Hydrophilic Excipients Research Articles

Effect of pharmaceutical excipients on aqueous stability of rabeprazole sodium

The chemical stability of a proton-pump inhibitor, rabeprazole sodium, was evaluated in simulated intestinal fluid (pH 6.8) containing various ‘Generally Recognized As Safe (GRAS)’-listed excipients, including Brij ® 58, Poloxamer 188, Cremophor RH40, Gelucire 44/14 and PEG 6000. After incubation at 37 and 60 °C, the amounts of rabeprazole and its degradation product, thioether-rabeprazole, were quantitated by HPLC analysis. The main degradation product was separated and characterized by LC/MS. The degradation of rabeprazole followed first-order kinetics. In the absence of any excipients, the rate constants ( k) obtained at 37 and 60 °C were 0.75 and 2.78 h −1, respectively. In contrast, the addition of excipients improved its stability. Among several excipients tested in this study, Brij ® 58 displayed the greatest stabilizing effect. For instance, at 37 and 60 °C, Brij ® 58 reduced the k values to 0.22 and 0.53 h −1, respectively. The stabilizing mechanisms of these hydrophilic polymeric excipients with optimal HLB values could be partially explained in terms of their solubilizing efficiency and micellar formation for thioether-rabeprazole. In conclusion, rabeprazole formulations that contain suitable excipients would improve its stability in the intestinal tract, thereby maximizing bioavailability.

Release of 5-aminosalicylate from an MMX mesalamine tablet during transit through a simulated gastrointestinal tract system

5-Aminosalicylate (5-ASA; mesalamine) is the current first-line treatment for mild to moderate ulcerative colitis, a chronic inflammatory condition that most commonly affects the distal part of the colon. MMXtrade mark mesalamine (Lialdatrade mark [US]; Mezavanttrade mark XL [UK and Ireland]; Mezavanttrade mark [elsewhere]; Shire Pharmaceuticals Inc., Wayne, Pa, under license from Giuliani SpA, Milan, Italy) was created to be a novel, once-daily 5-ASA formulation. MMX mesalamine in tablet form has a pH-dependent, gastroresistant coating and is designed to delay the release of 5-ASA during transit through the upper gastrointestinal tract; it consists of hydrophilic and lipophilic excipients that are designed to prolong the release of 5-ASA throughout the colon. The release kinetics of 5-ASA from an MMX mesalamine tablet were assessed with the use of a dynamic in vitro gastrointestinal tract system (TNO GastroIntestinal Model) that simulates physiologic conditions in the adult human gastrointestinal tract under standardized fed and fasted conditions. This system incorporates removal of released drug via dialysis and automated sampling taken at various sections of the system. Less than 1% of 5-ASA was found to be released from the tablet in the simulated stomach and small intestine (before introduction into the simulated colon). Most of the 5-ASA within each tablet was released in the simulated colon (fasted state conditions: 78.0%; fed state conditions: 68.5%). Substantial quantities were released during the 8- to 18-hour sampling period (49.6 mg/h[fasted] and 40.7 mg/h [fed]). In conclusion, with the use of an in vitro system, the investigators showed that 5-ASA release from an MMX mesalamine tablet was delayed until the tablet reached the simulated colon. Throughout the simulated colon, release of 5-ASA from an MMX mesalamine tablet was prolonged.

Photoimages and the release characteristics of lipophilic matrix tablets containing highly water-soluble potassium citrate with high drug loadings

Two types of the carnauba wax-based lipophilic matrix tablet using spray-dried granules (SDT) or directly compressible powdered mixtures (DCT) were prepared for sustained release. The model drug was a highly water-soluble potassium citrate and loaded about 74% of the total tablet weight. The SDT slowly eroded and disintegrated during the release study without showing sustained release when the hydrophilic excipients were added. In contrast, the DCT was more efficient for sustained release. The release rate decreased with increasing carnauba wax concentration. In particular, the sustained release rate was markedly pronounced when the lipophilic stearyl alcohol and stearic acid were combined with the carnauba wax. The surface of the intact DCT appeared to be smooth and rusty. The DCT rose to the surface from the bottom of the vessel during the release test, and numerous pores and cracks with no signs of disintegration were also observed after the release test. The release profile was dependent on the formulation composition and preparation method of the matrix tablet. Diffusion-controlled leaching through the channels of the pores and cracks of the lipophilic matrix tablet (DCT) is a key to the sustained release.

