Solubility enhancement of poorly water soluble drugs using liposome technology

The aim of this work is to investigate the various parameters that could control the encapsulation of lipophilic drugs and investigate the influence of the physical properties of poorly water-soluble drugs on bilayer loading. Initial work investigated on the solubilisation of ibuprofen, a model insoluble drug. Drug loading was assessed using HPLC and UV spectrophotometric analysis. Preliminary studies focused on the influence of bilayer composition on drug loading to obtain an optimum cholesterol concentration. This was followed up by studies investigating the effect of longer alkyl chain lipids, unsaturated alkyl chain lipids and charged lipids. The studies also focused on the effects of pH of the hydration medium and addition of the single chain surfactant a-tocopherol. The work was followed up by investigation of a range of insoluble drugs including flurbiprofen, indomethacin, sulindac, mefenamic acid, lignocaine and progesterone to investigate the influence of drugs properties and functional group on liposomal loading. The results show that no defined trend could be obtained linking the drug loading to the different drug properties including molecular weight, log P and other drug specific characteristics. However, the presence of the oppositely charged lipids improved the encapsulation of all the drugs investigated with a similar effect obtained with the substitution of the longer chain lipids. The addition of the single chain surfactant a-tocopherol resulted in enhancement of drug loading and possibly is governed by the log P of the drug candidate. Environmental scanning-electron microscopy (ESEM) was used to dynamically follow the changes in liposome morphology in real time during dehydration thereby providing a alternative assay of liposome formulation and stability. The ESEM analysis clearly demonstrated ibuprofen incorporation enhanced the stability of PC:Chol liposomes.

Improving the solubility and dissolution of poorly soluble drugs by salt formation and the consequent effect on mechanical properties

The bioavailability of BCS II compounds may be improved by an enhanced solubility and dissolution rate. Four carboxylic acid drugs were selected, which were flurbiprofen, etodolac, ibuprofen and gemfibrozil. The drugs were chosen because they are weak acids with poor aqueous solubility and should readily form salts. The counterions used for salt formation were: butylamine, pentylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan­2-ol, 2-amino-2-methyl propan-1,3-ol and tromethamine. Solubility was partially controlled by the saturated solution pH with the butylamine counterion increasing the solution pH and solubility and dissolution to the greatest extent. As the chain length increased, solubility was reduced due to the increasing lipophilic nature of the counterion. The benzylamine and cyclohexylamine counterions produced crystalline, stable salts but did not improve solubility and dissolution significantly compared to the parent compound. The substitution of hydroxyl groups to tert-butylamine counterions produced an increase in solubility and dissolution. AMP2 resulted in the most enhanced solubility and dissolution compared to the parent drug but using the tris salt did not further improve solubility due to a very stable crystal lattice structure. The parent drugs were very difficult to compress due to orientation effects and lamination. Compacts were prepared of each parent drug and salt and their modulus of elasticity values were measured using a three-point bend (Young’s modulus, E0) were extrapolated to zero porosity and compared. Compressibility and E0 were improved with the butylamine, tert-butylamine, cyclohexylamine and AMP2 counterions. The most significant improvement in compression and E0 was with the AMP2 salts. Mechanical properties were related to the hydrogen bonding within the crystal lattice structure for the gemfibrozil salt series.

The accuracy of parameter estimation from noisy data, with application to resonance peak estimation in distributed Brillouin sensing

Distributed Brillouin sensing of strain and temperature works by making spatially resolved measurements of the position of the measurand-dependent extremum of the resonance curve associated with the scattering process in the weakly nonlinear regime. Typically, measurements of backscattered Stokes intensity (the dependent variable) are made at a number of predetermined fixed frequencies covering the design measurand range of the apparatus and combined to yield an estimate of the position of the extremum. The measurand can then be found because its relationship to the position of the extremum is assumed known. We present analytical expressions relating the relative error in the extremum position to experimental errors in the dependent variable. This is done for two cases: (i) a simple non-parametric estimate of the mean based on moments and (ii) the case in which a least squares technique is used to fit a Lorentzian to the data. The question of statistical bias in the estimates is discussed and in the second case we go further and present for the first time a general method by which the probability density function (PDF) of errors in the fitted parameters can be obtained in closed form in terms of the PDFs of the errors in the noisy data.

