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, enhancer

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Application of Design of Experiment for Polyox and Xanthan Gum Coated Floating Pulsatile Delivery of Sumatriptan Succinate in Migraine Treatment

BioMed Research International ◽

10.1155/2014/547212 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Swati C. Jagdale ◽

Chandrakala R. Pawar

Keyword(s):

Design Of Experiment ◽

Xanthan Gum ◽

Dosage Form ◽

Lag Time ◽

Migraine Treatment ◽

Burst Release ◽

Night Time ◽

Sumatriptan Succinate

Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR205 and xanthan gum. 32experimental design was applied. Optimized formulation was evaluated for physical characteristics andin-vitroandin-vivostudy. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 ± 2 sec, drug content of 100.35 ± 0.4%, hardness of 6 ± 0.1 Kg/cm2, and 98.69 ± 2% drug release in pulse manner with lag time of 7 ± 0.1 h. Optimized batch showed prolong gastric residence which was confirmed byin-vivoX-ray study.

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Significance of In-Vitro and In-Vivo Correlation in Drug Delivery System

Research in Pharmacy and Health Sciences ◽

10.32463/rphs.2018.v04i04.23 ◽

2018 ◽

Vol 4 (4) ◽

pp. 523-531

Author(s):

Hina Mumtaz ◽

Muhammad Asim Farooq ◽

Zainab Batool ◽

Anam Ahsan ◽

Ashikujaman Syed

Keyword(s):

Dosage Form ◽

Pharmaceutical Preparations ◽

Pharmacokinetic Profile ◽

In Vitro Dissolution ◽

Time Saving ◽

Pharmaceutical Dosage Form ◽

Short Period ◽

Form Development

The main purpose of development pharmaceutical dosage form is to find out the in vivo and in vitro behavior of dosage form. This challenge is overcome by implementation of in-vivo and in-vitro correlation. Application of this technique is economical and time saving in dosage form development. It shortens the period of development dosage form as well as improves product quality. IVIVC reduce the experimental study on human because IVIVC involves the in vivo relevant media utilization in vitro specifications. The key goal of IVIVC is to serve as alternate for in vivo bioavailability studies and serve as justification for bio waivers. IVIVC follows the specifications and relevant quality control parameters that lead to improvement in pharmaceutical dosage form development in short period of time. Recently in-vivo in-vitro correlation (IVIVC) has found application to predict the pharmacokinetic behaviour of pharmaceutical preparations. It has emerged as a reliable tool to find the mode of absorption of several dosage forms. It is used to correlate the in-vitro dissolution with in vivo pharmacokinetic profile. IVIVC made use to predict the bioavailability of the drug of particular dosage form. IVIVC is satisfactory for the therapeutic release profile specifications of the formulation. IVIVC model has capability to predict plasma drug concentration from in vitro dissolution media.

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Formulation and Evaluation of Galantamine Hydrobromide Floating Matrix Tablet

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.v8i2.13868 ◽

2018 ◽

Vol 8 (2) ◽

Author(s):

Poreddy Srikanth Reddy ◽

Penjuri Subhash Chandra Bose ◽

Vuppula Sruthi ◽

Damineni Saritha

Keyword(s):

Sodium Alginate ◽

Xanthan Gum ◽

Lag Time ◽

Matrix Tablets ◽

In Vitro Dissolution ◽

Matrix Tablet ◽

Compression Technique ◽

Weight Variation ◽

The Matrix

The aim of the present work was to prepare floating tablets of galantamine HBr using sodium alginate and xanthan gum as matrix forming carriers. Galantamine HBr is used for the treatment of mild to moderate Alzheimer's disease and various other memory impairments, in particular those of vascular origin. The matrix tablet formulations were prepared by varying the concentrations of sodium alginate and xanthan gum. The tablets were prepared by direct compression technique using PVP K-30 as a binder and sodium bicarbonate for development of CO2. The prepared matrix tablets were evaluated for properties such as hardness, thickness, friability, weight variation, floating lag time, compatibility using DSC and FTIR. In vitro dissolution was carried out for 12 hrs in 0.1N HCl at 37±0.5 ºC using USP paddle type dissolution apparatus. It was noted that, all the prepared formulations had desired floating lag time and constantly floated on dissolution medium by maintaining the matrix integrity. The drug release from prepared tablets was found to vary with varying concentration of the polymers, sodium alginate and xanthan gum. From the study it was concluded that floating drug delivery system for galantamine HBr can be prepared by using sodium alginate and xanthan gum as a carrier.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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Freeze-Dried Clopidogrel Loaded Lyotropic Liquid Crystal: Box-Behnken Optimization, In-Vitro and In-Vivo Evaluation

