Manual Lipospheres in Drug Targets and Delivery: Approaches, Methods, and Applications

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More and more molecules have to be formulated with a sophisticated drug delivery system to achieve predictable pharmacokinetics. Patents of other molecules e. Companies develop strategies to protect or to get market shares based on formulation technology using CDC. However, controlled drug release from nanoemulsions is very unlikely because of the small size and the liquid state of the carrier.

The use of solid lipids instead of liquid oils is a very attractive idea for achieving controlled drug release because drug mobility in a solid lipid should be considerably lower compared with a liquid oil. In addition, the stability of certain drugs might be higher in a solid matrix compared with in a liquid lipid. The pioneer in this field was Speiser, who developed nanopellets for peroral administration [7].

These nanopellets were produced by dispersing melted lipids with high-speed mixers or with ultrasound. A relatively large amount of microparticles was present in these formulations, which might not be a serious problem for peroral administration, but they exclude an intravenous injection. Lipospheres, produced by high-shear mixing or ultrasound, were developed by Domb and represent similar systems [8—10]. They also contain large amounts of microparticles. It was soon found that HPH is more effective for the production of submicronsized dispersions of solid lipids than is high-shear mixing or ultrasound [11—13].

Dispersions obtained in this way are called SLN. Most SLN dispersions produced by HPH are characterized by an average particle size of around to nm and a low microparticle content. It has been claimed that SLN combine the advantages of other colloidal carriers and avoid their disadvantages [18]. Depending on the application, other ingredients might be present osmotic agents, matrices for lyophilization, buffers, etc. The danger of acute and chronic toxicity resulting from the SLN lipids is rather low because, in general, physiological lipids are used there are few exceptions, such as amphiphilic calixarenes [19].

More attention should be given to the physicochemical properties of the lipid and to classifying them in relation to their interactions with water, according to Small [20]. The choice of emulsifier depends on the administration route and is more limited for parenteral administrations.

A large variety of ionic and nonionic emulsifiers of different molecular weight has been used to stabilize the lipid dispersion. The most frequently used compounds include different kinds of poloxamer, polysorbates, lecithin, and bile acids. In many cases, the combination of emulsifiers was more efficient at preventing particle agglomeration than was the use of a single surfactant.

Both methods are widespread and easy to handle. However, in many cases, bimodal size distributions are obtained with one population in the micrometer range. In addition, metal contamination has to be considered if ultrasound is used.

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Ahlin et al. They investigated the influence of different process parameters — including emulsification time, stirring rate, and cooling conditions — on the particle size and the zeta potential. In most cases, average particle sizes in the range of to nm were obtained using stirring rates of 20, to 25, rpm for 8 to 10 min and controlled cooling with a stirring rate of 5, rpm. HPH has been used for years for the production of nanoemulsions for parenteral nutrition. In contrast to other techniques, scaling up represents no or minor problems in most cases.

Very high-shear forces disrupt the particles down to the submicron range. Two general approaches of the homogenization step, the hot and the cold homogenization techniques, can be used for the production of SLN [13,23,24]. In both cases, a preparatory step involves incorporating the drug into the bulk lipid by dissolving or dispersing the drug in the lipid melt. A preemulsion of the drug-loaded lipid melt and the aqueous emulsifier phase same temperature is obtained by a high-shear mixing device Ultra-Turrax.

The quality of the preemulsion affects the quality of the final product to a large extent, and obtaining droplets in the size range of a few micrometers is desirable. HPH of the preemulsion is carried out at temperatures above the melting point of the lipid. In general, higher temperatures result in lower particle sizes because of the decreased viscosity of the inner phase [25].

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However, high temperatures may also increase the degradation rate of the drug and the carrier. Furthermore, many surfactants have decreased solubilities and HLB values at a higher temperature, which might have a negative impact on homogenization efficacy. The homogenization step can be repeated several times. In most cases, 3 to 5 homogenization cycles at to bar are sufficient.

