Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems

Components:In order to formulate a successful SMEDDS for maximum therapeutic effect, due consideration must be given to various factors such as physicochemical properties of the active moiety as well as excipients, potential for drug excipient interaction (in vitro and in vivo) and physiological factors that promote or inhibit the bioavailability. Further, other important factors such as regulatory status, solubilization capacity, miscibility, physical state of the excipients at room temperature, digestibility and compatibility with capsule shell, chemical stability and cost of the materials should also be considered during the formulation[15]. Such a rationale approach not only helps in reducing the time involved in the formulation development but also reduces the cost of its development[11].

Oil/lipid phase:

The function of oil phase in self-microemulsifying system is to solubilize the hydrophobic/lipophilic active moiety in order to improve both drug loading and bioavailability of the hydrophobic active moiety. Selection of oil plays a vital role in the formulation as it determines the amount of drug that can be solubilized in the system[16]. A lipid molecule with a large hydrophobic portion compared to hydrophilic portion is desirable as it maximizes the amount of drug that can be solubilized. Open in a separate windowLIST OF OILS USED IN FORMULATION OF SMEDDS

Long chain triglycerides:

Lipids that have fatty acid chains of 14-20 carbons are categorized as LCTs[17]. Fixed oils i.e., vegetable oils contain a mixture of glyceride esters of unsaturated long chain fatty acids. These are considered safe as they are commonly present in daily food and are easily digestible[15]. Large hydrophobic portion of triglycerides is responsible for their high solvent capacity for lipophilic moieties. Though it is difficult to microemulsify, some marketed formulations such as Neoral^® (composed of olive oil which, has shown superior oral bioavailability) and Topicaine^® gel (composed of Jojoba oil for transdermal application) have been successfully practicing the microemulsification of LCTs[18].

Medium chain triglycerides and related esters:

Lipids that have fatty acid chains of 6-12 carbons are categorized as MCTs[17]. MCTs are the most common choice of oil for SMEDDS as they are resistant to oxidation and possess high solvent capacity compared to LCT because of their high effective concentration of ester group. MCTs produced from the distillation of coconut oil are known as glyceryl tricaprylate and comprises of saturated C8 and C10 fatty acids in the liquid state[15]. Labrafac CM 10, a MCT, has shown superior solubility for fenofibrate and produced wider microemulsion region at all surfactant/co-surfactant combinations than Maisine 35, which, is a LCT[19]. Drug substance should possess minimum solubility of 50 mg/ml in LCTs for lymphatic absorption[20]. Upon digestion, products of short and medium chain triglycerides are directed towards portal vein whereas chylomicrons formed from LCTs triggers the lymphatic transport. Further, highly hydrophobic drug substances are easily soluble in vegetable oils and can easily be formulated as simple oil solutions which are readily emulsified in the gut. However, most conventional hydrophobic drug substances do not exhibit superior solubility in LCT such as vegetable oil[21,22].Moderately hydrophobic drug substances, on the other hand, cannot be formulated into simple oil solutions as their solubility is limited. In such cases, SMEDDS are promising alternative where the drug solubility in the oil will be enhanced due to microemulsification of oil by surfactants. It is well accepted that oils with long hydrocarbon chains (high molecular volume) such as soybean oil, castor oil are difficult to microemulsify compared to MCT (low molecular volume) such as capmul MCM and Miglyol. However, solubilizing capacity of oil for lipophilic moiety increases with chain length (hydrophobic portion) of the oil. Hence the selection of oil is a compromise between the solubilizing potential and ability to facilitate the formation of microemulsion[23]. Malcolmson et al. studied the solubility of testosterone propionate in various oils for the formulation of O/W microemulsion and concluded that oils with larger molecular volume such as triglycerides show superior solubility than the corresponding micellar solution containing only surfactants without oil[24,25]. Enhancement of drug solubility in SMEDDS not only relies on the solubility of the drug in the oil but also on the surfactant(s). For instance, ethyl butyrate, small molecular volume oil, has shown higher solubility for testosterone propionate but its ME formulation has only improved the solubility slightly than the corresponding micellar solution. On the contrary, Miglyol 812 which is a larger molecular volume oil has shown improved solubilization in the ME formulation though the solubility of testosterone propionate is less in the individual components compared to ethyl butyrate[24].

