Parameter estimation for roller compaction process using an instrumented vector TF mini roller compactor.

Using instrumented roll technology, statistical models relating process parameters such as hydraulic pressure, roll speed and screw speed of Vector TF mini roller compactor to ribbon normal stress and density were developed for placebo blends. Normal stress was found to be directly proportional to hydraulic pressure, roll speed and inversely to screw to roll speed ratio. A power-law relationship between ribbon density and normal stress was observed for placebo blends. Models developed for placebo were found to predict ribbon densities of active blends with good accuracy. Standard optimization of roller compaction process parameters involves the investment of a large amount of time and active ingredient. These models can, therefore, be utilized to predict starting instrument settings required to generate a ribbon of desired solid fraction during early-stage development where material availability & time is limited.

Relationships between response surfaces for tablet characteristics of placebo and API-containing tablets manufactured by direct compression method.

In this study, we evaluated the correlation between the response surfaces for the tablet characteristics of placebo and active pharmaceutical ingredient (API)-containing tablets. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Ten tablet formulations were prepared. The tensile strength (TS) and disintegration time (DT) of tablets were measured as tablet characteristics. The response surfaces for TS and DT were estimated using a nonlinear response surface method incorporating multivariate spline interpolation, and were then compared with those of placebo tablets. A correlation was clearly observed for TS and DT of all APIs, although the value of the response surfaces for TS and DT was highly dependent on the type of API used. Based on this knowledge, the response surfaces for TS and DT of API-containing tablets were predicted from only two and four formulations using regression expression and placebo tablet data, respectively. The results from the evaluation of prediction accuracy showed that this method accurately predicted TS and DT, suggesting that it could construct a reliable response surface for TS and DT with a small number of samples. This technique assists in the effective estimation of the relationships between design variables and pharmaceutical responses during pharmaceutical development.

Design, formulation and sensory evaluation of a polyphenol-rich food placebo: an example of aronia juice for food intervention studies.

Products suitable for use as controls in food interventions designed to demonstrate the role of minor components are largely lacking. In the present study, we aimed to develop a formulation to be used as a placebo in a clinical trial designed to assess the effects of aronia juice polyphenols on platelet function. Three formulations with the same nutrient composition as aronia juice were prepared by mixing various nutrients, artificial colours and flavours with water. The similarity of formulations to aronia juice in terms of taste, colour, smell and texture was assessed by six food panellists. The final placebo was tested for its impact on platelet function, biochemical and anthropometric parameters in a 4-week long study. No significant changes in platelet function, or in several cardiovascular and safety markers were recorded. Formulation suitable for use as a placebo for dietary intervention studies using aronia juice has been developed and demonstrated to be well tolerated in humans.

Granulation of increasingly hydrophobic formulations using a twin screw granulator.

The application of twin screw granulation in the pharmaceutical industry has generated increasing interest due to its suitability for continuous processing. However, an understanding of the impact of formulation properties such as hydrophobicity on intermediate and finished product quality has not yet been established. Hence, the current work investigated the granulation behaviour of three formulations containing increasing amounts of hydrophobic components using a Consigma™-1 twin screw granulator. Process conditions including powder feed rate, liquid to solid ratio, granulation liquid composition and screw configuration were also evaluated. The size of the wet granules was measured in order to enable exploration of granulation behaviour in isolation without confounding effects from downstream processes such as drying. The experimental observations indicated that the granulation process was not sensitive to the powder feed rate. The hydrophobicity led to heterogeneous liquid distribution and hence a relatively large proportion of un-wetted particles. Increasing numbers of kneading elements led to high shear and prolonged residence time, which acted to enhance the distribution of liquid and feeding materials. The bimodal size distributions considered to be characteristic of twin screw granulation were primarily ascribed to the breakage of relatively large granules by the kneading elements.

Roller compaction process development and scale up using Johanson model calibrated with instrumented roll data.