Modulation of a Pulsatile Release Drug Delivery System Using Different Swellable/Rupturable Materials

Diclofenac sodium tablets consisting of core coated with two layers of swelling and rupturable coatings were prepared and evaluated as a pulsatile drug delivery system. Cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Drug release rate studies were performed using USP paddle method. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX 1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.

An Approach on Pregelatinized Cassava Starch Phosphate Esters as Hydrophilic Polymer Excipient for Controlled Release Tablet

An Approach on Pregelatinized Cassava Starch Phosphate Esters as Hydrophilic Polymer Excipient for Controlled Release Tablet

Comparative effects of some hydrophilic excipients on the rate of gabapentin and baclofen lactamization in lyophilized formulations

The aim of this study was to gain insights into the role played by some excipients on the stability of gabapentin 1 and baclofen 2 which can undergo degradation giving rise to the corresponding lactams 2-azaspiro[4.5]decan-3-one 3 and 4-(4-chlorophenyl)-2-pyrrolidone 4, respectively. A screening study was carried out on drug and drug-excipient freeze-dried mixtures at 50 °C and under three different humidity values by using a number of commonly available excipients. These include hydroxypropyl-β-(HP-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), lactose, raffinose, trehalose, PVP-K30 and mannitol. For most cases, it was found that the lactam formation can be satisfactory described by an apparent zero-order equation. Excipients shown to negatively impact gabapentin stability are HP-β-CD, SBE-β-CD, lactose and PVP K30 while only this last excipient had a significant effect on the degradation of baclofen. The results can be rationalized in terms of conformational factors favouring the intramolecular dehydration reaction . A positive effect of moisture on the lactamization process was observed under some circumstances. Water may provide a favourable environment for degradation. These findings, taken together, should be considered during the selection of excipients for a possible formulation of gabapentin and baclofen.

Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide

TMC 120 (Dapivirine) is a potent non-nucleoside reverse transcriptase inhibitor that is presently being developed as a vaginal HIV microbicide. To date, most vaginal microbicides under clinical investigation have been formulated as single-dose semi-solid gels, designed for application to the vagina before each act of intercourse. However, a clear rationale exists for providing long-term, controlled release of vaginal microbicides in order to afford continuous protection against heterosexually transmitted HIV infection and to improve user compliance. In this study we report on the incorporation of various pharmaceutical excipients into TMC 120 silicone, reservoir-type intravaginal rings (IVRs) in order to modify the controlled release characteristics of the microbicide. The results demonstrate that TMC 120 is released in zero-order fashion from the rings over a 28-day period and that release parameters could be modified by the inclusion of release-modifying excipients in the IVR. The hydrophobic liquid excipient isopropyl myristate had little effect on steady-state daily release rates, but did increase the magnitude and duration of burst release in proportion to excipient loading in the IVR. By comparison, the hydrophobic liquid poly(dimethylsiloxane) had little effect on TMC 120 release parameters. A hydrophilic excipient, lactose, had the surprising effect of decreasing TMC 120 burst release while increasing the apparent steady-state daily release in a concentration-dependent manner. Based on previous cell culture data and vaginal physiology, TMC120 is released from the various ring formulations in amounts potentially capable of maintaining a protective vaginal concentration. It is further predicted that the observed release rates may be maintained for at least a period of 1 year from a single ring device. TMC 120 release profiles and the mechanical properties of rings could be modified by the physicochemical nature of hydrophobic and hydrophilic excipients incorporated into the IVRs.

Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole

Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, to compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC(0-6h)) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 degrees C, without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.

Formulation Studies and In Vivo Evaluation of a Flurbiprofen-Hydroxypropyl β-Cyclodextrin System

The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl β-cyclodextrin (HPβCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPβCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans.HPβCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPβCD–containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug–HPβCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans.

Enhancement of dissolution rate of poorly soluble active ingredients by supercritical fluid processes: Part II: Preparation of composite particles

In this second of two articles, we show that several supercritical processes have been developed to prepare composite particles of poorly soluble active ingredients. Microencapsulation, cyclodextrin inclusion and impregnation allow to incorporate poorly soluble materials in fast-dissolving hydrophilic excipients, leading to promising results in terms of dissolution rate enhancement.

