Novel microparticle drug delivery systems based on chitosan and Eudragit(®)RSPM to enhance diltiazem hydrochloride release property

The aim of this study was to enhance the release properties of diltiazem hydrochloride (diltiazem HCl) by using microparticle system. For this reason, microparticle drug delivery systems based on chitosan and Eudragit(?)RSPM were developed. The microparticles were prepared by using double-emulsion solvent extraction method and the mean sizes of microparticles were less than 120?μm. The in vitro drug release from microparticles was studied in simulated gastric (pH 1.2) and intestinal media (pH 7.4) than the results were evaluated by kinetically. In vitro diltiazem HCl release from microparticles showed good zero order kinetic. For the microparticles with chitosan, the release of diltiazem HCl at pH 1.2 could be effectively sustained, while the release of diltiazem HCl increased at pH 7.4 when compared to Eudragit(?)RSPM microparticles. The highest release percent obtained was 1:1 ratio of drug: polymer at pH 1.2 and 7.4. All results clearly suggest that the release properties of diltiazem HCl were improved by using microparticle systems especially which contain chitosan.     

Novel oral dosage regimen based on self-nanoemulsifying drug delivery systems for codelivery of phytochemicals – Curcumin and thymoquinone

BackgroundCurcumin and Thymoquinone are very well-known phytochemicals for their potent anti-inflammatory and anticancer properties. The major challenges for curcumin is its poor aqueous solubility and erratic oral bioavailability.ObjectiveTo develop a novel liquid self-nanoemulsifying drug delivery system (SNEDDS) containing curcumin and thymoquinone and further converted into a solid dosage form using adsorbents Syloid® and Neusilin® as the solid carrier.MethodsThe characterization of the liquid and solid SNEDDS was performed by particle size & zeta potential analysis, scanning electron microscopy, differential scanning calorimetry, fourier transform infrared spectroscopy and X-ray powder diffraction. The drug loading, and in vitro release studies were carried out to investigate the efficiency of curcumin release from SNEDDS.ResultsThe liquid SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. The results of characterization studies showed that solidification using 50% (w/w) Syloid® and Neusilin® in the liquid formulation yield free flowing powder with no agglomeration but Neusilin® produced smooth granules than Syloid® and kept the drugs stable in amorphous state. In vitro dissolution studies indicated that liquid SNEDDS formulations of F4 and its solid SNEDDS using Neusilin® provided high dissolution efficiency and reproducibility for curcumin and thymoquinone. However, Neusilin® showed higher rate of dissolution (more than 65%, p < 0.05) compared to Syloid® for curcumin.ConclusionsCurcumin loaded-SNEDDS formulation containing thymoquinone in liquid & solid dosage forms were successfully developed with an increased drug loading and dissolution rate, which could be the potential combined delivery system for various anti-inflammatory and anti-cancer treatments.     

A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.     

Synthesis and characterization of a new carrier based on Eudragit® EPO/S100 interpolyelectrolyte complex for controlled colon-specific drug delivery

With a view to the development of peroral controlled drug delivery systems, a new interpolyelectrolyte complex (IPEC) between oppositely charged types of Eudragit?, EPO and S100, has been synthesized and investigated at neutral pH values. According to data of turbidimetry, capillary viscometry, gravimetry, and elemental analysis, the obtained IPEC has a composition of Z = [EPO]/[S100] = 1.26. Structural features of the IPEC samples have been evaluated by FTIR spectroscopy and modulated-temperature differential scanning calorimetry. The results confirmed that the IPEC is stabilized by cooperative intermacromolecular ionic bonds, is chemically homogeneous, and is characterized by a single glass transition temperature. The observed features of the carrier swelling and diclofenac sodium release from the matrix system confirm that the proposed IPEC has great potential to be used as a carrier for controlled colon-specific drug delivery.     

Interaction between Eudragit® E100 and anionic drugs: addition of anionic polyelectrolytes and their influence on drug release performance

In this work, we report results concerning the study of solid complexes compounded by a cationic polymethacrylate (Eudragit® E100, Eu) and mesalazine (M) (Eu–M_x complex). The influence of an anionic polyacrylic acid polymer (carbomer, C) on dissolution behavior of M from the complex was evaluated (Eu–M_xC_y complex). The dissolution profiles and solvent front movements of solid matrices in different media (water, buffer pH 7.4, 0.9% NaCl) were investigated and ionic interactions among Eu, M, and C were determined through Fourier transform infrared (FT‐IR) spectroscopy. For Eu–M_x complexes, the affinity between M and Eu modulated the delivery of free M in solution, with the dissolution media affecting the delivery rate mainly due to an ionic interchange process between M and anionic electrolytes (i.e., Cl^?). FTIR spectroscopy allowed the ionic interaction between Eu and M to be verified. The addition of C (Eu–M_xC_y) influenced the dissolution behavior of these matrices. As the amount of C was increased, the release mechanism changed from diffusion (Eu–M₅₀) or anomalous (Eu–M₁₀₀) to zero order (Eu–M_xC₅₀). This variation in rate delivery was also affected by the dissolution media, as occurred with Eu–M_x complexes. The formation of the gel layer during the dissolution process, as consequence of Eu–M_xC_y matrices hydration, was influenced by C amount and dissolution media. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4664–4673, 2011     

Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery

Parenteral sustained release drug formulations, acting as preferable platforms for longterm exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimal...     

