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 degrees 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.     

Formulation,in vitro and in vivo evaluation of halofantrine-loaded solid lipid microparticles

Abstract

Context: Formulation, characterization, in vitro and in vivo evaluation of halofantrine-loaded solid lipid microparticles (SLMs).

Objective: The objective of the study was to formulate and evaluate halofantrine-loaded SLMs.

Materials and methods: Formulations of halofantrine-loaded SLMs were prepared by hot homogenization and thereafter lyophilized and characterized using particle size, pH stability, loading capacity (LC) and encapsulation efficiency (EE). In vitro release of halofantrine (Hf) from the optimized SLMs was performed in SIF and SGF. In vivo study using Peter’s Four day suppressive protocol in mice and the mice thereafter subjected to histological studies in kidney and liver.

Results: Results obtained indicated that EE of 76.32% and 61.43% were obtained for the SLMs containing 7% and 3% of Hf respectively. The SLMs loaded with 3% of Hf had the highest yield of 73.33%. Time-dependent pH stability analysis showed little variations in pH ranging from 3.49?±?0.04 to 4.03?±?0.05.

Discussion: The SLMs showed pH-dependent release profile; in SIF (43.5% of the drug for each of H₂ and H₃) compared with SGF (13 and 18% for H₂ and H₃ respectively) after 8?h. The optimized SLMs formulation and Halfan® produced a percentage reduction in parasitemia of 72.96% and 85.71% respectively. The histological studies revealed that the SLMs formulations have no harmful effects on the kidney and liver.

Conclusion: SLMs formulations might be an alternative for patients with parasitemia as there were no harmful effects on vital organs of the mice.     

固体脂质纳米粒和纳米结构脂质载体在经皮给药系统中的研究进展

目的介绍固体脂质纳米粒和纳米结构脂质载体在经皮给药系统中的应用与优势,为其开发利用提供参考。方法查阅国内外相关文献共30余篇,从固体脂质纳米粒和纳米结构脂质载体用于经皮给药系统的优势、药物在固体脂质纳米粒和纳米结构脂质载体中的分布形式及固体脂质纳米粒和纳米结构脂质载体在经皮给药领域中的应用等方面进行综述。结果固体脂质纳米粒和纳米结构脂质载体可以增强药物稳定性,能在皮肤表面产生包封效应,增加皮肤水合作用,具有药物靶向性。结论固体脂质纳米粒和纳米结构脂质载体是极有发展前景的新型经皮给药系统。     

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.     

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.     

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.     

Solid lipid microparticles as an approach to drug delivery

Introduction: Solid lipid particles were introduced in the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. Although lipid nanoparticles have been the object of a substantial number of reviews, fewer are available on lipid microparticles (LMs), despite their distinct advantages, including biocompatibility, ease of production and characterisation, extended release properties and high loading.

Areas covered: This review presents an overview of the advantages and drawbacks of LMs, that is, lipid-based particles with dimensions in the micrometre range. Specific focus is on the role of the main excipients used for LM formulations, lipids and surfactants and their effects on LM properties. An update on preparation techniques and characterisation methods are also presented, with particular emphasis on more recent technologies. The interaction of LMs with biological systems and with cells in particular is reviewed. The various LM administration routes are examined, with special attention to most recent applications (i.e., pulmonary and nasal delivery).

Expert opinion: LMs represent attractive and versatile carrier systems; however, their pharmaceutical applicability has been rather limited. Investigation on the use of LMs for less-established administration routes, such as pulmonary delivery, may provide further interest within the area of LM-based systems, both in industry and in the clinic.     

固体脂质纳米粒作为维A酸经皮给药载体的研究

目的:采用固体脂质纳米粒作为维A酸载体以提高其稳定性,增加经皮给药时的局部药物浓度。方法:采用纳米乳法制备维A酸固体脂质纳米粒,通过相图研究确定处方组成并通过单因素试验进行优化,采用葡聚糖G50微型凝胶柱测定包封率。对维A酸固体脂质纳米粒稳定性、释放度、经皮渗透性和皮肤贮留量进行评价。结果:制得的固体脂质纳米粒为球形或类球形粒子,平均粒径为83.2 nm,包封率>95%。4℃,25℃和40℃避光贮存3个月,含量和包封率均无明显变化。其体外释放速率和经皮渗透速率较市售乳膏慢,皮肤贮留量大于市售乳膏。结论:固体脂质纳米粒作为维A酸载体有助于提高其稳定性,增加局部药物浓度。     

Testosterone ethosomes for enhanced transdermal delivery

Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel®). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm². This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.     

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.     