Hydrophilic excipients modulate the time lag of time-controlled disintegrating press-coated tablets

An oral press-coated tablet was developed by means of direct compression to achieve the time-controlled disintegrating or rupturing function with a distinct predetermined lag time. This press-coated tablet containing sodium diclofenac in the inner core was formulated with an outer shell by different weight ratios of hydrophobic polymer of micronized ethylcellulose (EC) powder and hydrophilic excipients such as spray-dried lactose (SDL) or hydroxypropyl methylcellulose (HPMC). The effect of the formulation of an outer shell comprising both hydrophobic polymer and hydrophilic excipients on the time lag of drug release was investigated. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) followed by a rapid and complete release phase, in which the outer shell ruptured or broke into 2 halves. The lag phase was markedly dependent on the weight ratios of EC/SDL or EC/HPMC in the outer shell. Different time lags of the press-coated tablets from 1.0 to 16.3 hours could be modulated by changing the type and amount of the excipients. A semilogarithmic plot of the time lag of the tablet against the weight ratios of EC/SDL or EC/HPMC in the outer shell demonstrated a good linear relationship, with r = 0.976 and r = 0.982, respectively. The predetermined time lag prior to the drug release from a press-coated tablet prepared by using a micronized EC as a retarding coating shell can be adequately scheduled with the addition of hydrophilic excipients according to the time or site requirements.

In Vitro–In Vivo Characterization of Release Modifying Agents for Parenteral Sustained‐Release Ketorolac Formulation

One of the prerequisites for a parenteral preparation is that the excipients incorporated are biocompatible and biodegradable. In the present study hydrophilic and hydrophobic excipients were investigated for developing an intramuscular sustained‐release formulation of ketorolac. Kollidon® 17 PF, Peceol (glyceryl monooleate), and castor oil were chosen as the potential release‐retarding agents, each with a distinct mechanism of action. They were evaluated by in vitro drug‐release profiles and in vivo pharmacodynamic and pharmacokinetic study in mice. Cumulative drug release was determined for standard and test formulations in modified Franz diffusion cell. Pharmacodynamic parameter, T = 70% response of peak analgesic response, was used to compare the performance of test formulations. Based on pharmacodynamic/pharmacokinetic correlation in the animal studies, Cssmax and Cssmin of 51.39 and 30.0 µg/mL, respectively, were determined and considered as performance markers for pharmacokinetic evaluation of test formulations. The study suggested that the sustained‐release capability of glyceryl monooleate was maximum followed by that of castor oil and Kollidon 17 PF, when compared to conventional ketorolac tromethamine formulation. It was inferred that water soluble excipient, though, showed release retarding property in vitro but could not maintain it in the in vivo environment. Glyceryl monooloeate‐based formulation produced the most favorable drug blood concentration vs. time profile.

Bioavailability of ibuprofen from hot-melt extruded mini-matrices

The bioavailability of ibuprofen from hot-melt extruded mini-matrices based on ethyl cellulose and a hydrophilic excipient was tested. During the in vivo evaluation an oral dose of 300 mg ibuprofen was administered to healthy volunteers ( n=9) in a randomized cross-over study and compared with a commercially available sustained release product (Ibu-slow ®). The plasma samples were analysed by a validated HPLC-UV method. One mini-matrix formulation (F-1) consisted of 30% ibuprofen, 35% ethyl cellulose and 35% hydroxypropyl methylcellulose (Metolose ® 60 SH 50), while the second formulation (F-2) contained 60% ibuprofen, 20% ethyl cellulose and 20% xanthan gum. These mini-matrices were administered in hard gelatine capsules. Both formulations behaved in vivo as sustained release formulations with an HVD t 50% C max value (time span during which the plasma concentration is at least 50% of the C max value) of 7.6 and 12.0 h for formulations F-1 and F-2, respectively, whereas a value of 5.2 h was obtained for Ibu-slow ®. Although a significantly higher C max and AUC 0–24 h was seen for the reference product, the relative bioavailability of both experimental formulations was about 80%.

Physical Stability of Micronized Powders Produced by Spray-Freezing into Liquid (SFL) to Enhance the Dissolution of an Insoluble Drug

