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ABSTRACT: Abstract A non-destructive method for monitoring creaming of emulsion-based formulations is in great demand because it allows us to understand fully their instability mechanisms. This study was aimed at demonstrating the usefulness of magnetic resonance (MR) techniques, including MR imaging (MRI) and MR spectroscopy (MRS), for evaluating the physicochemical stability of emulsion-based formulations. Emulsions that are applicable as the base of practical skin creams were used as test samples. Substantial creaming was developed by centrifugation, which was then monitored by MRI. The creaming oil droplet layer and aqueous phase were clearly distinguished by quantitative MRI by measuring T1 and the apparent diffusion coefficient. Components in a selected volume in the emulsions could be analyzed using MRS. Then, model emulsions having different hydrophilic-lipophilic balance (HLB) values were tested, and the optimal HLB value for a stable dispersion was determined. In addition, the MRI examination enables the detection of creaming occurring in a polyethylene tube, which is commonly used for commercial products, without losing any image quality. These findings strongly indicate that MR techniques are powerful tools to evaluate the physicochemical stability of emulsion-based formulations. This study will make a great contribution to the development and quality control of emulsion-based formulations.
Drug Development and Industrial Pharmacy 04/2013; · 1.49 Impact Factor
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets.
International journal of pharmaceutics 04/2013; · 2.96 Impact Factor
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ABSTRACT: The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations.
Chemical & pharmaceutical bulletin 01/2013; 61(3):304-9. · 1.70 Impact Factor
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ABSTRACT: A novel approach to establishing the design space for the oral formulation manufacturing process was investigated. A response surface method incorporating multivariate spline interpolation was applied to overcome the nonlinear problem, which is always problematic in pharmaceutical development studies, and a bootstrap resampling technique, polynomial approximation technique, and 95% confidence intervals based on a nonparametric approach were applied to estimate the reliability of the established design space derived from the nonlinear response surface model. The critical quality attributes (CQAs) of intermediate material rather than the critical process parameters (CPPs) were chosen as the causal factors for the response variables, which were CQAs of the final product to avoid scale-gap and equipment-gap. This enabled the effective use of data sets accumulated during all pharmaceutical development studies. It was confirmed that a conservative border as well as an optimistic border of the design space for practical use was obtained considering the variability of the border of the design spaces on nonlinear response surfaces. Furthermore, the nonlinear response surface model using CQAs of intermediate material derived from data sets of a laboratory scale study and pilot scale studies could predict the CQA of the final product (2.5 h dissolution of commercial-scale study) with high accuracy. Consequently, the proposed novel approach overcame all of the difficulties for the manufacturing process development of oral formulations and this is the first study to demonstrate the effectiveness of the design space using CQA of intermediate material for the oral formulation manufacturing process.
Chemical & pharmaceutical bulletin 01/2013; 61(1):39-49. · 1.70 Impact Factor
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ABSTRACT: Our recent work has shown that the intestinal absorption of insulin can be improved significantly by coadministration of cell-penetrating peptides (CPPs), especially penetratin. However, a relatively high dose of penetratin is required to adequately stimulate the intestinal absorption of insulin. Therefore, in this study, we sought to determine the CPP that most effectively enhanced intestinal insulin absorption. An in situ loop absorption study using 26 penetratin analogues suggested that the chain length, hydrophobicity, and amphipathicity of the CPPs, as well as their basicity, contribute to their absorption-enhancing efficiency. Moreover, a molecular orbital method with self-organizing maps (SOMs) classification suggested that multiple factors, including the molecular weight, basicity, the lowest unoccupied molecular orbital energy, absolute hardness, and chemical potential of CPPs, are associated with their effects on intestinal insulin absorption. Furthermore, the new CPPs proposed by SOM clustering had a marked capacity to interact with insulin, and their ability to enhance insulin absorption was much stronger than that of the original penetratin. Therefore, the peptide sequence that optimally enhances intestinal insulin absorption could be defined by SOM with the molecular orbital method, and our present work emphasizes the utility of such methodologies in the development of effective drug delivery systems. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Journal of Pharmaceutical Sciences 11/2012; · 3.06 Impact Factor