Increasing the homogenization pressure or the number of cycles often results in an increase of the particle size because of particle coalescence, which occurs as a result of the high kinetic energy of the particles [27]. The primary product of the hot homogenization is a nanoemulsion resulting from the liquid state of the lipid. Solid particles are expected to be formed by the cooling of the sample to room temperature or below. Because of the small particle size and the presence of the emulsifiers, lipid crystallization may be highly retarded, and the sample may remain as a supercooled melt nanoemulsion for several months [28].

Effective temperature control and regulation is needed to ensure the unmolten state of the lipid because of the increase in temperature during homogenization [26]. However, different steps follow. The drug-containing melt is cooled very rapidly e. The high cooling rate favors a homogenous distribution of the drug within the lipid matrix. Low temperatures increase the fragility of the lipid and, therefore, favor particle disruption. The solid lipid microparticles are dispersed in a chilled emulsifier solution. The presuspension is subjected to HPH at or below room temperature.

In general, compared with hot homogenization, larger particle sizes and a broader size distribution are observed in cold-homogenized samples [30]. Most investigators use the hot homogenization process because of its higher efficacy and the avoidance of the cold milling process. It must be also mentioned that the rapid cooling of the lipid melt in the first step favors metastable lipid modifications with higher drug loading capacity , which might transform with time into more stable polymorphs with the expulsion of the incorporated drug.

The lipophilic material is dissolved in a waterimmiscible organic solvent e. On evaporation of the solvent by reduced pressure, a solid lipid nanoparticle dispersion is formed. The reproducibility of these results was confirmed by Siekmann and Westesen [31], who also prepared nanoparticles of tripalmitin by dissolving triglyceride in chloroform. The smallest particle diameters were obtained by using bile salts as cosurfactants. Comparable small-particle-size distributions are not achievable by melt emulsification of a similar composition.

The mean particle size depends on the concentration of the lipid in the organic phase. With increasing lipid content, the efficiency of the homogenization declines because of the higher viscosity of the dispersed phase. The advantage of this procedure over the cold homogenization process described before is the avoidance of any thermal stress. A clear disadvantage is the use of organic solvents. The particle size is critically determined by the velocity of the distribution processes. Nanoparticles were produced only with polar solvents, which distribute very rapidly into the aqueous phase e.

The process also can be easily used for the production of lipid nanodispersions [17]. A requirement is the solubility of the lipid in the polar organic solvent, which limits the application range of this procedure. Higher amounts of the organic solvent increase the solubility of the lipid in the aqueous phase and lead to an increase in particle size resulting from Ostwald ripening. The main advantage of the method is the avoidance of thermal stress.

It should be mentioned that there are different definitions and opinions about the structure and dynamics of microemulsion in the scientific community. An extended review has recently been published by Moulik and Paul [33]. Gasco and other scientists describe microemulsions as two-phase systems composed of an inner and outer phase e. Typical volume ratios of the hot microemulsion to cold water are in the range of to The dilution process is critically determined by the composition of the microemulsion. According to the literature [34,35], the droplet structure is already contained in the microemulsion, and, therefore, no energy is required to achieve submicron particle sizes.

In addition to the composition, the temperature gradient and the pH value are key parameters for the quality of the final lipid nanosuspension. High-temperature gradients facilitate rapid lipid crystallization and prevent aggregation [36,37]. Because of the dilution step, achievable lipid contents are considerably lower compared with the HPH-based formulations. Otherwise, impurities in the ingredients and differences in particle-sizing technologies might lead to misleading results. Siekmann and Westesen investigated the influence of the formulation procedure on the quality of tyloxapol- 1.

They demonstrated the principal possibility of obtaining size distributions in the range of 30 to nm by ultrasonification. However, HPH proved to be a very effective dispersing technique in this study. A reduction of the average particle size from to nm was obtained after just the first homogenization cycle bar. The maximum dispersing grade was observed after five homogenization cycles. Results reported by other investigators show similar dependences of the particle size from the homogenization pressure and the number of cycles [13,38].

The mean particle size of the melt-homogenized tripalmitin nanoparticles was nm, and that of the evaporated solvent only 28 nm. However, solvent emulsification is not always superior to melt homogenization with respect to the dispersing degree. In contrast, for systems stabilized by phospholipids and nonionic surfactants, melt homogenization produced smaller particles than the solvent emulsification procedure.

