International Journal of Pharmaceutics (v.199, #1)

Percutaneous absorption of isosorbide dinitrate (ISDN) from a transdermal therapeutic system (TTS) with or without penetration enhancers was studied. The concentration of ISDN and its metabolites, isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN), was determined in rat plasma during a 48 h application of TTS. The increased skin-penetration enhancing effect of oleic acid and propylene glycol in comparison to polyethylene glycol 400 and isopropyl myristate on percutaneous permeation of ISDN was shown. It was expressed by higher values of C max and AUC. After the application of TTS, a lower ISDN and molar ratio of its metabolites was observed than after oral administration.
Keywords: Isosorbide dinitrate; Isosorbide mononitrate; Percutaneous absorption; Skin penetration enhancers;

Mapping PET-measured triamcinolone acetonide (TAA) aerosol distribution into deposition by airway generation by Zhenghong Lee; Marc S Berridge; Warren H Finlay; Donald L Heald (7-16).
The three dimensional (3D) distribution of inhaled drugs was measured using Positron Emission Tomography (PET) (Berridge, M.S, Muswick, G.J., Lee, Z., Leisure, G.L., Nelson, A.D., Muzic, R.F. Jr., Miraldi, F., Heald, D.L., 1997. PET evaluation of Azmacort® ([C-11]triamcinolone acetonide) dose administration. J. Nucl. Med. 38 (5) Suppl., 4–5). Data analysis was based upon regional ratios or penetration indices. To improve the analytical usefulness and objectivity, labeled drug from dynamic PET images was mapped into 23 airway generations following a general framework from a SPECT-based methodology (Fleming, J.S., Nassim, M.A., Hashish, A.H., Bailey, A.G., Conway, J., Holgate, S., Halson, P., Moore, E., Martonen, T.B., 1995. Description of pulmonary deposition of radiolabeled aerosol by airway generation using a conceptual three dimensional model of lung morphology. J. Aerosol Med. 8, 341–356). A recently developed airway network model was used in this study. Quantitative PET scans of [C-11]triamcinolone acetonide distribution in the lung were determined following administration of Azmacort®, a commercial metered dose inhaler with an integrated spacer device. Distributions at varying time periods after drug administration were investigated to explore the dynamics and kinetics of the aerosolized drug. Initially, deposition of labeled drug on conducting airways (generations 1–14) was found to be higher than those on acinar airways (generation 15–23), 64% versus 36%. The distribution pattern changed slowly with time. By 47 min, 51% of the dose remaining in the lung was found on conducting airways while 49% was on acinar airways. This study illustrates the value of PET imaging for the evaluation and design of drug formulations.
Keywords: Aerosol; Inhalation mapping; Three-dimensional measurement; Pulmonary deposition; Dynamic analysis;

The bioavailability (BA) of radio-labelled N-acetylglucosaminyl-N-acetylmuramyl dipeptide (GMDP) was low when administered by oral gavage as an aqueous solution to conscious male Sprague–Dawley rats (8.3±4.4% (mean±S.D., n=3)). To assess the likely factors contributing to the poor BA of GMDP, the stability of GMDP in the lumen of the gastrointestinal (GI) tract was examined in vitro, using ex vivo GI contents. GMDP was degraded by the contents of the small intestine, caecum and large intestine but was more stable in stomach contents. The permeability coefficient (papp) of GMDP in isolated sections of rabbit ileum was 1.67×10−6 cm/s in the mucosal to serosal direction and was not significantly different in the serosal to mucosal direction, indicating that GMDP is poorly permeable and passively transported across the intestinal wall. First pass metabolism was considered to be unlikely to be the primary limitation to the oral bioavailability of GMDP and therefore, that the oral bioavailability of GMDP was likely limited by instability in the lumen of the gastrointestinal tract and low intestinal permeability. A water-in-oil (w/o) microemulsion formulation subsequently developed to address these problems was trialed in a preliminary bioavailability study in rats and enhanced the bioavailability of GMDP ten-fold when administered intraduodenally, indicating that w/o microemulsions may represent a viable mechanism for enhancing the bioavailability of poorly GI-stable and poorly permeable peptide-based molecules.
Keywords: Microemulsion; GMDP; Intestinal instability; Intestinal permeability; Peptide; Absorption;

Physical evaluation of a new patch made of a progestomimetic in a silicone matrix by D.G. Maillard-Salin; Ph. Bécourt; G. Couarraze (29-38).
The adhesion of a new Transdermal Therapeutic System (TTS) made of silicone and loaded with a progestomimetic drug was characterised. The goal of this study was to use well-known methods or to adapt them to collect representative data. Individually, methods such as surface tension, peel test and rheology are already widely used. Results show that the choice of a substrate for peel tests can be made in the light of surface tension data and that polymers like poly(tetrafluoroethylene) (PTFE) are good alternatives to skin. Peeling characterisations are made a function of thickness of films, drug content in active, conditions of preparation and conditions of use such as pressure. Dynamic rheology is more difficult to link to other methods as it mainly reflects internal phenomena and properties that arise in the bulk, as opposed on its surface. Master curves enable results to be used more easily, but the theories to interpret the data are still not powerful enough to replace peel testing.
Keywords: Surface tension; Peel testing; Rheology; Adhesion; Silicone; Transdermal Therapeutic System;

