International Journal of Pharmaceutics (v.235, #1-2)

The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. In the past, the primary approaches to obtain colon-specific delivery achieved limited success and included prodrugs, pH- and time-dependent systems, and microflora-activated systems. Precise colon drug delivery requires that the triggering mechanism in the delivery system only respond to the physiological conditions particular to the colon. Hence, continuous efforts have been focused on designing colon-specific delivery systems with improved site specificity and versatile drug release kinetics to accommodate different therapeutic needs. Among the systems developed most recently for colon-specific delivery, four systems were unique in terms of achieving in vivo site specificity, design rationale, and feasibility of the manufacturing process (pressure-controlled colon delivery capsules (PCDCs), CODES™, colonic drug delivery system based on pectin and galactomannan coating, and Azo hydrogels). The focus of this review is to provide detailed descriptions of the four systems, in particular, and in vitro/in vivo evaluation of colon-specific drug delivery systems, in general.
Keywords: Colon-specific drug delivery; Polysaccharides; Colon targeting; Microflora;

Preparation and in vitro evaluation of solid dispersions of halofantrine by Ahmad M Abdul-Fattah; Hridaya N Bhargava (17-33).
The low aqueous solubility of halofantrine (HF) and its low bioavailability from commercially available tablets (Halfan®) suggested the formulation of solid dispersions (SDs) of HF to reduce its particle size and improve its wettability and aqueous solubility. Preformulation studies involved the development of a high performance liquid chromatography (HPLC) method for the analysis of HF. In addition, solubility studies were conducted on HF in aqueous solutions containing different concentrations of various carriers. Formulation studies included the preparation of SDs and physical mixtures (PMs) of HF with different carriers and their physicochemical characterization using differential scanning calorimetry (DSC), Fourier-Transform infra-red (FT-IR) spectroscopy and dissolution studies. A 3-month stability study at elevated temperatures was conducted on representative SDs of HF with selected carriers.
Keywords: Halofantrine; Solid dispersion; PEG 8000; PVP K30; Gelucire® 44/14; Sodium taurocholate; Dissolution rate;

Sonophoresis at a frequency of 20 kHz has been shown to enhance transdermal drug delivery, a phenomenon referred to as low-frequency sonophoresis. This study provides an investigation of the dependence of low-frequency sonophoresis on various ultrasound parameters, including the distance of the horn from the skin, intensity, and frequency. We performed in vitro experiments with full thickness pig skin to measure enhancements of skin conductivity and drug permeability. Ultrasound was applied to pretreat the skin using a sonicator operating at a frequency of either 20 or 40 kHz. We also measured pitting of aluminum foil to measure cavitation, which is the principal mechanism of low-frequency sonophoresis. The skin conductivity enhancement was found to be inversely proportional to the distance of the horn from the skin. As the intensity increased, skin conductivity enhancement also increased up to a certain threshold, and then dropped off. The intensities (I max) at which maximum enhancement occur are about 14 W/cm2 for 20 kHz and 17 W/cm2 for 40 kHz. These findings may be useful in optimizing low-frequency sonophoresis. Overall, the dependence of transport on ultrasound parameters is similar to that of aluminum foil pitting. These results support the role of cavitation in low-frequency sonophoresis.
Keywords: Sonophoresis; Cavitation; Transdermal; Drug delivery;

A novel thermo-responsive drug delivery system with positive controlled release by Xian-Zheng Zhang; Ren-Xi Zhuo; Jing-Zhou Cui; Jiao-Tao Zhang (43-50).
The model drug, 5-fluorouracil (5-FU) was loaded into the poly(N-isopropylacrylamide) (PNIPA) hydrogel at 25 °C, then the drug-loaded, swollen hydrogel sample was carefully enveloped in the dialysis bag to form a novel thermo-responsive drug delivery system (DDS). The concentration of released 5-FU was monitored at 266 nm on the UV spectrophotometer. We found that this novel DDS provides a positive drug release pattern and the drug, 5-FU, was released faster at the increased temperature (37 °C, >25 °C) than the one at the decreased temperature (10 °C, <25 °C). This was attributed to the double control of the thermo-sensitivity of the hydrogel matrix and the dialysis membrane. By employing the fast response PNIPA hydrogel instead of the conventional hydrogel in this novel DDS, we can further control the drug release rate and/or drug release amount etc., without changing the positive, thermo-responsive drug release pattern.
Keywords: Thermo-responsive; Poly(N-isopropylacrylamide); Hydrogel; Controlled release; Drug delivery system;