蟾酥固体脂质纳米粒冻干工艺及其表征

目的 研究了蟾酥固体脂质纳米粒冻干剂的工艺及表征。方法以外观、色泽、再分散性为指标，考察了不同工艺条件对蟾酥固体脂质纳米粒冻干剂重建的影响，对冻干工艺参数进行了优化，并对蟾酥固体脂质纳米粒冻干剂进行了研究。结果5％乳糖和5％葡萄糖显示了优良的保护作用和再分散性，优化的冻干工艺为：-45℃预冻10h，升温至-30℃维持6h，再升温至-10℃维持3h，再升温至0℃维持2h，最后升温至25℃维持3h。结论通过支架剂的筛选和优化冻干工艺参数可以获得稳定的固体脂质纳米粒冻干剂。     

Preparation and characterization of biodegradable urea-loaded microparticles as an approach for transdermal delivery

This work describes the formulation and characterization of urea-loaded microspheres prepared using various polymers such as ethyl cellulose (EC), cellulose acetate phthalate (CAP) and poly (D,L-lactic-co-glycolic acid) (PLGA), along with the utilization of a solvent evaporation technique. The effect of various formulation parameters (i.e. polymer type and concentration, vehicle type, polymer solution/vehicle volume ratio, drug/polymer ratio, homogenizer and stirrer speed, sonication time and speed, type of washing solution, drying and separation method) on the characteristics of microspheres was also evaluated. Results obtained indicated that, in the presence of urea, highest rate of EC microsphere production could be obtained at a drug/polymer ratio of 1:2 and a polymer solution/vehicle volume ratio of 1:50. In some cases, crystallization of urea was observed during the encapsulation process using cellulose derivative polymers. CAP microparticles showed a rough and tortuous surface while EC microparticles had a wider range of particle size. However, with the PLGA polymer, much better desired microparticles with a smaller size range of 1–3?µm were obtained. In general, PLGA microspheres were spherical in shape and possessed smooth surfaces with less pores in comparison with those obtained by the other polymers. The yield of particle production and the extent of urea encapsulation in PLGA particles were measured to be 68.87%?±?5.3 and 40.5%?±?3.4, respectively. The release study from PLGA microspheres revealed that up to 70% of the drug was released within a few days, through a four-stage release pattern.     

Preparation and characterization of nocodazole-loaded solid lipid nanoparticles

Abstract

Nocodazole (NCD) has more carcinogenic effect than similar drugs. Moreover, it has low drug release time and high particle size. Solid Lipid Nanoparticles (SLNs) have been evaluated for decrease in particle size and therefore increase in drug release time, for such drugs. In this study, NCD has been successfully incorporated into SLNs systems and remained stable for a period of 90 days. NCD structure related to the chemical nature of solid lipid is a key factor to decide whether anticarcinogenic agent will be incorporated in the long term and for a controlled optimization of active ingredient incorporation and loading, intensive characterization of the physical state of the lipid particles were highly essential. Thus, NMR, FT-IR, DSC (for thermal behavior) analyses were performed and the results did not indicate any problem on stability. Moreover, SLNs were decreased size of NCD in addition to increase in time of the drug release. After SLN preparation, particle size, polydispersity index, electrical conductivity and zeta potential were measured and drug release from NCD-loaded SLNs were performed. These values seem to be of the desired range.     

雷公藤内酯醇固体脂质纳米粒的制备及理化性质

目的：以聚乙二醇单硬脂酸酯表面修饰材料结合到固体脂质纳米粒（solid lipid nanoparticles,SLN）,以雷公藤内酯醇（triptolide,TPL）为模型药,制备一种具有良好亲水亲脂性的雷公藤内酯醇固体脂质纳米粒。方法：采用熔融-乳化法制备固体脂质纳米粒。通过单因素考察、中心复合设计（central composite design,CCD）,考察脂质材料、聚山梨醇酯-80和PEG-stearate（PEG-SA）三个因素对TPL-SLN粒径、包封率和载药量的影响。通过透射电镜、热分析和X-射线衍射考察TPL-SLN的理化性质,并考察其固体脂质纳米粒的稳定性以及体外释放情况。用MTT法测定其对人正常肝L02细胞和肝癌细胞HepG2的增殖抑制作用并计算其IC₅₀。结果：最优的处方：脂质材料为7.5%,聚山梨醇酯80（Tween 80）为2%和PEG-SA为2%,其粒径（193.43±6.07）nm,包封率（87.63±0.09）%,载药量（0.33±0.01）%。透射电镜观察所制备的纳米粒的形态近似于球形,DSC分析和X-射线衍射证实TPL以非晶型的形式存在于固体脂质纳米粒中。稳定性考察发现纳米粒粒径在一个月的贮存期基本没有变化（P>0.05）,体外释放表明TPL-SLN具有体外缓释特性。TPL-SLN对肿瘤细胞的抑制作用强于正常肝细胞。结论：雷公藤内酯醇聚乙二醇修饰固体脂质纳米粒有望开发为临床口服用药新剂型。     

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.     

新型纳米粒给药系统——纳米结构的脂质载体

固体脂质纳米粒（SLN）已被公认是一种新型的纳米粒给药系统，但SLN有不同程度的潜在问题。作为新一代的纳米粒给药系统——纳米结构的脂质载体（Nanostructured lipid carriers，NLC）可减小或者避免SLN有限载药能力及储藏过程包封药物泄漏的问题，而且能调整SLN的释放曲线。NLC以固体脂质与物态上相异的液体脂质混合制备得到，形成3种类型特殊结构的脂质骨架：结晶不完全态、无定形态、复合态。现介绍一种特殊的制备方法，不仅适合于制备NLC，而且也可作为制备高粒子浓度（30％～95％）SLN分散液的方法。描述了NLC作为给药系统潜在的应用前景。     

Development and characterization of itraconazole-loaded solid lipid nanoparticles for ocular delivery

Abstract

The purpose of this study was to investigate the feasibility of entrapping water-insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199?nm, while the SLNs prepared with palmitic acid had particle size in the range of 126–160?nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X-ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations.