Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

Purpose: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.

Methods: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5?mg TS?g^?1. Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24?h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.

Results: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7–95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM?<?5% GD?<?5% SA?<?5% GB?<?2.5% GM?<?2.5% SA?<?10% GD?<?10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB–2.5?mg TS?g^?1 SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB–2.5?mg TS?g^?1 stored at 5°C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.

Conclusions: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride

Abstract

The low encapsulation efficiency of conventional solid lipid microparticles (SLMs) especially for hydrophilic drugs has remained a challenge to drug formulation experts. This work seeks to address the issue of inefficient delivery of metformin hydrochloride (MTH), a potent hydrophilic oral antihyperglycemic agent, using novel SLMs based on solidified reverse micellar solutions (SRMS) prepared by melt-emulsification using a lipid derived from Capra hircus and Phospholipon® 90H. Characterization based on size, morphology, zeta potential, polydispersity index, encapsulation efficiency (EE%), loading capacity (LC) and time-resolved stability were carried out on the SLMs. The in vitro release of MTH from the SLMs was performed in phosphate buffer (pH 7.4) while the in vivo antidiabetic properties were investigated in alloxan-induced diabetic rats. Stable, spherical and smooth SLMs were obtained. Loading of MTH into the SLMs had no effect on the surface charge of the particles. The SLMs with 1.0%w/w PEG 4000 resulted in significantly (p?<?0.05) higher EE% while those with 2.0%w/w gave the least. The LC values ranged from 20.3 to 29.1 and 14.6 to 24.1 for SLMs containing 500?mg and 250?mg of MTH, respectively. The in vitro release studies revealed significant release of MTH from the SLMs whereas the in vivo antidiabetic studies indicated that novel SLMs containing 500?mg of MTH gave significantly (p?<?0.05) higher glucose reduction than glucophage®. This research has shown that SLMs based on SRMS offer a new and better approach of delivering MTH, thus encouraging further development of this formulation.     

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery,characterization and in vitro deposition study

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20?μm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40?μM of resveratrol.     

Preparation of novel solid lipid microparticles loaded with gentamicin and its evaluation in vitro and in vivo

Objective: To formulate and evaluate solid-reversed-micellar-solution (SRMS)-based solid lipid microparticles (SLMs) for intramuscular administration of gentamicin.

Methods: SRMS formulated with Phospholipon® 90G and Softisan® 154 were used to prepare gentamicin-loaded SLMs. Characterizations based on size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release of gentamicin from the SLMs was performed in phosphate buffer while in vivo release studies were conducted in rats.

Results: Maximum EE% of 90.0, 91.6 and 83.0% were obtained for SLMs formed with SRMS 1:1, 1:2 and 2:1, respectively. Stable, spherical and smooth SLMs of size range 9.80?±?1.46?µm to 33.30?±?6.42?µm were produced. The release of gentamicin in phosphate buffer varied widely with the lipid contents. Moreover, significant (p?<?0.05) amount of gentamicin was released in vivo from the SLMs.

Conclusion: SRMS-based SLMs would likely offer a reliable means of delivering gentamicin intramuscularly.     

Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development,in-vitro and in-vivo clinical evaluation

Objective: To formulate solid lipid microparticles (SLMs) encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) for the treatment of periodontal diseases.

Methods: SLMs were prepared applying hot homogenization method, using different types of lipids and stabilized with various types and concentrations of surfactants. The optimized formula was subjected to freeze-drying followed by incorporation into poloxamer gel. Microbiological and clinical evaluation of the selected SLMs on patients suffering from periodontal diseases was performed.

Results: SLMs could entrap high percentage of both drugs (81.14% and 68.75 % for doxycycline hydrochloride and metronidazole respectively). Transmission electron microscopy images of SLMs showed nearly spherical particles. Freeze-dried SLMs showed satisfactory stability for three months. Combined drugs were molecularly dispersed in SLMs. Incorporation of the freeze-dried SLMs powder in poloxamer gel could control the drugs release for 72 h. In-vivo study revealed effective and safe use of SLMs gel for periodontitis treatment. Significant improvement in both microbiological and clinical parameters was observed as compared to scaling and root planing alone.

Conclusion: The formulated SLMs gel offers an applicable dosage form that can be injected directly into the periodontal pocket as adjunctive to scaling and root planing.     

Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate

Objectives The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs). Methods Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5: 1, 10: 1 and 12.5: 1 lipid: drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex‐vivo drug permeation tests using porcine epidermis. Key findings SLMs had particle sizes of 18–45 μm, while SLNs showed a mean diameter of 130–270 nm. The encapsulation efficiency was 80–100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid. Conclusions The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.     

Design,in vitro and in vivo evaluation of glipizide Eudragit microparticles

Glipizide microparticles made with Eudragit (RS 100 and RL 100), prepared by emulsion solvent evaporation technique were evaluated for various in-vitro properties viz. encapsulation efficiency, particle size and surface morphology, drug release pattern and in-vivo hypoglycaemic activity. The optimized formulation parameters were used to prepare smooth and spherical microparticles (2–32 µm) with higher entrapment efficiency (67–89%). Drug release patterns of glipizide microparticles of Eudragit RS 100 and Eudragit RL 100 with drug-to-polymer ratio of 1 : 4 (i.e. EGM14 and ELGM14) have shown gradual and extended release for 24 h with cumulative release of glipizide to the extent of 72.3% and 83.9%, respectively. However, EGM14 showed a significant in-vivo hypoglycaemic effect up to 12 h in rabbits while ELGM14 showed for 9 h. Hence, glipizide microparticles of Eudragit RS 100 (glipizide: polymer 1 : 4) is better suited for oral sustained release formulation.     

Formulation and evaluation of verapamil hydrochloride loaded solid lipid microparticles

The present study aimed to produce verapamil hydrochloride-loaded solid lipid microparticles (SLM) by the w/o/w emulsion solvent evaporation technique, using diethyl ether as solvent phase, glyceryl monostearate as biodegradable polymer and Span 60 as surfactant. SLM of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogenizer was used. The encapsulation efficiency of prepared SLM reached 74.29 +/- 0.76%. Particle size (98.55 +/- 1.42 microm), surface morphology (spherical) and drug loading efficiency (18.57 +/- 1.25% w/w) were investigated. And optimization of drug polymer ratio (3:1), nature and concentration of emulsion stabilizer in the external aqueous (0.1%), phase viscosity of external aqueous phase (0.5%), volume of external aqueous phase and stirring rate (1000 rpm) were detected. Analysis of microsphere content after processing showed that verapamil did not undergo any chemical modification within the micro-particles. The in-vitro release of verapamil from the microparticles was very low and an initial burst effect of 17% of the dose was observed. The slow release may help to avoid a high frequency of administration. The prepared solid lipid microparticles appear to have interesting perspectives as delivery systems for the oral administration of verapamil hydrochloride with improved half-life, improved bioavailability, and minimized local and systemic gastrointestinal disturbances of the drug.     

Solid lipid microparticles: formulation,preparation, characterisation,drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The invitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary invivo aspects (invivo drug release studies, b-iocompatibility studies and invivo fate) are also considered.     

Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation

This work aimed to develop a sustained release solid dispersion of ivermectin (IVM-SD) in a lipid matrix (hydrogenated castor oil, HCO) for subcutaneous delivery. Solvent-melting technology was employed to prepare IVM-SDs using HCO. The physicochemical properties of the IVM-SDs were evaluated by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). The release of IVM from IVM-SDs was evaluated with HPLC in vitro. Pharmacokinetics of IVM was studied in rabbits following a single subcutaneous administration of IVM-SD formulations. The efficacy of IVM-SD against the ear mange mite was evaluated in rabbits. IVM was completely dispersed in HCO in an amorphous state at a drug:carrier ratio lower than 1:3. No chemical interactions between drug and carrier were found besides hydrogen bonding for the amorphous IVM-SDs. The amorphous IVM-SDs formulations exhibited a sustained release of IVM versus physical mixtures (PMs) of IVM and HCO. The drug release decreased as the drug:carrier ratios decreased, and the release kinetics of IVM were controlled via diffusion. Cytotoxicity of IVM-SD to MDCK cells was lower than native IVM. The IVM plasma concentration of SD1:3 remained above 1?ng/mL for 49 d. Higher AUC, MRT, and T_max values were obtained at a SD1:3 relative to the IVM group. The IVM-SD improved almost 1.1-fold bioavailability of drug compared with IVM in rabbits. IVM-SD could provide longer persistence against rabbit’s ear mites than a commercial IVM injection. This study shows that these solid lipid dispersions are a promising approach for the development of subcutaneous IVM formulations.     

