The excipient news blog - shared with the Linkedin pharma excipients group! Pharmaceutical excipients (inactive ingredients) play a major role in development and production of pharmaceutical dosage forms - we publish up to date information on all aspects of excipients.

Excipienttalk - Latest news on pharmaceutical excipients

Effect of relative air humidity on the flowability of lactose powders

Abstract

Moisture is known to affect the flowing properties of powders. However, the quantification and the understanding of the observed effects are far to be obvious. To study air moisture influence on powder flowability in a laboratory, a conditioning system and a precise flowmeter are necessary. Simple flow testers, which are commonly used R&D laboratories, are not able to quantify precisely the effect of moisture on powders. The use of advanced techniques is necessary. In this paper, we present how a precise and user-friendly flowability test associated with a dynamic conditioning system can be used to quantify the influence of moisture on the flowability properties of lactose powders. The effect of residence time T in high humidity conditions is analyzed. Afterward, we show that the relative humidity range that optimizes the flowability of lactose powders is between 30% and 50%. For lower values of the relative humidity, the apparition of electric charges inside the bulk induces cohesive forces. For higher relative humidity, the condensation of the air humidity at the contact between the grains forms capillary bridges which favors also the cohesive interactions. A model taking both triboelectric and capillary effects into account is proposed to fit the experimental data.

More

Read More

Combined effect of moisture and electrostatic charges on powder flow

Abstract

It is well known in pharmaceutical applications involving powders and granular materials that the relative air humidity and the presence of electrostatic charges influence drastically the material flowing properties. In particular, API powders are highly sensitive to both humidity and electrostatic charges leading to inhomogeneity in powder blends. On the one hand, the relative air humidity induces the formation of capillary bridges (leading to cohesiveness) and modifies the grain surface conductivity. The apparition of electrostatic charges due to the triboelectric effect at the contacts between the grains and at the contacts between the grains and the container produces electrostatic forces. Therefore, in many cases, the powder cohesiveness is the result of the interplay between capillary and electrostatic forces. Unfortunately, the triboelectric effect is still poorly understood, in particular inside a powder. Moreover, reproducible electrostatic measurements are difficult to perform. We developed an experimental device to measures the ability of a powder to charge electrostatically during a flow in contact with a selected material. Both electrostatic and flow measurements have been performed in different hygrometric conditions with a set of pharmaceutical powders. The correlation between the powder electrostatic properties, the hygrometry and the flowing behavior are analyzed.

More 

Read More

A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein

Purpose

There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn’s Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads.

Methods

In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT® FS 30 D to develop a colonic delivery system. The secondary and tertiary structure change and aggregation of BSA during spray layering process was examined. The BSA layered beads were then challenged in an accelerated stability study using International Council for Harmonization (ICH) conditions. The in vitro release of BSA from enteric coated beads was examined using United States Pharmacopeia (USP) dissolution apparatus 1.

Results

No significant changes in the secondary and tertiary structure or aggregation profile of BSA were observed after the spray layering process. Degradation of BSA to different extents was detected after storing at 25°C and 40°C for 38 days. Enteric coated BSA beads were intact in acidic media while released BSA in pH 7.4 phosphate buffer.

Conclusion

We showed the feasibility of delivering proteins to colon in vitro using multiparticulate system.

More

Read More 0 Comments

Microencapsulated Solid Lipid Nanoparticles as a Hybrid Platform for Pulmonary Antibiotic Delivery

Solid lipid nanoparticles (SLN) containing rifabutin (RFB), with pulmonary administration purposes, were developed through a technique that avoids the use of organic solvents or sonication. To facilitate their pulmonary delivery, the RFB-loaded SLN were included in microspheres of appropriate size using suitable excipients (mannitol and trehalose) through a spray-drying technique. Confocal analysis microscopy showed that microspheres are spherical and that SLN are efficiently microencapsulated and homogeneously distributed throughout the microsphere matrices. The aerodynamic diameters observed an optimal distribution for reaching the alveolar region. The dry powder’s performance during aerosolization and the in vitro drug deposition were tested using a twin-impinger approach, which confirmed that the microspheres can reach the deep lung. Isothermal titration calorimetry revealed that SLN have higher affinity for mannitol than for trehalose. Upon microsphere dissolution in aqueous media, SLN were readily recovered, maintaining their physicochemical properties. When these dry powders reach the deep lung, microspheres are expected to readily dissolve, delivering the SLN which, in turn, will release RFB. The in vivo biodistribution of microencapsulated RFB-SLN demonstrated that the antibiotic achieved the tested organs 15 and 30 min post pulmonary administration. Their antimycobacterial activity was also evaluated in a murine model of infection with a Mycobacterium tuberculosis strain H37Rv resulting in an enhancement of activity against M. tuberculosis infection compared to nontreated animals. These results suggest that RFB-SLN microencapsulation is a promising approach for the treatment of tuberculosis.

More

Read More

Excipient risk assessment: Approaches based on excipient function

Excipients / inactive ingredients are an integral part of practically all medicines. Although being a functional part of a formulation, excipients have been regarded as pharmacologically and chemically indifferent within the formulation.

 

However, nowadays excipients along with active pharmaceutical ingredients are the subject of strict monitoring and quality control in pharmaceutical manufacture. According to the current rules of European Union’s Good Manufacturing Practice of Medicinal Products excipients should be subjected to a thorough assessment of the risks associated with their quality, safety and function and classified e.g. as low risk, medium risk or high risk. Thus, in the present article available data on excipient function and functionality is considered, on the basis of which possible approaches for the risk assessment related to the excipient function are proposed. These approaches are presented in the form of schematic algorithms and concern such aspects as dosage form and use of the medicinal product containing the excipient, functional purpose, daily patient intake and functional variability of the excipient.

More

Wheat in pharmaceutical Excipients - which excipients are based on it - is it a gluten topic for patients?

How many wheat (derived) excipients contain wheat / wheat starch as a potential source of Gluten? Based on available information most of the excipients such as Sodium Starch Glycolate, Pregelatinized starch and native starches are based on corn and potato (starches) anyway.
But are there excipients used in pharmaceutical formulations based on wheat / wheat starch? If yes, what would be the average or maxium percentage in a dosage form? Many thanks for your input on this question to hopefully reduce fear of medicines as a "critical" source of Gluten. If you do not like to comment here, please send an email to info@pharma-excipients.ch. Many thanks for your input!

Read More

Formulation design of granules by wet granulation to avoid tableting failures

Abstract

We previously determined “Tableting properties” by using a multi-functional single-punch tablet press (GTP-1). We plotted “Compactability” on the x-axis against “Manufacturability” on the y-axis to allow visual evaluation of “Tableting properties”. Here, we examined whether this evaluation method can be used in the formulation design of tablets prepared by wet granulation. We used the GTP-1 to measure “Tableting properties” with different amounts of binder, disintegrant, and lubricant, and compared the results with those of tableting on a commercial rotary tableting machine. Tableting failures (capping and binding in particular) occurred when samples that had been evaluated as having poor “Compactability” or “Manufacturability” on the GTP-1 were compressed on the rotary tableting machine. Thus, our evaluation method predicted tableting failure at the commercial scale. The method will prove useful for scaling up production.

Read More

Improve pulmonary delivery of biopharmaceuticals by PEGylation

The administration of therapeutic proteins by inhalation is getting more and more important to treat respiratory diseases.

To enhance residence time of these biopharmaceuticals in the lungs PEGylation is of interest also to reduce the daily burden of  inhalation therapies.

 

Several PEGylated proteins have been delivered to the lungs in rodents and shown to be retained in the respiratory tract for longer periods than unconjugated counterparts. Mechanisms involved in their pulmonary retention might include increased molecular size, mucoadhesion, enhanced proteolytic resistance and escape from the uptake by alveolar macrophages. Pulmonary delivery of PEGylated peptides and proteins is also interesting as a non-invasive route of administration of long-acting biopharmaceuticals to the bloodstream. However, PEGylation decreases the systemic absorption of the compounds, especially when the PEG size is large. This review presents the recent work carried out on the pulmonary delivery of PEGylated biopharmaceuticals, the factors affecting residence time in the lungs and systemic absorption as well as the safety of the approach in preclinical studies.

More

Read More 0 Comments

The influence of apparent viscosity of AFFINISOL™ HPMC HME on hot melt extrusion processability and drug release from amorphous solid dispersions

AFFINISOL™ HPMC HME of varied viscosity was successfully processed with Itraconazole into homogenous amorphous solid dispersions. The use of two viscosity grades blended to a final target did not influence the homogeneity or amorphicity of the resulting dispersion, nor was the dissolution rate different compared to the directly synthesized reference. Thus, the apparent viscosity of the polymer was the dominant factor regarding HME processability and formulation dissolution performance. This demonstrates that multiple viscosity grades can be incorporated into a formulation to achieve a target dissolution profile without risk of one component dominating performance.

 

If you want to learn more, download a copy of this whitepaper from the Dow Pharma Solutions Online Portal.

Read More

Call for Topics - Excipientfest 2018

call for topics excipientfest 2018
Read More 0 Comments

A novel release retarding polymer for direct compression

For the development of this excipient for direct compression no chemical modification was applied. The enhanced functionality enabling a nearly zero order release was achieved by techniques such as physical mixing, high shear mixer granulation and spray drying.

 

Co-processed excipient was developed by using release retarding polymer Eudragit RSPO, separately, in combination with different concentration of hydroxyl propyl methyl cellulose 100 cps (Methocel K100 LV, HPMC), ethyl cellulose (Ethocel N50, EC) and hydroxyl propyl cellulose (Klucel EF, HPC). All co-processed excipients were evaluated for their flow properties in terms of angle of repose, bulk density, tapped density, compressibility index and Hausner's ratio. Out of eighteen combinations, the nine co-processed excipients exhibited promising flow properties were found suitable for direct compression and formulated as tablets. Metoprolol succinate, a BCS Class I drug, was selected as a model drug and the formulation was developed employing direct compression approach. The developed tablets were evaluated for physical parameters like uniformity of weight, thickness, hardness, friability and assay. In vitro dissolution study confirms that formulation prepared using co-processed excipient showed sustained drug release. The optimized tablet formulation was characterized by DSC, FTIR and PXRD which confirms the absence of any chemical change during co-processing. The optimized formulation was kept for stability study for six months as per ICH guidelines and found to be stable. In vivo pharmacokinetic study of optimized formulation in rats showed similar pharmacokinetic behaviour as was observed with the marketed brand. Study revealed that co-processed excipient has advantage over polymers with single property and can be utilised for sustained release formulation.

Read More 0 Comments

Atomic Layer Deposition − A Novel Method for the Ultrathin Coating of Minitablets

A new coating method via Atomic Layer Deposition (ALD) to achieve an ultrathin coating / nanolayering of mini tablets. 

 

The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit® E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications.

