Supersaturated Formulations Research Articles

Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer.

The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended "spring-parachute" process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.

Inhibition of Crystal Nucleation and Growth in Aqueous Drug Solutions: Impact of Different Polymers on the Supersaturation Profiles of Amorphous Drugs-The Case of Alpha-Mangostin.

The polymer used in supersaturated solutions plays a critical role in maintaining supersaturation levels of amorphous drugs. The prevention of drug crystallization in the supersaturated solutions by adding polymers depends on their ability to inhibit nucleation and crystal growth of drugs. This showed that understanding the mechanism of nucleation inhibition by polymers is necessary to develop the drug formulation in supersaturated solutions. Therefore, this study aims to evaluate the impact of water-soluble polymers on the supersaturation behavior of drugs and elucidate the mechanism of maintaining the supersaturation levels in an aqueous solution. It was carried out using alpha-mangostin (AM) as a model of the poorly water-soluble drug, while hypromellose (HPMC), polyvinylpyrrolidone (PVP), and eudragit were used as polymers. Their ability to inhibit the nucleation and crystal growth of AM was also evaluated. The supersaturation profiles of AM were measured in biorelevant dissolution media, while the crystal growth rate of AM was evaluated from the decrease in dissolved drug concentration by determining the induction time for AM nucleation. The interaction of AM with each polymer was evaluated and predicted by FT-IR, NMR measurement, and an in silico study, respectively. Based on observation, the PVP effectively maintained AM in a supersaturated state for the long term while eudragit conserved for 15 min. Meanwhile, an inhibitory effect of HPMC on the AM crystal nucleation was not observed. It was also \]-+discovered that the effectiveness of the various polymers depends on the interaction between the polymer and the drug. FT-IR and in silico studies demonstrated that the interaction of PVP-AM had the best polymer compared to eudragit and HPMC. NMR analysis suggested that the interaction between the methyl group from PVP with the carbonyl group of AM occurred in the PVP solution. The viscosity measurement revealed that the inhibition of nucleation and crystal growth of AM was not caused by increasing the viscosity. These results indicated that polymer-AM interactions could contribute to the crystallization inhibition and maintenance of AM in a supersaturated state. Therefore, an investigation of the mechanism of drug nucleation inhibition by polymers is recommended in the selection of crystallization inhibitors and a planned strategy to develop supersaturated formulations of drugs.

Artificial Neural Networks to Predict the Apparent Degree of Supersaturation in Supersaturated Lipid-Based Formulations: A Pilot Study.

In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.

“Felodipine-indomethacin” co-amorphous supersaturating drug delivery systems: “Spring-parachute” process, stability, in vivo bioavailability, and underlying molecular mechanisms

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation (“spring-parachute“ process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize “felodipine-indomethacin” CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous “spring-parachute” process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current “drug-drug” CAS supersaturable formulations.

An enteric polymer mitigates the effects of gastric pH on oral absorption of poorly soluble weak acid drugs from supersaturable formulations: A case study with dantrolene

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively. In vivo study with rats and in vitro study with a dissolution/permeation (D/P) system were performed to evaluate oral DNT absorption from each formulation under normal and high gastric pH conditions in rats and humans, respectively. The oral absorption of DNT from both IR-SFs in rats with a high gastric pH was significantly higher than that in rats with a normal gastric pH. In contrast, ASD-HPMCAS attenuated the difference in oral absorption between normal and high gastric pH conditions with significant improvement of DNT absorption. In vivo results implied that an enteric polymer delayed the onset of dissolution until after gastric emptying. ASD-HPMCAS generated supersaturation in the small intestine irrespective of gastric conditions, which was supported bythe in vitrostudy using the D/P system. This study suggested that an enteric polymer is useful to mitigate the inter- and intra-individual differences in oral absorption of poorly water-soluble weak acid drugs.

A Review on Precipitation inhibitors in supersaturable self emulsifying drug delivery system

