International Journal of Pharmaceutics (v.240, #1-2)

The influence of medium-chain triglycerides on the stability of all-in-one formulations by David F Driscoll; Jorg Nehne; Horst Peterss; Rolf Franke; Bruce R Bistrian; Wilhelm Niemann (1-10).
When mixed with parenteral nutrients as an all-in-one admixture, previous data have demonstrated that lipid emulsions composed of medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) yield more stable formulations compared with those compounded with pure LCT lipid emulsions. We investigated the physical stability of various preparations of intravenous lipid emulsions as all-in-one admixtures. Each final lipid emulsion used to compound the all-in-one formulation was a 20% w/v mixture containing MCTs and LCTs as either a single emulsion containing both triglycerides, or an emulsion made extemporaneously from separate starting emulsions of pure MCT and LCT. The first emulsion was composed of a 50:50 (by weight) physical mixture of MCTs and LCTs, and consisted of 50% MCT:40% ω-6 LCT (soybean oil):10% ω-3 LCT (fish oil) that was available as a single 20% w/v lipid emulsion. The second and third emulsions were specially prepared from separate stock dispersions containing pure 20% w/v MCT and pure 20% w/v LCT (soybean oil) lipid emulsions, and were made in volume ratios of 75% MCT:25% ω-6 LCT and 50% MCT:50% ω-6 LCT, respectively. This was done in order to investigate whether the method of emulsion preparation and/or ratio of MCT to LCT influenced all-in-one admixture stability. Each all-in-one admixture was studied at four intervals over 30 h at room temperature conditions by light extinction (or obscuration) using a single-particle optical sensing (LE/SPOS) technique. The data, performed in duplicate at each interval, is expressed as the volume-weighted percent of fat (PFAT) globules >5 μm. The results confirm the stabilizing effects of MCTs when made as a physical oil mixture as a single lipid emulsion. However, stabilization is lost if the MCT and LCT emulsions are mixed from separate starting emulsions and then compounded as an all-in-one formulation. The extemporaneous mixing of commercial lipid emulsions is not recommended.
Keywords: Long-chain triglycerides; Medium-chain triglycerides; Emulsion; Stability;

Purpose: Influence of polymers on the polymorphic transition of drugs has received limited attention in the literature. The main objective of this study was to gain an understanding of the influence of polyethylene glycol and povidone on the crystalline modification and subsequently the solubility of carbamazepine in solid dispersions. Methods: The physical state of the drug within the dispersions was determined using DSC and powder X-ray diffractometer. DSC and optical microscopy was used to study the kinetics and morphology of dihydrate formation, respectively. Results: Both the polymeric dispersions showed an improved dissolution profile for carbamazepine. Carbamazepine was present in an amorphous form within the povidone dispersions. In contrast, the PEG dispersions showed the presence of crystalline drug. Higher ratios of drug/PEG resulted in the metastable form I of carbamazepine. Dihydrate formation from both the polymeric dispersions was higher compared with pure carbamazepine. The physical state of the drug and the amount of drug in solution accounted for the higher dihydrate formation from these dispersions. Conclusions: Knowledge of the factors contributing to enhanced solubility is critical to the stability of solid dispersions. Additionally, influence of polymers like povidone on the crystalline transitions of polymorphic drugs may be crucial during its use as a binder in granulation.
Keywords: Carbamazepine; Polymorphism; Dihydrate; Solid dispersions; Polyethylene glycol; Povidone;

