[Drug delivery systems: a real therapeutic advance]. / Les systèmes de délivrance des médicaments: un réel progrès pour la thérapeutique.

Established at the request of the Research Committee of the French National Academy of Pharmacy, this report on drug delivery systems (DDS) is a summary of information gathered by interviewing leaders in the pharmaceutical community and from the international literature. This report includes: a rapid recall of pharmaceutical formulations and changes over the last decades; a definition of DDS, indications on their evolution and a discussion on their contribution to drug administration; information on firms specialized in the elaboration of DDS, their interactions with the drug industry and the current and future market for DDS; a presentation of the potential offered by DDS for the drug industry; a discussion on technical, regulatory, and economic issues which could obstruct drug administration using a DDS; a description of certain DDS selected for their therapeutic contributions and a brief presentation of perspectives; a presentation of certain recommendations for organizations concerned with DDS.

Factors influencing macrophage activation by muramyl peptides: inhibition of NO synthase activity by high levels of NO.

Treatment with muramyldipeptide (MDP) or a lipophilic derivative (MTP-Chol) included in nanocapsules renders macrophages cytostatic towards tumor cells. At the same time, nitric oxide (NO) synthase (EC 1.14.23) activity is induced, as determined by measurement of the two end products of the reaction (nitrite and L-citrulline). The objective of this study was to investigate some factors which might influence this activation and explain the decreased response observed at high nanocapsule concentrations. The glucose content of the medium did not seem to be limiting. Addition of indomethacin decreased nitrite production in the effector phase, suggesting a role for prostaglandins in the maintenance of the activated state. We also tested the hypothesis that NO itself might regulate inducible nitric oxide synthase activity. The addition of NO donors (SIN-1 and nitrosoglutathione) or superoxide dismutase to cultures of activated macrophages inhibited the NO synthase activity. Since these NO donors were non toxic towards macrophages, these observations indicate clearly that the addition of exogenous NO to that formed by the enzymatic reaction can cause inhibition of the inducible NO synthase.

Modulation of nitric oxide production in RAW 264.7 cells by transforming growth factor-beta and interleukin-10: differential effects on free and encapsulated immunomodulator.

The mouse macrophage cell line RAW 264.7 can be stimulated to produce nitric oxide (NO) by muramyltripeptide cholesterol included within biodegradable poly(D,L-lactide) nanocapsules (NC MTPChol). The aim of this work was to determine whether one or both of the cytokines transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) could be responsible for feedback control seen at high concentrations. Activated RAW 264.7 cells produced TGFbeta1. When exogenous TGF-beta1 was added during stimulation, a dose-dependent inhibition of NO production was observed when NC MTP-Chol was used, whereas activation by the soluble muramyl dipeptide (MDP) was not affected. Furthermore, addition of a blocking antibody to TGF-beta arrested the fall in NO production seen at high concentrations of NC MTP-Chol. Addition of IL-10 during RAW 264.7 cell activation also reduced NO production; however, in this case, both NC MTP-Chol and MDP were equally affected. The presence of anti-IL-10 antibody during activation significantly increased NO production.

Synthesis and immunostimulating properties of lipophilic ester and ether muramyl peptide derivatives.

Macrophages can become cytotoxic toward tumor cells when activated by immunomodulators. Three different muramyl peptides were synthesized: one hydrolyzable lipophilic ester derivative (MTP-Chol) and two nonhydrolyzable lipophilic ether derivatives (MTP-octadecane and MTP-heptadecafluorooctadecane). Activation of the RAW 264.7 cell line was studied by measuring nitrite production as an indication of NO-synthase activity. The lipophilic ester derivative, incorporated within nanocapsules, was as active as free muramyl dipeptide, whereas the lipophilic ether derivatives were unable to activate macrophages. MTP-octadecane in micellar form was not capable of inducing macrophage cytotoxicity either. These results indicate that lipophilic muramyl peptides need to be hydrolyzed to yield a hydrosoluble metabolite in order to activate macrophages.

Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration.

The pharmacokinetics of fluvoxamine maleate were investigated in 13 patients with biopsy-proven liver cirrhosis. They received a single oral 100mg dose as an enteric-coated tablet, and plasma samples were collected up to 168h after administration. Geometric mean values for peak plasma concentrations and area under the plasma concentration-time curves (AUC) were 39 micrograms/L and 1338 micrograms.h/L, respectively. Mean (+/- SD) elimination half-life (t1/2) was 25 +/- 11h, and increased with higher plasma bilirubin levels, although no relationship between bilirubin and AUC was observed. AUC was about 50% higher in patients than in healthy volunteers from another similar study. This was mainly because of a longer t1/2. Although there is a great overlap between AUC values of fluvoxamine in patients and healthy volunteers, it is nevertheless concluded that in patients with signs of active liver disease, e.g. raised bilirubin, it is wise to lower the initial daily dose and to carefully monitor the patient during subsequent upward dose adjustments.

