CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of As^Ⅲ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate As^Ⅲ in arsenic-nickel complex by nickel acetate gradient method. The As^Ⅲ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release As^Ⅲ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of As^Ⅲ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by ⁶⁰CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’ apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified As^Ⅲ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.     

全反式维甲酸与亚砷酸联合化疗对急性早幼粒细胞白血病高危患者的疗效

目的观察全反式维甲酸(ATRA)与亚砷酸(ATO)联合化疗对急性早幼粒细胞白血病(APL)患者的疗效。方法回顾性分析86例不同危险分级的初治APL患者的临床资料。根据治疗前白细胞和血小板数将APL患者分为低、中、高危三组。采用ATRA+ATO+蒽环类药诱导缓解,蒽环类药+阿糖胞苷巩固治疗,ATRA+ATO+甲氨蝶呤(MTX)[部分加用6-巯基嘌呤(6-MP)]维持治疗。结果治疗后,完全缓解(CR)率高达95.3%(82/86)。中位随访37个月,高危组和中低危组无事件生存率及中枢神经系统累积复发率差异均无统计学意义(P>0.05)。维持治疗单用MTX者或MTX+6-MP者CR率均为100%。结论 APL患者尤其是高危患者可以从ATO+ATRA+化疗中受益;该方案作为初治APL的一线治疗方案优势明显。     

Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.     

Effects of arsenic trioxide, all-trans-retinoic acid and dexamethasone on NB4 cell line

Background and the purpose of the study

Experimental and preclinical observations have indicated that combination therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may strongly enhance their therapeutic effects in the treatment of acute promyelocytic leukemia (APL). Whilst dexamethasone (Dex) is routinely used for the control of APL- differentiation syndrome, its effect on the pharmacodynamics of ATO is not clear. Therefore, in this study, effects of therapeutic concentrations of ATO, ATRA and Dex and their sequential usages on the proliferation, differentiation and apoptosis in t(15;17)-positive NB4 cells was investigated.

Methods

Cells were treated with therapeutic concentrations of ATO, ATRA and Dex either as single or in combination and cell proliferation was assessed by XTT assay. Expression of CD11b as an indicator of cell differentiation and the percentage of 7-AAD positive cells as a marker of apoptosis were determined by flow cytometry.

Results

ATO, but not ATRA and Dex, decreased proliferation of the cells dose-dependently. Pre-treatment of the cells with any of the drugs did not alter the effects of other drugs on the proliferation. Pre-treatments with Dex blocked the apoptotic effect of ATO (1 µM).

Conclusion

No improvement or antagonistic effects was observed with the pretreatment/ combination of the ATO and ATRA on the differentiation and apoptosis of the cells. It is possible that concomitant usage of Dex with apoptotic doses of ATO in APL patients counteract therapeutic effects of ATO.     

Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease

INTRODUCTION: Acute promyelocytic leukemia (APL), the most rapidly fatal leukemia only two decades ago, has been converted into the most frequently curable leukemia by the advent of all-trans retinoic acid (ATRA) and its combination with anthracycline-based chemotherapy. More recently, arsenic trioxide (ATO) has been shown to be the most effective single agent in this disease and has been approved for the treatment of relapsed patients both in the United States and Europe. Moreover, ATO has been included in the design of several front-line studies, with the aim to reduce therapy-related toxicity while maintaining the potential of cure. AREAS COVERED: First, this review briefly discusses the mechanisms of action and the toxicity profile of ATO. Furthermore, the reported experience on the use of ATO as single agent or in combinatorial schemes both in relapsed and in newly diagnosed patients with APL is critically reviewed. Finally, the use of this agent in special subsets of patients unfit to receive conventional chemotherapy is discussed, along with its potential role in maintenance therapy. EXPERT OPINION: While the role of ATO as single agent or in combination with ATRA is well established and recommended by the European LeukemiaNet guidelines as a first option for relapsed patients, the role of the drug in newly diagnosed patients is still uncertain and based only on evidence levels mostly originating from non-randomized trials. The results of ongoing randomized studies should better define the role of ATO in front-line therapy.     

Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-β1 expression

Arsenic trioxide (As₂O₃; ATO) is clinically effective in treating acute promyelocytic leukemia (APL); however, it frequently causes cardiotoxic effects. This study was designed to investigate whether ATO could induce apoptosis of cardiac fibroblasts (CFs) that play very important roles in maintaining the structure integrity and function of the heart. Cardiac fibroblasts from guinea pigs administered with ATO (1 mg/kg bw) were used to test the pro-apoptotic role of ATO in vivo. The current study demonstrated that ATO induced morphological characteristics of apoptosis and Caspase-3 activation in CFs of guinea pigs along with a significant up-regulation in TGF-β1 protein expression, Bax/Bcl-2 ratio and ERK1/2 phosphorylation. In vitro MTT assay showed that ATO remarkably reduced the viability of cultured cardiac fibroblasts (NRCFs) from neonatal rat in a concentration- and time-dependent manner. Consistent with the notions in vivo, ATO significantly induced the apoptosis in NRCFs, dramatically up-regulated TGF-β1 protein level and Bax/Bcl-2 ratio in a time-dependent fashion and activated Caspase-3 and ERK1/2. Finally, pretreatment with LY364947, an inhibitor of TGF-β signaling could apparently reverse these changes. We therefore conclude that TGF-β is functionally linked to ERK1/2 and that TGF-β signaling is responsible for ATO-induced CFs apoptosis, which provides a novel mechanism of ATO related cardiac toxicology.     

亚砷酸持续输注联合小剂量维A酸治疗急性早幼粒细胞性白血病临床观察

目的 探讨亚砷酸（ATO）持续输注联合小剂量维A酸（LD—ATRA）治疗急性早幼粒细胞白血病（APL）的有效性及安全性。方法6例初治APL采用ATO持续输注联合LD—ATRA方法治疗,ATO按10mg·d^-1加入5％葡萄糖500ml稀释,持续输注18h;ATRA按15mg·d^-1,连续口服1周：观察疗效、外周WBC、出凝血指标及不良反应？结果6例均达到CR,获CR时间为（25．3±1．03）d,无早期死亡与CNS—L发生。所有病例在治疗1周后,出凝血指标均恢复正常。外周血WBC均有增多,仅1例WBC超过30×10^9／L。不良反应轻,主要为Ⅰ～Ⅱ度肝功能损害,Ⅰ度恶心呕吐。结论ATO持续输注联合LD—ATRA方法治疗APL,具有疗效好,不良反应轻等优点,值得进一步研究.     

Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease

Introduction: Acute promyelocytic leukemia (APL), the most rapidly fatal leukemia only two decades ago, has been converted into the most frequently curable leukemia by the advent of all-trans retinoic acid (ATRA) and its combination with anthracycline-based chemotherapy. More recently, arsenic trioxide (ATO) has been shown to be the most effective single agent in this disease and has been approved for the treatment of relapsed patients both in the United States and Europe. Moreover, ATO has been included in the design of several front-line studies, with the aim to reduce therapy-related toxicity while maintaining the potential of cure.

Areas covered: First, this review briefly discusses the mechanisms of action and the toxicity profile of ATO. Furthermore, the reported experience on the use of ATO as single agent or in combinatorial schemes both in relapsed and in newly diagnosed patients with APL is critically reviewed. Finally, the use of this agent in special subsets of patients unfit to receive conventional chemotherapy is discussed, along with its potential role in maintenance therapy.

Expert opinion: While the role of ATO as single agent or in combination with ATRA is well established and recommended by the European LeukemiaNet guidelines as a first option for relapsed patients, the role of the drug in newly diagnosed patients is still uncertain and based only on evidence levels mostly originating from non-randomized trials. The results of ongoing randomized studies should better define the role of ATO in front-line therapy.     

