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pH-responsive CAP-co-poly(methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation

Shah SA, Sohail M, Minhas MU, Nisar-Ur-Rehman, Khan S, Hussain Z, et al.

Drug Deliv Transl Res, 2019 Apr;9(2):555-577.
PMID: 29450805 DOI: 10.1007/s13346-018-0486-8

Cellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pH 7.4, while swelling and release rate was very low at pH 1.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents. Graphical abstract.

Matched MeSH terms: Drug Stability
Fulltext Zerumbone-loaded nanostructured lipid carriers: preparation, characterization, and antileukemic effect

Rahman HS, Rasedee A, How CW, Abdul AB, Zeenathul NA, Othman HH, et al.

Int J Nanomedicine, 2013;8:2769-81.
PMID: 23946649 DOI: 10.2147/IJN.S45313

Zerumbone, a natural dietary lipophilic compound with low water solubility (1.296 mg/L at 25°C) was used in this investigation. The zerumbone was loaded into nanostructured lipid carriers using a hot, high-pressure homogenization technique. The physicochemical properties of the zerumbone-loaded nanostructured lipid carriers (ZER-NLC) were determined. The ZER-NLC particles had an average size of 52.68 ± 0.1 nm and a polydispersity index of 0.29 ± 0.004 μm. Transmission electron microscopy showed that the particles were spherical in shape. The zeta potential of the ZER-NLC was -25.03 ± 1.24 mV, entrapment efficiency was 99.03%, and drug loading was 7.92%. In vitro drug release of zerumbone from ZER-NLC was 46.7%, and for a pure zerumbone dispersion was 90.5% over 48 hours, following a zero equation. Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in human T-cell acute lymphoblastic leukemia (Jurkat) cells, the half maximal inhibitory concentration (IC50) of ZER-NLC was 5.64 ± 0.38 μg/mL, and for free zerumbone was 5.39 ± 0.43 μg/mL after 72 hours of treatment. This study strongly suggests that ZER-NLC have potential as a sustained-release drug carrier system for the treatment of leukemia.

Matched MeSH terms: Drug Stability
Validation of high performance liquid chromatography-electrochemical detection methods with simultaneous extraction procedure for the determination of artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine in human plasma for application in clinical pharmacological studies of artesunate-amodiaquine drug combination

Lai CS, Nair NK, Muniandy A, Mansor SM, Olliaro PL, Navaratnam V

J Chromatogr B Analyt Technol Biomed Life Sci, 2009 Feb 15;877(5-6):558-62.
PMID: 19147417 DOI: 10.1016/j.jchromb.2008.12.037

With the expanded use of the combination of artesunate (AS) and amodiaquine (AQ) for the treatment of falciparum malaria and the abundance of products on the market, comes the need for rapid and reliable bioanalytical methods for the determination of the parent compounds and their metabolites. While the existing methods were developed for the determination of either AS or AQ in biological fluids, the current validated method allows simultaneous extraction and determination of AS and AQ in human plasma. Extraction is carried out on Supelclean LC-18 extraction cartridges where AS, its metabolite dihydroartemisinin (DHA) and the internal standard artemisinin (QHS) are separated from AQ, its metabolite desethylamodiaquine (DeAQ) and the internal standard, an isobutyl analogue of desethylamodiaquine (IB-DeAQ). AS, DHA and QHS are then analysed using Hypersil C4 column with acetonitrile-acetic acid (0.05M adjusted to pH 5.2 with 1.00M NaOH) (42:58, v/v) as mobile phase at flow rate 1.50ml/min. The analytes are detected with an electrochemical detector operating in the reductive mode. Chromatography of AQ, DeAQ and IB-DeAQ is carried out on an Inertsil C4 column with acetonitrile-KH(2)PO(4) (pH 4.0, 0.05M) (11:89, v/v) as mobile phase at flow rate 1.00ml/min. The analytes are detected by an electrochemical detector operating in the oxidative mode. The recoveries of AS, DHA, AQ and DeAQ vary between 79.1% and 104.0% over the concentration range of 50-1400ng/ml plasma. The accuracies of the determination of all the analytes are 96.8-103.9%, while the variation for within-day and day-to-day analysis are <15%. The lower limit of quantification for all the analytes is 20ng/ml and limit of detection is 8ng/ml. The method is sensitive, selective, accurate, reproducible and suited particularly for pharmacokinetic study of AS-AQ drug combination and can also be used to compare the bioavailability of different formulations, including a fixed-dose AS-AQ co-formulation.

