was determined in the clear super- Considering this lack of information, the goal natant following separation of nanoparticles of the present work was to develop and charac- from the aqueous medium by a combined ultra- terize nanoparticles containing dexamethasone, filtration-centrifugation technique (Ultrafree- or its acetate derivative, prepared by nanodis- MC® 10,000 MW, Millipore, Bedford, U.S.A.).
persion of different biodegradable polymers and Total drug was determined after dissolution of to evaluate the anti-inflammatory activities of nanoparticles in acetonitrile (1 mL of suspension to 25 mL of acetonitrile). The drug content wascalculated from the difference between the totaland free drug concentrations measured in the MATERIALS AND METHODS
nanoparticles suspension (total drug) and the fil- Materials
trate (nonentrapped drug), respectively. Poly (ε-caprolactone) (PCL, MW: 65 000) and poly (DL-lactide) (PLA, MW: 103 000) were pur- high-performance liquid chromatography 7. The chased from Sigma-Aldrich Co. (Steinheim, Ger- system consisted of a Merck Lichrospher® RP 18 many). Tween 80® and Span 80® were sup- column (Darmstadt, Germany), an Intralab 5050 plied by Delaware (Porto Alegre, Brazil). Dex- pump, an Intralab 5100 detector and an Intralab amethasone and dexamethasone acetate were 4290 integrator. The mobile phase consisted of gift from Hoechst-Roussel (Romainville, France) water/acetonitrile (55:45% v/v). The total sample and Merck S/A (Rio de Janeiro, Brazil), respec- amount injected was 20 µl. Dexamethasone (D tively. All other chemicals and solvents used or DA) was detected by absorption at 254 nm.
were of pharmaceutical grade. All reagents were The linear response range was 3.125-50.000 µg/mL with a correlation coefficient of 0.9999.
Male Wistar rats (Biotério Central, UFSM) weighing between 200 e 400 g were used in the Drug/Polymer Ratio
in vivo anti-inflammatory activity evaluation. The This parameter was determined by the quo- rats were fed a regular diet with no restrictions tient between the total amount of incorporated on the amount of food or water consumed.
drug (mg) and polymer (mg) presented in sus-pensions.
Preparation of PLA and PCL Nanoparticles
Particle Size Determination
to the procedure of preformed polymer disper- The particle size of nanoparticles was esti- sion 6, using poly (DL-lactide) - PLA and poly mated by photon correlation spectroscopy using (ε-caprolactone) - PCL, as polymers, and dexam- ethasone as drug, both in its baseform (D) or asacetate ester (DA). The colloidal suspensions Morphologic Examination
were abbreviated for NS-PLA-D; NS-PCL-D; NS- Nanoparticles samples were observed with a PLA-DA; NS-PCL-DA, respectively. The final transmission electron microscope (Jeol, Jem concentration was 0.5 mg/mL. Briefly, 200 mg 1200 Ex-II, Japan) after negative staining with of polymer (PLA or PCL), 300 mg of Span 80® 2% (p/v) aqueous solution of uranyl acetate.
and the drug (D or DA) were first dissolved in40 mL of acetone. This organic solution was Stability Studies
poured, with moderate magnetic stirring, into 80 The formulations were monitored following mL of an aqueous phase containing 300 mg of preparation, at time 0, 1, 2 and 3 months, deter- Tween 80®. The resulting mixed phase immedi- mining the efficiency of drug entrapment. The ately turned milky with bluish opalescence as a suspensions were stored at room temperature result of the formation of nanoparticles. The and protected from light. The kinetic of drug acetone was finally removed under reduced leakage from polymeric matrix was calculated pressure and the colloidal suspension concen- trated to the desired final volume (20 mL). Emp-ties NS were also prepared (NS-PLA and NS- Anti-Inflammatory activity evaluation
PCL) as described above. Formulations were The anti-inflammatory activity was evaluated for the formulation that presented the best re- acta farmacéutica bonaerense - vol. 22 n° 1 - año 2003 sults in the characterization step and stability tions and the in vivo anti-inflammatory evalua- study. Two methods were used in testing the tion. p-values less than 0.05 and 0.10 were con- anti-inflammatory activity in rats: the inhibition sidered as representing a significant difference of acute edema produced by injection of car- of the characterization step and anti-inflammato- rageenin and inhibition of cotton pellet granulo- ry activity evaluation, respectively.