Development of an injectable formulation of albendazole and in vivo evaluation of its efficacy against Echinococcus multilocularis metacestode.

The loading of poly (D, L-lactide) nanoparticles with ABZ has led us to evaluate the potential of this new colloidal drug delivery system against E. multilocularis, using a murine model of hepatic alveolar echinococcosis. ABZ-loaded nanoparticles had a monodisperse size distribution between 100 and 150 nm. The efficiency of drug loading to nanoparticles was over 97%. In vitro, at an ABZ concentration of 1.0 microgram ml-1, the formulation had no toxicity for peritoneal macrophages harvested from uninfected mice. In vivo, the ABZ-loaded nanoparticles exhibited no signs of toxicity at any of the doses tested. Intravenous injections of 6 mg kg-1 of bound ABZ to infected mice had an equivalent antiparasitic effect on the metacestode growth to that of a treatment with 1500 mg kg-1 of orally administered free ABZ. The parasite hepatic superficial size as well as the peritoneal metastatic burden was significantly reduced by these 2 courses of treatment, as compared to those of untreated mice. Our results should encourage further study in order to explain the absence of dose-dependent efficacy of ABZ-loaded nanoparticles demonstrated in the present study.

Influence of sterilization processes on poly(epsilon-caprolactone) nanospheres.

Polymeric vectors and especially poly(epsilon-caprolactone) nanoparticles have already shown promising results in the optimization of the ophthalmic bioavailability of drugs. Any formulation instilled in the eye must be sterile, and preferentially isotonic. Poly(epsilon-caprolactone) nanospheres were thus formulated with Synperonic PE/F68, Synperonic PE/F127, or Cremophor RH40. A tonicity agent, a preservative and, in some cases, a viscosifiant were then added. The pH was finally adjusted to pH 4 or buffered to pH 7. Different sterilization processes were studied to investigate their influence on the physicochemical characteristics of vectors. Autoclaving did not induce any modification on polymer molecular weight or Synperonic nanospheres diameter, but catalysed some reactions with surfactants and tonicity agents. This method could thus be used if the nanosphere excipients are chosen with care. gamma radiation induced preservative degradation and viscosifiant depolymerization. A cross-linking of poly(epsilon-caprolactone) chains was observed, as reflected by a sharp increase of its molecular weight. However, no variation of the mean particle size was detected. Finally, sterile filtration was the only process which ensured the conservation of physicochemical integrity of nanospheres. This process was successfully applied on non-viscosified vectors with a sufficiently small diameter.

Hepatic tissue distribution of doxorubicin-loaded nanoparticles after i.v. administration in reticulosarcoma M 5076 metastasis-bearing mice.

In our previous studies, doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles have been proven to increase dramatically the antitumoral activity of the cytotoxic agent in metastasis-bearing mice. The experimental model consisted of metastases induced by i.v. inoculation of reticulosarcoma M 5076 cell suspension to C57BL/6 mice. The improved efficacy of the drug was noted in terms of either metastasis count or survival. Therefore, tissue-distribution studies of this drug delivery system within the metastatic liver after i.v. administration were undertaken to gain more insight into the mechanism of action. Doxorubicin measurements in healthy hepatic or neoplastic tissue were carried out together with histological examinations using transmission electron microscopy. These results demonstrated the hepatic tissue to be an efficient reservoir of the drug when it was injected associated with nanoparticles. Accumulation of biodegradable nanoparticles with associated doxorubicin in Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug towards the neoplastic tissue.

Interactions of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate) with the complement system.

The efficient uptake of injected nanoparticles by cells of the mononuclear phagocyte system (MPS) limits the development of long-circulating colloidal drug carriers. The complement system plays a major role in the opsonization and recognition processes of foreign materials. Since heparin is an inhibitor of complement activation, nanoparticles bearing heparin covalently bound to poly(methyl methacrylate) (PMMA) have been prepared and their interactions with complement evaluated. The particles retained the complement-inhibiting properties of soluble heparin. Nanoparticles bearing covalently bound dextran instead of heparin were weak activators of complement as compared with crosslinked dextran (Sephadex) or bare PMMA nanoparticles. In addition to the specific activity of bound heparin, the protective effect of both polysaccharides is hypothesized to be due to the presence of a dense brush-like layer on the surface of the particles. Such properties are expected to reduce the uptake by MPS in vivo.

Pharmacokinetics of perindopril and its metabolites in healthy volunteers.