The most common treatment method is known as the transurethral resection (TUR) for the therapy of bladder cancer. Unfortunately, because of the recurrency of the tumoral tissues after TUR the chemotherapy or immunotherapy should be performed. In these kind of therapies the pharmacotherapeutics are infused intravesically into the bladder after TUR periodically (i.e. upto 6–36 weeks, each week). But these therapies are having very big problems (i.e. disturbancy to patients, adjustment of the suitable dosage, loss of active agents without using etc.). An alternative approach can be proposed as to design a pharmacotherapeutic agent delivery system, which will supply the suitable dosage of the agent for a certain time period to solve those problems. In this study; the pharmacotherapeutic agent (i.e. Mytomycin-C) delivery system was prepared by using a mucoadhesive polymer (i.e. chitosan) in the form of cylindirical geometry to facilitate the insertion of the carrier for in vivo studies. The chitosan carriers were prepared by cross-linking during the solvent evaporation technique. In the preparation of the chitosan carriers the chitosan polymers with different molecular weights, different amounts of cross-linker (i.e. glutaraldehyde) and different amounts of pharmacotherapeutic agent were used to obtain desired attachment onto the bladder wall and optimum release rate of the agent. On the other hand because of the gelous structure of the chitosan, the swelling behaviour of the polymer was evaluated by gravimetric determinations in aqueous media periodically.
Keywords: Bladder cancer; Transurethral resection (TUR); Chitosan; Mitomycin-C; Controlled release;

Development of novel topical tranexamic acid liposome formulations by A Manosroi; K Podjanasoonthon; J Manosroi (61-70).
The aims of this study were to develop novel liposome formulations for tranexamic acid (TA) from various lipid compositions {neutral (hydrogenated soya phosphatidylcholine and cholesterol), positive (stearylamine) or negative (dicetyl phosphate) charged lipid}, and to investigate the effects of concentrations of TA (5 and 10% in DI water) and charges on the physicochemical properties of liposomes. Liposomes were prepared by chloroform film method with sonication. The physical (appearance, pH, size, morphology) and chemical (drug encapsulation efficiency, transition temperature, enthalpy of transition) properties of liposomes were characterized. The TA contents were determined spectrophotometrically at 415 nm, following derivatization with 2,4,6-trinitrobenzosulfonic acid. The charged liposomes demonstrated better physical stability than the neutral liposomes. The percentages of TA entrapped in all liposome formulations varied between 13.2 and 15.6%, and were independent of TA concentrations and charges of liposomes. Charges affected the physical stability, pH and size of liposomes. The particle sizes of negative blank and positive liposomes (with and without the entrapped drug) were ∼10 times larger than the negative liposome with the entrapped TA. The multilamellar 7:2:1 molar ratio of hydrogenated soy phosphatidylcholine/cholesterol/dicetyl phosphate entrapped with 10% TA liposome (10%TA, −) was selected for further release study, due to its high physical stability, small particle size and relatively high drug encapsulation efficiency.
Keywords: Tranexamic acid; Topical liposomes; Hydrogenated soya phosphatidylcholine; Cholesterol; Dicetyl phosphate; Stearylamine;

Continued interest in in vitro methods for performing bioavailability/bioequivalence (BA/BE) studies for drug registration purposes, prompted us to investigate the suitability of a continuous flow-through perfusion system to determine diffusion of a wide variety of permeants, through human intestinal mucosa. Permeability of fresh and frozen intestinal mucosa towards water, 17β-estradiol, sumatriptan, arecoline and vasopressin was compared. Furthermore, diffusion studies of water, sumatriptan, arecoline, arecaidine, estradiol, cyclosporin and vasopressin across frozen/thawed intestinal mucosa specimens (−85 °C) were performed. No statistically significant differences between the flux values of the five compounds tested across fresh and frozen intestinal tissue, were found. Furthermore, it was demonstrated that the flux rates of the various compounds across these tissues decreased with increasing molecular size. However, the flux rates across frozen intestinal mucosa for compounds with molecular weights >300 Da, were low. Flux rates for the compounds studied across frozen/thawed human vaginal and buccal mucosa were 36–160% higher than those across frozen intestinal mucosa. We concluded that the continuous flow-through perfusion system used shows promise as an in vitro method for permeability determination through intestinal mucosa. However, other human mucosa e.g. vaginal mucosa, may have to be considered as alternatives to intestinal mucosa if therapeutic agents with molecular weights >500 Da are to be compared for in vitro BA/BE purposes, and further studies in this respect are warranted.
Keywords: Human intestinal mucosa; Permeability studies; Various compounds;