Matched MeSH terms: Drug Stability
Validation of LC for the determination of alpha-mangostin in mangosteen peel extract: a tool for quality assessment of Garcinia mangostana L

Yodhnu S, Sirikatitham A, Wattanapiromsakul C

J Chromatogr Sci, 2009 Mar;47(3):185-9.
PMID: 19298703

Mangosteen, Garcinia mangostana L., is known as the "Queen of fruits" and can be cultivated in the tropical rainforest such as Malaysia, Indonesia, and Thailand. Compounds isolated from the fruit peel of mangosteen contain abundant xanthones (especially alpha-mangostin). It has been used as traditional medicine such as anti-inflammatory and antibacterial and is popularly applied to cosmetic and pharmaceutical products. However, there is little information for quality and quantity determination of alpha-mangostin in mangosteen. Thus, the aim of this study was to set up a validated and stability-indicated isocratic reverse-phase high-performance liquid chromatographic (HPLC) method for quality control and quantity determination of a-mangostin from mangosteen peel extract. The assay was fully validated and shown to be linear (r(2) > 0.999), sensitive (LOD = 0.02 microg/mL and LOQ = 0.08 microg/mL), accurate (intra-day was between 98.1-100.8%, inter-day was between 90.0-101.3%), precise (intra-day variation < or = 1.8%, inter-day variation < or = 4.3%), specific, and with good recovery. Total analysis was approximately 8 min. The finalized method is also a stability-indicating assay. The present method should be useful for analytical research and for routine quality control analysis of alpha-mangostin in mangosteen peel extract and products of mangosteen.

Matched MeSH terms: Drug Stability
Transdermal delivery of oxybutynin chloride proniosomal gels for the treatment of overactive bladder

Rajabalaya R, David SR, Chellian J, Xin Yun G, Chakravarthi S

Drug Deliv, 2016 Jun;23(5):1578-87.
PMID: 26634274 DOI: 10.3109/10717544.2015.1116027

CONTEXT: Overactive bladder (OAB) is a common problem and anticholinergic drugs are first-line therapy, but they have side effects.
OBJECTIVE: Development of oxybutynin chloride (OC) proniosomal gels and analyses of its efficacy for OAB treatment.
MATERIALS AND METHODS: Phase separation coacervation was used to prepare proniosomal gels using various non-ionic surfactants, lipids, soy lecithin and isopropyl alcohol. Gels were characterized with regard to entrapment efficiency (EE), vesicle size, surface morphology (using environmental scanning electron microscopy [E-SEM]), stability, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, in vivo animal studies and histopathology.
RESULTS AND DISCUSSION: EE was 87-92%, vesicle size was 0.38-5.0 μm, and morphology showed some loosened pores in proniosomes after hydration. ATR-FTIR spectroscopy showed no significant shifts in peaks corresponding to OC and excipients. Most formulations exhibited >50% permeation but the cholesterol-containing formulations P3 (Span 20:Span 60 [1:1]) and P4 [Tween 20:Tween 80 (1:1)] had the highest percent cumulative permeation. P3 and P4 also showed faster recovery of cholinergic effects on salivary glands than oral formulations. P3 and P4 had pronounced therapeutic effects in reduction of urinary frequency and demonstrated improvements in bladder morphology (highly regenerative surface of the transitional epithelium).
CONCLUSION: These results suggest that OC could be incorporated into proniosomal gels for transdermal delivery in the treatment of OAB.

Matched MeSH terms: Drug Stability
Fulltext Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

Hariono M, Choi SB, Roslim RF, Nawi MS, Tan ML, Kamarulzaman EE, et al.

PLoS One, 2019;14(1):e0210869.
PMID: 30677071 DOI: 10.1371/journal.pone.0210869

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.