In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents by Antonella Saija; Antonio Tomaino; Domenico Trombetta; Anna De Pasquale; Nicola Uccella; Tony Barbuzzi; Donatella Paolino; Francesco Bonina (39-47).
Topically-applied antioxidant drugs represent a successful strategy for protecting the skin against UV-mediated oxidative damage. However, they can afford to the skin a satisfactory photoprotection only if able to permeate through the stratum corneum and thus to reach deeper cutaneous layers. Caffeic and ferulic acids, dissolved in saturated aqueous solutions at pH 3 or 7.2, have been tested for their capability to permeate through excised human skin mounted in Franz cells. At both pH values, ferulic and, at a lower degree, caffeic acids appeared able to permeate through the stratum corneum. The known higher lipophilicity of ferulic acid may explain the fact that it permeates through the stratum corneum better than caffeic acid. However, vehicle pH values proved to have no influence on biophenol skin permeation profile; this observed lack of pH effect may reflect the drug higher concentration attainable in saturated solutions at high pH. On the basis of the findings obtained in these in vitro experiments, we designed the schedule of a series of in vivo experiments, carried out to evaluate the ability of caffeic and ferulic acids to reduce, in healthy human volunteers, UVB-induced skin erythema, monitored by means of reflectance spectrophotometry. Caffeic and ferulic acids, dissolved in saturated aqueous solution pH 7.2, proved to afford a significant protection to the skin against UVB-induced erythema. To conclude, we have confirmed, by means of in vitro and in vivo experiments, that caffeic and ferulic acids may be successfully employed as topical protective agents against UV radiation-induced skin damage; however their skin absorption is not influenced by the pH of the formulation.
Keywords: Caffeic acid; Ferulic acid; Antioxidant; Skin permeation; Photooxidative damage;

Tretinoin, a drug that is used in topical preparations for the treatment of acne vulgaris, is known to be very susceptible to degradation under daylight. The objective of this work was to investigate the degradation of a tretinoin lotion placed in front of a xenon lamp. Analysis was performed with HPLC. The tretinoin lotion was degraded to about 20% of its initial concentration within 30 min. Incorporation of tretinoin in β-cyclodextrin or in some surfactants (Brij®s) did not have any effect on the photodegradation of tretinoin. Neither could a UV-B sunscreen retard the photodegradation of tretinoin while a UV-A sunscreen had very little effect. Irradiation with selected wavelengths revealed that 420 nm seemed to be the most harmful wavelength for the degradation of tretinoin and not the wavelength of maximum absorption (350 nm) as expected. Then the addition of the yellow colourants chrysoin and fast yellow, absorbing in the region of 420 nm, was tested. These colourants did indeed retard the photo-degradation of tretinoin more or less depending on the concentration of the dye. Finally we only had to select a concentration that was still effective but that did not colour the skin.
Keywords: Tretinoin; Topical lotion; Photostability; Stabilization with yellow colourants;

Conformational analysis of 7-oxoacyl-l-alanyl-d-isoglutamines by T. Solmajer; O. Planinšek; S. Srčič (59-64).
In a recent article (Planinšek, O., Srčič, S., 1999. Int. J. Pharm. 87, 199–207) some interesting physicochemical properties of a series N-(7-oxoacyl)-l-alanyl-d-isoglutamines with n=0–6 methylene groups between the terminal methyl and 7-oxo group were measured. In view of the practical importance of these N-acetylmuramyldipeptide(MDP) immunomodulator analogues and their interesting biological properties a detailed conformational analysis was undertaken for the series with n=3–6 methylene spacers between the 7-oxo and terminal methyl groups. The puzzle posed by the reversal of the measured water solubility and lipophylicity could be resolved by using the Monte Carlo approach to searching the conformational space of the molecules in this series. We have found that the increase in water solubility and drop in lipophylicity when the number of methylene groups is increased from 5 to 6 can be attributed to the change in predominant conformation in the conformational family as described by the Boltzmann distribution of conformations. Notwithstanding this, we point out the changes in biological response coupled to the nonlinearity of the physicochemical behaviour in the series.
Keywords: Desmuramyldipeptide; 7-Oxoacyl-l-alanyl-d-isoglutamines; Conformational analysis; Monte Carlo;

Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications. In order to assess the feasibility of this approach for the emergency treatment of status epilepticus, three anticovulsants, i.e. diazepam (DZ), clonazepam (CZ), and a monocarbamate-based new compound (MCA) were studied in rabbits for the pharmacokinetics (PK) and pharmacodynamic (PD) response following intravenous (IV) and IN administrations. The animals were intranasally dosed with DZ (1 mg/kg), CZ (0.2 mg/kg), and MCA (5 mg/kg), dissolved in 200 μl of vehicle consisting of propylene glycol (PG), ethanol (EtOH), and water in the presence or absence of 1% sodium glycocholate (SGC) using single and repeated dosing schedules. Both DZ and CZ were absorbed very rapidly from 1% SGC/60% PG-30% EtOH-10% Water after IN single application; the T max’s were less than 2 min. The absorption rate of MCA was relatively slower with the peak time of 13–32 min. The bioavailability of single IN administration for DZ, CZ, and MCA determined over the first 2 or 4 h was found to be 77, 45, and 79%, respectively. The peak plasma level of DZ increased linearly with increasing the volume fraction of EtOH in the ternary cosolvent (20% to 60%). A repeated IN application of DZ, 5 min after the first dose, doubled the C max and AUC0–2 h values of the first one, whereas those of CZ and MCA resulted in an increase of 73–94% of the first dose. A single IN application of DZ- and CZ-containing formulations produced a PD response within 1.5 min, which was comparable to that of an IV injection. These results suggest that single or repeated IN applications of DZ, CZ, and MCA in a hydroalcohol-glycolic formulation might represent a viable approach to achieving a rapid systemic absorption of these anticonvulsants during the emergency treatment of status epilepticus and other types of seizures.
Keywords: Diazepam; Clonazepam; Monocarbamate derivative; Intranasal administration; Repeated intranasal dosing; Status epilepticus;

Application of Carbopol® to controlled release preparations I. Carbopol® as a novel coating material by Mitsuo Muramatsu; Ken Kanada; Ayumu Nishida; Kiyohisa Ouchi; Noriyasu Saito; Minoru Yoshida; Akihiro Shimoaka; Tetsuya Ozeki; Hiroshi Yuasa; Yoshio Kanaya (77-83).
We investigated the application of Carbopol® (CP) as a novel coating material prepared with various grades of CP having different degrees of cross-linking and molecular weights. Viscosity and spray mist size of CP aqueous solutions at various concentrations of CP were measured. Core tablets containing theophylline (TP), as a model drug, were coated with CP at various coating ratios. The TP release profile from the CP-coated tablets was studied by the JP13 paddle method. CP tablets were prepared by compressing CP powder, and the swelling behavior of the CP tablets in JP 1st fluid, purified water, and JP 2nd fluid was observed. The spray mist size of all CP aqueous solutions was small at a concentration of 1% and below, and drastically increased over a concentration of 1%. This result suggests that the appropriate concentration of the CP solution for coating is 1% or below. Sustained release of TP from the CP-coated tablets at a coating ratio of only 3% was observed in the JP 1st fluid and purified water, although fast release was observed in the JP 2nd fluid. The fast release in the latter fluid may be due to the fact that CP is an acid material. These results suggest that it is feasible to control the drug release by use of an extremely small amount of CP coating and that CP is useful as a novel coating material.
Keywords: Carbopol®; Coating material; Controlled release; Cross-linking; Spray mist; Swelling;

Controlled release injectable liposomal gel of ibuprofen for epidural analgesia by Anne Paavola; Ilkka Kilpeläinen; Jouko Yliruusi; Per Rosenberg (85-93).
The epidural administration is used commonly in the treatment of pain. Nonsteroidal anti-inflammatory drugs, especially ibuprofen, would have potential in epidural use. Like many epidurally useful drugs it, however, has a short duration of action, which is a limiting factor. To improve epidural pain treatment, a long-acting, single-dose gel injection is being developed. In the present study, the possibility of using liposomal systems to control the release and dural permeation of ibuprofen was investigated in vitro. Liposomal solutions of ibuprofen·Na (20 mg/ml) were prepared by high-pressure homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer 407 and the liposomal solution. No signs in the 1H-NMR spectroscopy of line broadenings or chemical shifts were observed. The liposomal formulations were reproducible and stable. Ibuprofen release in phosphate buffer, pH 7.4, at 37°C from the liposomal solution and the liposomal gel were prolonged significantly compared with their respective solution and gel controls. The liposomal gel controlled ibuprofen release and dural permeation in vitro and showed a permeation pattern favourable for maintaining constant drug levels. The liposomal poloxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen. It appeared to be a promising injectable controlled-release drug delivery system.
Keywords: Controlled release; Dural permeation; Ibuprofen·Na; Injectable; Liposome; Poloxamer 407 gel;

Defining the drug incorporation properties of PLA–PEG nanoparticles by Thirumala Govender; Trevor Riley; Touraj Ehtezazi; Martin C. Garnett; Snjezana Stolnik; Lisbeth Illum; Stanley S. Davis (95-110).
The drug incorporation and physicochemical properties of PLA–PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA–PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3–110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA–PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA–PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA–PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings. Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA–PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers.
Keywords: PLA–PEG; Drug incorporation; Nanoparticles; Micelles; Calorimetry; Targeting;

by Richard J Prankerd (111-112).