Novel GO-COO-β-CD/CA inclusion: its blood compatibility,antibacterial property and drug delivery

Abstract

GO-COO-β-CD/CA inclusion (carboxylated graphene-β-cyclodextrin/chlorhexidine acetate) was fabricated with a graphene-based drug carrier. The reaction time and ratio of carrier to drug were optimized by X-ray diffraction spectra to ensure the complete wrapping of CA. Hemolysis test and recalcification test demonstrated that the inclusion possessed good blood compatibility due to the inherent biocompatibility of β-CD molecules in the carrier. The inclusion displayed excellent inhibition effect on both gram negative bacteria of Escherichia coli and gram positive bacteria of Staphylococcus Aureus, while showing no cytotoxicity. More importantly, the drug efficiency was greatly improved with CA dosage as less as one-third of the pure drug due to the synergistic effect of the drug and carrier. Dynamic simulation implies that the delivery profile of CA from the inclusion is in accordance with the first-order dynamic equation, i.e. ln(1-M_t/M)?=??kt.     

Effect of substitution of plasticizer dibutyl phthalate with dibutyl sebacate on Eudragit® RS30D drug release rate control

In the current study, the influence of type of plasticizer used with Eudragit^® RS 30D on the drug release was investigated in solid dosage form extrusion/spheronization, and film coating. The drug pellets were coated for controlling drug release with Eudragit^® RS 30D containing dibutyl phthalate and compared with dibutyl sebacate as an alternative plasticizer. To study the influence of pH of the dissolution medium on the drug release profile, capsules are tested for drug release profile at pH 1.2, 4.4, and 6.3. Additionally, the aging effect on the curing of Eudragit^® RS 30D is evaluated by exposing the capsules dosage form to room temperature (25?°C?±?2?°C/60%?±?5% RH) for time 0, 3, 6, and 9?months, accelerated temperature (40?°C?±?2?°C/75%?±?5% RH) for time 0, 3, and 6?months, and intermediate temperature (30?°C?±?2?°C/65%?±?5% RH) for time 0, 6, and 9?months. The replacement of dibutyl phthalate, with dibutyl sebacate for polymer coating system in similar concentration is comparable with respect to plasticization effect. The coalescence of the polymer particles is not changed and requires no additional processing parameter control or additional curing time.     

Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design

 The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components).The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor? RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor? RH40 as a reference for formulation developers.     

Influence of polymers ratio on insulin-loaded nanoparticles based on poly-ε-caprolactone and Eudragit® RS for oral administration

Nanoparticles loaded with two different commercial insulins (Actrapid^®, Novorapid^®) and based on different blends of a biodegradable polyester (poly-ε-caprolactone) and a polycationic non-biodegradable acrylic polymer (Eudragit^® RS) were characterized in vitro. The zeta potential was positive whenever Eudragit^® RS was part of the nanoparticles matrix. The encapsulation efficiency was ~ 96% except for Novorapid^®-loaded particles of poly-ε-caprolactone (only 35%). In vitro release studies revealed a burst release from nanoparticles, which may be of interest for oral delivery. Novorapid-loaded nanoparticles were orally administered to diabetic rats and allowed the glycemia to be decreased when compared with free nanoparticles.     

Influence of water soluble additives and HPMCP on drug release from sureleaseê-coated pellets containing tamsulosin hydrochloride

The objective of this study was to investigate the influence of various water-soluble additives and HPMCP as an enteric polymer into Surelease for the developement of oral controlled release system containg tamsulosin hydrochloride. The drug loaded pellets were coated with only Surelease or Surelease containing HPMC, PEG 4000, mannitol and HPMCP (20% w/w). In case of HPMC and PEG 4000 as additives into Surelease film, the rapid drug release was observed in pH 1.2 while the higher drug release was achieved by adding HPMCP into Surelease as well as by increasing the amount of HPMCP (10, 20, and 30% w/w) in pH 7.2. The incorporation of HPMCP into Surelease showed pH-denpendent drug release due to its pH-dependent nature. Therefore, the incorporation of HPMCP into Surelease based on aqueous coating formulation is an effective way to develop oral controlled release delivery systems containing tamsulosin hydrochloride.     