Matched MeSH terms: Drug Stability
The wound healing properties of Channa striatus-cetrimide cream-- tensile strength measurement

Baie SH, Sheikh KA

J Ethnopharmacol, 2000 Jul;71(1-2):93-100.
PMID: 10904151

Channa striatus, a fresh water snakehead fish, is reported to enhance dermal wound healing. Biochemical components such as amino acids and fatty acids are important for the synthesis of collagen fibers during wound healing. Arachidonic acid, a precursor of prostaglandin plays a vital role in healing the wounds. Haruan (C. striatus) contains all the essential amino acids for wound healing particularly glycine as well as high contents of arachidonic acid and polyunsaturated fatty acids that can promote prostaglandin synthesis. In the present work we have studied the wound healing effect of C. striatus in Sprague-Dawley rats. Cream formulations having different haruan fish extract concentrations as the active ingredient were prepared and stabilized, and they were applied to the wounds. The healing of wounds was characterized by an increase in the tensile strength of the skin, determined on the 7th post-operative day in each case. Haruan treatment of wounds promotes remodeling of collagen, by the synthesis of inter- and intra-molecular protein crosslinking and thus produces a marked increase (P<0.05) in tensile strength as compared to the cetrimide treated group. On the basis of our experiment we conclude that C. striatus helps in wound healing as indicated by the increase in tensile strength. We hypothesise that this effect may be due to its high content of arachidonic acid, glycine and polyunsaturated fatty acids. The mechanism of wound healing will be investigated in future studies.

Matched MeSH terms: Drug Stability
Fulltext The effect of laser repetition rate on the LASiS synthesis of biocompatible silver nanoparticles in aqueous starch solution

Zamiri R, Zakaria A, Ahangar HA, Darroudi M, Zamiri G, Rizwan Z, et al.

Int J Nanomedicine, 2013;8:233-44.
PMID: 23345971 DOI: 10.2147/IJN.S36036

Laser ablation-based nanoparticle synthesis in solution is rapidly becoming popular, particularly for potential biomedical and life science applications. This method promises one pot synthesis and concomitant bio-functionalization, is devoid of toxic chemicals, does not require complicated apparatus, can be combined with natural stabilizers, is directly biocompatible, and has high particle size uniformity. Size control and reduction is generally determined by the laser settings; that the size and size distribution scales with laser fluence is well described. Conversely, the effect of the laser repetition rate on the final nanoparticle product in laser ablation is less well-documented, especially in the presence of stabilizers. Here, the influence of the laser repetition rate during laser ablation synthesis of silver nanoparticles in the presence of starch as a stabilizer was investigated. The increment of the repetition rate does not negatively influence the ablation efficiency, but rather shows increased productivity, causes a red-shift in the plasmon resonance peak of the silver-starch nanoparticles, an increase in mean particle size and size distribution, and a distinct lack of agglomerate formation. Optimal results were achieved at 10 Hz repetition rate, with a mean particle size of ~10 nm and a bandwidth of ~6 nm 'full width at half maximum' (FWHM). Stability measurements showed no significant changes in mean particle size or agglomeration or even flocculation. However, zeta potential measurements showed that optimal double layer charge is achieved at 30 Hz. Consequently, Ag-NP synthesis via the laser ablation synthesis in solution (LASiS) method in starch solution seems to be a trade-off between small size and narrow size distributions and inherent and long-term stability.

Matched MeSH terms: Drug Stability
Fulltext The Potential Anticancer Activity of 5-Fluorouracil Loaded in Cellulose Fibers Isolated from Rice Straw

Yusefi M, Shameli K, Jahangirian H, Teow SY, Umakoshi H, Saleh B, et al.