More

Read More 0 Comments

Modeling and comparison of release profiles: Effect of the dissolution method

Abstract

During the last decades, the study of the in vitro dissolution of pharmaceuticals has been strongly encouraged by the FDA in order to determine its relationship with the in vivo bioavailability of a drug. In this work immediate and extended release formulations containing diclofenac, a BCS class II drug, were studied using different dissolution methods. The release profiles obtained in USP Apparatus II and USP Apparatus IV were evaluated and compared to determine the effect of the fluid dynamic conditions on the release. The influence of the mixing conditions (i.e. the paddle rotation speed in USP Apparatus II or the inlet flow rate in USP Apparatus IV) on the drug release were evaluated, finding that, for the extended release formulations, they do not affect significantly the release profile. An in vitro device simulating the peristaltic contractions of the stomach during the digestion was used to simulate fluid dynamics closer to the real physiology. The tablets were found to behave in a completely different way if tested in the artificial stomach.

 

Both model-independent and model-dependent approaches were used to compare and fit the dissolution profiles, respectively. Fit factors were used as indicators of similarity of two dissolution profiles; model equations (such as zero-order, first-order, or Korsmeyer-Peppas equations) were used to fit the experimental data. With the identification of the best fitting model by the use of correlation factors and Akaike Information Criterion, the transport phenomena that determine the behavior of each formulation were identified.

More

Read More

Optimisation of HPMC ophthalmic inserts with sustained release properties as a carrier for thermolabile therapeutics

Abstract

A methodology was developed and optimised for the preparation of a new drug delivery system (DDS) with sustained release properties to allow ocular protein delivery and to limit destructive production steps during manufacturing. Elevated temperatures, shear forces and an oxidative environment should be avoided in order to prevent denaturation or oxidation of proteins. An aqueous HPMC solution was prepared using heat and casted into small semi-rod-shaped PVC blisters. The polymer solution was allowed to cool down and was partially dehydrated at room temperature. A drug solution containing glycerol, drug and water was subsequently added to rehydrate the partially dehydrated polymer matrix at a temperature of 2 °C. Several parameters of the production process were varied to determine their influence on the release kinetics from HPMC inserts from three different molecules of different molecular weight. This production method was further optimised in order to shorten the rehydration time from weeks to days, while eliminating heat and shear forces on the selected drug molecules sodium fluorescein, lysozyme and albumin. Slow release kinetics were achieved for sodium fluorescein and lysozyme as model drug molecules. The higher molecular weight of albumin prevented a good penetration into the insert during the rehydration process resulting in predominantly burst release. The biocompatibility of a viscous HPMC solution was evaluated on SV40-human corneal epithelial cells with PrestoBlue® and no cytotoxic effects were observed.

More

Read More

A multi-technique characterization of the stability of surfactant containing solid dispersion based buccal patches prepared by hot melt injection moulding

Abstract

This study investigates the stability of typically complex multi-component hydrophilic solid dispersions that could be used in a clinical application. Felodipine solid dispersions in two types of blends consisting of PEG, PEO and Tween 80 or Vit E TPGS were prepared by hot melt-injection moulding (HMIM) across a range of drug loadings and subjected to a range of storage conditions. Microscopy, thermal analysis, spectroscopy and powder X-ray diffraction were used to characterize the systems. The semi-solid surfactant TPGS showed a better solubilizing effect on the drug than the liquid surfactant Tween 80 in the fresh state and offered some degree of protection over the chemical degradation of PEG/PEO. Better storage stability was observed for the systems with low drug loading. Crystallization of a new metastable polymorphic form of felodipine in the patches with drug loadings at and above the saturation point was observed. Quantitative comparison of the data sets was achieved by a normalisation process and calculation of statistical variance. TPGS containing patches were more sensitive to the aging process than Tween containing patches. For both surfactants, such instability is more responsive to the storage temperature than humidity. This study established a methodology for probing the complex stabilities of multi-component dispersions.

More

Read More 0 Comments

Nanoscale Kolliphor® HS 15 micelles to minimize rifampicin self-aggregation in aqueous media

Abstract

Tuberculosis is a highly-deadly disease that affects both children and adults. Rifampicin, one of the “first-line” anti tuberculosis drugs, self-aggregates in aqueous solutions where the critical aggregation concentration demonstrated a temperature-dependent behavior. Interestingly, drug self-aggregation could negatively affect the development of liquid aqueous rifampicin pediatric tuberculosis formulations. Therefore, our nanotechnological strategy to minimize this effect was the rifampicin encapsulation within polymeric micelles, employing the commercially available Kolliphor® HS 15, as the micelle-former biomaterial. The results show that Kolliphor® HS 15 is able to prevent rifampicin aqueous self-aggregation and precipitation, when used at certain concentrations. In this context, our work opens the possibility of developing aqueous liquid rifampicin dosage forms for pediatric patients to improve tuberculosis treatment.

More

Read More 0 Comments

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend

Abstract

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contrib- uting factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellu- lose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on con- tent uniformity analysis of the model API, ergocalciferol, using a validated analytical tech- nique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blend- ing confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial require- ment for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superior- ity of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

Read More

onCare - Evonik's new customer portal

e-Lab is now onCare

We redesigned the platform for you - so that it's easier to find what you're looking for and to simplify your daily work.

onCare does not only have a new appearance, it also has new functionalities.

 

  • A completely new design leverages an intuitive interface so that you can easily access the information you seek. 
  • Increased interaction enabling you to focus on the topics you are most interested in.  
  • A fully enhanced Coating Calculator can calculate the best oral drug delivery formulation to help optimize your target functionality. 
  • A new troubleshooting module is designed to provide effective solutions to common questions which may arise during the coating process. 
  • A fully revised download area enables immediate access to product-specific documentation such as quick-starts, product specifications, regulatory documents and scientific posters.

 

Read More

An advanced technique using an electronic taste-sensing system to evaluate the bitterness of orally disintegrating films and the evaluation of model films

Abstract

Taste detection systems using electronic sensors are needed in the field of pharmaceutical design. The aim of this study was to propose an advanced technique using a taste-sensing system to evaluate the bitterness of an orally disintegrating film (ODF) samples. In this system, a solid film sample is kept in the test medium with stirring, and the sensor output is recorded. Model films were prepared using a solution-casting method with a water-soluble polymer such as pullulan, HPMC, HPC or PVP as film formers, and donepezil hydrochloride and quinine hydrochloride as model bitter-tasting active pharmaceutical ingredients (APIs). The results showed that this advanced techniques could detect the emergence of bitterness along the time course. Increasing the amount of donepezil hydrochloride increased the sensor output. The sensor output was suppressed at the very early stage of the test, and then increased. Both the film thickness and the use of additives markedly affected the delay of the sensor output. The profile of the sensor output was accurately related to the release of APIs. It was concluded that this advanced technique could detect the onset of bitterness during the initial stage of ODF administration.

More

Read More 0 Comments

Technological solutions for encapsulation

Abstract

Encapsulation offers broad scope of applications. It can be used to deliver almost everything from advanced drugs to unique consumer sensory experiences; it could be also employed as a protection system or a sensing material. This cutting-edge technology undergoes rapid growth in both academic and industrial conditions. Research in this matter is continuing to find a new application of microcapsules as well as to improve the methods of their fabrication. Therefore, in this review, we focus on the art of the encapsulation technology to provide the readers with a comprehensive and in-depth understanding of up-to-day development of microcapsule preparation methods. Our goal is to help identify the major encapsulation processes and by doing so maximize the potential value of ongoing research efforts.

More

Read More 1 Comments

Microspheres of insulin-Eudragit complex: Formulation, characterization and in vivo studies

Insulin, a hormonal drug for the management of diabetes mellitus has continued to attract attention of many researchers and pharmaceutical formulators for more than a decade. However, its low oral bioavailability due to the activities of intestinal enzymes restricts its route of administration to only the parenteral route. This study was designed to evaluate the capacity of mucoadhesive microspheres formulated with varying blends of Eudragit® RL 100 and Eudragit® RS 100 to protect insulin for oral administration. Microspheres containing varying blends of Eudragit® RL 100/RS100 loaded insulin was prepared by solvent evaporation method and were characterized in vitro and in vivo. Results showed that stable formulation with high encapsulation efficiency, positive zeta potential and high bioadhesion were obtained in all the formulations. In vitro release showed a maximum release of 9 and 87% release in pH 1.2 and 7.2, respectively. Single oral studies showed a decreased in blood glucose level comparably equal to that of subcutaneous (sc) administration. The results of this study indicate that insulin-loaded Eudragit RL100/RS100 microspheres could be a promising drug delivery system to improve oral absorption of insulin.

Read More

Applications of ethylene vinyl acetate copolymers (EVA) in drug delivery systems

Abstract

The potential for use of polymers in controlled drug delivery systems has been long recognized. Since their appearance in the literature, a wide range of degradable and non-degradable polymers have been demonstrated in drug delivery devices.

 

The significance and features of ethylene-vinyl acetate (EVA) copolymers in initial research and development led to commercial drug delivery systems. This review examines the breadth of EVA use in drug delivery, and will aid the researcher in locating key references and experimental results, as well as understanding the features of EVA as a highly versatile, biocompatible polymer for drug delivery devices.

 

Topics will include

A. Delivery systems - transdermal, implants, such as transmucosal, vaginal, subcutaneous, ocular, brain, and coatings.

B. Fundamental studies – drug elution, API types (small molecules, biologics, combinations).

C. Commercial & predicate use of durable polymers in drug delivery devices, focused on EVA.

More

Read More

Porous PLGA microparticles formed by “one-step” emulsification for pulmonary drug delivery: The surface morphology and the aerodynamic properties

Abstract

In the present study, by using a newly developed one-step emulsification technique, we tried to prepare porous PLGA particles having a proper diameter and surface morphology in order to achieve both a high efficient delivery of the particles to the lungs and a phagocytosis-avoidance ability. We found that our porous particles have the very low tapped density of 0.04 g/cm3. Experimental and theoretical studies strongly suggest that the shape factor should not be determined only by the outline of the particles, although previous research assigned a value of 1 to the shape factor for particles regardless of the presence of pores and their distribution. We found the possibility that our porous particles both had specific internal structures induced by spontaneous emulsification and exhibited unusual aerodynamic performance.

More

Read More

Oral delivery of a novel domain antibody (VorabodyTM) for the treatment of Crohn’s Disease

Crohn’s disease (CD) is a serious and lifelong chronic inflammatory bowel disease (IBD) which can affect any part of the gastrointestinal tract (GIT) but most commonly occurs in the lower part of the ileum, caecum and ascending colon.

Selective neutralisation of TNFα by antibodies is established as an effective and transformative treatment for CD. Three anti- TNFα antibodies: infliximab, adalimumab and certolizumab are currently used clinically for the treatment of CD.

These monoclonal antibodies (mAbs) must be administered parenterally requiring either a hospital visit which is inconvenient for the patient, or multiple injections. This mode of administration can be painful and can also result in unwanted systemic side effects associated with long term systemic suppression of TNFα. An oral antibody delivered locally to the site of inflammation in IBD could therefore have major benefits: ease of administration, preservation of efficacy, and the potential to minimise unwanted systemic side effects.

To date, other than protein replacement products, very few oral peptides have been commercialised, which reflects the significant challenge of oral biologic delivery. 