RESULTS AND DISCUSSION
Inhibition of acute edema produced by injection Physicochemical Characteristics
The main objective of this work was to ob- tain dexamethasone loaded nanoparticles and to rats (200-300 g, n = 6). Thirty minutes before investigate the possibility of increase its anti-in- the intraperitoneal injection of each compound, flammatory activity. Therefore, we prepared the basal volume of the hind paws was mea- nanospheres from two different biodegradable sured by means of a mercury plethysmometer polymers (PLA or PCL) and dexamethasone, as (Ugo Basile). Afterwards, the rats were injected its baseform (D) or as acetate ester (DA).
with one of the following compounds at the The formulations prepared with dexametha- dose of 30 µg/Kg 9: (a) dexamethasone nano- sone acetate (NS-PLA-DA and NS-PCL-DA) were particles suspension; (b) empties nanoparticles; unstable presenting a precipitate just after (c) water; (d) dexamethasone commercial form - preparation. These phenomenon could be ex- Decadron®. Thirty minutes after the treatment, plained by the low solubility of dexamethasone acetate in water (5.47 µg/mL) and thus, by the saline) was injected intraplantarly into the right diffusion of a certain amount of DA from the hind paw of each rat to induce inflammation nanoparticles to the aqueous medium, followed and 0.05 mL of saline into the contralateral paw.
by its precipitation as free crystals. On the other Paw volumes up to the ankle joints were mea- hand, dexamethasone, which is less hydropho- sured before and at hourly intervals for 6 h fol- bic (water solubility of 100.88 µg/mL) 10 than lowing carrageenin administration. The basal the acetate form, and had a hydrogen at C21, in- volume of each rat paw was taken as 100% and creasing the possibility of interactions by hydro- variations from this volume were given as per- used, allowed the preparation of nanospherescolloidal suspensions.
Inhibition of cotton pellet granuloma formation Table 1 shows pH, particle size, entrapment Cotton pellets weighing 38-42 mg were ster- efficiency (%) and drug/polymer ratio, just after ilized by autoclaving and implanted into male preparation, of the formulations containing dex- Wistar rats (300-400 g, n = 8) under chloroform amethasone. All formulations were acidic and anesthesia. A small dorsal, mid-line incision was particle sizes are in the submicrometric range, made, and the dermis was separated from the with no significant differences (p<0,05) in rela- underlying peritoneal wall by an insertion of a tion to their mean diameter size. The TEM mor- trocater. Two pellets were implanted in each rat, phologic observation of NS-PLA-D, NS-PLA, NS- one on each side of the incision. The incision was closed with a surgical suture. The following demonstrated uniform and rounded particles for compounds were administered to rats by injec- all formulations. Also, the presence of drug tion in the tail vein at the dose of 30 µg/Kg 9: nanocrystals around the nanoparticles were not (a) dexamethasone nanoparticles suspension; detected. These crystallization phenomenon (b) empties nanoparticles; (d) dexamethasone could be occured due to the low solubility of commercial form - Decadron®. Seven days af- dexamethasone in water. The visualization of in- ter, the rats were killed by decapitation. Cotton domethacin crystals around nanoparticles by pellets and the accompanying granulomatous TEM is reported by Calvo et al. 11. tissue were removed from the rats, placed in a Regarding to the entrapment efficiency, simi- glass Petri dish, air dried at 60 °C for 18 h, and lar results were measured for both formulations (76.30 ± 2.10% for NS-PLA-D and 77.11 ± 1.36%for NS-PCL-D). Despite the highest hydropho- Statistical Analysis
bicity of PCL, the polymer has not significantly influenced on this parameter. The drug/polymer chemical parameters of the control of formula- ratio was 3.65 ± 0.12 for NS-PLA-D and 3.83 ± Beck, R.C.R, S.S. Guterres, R.J. Freddo, C.B. Michalowski, I. Barcellos & J.A.B. Funck Particle size
Entrapment
Drug/polymer
Formulation
efficiency (%)
Table 1. pH, particle size, entrapment efficiency and drug/polymer ratio of formulations after preparation.
a The data showed are the mean ± standard deviation (n = 3). Means with the same letter are not significantly
different (ANOVA, F test).
Figure 2. Percentage of the initial load of dexametha-
sone found as a function of storage time in nano-
spheres prepared at different polymers (NS-PLA-D or
NS-PCL-D) and dexamethasone.
Stability Studies
Figure 1. TEM of (a, top left) dexamethasone loaded
sented a similar significant decline of entrap- PLA nanoparticles (NS-PLA-D), (b, top right) PLA ment efficiency during storage time (Figure 2), nanospheres without drug (NS-PLA), (c, bottom left) indicating drug leakage (surface desorption dexamethasone loaded PCL nanospheres (NS-PCL-D) and/or difusion to the aqueous medium). How- and (d, bottom right) PCL nanospheres without drug leakage (desorption and/or diffusion) followinga second order kinetics (r = 0.9905), whereas 0.05 for NS-PCL-D. These values were in agree- the NS-PCL-D suspension showed drug leakage ment with those reported by Seijo et al. 3 for following a zero order kinetics (r = -0.99009).