Tamibarotene

Tamibarotene is a new synthetic retinoid drug recently approved for relapsed or refractory acute promyelocytic leukemia (APL) in Japan. It is a specific agonist for retinoic acid receptor alpha/beta. Compared to all-trans retinoic acid (ATRA), a natural retinoid indicated for a first-line treatment of APL, tamibarotene is chemically more stable and several times more potent as an inducer of differentiation in promyelocytic leukemia cells. In contrast to ATRA, whose plasma concentration declines considerably during daily administration, tamibarotene sustains plasma level probably due to a lower affinity for cellular retinoic acid binding protein. Furthermore, adverse side effects were milder than those of ATRA in clinical trials. Clinical trials held in Japan showed that tamibarotene had efficacy in APL patients who had relapsed from ATRA-induced complete remission. Recently, better understanding of the various mechanisms of action of retinoids has stimulated great interest in its potential use for treatment of various diseases. Tamibarotene is being investigated for treatment of multiple myeloma and Crohn's disease in clinical trials. This review focuses on tamibarotene's mechanisms of action, chemical properties, pharmacokinetics and its use in APL as well as its potential use in various disorders.     

Biotransformation of arsenic trioxide by AS3MT favors eradication of acute promyelocytic leukemia: revealing the hidden facts

Abstract

Arsenic trioxide (ATO) is one of the most effective drugs for treatment of acute promyelocytic leukemia (APL). It could specifically target the PML/RARα fusion oncoprotein stability and induces APL cell differentiation as well as apoptosis. Although many studies have been conducted to document the anticancer effects and mechanism of ATO, there is little information about the association between biotransformation of ATO to active arsenic metabolites and APL therapy. Generally, ATO can be rapidly converted into trivalent methylated metabolites by arsenic (+3 oxidation state) methyltransferase (AS3MT) mostly in liver and redistributed to bloodstream of APL patients who receiving ATO treatment, thereby leading to a balance between cytotoxicity and differentiation, which is proposed to be the key event in successful treatment of APL. In this review, we comprehensively discussed possible roles of AS3MT and methylated arsenic metabolites in APL therapy, so as to reveal the association between individual differences of AS3MT expression and activity with the therapeutic efficacy of ATO in APL patients.     

The combination of MnO2@Lipo-coated gefitinib and bevacizumab inhibits the development of non-small cell lung cancer

It can be found from a large number of cancer treatments that use of anti-cancer drugs alone often presents low efficacy and high side effects. This study aims to develop a new drug carrier with tumor-specific response, controlled release in vivo and high tumor-suppressive property. Inorganic nano-materials MnO₂ with pH and glutathione (GSH, abundant in cancer cells) responsiveness were used to construct sustained-release functional nano-liposome to be an excellent in vivo pH-sensitive drug delivery system. Some hydrophilic MnO₂, gefitinib (Geb), and bevacizumab (Beb) were encapsulated in the phospholipid vesicles (liposomes), so as to integrate several anti-tumor drugs (MnO₂-PDA@Lipo@Geb@Beb) to achieve effective treatment of non-small cell lung cancer (NSCLC). Part of the MnO₂ nanorods on the lipid shell had the properties of pH and GSH responsiveness, which could further enhance anti-cancer efficacy. Cell assay results showed that MnO₂-PDA@Lipo@Geb@Beb nano-drug had an effective inhibition on A549 cell progression and showed excellent biocompatibility. In vivo results further confirmed that MnO₂-PDA@Lipo@Geb@Beb nano-drug could effectively inhibit the growth of NSCLC cells. Overall, it can be inferred from the above experimental results that the nanocomposite drug is expected to be widely used in the clinical application of lung cancer.     