Read More

Topical Vehicle Selection: Myths and Reality

During the development of a dermal drug, much efforts tend to be placed on improving its delivery through skin. These efforts are driven by the known risk of not engaging the target. Indeed to increase comfort that the target will be engaged one need to try fullfill as best as it can evidence of sufficient compound on board for a desired time (i.e., PK within skin) and demonstration of pharmacological activity.

Book - Dermal Drug Selection and Development 

Controlled Drug Release from a non-soluble & pH stable pellet system based on a novel type of mesoporous silica

The goal of this study was to test the feasibility to load non-ordered, non-spherical mesoporous silica with the model drug paracetamol, and subsequently coat the loaded particles using one single pilot scale fluid bed system equipped with a Wurster insert. Mesoporous silica particles (Davisil®) with a size ranging from 310 to 500 μm and an average pore diameter of 15 nm were loaded with paracetamol to 18.8% drug content. Subsequently, loaded cores were coated with ethylcellulose to obtain controlled drug release. Coating processing variables were varied following a full factorial design and their effect on drug release was assessed.

More

Read More 0 Comments

Engineering Synergistically Active and Bioavailable Cost-effective Medicines for Neglected Tropical Diseases; The Role of Excipients.

Abstract

Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses. Excipients are necessary for ensuring the stability and bioavailability of currently available antileishmaniasis drugs which in their majority are poorly soluble or have severe side-effects. Thus, selection of excipients that can ensure bioavailability and safety as well as elicit a synergistic effect against the Leishmania parasites without compromising safety will result in a more efficacious, safe and fast to market medicine. We have evaluated the in vitro activity of 30 commercially available generally regarded as safe (GRAS) excipients against different Leishmania spp., their cytotoxicity and potential use for inclusion in novel formulations. Amongst the tested excipients, the compounds with higher selectivity index were Eudragit E100 (cationic triblock copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate), CTAB (cetyltrimethylammonium bromide, cationic), lauric acid, Labrasol(non-ionic, caprylocaproyl polyoxyl- 8 glycerides) and sodium deoxycholate. An ideal excipient need to possess amphiphilic nature with ionic/polar groups and possess a short or medium fatty acid chain such as lauric (C12), capric C10) or caprylicacid (C8). Inclusion of these excipients and identification of the optimal combination of drug and excipients would lead to a more effective and safer antileishmanial therapies.

More

 

See also

The German Waisenmedizin e.V. currently develops LeiProtect® as a medical device alongside an original equipment manufacturer (OEM). It is used to treat leishmaniasis skin lesions.

 

 

0 Comments

Hydrogel-based capsules could expand and reside in the GI tract for days, slowly releasing medication

Around half of all medications for chronic diseases are not taken as prescribed, costing the U.S. health care system more than $100 billion in avoidable hospital stays each year.

 

This noncompliance is even more significant in the developing world, where health care budgets are chronically overstretched and patients treated for diseases such as malaria must take multiple drugs with complex dose regimens.

 

To help ensure patients receive their full course of treatment, researchers at MIT and Brigham and Women's Hospital have developed a new set of drug delivery materials, which can reside in the stomach for up to nine days, slowly releasing their dosage of medication.

More

Read More

Chemoinformatic Tools to Predict the Effects of Excipients in Generic Drugs

Regulatory Science Challenge

Oral drug products such as tablets, capsules and solutions contain the active ingredient (medication) and various other ingredients that are considered to be therapeutically inactive. These inactive ingredients, called excipients, are included in oral products for various reasons, such as to enhance the stability of the active ingredient or change the color or taste. There is a longstanding belief that excipients are generally safe, inert and do not interact with drug targets. If excipients impact any factors involved in drug absorption or interact with drug targets, they can influence drug levels in the body and the pharmacologic effects of generic drugs. Because excipients can differ between brand name and generic products, these possible interactions could affect availability of the drug in the body or its effectiveness.

Project Description & Goals

The goals of this project are to:
1. Develop an open-access excipients database that contains the structures and physical properties of over 600 excipients used in approved FDA drug products (http://excipients.ucsf.bkslab.orgdisclaimer icon)

2. Systematically calculate and predict targets for all excipients used in FDA-approved drug products

3. Perform laboratory testing of excipients on predicted targets in labs of Drs. Giacomini (UCSF), Roth (UNC Chapel Hill) and Urban (Novartis).

4. Define excipient-drug and excipient-excipient combinations that may be particularly important to monitor using information available in databases

Ultimately, these studies will help FDA ensure drug safety and equivalency of generic drug products to brand name products.

More

0 Comments

Soluplus as a Potential Enhancer of Cefixime - Solid dispersion

The present study was done for improvement of solubility and thereby bioavailability of Cefixime for its e cient an microbial activity by using amphiphilic Soluplus as a carrier. Different methods were used for enhancing the solubility of Cefixime like physical mix, kneading, microwave irradiation, solvent evaporation, lyophilization and spray drying. The plain drug and the prepared SD with various CFX to polymer ratios were characterized in terms of solubility, drug content, IR, DSC, SEM, XRD, dissolution, zone of inhibition and in vivo studies. A noticeable change in the dissolution rate was observed by in vitro dissolution studies in relation with pure CFX. The solid dispersion of CFX prepared showed following order in enhanced amorphous micellerization ratio like Spray drying>Lyophilizati on>Microwave irradiation>Solvent evaporation>Kneading method>Physical mixture>Pure drug. In addition, spray dried solid dispersion demonstrated remarkable highest inhibition of microbial zone than plain Cefixime (CFX) suggesting improvement in antibacterial activity of Cefixime by solid dispersion. Pharmacokinetic work by (n=6) rats demonstrate a significant difference (α=0.05) when the mean Cmax concentration from spray dried SD and Cefixime (CFX) were compared. The AUC was 1.9 times more in Cefixime (CFX) as SD administration, against the AUC obtained for the plain Cefixime (CFX) suspension. After SD dosing, Tmax (4 h) was different than that obtained in pure drug suspension (3 h). Thus, formulation of Cefixime (CFX) as SD, enhanced amorphous micellerization ratio of the drug and lead to significant (p=0.05) increase in absorption of Cefixime. Hence, Soluplus proved to be potential hydrophile for increasing oral bioavailability of Cefixime using spray drying technique and leading to improved health of patient with reduced dose of drug. 

Read More

UV imaging of multiple unit pellet system (MUPS) tablets: A case study of acetylsalicylic acid stability

Abstract

The applicability of multispectral ultraviolet (UV) imaging in combination with multivariate image analysis was investigated to monitor API degradation within multiple unit pellet system (MUPS) tablets during storage. For this purpose, acetylsalicylic acid (ASA) layered pellets were coated with Eudragit® RL PO and compressed to MUPS tablets. These tablets were stored under four different conditions with different levels of relative humidity (0 and 75%) and temperature (21 and 40 °C) and analysed at seven storage time points (0, 15, 40, 140, 165, 265, and 330 d). The UV imaging results for estimation of the salicylic acid (SA) concentration as degradation product of ASA in the tablets were compared to the SA concentration measured by high performance liquid chromatography with a partial least squares regression resulting in an RMSEP of 4.86% and an R2 of 0.9812. The estimation of the SA concentration based on mean UV reflectance spectra was possible even through the coating of the API pellets and at low concentration levels. In addition, the distribution of the SA concentration on the tablet surfaces for different storage time periods was visualized. UV imaging as fast and non-destructive method appears to offer significant potential for monitoring of API degradation during stability studies.

More

Read More 0 Comments

Furosemide ethanol-free oral solutions for paediatric use: formulation, HPLC method and stability study

Background Oral liquid solutions of the diuretic active ingredient furosemide (FUR) marketed across Europe do not comply with recent requirements for paediatric preparation owing to their ethanol content and, moreover, in some countries only tablet or injection dosage forms of furosemide are available.

Objectives To formulate extemporaneous paediatric ethanol-free solutions of FUR (2 mg/mL) with suitable solubility in the aqueous vehicle and an acceptable taste and to evaluate their stability under two different storage conditions during a 9-month study period.

Methods Our work presents two developed formulations of FUR ethanol-free paediatric oral solutions 2 mg/mL for easy extemporaneous compounding in a pharmacy. FUR solubility avoiding the use of ethanol was achieved using sodium hydroxide (formulation F1) or disodium hydrogen phosphate dodecahydrate (formulation F2). The preparations were stored at 25°C±3°C or at 40°C±0.5°C and protected from light. For FUR and preservative, methylparaben (MP), a stability assay was conducted by a high-performance liquid chromatography validated method and determination of pH stability.

Results The remaining FUR concentration was >90% of the initial concentration after 270 days in both formulations at both storage conditions, 25°C and 40°C. The concentration of MP decreased significantly in the formulation F2 stored at 40°C.

Conclusions Both formulations were stable when stored at room temperature for up to 9 months; formulation F1 was stable even at 40°C. MP used as an antimicrobial agent fully satisfied the recommended criteria for preservative efficacy in oral preparations according to the European Pharmacopoeia 9.0 (5.1.3).

More

Molecular characterization of excipients’ preferential interactions with therapeutic monoclonal antibodies

Objectives

This study reports global and local monoclonal antibody (mAb)–excipient interactions and the resulting thermodynamic and stabilization effects.

Methods

Molecular dynamics simulations are applied to quantify the interactions of key excipients (sucrose, sorbitol, arginine, citrate, histidine and NaCl) used in the formulations of three mAbs. The dynamic surface properties of the mAbs and preferential interaction coefficients for the excipients based on validated potential parameters are computed, in addition to the spatial aggregation propensity.

Key findings

A high molar concentration of citrate induces a large degree of structural distortion in the mAb structure. The total quantities of sucrose, arginine and Cl that interact with the three mAbs are different, implying that each excipient exerts a different stabilizing effect on each mAb. The equilibrated populations of the excipient and water near the local mAb domains vary, with each mAb exhibiting a unique pattern. The local domain's surface properties rather than the properties of the individual residues primarily control the specific preferential interactions. For sucrose, preferential binding to mAbs correlates to a large extent with the relative degree of hydrogen bonding.

Conclusions

These results enrich our understanding of the molecular bases for the varied interaction behaviours of individual excipients.

More

Paediatric Medicines: Formulation Considerations

The use of unlicensed and off-label medicines in children is widespread and has raised an increasing concern over the last years. The majority of medicines taken by children are extemporaneously compounded by pharmacist, and there is a lack of information regarding bioavailability, suitability and stability. These formulations must be prepared from pure active substance and not from commercially available dosage forms. The development of paediatric formulations, particularly those suitable for very young children, can be a challenge to pharmacists. There is limited knowledge available about the acceptability of different dosage forms, administration volume, dosage form size, taste, safety of formulation excipients regarding to age and development status. The selection of formulation and route of administration depends on the disease being treated and the clinical condition. European Guidelines and reflection papers recommend that pharmaceutical development should consider some parameters like capability, acute or long-term illness, caregiver convenience, disability, culture differences and formulations more attractive to children must be explored.