The effects of cryoprotectants on the freeze-drying of ibuprofen-loaded solid lipid microparticles (SLM)

The effects of cryoprotectants on the diameter and the entrapment efficiency of ibuprofen-loaded solid lipid microparticles (SLM) during the freeze-drying process were investigated extensively. The SLM were prepared by the emulsion-congealing technique in which a glycerol behenate was used as the lipid matrix for the SLM and a soybean lecithin/bile salt used as the stabilizer. Also, trehalose, glucose, mannitol, and sucrose were chosen as the cryoprotectants. Trehalose and glucose proved to be the most effective in preventing particles aggregation and in inhibiting leakage from drug-loaded particles during the SLM freeze-drying process. The most suitable concentrations were proved to be 15% and 5% (wt), respectively.     

In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles

Abstract

The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid:triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180?nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0–5000?µg/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD₅₀) values for A549 cells and PCLS were found to be in the range of 1200–1900?µg/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800?µg/ml. PCHS showed slightly higher LD₅₀ values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.     

Formulation of acyclovir-loaded solid lipid nanoparticles: design,optimization, and in-vitro characterization

The goal of this study was to design, optimize, and characterize Acyclovir-loaded solid lipid nanoparticles (ACV-SLNs) concerning particle size, zeta potential, entrapment efficiency, and release profile. Full factorial design (2³) was applied and the independent variables were surfactant type (Tween 80 and Pluronic F68), lipid type (Stearic acid and Compritol 888 ATO), and co-surfactant type (Lecithin and Sodium deoxycholate). The microemulsion technique was used followed by ultrasonication. The ACV-SLNs had a particle size range of about 172–542?nm. The polydispersity index (PDI) was found to be between 0.193 and 0.526. Zeta potential was in the range of –25.7 to –41.6?mV indicating good physical stability. Entrapment efficiency values were in the range of 56.3–80.7%. The drug release kinetics of the prepared formulations was best fitted to Higuchi diffusion model. After storing ACV-SLNs at refrigerated condition (5?±?3?°C) and room temperature (25?±?2?°C) for 4 weeks; we studied the change in the particle size, PDI, and zeta potential. The selected optimized formulation (F4) was containing Compritol, Pluronic F68, and Lecithin. These results indicated the successful application of this design to optimize the ACV-SLNs as a promising delivery system.     

Formulation of novel sustained release rifampicin-loaded solid lipid microparticles based on structured lipid matrices from Moringa oleifera

Abstract

Objectives: To formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G).

Methods: Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized in terms of particle morphology and size, percentage drug content (PDC), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats.

Results: Rifampicin-loaded SLMs had particle size range of 32.50?±?2.10 to 34.0?±?8.40?μm, highest PDC of 87.6% and showed stable pH. SLMs had good sustained release properties with about 77.1% release at 12?h in phosphate buffer (pH 6.8) and 80.3% drug release at 12?h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51% degradation of rifampicin in SGF at 3?h, while rifampicin pure sample had 95.5% degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5?μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p?<?0.05).

Conclusion: Rifampicin-loaded SLMs could be used once daily for the treatment tuberculosis.     

Novel formulation of solid lipid microparticles of curcumin for anti‐angiogenic and anti‐inflammatory activity for optimization of therapy of inflammatory bowel disease

Objectives This project was undertaken with a view to optimize the treatment of inflammatory bowel disease through a novel drug delivery approach for localized treatment in the colon. Curcumin has poor aqueous solubility, poor stability in the gastrointestinal tract and poor bioavailability. The purpose of the study was to prepare and evaluate the anti‐inflammatory activity of solid lipid microparticles (SLMs) of curcumin for the treatment of inflammatory bowel disease in a colitis‐induced rat model by a colon‐specific delivery approach. Methods We have developed a novel formulation approach for treating experimental colitis in the rat model. SLMs of curcumin were prepared with various lipids, such as palmitic acid, stearic acid and soya lecithin, with an optimized percentage of poloxamer 188. The SLMs of curcumin were characterized for particle size, drug content, drug entrapment, in‐vitro release, surface morphology and infrared, differential scanning calorimetry and X‐ray studies. The colonic delivery system of SLM formulations of curcumin were further investigated for their anti‐angiogenic and anti‐inflammatory activity using chick embryo and rat colitis models. Key findings Particle size, drug content, drug entrapment and in‐vitro release studies showed that formulation F4 containing one part stearic acid and 0.5% surfactant had the smallest diameter of 108 μm, 79.24% entrapment and exhibited excellent in‐vitro release characteristics when compared with other formulations and pure curcumin. SLMs of curcumin (F4) proved to be a potent angio‐inhibitory compound, as demonstrated by inhibition of angiogenesis in the chorioallantoic membrane assay. Rats treated with curcumin and its SLM complex showed a faster weight gain compared with dextran sulfate solution (DSS) control rats. The increase in whole colon length appeared to be significantly greater in SLM‐treated rats when compared with pure curcumin and DSS control rats. An additional finding in the DSS‐treated rats was chronic cell infiltration with predominance of eosinophils. Decreased mast cell numbers in the mucosa of the colon of SLMs of curcumin and pure curcumin‐treated rats was observed. Conclusions The degree of colitis caused by administration of DSS was significantly attenuated by colonic delivery of SLMs of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for inflammatory bowel disease patients.     