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ABSTRACT: Ritonavir dramatically increases the bioavailability of a variety of concurrently administered drugs by inhibition of metabolic enzymes and drug transporters. The purpose of this study was to investigate the extent to which ritonavir's inhibition of drug transporters and/or CYP3A contributes to the increased oral bioavailability in mice. The area under the plasma concentration-time curves (AUC) for orally administered saquinavir after coadministration with 50 mg/kg ritonavir dramatically increased (325-fold). As a result, the bioavailability, F(a)·F(g) and F(h) increased 75-, 38- and twofold, respectively. In addition, the increase in the AUC predicted from the in vitro Ki value was ninefold, which is derived from the inhibition of metabolic enzymes by ritonavir in the liver. The remaining 36-fold increase in the AUC was considered to be derived from the inhibition in the small intestine. The AUC(inf) for probe substrate midazolam, fexofenadine, and pravastatin increased after the oral administration of ritonavir by only five-, 13-, and sevenfold, respectively. Moreover, the AUC(0-12) for saquinavir was affected negligibly by itraconazole. These results indicate ritonavir mainly affects the first-pass effect of saquinavir in the small intestine, increasing the bioavailability of orally administered saquinavir. Furthermore, cyp isoforms other than CYP3A, which contribute to the metabolism of saquinavir in human, are involved in the metabolism of saquinavir in mice.
Drug Metabolism and Pharmacokinetics 09/2012; · 2.32 Impact Factor
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ABSTRACT: A multivariate statistical technique was applied to the design of an orally disintegrating tablet and to clarify the causal correlation among variables of the manufacturing process and pharmaceutical responses. Orally disintegrating tablets (ODTs) composed mainly of mannitol were prepared via the wet-granulation method using crystal transition from the d to the b form of mannitol. Process parameters (water amounts (X(1)), kneading time (X(2)), compression force (X(3)), and amounts of magnesium stearate (X(4))) were optimized using a nonlinear response surface method (RSM) incorporating a thin plate spline interpolation (RSM-S). The results of a verification study revealed that the experimental responses, such as tensile strength and disintegration time, coincided well with the predictions. A latent structure analysis of the pharmaceutical formulations of the tablet performed using a Bayesian network led to the clear visualization of a causal connection among variables of the manufacturing process and tablet characteristics. The quantity of b-mannitol in the granules (Q(b)) was affected by X(2) and influenced all granule properties. The specific surface area of the granules was affected by X(1) and Q(b) and had an effect on all tablet characteristics. Moreover, the causal relationships among the variables were clarified by inferring conditional probability distributions. These techniques provide a better understanding of the complicated latent structure among variables of the manufacturing process and tablet characteristics.
Chemical & pharmaceutical bulletin 08/2012; · 1.70 Impact Factor
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ABSTRACT: Oral sulfasalazine (SASP) is now used clinically as a probe substrate of a breast cancer resistance protein (BCRP) activity; however the intestinal absorption characteristics of SASP are not well understood. The purpose of this study was to clarify the characteristics of SASP transport in the mouse intestine. The everted ileum was incubated with SASP in the absence or presence of the Bcrp inhibitor Ko134. The steady-state intestinal absorptive clearance was 0.14 µL/min/cm in the absence of Ko134 and increased by 4.8-fold in the presence of Ko134. These results indicate that Bcrp mediates the efflux of SASP in the intestine. The absorptive clearance of SASP did not change in a concentration-dependent manner in the range of 0.1 to 50 µM in wild-type mice. By contrast, the absorptive clearance of SASP decreased significantly in a concentration-dependent manner in the presence of Ko134. Similar results were obtained in Bcrp(-/-) mice. These results suggest the possible involvement of some influx transporters in the intestinal absorption of SASP. In conclusion, both the influx and efflux transporters are involved in the intestinal absorption of SASP, which would explain why the absorptive clearance did not appear to change at various SASP concentrations in wild-type mice.