The super saturable formulation has been widely used as an effective method to improve solubility and oral absorption of poorly aqueous-soluble drugs. When the super saturable formulation comes in contact with gastrointestinal fluids, its drug concentration goes over the equilibrium solubility, but this state does not exist for too long, the drug may precipitate before being absorbed, which minimizes the efficacy and bioavailability of the drug. Therefore, it is necessary to inhibit or retard the precipitation of drugs to achieve the maximum benefits of the super saturable formulation. Polymers (watersoluble and insoluble) are the commonly used excipients to inhibit precipitation. Cyclodextrins and surfactants are the other two excipients used as precipitation inhibitors. In some of the cases, even solid carriers can effectively retard precipitation. The precipitation inhibitors (PI) have the capacity to maintain a super saturable state of the formulation in GI for a particular time period. Therefore, it is important to properly select the precipitation inhibitor; too frequently used methods to select precipitation inhibitor are casting film method and solvent-shift method. Such selected and successfully used precipitation inhibitors are HPMC E5LV, PVP K17, HPMC E5, soluplus, poloxamer 407, HPMCAS, maltodextrin (mal) and microcrystalline cellulose (mcc). Since the super saturable technique has been widely used for delivering poorly water-soluble drugs like ezetimibe, indirubin, feno fibrate, butyl paraben and rosu vastatin calcium. There is a necessity for bio relevant evaluation of supersaturation/precipitation because simple methods like dissolution tests cannot be bio relevant in a supersaturation/precipitation context. Some of the important factors like sink versus non-sink conditions, hydrodynamic, medium selection and temperature play a vital role in the evaluation of in-vitro supersaturation

New insight into transdermal drug delivery with supersaturated formulation based on co-amorphous system.

The objective of this study was to prepare a supersaturated formulation based on formation of a co-amorphous system of a drug and a coformer in order to enhance skin permeation. Atenolol (ATE) and urea (URE) were used as the model drug and the coformer, respectively. Thermal analysis of physical mixtures of ATE and URE showed decreases in the melting points and the formation of a co-amorphous system which was in a supercooled liquid state because of a low glass transition temperature. Supersaturated solutions of ATE and URE at different molar ratios in polyethylene glycol 400 (PEG400) were prepared. The precipitations were observed under storage at 25 °C for all formulations except for ATE-URE at 1:8 molar ratio which remained in the supersaturated state for 2 months. 1H NMR analysis confirmed the interactions between ATE and URE in PEG400. The ATE-URE supersaturated formulation showed higher permeability for mice skin than that of ATE saturated formulation, which was superior to the expected permeability from the degree of supersaturation. We concluded that co-amorphous based supersaturated formulation offers much promise for transdermal drug delivery.

In Vitro Assessment of Supersaturation/Precipitation and Biological Membrane Permeation of Poorly Water-Soluble Drugs: A Case Study With Albendazole and Ketoconazole

This study aimed to elucidate the relationship between supersaturation and precipitation and the effect of a supersaturated state on drug membrane permeation. Stock solutions of albendazole (ALB) and ketoconazole (KTZ) dissolved in dimethyl sulfoxide (0.1-50 mg/mL) were diluted 100-fold with buffer solution (pH 6.8, 37°C). In the case of ALB, a supersaturated state and immediate precipitation were observed at 10 μg/mL or less and 20 μg/mL or higher, respectively. When KTZ was used, at an initial concentration of 200 μg/mL or higher, precipitation was observed, although the dissolved concentration remained at approximately 120 μg/mL for at least 30 min. These dissolved concentrations of ALB and KTZ related to approximately 10-fold and 14-fold over the saturated solubility from respective bulk powder. An in vitro permeation study implied that the rate of drug permeation across a biological membrane increased with increasing supersaturation. These results suggested favorable strategies for development of a supersaturable formulation could depend on the precipitation properties of the drug. Immediate- and controlled-release forms might be suitable for supersaturable formulations for KTZ and ALB, respectively.

Supersaturated Self Emulsifying Drug Delivery System: A Recent approach

For poorly water soluble compounds, formulation development has been a great challenge because of its lower solubility and poor oral absorption. Supersaturable selfemulsifying drug delivery system (SS-SEDDS) has been demonstrated as an most effective approach which improves the thermodynamic stability of a supersaturable formulation by inhibiting their precipitation In vivo and provide significantly higher intraluminal concentration of the drug through achieving supersaturation. Maintenance of supersaturation In vivo and the rate and degree of supersaturation by different precipitation inhibitors are the major challenging attributes for the pharmaceutical scientist. Presently, this review will focus on supersaturating drug delivery system including challenges of supersaturated solution and some measures to overcome these circumstances.

Optimizing Anti-Inflammatory and Immunomodulatory Effects of Corticosteroid and Vitamin D Analogue Fixed-Dose Combination Therapy.