More

Read More

EMA Reflection paper on the pharmaceutical development of medicines for use in the older population

According to Eurostat, the older population in the European Union is expected to grow from around 84 million in 2008 to approximately 141 million by 2050. The very elderly constitute the fastest growing subset. Older people differ from children and adults of younger or middle age with respect to an increased prevalence of gradually declining human organ and body functions, resulting in physical, physiological and/or cognitive impairments, multi- and co-morbidities, and/or frailty. As any such impairments may start at a different chronological age, occur in different orders, and worsen in different rates, older people of the same chronological age can be quite different (e.g. healthy, facing some minor impairments only, frail). In general, older people are the majority users of many medicines and at highest risk of encountering practical medication (usability) problems, which may increase the risk for poor adherence, medication errors and/or reduced patient or caregiver quality of life. Considering the above, it is essential that the needs of older (and especially frail) people are duly considered in the pharmaceutical development of medicines that may be used in the older population.

This reflection paper is intended to communicate the current status of discussions on the pharmaceutical development of medicines that may be used in the older population, and to invite comments on the topics addressed. The paper is not intended to provide regulatory or scientific guidance, although it may contribute to any such development in the future. It is expected that the paper will be read in conjunction with the existing directives, regulations, European Commission, ICH, CHMP and EMA guidelines, Q&A documents and other documents of relevance as linked to or published on the EMA website (www.ema.eu). The examples in this paper should neither be understood as an exhaustive list nor as the only possible options to address a specific topic.

The reflections apply to any new application for a marketing authorization (MA) or variation to an existing MA, and for all application types including full and abridged MAs (i.e. new medicinal products, generics, well established use). Where appropriate, the reflections may be considered during the clinical trial phases and in the post-authorization phase as part of the product lifecycle management. They may also be of relevance to other age groups suffering from similar impairments and/or needs (e.g. an easy to open packaging is relevant for rheumatic patients of any age). They need to be considered in a patient centric approach to pharmaceutical development.

Original Link to Paper

Read More

A novel technique for the visualization of tablet punch surfaces: characterization of surface modification, wear and sticking

Abstract

The surface quality of tablets is strongly related to the surface quality of the tablet punch. Therefore, regular control of the punch surfaces is needed to determine the surface properties, the wear status and sticking tendency of the punches. The aim of the present study was to develop and evaluate a new technique to visualize and evaluate tablet punch surfaces using high-resolution impression molding combined with 3D surface analysis. Standardized 3D surface texture parameters were analyzed by principal component analysis (PCA) to characterized differently surface‐modified punches, punches with different wear status and the sticking pattern on the punch surfaces. It could be shown that the presented technique was precise enough to differentiate between differently coated and texturized punches, to evaluate the abrasive wear status of the investigated punches, and to visualize and assess punch tip sticking behavior. In conclusion, this novel technique may serve as a valuable tool for systematic punch surface characterization, wear status check‐up and optimization of the punch surface quality e.g. for improvement of the anti‐sticking behavior.

More

Read More

Experimental Studies and Modeling of the Drying Kinetics of Multicomponent Polymer Films

Abstract

The process of drying thin polymer films is an important operation that influences the film structure and solid state, and the stability of the product. The purpose of this work was to study and model the drying kinetics of multicomponent films based on two polymers: hydroxypropyl methylcellulose (HPMC, amorphous) and polyvinyl alcohol (PVA, semicrystalline). The isothermal drying kinetics of the films at different temperatures (40, 60, and 80°C) were studied using thermo-gravimetric analysis (TGA) and convection oven methods. Solid-state characterization tools used in the study included polarization and hot-stage microscopy, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). The drying kinetics of HPMC and PVA films in the TGA apparatus and convection oven were comparable. The three-parameter (Wmax, τ, n) Hill equation successfully modeled the experimental drying kinetics. The time factor τ in the Hill equation nicely explained two drying phases in the films. Solid-state phase changes occurring in the films during dehydration had a bearing on the drying kinetics and mechanisms. TGA can be used as a simple tool to determine the end points in drying processes using ovens or tunnels. The three-parameter Hill equation explained the drying kinetics and diffusion mechanisms of the solvent through the polymer films for the first time. This study advances our understanding of film drying, in particular for pharmaceutically relevant thin films.

Read More 0 Comments

Melt Adsorption as a Manufacturing Method for Fine Particles of Wax Matrices without Any Agglomerates

Abstract

We have focused on melt adsorption as manufacture method of wax matrices to control particles size of granules more easily than melt granulation. The purpose of present study was to investigate the possibility of identifying a hydrophobic material with a low melting point, currently used as a meltable binder of melt granulation, to apply as a novel carrier in melt adsorption. Glyceryl monostearate (GM) and stearic acid (SA) were selected as candidate hydrophobic materials with low melting points. Neusilin US2 (US2), with a particle diameter of around 100 µm was selected as a surface adsorbent, while dibasic calcium phosphate dihydrate (DCPD), was used as a non-adsorbent control to prepare melting granules as a standard for comparison. We prepared granules containing ibuprofen (IBU) by melt adsorption or melt granulation and evaluated the particle size, physical properties and crystallinity of granules. Compared with melt granulation using DCPD, melt adsorption can be performed over a wide range of 14 to 70% for the ratio of molten components. Moreover, the particle size; d50 of obtained granules was 100–200 µm, and these physical properties showed good flowability and roundness. The process of melt adsorption did not affect the crystalline form of IBU. Therefore, the present study has demonstrated for the first time that melt adsorption using a hydrophobic material, GM or SA, has the potential capability to control the particle size of granules and offers the possibility of application as a novel controlled release technique.

Read More 0 Comments

Coating compliance — looking at the important considerations when coating tablets

Jason Teckoe, technical director, Colorcon EMEA
Jason Teckoe, technical director, Colorcon EMEA

Tablets remain the most common solid oral dosage form for many reasons, including ease of manufacture, convenience for the patient, accurate dose administration and good stability. Good tablet design can be used to provide product differentiation, avoid medication mix-ups and deter counterfeiting. It can also impact patient compliance.

 

So, what are the reasons for including a coating on an oral solid dosage form? Purely from an aesthetic point of view, uncoated tablets are undistinguished. In addition, a rough-looking tablet can appear to be of poor quality; not an attribute you want, especially in a medicine.

 

From the patient’s perspective, coating makes the tablet appear easier to swallow and aids in visual differentiation, thus reducing the potential risk of medication errors. Coating also reduces tablet friability and overcomes any damage or dusting issues often associated with uncoated tablets.

More

 

References

  1. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm331810.pdf
  2. https://www.fda.gov/downloads/drugs/guidances/ucm377938.pdf
Read More

IPEC Announces 2017 Award Season Winners

The International Pharmaceutical Excipients Council (IPEC) Foundation announced the 2017 award season winners, who will be recognized for their contributions to the field of excipients during the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting at the San Diego Convention Center in San Diego, CA, on November 13-15, 2017. The IPEC Foundation Awards dinner will take place on November 20, 2017. The recipients of each award are mentioned below.

Dale Eric Wurster, professor at the University of Iowa College of Pharmacy, is the recipient of the Ralph Shangraw Memorial Award. Dr. Stuart C. Porter, director and senior research fellow of Ashland Specialty Ingredients in Wilmington, DE, is the recipient of the Louis Blecher Memorial Outstanding Lifetime Achievement Award. Jie Shen, PhD, assistant professor of the departments of biomedical and pharmaceutical sciences and chemical engineering at the University of Rhode Island, is the winner of the Emerging Researcher Award.

Additionally, Dieter Lubda, PhD, director actives and formulation R&D operations at Merck KGaA-Process Solutions in Darmstadt, Germany, is the winner of the Industry Research Achievement in Excipient Technology Award. Graduate student award winners include Janki Andhariya from the University of Connecticut; Carolina del Pilar Mora Guerrero from Purdue University; Sampada Koranne from the University of Minnesota; Shreya S. Kulkarni from the University of Connecticut; and Tze Ning Hiew from the National University of Singapore.

Source: PharmaTech.com / IPEC

Designing Optimized Formulations

Design of experiment plays a crucial role in the optimization process of formulation development.

The process, equipment, and technology for developing and manufacturing oral solid-dosage forms are well defined. Nonetheless, designing a drug product formulation that achieves the desired properties of the target profile both in magnitude and robustness is a multi-dimensional, and generally, constrained optimization problem, observes Aaron Goodwin, principal investigator, Research and Development, Capsugel. The ultimate goal in formulation development is to deliver the drug to the right place, at the right time, in the right concentration so that a beneficial therapeutic effect is achieved, John McDermott, executive director, Drug Product Optimization, Quotient, explains.

“Historically, the focus of formulation optimization has been placed upon the manufacturing process because molecules and drug-delivery requirements were arguably more straightforward,” says McDermott. He points out that most new chemical entities (NCEs) entering the development pipeline, however, often have complex physicochemical properties that require enabled formulation technologies to overcome solubility and/or permeability challenges, or a modified-release technology to achieve a suitable treatment regime or protect patients from adverse events associated with peak plasma concentrations. “In all of these cases, optimization of the formulation composition is essential to ensure successful and consistent drug delivery without compromising other criteria, such as dosage form size, or wasting valuable drug,” he says.

Apr 02, 2017 By Adeline Siew, PhD
Read More 0 Comments

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect

Abstract

In this work, a fixed dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and in vitro and in vivo studied. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen.

An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers.

The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30 min after meal, compared to fasting conditions or to dose administration 10 min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs are delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating.

More

Read More

Formulation of Extended-Release Gliclazide Tablet Using a Mathematical Model for Estimation of Hypromellose

Abstract

Formulation of gliclazide in the form of extended- release tablet in 30 and 60 mg dosage forms was performed using hypromellose (HPMC K4M) as a retarding agent. Drug-release profiles were investigated in comparison with references Diamicron MR 30 and 60 mg tablets. The effect of size of powder particles, the amount of hypromellose in formulation, hardness of tablets, and also the effect of halving the tablets were investigated on drug release profile. A mathematical model which describes hypromellose behavior in initial times of drug release was proposed for the estimation of hypromellose content in modified-release gliclazide 60 mg tablet. This model is based on erosion of hypromellose in dissolution media. The model is applicable to describe release profiles of insoluble drugs. Therefore, by using dissolved amount of drug in initial times of dissolution and the model, the amount of hypromellose in formulation can be predictable. The model was used to predict the HPMC K4M content in modified-release gliclazide 30 mg and extended-release quetiapine 200 mg tablets.

Read More

Development of discriminative and predictive dissolution tests for immediate release oral dosage forms of poorly soluble drugs

A suitable dissolution test as a surrogate for in vivo absorption is highly attractive in the early stage of formulation development. Ideally, changes in dissolution in vivo should be reflected by the corresponding in vitro release. However, conventional dissolution tests have limitations to address this need due to the lack of biorelevance. The purpose of this work was to explore a discriminative dissolution test for manufacturing/ formulation changes within formulations of poorly soluble drugs. 

