The influence of oleic acid-propylene glycol mixture and iontophoresis to propranolol transdermal transport

Propranolol has an intensive first pass metabolism, resulted in a low oral bioavailability. One alternative to circumvent such problem is the delivery by transdermal route. The objective of this study was to evaluate the effect of oleic acid 10 % (in propylene glycol 20 %) as enhancer, with and without iontophoresis, on transdermal transport of propranolol. Propranolol delivery was examined based on the in vitro transport studies across the rat skin (after hair removal) in a vertical diffusion cells system. Skin was pretreated with the mixture of oleic acid 10 % (in propylene glycol 20 %) for 3 hours. Iontophoresis was performed at a current density of 0.25 mA/cm2 for 3 hours. Donor compartment was filled with propranolol solution (5 mg/mL in citric buffer pH 5), while the acceptor phase was filled with phosphate buffer saline at pH 7.4. The results indicate that the enhancement methods increase the transdermal penetration of propranolol (p<0.05). The flux without any enhancement methods was 13.16 ± 0.79 mg/cm2/hour. The flux with either oleic acid-propylene glycol pretreatment, iontophoresis or combination of both were 28.75 ± 3.04 mg/cm2/hour, 40.47 ± 5.78 mg/cm2/hour, and 85.42 ± 16.94 mg/cm2/hour respectively. Based on mathematics calculation, if an iontophoretic patch of 12 cm2 is used after skin pretreatment with oleic acid - propylene glycol mixture, the steady state plasma concentration of propranolol could reach 24.65 mg/mL. Therefore, therapeutic level might be achieved. This indicated a promising future of transdermal delivery of propranolol.Key words : propranolol, transdermal, enhance

The capability of Several Population-based Approach Software to Analyze Sparse Drug Plasma Concentration Data after Intra-Venous Bolus Injection

Monolix, NONMEM, and WinBUGS-PKBUGS are among available software package for population-based modeling. The sparse condition of drug plasma concentration versus time (Cp-time) data is prevalent in clinically based studies involving patients. It is not ethical in this case, to collect a many and large volumes of blood samples. This study was aimed to simulate the capability of Monolix, NONMEM, and WinBUGS-PKBUGS to analyze very sparse Cp-time data after an intravenous bolus drug administration and to estimate the minimum number of Cp-time data required for an adequate analysis. Data of Cp-time were obtained based on simulation using the pharmacokinetic one-compartment open model following an intravenous bolus administration of 50 mg of a hypothetical drug. In this respect, six random values of k (rate constant of elimination) and Vd (volume of distribution) with mean and standard deviation values of 0.3 ±0.1 per hour and 30 ± 10 L, respectively, were used to create simulated Cp-time data of 6 subjects. Simulated Cp-time data in each subject were randomly ranked to choose data based on the intended number of samples in each subject. Several sparse Cp-time data scenarios, starting from a very limited state, i.e., with a total of 6 Cp-time data (1 datum per subject) to a rich situation with 48 Cp data (8 data per subject), were examined.The goodness of fit evaluations, as well as the similarity of individual values of k and Vd to the respective real values  (p>0.05), indicate that nonlinear-mixed-effect-model using Monolix, NONMEM and WinBUGS-PKBUGS can appropriately describe sparse Cp-time data even with only 2 data per subject. This fact is an important finding to support the demand of analytical tool for a limited number of Cp-time data such as obtained in therapeutic drug monitoring event

Pengaruh Propilen Glikol, Asam Oleat, Dan Isopropilalkohol Pada Formula Patch Transdermal Kalium Losartan

Losartan merupakan obat antihipertensi poten dengan bioavailabilitas rendah dan waktu paruh eliminasi cepat. Penelitian ini bertujuan untuk mengetahui komposisi formula optimum, karakteristik dan profil transpor  in vitro  patch transdermal kalium losartan. Rancangan formula berdasarkan metode simplex lattice design menggunakan software Design Expert. Evaluasi  karakteristik meliputi  ketebalan, bobot, moisture uptake, loss on drying,  folding enduranc,  dan drug content. Uji transport in vitro menggunakan  sel difusi vertikal, penetapan kadar transpor losartan menggunakan instumen HPLC dan analisis data menggunakan software WinSAAM. Komposisi formula optimum patch transdermal  losartan adalah 44,4% propilen glikol, 29,3% asam oleat,  dan 26,3% isopropil alkohol,  dengan karakteristik  tebal 0,6 mm, bobot 82,2 mg, loss on drying12,8%, moisture uptake 6,4%, folding endurance 300 lipatan dan drug content 98,9%. Profil transpor in vitro losartan menghasilkan model lima kompartemen dengan kinetika orde pertama