Drug solubility in lipid:

Oil component alters the solubility of the drug in SMEDDS by penetrating into the hydrophobic portion of the surfactant monolayer. Extent of oil penetration varies and depends on the molecular volume, polarity, size and shape of the oil molecule. Overall drug solubility in SMEDDS is always higher than the solubility of drug in individual excipients that combine to form SMEDDS. However, such higher solubility considerably depends on the solubility of drug in oil phase, interfacial locus of the drug and drug-surfactant interactions at the interface[26]. In light scattering experiments, it was observed that oils with small molecular volume act like co-surfactants and penetrate into the surfactant monolayer. This forms thinner polyoxyethylene chains near the hydrophobic core of the micelle disrupting the main locus of the drug solubilization due to which, a higher solubility of drug is not observed. Large molecular volume oils, however, forms a distinct core and do not penetrate effectively into the surfactant monolayer. The locus of drug solubilization was found to be effected by the microstructure and solubility of the drug in the excipients. The locus of drug solubilization was found to be at the interface of micelle for phytosterols whereas the same for cholesterol was found to be between the hydrophobic head groups of surfactant molecules. This is attributed to altered side chain flexibility of phytosterol due to the additional substitution of alkyl side chain compared to cholesterol[27].In addition to molecular volume and polarity of the oil, drug solubility in oil is affected by physicochemical properties of drug molecule itself. Consideration of BCS classification and Lipinski''s rule of 5 for the selection of drug is only useful during initial screening stages. As per BCS classification, some of the acidic drugs are listed in Class II despite having good absorption and disposition as they do not satisfy the requirement of higher solubility at low pH values. Lipinski''s rule of 5, on the other hand, holds good only when the drug is not a substrate for the active transporter[4]. This suggests that aqueous solubility and log P alone are not sufficient to predict the solubility of drug in the oil. This further indicates that the solubility of any two drugs with similar log P would not be the same due to their different physicochemical properties.To demonstrate this, a study was conducted in our laboratory with two antihypertensive drugs having close partition coefficient (log P) values, different aqueous solubility and varying physicochemical properties. Candesartan cilexetil is hydrophobic and has log P value of 7.3, molecular weight 610.66 g/mol with a polar surface area 135.77 whereas, valsartan is slightly soluble in aqueous phase with log P value of 5.3, molecular weight 434.53 g/mol with a polar surface area 103.48 (clogP and polar surface area were calculated using chembiodraw ultra 11.0). Unlike candesartan cilexetil, valsartan exhibits pH dependent solubility[28].If only log P and aqueous solubility of these two drugs are considered, it is only natural to assume that candesartan cilexetil would be highly soluble in lipid phase whereas valsartan would be less soluble. A specific and sensitive HPLC-UV method was developed and validated to measure the super saturation solubility of these two drugs in various oils and the results showed a completely different solubility profiles. Solubility profile of these two drugs in different oil phase is given in fig. 2.Open in a separate windowFig. 2Solubility of active ingredients in various oils. Valsartan, candesartan cilexetil.Although log P and polar surface area of valsartan and candesartan cilexetil are closer, their solubility with triacetin, castor oil and capmul MCM C8 differs significantly. This may be attributed to the hydrogen bonding capacity and electrostatic interaction of both the scaffold with the oils. Nevertheless, valsartan is having aliphatic carboxylic group which is expected to be involved in hydrogen bond interaction with the hydrogen acceptor functionality of the triacetin as well as castor oil. We assume that the branched chain aliphatic ester moiety of triacetin, capmul MCM C8 and castor oil gets involved in the electrostatic repulsion with cilexetil part of candesartan. In case of valsartan, such electrostatic interactions are not possible. Furthermore, aliphatic ester chain of triacetin and castor oil may solvate the lipophilic chain of valsartan more favorably than candesartan in the absence of any electrostatic repulsion (proposed interaction is shown in fig. 3). However, significant difference was not observed with other oils such as olive oil, peanut oil, corn oil, miglyol 810, sunflower oil and soybean oil (data not shown).Open in a separate windowFig. 3Proposed interactions of valsartan and candesartan cilexetil with triacetin.     

