Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams.

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Development and Characterization of the Solvent-Assisted Active Loading Technology (SALT) for Liposomal Loading of Poorly Water-Soluble Compounds

Pharmaceutics ◽

10.3390/pharmaceutics11090465 ◽

2019 ◽

Vol 11 (9) ◽

pp. 465 ◽

Cited By ~ 12

Author(s):

Griffin Pauli ◽

Wei-Lun Tang ◽

Shyh-Dar Li

Keyword(s):

Small Volume ◽

Water Solubility ◽

Water Soluble ◽

Drug Solubility ◽

Active Loading ◽

Rapid Loading ◽

Poorly Soluble ◽

Poorly Water Soluble ◽

Formulation Stability

A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. The solvent-assisted active loading technology (SALT) was developed to promote active loading of poorly soluble drugs in the liposomal core to improve the encapsulation efficiency and formulation stability. By adding a small volume (~5 vol%) of a water miscible solvent to the liposomal loading mixture, we achieved complete, rapid loading of a range of poorly soluble compounds and attained a high drug-to-lipid ratio with stable drug retention. This led to improvements in the circulation half-life, tolerability, and efficacy profiles. In this mini-review, we summarize our results from three studies demonstrating that SALT is a robust and versatile platform to improve active loading of poorly water-soluble compounds. We have validated SALT as a tool for improving drug solubility, liposomal loading efficiency and retention, stability, palatability, and pharmacokinetics (PK), while retaining the ability of the compounds to exert pharmacological effects.

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Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles

Pharmaceutics ◽

10.3390/pharmaceutics11090476 ◽

2019 ◽

Vol 11 (9) ◽

pp. 476 ◽

Cited By ~ 1

Author(s):

Pescina ◽

Lucca ◽

Govoni ◽

Padula ◽

Favero ◽

...

Keyword(s):

Polymeric Micelles ◽

Ex Vivo ◽

Water Soluble ◽

Poloxamer 407 ◽

Conjunctival Epithelium ◽

Ocular Delivery ◽

Lipophilic Drugs ◽

Polyethylene Glycol 1000 ◽

The One

This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.

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Soft fluorescent organic nanodots as nanocarriers for porphyrins

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s108842461950158x ◽

2019 ◽

Vol 23 (11n12) ◽

pp. 1463-1469

Author(s):

Isabelle Sasaki ◽

Jonathan Daniel ◽

Sébastien Marais ◽

Jean-Baptiste Verlhac ◽

Michel Vaultier ◽

...

Keyword(s):

Water Solubility ◽

Photophysical Properties ◽

Blue Emission ◽

Soret Band ◽

Water Soluble ◽

Human Neuroblastoma ◽

Organic Nanoparticles ◽

Two Photon Microscopy ◽

Cell Internalization ◽

Fluorescent Organic Nanoparticles

Novel fluorescent organic nanoparticles made from citric acid and diethylenetriamine were used as biocompatible and highly water-soluble nanocarriers for hydrophobic tetraphenylporphyrin (TPP). The tetraphenylporphyrin units were covalently attached to the nanoparticles, generating conjugated nanoparticles which retain water solubility and preserve the photophysical properties of monomeric TPP. The conjugated nanoparticles show two distinct fluorescence features: blue emission from the nanoparticle when excited in the near-UV (360 nm) and characteristic far-red emission of the TPP when excited in the visible (Soret band or Q bands). The uptake of the conjugated nanoparticles in live human neuroblastoma cancer cells was evidenced using two-photon microscopy. These experiments demonstrate that the fluorescent organic nanoparticles do act as efficient nanocarriers, allowing cell internalization of hydrophobic porphyrins. These conjugated nanoparticles appear as promising nanotools for theranostic (based on the combination of imaging and monitoring of the nanoparticle fluorescence) and therapeutic (photodynamic therapy by selectively exciting the grafted porphyrin units) modalities.

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Poly(ethylene glycol)-poly(ε-caprolactone)-based micelles for solubilization and tumor-targeted delivery of silibinin

Bioimpacts ◽

10.34172/bi.2020.11 ◽

2019 ◽

Vol 10 (2) ◽

pp. 87-95 ◽

Cited By ~ 2

Author(s):

Ashkan Hassankhani Rad ◽

Farshid Asiaee ◽

Sevda Jafari ◽

Ali Shayanfar ◽

Afsaneh Lavasanifar ◽

...