The effect of an aqueous amylopectin subcoating on the acidic resistance and dissolution behaviour of enteric-coated pellets was studied. Freely water-soluble riboflavin sodium phosphate (RSP) was used as a model drug, and microcrystalline cellulose (MCC) and lactose as fillers in the pellet cores. The pellets were subcoated with 5% aqueous amylopectin solution or with 5% hydroxypropyl methylcellulose (HPMC) solution, and subsequently film-coated with aqueous dispersion of cellulose acetate phthalate (CAP). Drug release of enteric-coated pellets was investigated by confocal laser scanning microscopy (CLSM). Dissolution tests showed that amylopectin subcoating improved the acidic resistance of the enteric-coated pellets in 0.1 N hydrochloric acid (HCl) compared with HPMC subcoating. As the amylopectin subcoating load was increased to 4% and the aqueous CAP coating load to 35%, the coated pellets resisted in 0.1 N HCl solution for approximately 1 h (the amount of drug released was below 10%), and they dissolved in the SIF without enzymes in less than 10 min. Confocal microscopy images and profiles of mean fluorescence intensities of RSP (obtained in the range of the interface of the pellet core and the film and the film coating surface) showed consistent results with dissolution tests. It seems that amylopectin subcoating can prevent the influx of the dissolution medium into the pellet core, and thus decrease the premature dissolution and release of the drug from the enteric-coated pellets in 0.1 N HCl solution. The drug release mechanism appeared to be osmotically driven release, and followed by diffusion through the polymer film.
Keywords: Acidic resistance; Amylopectin; Aqueous CAP dispersion; CLSM; Enteric coating; Subcoating;

The main objective of the study was to develop a stomach-specific drug delivery system to increase the efficacy of tetracycline against Helicobacter pylori. Chitosan microspheres were prepared by ionic cross-linking and precipitation with sodium sulfate. Two different methods were used for drug loading. In method I, tetracycline was mixed with chitosan solution before the simultaneous cross-linking and precipitation. In method II, the drug was incubated with pre-formed microspheres for 48 h. The cumulative amount of tetracycline that was released from chitosan microspheres and the stability of the drug was examined in different pH medium at 37 °C. Microspheres with a spherical shape and an average diameter of 2.0–3.0 μm were formed. When the drug was added to the polymer solution before cross-linking and precipitation only 8% (w/w) was optimally incorporated in the final microsphere formulation. When the drug was incubated with the pre-formed microspheres, on the other hand, a maximum of 69% (w/w) could be loaded. Thirty percent of tetracycline either in solution or when released from microspheres was found to degrade at pH 1.2 in 12 h. The preliminary results from this study suggest that chitosan microspheres can be used to incorporate antibiotic drugs and may be effective when administered locally in the stomach against H. pylori.
Keywords: Chitosan microspheres; Tetracycline; Stomach-specific delivery; Helicobacter pylori infection;

Transdermal iontophoresis of sodium nonivamide acetate by Jia-You Fang; Tsong-Long Hwang; Yaw-Bin Huang; Yi-Hung Tsai (95-105).
The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium–aluminum–garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.
Keywords: Sodium nonivamide acetate; Transdermal absorption; Iontophoresis; Electroporation; Sonophoresis; Erbium:YAG laser;

Dynamic Mechanical Thermal Analysis of cast and sprayed films of an aqueous dispersion of polymethyl methacrylate (Eudragit NE30D) and mixtures with an aqueous dispersion of ethylcellulose (Aquacoat ECD-30) has been undertaken. Such analysis allows the identification of glass transition temperatures and the degree of miscibility of the polymers. It was found that the two polymers formed as cast or sprayed films were not miscible but had an optimal composition of 30% of the ethylcellulose dispersion in the polymethyl methacrylate dispersion.
Keywords: Dynamical mechanical thermal analysis (DMTA); Ethylcellulose dispersion (Aquacoat); Glass transition; Temperature; Miscibility; Polymethyl methacrylate dispersion (Eudragit NE30D);