In order to screen out an optimum complex for reducing the nephrotoxicity of cisplatin (CDDP), we investigated and compared CDDP–chondroitin sulfate complexes to CDDP in terms of in vivo pharmacokinetics and in vitro cytotoxicity. The polymeric carriers used in the study were chondroitin sulfate A (CSA, 4-sulfate) with mean molecular weights of 10 kDa (CSA-1) and 23 kDa (CSA-2), and chondroitin sulfate C (CSC, 6-sulfate) with mean molecular weights of 8 kDa (CSC-1) and 25 kDa (CSC-2). The resultant complexes (CDDP–CSA-1, CDDP–CSA-2, CDDP–CSC-1 and CDDP–CSC-2) were administered intravenously to rats. The obtained plasma concentration–time curves during the 3 h period studied for all complexes are biphasic. The plasma dispositions of complexes were dependent on the molecular sizes with urinary excretion as main elimination pathway. CDDP–CSA-1 and CDDP–CSC-1 were unable to effectively increase the plasma retention of platinum due to rapid renal excretion. Furthermore, CDDP–CSA-1 disappeared from plasma more quickly than CDDP–CSC-1. CDDP–CSA-2 and CDDP–CSC-2, with similar urinary excretion as CDDP, gave rise to approximately five and four-fold increase in AUC0–3 h values, respectively, than that was achieved with native CDDP treatment. Biodistribution was compared between CDDP–CSA-2 and CDDP–CSC-2. Both complexes effectively suppressed the extensive distribution of CDDP into most tissues, especially kidney. However, CDDP–CSC-2 showed less reduction effect than CDDP–CSA-2. In addition, a significantly higher accumulation in tumor tissue was found with the administration of CDDP–CSA-2 than CDDP. Moreover, CSA complexes displayed an IC50 of 6 μM Pt-equivalents against SW4800 human colon cancer cells, similar to that of CDDP, whereas CSC complexes were less active than CDDP. These studies indicate that the complex prepared with CSA, which is greater than 20 kDa of molecular size, is superior to that of CSC, exhibiting improved pharmacokinetics and similar pharmacological activity to the native drug.
Keywords: Cisplatin; Chondroitin sulfate A; Chondroitin sulfate C; Complex; Macromolecular carrier; Pharmacokinetics;

The enhancement of pipemidic acid permeation into the pig urinary bladder wall by M Kerec; V Švigelj; M Bogataj; A Mrhar (33-36).
The influence of interactions between polycarbophil and calcium on a model drug permeation into the pig urinary bladder wall was investigated. Pipemidic acid was used as a model drug. One percent w/v polycarbophil dispersion significantly increases the permeation of pipemidic acid into the urinary bladder wall. The enhanced absorption of pipemidic acid caused by polycarbophil is significantly less pronounced in polycarbophil dispersions containing calcium. The enhancement of pipemidic acid permeation into the urinary bladder wall could be due to the opening of tight junctions, which causes higher paracellular permeability. In the case of polycarbophil dispersion with calcium some carboxylic groups of polymer are already occupied with calcium, present in the dispersions. As a consequence extracellular calcium binds to polycarbophil in lower extent if compared with polycarbophil dispersion without calcium and transport is increased to a lesser degree. We concluded that the mechanism of drug absorption enhancement caused by polycarbophil could be similar for urinary bladder as described in the literature for intestinal mucosa.
Keywords: Polycarbophil; Calcium; Enhanced absorption; Urinary bladder wall;

Non-linear mixed effects models for the evaluation of dissolution profiles by E Adams; D Coomans; J Smeyers-Verbeke; D.L Massart (37-53).
The use of non-linear mixed effects models to describe dissolution data has been evaluated. A theoretical part is included to introduce this approach to scientists who are not familiar with this type of statistics. The standard settings of the statistical software package (S-plus) are used as much as possible. Several mathematical functions like the Weibull, logistic, first-order and Gompertz are employed as basis for the non-linear mixed effects models. Examples are given using dissolution data of immediate and extended release tablets. The results are compared with those obtained using linear mixed effects models.
Keywords: Dissolution; Non-linear mixed effects models; Pharmaceutical statistics; Longitudinal data;