Keyword(s):

Ethylene Glycol ◽

Targeted Delivery ◽

Water Solubility ◽

Polymeric Micelles ◽

Inhibitory Effect ◽

Water Soluble ◽

Poly Ethylene Glycol ◽

Poly Ethylene ◽

The One ◽

Dialysis Bag

Introduction: Silibinin is a naturally occurring compound with known positive impacts on prevention and treatment of many types of human illnesses in general and cancer in particular. Silibinin is poorly water soluble which results in its insufficient bioavailability and lack of therapeutic efficacy in cancer. Here, we proposed to examine the potential of micelles composed of poly(ethylene glycol) (PEG) as the hydrophilic block and poly(ε-caprolactone) (PCL), poly(α-benzylcarboxylate-ε-caprolactone) (PBCL), or poly(lactide)-(PBCL) (PLA-PBCL) as hydrophobic blocks for enhancing the water solubility of silibinin and its targeted delivery to tumor. Methods: Co-solvent evaporation method was used to incorporate silibinin into PEG-PCL based micelles. Drug release profiles were assessed using dialysis bag method. MTT assay also was used to analyze functional activity of drug delivery in B16 melanoma cells. Results: Silibinin encapsulated micelles were shown to be less than 60 nm in size. Among different structures under study, the one with PEG-PBCL could incorporate silibinin with the highest encapsulation efficiency being 95.5%, on average. PEG-PBCL micelles could solubilize 1 mg silibinin in 1 mL water while the soluble amount of silibinin was found to be 0.092 mg/mL in the absence of polymeric micelles. PEG-PBCL micelles provided the sustained release of silibinin indicated with less than 30% release of silibinin within 24 hours. Silibinin encapsulated in PEG-PBCL micelles resulted in growth inhibitory effect in B16 cancer cells which was significantly higher than what observed with free drug. Conclusion: Our findings showed that PEG-PBCL micellar nanocarriers can be a useful vehicle for solubilization and targeted delivery of silibinin.

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New Approach for Administration of Doxazosin Mesylate: Comparative Study between Liquid and Solid Self-nanoemulsifying Drug Delivery Systems

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i2.4638 ◽

2021 ◽

Vol 12 (2) ◽

pp. 1095-1101

Author(s):

Al Zahraa G. Al Ashmawy ◽

Noura G. Eissa ◽

Gehan F. Balata ◽

Hanan M. El Nahas

Keyword(s):

Drug Delivery ◽

Oleic Acid ◽

Drug Delivery Systems ◽

Water Solubility ◽

Tween 80 ◽

Delivery Systems ◽

Water Soluble ◽

Dissolution Enhancement ◽

Surfactant Mixture ◽

Doxazosin Mesylate

Self-nanoemulsifying drug delivery systems (SNEDDS) in both liquid and solid forms were suggested to improve water solubility of Doxazosin mesylate (DOX) a poorly water- soluble antihypertensive drug. Oleic acid: Smix (1:9 w/w) and Tween 80: co-surfactant mixture (Ethanol and PEG 400) (1:1, 2:1, 3:1 and 4:1) were chosen to prepare a liquid and solid forms of SNEDDS according to their solubility. TEM images revealed change in the crystalline nature of DOX into uniform particles with smooth surface. Characterization studies revealed droplet size ranges from 79.80±14.39 to 273.10±4.17 nm, zeta potential ranges from -5.57±0.10 to -21.13±0.46 mV and dissolution enhancement of more than two folds with more favorable properties for the solid forms. FTIR demonstrated significant physical changes in DOX crystalline structure. In conclusion, the solid SNEDDS containing oleic acid: Smix (1:9 w/w) and Tween 80: co-surfactant mixture (3:1 w/w) and adsorbent mixture of Avicel 101 and Aerosil 200 (40:1 w/w) might be a promising formula for better management of hypertension with expected shelf stability.