Novel reagents for the sensitive spectrophotometric determination of flutamide, an anticancer drug in pharmaceutical preparations by Padmarajaiah Nagaraja; Hassan R. Arun Kumar; Ramanathapura A. Vasantha; Hemmige S. Yathirajan (113-120).
Simple and sensitive spectrophotometric methods for the determination of flutamide (FLA) in either pure form or in its pharmaceutical preparations are described. The first method is based on the diazotisation of reduced FLA, followed by coupling with alcoholic iminodibenzyl (IDB) in acid medium to give a purple coloured product having a λ max of 570 nm. In the second method, the diazotisation of reduced FLA followed by coupling with 4-amino-5-hydroxy-2,7-naphthalenedisulphonic acid monosodium salt (AHND) in a buffer medium of pH 12, gives a red coloured product having a λ max of 520 nm. Common excipients used as additives in pharmaceutical preparations do not interfere in the proposed methods. Both the methods are highly reproducible and have been applied to a wide variety of pharmaceutical preparations and the results compare favourably with the reported method.
Keywords: Flutamide; Spectrophotometry; Iminodibenzyl; AHND; Pharmaceuticals;

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis by G İkinci; S Şenel; H Akıncıbay; S Kaş; S Erciş; C.G Wilson; A.A Hıncal (121-127).
Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.
Keywords: Chitosan film; Chitosan gel; Chlorhexidine; Periodontal drug delivery;

Preparation, characterization, and tabletting properties of a new cellulose-based pharmaceutical aid by Vijay Kumar; Maria de la Luz Reus-Medina; Dong Yang (129-140).
A new cellulose-based tabletting excipient, hereinafter referred to as UICEL, has been developed by treating cellulose powder with an aqueous solution of sodium hydroxide (conc. ≥5N) and subsequently precipitating it with ethyl alcohol. UICEL is similar in structure to Avicel® PH-102, a commercial direct compression excipient commonly referred to as microcrystalline cellulose (MCC). It, however, shows the cellulose II lattice, while Avicel® PH-102 belongs to the cellulose I polymorphic form. As produced, UICEL consisted of a mixture of aggregated and non-aggregated fibers. The degrees of polymerization (DP) and crystallinity (DC) of UICEL, determined by the viscosity and powder X-ray methods, were 189–207 and 47–58%, respectively. Avicel® PH-102, by comparison, showed an aggregated structure with DP and DC values corresponding to 248 and 76.9%, respectively. Compared to Avicel® PH-102, UICEL shows higher true density, bulk density, tap density, Carr's index and Hausner ratio values. The mean deformation pressure (P y) values calculated from the linear portion of the Heckel plots for UICEL and Avicel® PH-102 were about 104 and 87 MPa, respectively, suggesting that UICEL is less ductile than Avicel® PH-102. The hardness values of UICEL tablets increased nearly linearly with increasing compression pressures. Comparatively, Avicel® PH-102 formed stronger tablets. Irrespective of the compression pressure used, all UICEL tablets disintegrated within 15 s, whereas Avicel® PH-102 tablets of comparable strengths remained intact for over 12 h. In conclusion, the results show that UICEL can be used as a direct compression excipient, especially in the design and development of fast-disintegrating tablets.
Keywords: UICEL; Avicel®; Microcrystalline cellulose; Cellulose excipient; Direct compression excipient;

Transdermal delivery of triprolidine using TPX polymer membrane by Sang-Chul Shin; Jin Kim; Mi-Kyoung Yoon; In-Joon Oh; Jun-Shik Choi (141-147).
Triprolidine-containing matrix was fabricated with poly(4-methyl-1-pentene) (TPX) polymer to control the release of the drug. Effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping the mouse skin to remove the stratum corneum, which acts as a barrier of skin permeation. For the controlling delivery of triprolidine, the TPX matrix containing permeation enhancer could be developed.
Keywords: Triprolidine; TPX; Transdermal; Penetration enhancer; Matrix;