Realisation of an effective dual-parameter sensor employing a single fibre Bragg grating structure

A novel technology for simultaneous and independent measurement of dual parameters is proposed and experimented. The length of a single fibre Bragg grating (FBG) is divided into two parts. The temperature variation and another measurand can be measured independently and simultaneously, and the thermal effect can be erased with great ease.

Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Engineering liposomal systems to develop solubility enhancing technology

This research primarily focused on identifying the formulation parameters which control the efficacy of liposomes as delivery systems to enhance the delivery of poorly soluble drugs. Preliminary studies focused on the drug loading of ibuprofen within vesicle systems. Initially both liposomal and niosomal formulations were screened for their drug-loading capacity: liposomal systems were shown to offer significantly higher ibuprofen loading and thereafter lipid based systems were further investigated. Given the key role cholesterol is known to play within the stability of bilayer vesicles. the optimum cholesterol content in terms of drug loading and release of poorly soluble drugs was then investigated. From these studies a concentration of 11 total molar % of cholesterol was used as a benchmark for all further formulations. Investigating the effect of liposomc composition on several low solubility drugs, drug loading was shown to be enhanced by adopting longer chain length lipids. cationic lipids and. decreasing drug molecular weight. Drug release was increased by using cationic lipids and lower molecular weight of drug; conversely, a reduction was noted when employing longer chain lipids thus supporting the rational of longer chain lipids producing more stable liposomes, a theory also supported by results obtained via Langmuir studies· although it was revealed that stability is also dependent on geometric features associated with the lipid chain moiety. Interestingly, reduction in drug loading appeared to be induced when symmetrical phospholipids were substituted for lipids constituting asymmetrical alkyl chain groups thus further highlighting the importance of lipid geometry. Combining a symmetrical lipid with an asymmetrical derivative enhanced encapsulation of a hydrophobic drug while reducing that of another suggesting the importance of drug characteristics. Phosphatidylcholine liposornes could successfully be prepared (and visualised using transmission electron microscopy) from fatty alcohols therefore offering an alternative liposomal stabiliser to cholesterol. Results obtained revealed that liposomes containing tetradecanol within their formulation shares similar vesicle size, drug encapsulation, surface charge. and toxicity profiles as liposomes formulated with cholesterol, however the tetradecanol preparation appeared to release considerably more drug during stability studies. Langmuir monolayer studies revealed that the condensing influence by tetradecanol is less than compared with cholesterol suggesting that this reduced intercalation by the former could explain why the tetradecanol formulation released more drug compared with cholesterol formulations. Environmental scanning electron microscopy (ESEM) was used to analyse the morphology and stability of liposomes. These investigations indicated that the presence of drugs within the liposomal bilayer were able to enhance the stability of the bilayers against collapse under reduced hydration conditions. In addition the presence of charged lipids within the formulation under reduced hydration conditions compared with its neutral counterpart. However the applicability of using ESEM as a new method to investigate liposome stability appears less valid than first hoped since the results are often open to varied interpretation and do not provide a robust set of data to support conclusions in some cases.

An investigation into inductive parameter learning in complex hierarchical knowledge structures representing clinical expertise

This dissertation investigates the very important and current problem of modelling human expertise. This is an apparent issue in any computer system emulating human decision making. It is prominent in Clinical Decision Support Systems (CDSS) due to the complexity of the induction process and the vast number of parameters in most cases. Other issues such as human error and missing or incomplete data present further challenges. In this thesis, the Galatean Risk Screening Tool (GRiST) is used as an example of modelling clinical expertise and parameter elicitation. The tool is a mental health clinical record management system with a top layer of decision support capabilities. It is currently being deployed by several NHS mental health trusts across the UK. The aim of the research is to investigate the problem of parameter elicitation by inducing them from real clinical data rather than from the human experts who provided the decision model. The induced parameters provide an insight into both the data relationships and how experts make decisions themselves. The outcomes help further understand human decision making and, in particular, help GRiST provide more accurate emulations of risk judgements. Although the algorithms and methods presented in this dissertation are applied to GRiST, they can be adopted for other human knowledge engineering domains.