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Biodegradable polysarcosine with inserted alanine residues: Synthesis and enzymolysis

10.33774/chemrxiv-2021-vcfl6 ◽

2021 ◽

Author(s):

Peng Zhou ◽

Jun Ling

Keyword(s):

Ring Opening ◽

Water Solubility ◽

Water Soluble ◽

Random Copolymers ◽

Biodegradation Rate ◽

Pancreatic Elastase ◽

Molecular Weights ◽

Mild Conditions ◽

Protective Shield ◽

The One

Polysarcosine (PSar), a water-soluble polypeptoid, is gifted with biodegradability via random ring-opening copolymerization of sarcosine- and alanine-N-thiocarboxyanhydrides catalyzed by acetic acid in controlled manners. Kinetic investigation reveals the copolymerization behavior of the two monomers. The random copolymers, named PAS, with high molecular weights between 22.0 and 43.6 kg/mol and tunable Ala molar fractions varying from 6% to 43% are able to be degraded by porcine pancreatic elastase within 50 days in mild conditions (pH=8.0 at 37 °C). Both the biodegradation rate and water solubility of PAS depend on the content of Ala residues. PAS with Ala fractions below 43% are soluble in water while the one with 43% Ala self-assembles in water into nanoparticles. Moreover, PAS are non-cytotoxic at the concentration of 5 mg/mL. The biodegradability and biocompatibility endow the Ala-containing PSar with potential to replace PEG as protective shield in drug-delivery.

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BODIPY Fluorophores for Membrane Potential Imaging

10.26434/chemrxiv.8219057.v1 ◽

2019 ◽

Author(s):

Jenna Franke ◽

Benjamin Raliski ◽

Steven Boggess ◽

Divya Natesan ◽

Evan Koretsky ◽

...

Keyword(s):

Mammalian Cells ◽

Water Solubility ◽

Water Soluble ◽

Voltage Sensitivity ◽

Chemical Transformations ◽

Direct Modification ◽

Biological Compatibility ◽

Meso Position ◽

Ionizable Groups ◽

Boron Center

Fluorophores based on the BODIPY scaffold are prized for their tunable excitation and emission profiles, mild syntheses, and biological compatibility. Improving the water-solubility of BODIPY dyes remains an outstanding challenge. The development of water-soluble BODIPY dyes usually involves direct modification of the BODIPY fluorophore core with ionizable groups or substitution at the boron center. While these strategies are effective for the generation of water-soluble fluorophores, they are challenging to implement when developing BODIPY-based indicators: direct modification of BODIPY core can disrupt the electronics of the dye, complicating the design of functional indicators; and substitution at the boron center often renders the resultant BODIPY incompatible with the chemical transformations required to generate fluorescent sensors. In this study, we show that BODIPYs bearing a sulfonated aromatic group at the meso position provide a general solution for water-soluble BODIPYs. We outline the route to a suite of 5 new sulfonated BODIPYs with 2,6-disubstitution patterns spanning a range of electron-donating and -withdrawing propensities. To highlight the utility of these new, sulfonated BODIPYs, we further functionalize them to access 13 new, BODIPY-based voltage-sensitive fluorophores. The most sensitive of these BODIPY VF dyes displays a 48% ΔF/F per 100 mV in mammalian cells. Two additional BODIPY VFs show good voltage sensitivity (≥24% ΔF/F) and excellent brightness in cells. These compounds can report on action potential dynamics in both mammalian neurons and human stem cell-derived cardiomyocytes. Accessing a range of substituents in the context of a water soluble BODIPY fluorophore provides opportunities to tune the electronic properties of water-soluble BODIPY dyes for functional indicators.

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Improving Topical Skin Delivery of Monocrotaline Via Liposome Gel-based Nanosystems

Current Drug Delivery ◽

10.2174/1567201816666191029125300 ◽

2019 ◽

Vol 16 (10) ◽

pp. 940-950 ◽

Cited By ~ 1

Author(s):

Jiandong Yu ◽

Zhi Chen ◽

Yan-zhi Yin ◽

Chaoyuan Tang ◽

Enying Hu ◽

...