界面缩聚法制备聚芳酯复合纳滤膜的研究 Ⅰ.基膜的制备

分别以聚醚砜（ＰＥＳ）,磺化聚砜（ＳＰＳＦ）和ＰＥＳ合金膜为基膜,分析了相容性对膜性能以及不同种类基膜对界面缩聚的影响。用电镜分别观察ＰＥＳ单组分膜和合金膜的断面形貌。结果表明：用小孔径的合金膜为基膜得到的复合膜具有较好的脱盐能力,对Ｎａ２ＳＯ４的脱除率达到９０％。     

界面缩聚法制备聚芳酯复合纳滤膜.NF-1复合纳滤膜的性能及应用初探

考察了不同操作条件以及物料性质对 Ｎ Ｆ１ 复合膜分离性能的影响以及该膜的耐试剂性能。研究表明： Ｎ Ｆ１ 膜在 ０．２ Ｍ Ｐａ 操作压力下水通量为 １．９９ Ｌ／ｍ ２·ｈ,对 Ｎａ Ｃｌ、 Ｎａ２ Ｓ Ｏ４ 等无机盐的脱盐率达到 ９０％ 以上。     

醇在水-硝基乙烷体系中的界面吸附

:研究了正丁醇、异丁醇、正戊醇在硝基乙烷—水体系中的界面吸附 ,测定了不同实验体系中的界面吸附参数 .结果表明 ,不同体系中界面张力与溶液醇浓度间的关系均遵守Langmuir Szyszkowski方程 ,硝基乙烷的存在改变了醇的界面吸附参数 ,降低了醇的表面活性 .     

Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization with a Polymeric RAFT Agent Containing Multiple Trithiocarbonate Groups

Polytrithiocarbonates were prepared by the condensation polymerization of a dicarboxylic acid functional trithiocarbonate and a diol. These polymers were effective reversible addition fragmentation chain transfer (RAFT) agents for the bulk polymerization of polystyrene homopolymers and a poly[styrene‐block‐(tert‐butylstyrene)] block copolymer. Size exclusion chromatography (SEC) analysis of the original and amine cleaved polymers showed that the polydispersity of the polymer tended toward two with increasing polymerization time, but the polydispersity of the polymer units between trithiocarbonate groups was narrow (ca. 1.1–1.3) Also, the average number of trithiocarbonate groups per chain was found to be proportional to the number of trithiocarbonate groups in the starting RAFT agent. These polytrithiocarbonate RAFT agents will be useful for preparing multiblock copolymers over a range of chemistries, block numbers and molecular weights.

     

Controlled Growth of Polyamide Films atop Homogenous and Heterogeneous Hydrogels Using Gel–Liquid Interfacial Polymerization

Controlled growth of crosslinked polyamide (PA) thin films is demonstrated at the interface of a monomer‐soaked hydrogel and an organic solution of the complementary monomer. Termed gel–liquid interfacial polymerization (GLIP), the resulting PA films are measured to be chemically and mechanically analogous to the active layer in thin film composite (TFC) membranes. PA thin films are prepared using the GLIP process on both a morphologically homogeneous hydrogel prepared from poly(2‐hydroxyethylmethacrylate) and a phase‐separated, heterogeneous hydrogel prepared from poly(acrylamide). Two monomer systems are examined: trimesoyl chloride (TMC) reacting with m‐phenylene diamine (MPD) and TMC reacting with piperazine (PIP). Unlike the self‐limiting growth behavior in TFC membrane fabrication, diffusion‐limited, continuous growth of the PA films is observed, where both the thickness and roughness of the PA layers increase with reaction time. A key morphological difference is found between the two monomer systems using the GLIP process; TMC/MPD produces a ridge‐and‐valley surface morphology whereas TMC/PIP produces nodule/granular structures. The GLIP process represents a unique opportunity to not only explore the pore characteristics (size, spacing, and continuity) on the resulting structure and morphology of the interfacially polymerized thin films, but also a method to modify the surface of (or encapsulate) hydrogels.     