Drug Metabolism and Pharmacokinetics 07/2012; · 2.32 Impact Factor
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ABSTRACT: Multivariate statistical analysis has and will continue to play an important role in the development of pharmaceutical products.
Although many examples have been reported, few have applied multivariate statistical analysis to the overall manufacturing
process. In this study, the model drug core tablets were manufactured under different conditions, and the challenge to understand
the cause-and-effect relationship between process parameters and response variables was addressed by applying three different
multivariate statistical methods. It was confirmed that conventional multivariate statistical methods were able to extract
the process parameters (granulation time, drying temperature, blending time, and compression force) that affected both the
average and the variance of the response variables (hardness, content uniformity, and dissolution) with a science-based rationale.
In order to overcome the multiobjective optimization problem among the response variables, an advanced multivariate statistical
method was also applied. It was confirmed that the mathematical models of response variables were determined with sufficiently
high accuracy and the optimal levels of both process parameters and response variables were determined with high reliability,
which provided a more profound understanding of the process. These methods enable us to develop pharmaceutical products more
efficiently and accurately.
KeywordsQuality by design–Process understanding–Multivariate statistical analysis–Confidence intervals–Bootstrap resampling technique
Journal of Pharmaceutical Innovation 04/2012; 6(3):157-169. · 0.79 Impact Factor
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ABSTRACT: The aim of this study was to create a tablet database for use in designing tablet formulations. We focused on the contribution of active pharmaceutical ingredients (APIs) to tablet properties such as hardness and disintegration time (DT). Before we investigated the effects of the APIs, we optimized the tablet base formulation (placebo tablet) according to an expanded simplex search. The optimal placebo tablet showed sufficient hardness and rapid disintegration. We then tested 14 kinds of compounds as the model APIs. The APIs were characterized in terms of their physicochemical properties using Kohonen's self-organizing maps. We also prepared model tablets by incorporating the APIs into the optimal placebo tablet, and then examined the tablet properties, including tensile strength and DT. On the basis of the experimental data, an ensemble artificial neural network incorporating general regression analysis was conducted. A reliable model of the correlation between the physicochemical properties of the APIs and the tablet properties was thus constructed. From the correlation model, we clarified the detailed contributions of each physicochemical property to the tablet attributes.
Journal of Pharmaceutical Sciences 03/2012; 101(7):2372-81. · 3.06 Impact Factor
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ABSTRACT: A large-scale design space was constructed using a Bayesian estimation method with a small-scale design of experiments (DoE) and small sets of large-scale manufacturing data without enforcing a large-scale DoE. The small-scale DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. The constant Froude number was applied as a scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on a large scale by Bayesian estimation using the large-scale results. Large-scale experiments under three additional sets of conditions showed that the corrected design space was more reliable than that on the small scale, even if there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.
Drug Development and Industrial Pharmacy 02/2012; · 1.49 Impact Factor
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ABSTRACT: A reliable large-scale design space was constructed by integrating the reliability of a scale-up rule into the Bayesian estimation without enforcing a large-scale design of experiments (DoE). A small-scale DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. A constant Froude number was applied as a scale-up rule. Experiments were conducted at four different small scales with the same Froude number and blending time in order to determine the discrepancies in the response variables between the scales so as to indicate the reliability of the scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on the large scale by Bayesian estimation using the large-scale results and the reliability of the scale-up rule. Large-scale experiments performed under three additional sets of conditions showed that the corrected design space was more reliable than the small-scale design space even when there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.
Chemical & pharmaceutical bulletin 01/2012; 60(9):1155-63. · 1.70 Impact Factor
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ABSTRACT: The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice.