Pengaruh Propilen Glikol, Asam Oleat, Dan Isopropilalkohol Pada Formula Patch Transdermal Kalium Losartan

Losartan merupakan obat antihipertensi poten dengan bioavailabilitas rendah dan waktu paruh eliminasi cepat. Penelitian ini bertujuan untuk mengetahui komposisi formula optimum, karakteristik dan profil transpor  in vitro  patch transdermal kalium losartan. Rancangan formula berdasarkan metode simplex lattice design menggunakan software Design Expert. Evaluasi  karakteristik meliputi  ketebalan, bobot, moisture uptake, loss on drying,  folding enduranc,  dan drug content. Uji transport in vitro menggunakan  sel difusi vertikal, penetapan kadar transpor losartan menggunakan instumen HPLC dan analisis data menggunakan software WinSAAM. Komposisi formula optimum patch transdermal  losartan adalah 44,4% propilen glikol, 29,3% asam oleat,  dan 26,3% isopropil alkohol,  dengan karakteristik  tebal 0,6 mm, bobot 82,2 mg, loss on drying12,8%, moisture uptake 6,4%, folding endurance 300 lipatan dan drug content 98,9%. Profil transpor in vitro losartan menghasilkan model lima kompartemen dengan kinetika orde pertama

FORMULASI MATRIKS TRANSDERMAL PENTAGAMAVUNON-0 DENGAN KOMBINASI POLIMER PVP K30 DAN HIDROKSIPROPIL METILSELULOSA

Abstract: Transdermal delivery system is one of the delivery system for Pentagamavunon-0 (PGV-0) toavoid the high intensity of first pass metabolism of PGV-0 in peroral route. The purpose of this researchwas to optimize the formula of PGV-0 transdermal matrix with a combination of PVP K30 and HPMCpolymers.The simplex lattice optimization approach of the transdermal matrix formulas was performed byusing Design Expert 7.1.5 software. The visual appearance, weight, thickness, moisture content, moistureuptake, folding endurance, drug content, and dissolution efficiency of the release profil of PGV-0 from thematrix for 6 hours were evaluated as responses to determine optimum formula of matrix. The resultshowed that a combination of PVP K30 and HPMC polymers had a significant influence on the visualappearance, moisture content, and dissolution efficiency of PGV-0. Combination of 1.98% of PVP K30and 4.52% of HPMC as the optimum formula could produce homogeneous and flexible matrix withmoisture content of 3.21%. The dissolution efficiency was 9.11%, indicating that 101.93 g of PGV-0 wasreleased from the optimum formula during 6 hours.Keywords : Pentagamavunon-0, Transdermal matrix, PVP K30, HPM

Prediksi Kinetika Transpor Transdermal Propranolol HCl dengan Program WinSAAM

Transdermal transport was an alternate to propranolol HCl delivery to overcome the low bioavailability by oral route. Kinetics of transdermal transport can be predicted by model base on compartement theory. The aim of this research was to know kinetics of propranolol HCl transdermal transport with the present of enhancer oleic acid, propylene glycol and iontophoretics. Propranolol HCl transdermal transport was examined through the hairless rat as membrane on the vertical diffusion cell in the in vitro permeation. Enhancement methode used was oleic acid in propylene glycol and iontophoretics at varying concentrations. The donor phase contained 5 mg/ml propranolol HCl in citrate buffer, and the acceptor phase contained phosphate buffer saline at pH 7,4. Results of propranolol HCl transdermal transport analyzed by WinSAAM software. Parameters of transdermal transport were the rate of mass transfer from donor compartement to skin (Ka), available dose to transport (AD), and the rate of mass transfer from skin to acceptor compartement (KR). The results indicated that propranolol HCl transdermal transport with the present of enhancer can be explained by three compartement model and first order kinetics. Theoretically, value of AD influenced by oleic acid, interaction of oleic acid-iontophoretics and interaction of propylene glycol-iontophoretics. Value of Ka influenced by iontophoretics and interaction of oleic acid-propylene glycol-iontophoretics. Value of KR influenced by iontophoretics. Keywords: kinetics, transdermal, propranolol HCl, compartemen