Early marketing matters:a time-varying parameter approach to persistence modeling

Are persistent marketing effects most likely to appear right after the introduction of a product? The authors give an affirmative answer to this question by developing a model that explicitly reports how persistent and transient marketing effects evolve over time. The proposed model provides managers with a valuable tool to evaluate their allocation of marketing expenditures over time. An application of the model to many pharmaceutical products, estimated through (exact initial) Kalman filtering, indicates that both persistent and transient effects occur predominantly immediately after a brand's introduction. Subsequently, the size of the effects declines. The authors theoretically and empirically compare their methodology with methodology based on unit root testing and demonstrate that the need for unit root tests creates difficulties in applying conventional persistence modeling. The authors recommend that marketing models should either accommodate persistent effects that change over time or be applied to mature brands or limited time windows only.

Pluronic F127-modified liposome-containing tacrolimus-cyclodextrin inclusion complexes:improved solubility, cellular uptake and intestinal penetration

Objective The aim of this study was to investigate Pluronic F127-modified liposome-containing cyclodextrin (CD) inclusion complex (FLIC) for improving the solubility, cellular uptake and intestinal penetration of tacrolimus (FK 506) in the gastrointestinal (GI) tract. Methods Molecular modelling was performed to screen the optimal CD for the solubilization of FK 506. FLIC was prepared by thin-lipid film hydration with the inclusion complex solutions followed by membrane extrusion. Dilution tests were conducted in simulated gastric fluids and phosphate-buffered solution of sodium taurocholate to investigate the solubility improvement of FK506. The cellular uptake of nanocarriers was studied in Caco-2 cells, and intestinal mucous membrane penetration in the GI tract was evaluated in Sprague-Dawley rats. Key findings The results showed that β-CD had the strongest binding energy with the guest molecule among the CDs. The prepared FLIC has an average diameter of 180.8 ± 8.1 nm with a spherical shape. The solubility and cellular uptake of FK 506 was greatly improved by the incorporation of CD complexes in the Pluronic F127-modified liposomes. Intestinal mucous membrane penetration was also significantly improved by the preparation of FLIC. Conclusion With improved drug solubility and intestinal mucous membrane penetration, FLIC shows a promising oral delivery system for FK 506. © 2013 Royal Pharmaceutical Society.

Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs

Aim: Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Methods: Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol andtris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. Results and conclusion: The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility. © 2012 Informa Healthcare USA, Inc.

The accuracy of parameter estimation from noisy data, with application to resonance peak estimation in distributed Brillouin sensing

Distributed Brillouin sensing of strain and temperature works by making spatially resolved measurements of the position of the measurand-dependent extremum of the resonance curve associated with the scattering process in the weakly nonlinear regime. Typically, measurements of backscattered Stokes intensity (the dependent variable) are made at a number of predetermined fixed frequencies covering the design measurand range of the apparatus and combined to yield an estimate of the position of the extremum. The measurand can then be found because its relationship to the position of the extremum is assumed known. We present analytical expressions relating the relative error in the extremum position to experimental errors in the dependent variable. This is done for two cases: (i) a simple non-parametric estimate of the mean based on moments and (ii) the case in which a least squares technique is used to fit a Lorentzian to the data. The question of statistical bias in the estimates is discussed and in the second case we go further and present for the first time a general method by which the probability density function (PDF) of errors in the fitted parameters can be obtained in closed form in terms of the PDFs of the errors in the noisy data.

Realisation of an effective dual-parameter sensor employing a single fibre Bragg grating structure

A novel technology for simultaneous and independent measurement of dual parameters is proposed and experimented. The length of a single fibre Bragg grating (FBG) is divided into two parts. The temperature variation and another measurand can be measured independently and simultaneously, and the thermal effect can be erased with great ease. © 2005 Elsevier Ltd. All rights reserved.

Microfiber-based inline Mach-Zehnder interferometer for dual-parameter measurement

An approach to realizing simultaneous measurement of refractive index (RI) and temperature based on a microfiber-based dual inline Mach-Zehnder interferometer (MZI) is proposed and demonstrated. Due to different interference mechanisms, as one interference between the core mode and the lower order cladding mode in the sensing single-mode fiber and the other interference between the fundamental mode and the high-order mode in the multimode microfiber, the former interferometer achieves RI sensitivity of -23.67 nm/RIU and temperature sensitivity of 81.2 pm/oC, whereas those of the latter are 3820.23 nm/RIU, and -465.7 pm/oC, respectively. The large sensitivity differences can provide a more accurate demodulation of RI and temperature. The sensor is featured with multiparameters measurement, compact structure, high sensitivity, low cost, and easy fabrication.