Purpose. The objective of this study was to investigate the physical stability of micronized powders produced by the spray-freezing into liquid (SFL) particle engineering technology. Materials and Methods. Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 to form a cosolvent solution that was SFL processed. The dried micronized SFL powders were sealed in glass vials with desiccant and exposed to 25°C/60% RH for 3 and 6 mo, 40°C/75% RH for 1, 2, 3, and 6 mo, and conditions where the temperature was cycled between −5 and +40°C (6 cycles/24 hr) with constant 75% RH for 1, 2, 3 and 4 wk. The samples were characterized by using Karl–Fisher titration, differential scanning calorimetry, x-ray diffraction, specific surface area, scanning electron microscopy, and dissolution testing. Results. Micronized SFL powders consisting of porous aggregates with small-particle domains were characterized as having high surface areas and consisted of amorphous danazol embedded within a hydrophilic excipient matrix. Karl–Fischer titration revealed no moisture absorption over the duration of the stability studies. Differential scanning calorimetry studies demonstrated high degrees of molecular interactions between danazol, PVA, poloxamer, and PVP. Scanning electron microscopy studies confirmed these interactions, especially those between danazol and poloxamer. These interactions facilitated API dissolution in the aqueous media. Powder surface area remained constant during storage at the various stability conditions, and danazol recrystallization did not occur during the entirety of the stability studies. Micronized SFL powders containing danazol dissolved rapidly and completely within 5 min in aqueous media. No differences were observed in the enhanced dissolution profiles of danazol after exposure to the storage conditions investigated. Physically stable micronized powders produced by the SFL particle engineering technology were produced for the purpose of enhancing the dissolution of an insoluble drug. Conclusions. The potential of the SFL particle-engineering technology as a micronization technique for enhancing the dissolution of hydrophobic drugs was demonstrated in this study. The robustness of the micronized SFL powders to withstand stressed storage conditions was shown.

Spray freeze-drying - the process of choice for low water soluble drugs?

Most of the novel highly potent drugs, developed on the basis of modern molecular medicine, taking into account cell surface recognition techniques, show poor water solubility. A chemical modification of the drug substance enhancing the solubility often decreases the pharmacological activity. Thus, as an alternative an increase of the solubility can be obtained by the reduction of the size of the drug particles. Unfortunately, it is often difficult to obtain micro or nanosized drug particles by classical or more advanced crystallization using supercritical gases or by milling techniques. In addition, nanosized particles are often not physically stable and need to be stabilized in an appropriate matrix. Thus, it may be of interest to manufacture directly nanosized drug particles stabilized in an inert hydrophilic matrix, i.e. nanostructured and nanocomposite systems. Solid solutions and solid dispersions represent nanostructured and nanocomposite systems. In this context, the use of the vacuum-fluidized-bed technique for the spray-drying of a low water soluble drug cosolubilized with a hydrophilic excipient in a polar organic solvent is discussed. In order to avoid the use of organic solvents, a special spray-freeze-drying technique working at atmospheric pressure is presented. This process is very suitable for temperature and otherwise sensitive drugs such as pharmaproteins.

Long-acting microbicide delivery system

The use of certain amphiphilic acrylic graft copolymers for the development of a novel mucoadhesive drug delivery system has been investigated. These copolymers have a hydrophilic main chain and hydrophobic graft chains, which cause the formation of water-swollen but water-insoluble gels upon equilibration in an aqueous environment. Solutions of the copolymer in hydrophilic excipients were prepared as liquid dosage forms for intravaginal administration. It was found that the copolymer solutions, when brought in contact with a stimulated mucosal substrate or an animal mucosal tissue, underwent in situ gelation in a short period of time (» 2 minutes) to form a mucosa adhering gel. Strong mucoadhesion of the formed hydrogels was observed. It was also found that the hydrogels could provide sustained release of even hydrophilic microbicides (e.g. nonoxynol-9) over an extended period of time (>48 hours). This unique combination of mucoadhesivity and sustained drug release properties can be advantageous in the preparation of long acting microbicide formulations. Further, these in situ gelling liquid formulations can provide the necessary vaginal and cervical "coverage" because of their fluidity prior to gelation. We have tested biological activity of the copolymer solutions containing nonoxynol-9 (N-9) at concentrations comparable to those of other marketed products. A copolymer/N-9 formulation exhibited sperm immobilizing activity equivalent to that of the commercial 4% N-9 product, Conceptrol®. It was also found that the copolymer/N-9 formulations allow a much better biodiffusion of N-9 in the cervical mucous in comparison with Conceptrol®. This liquid mucoadhesive copolymer vehicle has the potential to enhance effectiveness and safety of microbicides for intravaginal administration, while improving user convenience and compliance.

Evaporative Drying of Aqueous Dispersions of Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) have been proposed as alternative colloidal drug carriers. SLNs are obtained by dispersing warm oil-in-water microemulsions into cold water. The aim of this research was to investigate an evaporative drying process for aqueous dispersions of SLNs. For this purpose, a special apparatus, namely, a thermostatic minidesiccator having alumina as the drying medium, was designed to carry out the evaporative drying at a controlled temperature. Besides the water removal kinetics, the mean particle size and the size distribution of SLNs were measured during the drying with the aim of detecting the highest temperature at which the drying process can be carried out without significantly affecting the SLN average diameter. The SLN dispersions were evaluated with and without a hydrophilic excipient, commonly used as a cryoprotector (trehalose). The drying temperature of 10°C was found to be the most suitable for obtaining SLNs as a powder, maintaining almost the same size as that of the SLNs in dispersion.

Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables

A novel in situ method for the preparation of injectable biodegradable poly(lactide-co-glycolide) (PLGA) microspheres for the controlled delivery of drugs is described here. A stable dispersion of PLGA microglobules (‘premicrospheres’ or ‘embryonic microspheres’) in a vehicle mixture on injection, comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion. The effect of the following formulation variables on the characteristics of the novel drug delivery system (NDDS) was investigated: (i) the concentrations of polyethylene glycol 400 (PEG 400), the encapsulated drug, and the hydrophilic excipient (mannitol); and (ii) the types of encapsulated drug (micromolecules and macromolecules such as protein) and vehicles (replacing triacetin and Miglyol 812 by triethyl citrate and soybean oil respectively). Also, the effect of formulation, process, and storage (15 days/4°C) conditions on the physical stability of the encapsulated protein was evaluated. The in vitro drug release was enhanced with decrease in the PEG 400 concentration and increase in the drug and mannitol concentration. The drug release was retarded with increase in the molecular weight of the encapsulated drug. Substitution of triacetin by triethyl citrate and miglyol 812 by soybean oil resulted in variation in the release of the drug from the in situ formed microspheres. A preliminary investigation of the physical stability of the myoglobin revealed that the α-helical structure was unaffected by the formulation, process, and the storage conditions.

Comparison of surface modification and solid dispersion techniques for drug dissolution

Surface modification and solid dispersion formulations using hydrophilic excipients can significantly alter the dissolution behaviour of hydrophobic drug materials. The effect of these techniques used individually and in combination on the dissolution properties of the hydrophobic drug, phenylbutazone (PB), are compared. PB was treated with a poloxamer, Synperonic ® F127 by an adsorption method. Solid dispersions (10 and 20% w/w) were prepared with untreated PB or PB previously modified with Synperonic ® F127 (PBT) in molten F127. Dissolution tests of capsule formulations of PB, PBT and solid dispersion formulations, in pH 6.4 buffer at 37±0.5°C demonstrated that after 140 min, release of PB was 16.7%, but 71.4% from the solid dispersion, whereas from the PBT formulation 85.6% was released. The Synperonic ® F127 content of PBT was only 0.05% of that in the solid dispersion formulation which suggests that it is the nature of the drug polymer contact rather than the amount of polymer which is more critical in influencing dissolution behaviour. Comparison of PBT and the 10% w/w solid dispersion of PBT in F127 showed similar amounts of drug in solution after 140 min. However there was a significantly higher release rate for PBT. Both formulation techniques offer significant improvements in drug release over untreated PB, and a combination of techniques changes the rate but not the extent of release in comparison with the surface modification technique alone.

In vitro delivery of a sparingly water soluble compound from PLA50 microparticles

The administration of a sparingly soluble drug is always problematic, especially when the drug has to be released from the degradable matrix of a polymeric drug delivery system. Attempts were made to achieve the complete release of 1-[2-(fluorobenzoyl) aminoethyl]-4-(7-methoxynaphtyl)piperazine (FAMP), a potential anxiolytic and antidepressor hydrophobic compound, from racemic poly(lactic acid) (PLA50)-based microparticles, 100% release was required at a low rate in order to allow monthly repeated S.C. or I.M. injections of this potent compound. FAMP-polymer combinations were made in the form of microspheres by the solvent evaporation technique. Release profiles were investigated under dynamic conditions by using a constant flow rate of pH 7.4 0.15 M phosphate buffer, used as a model of body fluids. Under these conditions, none of the microsphere compositions led to total release within a month, even when hydrophilic excipients, namely fructose and PEG were added. PLA50-FAMP microparticles with compositions and sizes similar to those of the microspheres, were then made by direct blending in dichloromethane, evaporation of the solvent, grinding and sieving. These formulations also failed in providing total drug release within 30 days, even at a high drug load. FAMP/PLA50/water-soluble additive, ternary grounded particles were finally prepared with fructose, PLA50 oligomers or poly(ethylene glycol) (PEG) as the additive. Only PLA50 grounded particles with percolating FAMP-PEG microdomains allowed 100% release of FAMP over a 30 day period, at a quasi constant rate which depended primarily on solubility and channelling provided the flow was slow enough. Data are discussed in terms of the accessibility of the entrapped drug to the aqueous medium.