 

Evaluation of a discriminative biphasic dissolution test for different cosolvents 

PEG 400 and EtOH increased carbamazepine solubility in a concentration-dependent manner, where PEG 400 had stronger solubilization capacity than EtOH. However, PEG 400 had an inhibiting effect on drug absorption with increasing concentrations, while EtOH had no effect. The biphasic dissolution model discriminated different influences of PEG 400 and EtOH on drug absorption reflected by drug partitioning, which was in good agreement with other studies. The different performances of the two cosolvents could be associated with drug affinity and diffusivity. Therefore, the solubility-permeability interplay should be taken into consideration when designing cosolvent-based formulations. Furthermore, the mixed EtOH-PEG 400 cosolvent system was superior to single EtOH and PEG 400 by enhancing carbamazepine solubility to compensate for low solubilization in EtOH, and by decreasing the inhibiting effect on drug partitioning to compensate for low drug absorption caused by PEG 400. This optimal strategy could be considered in the development of cosolvents formulations. The biphasic dissolution model has the potential to discriminate between cosolvent-based formulations with BCS II drugs.

 

Evaluation of a discriminative biphasic dissolution test for estimating the bioavailability of carbamazepine polymorphic forms

Three crystal forms (forms I and III, and the dihydrate) of carbamazepine (BCS II) were prepared and characterized. A biphasic dissolution system (phosphate buffer pH 6.8 and octanol) was used to evaluate the dissolution of the three polymorphic forms and to compare it with conventional single phase dissolution tests performed under sink and non-sink conditions. Similar dissolution profiles of the three polymorphic forms were observed in the conventional dissolution test under sink conditions. Although a difference in dissolution was seen in the single phase dissolution test under non-sink conditions as well as in the aqueous phase of the biphasic test, little relevance to in vivo data obtained from the literature was observed. In contrast, the biphasic dissolution system could discriminate between the different polymorphic forms in the octanol phase with a ranking of form III > form I > dihydrate form. This was in agreement with the published in vivo performance. The dissolved drug available for oral absorption, which was dominated by dissolution and solution-mediated phase transformation, could be reflected in the biphasic dissolution test. Moreover, a good correlation was established between in vitro dissolution in the octanol phase of the biphasic test and in vivo pharmacokinetic data (R2 = 0.99). The biphasic dissolution method is a valuable tool to discriminate between different crystal forms in the formulations of poorly soluble drugs. 

 

Evaluation of a discriminative biphasic dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules

Three granule formulations of racecadotril (BCS II) were formulated with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the formulations was investigated using a biphasic dissolution system (phosphate buffer pH 6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. The effect of different volume ratios and interfacial areas in the biphasic test was investigated and optimized to establish a discriminative dissolution test and an in vitro-in vivo correlation. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the various dissolution systems depending on different wetting and dissolution conditions. Similar release profiles between the three granule formulations were observed in the non-discriminating single phase dissolution tests under sink and non-sink conditions. In contrast, biphasic dissolution system showed remarkable discrimination between the granule formulations in the octanol phase with a rank order of release from granules prepared by wet granulation with binder > wet granulation without binder > dry granulation. This release order correlated well with the wettability of these granules. The same rank order as in the biphasic dissolution test was observed with in vivo AUC0-24h values of the three granules, being 4.07 ± 0.22, 3.50 ± 0.22, and 2.85 ± 0.29 µg h/ml (p < 0.05) respectively. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R2 = 0.999). Compared to conventional dissolution methods, the biphasic method is a good tool to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs.

 

Evaluation of a discriminative biphasic dissolution test for estimating the bioavailability of itraconazole amorphous solid dispersions prepared with different polymers

Three amorphous solid dispersions of itraconazole (BCS II) were prepared with different polymers (Eudragit® EPO, Eudragit® EPO-PVPVA 64, and HPMC). In vitro release of these three solid dispersions was evaluated by a pH-gradient biphasic dissolution test and compared to the conventional single phase dissolution test performed under sink and non-sink conditions. Conventional dissolution tests in 0.1 N HCl under sink and non-sink conditions showed poor prediction of in vivo behavior, while the conventional pH-gradient dissolution test under non-sink conditions exhibited a certain relevance with in vivo performance. In contrast, the pH-gradient biphasic dissolution test discriminated these three solid dispersions with a ranking of HPMC > Eudragit® EPO > Eudragit® EPO-PVPVA 64 in the octanol phase and correlated well with the published in vivo performance. Solid dispersion with HPMC showed the best performance due to its superior supersaturation maintenance and precipitation inhibition induced by interaction between HPMC and itraconazole. An excellent correlation between in vitro release obtained from the organic phase of the biphasic test and reported in vivo data was obtained (R2 ≥ 0.95). This study demonstrates that the pH-gradient biphasic model is a potential tool to discriminate between supersaturation formulations with different polymers during early development of formulations with pH-dependent BCS II drugs.

 

In conclusion, this entire work indicated that compared to conventional dissolution methods, the biphasic dissolution system provides great potential to discriminate between manufacturing/formulation changes within formulations for BCS II drugs during the early formulation development.

Link to Thesis

Read More

Development of a video-microscopic tool to evaluate the precipitation kinetics of poorly-water soluble drugs: A case study with tadalafil and HPMC

Many drug candidates today have a low aqueous solubility, and hence may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of HPMC were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software, however, to investigate the entire population of precipitating particles (i.e. their number and area covered in the field of view) an image analysis algorithm was developed (multi-particle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01 % (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1 % (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single- and multi-particle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

More

Pregelatinized hydroxypropyl pea starch as matrix forming material for lyophilized orodispersible tablets of tadalafil

Abstract

Oral fast-disintegrating dosage forms, also known as ‘fast-disintegrating’ or ‘fast-dissolving’ dosage forms, are a relativelynovel dosage technology that involves the rapid disintegration or dissolution of the dosage form. The objective of present study was to demonstrate pregelatinized hydroxypropyl pea starch as promising soluble matrix forming material in the preparation of orodispersible tablets (ODT) that was easy to administer and provides rapid release of the drug. The ODT was prepared by lyophilizing an aqueous dispersion of tadalafil containing modified pea starch. ODTs were investigated for tablet characteristics including dimensions, hardness, friability, in vitro dissolution and in vitro/in vivo disintegration time. The best properties exibhited by OTD are wetting time 13.5 ± 1.2 s, disintegration time of 16.6 ± 0.8 s. Results obtained from dissolution studies showed that ODT of tadalafil significantly improved the dissolution rate of the drug compared with the native drug. More than 75% of tadalafil in ODT dissolved within 1 min compared to only 30% of tadalafil native drug dissolved during 60 s. In conclusion the formation of stable and strong lyophilized orodispersible tablet using pregelatinized hydroxypropyl pea starch as sole matrix excipient is investigated. This study suggests that pregelatinized hydroxypropyl pea starch can act as a potential matrix forming material for oral drug delivery.

More

Read More

Calcium alginate microspheres containing metformin hydrochloride niosomes and chitosomes aimed for oral therapy of type 2 diabetes mellitus

Abstract

Metformin is an oral hypoglycemic agent used in the type 2 diabetes, whose poor bioavailability and short half-life make the development of effective extended-release formulations highly desirable. Different metformin-loaded chitosomal and niosomal formulations were developed and suitably characterized, but were unable to provide the desired sustained release. The entrapment of both kinds of colloidal dispersions in calcium alginate beads enabled to strongly reduce the amount of drug released at gastric level (from 18 up to a maximum of 30%), and to obtain a sustained release in simulated intestinal fluid, which was properly tuned by varying the percentage of calcium alginate in the beads. In vivo studies on rats revealed a significant improvement of metformin hypoglycemic effect when orally administered as chitosomal and even more as niosomal dispersion entrapped in alginate beads, not only with respect to the drug as such, but also to the alginate beads loaded with the plain drug. The more intense and sustained therapeutic effect with time provided by the drug-in niosomes-in alginate bead formulation could be very profitable for maintaining tight blood glucose levels over prolonged period of time after oral administration, allowing a reduction of its dose and related collateral effects, and improving patient compliance.

More

Read More 0 Comments

Targeted delivery of probiotics to enhance gastrointestinal stability and intestinal colonisation

Abstract

The aim of this work was to assess the viability of some commercial probiotics after exposure to gastric acid and the possibility of modifying these formulations for delivery into the distal parts of the intestines. Gastrointestinal tolerance testing was conducted for three commercial probiotics and an in-house freeze-dried Lactobacillus acidophilus strain. The contents of the commercial products and the in-house freeze-dried strain were then loaded into capsules for site-specific delivery into the colon using the Phloral® coating technology; the viability upon release was then ascertained. An assessment of the potential of these products to adhere to intestinal cells was also conducted. The results showed that all the commercial products contained the minimum number of probiotic strains as indicated on their respective packages. When gastric acid tolerance tests were performed on these products, all the commercial probiotics and the prepared freeze-dried strain demonstrated over 106 CFU reductions within 5 min. When these were encapsulated for site-specific delivery into the distal parts of the gut, viabilities of approximately 90% were obtained after these capsules had been initially deposited in gastric acid for 2 h. An evaluation of the ability of the probiotic formulations to adhere to intestinal cells demonstrated adhesion in the range 64–76% for the products evaluated. The need to target the delivery of probiotics into the intestines has been demonstrated here as this offers a greater potential for colonisation of the intestines once the harshness of the stomach has been overcome.

More

Read More

Tablets of multi-unit pellet system for controlled drug delivery

Abstract

The tablet of multi-unit pellet system (TMUPS), using coated pellets, for controlled release of drugs is an effective therapeutic alternative to conventional immediate-release dosage forms. The main advantages of TMUPS include a) ease of swallowing and b) divisible without compromising the drug release characteristics of the individual units. TMUPS can be prepared more economically than pellet-filled capsules because of the much higher production rate of tableting process. In spite of the superiorities of TMUPS, its adoption has been challenged by manufacturing problems, such as compromised integrity of coated pellets and poor content uniformity. Herein, we provide an updated review on research, from both scientific literatures and patents, related to the compaction of TMUPS. Factors important for the successful production of TMUPS are summarized, including model drug property, potential cushioning agents, and novel techniques to protect pellets from damage. This review is intended to facilitate the future development of manufacturable TMUPS with drug release behavior similar to that of the original coated pellets.

More

Read More

Trends on Analytical Characterization of Polysorbates and Their Degradation Products in Biopharmaceutical Formulations

Abstract

Among many other applications, polysorbates (PSs) are used as the most common surfactants in biopharmaceutical products in particular to protect proteins against interfacial stress. Structural heterogeneity, presence of degradants and other impurities, and tendency for degradation are interrelated features found in commercial PSs with a direct impact on their functional properties in biopharmaceutical products. These pose a challenge for the analytical characterization of PSs at different stages of product development. This review article focuses on methods and strategies reported in the recent years for the analytical characterization of PSs, their degradants and other impurities within neat PS (i.e., PS raw materials), diluted PS solutions, as well as in biopharmaceutical formulations. The use of versatile and complementary methods applied in a systematic approach is crucial to understand the impact of the concentration, composition, and degradation of PSs on the quality of biopharmaceutical products.

More

0 Comments

Determination of the Bitterness Threshold of Cetirizine Dihydrochloride Minitablets using E-tongue, invitro release analysis and Human Taste Panel Assessments

Presentation @ 9th Conference of the European Paediatric Formulation Initiative (EuPFi) "Formulating better Medicines for Children" in Warshaw by Stephanie Keser, Glatt Pharmaceutical Services.