Preparation,characterization, and in vivo study of rhein solid lipid nanoparticles for oral delivery

In this study, rhein‐SLN s were successfully produced by hot homogenization followed by ultrasonication. Precirol ATO 5 in which rhein exhibited higher partition coefficient was selected for preparation of SLN s. In the dynamic light scattering, the rhein‐SLN s showed a smaller size with a mean value of 120.8 ± 7.9 nm and with zeta potential of ?16.9 ± 2.3 mV. SLN s exhibited a good stability during the period of 2 months. The SLN s indicated faster drug release with a burst release within 2 hr and followed by a sustained release with a biphasic drug‐release pattern. Comparing with the same concentration (free drug), the cellular cytotoxicity of rhein‐loaded SLN s increased significantly at the same incubation condition. In vivo, the AUC _0‐t of rhein in the form of SLN s was significantly increased and was 2.06‐fold that of suspensions group. The results showed an increased oral absorption and improved the oral bioavailability of rhein by the formulation of SLN s.     

Anti-lung cancer effect of paclitaxel solid lipid nanoparticles delivery system with curcumin as co-loading partner in vitro and in vivo

The main aim of this study was to improve the therapeutic potential of a paclitaxel (PTX) and curcumin (CU) combination regimen using solid lipid nanoparticles (SLNs). PTX and CU were successfully co-encapsulated at a predetermined ratio in SLNs (PC-SLNs) with high encapsulation efficiency (CU: 97.6%, PTX: 95.8%), appropriate particle size (121.8 ± 1.69 nm), small PDI (0.267 ± 0.023), and negative zeta potential (–30.4 ± 1.25 mV). Compared with PTX or the combination of CU and PTX (CU + PTX), PC-SLNs can greatly reduce the dose of PTX while still achieving the same therapeutic effect on four cancer cell lines, among which the inhibitory effect on A549 lung cancer cells was the strongest. PC-SLNs improved the area under the curve (CU: 1.40-fold; PTX: 2.88-fold), prolonged the residence time (CU: 6.94-fold; PTX: 2.51-fold), and increased the half-life (CU: 5.62-fold; PTX: 6.46-fold), achieving long circulation. PC-SLNs were used to treat lung cancer in a nude mouse xenograft tumor model and the tumor suppression rate reached 78.42%, while those of PTX and (CU + PTX) were 40.53% and 51.56%, respectively. As PC-SLNs can prevent P-glycoprotein efflux, reverse MDR and downregulate the NF-κB pathway. PC-SLNs are a potential antineoplastic agent that is more effective and less toxic in treating lung cancer.     

Formulation,characterisation and in vivo evaluation of lipid-based nanocarrier for topical delivery of diflunisal

Diflunisal (DIF) is non-steroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis. The current engrossment was aimed at formulation and assessment of DIF-loaded solid lipid nanoparticles (SLNs) for topical/dermal application. SLNs formulated by hot homogenisation method based on microemulsification technique were spherical with a mean size of 124.0?±?2.07?nm; PDI 0.294?±?0.15. The cumulative amount permeated/area was 109.99?±?0.008?μg/cm², along with permeation flux (6.30?±?0.09?μg/cm²/h) and skin retention (11.74?±?0.155?μg/cm²) across mice skin. The SLNs of DIF showed significant decrease in fluid volume, granuloma tissue weight, leukocyte count/mm³ after application of SLN formulation in mice air pouch model. Similarly, in mice ear oedema and rat paw oedema model, there was 2.30 and 1.29 time increase in percentage inhibition of oedema after SLN formulation application, respectively, as compared with conventional cream. Hence, the SLNs of DIF may prove to be a potential nanocarrier to effectively treat the local inflammatory conditions associated with arthritis.