Perindopril, an angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to its active diacid metabolite, perindoprilat and to a perindoprilat glucuronide. The pharmacokinetic parameters of perindopril, perindoprilat and perindoprilat glucuronide were evaluated after single administration to healthy volunteers (N = 12) of 8 mg of perindopril tert-butylamine salt by oral route (treatment A), by intravenous route (bolus in 5 min, treatment B) and of an equimolar dose of perindoprilat (6.1 mg) by intravenous route (infusion over 2 h, treatment C). The treatments were administered as a randomised 3-way cross-over design. Plasma samples were collected up to 96 h and urines up to 120 h. Perindopril is rapidly absorbed with an oral bioavailability of 95% and is mainly eliminated by metabolic processes. The formation of perindoprilat is slow and about 20% of the available parent drug is transformed into this metabolite. Elimination profile of perindoprilat is biphasic, with a rapid renal excretion of the free fraction and a long terminal half-life of the fraction bound to ACE. Perindoprilat glucuronide is mainly obtained from perindopril by a pre-systemic first pass metabolism.

Biodegradable nanocapsules containing a lipophilic immunomodulator: drug retention and tolerance towards macrophages in vitro.

Nanocapsules (250 nm diameter) were prepared from poly (D, L-lactide) containing a lipophilic immunomodulator: MDP-L-alanyl cholesterol (MTP-Chol). High encapsulation rates were obtained at 37 degrees C in culture medium or in buffers imitating phagosomes and lysosomes. The tolerance of these particles by rat alveolar macrophages in vitro was tested. A slight toxicity was observed which was the result of two factors: the capacity of the immunomodulator to stimulate the generation of nitrite oxide by the L-arginine-dependent pathway and the polymer itself. The latter toxicity seemed to be mediated by a different mechanism.

Liposomal formulations for oral immunotherapy: in-vitro stability in synthetic intestinal media and in-vivo efficacy in the mouse.

The aim of this work was to develop a liposomal formulation which could act as a carrier for allergens during oral desensitization therapy. A model protein, ovalbumin, was associated with negatively charged, multilamellar vesicles of various compositions and their stability in the presence of synthetic intestinal media (bile salt, pancreatic enzymes and their combination) was investigated. Liposomes containing soya phosphatidylcholine as the main lipid, regardless of their cholesterol content (20-40%), were unable to protect ovalbumin against the combined action of pancreatic enzymes and bile salt. In contrast, liposomes prepared from distearoylphosphatidylcholine and cholesterol (6:3.5 molar ratio) were more stable: about 50% of the lipid remained as liposomes after a 4-h incubation at 37 degrees C and intact ovalbumin could be demonstrated therein by immunoblotting. The immunomodulating properties of liposomes were tested by following changes in serum IgE levels (by passive cutaneous anaphylaxis) in Balb/C mice sensitized to ovalbumin, after feeding various preparations. In this model, free ovalbumin was able to provoke a premature fall in IgE levels, and liposomes, whatever their composition, contributed no further effect.

In vitro release kinetic pattern of indomethacin from poly(D,L-lactide) nanocapsules.

Indomethacin nanocapsules were prepared by interfacial deposition of poly(D,L-lactide) polymer following displacement of acetone from a lipophilic phase to an aqueous phase. Highly solvated bilayers of phospholipids in excess in the formulation were formed and easily detected by TEM. In vitro release kinetic analysis of indomethacin from pure nanocapsules prepared with poloxamer as sole emulsifier, mixed colloidal suspension (nanocapsules and liposomal vesicules), and multiamellar phospholipidic bilayers revealed that drug release in phosphate buffer sink solution was drastically delayed and incomplete as a result of the high indomethacin solubility in the oily core, poloxamer micelles, and phospholipidic bilayers, respectively. The release process was thus dependent on drug partition from the colloidal suspension phases to the external sink solution. However, addition of albumin to the sink solution markedly enhanced the indomethacin release due to protein binding affinity. A kinetic model equation dealing with biphasic systems in which a drug is dissolved or partitioned between the lipophilic and hydrophilic phases of a dispersed system is proposed and found suitable for the description of indomethacin release from the mixed colloidal suspension only.

Disposition kinetics and oral bioavailability of vincamine-loaded polyalkyl cyanoacrylate nanoparticles.

Hexyl cyanoacrylate nanoparticles loaded with vincamine as a drug model were prepared. Disposition kinetics and oral bioavailability of vincamine in rabbits were compared after administration of an aqueous solution of the drug and an aqueous colloidal suspension of nanoparticles. After intravenous administration, total body clearance of vincamine was equal for both dosage forms, but a longer half-life (X 2) and larger distribution volume (X 2) were observed with the suspension of nanoparticles. After oral administration, the bioavailability of vincamine was considerably greater for the drug loaded onto nanoparticles.

Effect on cerebral blood flow of orally administered indomethacin-loaded poly(isobutylcyanoacrylate) and poly(DL-lactide) nanocapsules.