Permeasi Transdermal Losartan In Vitro dari Larutan dengan Variasi Kadar Losartan dan Propilen Glikol

Abstrak Losartan, senyawa antagonis reseptor angiotensin II, mempunyai bioavailabilitas oral 0.25-0.35.  Bioavailabilitas yang rendah ini dapat diatasi dengan penghantaran obat secara transdermal. Enhancer sering ditambahkan ke dalam formula sediaan transdermal, misalnya propilen glikol (PG).  Penelitian ini bertujuan mempelajari pengaruh kadar propilen glikol terhadap permeasi transdermal losartan pada kadar obat yang berbeda. Penelitian dilakukan secara in vitro dengan sel difusi tipe vertikal dilakukan terhadap empat formula yaitu 2% potasium losartan (k-los) :15% PG (F1), 10% k-los :15% PG (F2), 2% k-los :20% PG (F3), dan 10% k-los: 20% PG (F4) dengan dapar sitrat pH 5 sebagai mediumnya.  Kulit punggung tikus jantan galur wistar digunakan sebagai membran, PBS pH 7,4 sebagai medium kompartemen reseptor, dan HPLC untuk pengukuran kadar k-los dalam kompartemen reseptor dengan detektor UV. Hasil penelitian menunjukkan bahwa peningkatan kadar k-los dari 2% ke 10% pada kadar PG 15% meningkatkan fluks, sedangkan pada kadar 20% tidak berpengaruh terhadap fluks.  Peningkatan kadar PG dari 15% ke 20% justru menurunkan fluks pada kadar k-los 2%, dan tidak berpengaruh pada kadar k-los 10%.  Nilai lag time tidak berbeda diantara semua fomula. Hal ini berarti penggunaan enhancer PG lebih dari 15% justru merugikan permeasi transdermal. Kata Kunci : transdermal, losartan, propilen glikol, enhancer   Abstract Losartan is an angiotensin receptor antagonis which has low oral bioavailability (0.25-0.35).  Transdermal drug delivery system is needed as one solution for this low oral bioavailability drug.  Propilen glikol (PG), as enhancer, is frequently added in transdermal dosage form.  This research was purposed to explore the effect of PG as losartan permeation enhancer in various concentration of potasium losartan (k-los). The research was carried out in vitro using vertical tipe difusion cel for 4 formulas, i.e. 2% potasium losartan (k-los) :15% PG (F1), 10% k-los :15% PG (F2), 2% k-los :20% PG (F3), and 10% k-los: 20% PG (F4) using citric buffer pH 5 as donor medium, while PBS pH 7,4 was used as receptor medium.  The dorsal skin of white wistar male rat was used as membrane.  HPLC with UV detector was used to determine the concentration of k-los appear in receptor compartment. The results show that increasing of k-los concentration from 2% to 10% can increase the flux if PG concentration is 20%, but it does not have any significant effect to the flux if the PG concentration is 15%.  Increasing PG concentration from 15% to 20% decrease the flux permeation in k-los concentration of 2%, and does not have any significant effect in concentration of k-los of 10%.  The lag time permeation does not has any significant differencess.  It means that PG as enhancer in the concentration above 15% doesn’t have any adventages. Keywords : transdermal, losartan, propilen glycol, enhance

Optimasi formula gel ekstrak kubis ungu (Brassica Oleracea L. Var. Capitata F. Rubra) menggunakan simplex lattice design dan pengujian aktivitas antioksidan secara in vitro