Int J Nanomedicine, 2020;15:5417-5432.
PMID: 32801697 DOI: 10.2147/IJN.S250047

INTRODUCTION: Green-based materials have been increasingly studied to circumvent off-target cytotoxicity and other side-effects from conventional chemotherapy.
MATERIALS AND METHODS: Here, cellulose fibers (CF) were isolated from rice straw (RS) waste by using an eco-friendly alkali treatment. The CF network served as an anticancer drug carrier for 5-fluorouracil (5-FU). The physicochemical and thermal properties of CF, pure 5-FU drug, and the 5-FU-loaded CF (CF/5-FU) samples were evaluated. The samples were assessed for in vitro cytotoxicity assays using human colorectal cancer (HCT116) and normal (CCD112) cell lines, along with human nasopharyngeal cancer (HONE-1) and normal (NP 460) cell lines after 72-hours of treatment.
RESULTS: XRD and FTIR revealed the successful alkali treatment of RS to isolate CF with high purity and crystallinity. Compared to RS, the alkali-treated CF showed an almost fourfold increase in surface area and zeta potential of up to -33.61 mV. SEM images illustrated the CF network with a rod-shaped structure and comprised of ordered aggregated cellulose. TGA results proved that the thermal stability of 5-FU increased within the drug carrier. Based on UV-spectroscopy measurements for 5-FU loading into CF, drug loading encapsulation efficiency was estimated to be 83 ±0.8%. The release media at pH 7.4 and pH 1.2 showed a maximum drug release of 79% and 46%, respectively, over 24 hours. In cytotoxicity assays, CF showed almost no damage, while pure 5-FU killed most of the both normal and cancer cells. Impressively, the drug-loaded sample of CF/5-FU at a 250 µg/mL concentration demonstrated a 58% inhibition against colorectal cancer cells, but only a 23% inhibition against normal colorectal cells. Further, a 62.50 µg/mL concentration of CF/5FU eliminated 71% and 39% of nasopharyngeal carcinoma and normal nasopharyngeal cells, respectively.
DISCUSSION: This study, therefore, showed the strong potential anticancer activity of the novel CF/5-FU formulations, warranting their further investigation.

Matched MeSH terms: Drug Stability
Temperature-mediated absorption of phenylmercuric nitrate on polyethylene and polypropylene containers in chloramphenicol eye drops

Charoo N, Chiew M, Tay A, Lian L

Cutan Ocul Toxicol, 2014 Sep;33(3):242-6.
PMID: 24147942 DOI: 10.3109/15569527.2013.837058

The aim of this work was to find the effect of temperature and manufacturing source of phenylmercuric nitrate (PMN) on PMN absorption on low-density polyethylene (LDPE) and polypropylene containers in chloramphenicol eye drops. Two factorial experiments were designed to study the effect of temperature on PMN assay in chloramphenicol eye drops stored in LDPE and prepared from two different PMN sources. PMN source had no effect on PMN assay at 2-8 °C, however at stress conditions (30 °C/75%RH) for 3 weeks, the effect of PMN source on PMN assay was found significant (p

Matched MeSH terms: Drug Stability
Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients

Liew KB, Tan YT, Peh KK

Drug Dev Ind Pharm, 2015 Apr;41(4):583-93.
PMID: 24495273 DOI: 10.3109/03639045.2014.884130

Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly.

Matched MeSH terms: Drug Stability
Tamoxifen-loaded nanostructured lipid carrier as a drug delivery system: characterization, stability assessment and cytotoxicity

How CW, Rasedee A, Manickam S, Rosli R

Colloids Surf B Biointerfaces, 2013 Dec 1;112:393-9.
PMID: 24036474 DOI: 10.1016/j.colsurfb.2013.08.009

Cancer nanotherapeutics is beginning to overwhelm the global research and viewed to be the revolutionary treatment regime in the medical field. This investigation describes the development of a stable nanostructured lipid carrier (NLC) system as carrier for Tamoxifen (TAM). The TAM-loaded NLC (TAM-NLC) developed with 200mg of TAM showed a spherical particle with the size of 46.6nm, polydispersity index of 0.267, entrapment efficiency of 99.74% and with the zeta potential of -23.78mV. Besides, the equivalent cytotoxicity of TAM and TAM-NLC to human (MCF-7) and mice (4T1) mammary breast cancer cell lines were observed. Incubating the formulation at the physiological pH resulted into reduced Ostwald ripening rate but without any significant change in the absorptivity. When coupled with the measurements of zeta potential and Ostwald ripening rate, the absorbance assay may be used to predict the long-term stability of drug-loaded nanoparticle formulations. The results of the study also suggest that TAM-NLC is a promising drug delivery system for breast cancer therapy. This is the first encouraging report on the in vitro effect of TAM-NLC against human and mouse mammary adenocarcinoma cell lines.