Direct compression properties of melt-extruded isomalt by F Ndindayino; D Henrist; F Kiekens; G Van den Mooter; C Vervaet; J.P Remon (149-157).
Isomalt, a sugar alcohol, was melt-extruded prior to compression in order to improve its tabletting properties. After fusion, crystalline isomalt was transformed into an amorphous form as shown by X-ray diffraction and differential scanning calorimetry (DSC). The tabletting properties of amorphous isomalt were dramatically improved. Mixtures formulated with paracetamol (50%) and extruded isomalt yielded hard tablets. However, extruded isomalt powder showed agglomeration problems due to recrystallization of the amorphous phase into a stable crystalline form in the presence of atmospheric moisture. The evolution of the moisture content correlated well with the compressibility data. The tablets made of extruded isomalt powder had a lower friability in comparison to the tablets formulated with non-extruded isomalt powder. Their disintegration was fast and a rapid dissolution rate was recorded. Extruded isomalt displayed excellent tabletting properties; however, further experiments should be conducted to delay or even prevent recrystallization of amorphous isomalt.
Keywords: Isomalt; Melt-extrusion; Direct compression; Paracetamol, recrystallization;

Direct compression and moulding properties of co-extruded isomalt/drug mixtures by F Ndindayino; C Vervaet; G Van den Mooter; J.P Remon (159-168).
Isomalt, a disaccharide alcohol was co-extruded with paracetamol or hydrochlorothiazide (HCT) in order to improve its tabletting properties. After extrusion, isomalt was transformed into an amorphous form, while paracetamol remained crystalline. Hot stage microscopy showed that HCT was amorphous in the isomalt carrier up to a concentration of 1% (w/w). Direct compression of mixtures formulated with co-extruded isomalt/paracetamol powders yielded harder tablets compared with physical mixtures and no powder agglomeration was observed. Direct moulding of isomalt co-extruded with either paracetamol or HCT was feasible, yielding hard tablets. A fast dissolution rate was seen for both the compressed and the moulded tablets (>80% paracetamol and 60% HCT released within 20 min). The compressed tablets showed a dramatic decrease in tensile strength during storage at 85% RH, while the tensile strength of the moulded tablets remained above 0.80 MPa after 6 months storage at the same conditions. Co-extrusion of isomalt with paracetamol and HCT dramatically improved the tabletting properties of the mixtures (compared with physical mixtures of drug and isomalt). Direct moulding proved to be a suitable technique to produce isomalt based tablets.
Keywords: Isomalt; Co-extrusion; Direct compression; Paracetamol; Hydrochlorothiazide; Direct moulding;

Dry adsorbed emulsion: 2. Dissolution behaviour of an intricate formulation by O Chambin; V Bérard; M.H Rochat-Gonthier; Y Pourcelot (169-178).
The behaviour of a pharmaceutical form, called dry adsorbed emulsion (DAE), containing a sparingly soluble drug (i.e. theophylline) was studied for dissolution drug release kinetic, in relation with DAE structure characterisation. In vitro dissolution testings were performed under different experimental conditions (medium at pH 1.2 and 7.4, medium with or without surfactant addition, different particle sizes, discrete or densified particles). Discrete DAE particles showed an extended release, in comparison with the native drug powder, depending on both drug solubility in the medium and particle size. The relevance of dissolution data was not improved by surfactant addition (0.1% sodium lauryl sulfate: SLS). After an initial release due to theophylline of the DAE superficial layer, the dissolution followed the Higuchi model. This suggested that DAE behaved as an inert matrix, which controlled drug release by diffusion through the hydrophobic part of the DAE. Densified DAE particles showed a slower dissolution rate than discrete DAE particles, because of their weak wettability and their poor disintegrant properties due to the particulate rearrangement under pressure. Lastly in a technological point of view, DAE could be considered as a potential drug delivery system in capsules or tablets to better control bioavailability of drugs.
Keywords: Dry emulsion; Dissolution; Particle; Sustained release;

Paclitaxel and its formulations by Anil K Singla; Alka Garg; Deepika Aggarwal (179-192).
Paclitaxel (Taxol®) is a promising anti-tumor agent with poor water solubility. It is effective for various cancers especially ovarian and breast cancer. Intravenous administration of a current formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation on aqueous dilution. Moreover, the extensive clinical use of this drug is somewhat delayed due to the lack of appropriate delivery vehicles. Due to this there is a need for the development of alternate formulation of paclitaxel having good aqueous solubility and at the same time free of any side effects. Various approaches employed so far include cosolvents, emulsions, micelles, liposomes, microspheres nanoparticles, cyclodextrins, pastes, and implants etc. which are discussed in this paper.
Keywords: Paclitaxel; Taxol; Formulation; Solubility;