Fixed-dose combination topical therapy with corticosteroid and vitamin D analog provides effective treatment and possible long-term management of psoriasis. The anti-inflammatory and immunomodulatory effects of corticosteroids and vitamin D analogs in treating psoriasis are well investigated; their complementary effects lead to the disruption of the inflammatory feedback loop underlying psoriasis pathogenesis. Recent preclinical data showed that combination therapy is more effective than monotherapies of the active ingredients in preventing activation of resting pro-inflammatory cells, inducing immunomodulation, reducing inflammatory responses by regulating T cell production, and normalizing keratinocytes. The increased understanding of the mechanism of action of fixed-dose combination therapy from preclinical studies is supported by several clinical studies. As the efficacy of topical therapy is correlated with the skin penetration of the active ingredients, new drug delivery systems have been developed. The fixed-dose combination Cal/BD aerosol foam creates a modified supersaturated formulation when applied to the skin, which is maintained for at least 26 h in the laboratory setting. Clinical studies have demonstrated superior efficacy of fixed-dose combination calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g aerosol foam compared with monotherapies of the active ingredients. Furthermore, Cal/BD aerosol foam has shown significantly improved efficacy compared with more traditional formulations, such as Cal/BD ointment and gel, in other studies. Calcipotriol also mitigates risks associated with betamethasone dipropionate and vice versa, resulting in the favorable safety profile observed with fixed-dose combination treatment. Recent data also suggest that fixed-dose combination treatment could provide long-term management of psoriasis, although further clinical investigations are needed. Overall, these data support the value of fixed-dose combination therapy of corticosteroid and vitamin D analog and highlight the added potential of innovative drug delivery for the treatment of psoriasis.FundingLEO Pharma.

A Polyvinylpyrrolidone-Based Supersaturable Self-Emulsifying Drug Delivery System for Enhanced Dissolution of Cyclosporine A.

A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)—a poorly water-soluble immunosuppressant—was constructed in order to attain an apparent concentration–time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 °C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.

In vivo evaluation of supersaturation/precipitation/re-dissolution behavior of cinnarizine, a lipophilic weak base, in the gastrointestinal tract: the key process of oral absorption

The aim of this study is to evaluate how supersaturation, precipitation, and re-dissolution processes influence the intestinal absorption of cinnarizine (CNZ), a lipophilic weak base, by monitoring its plasma and luminal concentration–time profile, after oral administration as a HCl solution containing fluorescein isothiocyanate dextran (FD-4), a non-absorbable marker. In the in vitro pH shift experiment, the supersaturation stability was significantly lower when the higher-concentration solution of CNZ (pH1.5) was added to the simulated intestinal fluid. However, although the in vivo bioavailability after oral administration of high and low dose as HCl solutions was greatly improved compared to those as neutral suspensions, the difference in the supersaturation stability was not reflected in the improvement of the in vivo bioavailability. Analysis of CNZ and FD-4 concentrations in each segment of the gastrointestinal tract revealed that most of the CNZ precipitated in the duodenum after gastric emptying, and supersaturation was observed only in the duodenum. Thereafter, the precipitate was rapidly re-dissolved and absorbed in the upper and middle small intestine. The rapid re-dissolution may be caused by smaller particles of the precipitate. In this case, it is considered that the key process for the absorption of CNZ was re-dissolution, not supersaturation. Therefore, different supersaturation stabilities in different doses observed in in vitro precipitation experiment was not reflected to in vivo absorption. These findings may be useful to design efficient supersaturable formulations and to validate and improve current prediction methods.

Physicochemical properties of direct compression tablets with spray dried and ball milled solid dispersions of tadalafil in PVP-VA

The aim of this research was to develop immediate release tablets comprising solid dispersion (IRSDTs) of tadalafil (Td) in a vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA), characterized by improved dissolution profiles. The solid dispersion of Td in PVP-VA (Td/PVP-VA) in a weight ratio of 1:1 (w/w) was prepared using two different processes i.e. spray drying and ball milling. While the former process has been well established in the formulation of IRSDTs the latter has not been exploited in these systems yet. Regardless of the preparation method, both Td/PVP-VA solid dispersions were amorphous as confirmed by PXRD, DSC and FTIR. However, different morphology of particles (SEM) resulted in differences in water apparent solubility and disk intrinsic dissolution rate (DIDR). Both solid dispersions and crystalline Td were successfully made into directly compressible tablets at three doses of Td, i.e. 2.5mg, 10mgand20mg, yielding nine different formulations (D1–D9). Each of the lots met the requirements set by Ph.Eur. and was evaluated with respect to appearance, diameter, thickness, mass, hardness, friability, disintegration time and content of Td. IRSDTs performed as supersaturable formulations and had significantly improved water dissolution profiles in comparison with equivalent tablets containing crystalline Td and the marketed formulations. Tablets with both spray dried and ball milled Td/PVP-VA revealed the greatest improvement in dissolution depending on the investigated doses, i.e. 2.5mgand20mg, respectively. Also, dissolution of Td from Td/PVP-VA delivered in different forms occurred in the following order: powders>tablets>capsules.

Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update.

The formulation development for poorly soluble drugs still remains a challenge. Supersaturating drug delivery systems (SDDS) or drug delivery systems based on supersaturating provide a promising way to improve the oral bioavailability of poorly water-soluble drugs. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when exposed to gastrointestinal fluids, and the supersaturation state is maintained long enough to be absorbed, resulting in compromised bioavailability. In this article, the mechanism of generating and maintaining supersaturation and the evaluation methods of supersaturation assays are discussed. Recent advances in different drug delivery systems based on supersaturating are the focus and are discussed in detail.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Application of Quality by Design for the Optimization of an HPLC Method to Determine Ezetimibe in a Supersaturable Self-Nanoemulsifying Formulation

This paper describes the optimization of an isocratic stability indicating HPLC method for Ezetimibe (EZM). A five factor, three-level Box-Behnken experimental design optimized the method. The responses were (1) retention time, (2) tailing factor, and (3) theoretical plates. The quadratic effect of percentage (v/v) acetonitrile was the most significant (p < 0.001) factor to affect retention time and tailing factor, while interactions between percentage (v/v) acetonitrile and buffer pH had the most significant (p < 0.05) effect upon theoretical plates. The developed models for each response found to be well predictive bearing an acceptable adjusted correlation coefficient (0.9752 for retention time, 0.8557 for tailing factor, and 0.8336 for theoretical plates). The models were found to be significant (p < 0.001) having a high F value for each response (89.63 for retention time, 14.34 for tailing factor, and 12.27 for theoretical plates). The global desirability found to be 0.93 for the optimum chromatographic condition that achieved at a temperature of 35 ± 2°C using acetonitrile–potassium dihydrogen phosphate (pH 3.5; 20 mM) (45:55, v/v). The flow rate and injection volume kept at 0.8 mL min−1 and 20 µL, respectively. The optimized chromatographic method subsequently applied to quantify EZM from a novel supersaturable self-nanoemulsifying formulation.

Supersaturated polymeric micelles for oral cyclosporine A delivery

Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81–3.53 (p<0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6±24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption.

Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations.

Drug precipitation inhibitors in supersaturable formulations

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.

Clinical experience with lanreotide for the treatment of acromegaly

Acromegaly is a rare disease, characterized in adults by its distinctive appearance of facial dysmorphism and swollen fingers. It is caused by an overproduction of growth hormone (GH) in more than 99% of patients and in nearly all cases is due to a pituitary adenoma. If surgical resection of the adenoma is not effective, medical treatment is usually the next treatment option. The most commonly used medications are the somatostatin analogues octreotide and lanreotide. Lanreotide is a synthetic somatostatin analogue and is available as slow-release microparticle (every 7–14 days) and prolonged-release liquid (autogel, every 28–56 days) formulations. Lanreotide autogel is a supersaturated aqueous formulation for deep subcutaneous injection and is sold in a ready-to-use prefilled syringe. This ease of use allows self or partner administration at home. This article reviews the use of lanreotide in the treatment of acromegaly and its advantages and disadvantages compared with other somatostatin analogues.

Formulation issues associated with transdermal fentanyl delivery

Supersaturation has previously been studied as a mechanism to enhance membrane transport of fentanyl from propylene glycol:water formulations (PG:H 2O) across silicone. In this study these supersaturated fentanyl formulations were evaluated in human skin. A number of polymers were also screened for their ability to stabilise the supersaturated formulations and permeation was evaluated for both infinite and finite doses. For infinite dose studies, permeation in skin increased linearly with increasing degree of drug saturation (DS) for formulations containing 0.5, 1, 2 DS of fentanyl and a 3 DS formulation stabilised with 1% (w/v) hydroxypropylcellulose (HPC). An excellent correlation was obtained for flux values in silicone compared with flux values in skin, for infinite dose studies for formulations containing 0.5, 1, 2 DS of fentanyl and the 3 DS formulation stabilised HPC. The concentration of the fentanyl in the stratum corneum also increased in proportion to the DS. However the same trend was not observed for finite dose studies. This is because the depletion of the solvent carrier promotes drug crystallisation with consequent implications for membrane transport. Tape-stripping experiments indicated that supersaturation of the drug is maintained in the outer layers of the stratum corneum. The ideal vehicle must, therefore, maintain the drug in solution on and in the skin in a sustained manner for effective transdermal delivery.