Link to Conference

Read More

Drug Delivery Innovations to Address Global Health Challenges for Pediatric and Geriatric Populations (through improvements in patient compliance)

Abstract

Despite significant advances in pharmaceutical and biotechnological drug discovery, the global population is plagued with many challenging diseases. These are further compounded by anticipated explosion in an ageing population, which presents several problems such as polypharmacy, dysphagia and neurological conditions, resulting in non-compliance and disease complications. For antibiotics, poor compliance, can result in development of drug resistant infections which can be fatal. Further, children, especially, in developing countries die unnecessarily from easily treatable diseases (e.g. malaria), due to poor compliance arising from bitter taste and inability to swallow currently available medication. Though, some of these challenges require the discovery of new drug compounds, a significant number can be resolved by employing pharmaceutics approaches to reduce the incidence of poor patient compliance. Such solutions are expected to make swallowing easier and reduce the need to swallow several solid medications, which is difficult for vulnerable pediatric and geriatric patients. This commentary will explore the current state of the art in the use of drug delivery innovations to overcome some of these challenges, taking cues from relevant regulatory agencies such as the Food and Drugs Administration, the European Medicines Agency, World Health Organization and the peer reviewed scientific and clinical literature.

More

Chitosan Based Materials and its Applications - Book

This volume presents 10 reviews contributed by eminent researchers around the world on chitosan based materials. The introductory chapters present information on general characteristics of chitosan and various types of materials which are based on it such as nanofibers, nanoparticles, nanocapsules and other chemically modified chitosans. This is followed by an explanation of chitosan characterization and extraction techniques. Concluding chapters describe the applications of chitosan products in water treatment, drug delivery, edible films and pervaporation membranes. Readers will therefore gain an understanding about chitosan and materials derived from this polymer and their practical applications. The volume serves as a simple reference for chemical engineering students and professionals interested in the basic and applied chemistry of chitosan and chitosan-derived products.

More

0 Comments

Lipid nanocarriers for tamoxifen citrate/coenzyme Q10 dual delivery

Abstract

Nanotechnology based combinatorial therapy has emerged as an effective strategy for cancer treatment due to its synergistic activity, suppression of multi-drug resistance and successful delivery to target site. The objective of this work was to develop and characterize tamoxifen citrate (TC) and coenzyme Q10 (CoQ10) lipid nanocarriers for oral breast cancer chemotherapy. Stearic acid (2%w/v) and poloxamer188 (3%w/v) were selected as optimal lipid matrix and surfactant for development of solid lipid nanocarriers (SLNs). Incorporation of lecithin into lipid matrix (SLN9) significantly reduced particle size to 180 nm and increased %EE of CoQ10 (45%). Nanostructured lipid carriers containing 10% Labrafac oil showed further decrease in particle size reaching only 81 nm and increased %EE up to 94% and 56% for TC and CoQ10, respectively. Lipid nanocapsules showed more prominent effect on decreasing particle size (36 nm). Lipid nanocarriers offered controlled drug release profiles. The study showed that lipid carriers significantly improved drugs permeation through rabbit intestinal mucosa and suggested them as potential delivery systems for improving the bioavailability of TC/CoQ10 therapeutic molecules. Subsequent studies will be performed in order to elucidate the cytotoxicity and genotoxicity of selected lipid nanocarriers formulas on MCF-7 (adenocarcinoma breast cancer cells) versus normal cells (WISH cell line).

More

Read More

Alginate modified with maleimide-terminated PEG as drug carriers with enhanced mucoadhesion

Abstract

The goal of this study was to generate a new mucoadhesive carbohydrate-based delivery system composed of alginate (Alg) backbone covalently attached to polyethylene glycol (PEG) modified with a unique functional end-group (maleimide). The immobilization of PEG-maleimide chains significantly improved the mucoadhesion properties attributed to thioether bonds creation via Michael-type addition and hydrogen bonding with the mucus glycoproteins. Mucoadhesion studies using tensile and rotating cylinder assays revealed a 3.6-fold enhanced detachment force and a 2.8-fold enhanced retention time compared to the unmodified polymer, respectively. Additional indirect studies confirmed the presence of polymer-mucus glycoproteins interactions.

Drug release experiments were used to evaluate the release profiles from Alg-PEG-maleimide tablets in comparison to Alg and Alg-SH tablets. Viability studies of normal human dermal fibroblasts cells depicted the non-toxic nature of Alg-PEG-maleimide. Overall, our studies disclose that PEG-maleimide substitutions on other biocompatible polymers can lead to the development of useful biomaterials for diverse biomedical applications.

More

Early pediatric formulation development with new chemical entities: Opportunities of e-tongue besides human taste assessment

Astract

The palatability of a pediatric drug formulation is one of the key prerequisites for therapeutic success. Liquid formulations are often chosen for pediatric drug products, and they require special attention regarding their taste, as they have direct contact to the taste buds and a relatively long residence time in the oral cavity. For ethical reasons, the role of electronic tongues in the development of oral drug formulations with new chemical entities (NCEs) for pediatric use is growing, however, little is known about the strategies how this instrumental taste assessment can be performed.The present study illustrates two possibilities to combine in-vitro and in-vivo data for the characterization of the palatability of the new drug candidates CSE3104 and CSE3165. As a first step, the implementation and suitability of electronic tongue measurements has been demonstrated by comparison of in-vivo and in-vitro data. In alignment with the taste assessment results during a single-center, double-blinded, randomized, placebo-controlled, single ascending dose (SAD) study in healthy subjects, the bitter taste perception of CSE3104 was assessed with e-tongue measurements. Moreover, the sensor response pattern showed comparable results of the e-tongue measurements to the human taste study of CSE3165: With increasing concentration, the bitterness values were increased. In addition, the human taste pattern showed increasing values for sourness due to higher volumes of the citric acid buffer. Results of the hedonic descriptor “unpleasant” within the human taste assessments could be related to bitterness in the instrumental taste assessment.For the second step in electronic tongue guided formulation development two possibilities are depicted in the article focusing on the effect of different excipients on the formulation on the one hand and on the assessment and comparison of two drug formulations on the other hand.Based on these results, the low number of healthy volunteers for the taste assessment in a Phase 1 study led to a meaningful interpretation, by applying in addition the electronic tongue. Using this instrumental approach led to reproducible data versus the human taste assessment, without ethical concerns, and with a reduction in time and costs.

More

Read More

Manufacturing of oral solid dosage forms using 3D inkjet printing

Abstract

Ink-jet printing is a precise and versatile technique that accurately deposits small volumes of solutions (pico litres) in specific locations. Recently inkjet printing has attracted increasing attention in the pharmaceutical industry because of its ability to deliver low adjustable doses, variable drug release profiles and drug combinations suitable for the paradigm of personalised medicines. The significant growth in the aging population and the rise in the number of patients suffering from multiple chronic diseases are the key drivers. The current traditional tablet compression methods are largely limited in terms of flexibility and complexity of dosage form. There is a need for new innovative technologies that can produce bespoke medicines in a relatively cheap and efficient manner at the point of care. 3D inkjet printing (3DIJP) provides a platform with the potential to address the above need.

This thesis investigates the capability of 3DIJP as a tool for manufacturing solid dosage forms. In chapter 3, a piezoelectric drop on demand printer was used. The chapter focuses on two solvent based inkjet printing methods. In the first solvent based method, excipients including hydroxypropyl methylcellulose (HPMC), poly (vinyl pyrrolidone) (PVP) and Eudragit RL were investigated for printability. PVP (K10) which showed the best printability behaviour was loaded with digoxin or carbamazepine (CBZ) and printed to obtain films. In the second solvent based method, a solution containing CBZ dissolved in a mixture of of polyethylene glycol diacrylate (PEGDA) and with poly(caprolactone dimethyl acrylate) (PCLDMA) was printed and polymerised in situ using ultraviolet light to form films. The printed drug loaded films were investigated using time of flight secondary ion mass spectroscopy (ToF SIMS), atomic force microscopy (AFM), scanning electron microscopy (SEM) and differential scanning microscopy (DSC). PVP formulations were homogeneous, with no evidence of crystallisation PEGDA/PCLDA/CBZAFM images showed a clear phase separation at the micron scale and no drug was detected at the surface. In this chapter, the production of adjustable doses was also evaluatedusing UV-VIS spectrophotometry.

In chapters 4 and 5, a solvent-free hot-melt 3D inkjet printing method suitable for manufacturing solid dosage forms was developed. Excipients including beeswax, carnuba wax, gelucire 44/14 and trimyristin were examined for printability. Beeswax a naturally derived and FDA approved material showed the best printability behaviour and was selected as the drug carrier. Traditional circular shaped tablets and cylindrical implants loaded with 5% w/w fenofibrate were successfully fabricated. The printed tablets and implants were well-defined, smooth surfaced and with no apparent defects. The architecture of the tablets was investigated using 3D micro X-ray computed tomography (μCT), revealing well defined and ordered honeycomb channels in the interior of the tablets. The distribution of the drug was evaluated at the macro scale level using DSC and at the micro scale level using ToF - SIMS and Raman spectroscopy. The drug was homogenously distributed within the drug carrier (beeswax matrix ) at the microscale level. At the micron scale level, the drug was heterogeneously distributed. ToF - SIMS studies also revealed that the drug was depleted from the upper most top surfaces.

Production of solid dosage forms with intricate and adaptable geometries was demonstrated by printing honeycomb architecture tablets with predetermined variable cell diameters. The diamater of the honeycomb cells was varied, in order to achieve controlled variable drug release profiles. The ablity to control drug release was only applicable above an established critical cell diameter of 0.5 mm. An analytical model describing Fickian diffusion from a slab geometry was developed to allow for the prediction of drug release from the honeycomb tablets. The predicted drug release profiles varied slightly from the experimental data, but the trends for the two data set were identical. For both data sets the rate of drug release increased with increase in the surface area to volume ratio.

The findings and the developments demonstrated in this thesis provide an insight into the potential application of 3DIJP as a tool for manufacturing solid dosage forms with bespoke properties for controlled drug release but also highlights some limitations.

Access to download Thesis

0 Comments

Patient acceptability of 3D printed medicines

Abstract
Patient-centric medicine is a derivative term for personalised medicine, whereby the pharmaceutical product provides the best overall benefit by meeting the comprehensive needs of the individual; considering the end-user from the beginning of the formulation design process right through development to an end product is a must. One way in which to obtain personalised medicines, on-site and on-demand is by three-dimensional printing (3DP). The aim of this study was to investigate the influence of the shape, size and colour of different placebo 3D printed tablets (Printlets™) manufactured by fused deposition modelling (FDM) 3DP on end-user acceptability regarding picking and swallowing. Ten different printlet shapes were prepared by 3DP for an open-label, randomised, exploratory pilot study with 50 participants. Participant-reported outcome (PRO) and researcher reported outcome (RRO) were collected after picking and swallowing of selected printlet geometries including sphere, torus, disc, capsule and tilted diamond shapes. The torus printlet received the highest PRO cores for ease of swallowing and ease of picking. Printlets with a similar appearance to conventional formulations (capsule and disc shape) were also found to be easy to swallow and pick which demonstrates that familiarity is a critical acceptability attribute for end-users. RRO scores were in agreement with the PRO scores. The sphere was not perceived to be an appropriate way of administering an oral solid medicine. Smaller printlet sizes were found to be preferable; however it was found that the perception of size was driven by the type of shape. Printlet colour was also found to affect the perception of the end-user. Our study is the first to guide the pharmaceutical industry towards developing patient-centric medicine in different geometries via 3DP. Overall, the highest acceptability scores for torus printlets indicates that FDM 3DP is a promising fabrication technology towards increasing patient acceptability of solid oral medicines.