The effect of spray drying polyethylene glycol (PEG) 4000 and lactose/PEG solutions was investigated. Micro-spherical PEG particles were successfully prepared from ethanol, which allowed lower outlet temperatures than water. The product was crystalline and consisted of rough spheres or rod like particles. In the case of lactose/PEG composites, spray dried from water, the crystallinity of both components was reduced on spray drying, the extent being dependent on the starting composition. Spray dried lactose/PEG with PEG present as 10% by weight was found to be the most amorphous of the systems prepared. Conversion to more crystalline products occurred over time, the rates of conversion being dependent on temperature and humidity. On storage at low humidity (31–34%) amorphous lactose in lactose/PEG spray dried systems converts to anhydrous crystalline lactose while at high humidity (75% RH) the monohydrate is formed. The rate of transformation of amorphous lactose to the crystalline monohydrate form, at high relative humidity, was quantified using the Avrami equation applied both to X-ray diffraction (XRD) peak intensity and heat of fusion data. Crystallisation of lactose appeared to be retarded at low PEG concentrations, where PEG was present predominantly in a non-crystalline state, but was accelerated at higher PEG contents.
Keywords: Spray dried polyethylene glycol (PEG); Spray dried lactose/PEG composites, stability; Amorphous; Crystallinity;

Investigation of protein/carbohydrate interactions in the dried state. 2. Diffuse reflectance FTIR studies by Pierre O Souillac; C.Russell Middaugh; J.Howard Rytting (207-218).
Upon freeze-drying in the absence of lyoprotectants, Fourier transform infrared (FTIR) spectroscopy has detected changes in the secondary structures of proteins. Such FTIR studies have been typically conducted using protein/KBr pellets, where additional protein degradation could potentially occur due to pressure effects and partial dissolution of the chaotropic KBr. Diffuse reflectance FTIR spectroscopy, in which no sample preparation is necessary, was evaluated as an alternative spectroscopic method to examine protein structure upon freeze-drying. The therapeutic proteins recombinant human deoxyribonuclease I (rh-DNase) and recombinant human insulin like growth factor I (rh-IGF-I) were freeze-dried with mannitol, sucrose, trehalose, and two molecular weight dextrans (69 and 503 kDa) separately, at concentrations ranging from 0 to 100% (w/w). Upon freeze-drying, rh-DNase and rh-IGF-I underwent significant changes in their secondary structure. For both proteins, the presence of intermolecular β-sheets due to aggregation was detected and the α-helix content decreased significantly. The addition of carbohydrates to the formulations inhibited the protein secondary structure rearrangement in a concentration-dependent manner. Sucrose and trehalose appeared to be the most efficient excipients in preventing secondary structure changes. The conformational changes observed for both proteins appeared to be reversible upon rehydration.
Keywords: Freeze drying; Protein; Carbohydrate; FTIR; Solid state;

Binding of doxycycline to keratin, melanin and human epidermal tissue by Thomas P Banning; Charles M Heard (219-227).
Doxycycline is licensed for the prophylaxis of malaria and recent research has indicated the feasibility of delivering this drug across the skin. The binding of doxycycline to keratin could influence skin permeation rates and it has been suggested that the interaction of anti-malarials with melanin may contribute to side effects, such as retinal damage. Doxycycline HCl was incubated with keratin (bovine horn), melanin (Sepia officinalis) and human epidermal samples (native and delipidised). Dose dependent binding of doxycycline to keratin and melanin was observed, and was of similar magnitude for each protein. However, the binding of doxycycline to melanin was lower by an order of magnitude relative to data previously reported for some other anti-malarials, and may indicate reduced side-effects. Doxycycline also demonstrated significantly greater affinity for native epidermal skin than for delipidised skin showing that doxycycline, a charged polar molecule, has affinity for the intercellular lipid matrix in addition to the proteinaceous domain. For native skin it was estimated that saturation would be reached at approximately 140 μg cm−2; for delipidised skin it was estimated to be 60 μg cm−2. Overall, the data suggested that the partition-diffusion steps that are involved in transcellular permeation are possible.
Keywords: Doxycycline; Malaria; Epidermis; Keratin; Melanin; Transdermal delivery;