Chemical & pharmaceutical bulletin 01/2012; 60(1):86-93. · 1.70 Impact Factor
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ABSTRACT: Menthosomes, novel deformable carriers for the enhancement of transdermal delivery are introduced in this study. Meloxicam (MX)-loaded menthosomes were formulated, and their physicochemical characteristics and skin permeability were evaluated. A two-factor spherical and second-order composite experimental design was used to prepare the formulation of the menthosomes. Ten formulations of menthosomes composed of a phospholipid as the lipid bilayer carrier, cholesterol (Chol) as a stabilizer and cetylpyridinium chloride (CPC) and L-menthol as penetration enhancers were prepared. The amounts of Chol and CPC were selected as causal factors. Physicochemical characteristics (particle size, size distribution, zeta potential, elasticity and drug content) and an in vitro skin-permeation study of meloxicam-loaded menthosomes were evaluated. The concentrations of MX that permeated the skin at 2-12 h and the flux were selected as response variables. The optimal formulation was estimated using a nonlinear response-surface method incorporating thin-plate spline interpolation. The experimental values were very close to the values predicted by the computer programs in this study. A Bayesian network analysis was applied to gain a mechanistic understanding of the relationships between causal factors and response variables.
Biological & Pharmaceutical Bulletin 01/2012; 35(10):1720-8. · 1.66 Impact Factor
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ABSTRACT: Design spaces for multiple dose strengths of tablets were constructed using a Bayesian estimation method with one set of design of experiments (DoE) of only the highest dose-strength tablet. The lubricant blending process for theophylline tablets with dose strengths of 100, 50, and 25 mg is used as a model manufacturing process in order to construct design spaces. The DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) for theophylline 100-mg tablet. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) of the 100-mg tablet were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. Three experiments under an optimal condition and two experiments under other conditions were performed using 50- and 25-mg tablets, respectively. The response surfaces of the highest-strength tablet were corrected to those of the lower-strength tablets by Bayesian estimation using the manufacturing data of the lower-strength tablets. Experiments under three additional sets of conditions of lower-strength tablets showed that the corrected design space made it possible to predict the quality of lower-strength tablets more precisely than the design space of the highest-strength tablet. This approach is useful for constructing design spaces of tablets with multiple strengths.
Chemical & pharmaceutical bulletin 01/2012; 60(11):1399-408. · 1.70 Impact Factor
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ABSTRACT: Dividing a tablet into two halves and providing them to patients is a routine approach in clinical practice. Obviously, the drug release behavior of tablets should be constant, regardless of the dividing process. Here, we investigated the change in drug release behavior after dividing tablets into two halves. Five commercial theophylline sustained-release tablets designed to be taken once a day were used as test tablets (two original products and three generic products). A 24 h dissolution test was performed for each tablet, and changes in drug release behavior were evaluated using similarity factors, f2, calculated from the drug release profiles. The drug release rates were substantially increased by dividing the tablets into two halves. Analysis of variance (ANOVA) revealed that the effect of the dividing process on drug release behavior was more significant than that of changing the products. We further observed the feature of cross sectioning of the surface of the tablets using a scanning electron microscope (SEM) and a laser-scanning microscope (LSM). The microscopic observations confirmed that the surface became rough and developed many cavities with the prolongation of the duration of the dissolution test. This study clarified that the division of tablets into two halves exerts significant effects on their drug release behavior, and may offer a profound insight into the proper use of pharmaceutical products.
YAKUGAKU ZASSHI 01/2012; 132(2):225-30. · 0.37 Impact Factor
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ABSTRACT: We reported previously that sustained release matrix tablets showed zero-order drug release without being affected by pH change. To understand drug release mechanisms more fully, we monitored the swelling and erosion of hydrating tablets using magnetic resonance imaging (MRI). Three different types of tablets comprised of polyion complex-forming materials and a hydroxypropyl methylcellulose (HPMC) were used. Proton density- and diffusion-weighted images of the hydrating tablets were acquired at intervals. Furthermore, apparent self-diffusion coefficient maps were generated from diffusion-weighted imaging to evaluate the state of hydrating tablets. Our findings indicated that water penetration into polyion complex tablets was faster than that into HPMC matrix tablets. In polyion complex tablets, water molecules were dispersed homogeneously and their diffusivity was relatively high, whereas in HPMC matrix tablets, water molecule movement was tightly restricted within the gel. An optimal tablet formulation determined in a previous study had water molecule penetration and diffusivity properties that appeared intermediate to those of polyion complex and HPMC matrix tablets; water molecules were capable of penetrating throughout the tablets and relatively high diffusivity was similar to that in the polyion complex tablet, whereas like the HPMC matrix tablet, it was well swollen. This study succeeded in characterizing the tablet hydration process. MRI provides profound insight into the state of water molecules in hydrating tablets; thus, it is a useful tool for understanding drug release mechanisms at a molecular level.