ABSTRACTA study of optimization of red cabbage (Brassica oleracea.L. var. capitata f. rubra) gel extract formula has been performed by using Simplex Lattice Design (SLD) method and antioxidant activity of the formula gel was also evaluated by using in vitro method.The red cabbage was extracted by soxhletation by using ethanol 96% followed by optimization of red cabbage extract in antioxidant gel preparation used SLD method by Design-Expert® software version 7 (DX7) and determination of its IC50 used UV-Spectrophotometry. The stability of optimum gel formula is seen through comparison of physycal properties at the beginning and after four weeks storage used ANOVA, with a 95% significant level. Optimum gel formula of red cabbage extract obtained in the proportion of Metolose 3,883%, propilen glikol 13.5%, Tween 80 1.117%. The evaluation results of optimum gel formula of red cabbage extract is the surface area of gel dispersive of 38.99 ± 3.27cm2; viscosity gel dPa.s of 295.56 ± 1.93 and viscosity change 3.89 ± 0.96%. From the results of statistical analysis of one t-test sample was concluded that there was no difference between the prediction price of software with the observation result (p> 0.05). The IC50 test result of the optimum formula of red cabbage extract gel was 257.25 ± 0.35 µg / mL. The testing result of the physical stability of the optimum formula of red cabbage extract gel suffered a pH decrease after 4 weeks of storage (p <0.05)

OPTIMIZATION OF A NOVEL KINETIC-ASSISTED INFUNDATION FOR RICH-EGCG AND POLYPHENOLS OF WHITE TEA (CAMELLIA SINENSIS) USING CENTRAL COMPOSITE DESIGN

Objective: This research aimed to find modeling and optimization of a novel kinetic-assisted infundation for rich-epigallocatechin gallate (EGCG) and polyphenols extraction from white tea leaf (Camellia sinensis L.).Methods: The optimal conditions for the best extraction of kinetic-assisted infundation were determined using central composite design. The content of EGCG, catechin, gallic acid, caffeine, theobromine, and theophylline was quantified using high-performance liquid chromatography with ultraviolet detection (HPLC/UV-detection). The total polyphenolic content (TPC) and total flavonoid content (TFC) was measured using the spectrophotometric method. The semi-purified extract was characterized by HPLC, fourier transform infrared spectrophotometry-universal attenuated total reflectance (FTIR-UATR), and powder-X ray diffraction (P-XRD). The extraction mechanism of target compounds was analyzed using scanning electron microscopy (SEM) qualitatively.Results: The optimum process for the rich-EGCG and polyphenolic extraction using kinetic-assisted infundation was the concentration of simplicia 14.75 %, the stir rate 440 rpm, and extraction time 12.31 min. The yield of extracts, TPC, TFC, EGCG, caffeine, gallic acid, and theobromine contents in the optimal extraction process were 9.34 %, 70.97 %, 13.95 %, 29.02 %, 11.95 %, 1.33 %, and 0.33 %, respectively.Conclusion: The kinetic-assisted infundation method proved to be easy to apply with good results as an alternative technique for extracting polyphenolic compounds and rich-EGCG from white tea leaves

Application of Simplex Lattice Design on the Optimization of Andrographolide Self Nanoemulsifying Drug Delivery System (SNEDDS)

Background: Optimization of self-nanoemulsifying drug delivery system (SNEDDS) formulation is an important step to obtain optimal formulation with desired characteristics.Objective: This present study was aimed to utilize simplex lattice design in optimizing andrographolide SNEDDS.Method: Simplex lattice design was employed to optimize andrographolide SNEDDS in which component of SNEDDS was selected as the independent factor while the charactheristics of SNEDDS was used as the responses. Capryol-90, Kolliphor RH 40, and propylene glycol were selected as the oil, surfactant, and co-surfactant, respectively. Optimization of andrographolide SNEDDS formulation was based on their characteristics including emulsification time, droplet size, and drug content. The optimized SNEDDS formulation was evaluated for emulsification time, droplet size, drug content, and zeta potensial.Results: The emulsification time, droplet size, drug content, and zeta potensial of the optimized andrographolide SNEDDS was found to be 1.21±0.03 min, 44.02±0.67 nm, 6.69±0.08 mg/g, and -40.63±0.76 mV, respectively.Conclusion: This result suggested that simplex lattice design is a suitable for efficiently optimizing the formulation of andrographolide SNEDDS