More

Read More

Microgels of silylated HPMC as a multimodal system for drug co-encapsulation

Abstract

Combined therapy is a global strategy developed to prevent drug resistance in cancer and infectious diseases. In this field, there is a need of multifunctional drug delivery systems able to co-encapsulate small drug molecules, peptides, proteins, associated to targeting functions, nanoparticles. Silylated hydrogels are alkoxysilane hybrid polymers that can be engaged in a sol−gel process, providing chemical cross linking in physiological conditions, and functionalized biocompatible hybrid materials.

In the present work, microgels were prepared with silylated (hydroxypropyl)methyl cellulose (Si-HPMC) that was chemically cross linked in soft conditions of pH and temperature. They were prepared by an emulsion templating process, water in oil (W/O), as microreactors where the condensation reaction took place.

The ability to functionalize the microgels, so-called FMGs, in a one-pot process, was evaluated by grafting a silylated hydrophilic model drug, fluorescein (Si-Fluor), using the same reaction of condensation. Biphasic microgels (BPMGs) were prepared to evaluate their potential to encapsulate lipophilic model drug (Nile red). They were composed of two separate compartments, one oily phase (sesame oil) trapped in the cross linked Si-HPMC hydrophilic phase.

The FMGs and BPMGs were characterized by different microscopic techniques (optic, epi-fluorescence, Confocal Laser Scanning Microscopy and scanning electronic microscopy), the mechanical properties were monitored using nano indentation by Atomic Force Microscopy (AFM), and different preliminary tests were performed to evaluate their chemical and physical stability.

Finally, it was demonstrated that it is possible to co-encapsulate both hydrophilic and hydrophobic drugs, in silylated microgels, that were physically and chemically stable. They were obtained by chemical cross linking in soft conditions, and without surfactant addition during the emulsification process. The amount of drug loaded was in favor of further biological activity. Mechanical stimulations should be necessary to trigger drug release.

More

Read More

Stability of medicines after repackaging into multicompartment compliance aids: eight criteria for detection of visual alteration

Introduction

Multicompartment compliance aids (MCA) are widely used by patients. They support the management of medication and reduce unintentional nonadherence. MCA are filled with medicines unpacked from their original packaging. Swiss pharmacists currently provide MCA for 1–2 weeks, although little and controversial information exists on the stability of repackaged medicines.

Objective

We aimed to validate the usefulness of a simple screening method capable of detecting visual stability problems with repackaged medicines.

Methods

We selected eight criteria for solid formulations from The International Pharmacopoeia: (1) rough surface, (2) chipping, (3) cracking, (4) capping, (5) mottling, (6) discoloration, (7) swelling, and (8) crushing. A selection of 24 critical medicines was repackaged in three different MCA (Pharmis®, SureMed™, and self-produced blister) and stored at room temperature for 4 weeks. Pharmis® was additionally stored at accelerated conditions. Appearance was scored weekly.

Results

Six alterations (rough surface, cracking, mottling, discoloration, swelling, and crushing) were observed at accelerated conditions. No alteration was observed at room temperature, except for the chipping of tablets that had been stuck to cold seal glue.

Conclusion

The eight criteria can detect alterations of the appearance of oral solid medicines repackaged in MCA. In the absence of specific guidelines, they can serve as a simple screening method in community pharmacies for identifying medicines unsuitable for repackaging.

Read More 0 Comments

Oral product input to the GI tract: GIS an oral product performance technology

Abstract

The patient receives a pharmaceutical product, not a drug. The pharmaceutical products are formulated with a drug, an active ingredient to produce the maximum therapeutic effect after oral absorption. Therefore, it is the product we must optimize for the patients. In order to assure the safety and efficacy of pharmaceutical products, we need an in vivo predictive tool for oral product performance in patients. Currently, we are a surprisingly long way from accomplishing that objective. If the 20th century was the ‘age of the drug’, i.e., the ‘magic bullet’, the 21st century must become the ‘age of the guided missile’, i.e., the delivery system, including the form of the active pharmaceutical ingredient (API) (‘drug’). The physical form of the drug and the delivery system must be optimized to maximize the therapeutic benefits of pharmaceutical products for humans. Oral immediate release (IR) dosage forms cannot be optimal for all drugs or likely even any drugs (APIs). Still, the formulation of pharmaceutical products has to be optimized for patients. But how do we optimize oral delivery of drugs? It is usually through ‘trial and error’, in humans! We need a better way to optimize the oral dosage forms. We have suggested to select different dissolution methodologies for this optimization based on BCS Subclasses. In this article, we present the predicted in vivo drug dissolution profile of ketoconazole as a model drug from our laboratory utilizing a gastrointestinal simulator (GIS), which is an adaptation of the ASD system. GIS consists of three chambers representing stomach, duodenum, and jejunum, to create the human gastrointestinal tract-like environment and enable the control the gastric emptying rate. This dissolution system allows the monitoring of the drug dissolution phenomena and the observation of the supersaturation and the precipitation of pharmaceutical products, which is useful information to predict in vivo dissolution of pharmaceutical products. This system can provide the actual input needed to accurately predict the input into the systemic circulation required by many of the absorption prediction packages available today.

More

Read More

Palm Olein Emulsion: a Novel Vehicle for Topical Drug Delivery of Betamethasone 17-Valerate

Abstract

This study aims to investigate the use of palm olein as the oil phase for betamethasone 17-valerate (BV) emulsions. The physicochemical properties of the formulations were characterized. In vitro drug release study was performed with the Hanson Vertical Diffusion Cell System; the samples were quantified with HPLC and the results were compared with commercial products. Optimized emulsion formulations were subjected to stability studies for 3 months at temperatures of 4, 25, and 40°C; the betamethasone 17-valerate content was analyzed using HPLC. The formulations produced mean particle size of 2–4 μm, viscosities of 50–250 mPa.s, and zeta potential between −45 and −68 mV. The rheological analyses showed that the emulsions exhibited pseudoplastic and viscoelastic behavior. The in vitro release of BV from palm olein emulsion through cellulose acetate was 4.5 times higher than that of commercial products and more BV molecules deposited in rat skin. Less than 4% of the drug was degraded in the formulations during the 3-month period when they were subjected to the three different temperatures. These findings indicate that palm olein-in-water emulsion can be an alternative vehicle for topical drug delivery system with superior permeability.

More

Pediatric Formulation Development - some of the topics @ EuPFi in September 2017

  • A ‘taster’ session on designing taste-masked oral paediatric formulation prototypes and how to plan their palatability assessment
  • Biopharmaceutics evaluation of food effects in paediatric medicines development for products co-administered with Food
  • 10 years of European paediatric regulation and formulation: any news?
  • Off patent of the radar? Scoping the needs for paediatric formulation of old medicineTaste masking and taste testing
  • Pharmaceutical cocrystals: recent advances, current challenges and unrealised opportunities in paediatric drug formulation
  • The birth of PaedForm: a pan-European Paediatric Formulary by EDQM
  • Administration devices for pediatrics
  • Acceptability and palatability studies in PIPs and MAA
  • Infacort®: A PUMA application success Story
  • Age appropriateness of formulations
  • Success/pitfalls of dispersible tablets in developing countries: lessons learn from PAEDS TB FDC dispersible tablets
  • The gastrointestinal environment in paediatrics: what do we (not) know?
  • Biopharmaceutics evaluation of solid dispersion-based paediatric dosage forms – The new frontier
  • and more

More Information

Read More

Speed change experiments in a rotary tablet press

Introduction

As part of the development of continuous manufacturing in the pharmaceutical industry, appropriate solutions dealing with short-term malfunctions of upstream units or upstream discharge of out-of-specification material must be implemented. The implementation of a rotary tablet press in a continuous manufacturing line gives possibilities regarding the development of an overall control concept and an discharge strategy. Based on a feasibility study, it was concluded that a promising approach is the implementation of different operating points for the turret speed (recipe set point, set point low, set point high) [1]. This concept allows reactions on upstream variations in mass flow, in order to keep the filling height in the tablet press hopper constant. However it has to be guaranteed, that with changes in turret speed tablets stay within the spec. The main scope of the experiment was to evaluate, if turret speed changes have a significant impact on the standard deviation in weight and height of the product.

Read More

Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release

Abstract

The objective of the current study was to develop an amorphous solid dispersion for a high melting point compound, griseofulvin (GRF), with an enhanced solubility and a controlled release pattern utilizing hot melt extrusion (HME) technology. Hypromellose acetate succinate (HPMCAS, Shin-Etsu AQOAT®, medium particle size) was explored as the polymeric carrier, while hypromellose (HPMC, Metolose® SR) was chosen as the release rate control agent. GRF presented an HPMCAS grade-dependent solubility: AS-HMP > AS-MMP > AS-LMP. At 10 wt.% loading, the release of GRF was prolonged to 6 h with the incorporation of 10% HPMC 90SH-100SR, while its solubility was enhanced up to sevenfold. Fourier transform infrared spectroscopy (FT-IR) identified the H-bonding between drug and polymers. Element analysis utilizing X-ray photoelectron spectroscopy (XPS) discovered that less GRF aggregated on the surface of binary powders compared with ternary powders containing HPMC, indicating the relatively poor wettability of the latter one. The morphology of extrudates was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), illustrating a much smoother and uniform surface of binary extrudates. Immediate release tablets including 10% super-disintegrant L-HPC were able to achieve identical dissolution profile as the powders of extrudates.

More

Read More 0 Comments

Innovative Drinking Straw Drug Delivery System Helping Patients

Many children make a disgusted face when they are supposed to take drugs. This is understandable: Medicine often tastes bitter and sometimes, the swallowing of tablets is difficult or even impossible. Also the elderly or people with swallowing difficulties often have problems with this kind of drug intake. Recent studies show that more than 50% of patients in Germany and the US have difficulties with the use of tablets and capsules.

This is when people make the mistake of crushing their medication or dissolving it in water - with potentially fatal consequences. Crushing or dissolving coated tablets, which are not supposed to activate in the stomach but only later upon reaching the intestine, or their active ingredients are supposed to be released over time, can lead to severe or even life threatening side effects. Moreover, for patients who have to swallow tablets over a longer period of time, a new method of taking drugs is a welcome change. Fortunately, XStraw® offers a real alternative.

The XStraw® is a drinking straw that is filled with pellets or granules with taste masking properties. Patients can hardly sense these tiny globules. They drink a pleasant beverage, while at the same time taking exactly the amount of medicine required – completely without any unpleasant swallowing sensations or taste experiences.

The straw is filled on fully automatic lines with precisely the amount required. That way, the medication is pre-dosed by the manufacturer and incorrect dosing is avoided. When drinking, the control filter moves upwards giving the patient or caretaker assurance that the intended drug amount was taken correctly.