Roller compaction is a dry granulation process used to convert powder blends into free flowing agglomerates. During scale up or transfer of roller compaction process, it is critical to maintain comparable ribbon densities at each scale in order to achieve similar tensile strengths and subsequently similar particle size distribution of milled material. Similar ribbon densities can be reached by maintaining analogous normal stress applied by the rolls on ribbon for a given gap between rolls. Johanson (1965) developed a model to predict normal stress based on material properties and roll diameter. However, the practical application of Johanson model to estimate normal stress on the ribbon is limited due to its requirement of accurate estimate of nip pressure i.e. pressure at the nip angle. Another weakness of Johanson model is the assumption of a fixed angle of wall friction that leads to use of a fixed nip angle in the model. To overcome the above mentioned limitations, we developed a novel approach using roll force equations based on a modified Johanson model in which the requirement of pressure value at nip angle was eliminated. An instrumented roll on WP120 roller compactor was used to collect normal stress data measured at three locations across the width of a roll (P1, P2, P3), as well as gap and nip angle data on ribbon for placebo and various active blends along with corresponding process parameters. The nip angles were estimated directly using experimental pressure profile data of each run. The roll force equation of Johanson model was validated using normal stress, gap, and nip angle data of the placebo runs. The calculated roll force values compared well with those determined from the roll force equation provided for the Alexanderwerk(®) WP120 roller compactor. Subsequently, the calculation was reversed to estimate normal stress and corresponding ribbon densities as a function of gap and RFU (roll force per unit roll width). A placebo model was developed and calibrated using a subset of placebo run data obtained on WP120. The roll force values were calculated using vendor supplied equation. The nip angle was expressed as a function of gap and RFU. The nip angle, gap and RFU were used in a new roll force equation to estimate normal stress P2 at the center of the ribbon. Using ratios P1/P2 and P3/P2 from the calibration data set, P1 and P2 were estimated. The ribbon width over which P1, P2, and P3 are effective was determined by minimizing sum square error between the model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the placebo runs compared well with the experimental data. The placebo model also predicted with reasonable accuracy the ribbon densities of active A, B, and C blends prepared at various combinations of process parameters. The placebo model was then used to calculate scale up parameters from WP120 to WP200 roller compactor. While WP120 has a single screw speed, WP200 is equipped with a twin feed screw system. A limited number of roller compaction runs on WP200 was used as a calibration set to determine normal stress profile across ribbon width. The nip angle equation derived from instrumented roll data collected on WP120 was applied to estimate nip angles on WP200 at various processing conditions. The roll force values calculated from vendor supplied equation and the nip angle values were used in roll force equation to estimate normal stress P2 at the tip of the feed screws. Based on feed screw design, it was assumed that the normal stress at the center of the ribbon was equal to those calculated at the tip of the feed screws. The ratio of normal stress at the edge of the ribbon Pe to the normal stress P2 at the feed screw tip was optimized to minimize sum square error between model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the batches prepared on WP200 compared well with the experimental data thus indicating success of the scale up procedure. For the demonstration purpose, the model was also calibrated using instrumented roll data of active C batches. This would be applicable when sufficient amount of API is available or placebo model cannot predict ribbon density of active batches.

Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles: a porcine model.

PEGylated liposomal doxorubicin (Doxil) has been used in cancer chemotherapy for 16 years. Clinical experience shows that it can cause mild-to-severe hypersensitivity (infusion) reactions, which are manifestations of complement (C) activation-related pseudoallergy (CARPA). Although in most cases CARPA is inconsequential, a main symptom, cardiopulmonary distress, may be life threatening in hypersensitive individuals. To date, the prevention of Doxil-induced CARPA is based on premedication and a slow infusion protocol. The present study suggests desensitization by Doxil-like empty liposomes, called placebo Doxil (Doxebo), as an alternative strategy, which is based on the tachyphylactic nature of Doxil reactions. Doxebo-induced tolerance to Doxil was shown to develop within minutes and to be specific to Doxil-like PEGylated liposomes. The procedure of desensitization involves slow, low-dose pre-infusion of Doxebo before Doxil treatment which minimizes the ensuing physiological changes or keeps them subclinical. Although the mechanism of tolerance induction is not yet clear, the effector arm of C response is unlikely to be affected, as the vascular reactivity of desensitized pigs to zymosan remains intact. Desensitization with empty vesicles represents a novel approach for reducing the risk of anaphylactic reactions to drug carrier liposomes. The underlying immediate, most likely passive silencing of an innate immune response may represent a novel mechanism of tolerance induction which may work for other reactogenic nanosystems as well.

A material sparing test to predict punch sticking during formulation development.