Matched MeSH terms: Drug Stability
Synthesis, characterization and physicochemical properties of oleic acid ether derivatives as biolubricant basestocks

Salimon J, Salih N, Yousif E

J Oleo Sci, 2011;60(12):613-8.
PMID: 22123242

Petroleum is a finite source as well as causing several environmental problems. Therefore petroleum needs to be replaced by alternative and sustainable sources. Plant oils and oleochemicals derived from them represent such alternative sources; the use of oleochemicals as biobased lubricants is of significant interest. This article presents a series of chemical modification on oleic acid to yield synthetic biolubricant basestocks. Measuring of density, volatility, cloud point (CP), pour point (PP), flash point (FP), viscosity index (VI), onset temperature (OT) and signal maximum temperature (SMT) was carried out for each compound. Furthermore, the friction and wear properties were measured using high-frequency reciprocating rig (HFRR). The results showed that octadecyl 9-octadecyloxy-10-hydroxyoctadecanoate exhibited the most favorable low-temperature performance (CP %ndash;26°C, PP %ndash;28°C) and the lowest ball wear scan diameter (42 µm) while propyl 9-propyloxy-10-hydroxyoctadecanoate exhibited the higher oxidation stability (OT 156°C).

Matched MeSH terms: Drug Stability
Fulltext Synthesis, antibacterial and thermal studies of cellulose nanocrystal stabilized ZnO-Ag heterostructure nanoparticles

Azizi S, Ahmad MB, Hussein MZ, Ibrahim NA

Molecules, 2013 May 28;18(6):6269-80.
PMID: 23760028 DOI: 10.3390/molecules18066269

Synthesis of ZnO-Ag heterostructure nanoparticles was carried out by a precipitation method with cellulose nanocrystals (CNCs) as a stabilizer for antimicrobial and thermal studies. ZnO-Ag nanoparticles were obtained from various weight percentages of added AgNO₃ relative to Zn precursors for evaluating the best composition with enhanced functional properties. The ZnO-Ag/CNCs samples were characterized systematically by TEM, XRD, UV, TGA and DTG. From the TEM studies we observed that ZnO-Ag heterostructure nanoparticles have spherical shapes with size diameters in a 9-35 nm range. The antibacterial activities of samples were assessed against the bacterial species Salmonella choleraesuis and Staphylococcus aureus. The CNC-stabilized ZnO-Ag exhibited greater bactericidal activity compared to cellulose-free ZnO-Ag heterostructure nanoparticles of the same particle size. The incorporation of ZnO-Ag hetreostructure nanoparticles significantly increased the thermal stability of cellulose nanocrystals.

Matched MeSH terms: Drug Stability
Fulltext Synthesis of silver/montmorillonite nanocomposites using γ-irradiation

Shameli K, Ahmad MB, Yunus WM, Ibrahim NA, Gharayebi Y, Sedaghat S

Int J Nanomedicine, 2010 Dec 01;5:1067-77.
PMID: 21170354 DOI: 10.2147/IJN.S15033

Silver nanoparticles (Ag-NPs) were synthesized into the interlamellar space of montmorillonite (MMT) by using the γ-irradiation technique in the absence of any reducing agent or heat treatment. Silver nitrate and γ-irradiation were used as the silver precursor and physical reducing agent in MMT as a solid support. The MMT was suspended in the aqueous AgNO(3) solution, and after the absorption of silver ions, Ag(+) was reduced using the γ-irradiation technique. The properties of Ag/MMT nanocomposites and the diameters of Ag-NPs were studied as a function of γ-irradiation doses. The interlamellar space limited particle growth (d-spacing [d(s)] = 1.24-1.42 nm); powder X-ray diffraction and transmission electron microscopy (TEM) measurements showed the production of face-centered cubic Ag-NPs with a mean diameter of about 21.57-30.63 nm. Scanning electron microscopy images indicated that there were structure changes between the initial MMT and Ag/MMT nanocomposites under the increased doses of γ-irradiation. Furthermore, energy dispersive X-ray fluorescence spectra for the MMT and Ag/ MMT nanocomposites confirmed the presence of elemental compounds in MMT and Ag-NPs. The results from ultraviolet-visible spectroscopy and TEM demonstrated that increasing the γ-irradiation dose enhanced the concentration of Ag-NPs. In addition, the particle size of the Ag-NPs gradually increased from 1 to 20 kGy. When the γ-irradiation dose increased from 20 to 40 kGy, the particle diameters decreased suddenly as a result of the induced fragmentation of Ag-NPs. Thus, Fourier transform infrared spectroscopy suggested that the interactions between Ag-NPs with the surface of MMT were weak due to the presence of van der Waals interactions. The synthesized Ag/MMT suspension was found to be stable over a long period of time (ie, more than 3 months) without any sign of precipitation.