Malarial resistance is an escalating global problem and consequently new and more efficacious treatments to combat malaria are urgently needed. The transdermal delivery of anti-malarials may provide an effective alternative or adjunct to conventional regimens. Triclosan is widely used as an anti-bacterial agent and it has recently been demonstrated that this compound has anti-malarial properties. Its high lipophilicity makes it a potential candidate for delivery across the skin and this paper examines in vitro the potential for the transdermal delivery of triclosan from ‘drug-in-glue’ formulations. Model patches were prepared using DuroTak® 2287, 2516 and 2051 acrylic polymer adhesives loaded with 0, 30 and 50 mg per 0.785 cm−2 triclosan and dissolution was measured over a 12-h period. There was no apparent difference between the adhesives at the 30 mg patch loading, but at 50 mg, the trend for increased release was 2051>2516>2287. No significant burst effect was apparent. Patches of 50 mg per 0.785 cm2 were then used to determine the permeation of triclosan across heat-separated human epidermal membranes in Franz diffusion cells, over a period of 48 h. The above general trend was reflected in the steady state flux values obtained: 2051:16.91 μg cm−2 h−1 (S.E.M. 1.29), 2516:15.05 μg cm−2 h−1 (S.E.M. 1.00), 2287 12.83 μg cm−2 h−1 (S.E.M. 2.81). Although pharmacokinetic data are not currently available to permit calculation of an efficacious patch size, the transdermal delivery of triclosan is feasible.
Keywords: Triclosan; Trandermal delivery; Malaria; Transdermal adhesive; Skin;

The effect of several formulation variables on some of the physico-chemical characteristics of poly (ethyl cyanoacrylate) (PECA) nanocapsules prepared by the interfacial polymerisation of biocompatible water-in-oil microemulsions was investigated. In all cases, yields were high (>90%) and the polydispersity in size of nanocapsules was narrow. The molecular weight of the nanocapsules formed was influenced by the pH of the aqueous component of the microemulsion, increasing with increasing pH. The size of the nanocapsules formed (ranging from around 130 to 180 nm) was a function of the ratio of the mass of monomer used to the water weight fraction of the microemulsion, increasing as this ratio was increased. This is due to the formation of a thicker polymer wall resulting from the increased mass of monomer available per unit interfacial area as this ratio is increased. The rate of release of insulin from nanocapsules was also influenced by this ratio, in agreement with its effect on wall thickness. This study demonstrates that many pharmaceutically relevant physico-chemical properties of poly (alkyl cyanoacrylate) (PACA) nanocapsules prepared by interfacial polymerisation of microemulsions can readily be manipulated by changing either the pH of the aqueous component, the water weight fraction of the microemulsion or the mass of monomer used for polymerisation.
Keywords: Insulin; Interfacial polymerisation; Microemulsions; Nanocapsules; Peptides; Poly (alkyl cyanoacrylate);

The objectives of the present work were, first, to develop a self-nanoemulsified drug delivery system (SNEDDS) based on the eutectic properties of ubiquinone (CoQ10); and second, to study the progress of emulsion formation and drug release mechanisms by turbidimetry and droplet size analysis. Binary phase diagrams of CoQ10 with menthol and essential oils were constructed and used to develop the self-nanoemulsified formulation. Pseudo ternary phase diagram was constructed to identify the efficient self-emulsification region. Release mechanisms of the resultant formulas were quantified using turbidimetry in combination with dissolution studies. Turbidity time profiles revealed three distinctive regions: lag phase, plateau, and the pseudolinear phase. Lag phase was attributed to the liquid crystalline properties of the formula. Plateau turbidity was correlated with droplet size. Laser diffraction analysis revealed an average droplet diameter of 100 nm. Emulsification rate was obtained from the corrected slope of the pseudolinear phase of the profile. Stability of the formula was further evaluated using Fourier transform-infrared (FT-IR) attached to an attenuated total reflectance (ATR) accessory. The present study revealed a eutectic based semisolid self-emulsified delivery system that can overcome the drawbacks of the traditional emulsified systems such as low solubility and irreversible precipitation of the active drug in the vehicle with time.
Keywords: Coenzyme Q10; Eutectic mixture; Self-nanoemulsified drug delivery system; SNEDDS; Turbidimetry; Liquid crystals;

Noticeboard (267-269).