CONTEXT: A qualitative and material sparing test for punch sticking was developed as a predictive development screening tool for comparison of formulation strategies and processing methods to eliminate punch adhesion. OBJECTIVE: To develop a predictive test for a formulation's potential to adhere to tablet punches during compression. MATERIALS AND METHODS: Two proprietary compounds, A and B, with histories of punch sticking during manufacturing but not in development, were formulated with microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate. Matching placebos were also prepared by the same methods. Flat faced bevel edge (FFBE) punches of 1/2" diameter were compared with 1/4" SRC punches and 1/4" Flat Faced (FF) punches for adhesion potential using a Kilian rotary tablet press and a Huxley Bertram compaction simulator. RESULTS AND DISCUSSION: Formulation accumulated on the punches after compression, which indicated potential for punch sticking that resulted in defective tablets with successive compactions. In all cases, only active formulations adhered to the FFBE and FF punches during tableting runs and with fewer compactions than the SRC punches. Those APIs were then reformulated and successfully manufactured using the predictive test results. Reducing the punch size to 1/4" permitted testing with 50 g of formulation, a ten-fold reduction in consumption compared to the 1/2" punches. CONCLUSION: Flat surfaced punches were shown to be more challenging to adhesive formulations than SRC punches. Adhesive formulations were reformulated and successfully manufactured without punch sticking.

A compressibility and compactibility study of real tableting mixtures: the impact of wet and dry granulation versus a direct tableting mixture.

The purpose of this study was to investigate the influence of various powder agglomeration processes on tableting mixture flow and compaction properties. Four different granulation methods of the same model placebo formulation were tested at a semi-industrial scale and their properties were compared to those of the directly compressed mixture. The wet granulated mixtures had superior flow properties compared to other mixtures and showed better compressibility, measured by the Heckel and Walker models. This was attributed to work hardening due to the double particle processing and also to shorter contact times due to higher initial densities of dry granulated mixtures, allowing a shorter time for deformation. A strong linear correlation was established between the Heckel and Walker coefficients, which was further confirmed by the net energy results of force-displacement measurements. It was shown that the Walker model had slightly better discriminative power to differentiate tableting mixtures according to compressibility. The compactibility was considerably lower for the slugged mixture; however, the roller-compacted mixture produced tablets with unexpectedly high tensile strength. In conclusion, it is important to emphasize that general assumptions like higher porosity => better compressibility or better compressibility => better compactibility cannot be established for complex tableting mixtures.

What's in placebos: who knows? Analysis of randomized, controlled trials.

BACKGROUND: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting. PURPOSE: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials. DATA SOURCES: 4 English-language general and internal medicine journals with high impact factors. STUDY SELECTION: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009. DATA EXTRACTION: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus. DATA SYNTHESIS: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002). LIMITATION: Journals with high impact factors may not be representative. CONCLUSION: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a reappraisal of their limitations and real indications.

PURPOSE OF REVIEW: The double-blind, placebo-controlled food challenge (DBPCFC) is widely considered as the 'gold standard' for the diagnosis of food allergy. However, in adult patients, this procedure is rather rarely performed outside the academic context. This review article aims to reappraise the pros and cons of DBPCFC and to elicit some critical thoughts and discussions about the real indications of this diagnostic procedure in adult patients in everyday practice. RECENT FINDINGS: There are many data showing that the DBPCFC poses a number of critical problems that are difficult to overcome in normal outpatient clinics and hospitals, and that are generally not addressed in most articles dealing with this issue. SUMMARY: Performing DBPCFC poses a number of practical problems and has several pitfalls, which make its routine use in normal clinical settings generally impossible. This review article shows that the need for this procedure in adult patients seems in effect very little and specifies new, more limited indications to its use in everyday practice. Further, it suggests a role for the open challenge, which lacks several of the disadvantages of DBPCFC.

Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink.

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.

The design and evaluation of placebo material for crude herbals: Artemisia afra herb as a model.

Herbal materials are known to present significant challenges with regard to designing credible placebos. This study intended to demonstrate the possibility of designing placebo material for crude herbals and used Artemisia afra, a popular traditional herbal medicine in South Africa, as a model. To produce the placebo, step-wise solvent extractions were conducted on the plant leaves and the process was monitored spectrophotometrically and using high performance liquid chromatography (HPLC) with diode array detection. The odour and taste between the placebo and A. afra was matched by inclusion of linalool and sodium saccharin, respectively. The muscle relaxant activity of the placebo was evaluated using an isolated guinea-pig tracheal muscle preparation. The UV absorbance of the extracts and the HPLC chromatograms, showed that most of the phytochemical constituents had been removed and the placebo closely resembled the A. afra leaves. The EC(50) of the placebo and the leaves were 4846.00 and 68.49 mg/mL, respectively, which showed that not only did the A. afra leaves possess muscle relaxant activity, but that the placebo did not possess any significant activity compared with the A. afra leaves (p value 0.0001). These results demonstrated that it is possible to design credible, pharmacologically inert placebo material for crude herbals.