The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: Formulation and in vitro/in vivo evaluation

This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5 × 3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T_50%) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8 h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar^® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r² = 0.9805) between fractions dissolved in vitro and fractions absorbed in vivo.     

Influence of polyethylene glycol/polyethylene oxide on the release characteristics of sustained-release ethylcellulose mini-matrices produced by hot-melt extrusion: in vitro and in vivo evaluations

Mini-matrices with release-sustaining properties were developed by hot-melt extrusion (diameter 3 mm, height 2 mm) using metoprolol tartrate as model drug (30%, w/w) and ethylcellulose as sustained-release agent. Polyethylene glycol or polyethylene oxide was added to the formulation to increase drug release. Changing the hydrophilic polymer concentration (0%, 1%, 2.5%, 5%, 10%, 20% and 70%, w/w) and molecular weight (6000, 100,000, 1,000,000 and 7,000,000) modified the in vitro drug release: increasing concentrations yielded faster drug release (irrespective of molecular weight), whereas the influence of molecular weight depended on concentration. Smooth extrudates were obtained when processed at 40 and 70 °C for polyethylene glycol and polyethylene oxide formulations, respectively. Raman analysis revealed that metoprolol tartrate was homogeneously distributed in the mini-matrices, independent of hydrophilic polymer concentration and molecular weight. Also drug and polymer crystallinity were independent of both parameters. An oral dose of 200 mg metoprolol tartrate was administered to dogs in a randomized order either as immediate-release preparation (Lopresor^® 100), as sustained-release formulation (Slow-Lopresor^® 200 Divitabs^®), or as experimental mini-matrices (varying in hydrophilic polymer concentration). The sustained-release effect of the experimental formulations was limited, and relative bioavailabilities of 66.2% and 148.2% were obtained for 5% and 20% PEO 1,000,000 mini-matrices, respectively.     

Evolution of a physiological pH 6.8 bicarbonate buffer system: Application to the dissolution testing of enteric coated products

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH 7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1 M HCl for 2 h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer.     

Novel extended-release formulation of lovastatin by one-step melt granulation: In vitro and in vivo evaluation

The objective of this study was to apply a one-step melt granulation method to develop an extended-release formulation of lovastatin (LOV-ER). We prepared a formulation using PEG 6000 as binder agent in a laboratory scale high-shear mixer. In vitro dissolution studies showed that the release of the drug from the new formulation followed a zero-order kinetic with no differences in the release profile with either the pH media or the agitation rate. The pharmacokinetic of lovastatin and its metabolite lovastatin acid was evaluated after the administration of the new formulation to Beagle dogs in fasted conditions and after a high-fat meal, and compared to the marketed formulation Altoprev®. After the administration of LOV-ER, extended plasma profiles of lovastatin and its active metabolite were achieved in both fasted conditions and after the high-fat meal. Plasma levels of lovastatin and lovastatin acid were always higher when the LOV-ER formulation was administered with the high-fat meal. A high variability in plasma levels and pharmacokinetic parameters was obtained, being this variability higher when the formulation was administered under fasting conditions. Our results suggest that there is an increase in lovastatin bioavailability when the formulation is administered after the high-fat meal. When we compare LOV-ER and Altoprev®, both administered after the high-fat meal, we found significant differences (p < 0.05) in C_max of lovastatin and in AUC_0-∞ and MRT of lovastatin acid. No differences were detected between both formulations in fasting conditions. In this regard, the high-fat meal seems to increase the absorption extent of lovastatin from LOV-ER formulation and to delay the absorption rate of the drug from Altoprev®. In conclusion, we developed a lovastatin formulation that provided extended plasma levels that confirm that one-step melt granulation in high-shear mixer could be an easy and cost-effective technique for extended-release formulation development.     

Terahertz pulsed imaging as an analytical tool for sustained-release tablet film coating

The ability of terahertz pulsed imaging (TPI) to be employed as an analytical tool for monitoring a film coating unit operation and to assess the success of a subsequent process scale-up was explored in this study. As part of a process scale-up development, a total of 190 sustained-release tablets were sampled at 10% increments of the amount of polymer applied, from a lab-scale and a pilot-scale coating run. These tablets were subjected to TPI analysis, followed by dissolution testing. Information on tablet film coating layer thickness and variations in coating density were extracted using TPI. It was found that both terahertz parameters were more sensitive and informative to product quality when compared with measuring the amount of polymer applied. For monitoring the film coating unit operation, coating layer thickness showed a strong influence on the dissolution behaviour for both the lab-scale and the pilot-scale batches. An R² of 0.89, root mean square error (RMSE) = 0.22 h (MDT range = 3.21-5.48 h) and an R² of 0.92, RMSE = 0.23 h (MDT range = 5.43-8.12 h) were derived from the lab-scale and pilot-scale, respectively. The scale-up process led to significant changes in MDT between the lab-scale and pilot-scale. These changes in MDT could be explained by the differences observed in the film coating density on samples with similar amount of polymer applied between the lab and the pilot-scale. Overall, TPI demonstrated potential to be employed as an analytical tool to help refine the coating unit operation and the scale-up procedure.     

Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.     

Establishing the optimal nebulization system for paclitaxel,docetaxel, cisplatin,carboplatin and gemcitabine: Back to drawing the residual cup

Background

Chemotherapy drugs have still the major disadvantage of non-specific cytotoxic effects. Although, new drugs targeting the genome of the tumor are already in the market, doublet chemotherapy regimens still remain the cornerstone of lung cancer treatment. Novel modalities of administration are under investigation such as; aerosol, intratumoral and intravascular.

Materials and methods

In the present study five chemotherapy drugs; paclitaxel, docetaxel, gemcitabine, carboplatin and cisplatin were nebulized with three different jet nebulizers (Maxineb^®, Sunmist^®, Invacare^®) and six different residual cups at different concentrations. The purpose of the study was to identify the “ideal” combination of nebulizer-residual cup design-drug–drug loading for a future concept of aerosol chemotherapy in lung cancer patients. The Mastersizer^® 2000 was used to evaluate the aerosol droplet mass median aerodynamic diameter.

Results

The drug, nebulizer and residual cup design greatly influences the producing droplet size (p < 0.005, in each case). However; the design of the residual cup is the most important factor affecting the produced droplet size (F = 834.6, p < 0.001). The drug loading plays a vital role in the production of the desired droplet size (F = 10.42, p < 0.001). The smallest droplet size was produced at 8 ml loading (1.26 μm), while it remained the same at 2, 4 and 6 mls of drug loading.

Conclusion

The ideal nebulizer would be Maxineb^®, with a large residual cup (10 ml maximum loading capacity) and 8 mls loading and the drug with efficient pulmonary deposition would be docetaxel.     

Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets

The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono^®, providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit^® L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono^®.     

Roll compaction of mannitol: Compactability study of crystalline and spray-dried grades

Purpose of this project was to investigate the roll compaction behavior of various mannitol grades. Therefore, five spray-dried grades as well as unprocessed β-d-mannitol were roll compacted with different compaction forces. The resulting granules were characterized with regard to their particle size distribution, flow properties, and BET surface area and compressed to tablets. Granules of unprocessed mannitol, even when applying high compaction forces during dry granulation, were characterized by a high amount of fines (about 21%), a small surface area (0.83 m²/g), and solely fair flowability (ff_c = 7.2). Tablets revealed either high friability or insufficient disintegration behavior. However, the use of spray-dried mannitol led to better results. Granules showed improved flow properties and a reduced amount of fines. Robust tablets with low friability were produced. Within the various spray-dried grades huge differences concerning the compactability were observed. Large BET surface areas of the granules resulted in advanced tensile strengths of the tablets, but acceptable disintegration behavior was maintained. These findings are relevant for the development of mannitol based drug formulations, in particular (oro)dispersible tablets containing a low dose or poor flowing active pharmaceutical ingredient, where direct compression is inappropriate and a granulation process prior to tableting is mandatory.     

Application of melt granulation technology to enhance stability of a moisture sensitive immediate-release drug product

The preparation of tablets by the melt granulation process was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR^®) improved the stability of the drug, while still maintaining immediate-release characteristics of the drug product. The drug to binder ratio was shown to impact the degradation behavior of the drug product. With higher binder levels, the sensitivity of the drug to degradation under humidity conditions decreased. It is postulated that the lipophilic binder coated drug particles at the surface protecting them from the influence of moisture. The granules had good flow properties and good compressibility and tablets prepared from them exhibited low weight variation and low friability.     

Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol? 888ATO as Lipid Excipient

Tablets containing metoprolol succinate and Compritol^® 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol^® 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol^® 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol^® 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm² exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm² with 6.90% of total porosity revealing influence of compression force. Compritol^® 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.     

Comparison of two twin-screw extruders for continuous granulation

A comparison was made between two twin-screw extruders (APV Baker and Leistritz Micro) used for continuous wet granulation. Both extruders had similar screw configurations, based on the length-to-diameter ratio of the screws, existing out of a conveying zone of 20 D, i.e. 20 times the screw diameter and a granulation zone of 4 D. The kneading blocks in the granulation zone were 2.2 and 2.5 D for the Leistritz and APV extruders, respectively. An experimental design was used to investigate the influence of process parameters (total input rate and screw speed) and extruder type on granule and tablet quality. Dicalcium phosphate and α-lactose monohydrate were used as water-insoluble and water-soluble excipients, respectively. For dicalcium phosphate, the amount of fines (<125 μm), median granule size and granule friability were significantly influenced by extruder type and total input rate. For lactose, the amount of oversized agglomerates and median granule size were significantly affected by extruder type and total input rate. The granule formulations were properly agglomerated on both the extruders, although the extruder type had an important influence on the granule properties, which was more pronounced for dicalcium phosphate. This study shows that a given formulation cannot simply be interchanged between the two extruders without further work on the geometrics of the extruders.     