Novel vaginal delivery systems for calcitonin: II. Preparation and characterization of HYAFF® microspheres containing calcitonin

Microspheres prepared from hyaluronan esters (HYAFF®) have been evaluated as a novel delivery system for the vaginal administration of salmon calcitonin (sCT). HYAFF® microspheres containing sCT were prepared by a solvent extraction method. Spherical microspheres of about 10 mm in diameter with smooth surfaces were obtained. An HPLC method was developed for the determination of sCT incorporated into the microspheres. The efficiency of incorporation was high, with approximately 80 to 90% of the peptide recovered by extraction from the microspheres. Quantification of the extracted peptide in vivo confirmed that the biological activity of sCT was unaffected by the microsphere preparation process.     

Preparation and in vitro–in vivo evaluation of Witepsol® H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q10

Coenzyme Q₁₀ (CoQ₁₀) was formulated into self-nanoemulsifying drug delivery systems (SNEDDS) to overcome low bioavailability attributed to hydrophobic nature of the drug. Screening of oil phase, surfactants and co-surfactants were performed to select Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC, respectively. Ternary phase diagrams were drawn to identify nanoemulsifying region followed by optimization of SNEDDS formulation. The optimized formulation, CoQ₁₀, Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC in the weight ratio of 1:0.7:4:2, respectively, emulsified readily at 37 °C with mean emulsion droplet size of 32.4 nm. The stability test of the optimized formulation in pH 1.2 and 6.8 buffers confirmed no pH effect on emulsion droplet size. In vitro dissolution (emulsification) test and in vivo animal study of the formulation elucidated the complete emulsification of drug and improved oral bioavailability of poorly soluble CoQ₁₀.     

Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers

Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin (CPT) in a reductive environment inside cancer cells. The host-guest supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin (mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The guest prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against HeLa cells comparable to the free drug. The host-guest polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.     

Synthesis and physicochemical evaluation of a new carrier based on an interpolyelectrolyte complex formed by Eudragit® EPO and Carbomer 940

The formation of interpolyelectrolyte complexes (IPEC) between Eudragit^? EPO (EPO) and Carbomer 940 (C940) was investigated with a view to their use in peroral controlled-release drug delivery systems. The structure of the synthesized products was investigated using FTIR spectroscopy and MT—DSC methods, which indicated that the synthesized product can be considered to be an IPEC stabilized by a cooperative system of ionic bonds. Based on results of capillary viscosimetry and elemental analysis, the IPEC prepared at pH 4.0 has a characteristic composition with a C940:EPO mole ratio of 1.75:1.     

The road to market implantable drug delivery systems: a review on US FDA’s regulatory framework and quality control requirements

Abstract

The scope of Implantable Drug Delivery Systems (IDDSs) comprehends a variety of sterile therapeutic implements placed inside the body to exert a certain therapeutic action for extended duration. They are classified under different categories from pharmaceutical science and regulatory perspectives. The novelty and variety of IDDSs prevent the application of a uniform regulation for all IDDS products; therefore, sponsors face regulatory challenges to register and market their products. This review investigates pharmaceutical science literature and the United States Food and Drug Administration (US FDA) regulatory guidance to find how any IDDS is classified, regulated, and introduced in the market. The regulatory classification of any IDDS, as a ‘drug’, ‘medical device’ or a ‘combination product’, is the cornerstone in determining the regulatory pathway, which decides the quality control requirements preceding the marketing approval. IDDSs are generally recognized as combination products as they consist of two or more regulated components (drugs, medical devices or biological products) combined prior to use to function as a single entity. Although robust and defined US FDA regulatory pathways exist for each component independent of one another, the regulatory pathways for combination products are less formalized.     

Evaluation of change in the skin concentration of tazarotene and betamethasone dipropionate based on drug–drug interaction for transdermal drug delivery in miniature pig

Abstract

1.?The present study was designed to investigate drug–drug interaction in a new combination cream which contains both tazarotene (TZRT) and betamethasone dipropionate (BTMSDP) by comparing the pharmacokinetic (PK) behaviors of TZRT, BTMSDP, and their major metabolites, tazarotenic acid (TZRTAC) and betamethasone (BTMS) with those in the commonly prescribed TZRT gel and BTMSDP cream.

2.?The trial was performed on six Bama mini-pigs. The different regions on the back side of each pig were randomly assigned to one of three treatment groups: TZRT 0.05% gel, BTMSDP 0.05% cream, and combination cream. The stratum corneum and epidermis–dermis samples were collected at various times after drug administration and analyzed for TZRT, TZRTAC, BTMSDP, and BTMS by LC-MS/MS. Compared with TZRT gel alone, TZRT?+?BTMSDP did not significantly change the PK profiles of TZRT; neither did BTMSDP?+?TZRT significantly change the PK profiles of BTMSDP, compared with the BTMSDP cream alone. In addition, the concentrations of TZRTAC and BTMS in most samples were below the lower limit of quantitation (LLOQ).

3.?The results suggest that there was no significant drug–drug interaction trend between TZRT and BTMSDP in the process of transdermal permeation of combination cream into the stratum corneum and epidermis–dermis of mini-pigs.