Gastroretentive Cosolvent-Based In Situ Gel as a Promising Approach for Simultaneous Extended Delivery and Enhanced Bioavailability of Mitiglinide Calcium

Ion cross-linking in situ gels are novel liquid sustained-release drug delivery systems. These systems are unsuitable for poorly water-soluble drugs such as the novel antidiabetic drug mitiglinide calcium (MTG). Thus, our goal was to assess the possibility of using cosolvency approach in formulating gastroretentive in situ gel of the short half-life MTG to simultaneously enhance its bioavailability and sustain its release. MTG in situ gel formulations were developed using propylene glycol as a cosolvent to dissolve MTG in the polymer solution, followed by characterization of viscosity, gel strength, floating ability, and in vitro MTG release and phramacokinetics evaluation. The optimized formulation (composition: 1% gellan gum, 0.75% sodium alginate, 0.75% calcium carbonate, and 7.5% propylene glycol) exhibited reasonable viscosity but on introduction into simulated gastric fluid, it formed firm gel that floated within seconds over the surface and remained buoyant for 24 h. The formula exhibited in vivo sustained release manner of MTG over 24 h and improved the bioavailability of the drug. Thus, cosolvency presents a promising approach to deliver hydrophobic drugs in sustained-release liquid formulations. These formulations will improve diabetic patients' compliance by eliminating the necessity of frequent dosing with a better disease management.     

Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes

Purpose: Topical administration is the preferred route of drug delivery for ophthalmic ailments. However, poor permeation through ocular surface and significant systemic absorption, makes the topical drug delivery challenging. Furthermore, distribution of topically delivered drugs varies with their physicochemical properties and the type of formulation used. Hence, this study was done to understand the pattern of ocular drug distribution of topically applied hydrophilic and lipophilic substances in two different formulations.

Methods: 5-Carboxyfluorescein and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate were used as representative candidates for hydrophilic and lipophilic substances, respectively. They were formulated in solution and liposomes. Single drop of either formulation containing hydrophilic or lipophilic substance was instilled topically, unilaterally to rat eyes. Subsequently, rats were sacrificed at 10, 30 and 120?min post-instillation. Eyes were cryosectioned and examined under confocal microscope to determine the fluorescence intensity in ocular tissues.

Results: Corneal permeation of hydrophilic and lipophilic substances in both formulations peaked at 30?min post-instillation. Liposomal–lipophilic dye and non-liposomal–hydrophilic dye showed better corneal distribution. Fluorescence was absent in contralateral eyes of non-liposomal–hydrophilic dye-treated animals but was present in contralateral eyes of liposomal–hydrophilic dye-treated animals. Fluorescence in contralateral eyes of liposomal–lipophilic dye-treated animals was significantly higher compared to non-liposomal–lipophilic dye-treated animals.

Conclusions: Topically applied liposomal formulation of lipophilic substance provides higher corneal concentration of drug with lesser systemic absorption compared to its solution. For hydrophilic substance, topical use of solution provides greater corneal concentration compared to liposomes which is more likely to be absorbed systemically.     

Biodistribution characteristics of all-trans retinoic acid incorporated in liposomes and polymeric micelles following intravenous administration

The aim of this study was to investigate the biodistribution characteristics of all-trans retinoic acid (ATRA) incorporated in liposomes and polymeric micelles following intravenous administration. [3H] ATRA were incorporated in distearoylphosphatidylcholine (DSPC)/cholesterol (6:4) liposomes. Two types of block copolymers, poly (ethylene glycol)-b-poly-(aspartic acid) derivatives with benzyl (Bz-75) groups, were synthesized to prepare the polymeric micelles for [(3)H]ATRA incorporation. ATRA were dissolved in mouse serum to analyze their inherent distribution. After intravenous administration, the blood concentration of [3H] ATRA in liposomes and polymeric micelles (Bz-75) was higher than that of inherent [3H]ATRA, suggesting that liposomes and polymeric micelles (Bz-75) control the distribution of ATRA. Pharmacokinetic analysis demonstrated that [3H]ATRA incorporated in polymeric micelles (Bz-75) exhibit the largest AUC(blood) and lowest hepatic clearance of ATRA, suggesting that polymeric micelles (Bz-75) are an effective ATRA carrier system for acute promyelocytic leukemia (APL) therapy. These results have potential implications for the design of ATRA carriers for APL patients.     

Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs

The purpose of this work was to improve the oral bioavailability of poorly soluble drugs by incorporation into solid lipid nanoparticles (SLNs). All-trans retinoic acid (ATRA) was used as a poorly soluble model drug. Different formulations of SLNs loaded with ATRA were successfully prepared by a high-pressure homogenization method and using Compritol 888 ATO as lipid matrix. The particle size and distribution, drug loading capacity, drug entrapment efficiency (EE %), zeta potential, and long-term physical stability of the SLNs were investigated in detail. Drug release from two sorts of ATRA-SLN was studied and compared with the diffusion from ATRA solution in 0.1 M HCl, distilled water and phosphate buffer (pH 7.40), using a dialysis bag method. A pharmacokinetic study was conducted in male rats after oral administration of 8 mg kg(-1) ATRA in different formulations and it was found that the relative bioavailability of ATRA in SLNs was significantly increased compared with that of an ATRA solution. The amount of surfactant also had a marked effect on the oral absorption of ATRA with SLN formulations. Although an emulsion formulation also increased ATRA absorption, it was too unstable for use in clinical situations. The absorption mechanism of the SLN formulations was discussed. These results indicate that ATRA absorption is enhanced significantly by employing SLN formulations. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.     

Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro–in silico approach

Abstract

Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro–in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro–in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.     

Succinylated whey protein isolate as a sustained-release excipient of puerarin derivative oral tablets: Preparation,optimization and pharmacokinetics

This work was done to investigate succinylated commercial whey protein isolate (S-WPI) as an oral sustained-release delivery carrier for puerarin 5 (PR-5). The succinylation conditions were established for S-WPIs by optimization of single factor study and Box–Beehnken design. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochemical properties of S-WPIs dried by different three methods on their flow ability, particle size, morphology and in vitro release behavior were studied. After preparing PR-5 sustained release protein tablets with S-WPIs as the carrier by direct powder compression method, the drug release were studied in vitro and the oral pharmacokinetics and bioavailability was evaluated using in vivo dog model. It was observed that concentration of substrate has a significant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with 100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism (protein loss). Compared with PR-5 conventional tablet with oral administration, T_max value of PR-5 sustained-release protein tablets was approximately 1.58 fold greater than those of the conventional tablets as further evidenced by the significantly prolonged MRT and T_1/2. The findings demonstrated that spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability.     

Critical Factors Influencing the In Vivo Performance of Long-acting Lipophilic Solutions—Impact on In Vitro Release Method Design

Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the “state” of sink condition, the stirring conditions, and the oil–water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.     

Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing Precirol ATO 5

Lipid excipients are usually used for the development of sustained-release formulations. When used in relatively high quantities, Precirol ATO 5 imparts sustained-release properties to solid oral dosage forms, by forming a lipid matrix. To control or adjust the drug release kinetics from such lipid matrix however, one must often resort to complementary ingredients or techniques. This study investigates the influence of poloxamers (Lutrol) included in lipid matrices composed of glyceryl palmitostearate (Precirol ATO 5) on their dissolution performance and their stability. The addition of these hydrophilic polymers in the lipid matrix increased the amount of theophylline released thanks to the swelling of the hydrophilic polymer and the creation of a porous network into the inert lipid matrix. The grade and the quantity of Lutrol could modulate the extent of drug release. Theophylline was released mainly by the matrix erosion but also by diffusion through the pores as suggested by the Peppas' model. Moreover, the addition of Lutrol enhanced the stability during storage. The theophylline release was quite steady after 6 months in different conditions (temperature and humidity). Thus, the mixture of glyceryl palmitostearate and poloxamers is an approach with many advantages for the development of controlled-release formulations by capsule molding.