Preventing addiction related suicide: A pilot study

Persons addicted to alcohol and drugs are at 5–10 times higher risk for suicide as compared to the general population. To address the need for improved suicide prevention strategies in this population, the Preventing Addiction Related Suicide (PARS) module was developed. Pilot testing of 78 patients demonstrated significant post-treatment changes in knowledge [t(66) = 12.07, p = .000] and attitudes [t(75) = 6.82, p = .000] toward suicide prevention issues. Significant gains were maintained at 1-month follow-up for changes in knowledge [t(55) = 6.33, p = .000] and attitudes [t(61) = 3.37, p = .0001], with changes in positive help seeking behaviors in dealing with suicidal issues in friends [χ²(1) = 10.49, p = .007], family [χ²(1) = 9.81, p = .015], and self [χ²(1) = 19.62, p = .008] also observed. The PARS was also highly rated by treatment staff as feasible within their standard clinical practice.     

Investigating the Use of Polymeric Binders in Twin Screw Melt Granulation Process for Improving Compactibility of Drugs

Traditionally, the melt granulation for pharmaceutical products was performed at low temperature (<90°C) with high-shear granulators using low-melting waxy binders, and tablets produced using such granules were not amenable to large-scale manufacturing. The situation has changed in recent years by the use of twin screw extruder where the processing temperature could be increased to as high as 180°C and polymers with high T_g could be used as binders. In this study, different polymeric binders were screened for their suitability in improving compactibility of 2 drugs, metformin hydrochloride and acetaminophen, by twin screw melt granulation. Processing temperatures for the 2 drugs were set at 180°C and 130°C, respectively. Screw configuration, screw speed, and feed rate were optimized such that all polymeric binders used produced granules. Several hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and methacrylate-based polymers, including Klucel^® EXF, Eudragit^® EPO, and Soluplus^®, demonstrated good tablet tensile strength (>2 MPa) when granules were produced using only 10% wt/wt polymer concentration. Certain polymers provided acceptable compactibility even at 5% wt/wt. Thus, twin screw melt granulation process may be used with different polymers at a wide range of temperature. Due to low excipient concentration, this granulation method is especially suitable for high-dose tablets.     

Gamma scintigraphy in the analysis of ketoprofen behaviour from matrix tablets

The aim of this work was to study in vitro and in vivo the behaviour of matrix tablets (quick and extended release) containing ketoprofen (KTP) as a model drug and cellulose ether polymers, using gamma scintigraphy. The matrix tablets were prepared by the direct compression method and labelled by incorporating a drop of technetium (^99mTc). It was spectrophotometricaly confirmed that the radioisotope inclusion did not modify the kinetics of KTP release. In vitro studies were carried out for the tablets using the paddle method of the USP 35/NF30. The images were processed by defining regions of interest over the tablet ^99mTc and the percentage of remaining activity/time curves were generated for both formulations. In vitro gamma scintigraphy studies showed significant differences (p < 0.05) between both formulations. Identical results were obtained from the in vivo studies. In vivo tests were performed on five healthy volunteers. The scintigraphy images were acquired during 2.5 and 7.5 h for quick and extended release formulations, respectively. The position of the extended release formulation tablet along the gastrointestinal tract (GIT) was assessed. The described results demonstrate the in vitro/in vivo correlation for the drug release profile and exhibit the importance of gamma scintigraphy for the drug location through the GIT.     

Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy

In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC > MG > DS tablets. The mean in vivo onset time for all tablets (DC: 6.7 ± 3.8 min, MG: 18.3 ± 8.1 min, DS: 67 ± 18.9 min) did not differ significantly from in vitro onset time (DC: 5.3 ± 1 min, MG: 16.8 ± 3.9 min, DS: 61.8 ± 4.7 min). The mean in vivo completion times were found to be 36.6 ± 9.7 (DC tablets), 70 ± 18.3 min (MG tablets) and 192.5 ± 39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds.     