polyisobutylcyanoacrylate nanoparticles contain- These kinetics difference could be attributed to ing dexamethasone prepared by interfacial the drug incorporation pattern, where in the polimerization (entrapment efficiency: 75.00 ± PLA nanospheres the drug is more incorporated 10.00% and drug/polymer ratio: 3.75 w/w) and into polymeric matrix, than in the PCL nano- by Song et al. 4 for poly(lactic-co-glycolic acid) spheres in which the drug is more adsorbed on- nanoparticles obtained using as emulsification/ solvent evaporation technique (entrapment effi-ciency: 79.60%). On the other hand, these re- Anti-Inflammatory Activity
sults are better than that demonstrated by Fessi et al. 5 for PLA nanocapsules containing dexam- physicochemical characterization, NS-PCL-D for- ethasone prepared by interfacial polymer depo- mulation was chosen to undergo the pharma- cological studies. Figure 3 shows the increase in acta farmacéutica bonaerense - vol. 22 n° 1 - año 2003 Figure 4. Granuloma weight, in mg, in anti-inflam-
Figure 3. Increase in edema volume (%) in anti-in-
matory activity evaluation of nanospheres containing flammatory activity evaluation of nanospheres con- dexamethasone (NS-PCL-D), empties nanospheres taining dexamethasone (NS-PCL-D), empties nano- (NS-PCL) and free dexamethasone (Decadron®), us- spheres (NS-PCL), free dexamethasone (Decadron®) ing the method of inhibition of cotton pellet granulo- and water using the method of acute edema inhibi- ma formation in rats (8 rats per group). Means with tion produced by carrageenin injection (6 rats per the same letter are not significantly different (ANOVA, edema volume (%) using the method of acute poorly stables. Work is in progress to optimize edema inhibition produced by carrageenin in- the stability of the preparation by means of jection, as a function of time. The evaluation of the anti-inflammatory activities was performedby the comparison of NS-PCL-D with a dexam- REFERENCES
1. Schimmer, B. P.& K. L. Parker (1996) “Hormô- (Decadron®) used as reference. When dexam- nio Adreno-Corticotrófico: Esteróides Adreno-corticais e seus Análogos Sintéticos: Inibidores ethasone was associated with NS and its anti-in- da Síntese e das Ações dos Hormônios Adre- flammatory activity evaluated by inhibition car- nocorticais” en As bases farmacológicas da te- rageenin-edema a significant reduction of ede- rapêutica, (Gilman, A.G., Rall, T. W., Nies, A.& ma (p<0.10) was measured in comparison to the P. Taylor, eds.); Impressos Universitária SA, commercial product. On the other hand, the an- ti-inflammatory activity evaluated by the inhibi- 2. Yokoyama, M. & T. Okano (1996) Adv. Drug tion of cotton pellet granuloma formation (Fig- Del. Rev. 21: 77-80.
ure 4) did not show statistically significant dif- 3. Seijo, B., Fattal, E., Roblot-Treupel, L. & P.
ference between the products containing dexa- Couvreur (1990) Int. J. Pharm. 62: 1-7.
methasone (NS-PCL-D and Decadron®), howev- 4. Fessi, H., Puisieux, F., Devissaguet, J.-P., N.
Ammoury & S. Benita (1989) Int. J. Pharm. 55:
er a tendency of bigger activity of NS can be ob- 5. Song, C. X., Labhasetwar, V., Murphy, H., Qu, X., Humphrey, W. R., Shebuski, R.J. & R. J.
CONCLUSIONS
Levy (1997) J. Control. Release 43: 197-212
This paper describes the preparation feasibil- 6. Fessi, H., Devissaguet, J.P. & F. Puisieux ity of colloidal systems, PLA and PCL nanoparti- cles containing dexamethasone. The drug form 7. Beck, R.C.R. (2001) Acta Farm. Bonaerense 20:
(dexamethasone or dexamethasone acetate) has influence in drug entrapment efficiency. Howev- 8. Martin, A.N., J. Swarbrick & A. Cammarata er, all formulations presented a decline in this (1993) “Kinetics” en Physical Pharmacy, Lea &Febiger, Philadelphia, págs. 284-323.
entrapment efficiency on aging. The importance 9. Winter, C.A., Risley, E.A. & G.W. Nuss (1963) of the dexamethasone nanoparticles was further J. Pharmacol. Exp. Therap. 141: 369-76.
evidenced by the fact they significantly improve 10. Huuskonen, J., Solo, M. & J. Taskinen, J.
the pharmacological activity of drug in compari- (1997) J. Pharm. Sci. 86: 450-4.
son to a commercial formulation. Nevertheless, 11. Calvo, P., Vila-Jato, J. L. & M. J. Alonso (1996) dexamethasone nanoparticles suspensions are J. Pharm. Sci. 85: 530-6.

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