Current Drug Delivery ◽

10.2174/1567201817666200122161433 ◽

2020 ◽

Vol 17 (3) ◽

pp. 207-217

Author(s):

Eman A. Hakeem ◽

Galal M. El-Mahrouk ◽

Ghada Abdelbary ◽

Mahmoud H. Teaima

Keyword(s):

Statistical Analysis ◽

Oral Bioavailability ◽

Quadratic Model ◽

Lipid Phase ◽

Individual Response ◽

In Vivo Evaluation ◽

Freeze Dried ◽

Suggested Formula

Background: Clopidogrel (CLP) suffers from extensive first pass metabolism results in a negative impact on its oral systemic bioavailability. Cubosomes are Lyotropic Liquid Crystalline (LLC) nano-systems comprising monoolein, a steric stabilizer and an aqueous system, it considered a promising carrier for different pharmaceutical compounds. Box-Behnken Design (BBD) is an efficient tool for process analysis and optimization skipping forceful treatment combinations. Objective: The study was designed to develop freeze-dried clopidogrel loaded LLC (cubosomes) for enhancement of its oral bioavailability. Methods: A 33 BBD was adopted, the studied independent factors were glyceryl monooleate (GMO lipid phase), Pluronic F127 (PL F127steric stabilizer) and polyvinyl alcohol powder (stabilizer). Particle Size (PS), Polydispersity Index (PDI) and Zeta Potential (ZP) were set as independent response variables. Seventeen formulae were prepared in accordance with the bottom up approach and in-vitro evaluated regarding PS, PDI and ZP. Statistical analysis and optimization were achieved using design expert software®, then the optimum suggested formula was prepared, in-vitro revaluated, freeze-dried with 3% mannitol (cryoprotectant), solid state characterized and finally packed in hard gelatin capsule for comparative in-vitro release and in-vivo evaluation to Plavix®. Results: Results of statistical analysis of each individual response revealed a quadratic model for PS and PDI where a linear model for ZP. The optimum suggested formula with desirability factor equal 0.990 consisting of (200 mg GMO, 78.15 mg PL F127 and 2% PVA). LC/MS/MS study confirmed significant higher C>max, AUC>0-24h and AUC>0-∞ than that of Plavix®. Conclusion: The results confirm the capability of developed carrier to overcome the low oral bioavailability.

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Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Current Cancer Drug Targets ◽

10.2174/1568009617666170623104030 ◽

2018 ◽

Vol 18 (4) ◽

pp. 365-371 ◽

Cited By ~ 2

Author(s):

Denis V. Mishchenko ◽

Margarita E. Neganova ◽

Elena N. Klimanova ◽

Tatyana E. Sashenkova ◽

Sergey G. Klochkov ◽

...

Keyword(s):

Lipid Peroxidation ◽

Acute Toxicity ◽

Histone Deacetylases ◽

Hydroxamic Acids ◽

Water Soluble ◽

Male Rat ◽

Hybrid Male ◽

Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

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1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.1082 ◽

1997 ◽

Vol 41 (5) ◽

pp. 1082-1093 ◽

Cited By ~ 276

Author(s):

S M Daluge ◽

S S Good ◽

M B Faletto ◽

W H Miller ◽

M H St Clair ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Oral Bioavailability ◽

Human Peripheral Blood ◽

Cross Resistance ◽

Immunodeficiency Virus ◽

Carbocyclic Nucleoside ◽

Hiv 1 ◽

In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

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