Iontophoretic estradiol skin delivery and tritium exchange in ultradeformable liposomes by Ebtessam A Essa; Michael C Bonner; Brian W Barry (55-66).
This work evaluated the in vitro transdermal iontophoretic delivery of tritiated estradiol from ultradeformable liposomes compared with saturated aqueous solution (control). Effects of current density and application time on tritium exchange with water were also determined. Penetration studies used three Protocols. Protocol I involved occluded passive steady state estradiol penetration from ultradeformable liposomes and control. The effect of current densities on drug penetration rates was also assessed (Protocol II). In Protocol III, three consecutive stages of drug penetration (first passive, iontophoresis and second passive) through the same human epidermal membranes were monitored. Such an experimental design investigated the possible effect of high current density (0.8 mA/cm2) on skin integrity. The tritium exchange study showed that extent of exchange correlated well with current density and time of application, with some shielding of estradiol by the liposomal structure. Liposomes enhanced estradiol passive penetration after occlusion. Protocol II showed that estradiol flux increased linearly with current density, although being delivered against electroosmotic flow. In Protocol III, reduction in flux of the second passive stage to near that of the first reflected a reversibility of the structural changes induced in skin by current.
Keywords: Skin delivery; Estradiol; Liposomes-ultradeformable; Transfersomes; Iontophoresis; Tritium exchange;

Chemical characterisation of sodium starch glycolate particles by S Edge; A.M Belu; U.J Potter; D.F Steele; P.M Young; R Price; J.N Staniforth (67-78).
The internal and surface chemical compositions of three sodium starch glycolate (SSG) products, Explotab, Primojel and Vivastar P were studied using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), time of flight secondary ion mass spectrometry (TOF-SIMS) and 23Na nuclear magnetic resonance spectroscopy (NMR). The surfaces of Explotab and Primojel contained very distinct features containing Na and Cl, however, Primojel also contained features which contained Na which may reflect the presence of Na glycolate and/or Na citrates. Vivastar P contained relatively few surface Cl containing features. Analysis of cross-sections of the particles showed that Na appeared to be uniformly distributed throughout the particles of all the products. Additionally, there was a significant concentration of Cl in the periphery of Explotab and Primojel. In the case of Vivastar P, significant levels of Na and Cl were detected in the internal regions of the particles which, together with 23Na NMR, suggests that NaCl is uniformly distributed within Vivastar P. 23Na NMR also suggested that the ratio of organic Na to NaCl was considerably lower in Vivastar P than Primojel and Explotab. Overall, even though all these three products satisfy the pharmacopeial descriptions of SSG, these studies suggest that Primojel and Explotab exhibit different chemical compositions to Vivastar P. Since the three products studied are reported to be prepared from potato starch, the apparent differences in chemical composition probably reflect the different manufacturing processes used, however, batch to batch variations may account for some of the subtle differences.
Keywords: Disintegrant; Starch; Composition; Spectroscopy;

In vivo evaluation of matrix pellets containing nanocrystalline ketoprofen by G.J Vergote; C Vervaet; I Van Driessche; S Hoste; S De Smedt; J Demeester; R.A Jain; S Ruddy; J.P Remon (79-84).
The aim of this study was to evaluate the in-vivo behaviour of matrix pellets formulated with nanocrystalline ketoprofen after oral administration to dogs. No significant differences in AUC-values were seen between pellet formulations containing nanocrystalline or microcrystalline ketoprofen and a commercial ketoprofen formulation (reference: Rofenid® 200 Long Acting). C max of the formulations containing nano- or microcrystalline ketoprofen was significantly higher compared to reference, whereas t max was significantly lower. The in-vivo burst release observed for the spray dried nanocrystalline ketoprofen matrix pellets was reduced following compression of the pellets in combination with placebo wax/starch pellets. These matrix tablets sustained the ketoprofen plasma concentrations during 5.6 and 5.4 h for formulations containing nano- and microcrystalline ketoprofen, respectively.
Keywords: Ketoprofen; Nanocrystals; Sustained release; Matrix; In vivo;