Keyword(s):

Gradient Method ◽

Encapsulation Efficiency ◽

Ph Value ◽

Topical Administration ◽

Ph Gradient ◽

Stability Factor ◽

Buffer Solution ◽

Skin Delivery ◽

Skin Retention

Background: In this study, a liposomal gel based on a pH-gradient method was used to increase the skin-layer retention of monocrotaline (MCT) for topical administration. Methods: Using the Box-Behnken design, different formulations were designed to form liposome suspensions with optimal encapsulation efficiency (EE%) and stability factor (KE). In order to keep MCT in liposomes and accumulate in skin slowly and selectively, MCT liposome suspensions were engineered into gels. Results: A pH-gradient method was used to prepare liposome suspensions. The optimal formulation of liposome suspensions (encapsulation efficiency: 83.10 ± 0.21%) was as follows: MCT 12 mg, soybean phosphatidyl choline (sbPC) 200 mg, cholesterol (CH) 41 mg, vitamin E (VE) 5 mg, and citric acid buffer solution (CBS) 4.0 10 mL (pH 7.0). The final formulation of liposomal gels consisted of 32 mL liposome suspensions, 4.76 mL deionized water, 0.40 g Carbopol-940, 1.6 g glycerol, 0.04 g methylparaben, and a suitable amount of triethanolamine for pH value adjustment. The results of in vitro drug release showed that MCT in liposomal gels could be released in 12 h constantly in physiological saline as a Ritger-Peppas model. Compared with plain MCT in gel form, liposomal MCT in gel had higher skin retention in vitro. Conclusion: In this study, liposomal gels were formed for greater skin retention of MCT. It is potentially beneficial for reducing toxicities of MCT by topical administration with liposomal gel.

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Synthesis, Characterization and Bactericidal Activity of a 4-Ammoniumbuthylstyrene-Based Random Copolymer

Polymers ◽

10.3390/polym13071140 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1140

Author(s):

Silvana Alfei ◽

Gabriella Piatti ◽

Debora Caviglia ◽

Anna Maria Schito

Keyword(s):

Antibacterial Activity ◽

Bactericidal Activity ◽

Antimicrobial Agents ◽

Water Solubility ◽

Physicochemical Characterization ◽

Random Copolymer ◽

Water Soluble ◽

Cationic Polymers ◽

Severe Infections

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

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Smart Design Nano-Hybrid Formulations by Machine Learning

Proceedings ◽

10.3390/iecp2020-08700 ◽

2020 ◽

Vol 78 (1) ◽

pp. 5

Author(s):

Raquel de Melo Barbosa ◽

Fabio Fonseca de Oliveira ◽

Gabriel Bezerra Motta Câmara ◽

Tulio Flavio Accioly de Lima e Moura ◽

Fernanda Nervo Raffin ◽

...

Keyword(s):

Machine Learning ◽

Experimental Data ◽

Water Solubility ◽

Inorganic Materials ◽

Fine Tuning ◽

Support Vector ◽

Drug Solubility ◽

Physical Behavior ◽

Best Fit

Nano-hybrid formulations combine organic and inorganic materials in self-assembled platforms for drug delivery. Laponite is a synthetic clay, biocompatible, and a guest of compounds. Poloxamines are amphiphilic four-armed compounds and have pH-sensitive and thermosensitive properties. The association of Laponite and Poloxamine can be used to improve attachment to drugs and to increase the solubility of β-Lapachone (β-Lap). β-Lap has antiviral, antiparasitic, antitumor, and anti-inflammatory properties. However, the low water solubility of β-Lap limits its clinical and medical applications. All samples were prepared by mixing Tetronic 1304 and LAP in a range of 1–20% (w/w) and 0–3% (w/w), respectively. The β-Lap solubility was analyzed by UV-vis spectrophotometry, and physical behavior was evaluated across a range of temperatures. The analysis of data consisted of response surface methodology (RMS), and two kinds of machine learning (ML): multilayer perceptron (MLP) and support vector machine (SVM). The ML techniques, generated from a training process based on experimental data, obtained the best correlation coefficient adjustment for drug solubility and adequate physical classifications of the systems. The SVM method presented the best fit results of β-Lap solubilization. In silico tools promoted fine-tuning, and near-experimental data show β-Lap solubility and classification of physical behavior to be an excellent strategy for use in developing new nano-hybrid platforms.

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