A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery.

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review.

OBJECTIVES: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. KEY FINDINGS: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. SUMMARY: Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs - a PEARRL review.

OBJECTIVES: Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water-soluble drugs. KEY FINDINGS: An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid-based delivery, solid dispersions and nano- or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. SUMMARY: In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early-stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour-intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.

Extrapolation of Valacyclovir Posology to Children Based on Pharmacokinetic Modeling.

BACKGROUND: Valacyclovir is a prodrug of acyclovir. Although acyclovir is approved for children in Europe, valacyclovir is not approved, despite being used off-label. The aim of the study was to extrapolate the approved dosages of acyclovir, to valacyclovir dosages, in children using Monte Carlo simulations based on the population pharmacokinetic (PopPK) models of valacyclovir and acyclovir. METHODS: Assuming that the recommended dosages of acyclovir are efficacious, a PopPK model of acyclovir was used to perform simulations to determine a critical concentration (Ccrit) for which a target criterion is fulfilled, ie, 90% of the simulated patients have acyclovir levels above Ccrit for at least half the time. The same was done for a secondary target, drug exposure, determining a critical area under the curve in 24 hours at steady state. Then a PopPK model of valacyclovir was used to determine by simulations, dosage regimens that fulfill the criteria for both targets. This was repeated for various indications and age groups. RESULTS: Indicatively, for the treatment of varicella zoster virus, in ages 2-12 years, Ccrit and critical area under the curve in 24 hours at steady state were found to be 0.39 mg/L and 9.6 mg/L × h, respectively, using the acyclovir approved doses 20 mg/kg 4 times daily. For these breakpoints, a 20 mg/kg, 3 times daily, valacyclovir dose achieves the targets in 97% and 100% of the patients, respectively. We found that some patients receive higher than the ideal doses of acyclovir. CONCLUSIONS: Simulations were used to determine the appropriate doses of valacyclovir in children to support a pediatric investigation plan targeting a paediatric-use marketing authorization application in the European Medicines Agency.

Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling.

OBJECTIVES: To extrapolate enalapril efficacy to children 0-6 years old, a pharmacokinetic/pharmacodynamic (PKPD) model was built using literature data, with blood pressure as the PD endpoint. METHODS: A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses. The final PKPD model was validated with literature paediatric efficacy observations (diastolic blood pressure (DBP) drop after 2 weeks of treatment) in children of age 6 years and higher. The model was used to predict enalapril efficacy for ages 0-6 years. KEY FINDINGS: A two-compartment PK model was chosen with weight, reflecting indirectly age as a covariate on clearance and central volume. An indirect link PD model was chosen to describe drug effect. External validation of the model's capability to predict efficacy in children was successful. Enalapril efficacy was extrapolated to ages 1-11 months and 1-6 years finding the mean DBP drop 11.2 and 11.79 mmHg, respectively. CONCLUSIONS: Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application.

Recent advances in oral pulsatile drug delivery.

Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action. Currently, it is gaining increasing attention as it offers a more sophisticated approach to the traditional sustained drug delivery i.e: a constant amount of drug released per unit time or constant blood levels. Technically, pulsatile drug delivery systems administered via the oral route could be divided into two distinct types, the time controlled delivery systems and the site-specific delivery systems. The simplest pulsatile formulation is a two layer press coated tablet consisted of polymers with different dissolution rates. Homogenicity of the coated barrier is mandatory in order to assure the predictability of the lag time. The disadvantage of such formulation is that the rupture time cannot be always adequately manipulated as it is strongly correlated with the physicochemical properties of the polymer. Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.

In vitro methods can forecast the effects of intragastric residence on dosage form performance.

Intragastric conditions can affect the performance of solid dosage forms. For two cases, the ability of in vitro methods to forecast these effects was investigated: first, the ability of cholestyramine to sequester bile salts in the fed small intestine and, second, disintegration times of hard gelatin capsules. After incubating cholestyramine for 90 min in milk gradually digested with pepsin, the binding of taurocholates from fed state simulating intestinal fluid onto the resin became non-specific and the affinity constant was reduced from 220 l/mole (without prior incubation) to 60 l/mole. These data are consistent with the comparatively poor performance of cholestyramine products when administered in the fed state. Scintigraphic studies showed that intragastric disintegration times of hard gelatin capsules are delayed in both the fasted and fed states according to the degree of cross-linking. These results were satisfactorily predicted by the in vitro disintegration times in fasted state simulating gastric fluid and in milk gradually digested with pepsin, whereas results were poorly predicted in compendial media. This work illustrates that recently proposed methods for simulating intragastric environment may be useful in predicting the performance of solid dosage forms.

Predictive models for oral drug absorption: from in silico methods to integrated dynamical models.

Poor oral absorption is one of the most common reasons for a drug to be terminated during development. Oral drug absorption is a complex process affected by many competing factors related to the compound, the formulation and the gastrointestinal physiology. Throughout drug development, in silico, computational and mathematical models play important roles in the support of drug development and decision making in absorption-related issues. These models range from simple empirical rule of thumb tools to sophisticated dynamic systems. This article reviews the different computational methods for oral drug absorption for the various processes, with emphasis on solubility, permeability, dissolution and release rates, and gastrointestinal transit, but also on the modern integrated absorption prediction systems and computer software.

Estimation of intragastric solubility of drugs: in what medium?

PURPOSE: To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. MATERIALS AND METHODS: Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF(SLS), SGF(Triton), FaSSGF, FaSSGF(NaCl), and in various HCl solutions with pH values ranging from 1.2 to 2.9. RESULTS: In all cases, FaSSGF performed better than canine aspirates, SGF(SLS), SGF(Triton), or FaSSGF(NaCl) in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, -39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. CONCLUSIONS: Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.

Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents.

PURPOSE: This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies. METHODS: After administration of 250 mL of water or 500 mL of Ensure plus [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids. The shake-flask method was used to measure the solubility of dipyridamole and ketoconazole in pooled human and canine intestinal contents and in fasted-state-simulating intestinal fluid (FaSSIF) and fed-state-simulating intestinal fluid (FeSSIF) containing various bile salts and pH-buffering agents. RESULTS: For both compounds, solubility in canine contents may be predictive of human intralumenal solubility in the fasting state but not in the fed state. The poor agreement of results in canine and human aspirates can be attributed to the higher bile salt content in canine bile. Solubility in FaSSIF containing a mixture of bile salts from crude bile predicted satisfactorily the intralumenal solubility of both drugs in the fasted state in humans. Solubility in FeSSIF, regardless of the identity of bile salts or of the buffering species, deviated from intralumenal values in the fed human aspirates by up to 40%. This was attributed to the lack of lipolytic products in FeSSIF, the higher bile salt content of FeSSIF, and the lower pH of FeSSIF. CONCLUSIONS: FaSSIF containing a mixture of bile salts from crude bile, and FeSSIF containing lipolytic products and, perhaps, having lower bile salt content but slightly higher pH, should be more useful than canine intestinal aspirates for predicting intralumenal solubilities in humans.

Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies.

PURPOSE: This study was conducted to compare the luminal composition of the upper gastrointestinal tract in the fasted and fed states in humans, with a view toward designing in vitro studies to explain/predict food effects on dosage form performance. METHODS: Twenty healthy human subjects received 250 mL water or 500 mL Ensure plus (a complete nutrient drink) through a nasogastric tube and samples were aspirated from the gastric antrum or duodenum for a period up to 3.5 h, depending on location/fluid combination. Samples were analyzed for polyethylene glycol, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, and bile salts. RESULTS: Following Ensure plus administration, gastric pH was elevated, buffer capacity ranged from 14 to 28 mmoL L-1 DeltapH-1 (vs. 7-18 mmol L-1 DeltapH-1), contents were hyperosmolar, gastric pepsin levels doubled, and surface tension was 30% lower than after administration of water. Post- and preprandial duodenal pH values were initially similar, but slowly decreased to 5.2 postprandially, whereas buffer capacity increased from 5.6 mmol L-1 DeltapH-1 (fasted) to 18-30 mmol L-1 DeltapH-1 (p<0.05). Postprandial surface tension in the duodenum decreased by >30%, bile salt levels were two to four times higher, luminal contents were hyperosmotic, and the presence of peptides and sugars was confirmed. CONCLUSIONS: This work shows that, in addition to already well characterized parameters (e.g., pH, and bile salt levels), significant differences in buffer capacity, surface tension, osmolality, and food components are observed pre-/postprandially. These differences should be reflected in test media to predict food effects on intralumenal performance of dosage forms.

The delayed dissolution of paracetamol products in the canine fed stomach can be predicted in vitro but it does not affect the onset of plasma levels.

Although it is generally believed that paracetamol can be used as a marker of gastric emptying, there have been reports in the literature that show delayed dissolution of immediate release paracetamol tablets using standard in vitro setups and food-simulating media, delayed disintegration of paracetamol products in the fed stomach, and no correlation of paracetamol absorption with gastric emptying in the fed state. In this study, we confirmed that dissolution of Panodil and Apotel tablets is delayed in food-simulating media regardless of the in vitro hydrodynamics and on a formulation dependent manner. Further, we assessed the usefulness of in vitro dissolution data in the prediction of delayed disintegration time in the fed stomach and we examined the importance of delayed gastric disintegration on the onset of plasma levels using the canine model. In vitro dissolution data in cow's milk reflected the delayed disintegration of Panodil tablets in the fed stomach. In vitro dissolution of Apotel tablets in milk was delayed less than of Panodil and the effect of dosing conditions on the in vivo disintegration was not apparent. However, for the products tested in this study, there was no correlation between intragastric disintegration and onset of plasma levels probably because gastric emptying in also delayed in the fed state.