Chemical & pharmaceutical bulletin 01/2012; 60(4):536-42. · 1.70 Impact Factor
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ABSTRACT: Formulation design space of indomethacin tablets was investigated using a nonlinear response surface method incorporating multivariate spline interpolation (RSM-S). In this study, a resampling method with replacement was applied to evaluate the reliability of border on the design space estimated by RSM-S. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Response surfaces were estimated using RSM-S, and the nonlinear design space was defined under the restriction of more than 3 kgf hardness and more than 70% dissolution 30 min before and after an accelerated test. The accuracy of the resampling method was elucidated and high correlation coefficients were produced. However, the distribution of the border on the design space generated by the resampling method was far from normal, and the confidence interval of the border was estimated using a nonparametric percentile technique. Consequently, the reliability of the design space was decreased by approaching the edge of the experimental design. RSM-S and this resampling method might be useful for estimating the reliability of nonlinear design space.
Journal of Pharmaceutical Sciences 08/2011; 101(1):333-41. · 3.06 Impact Factor
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ABSTRACT: When designing pharmaceutical products, the relationships between causal factors and pharmaceutical responses are intricate. A Bayesian network (BN) was used to clarify the latent structure underlying the causal factors and pharmaceutical responses of a tablet containing solid dispersion (SD) of indomethacin (IMC).
IMC, a poorly water-soluble drug, was tested with polyvinylpyrrolidone as the carrier polymer. Tablets containing a SD or a physical mixture of IMC, different quantities of magnesium stearate, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose, and subjected to different compression force were selected as the causal factors. The pharmaceutical responses were the dissolution properties and tensile strength before and after the accelerated test and a similarity factor, which was used as an index of the storage stability.
BN models were constructed based on three measurement criteria for the appropriateness of the graph structure. Of these, the BN model based on Akaike's information criterion was similar to the results for the analysis of variance. To quantitatively estimate the causal relationships underlying the latent structure in this system, conditional probability distributions were inferred from the BN model. The responses were accurately predicted using the BN model, as reflected in the high correlation coefficients in a leave-one-out cross-validation procedure.
The BN technique provides a better understanding of the latent structure underlying causal factors and responses.
Drug Development and Industrial Pharmacy 06/2011; 37(11):1290-7. · 1.49 Impact Factor
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ABSTRACT: A latent structure analysis of pharmaceutical formulations was performed using Kohonen's self-organizing map (SOM) and a Bayesian network. A hydrophilic matrix tablet containing diltiazem hydrochloride (DTZ), a highly water-soluble model drug, was used as a model formulation. Nonlinear relationship correlations among formulation factors (oppositely charged dextran derivatives and hydroxypropyl methylcellulose), latent variables (turbidity and viscosity of the polymer mixtures and binding affinity of DTZ to polymers), and release properties [50% dissolution times (t50s) and similarity factor] were clearly visualized by self organizing feature maps. The quantities of dextran derivatives forming polyion complexes were strongly related to the binding affinity of DTZ to polymers and t50s. The latent variables were classified into five characteristic clusters with similar properties by SOM clustering. The probabilistic graphical model of the latent structure was successfully constructed using a Bayesian network. The causal relationships among the factors were quantitatively estimated by inferring conditional probability distributions. Moreover, these causal relationships estimated by the Bayesian network coincided well with estimations by SOM clustering, and the probabilistic graphical model was reflected in the characteristics of SOM clusters. These techniques provide a better understanding of the latent structure between formulation factors and responses in DTZ hydrophilic matrix tablet formulations.
Journal of Pharmaceutical Sciences 03/2011; 100(3):964-75. · 3.06 Impact Factor