Vitamin A and vitamin A palmitate photostability were tested in different media. Ethanol and octyl octanoate solutions of these two vitamins, as such and with the addition of sunscreens (3,4 methylbenzilidencanfora, butyl methoxy dibenzoylmethane and octyl methoxycinnamate) or β-carotene and butylated hydroxy toluene, were analysed spectrophotometrically after UVB or UVA irradiation. An O/W fluid emulsion with 0.5% w/w of retinyl palmitate, with and without butylated hydroxy toluene, was prepared. The oil containing the vitamin was extracted with HCl and aluminium sulfate and analysed spectrophotometrically after UVB or UVA irradiation. The fluid emulsion containing retinyl palmitate with and without butylated hydroxy toluene was stored at different temperatures and analysed every week spectrophotometrically for a month. Of the sunscreens tested butyl methoxy dibenzoylmethane showed the strongest protective action towards vitamin A and vitamin A palmitate, whereas β-carotene did not protect either vitamin. Butylated hydroxy toluene inhibited the photodegradation of both vitamins dissolved in octyl octanoate, suggesting that oxygen may be involved in their degradation. O/W emulsion promoted slightly the degradation of vitamin A ester. Butylated hydroxy toluene protected retinyl palmitate from degradation induced by light and heat.
Keywords: Vitamin A; Vitamin A palmitate; Photostability; O/W emulsion; Solutions; Wrinkled skin;

Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating by Tatiana S Levchenko; Ram Rammohan; Anatoly N Lukyanov; Kathleen R Whiteman; Vladimir P Torchilin (95-102).
The purpose of our work was to compare the biodistribution of liposomes with different surface properties. Phosphatidylcholine (PC)/cholesterol (Chol) liposomes were prepared containing 6% mol of a charged lipid (stearylamine, SA; phosphatidic acid, PA; or phosphatidyl serine, PS) and/or polyethylene glycol (PEG)-PE of different MW (750 and 5000). ζ-Potentials and liposome clearance in mice were investigated. In vitro, the attachment of PEG in a similar fashion neutralizes the effect of any charged component. In vivo, the chemical nature of a charged lipid becomes important. Both short PEG750 and longer PEG5000 inhibit the clearance of positively charged SA-liposomes, while only longer PEG5000 inhibits the clearance of negatively charged PA-liposomes and none of the PEGs inhibit the clearance of negatively charged PS-liposomes. The opsonins with different molecular size may be involved in the clearance of liposomes containing different charged lipids.
Keywords: Liposome; Charged lipids; Polyethylene glycol; ζ-Potential; Circulation time;

The objectives of the present study were (1) to evaluate the effect of formulation ingredients on the release rate of Ubiquinone from its adsorbing solid compact; and (2) to prepare and evaluate an optimized self-nanoemulsified tablet formulation. A three factor, three-level Box–Behnken design was used for the optimization procedure, with the amounts of copolyvidone (X 1), maltodextrin (X 2) and microcrystalline cellulose (X 3) as the independent variables. The response variable was cumulative percent of Ubiquinone emulsified in 45 min with constraints on weight, flowability index, tensile strength, friability and disintegration time of the dry powdered emulsion and the resultant compact. Based on the experimental design, different Ubiquinone release rates and profiles were obtained. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percent emulsified in 45 min was Y 6=64.10−12.32X 1−4.36X 2−25.53X 3+6.99X 1 X 2+3.97X 1 X 3+9.70X 2X3−8.98X 1 2−16.22X 2 2+17.10X 3 2. The optimization model predicted an 85.4% release with X 1, X 2 and X 3 levels of 66.6, 560.1 and 100, respectively. A new formulation was prepared according to these levels. The observed responses were in close agreement with the predicted values of the optimized formulation.
Keywords: Self-nanoemulsified drug delivery system; Coenzyme Q10; Optimization; Box–Behnken; Response surface methodology;

Noticeboard (116-118).