Matched MeSH terms: Drug Stability
Fulltext Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents

Leong SW, Faudzi SM, Abas F, Aluwi MF, Rullah K, Wai LK, et al.

Molecules, 2014 Oct 09;19(10):16058-81.
PMID: 25302700 DOI: 10.3390/molecules191016058

A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 µM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 µM and 9.6 ± 0.5 µM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.

Matched MeSH terms: Drug Stability
Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability

Petersen AB, Andersen NS, Konotop G, Hanafiah NH, Raab MS, Krämer A, et al.

Eur J Med Chem, 2017 Apr 21;130:240-247.
PMID: 28258034 DOI: 10.1016/j.ejmech.2017.02.055

Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.

Matched MeSH terms: Drug Stability
Fulltext Sustainable drug release from polycaprolactone coated chitin-lignin gel fibrous scaffolds

Abudula T, Gauthaman K, Mostafavi A, Alshahrie A, Salah N, Morganti P, et al.

Sci Rep, 2020 11 24;10(1):20428.
PMID: 33235239 DOI: 10.1038/s41598-020-76971-w

Non-healing wounds have placed an enormous stress on both patients and healthcare systems worldwide. Severe complications induced by these wounds can lead to limb amputation or even death and urgently require more effective treatments. Electrospun scaffolds have great potential for improving wound healing treatments by providing controlled drug delivery. Previously, we developed fibrous scaffolds from complex carbohydrate polymers [i.e. chitin-lignin (CL) gels]. However, their application was limited by solubility and undesirable burst drug release. Here, a coaxial electrospinning is applied to encapsulate the CL gels with polycaprolactone (PCL). Presence of a PCL shell layer thus provides longer shelf-life for the CL gels in a wet environment and sustainable drug release. Antibiotics loaded into core-shell fibrous platform effectively inhibit both gram-positive and -negative bacteria without inducting observable cytotoxicity. Therefore, PCL coated CL fibrous gel platforms appear to be good candidates for controlled drug release based wound dressing applications.

Matched MeSH terms: Drug Stability
Fulltext Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

Edueng K, Mahlin D, Gråsjö J, Nylander O, Thakrani M, Bergström CAS

Molecules, 2019 Jul 27;24(15).
PMID: 31357587 DOI: 10.3390/molecules24152731

This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

Matched MeSH terms: Drug Stability
Successful transfer of plasmid DNA into in vitro cells transfected with an inorganic plasmid-Mg/Al-LDH nanobiocomposite material as a vector for gene expression

Masarudin MJ, Yusoff K, Rahim RA, Hussein MZ

Nanotechnology, 2009 Jan 28;20(4):045602.
PMID: 19417322 DOI: 10.1088/0957-4484/20/4/045602

The delivery of a full plasmid, encoding the green fluorescent protein gene into African monkey kidney (Vero3) cells, was successfully achieved using nanobiocomposites based on layered double hydroxides. This demonstrated the potential of using the system as an alternative DNA delivery vector. Intercalation of the circular plasmid DNA, pEGFP-N2, into Mg/Al-NO(3)(-) layered double hydroxides (LDH) was accomplished through anion exchange routes to form the nanobiocomposite material. The host was previously synthesized at the Mg(2+) to Al(3+) molar ratio R(i) = 2 and subsequently intercalated with plasmid DNA. Size expansion of the interlamellae host from 8.8 A in LDH to 42 A was observed in the resulting nanobiocomposite, indicating stable hybridization of the plasmid DNA. The powder x-ray diffraction (PXRD) results, supplemented with Fourier-transform infrared (FTIR) spectroscopy, compositional and electrophoresis studies confirmed the encapsulation episode of the biomaterial. In order to elucidate the use of this resulting nanobiocomposite as a delivery vector, an MTT assay was performed to determine any cytotoxic effects of the host towards cells. The intercalated pEGFP-N2 anion was later successfully recovered through acidification with HNO(3) after treatment with DNA-degrading enzymes, thus also showing the ability of the LDH host to protect the intercalated biomaterial from degradation. Cell transfection studies on Vero3 cells were then performed, where cells transfected with the nanobiocomposite exhibited fluorescence as early as 12 h post-treatment compared to naked delivery of the plasmid itself.

Matched MeSH terms: Drug Stability

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