Leptin and IL-8: Two novel cytokines screened out in childhood lead exposure

Lead is a toxic heavy metal with many recognized adverse health side effects. The central nervous system is the main target of lead toxicity. Although many studies on lead toxicity were conducted, the mechanism of lead toxicity remains uncertain. One possible attribution is the immature blood–brain barrier that causes lead exposure in children. Few studies have investigated the cytokine changes caused by this exposure. Novel cytokines were detected by RayBio^® Human Cytokine Antibody Array and validated by enzyme-linked immunosorbent assay. Several children were admitted to West China Second University Hospital, after a serious lead pollution event in longchang, Sichuan, China. A total of 4 children with elevated blood lead levels (BLLs) and 4 children with low BLLs were randomly chosen in the discovery set, and 40 children with elevated BLLs and 40 children with low BLLs were included in the validation set. Leptin and interleukin-8 (IL-8) were identified to be significantly different between children with elevated and low BLLs via RayBio^® Human Cytokine Antibody Array. In the validation set, IL-8 was higher in children with elevated BLLs [median(P₂₅–P₇₅), 117.69(52.31–233.63) pg/mL] than in children with low BLLs [median(P₂₅–P₇₅): 17.70(10.75–26.52) pg/mL] (p = 0.000). Leptin was lower in children with elevated BLLs [median(P₂₅–P₇₅): 1658.23(1421.86–2606.55) pg/mL] than in children with low BLLs [median(P₂₅–P₇₅): 4168.68(3246.32–4744.94) pg/mL] (p = 0.000). In children with low BLLs, leptin was higher in children with BLLs < 3 μg/dL (N = 7) [median(P25–P75): 7220.86(4265.72–7555.15) pg/mL] than in children with BLL ≥ 3 μg/dL (N = 33) [median(P₂₅–P₇₅): 4103.86(3163.40–4678.34) pg/mL] (p = 0.026); IL-8 was significantly different in children with BLL < 4 μg/dL (N = 13) [median(P₂₅–P₇₅): 12.49(8.25–14.86) pg/mL] than in children with BLL ≥ 4 μg/dL (N = 27) [median(P₂₅–P₇₅): 21.98(13.64–33.50) pg/mL] (p = 0.013). The results defined specific changes in cytokine expressions to lead exposure, which can be used to explore the mechanism of lead toxicity and monitor lead exposure.     

Young adult waterpipe smokers: Smoking behaviors and associated subjective and physiological effects

Introduction

The purpose of this pilot study was to investigate smoking behaviors and subjective and physiological effects of nicotine on young adult occasional waterpipe smokers.

Methods

This study utilized a repeated-measures design that included one repeated factor for condition (nicotine and non-nicotine). For each participant, the sequencing of the repeated factor was assigned using random allocation. The two nicotine conditions were nicotine (0.75 g) and non-nicotine (0 g placebo) tobacco. Over the course of two weeks, twenty-two participants completed subjective (Acute Subjective Effects of Nicotine) and physiological (blood pressure, heart rate, and CO level) measures. Additional measures (QSU and MNWS-R) were used to assess for withdrawal symptoms.

Sample

The participants (n = 22) were young adults (23 ± 3.1 years); 71% smoked waterpipe once a month in the past year and 29% smoked waterpipe 1–2 times per week. In addition, 60% reported sharing their waterpipe with friends while smoking. None of the participants reported using any other forms of tobacco products.

Results

Under the nicotine condition, participants tended to smoke longer (i.e. smoking duration, p = 0.004), take more puffs (p = 0.03), take shorter puffs (p = 0.03), and inhale less volume with each puff (p = 0.02). The repeated measures analysis of the factor headrush revealed an effect of the nicotine condition (F = 9.69, p < 0.001, partial η² = 0.31) and time (F = 8.17, p = 0.02, partial η² = 0.30). Heart rate increased significantly across the nicotine condition (F = 7.92, p = 0.01, partial η² = 0.31) and over time (F = 12.64, p = 0.01, partial η² = 0.41).

Conclusions

This study demonstrates how differences between nicotine and non-nicotine waterpipe smoking are associated with changes in smoking behaviors, experiencing a headrush and an increase in heart rate.     

Gastroresistant capsular device prepared by injection molding

In the present work, the possibility of manufacturing by injection molding (IM) a gastro-resistant capsular device based on hydroxypropyl methyl cellulose acetate succinate (HPMCAS) was investigated. By performing as an enteric soluble container, such a device may provide a basis for the development of advantageous alternatives to coated dosage forms. Preliminarily, the processability of the selected thermoplastic polymer was evaluated, and the need for a plasticizer (polyethylene glycol 1500) in order to counterbalance the glassy nature of the molded items was assessed. However, some critical issues related to the physical/mechanical stability (shrinkage and warpage) and opening time of the device after the pH change were highlighted. Accordingly, an in-depth formulation study was carried out taking into account differing release modifiers potentially useful for enhancing the dissolution/disintegration rate of the capsular device at intestinal pH values. Capsule prototypes with thickness of 600 and 900 μm containing Kollicoat^® IR and/or Explotab^® CLV could be manufactured, and a promising performance was achieved with appropriate gastric resistance in pH 1.2 medium and break-up in pH 6.8 within 1 h. These results would support the design of a dedicated mold for the development of a scalable manufacturing process.