Nanocapsules, containing indomethacin, were prepared either by interfacial polymerization of isobutylcyanoacrylate monomers or by interfacial deposition of a performed (DL-lactide) polymer. In-vitro release of indomethacin from nanocapsules was dependent on the pH of the sink solution and was enhanced by addition of albumin. A decrease in cerebral blood flow was noted 15 min after oral administration to rats of indomethacin nanocapsules (5 mg kg-1) and lasted over 3 h. Empty nanocapsules had no effect. Since release of indomethacin from nanocapsules is unlikely to occur in the lumen of the stomach, due to unsuitable pH conditions, and nanocapsules have been previously shown to be able to cross the intestinal barrier, to reach the villi vessels intact and to protect against the ulcerating effect of the free drug, it is suggested that the rapid onset of the pharmacological effect was sufficiently induced by free indomethacin released in the plasma following absorption of the intact nanocapsules.

Preparation and in vivo studies of a new drug delivery system. Nanoparticles of alkylcyanoacrylate.

Polyhexylcyanoacrylate nanoparticles have been prepared with vincamine as the model drug. These particles had an average size of 200 nm and adsorbed approximately 43% of vincamine. The adsorption of vincamine to nanoparticles modified the distribution of vincamine in tissues. After iv injection the distribution volumes were increased in comparison with an aqueous solution of drug. In comparison with an aqueous solution of drug, the absolute bioavailability of vincamine was also increased after an oral administration of nanoparticles.

Pulsed estrogen therapy: pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations.

Pharmacokinetics of estradiol and estrone were assessed in postmenopausal women receiving S21400, a novel 17beta-estradiol formulation administered by nasal route; the results were compared with those obtained with oral and transdermal routes. Thirty six women received three treatments: a specified dose of 17beta-estradiol (100, 300 or 450 microg) given once and as 2 doses, 12 h apart, using three parallel dose groups in a randomised, crossover study. Thereafter, a reservoir patch (50 microg/day of 17beta-estradiol) or a tablet of 2 mg micronised 17beta-estradiol were randomly administered. Plasma concentrations of estradiol and estrone were measured by radioimmunoassays. Following intranasal dosing, estradiol was rapidly absorbed with plasma concentrations reaching maximal values (approximately 1400 pg/ml with a single 300 microg dose) after 10-30 min and returning within 12 h to levels of untreated postmenopausal women. Systemic exposure to estradiol was dose proportional and independent of the treatment regimen. Moreover, the dose of 300 microg gave an estimated 24 h systemic exposure to exogenous estradiol close to that of the 50 microg/day reservoir patch or the 2 mg tablet. The mean estrone to estradiol ratio was similar and 4-fold lower than those with the patch and the tablet, respectively. In conclusion, by this new route for estrogen replacement therapy, the nasal route, the pharmacokinetics of estradiol as S21400 were linear and displayed a 'pulsed' kinetic profile, different from those obtained with the usual routes of administration.

[Pharmacoclinical comparison of 2 dosage forms of trihexyphenidyl]. / Comparaison pharmacoclinique de deux formes galéniques de trihexyphénidyle.

The peak plasma level of Trihexyphenidyl sustained release from (THR = Parkinane sustained release) is lower than that produced by the simple form (THS = Artane) while it provides a quantitatively equivalent serum concentration. The less noticeable with sustained release Trihexyphenidyl. THR plasma levels, maintained relatively constant by a progressive release of the active principle, are sustained over a 24-hour period, allowing a simplified mode of administration: the drug may be given once a day.

[Contrast agents in magnetic resonance imaging]. / Les agents de contraste en imagerie par résonance magnétique.

The origin of nuclear magnetic resonance signal is reminded in this paper. Different ways of increasing the contrast in magnetic resonance imaging are presented, especially modifications of tissues relaxation times by the use of paramagnetic ions or nitroxides. The potential of these substances is illustrated by several examples of application in the animal.

[Modulation of in vivo fate of drugs: fundamental biopharmaceutical and pharmacokinetic aspects]. / Peut-on moduler le devenir in vivo des médicaments? (Bases biopharmaceutiques et pharmacocinétiques).

The in vivo fate of drugs is basically regulated by the drug's physico-chemical properties, and thus depends on its chemical structure. Three successive phases describe the fate of exogenous compounds (absorption, distribution, elimination). The first two phases can be modulated by galenic formulation. Controlling the available dose and release rate by administration route and formulation, allows to modulate bioavailability of the active substance and its delivery to the general circulation. For distribution, vectorization techniques aim at improving the benefit/risk ratio. Two approaches are used: targeting the site of action (or avoiding site(s) leading to undesirable effects) and/or specific release rates.