Versatile Biodegradable Poly(ester amide)s Derived from α-Amino Acids for Vascular Tissue Engineering

Biodegradable poly(ester amide) (PEA) biomaterials derived from α-amino acids, diols, and diacids are promising materials for biomedical applications such as tissue engineering and drug delivery because of their optimized properties and susceptibility for either hydrolytic or enzymatic degradation. The objective of this work was to synthesize and characterize biodegradable PEAs based on the α-amino acids l-phenylalanine and l-methionine. Four different PEAs were prepared using 1,4-butanediol, 1,6-hexanediol, and sebacic acid by interfacial polymerization. High molecular weight PEAs with narrow polydispersity indices and excellent film-forming properties were obtained. The incubation of these PEAs in PBS and chymotrypsin indicated that the polymers are biodegradable. Human coronary artery smooth muscle cells were cultured on PEA films for 48 h and the results showed a well-spread morphology. Porous 3D scaffolds fabricated from these PEAs were found to have excellent porosities indicating the utility of these polymers for vascular tissue engineering.     

Using TOF-SIMS Spectrometry to Study the Kinetics of the Interfacial Retro Diels–Alder Reaction

In this work, the use of Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS) was explored as a technique for monitoring the interfacial retro Diels–Alder (retro DA) reaction occurring on well-controlled self-assembled monolayers (SAMs). A molecule containing a Diels–Alder (DA) adduct was grafted on to the monolayers, then the surface was heated at different temperatures to follow the reaction conversion. A TOF-SIMS analysis of the surface allowed the detection of a fragment from the molecule, which is released from the surface when retro DA reaction occurs. Hence, by monitoring the decay of this fragment’s peak integral, the reaction conversion could be determined in function of the time and for different temperatures. The viability of this method was then discussed in comparison with the results obtained by ¹H NMR spectroscopy.     

Simulation of the θ′ Precipitation Process with Interfacial Anisotropy Effects in Al-Cu Alloys

The effects of anisotropic interfacial properties and heterogeneous elasticity on the growth and ripening of plate-like θ′-phase (Al₂Cu) in Al-1.69 at.% Cu alloy are studied. Multi-phase-field simulations are conducted and discussed in comparison with aging experiments. The precipitate/matrix interface is considered to be anisotropic in terms of its energy and mobility. We find that the additional incorporation of an anisotropic interfacial mobility in conjunction with the elastic anisotropy result in substantially larger aspect ratios of the precipitates closer to the experimental observations. The anisotropy of the interfacial energy shows comparably small effect on the precipitate’s aspect ratio but changes the interface’s shape at the rim. The effect of the chemo-mechanical coupling, i.e., the composition dependence of the elastic constants, is studied as well. We show that the inverse ripening phenomenon, recently evidenced for δ’ precipitates in Al-Li alloys (Park et al. Sci. Rep. 2019, 9, 3981), does not establish for the θ′ precipitates. This is because of the anisotropic stress fields built around the θ′ precipitates, stemming from the precipitate’s shape and the interaction among different variants of the θ′ precipitate, that disturb the chemo-mechanical effects. These results show that the chemo-mechanical effects on the precipitation ripening strongly depend on the degree of sphericity and elastic isotropy of the precipitate and matrix phases.     

Effect of Cu Content on Performance of Sn-Zn-Cu Lead-Free Solder Alloys Designed by Cluster-Plus-Glue-Atom Model

The mechanical properties of solder alloys are a performance that cannot be ignored in the field of electronic packaging. In the present study, novel Sn-Zn solder alloys were designed by the cluster-plus-glue-atom (CPGA) model. The effect of copper (Cu) addition on the microstructure, tensile properties, wettability, interfacial characterization and melting behavior of the Sn-Zn-Cu solder alloys were investigated. The Sn₂₉Zn_4.6Cu_0.4 solder alloy exhibited a fine microstructure, but the excessive substitution of the Cu atoms in the CPGA model resulted in extremely coarse intermetallic compound (IMC). The tensile tests revealed that with the increase in Cu content, the tensile strength of the solder alloy first increased and then slightly decreased, while its elongation increased slightly first and then decreased slightly. The tensile strength of the Sn₂₉Zn_4.6Cu_0.4 solder alloy reached 95.3 MPa, which was 57% higher than the plain Sn-Zn solder alloy, which is attributed to the fine microstructure and second phase strengthening. The spreadability property analysis indicated that the wettability of the Sn-Zn-Cu solder alloys firstly increased and then decreased with the increase in Cu content. The spreading area of the Sn₂₉Zn_0.6Cu_0.4 solder alloy was increased by 27.8% compared to that of the plain Sn-Zn solder due to Cu consuming excessive free state Zn. With the increase in Cu content, the thickness of the IMC layer decreased owing to Cu diminishing the diffusion force of Zn element to the interface.