These results show that the particle size heavily depends on the composition of the emulsifiers. Solvent emulsification is a suitable alternative method to prepare small, homogeneously sized lipid nanoparticle dispersions. An important advantage of that technique is the avoidance of any heat. However, solvent-emulsified suspensions are relatively diluted 0. Furthermore, it has to be considered that solvent emulsification may cause regulatory and toxicological problems arising from the solvent residues.

The dispersing grade depends on the power density and the power distribution in the dispersion volume. A homogeneous distribution of the power density is necessary to obtain narrow size distributions. Otherwise, particles localized in different volumes of the sample will experience different dispersing forces, and, therefore, the degree of particle disruption will vary within the sample volume. Inhomogeneous power distributions are observed in high-shear homogenizers and ultrasonifiers.

A monoglyceride and a triglyceride will behave differently in an aqueous environment. This classification is very helpful for understanding the interplay among drug, lipid emulsifier, and water. The general lipid composition mixed chain lengths or triglycerides made from one fatty acid will have different crystallinities and capacities for accommodating foreign molecules.

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In addition, pH levels may change the behavior of lipids considerably. Fatty acids are, in the protonated form e. Unprotonated fatty acids e. Around the pKa which varies in strong dependency of the environment , fatty acid—fatty acid salt complexes form lyotropic liquid crystalline lamellar phases and represent insoluble swelling lipids. The interaction between the fatty acid and the drug will be very different for each species.

Furthermore, even triglycerides with the same fatty acid composition will behave differently, depending on the localization of the fatty acid on the glycerol. For example, cacao butter has a rather sharp melting point because of the defined localization of the oleic 2 position and palmitic and stearic acids 1 and 3 positions. Random localization of the fatty acids leads to a broadening of the melting point to a melting range, which means that a certain amount of liquid lipids will be present over a large temperature range.

Jenning and Gohla found that high crystallinity of lipid matrices was linked with good physical stability but a low degree drug incorporation, whereas lipid matrices with low crystallinity were able to accommodate higher amounts of drug and showed poor physical stability [39].

However, further parameters for nanoparticle formation will be different for different lipids. Examples include the melting point, the velocity of lipid crystallization, and the shape of the lipid crystals and therefore the surface area. Higher-melting lipids led to an increase in particle size [11,30]. These results are in agreement with the general theory of HPH [26] and can be explained by the higher viscosity of the dispersed phase. It is also noteworthy that most of the lipids used represent a mixture of several chemical compounds.

The composition might, therefore, vary among different suppliers and might even vary for different batches from the same supplier. Small differences in the lipid composition e. For example, lipid nanodispersions made with cetyl palmitate from different suppliers had different particle sizes and storage stabilities A.

Lippacher, personal communication. The influence of lipid composition on particle size was also confirmed for SLN produced via high-shear homogenization [21]. Witepsol W35 contains shorter fatty acid chains and considerable amounts of mono- and diglycerides, which possess surface-active properties. Both a decrease of the homogenization efficiency and an increase in particle agglomeration cause this phenomenon. High concentrations of the emulsifier reduce the surface tension and facilitate the particle partition during homogenization.

The decrease in particle size is connected with a tremendous increase in surface area. The increase of the surface area during HPH occurs very rapidly.

Therefore, kinetic aspects have to be considered. The process of a primary coverage of the new surfaces competes with the agglomeration of uncovered lipid surfaces. The primary dispersion must contain excessive emulsifier molecules, which should rapidly cover the new surfaces. The excessive emulsifier molecules might be present in different forms, for example, molecularly solubilized or in the form of micelles or liposomes.

The timescale of the redistribution processes of emulsifier molecules between particle surfaces, water-solubilized monomers, and micelles or liposomes is different. In general, SDS and other micelleforming, low-molecular weight surfactants will rapidly achieve the new equilibrium. And the Tw knows effectively action, half a academy last, when an selfish interested myelinization shows up on a choice staff's supplemental X-ray - Maximising for the convenient XRD he consciously were at his device parasitoses earlier.

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