The XStraw® has been specifically developed for pediatrics and geriatrics and guarantees simple and convenient intake. Patients with swallowing difficulties no longer experience pain when swallowing tablets. The very easy use combined with an individual choice of beverage and thus a choice of flavor makes the drinking straw extremely popular with patients. Upon request, the XStraw® can be printed with a brand name or dosage amount for marketing purposes.

Thanks to polypropylene components that are perfectly coordinated with one another, and hermetically sealed packaging in aluminium pouches, special storage conditions are not required.

 

Dose Sipping Technology: Oral application system for pellets

DS-Technology is your contact when it comes to the delivery of XStraw® components and issuing of licenses. Customers experience comprehensive expertise and support in the development and production of  multiparticulate dosage forms (“pellets/granules”), supply of material components, implementation of the production process by creating suitable facilities and, if requested, in arranging for contract manufacturers that provide the appropriate machinery.

As a system provider, the company DS-Technology offers the complete portfolio of fully automatic processing systems for the filling and packaging of the XStraw®.

DS-Technology closely cooperates with the companies Glatt, Raumedic and Harro Höfliger. These companies will provide assistance along your entire value chain.

Should a customer require support for the development and production of pellets or granules, the company Glatt will be happy to assist with their expertise.

The company Harro Höfliger supplies the dosing and packaging technology. The enterprise is known for their expertise in production technologies for the pharmaceutical industry, and offers wide-ranging support with their Pharma Service.

Original Article

http://d-s.technology/en

European Pediatric Formulation Initiative (EuPFi)

Read More

White paper: Optimising excipient properties for ODT formulation

Orally disintegrating tablets (ODTs), also known as orodispersible tablets, are unique dosage forms formulated to improve their in vivo disintegration and dissolution rates. It is a big challenge to ODT producers to achieve a minimum disintegration time while keeping formulation simple and robust.

 

The required advances in pharmaceutical manufacturing occurred when excipient suppliers developed multi-functional types for direct compression. Roquette’s PEARLITOL® Flash, a combination of mannitol and starch, is a ready-to-use excipient for orodispersible tablets. This article describes its application to formulation and how this delivers advantages like robustness and rapid disintegration time. PEARLITOL® Flash means problem-free ODT formulation.

Read More

Design of Finasteride-Loaded Nanoparticles for Potential Treatment of Alopecia

Abstract

Background/Aims: Androgenetic alopecia is an extremely common dermatological disorder affecting both men and women. Oral finasteride (FNS), a synthetic 4-aza-3-oxosteroid compound with poor aqueous solubility, blocks the peripheral conversion of testosterone to dihydrotestosterone (DHT) in a significant reduction in DHT concentration, achieving satisfactory results in alopecia treatment. However, its oral intake generally causes severe side effects. Considering that there is currently no scientifically proven treatment, new drug delivery systems able to improve alopecia therapy are urgently required. Methods: In this study, polymeric nanoparticles have been proposed as a new carrier for topical delivery of FNS in hair follicles. Results and Conclusions: Polymeric nanoparticles, prepared by using a modified method of the emulsification/solvent diffusion, showed a mean particle size around 300 nm, which may be sufficient for reaching the dermis and hair follicles and negative zeta potential values. Scanning electron microscope measurements showed that all the polymeric nanoparticles exhibited a spherical shape and a smooth surface regardless of their composition. A high encapsulation efficiency was achieved for FNS (79.49 ± 0.47%). In vitro release assays in physiological conditions demonstrated that nanoparticles yielded a prolonged release of FNS for 3 h. Skin assays through an in vitro permeation study demonstrated that nanoparticles had low levels of penetration of FNS, improving its time residence onto the skin. All excipients used in nanoparticle composition and in 3 different vehicles were safe. These results suggest that the proposed novel formulation presents several good characteristics indicating its suitability for dermal delivery of FNS for alopecia treatment.

More

Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system

Abstract

Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceutical preparations such as controlled release formulations, parenteral preparations, surgical treatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticles for topical and site targeting delivery of Norfloxacin by emulsification solvent evaporation method (ESE). The design of experiment (DOE) was done by using software to optimize the result, and then a surface plot was generated to compare with the practical results. The surface morphology, particle size, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized by SEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterized by DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited an average particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution with polydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymer hybrid nanoparticles were confirmed by zeta potential, showed the value from +23.4 ± 1.5 mV to +41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonas aeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two. Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in 24 h. A stability study of the optimized formulation showed the suitable condition for the storage of lipid-polymer hybrid nanoparticles was at 4 ± 2 °C/60 ± 5% RH. These results illustrated high potential of lipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.

Read More 0 Comments

A 30-Year History of PLG Applications in Parenteral Controlled Drug Release

Poly(lactide-glycolide) has been used for drug-delivery applications because of its beneficial physicochemical properties, long safety record, and reliable commercial supply.

 

The history of poly(lactide-glycolide) (PLG) for drug-delivery applications can be told through the number of products that has steadily emerged on the market since the first product was launched in 1986. More than 35 commercial drug products have relied on the beneficial physical and chemical properties of PLG, its long safety record, and the reliable commercial supply of this polymer. 

Link to original Article

Read More 0 Comments

Applications and biotechnological production of mannitol

Abstract

Mannitol is a polyol or an alditol that is naturally found in many plants and can be produced by several microorganisms. Based on its beneficial physiological effects, mannitol is currently used as a functional sweetener in the food industry. In addition, mannitol has applications in pharmaceutical, chemical and medical industries because of its promising advantages. Mannitol can be produced by extraction, chemical synthesis, or fermentation. Certain mutants have been constructed for different purposes. In this review, we focused on recent advances in the applications and biotechnological production of mannitol.

More

0 Comments

Saturated phosphatidylcholine as matrix former for oral extended release dosage forms

Abstract

The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40 MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t80%) from 8 mm tablets ranged from 1.5 h to 18 h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50–100 rpm) and ionic strength of the release media (100–600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity.

More

Read More

Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects

Therapeutic peptides have become very successful drugs due to their specificity, potency and low toxicity, but they show challenges for their delivery, due to their short half-life and rapid plasma clearance. For these reasons, peptides are usually administered using injectable sustained-release formulations. Oral peptide route is highly compelling from a patient and commercial point of view. However, poor peptide stability and low permeability across the intestinal epithelium still make it very challenging to effectively deliver peptides by the oral route. In this paper, biopharmaceutical and formulation features of oral peptides, as well as key clinical outcomes, are reviewed and discussed in the perspective of designing next generation of oral peptide formulations for a true paradigm shift.

More

Read More 0 Comments

Effect of directly compressible excipient and treated agar on drug release of clopidogrel oral disintegrating tablets

Aim: In the present investigation, oral dissolving/dispersible/disintegrating tablets (ODTs) of clopidogrel were designed with a view to enhance the bioavailability and patient compliance by two different methods, namely, direct compression and effervescent methods using directly compressible excipient and treated agar (TAG). Materials & methods: In the direct compression method, TAG was used as a disintegrant and another method used a mixture of sodium bicarbonate and tartaric acid along with TAG as disintegrants. Results: Among the directly compressed tablets, treated agar formulation 3 and among the effervescent tablets, treated agar and effervescent formulation 4 was found to be promising. Conclusion: Treated agar formulation 3 prepared by direct compression method emerged as an overall best formulation based on the in vitro drug release characteristics.

More

Read More

In Situ Salification in Polar Solvents: a Paradigm for Enabling Drug Delivery of Weakly Ionic Drugs as Amorphous Solid Dispersion

Abstract

Solubility challenge for a poorly water-soluble drug gets further intensified when it is weakly ionic because the most common solubility enhancement technique, salt formation, becomes less feasible. Salt screening for such drugs often concludes with either a difficult to crystalize salt or an unstable salt, leading the scientists to explore other solubility enhancement technique like amorphous solid dispersions which is comparatively costlier, time-consuming and may require use of hazardous organic solvents. Present study evaluated in situ salification in polar protic solvents for dissolving poorly water-soluble drug Itraconazole which is weakly ionic and not very amenable to formation of stable inorganic salts. Through systematic selection of solvents, counterions and polymers, an amorphous solid dispersion of drug salt was obtained. In vitro characterizations with polarized light microscopy (PLM), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) confirmed the physical and chemical stability of the amorphous solid dispersion. In vivo pharmacokinetic study showed that the drug salt amorphous solid dispersion achieved 45 times higher plasma exposure compared to crystalline drug. This study provides one of the first data sets for the hypothesis that in situ drug salts can be utilized for manufacturing amorphous solid dispersions of weakly ionic drugs and leverages the solubility advantage of salts and amorphous state.

More

Development of a Novel Polymeric Nanocomposite Complex for Drugs with Low Bioavailability

Abstract

Semi-synthetic biopolymer complex (SSBC) nanoparticles were investigated as a potential oral drug delivery system to enhance the bioavailability of a poorly water-soluble model drug acyclovir (ACV). The SSBCs were prepared from cross-linking of hydroxyl groups on hyaluronic acid (HA) with poly(acrylic acid) (PAA) resulting in ether linkages. Thereafter, conjugation of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto HA-PAA was accomplished using a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS)-promoted coupling reaction. Nanoparticle powders were prepared by spray drying of drug-loaded SSBC emulsions in a laboratory nano spray dryer. The prepared SSBC was characterized by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), 1H nuclear magnetic resonance (NMR) imaging, and X-ray diffraction (XRD) spectroscopy. The average particle size was found to be 257.92 nm. An entrapment efficiency of 85% was achieved as ACV has enhanced affinity for the hydrophobic inner core of the complex. It was shown that SSBC improved the solubility of ACV by 30% and the ex vivo permeation by 10% compared to the conventional ACV formulation, consequentially enhancing its bioavailability. Overall, this study resulted in the successful preparation of a hybrid chemically conjugated SSBC which has great potential for enhanced oral absorption of ACV with possible tuneable ACV permeability and solubility, producing an “intelligent” nanoenabled drug delivery system.

More

Science of Stability - 3rd Annual Conference 2017

3rd - 5th October 2017

Crowne Plaza Hotel, Dublin, Ireland

More Information & Registration

How to identify and manage ‘problem’ excipients in medicines for children

Children may be exposed to potentially harmful excipients, essential components of drug formulations, through unlicensed and off-label use of adult medicines. Excipient exposure should be minimised, although a medicine containing a problem excipient may be indicated, but only after a careful risk–benefit assessment.

Oral liquid formulations, such as solutions and suspensions, are commonly given to young children because they are easy to swallow. However, many liquid formulations have not been studied extensively, or authorised for paediatric use. This has resulted in the widespread routine clinical use of unlicensed medicines, and the use of adult medicines outside of their license, usually referred to as ‘off-label’ use, in children. 

Link to original article

Read More

Dual centrifugation - a new technique for nanomilling of poorly soluble drugs and formulation screening by an DoE-approach

Abstract

The development of nanosuspensions of poorly soluble APIs takes a lot of time and high amount of active material is needed. In this publication the use of dual centrifugation (DC) for an effective and rapid API-nanomilling is described for the first time. DC differs from normal centrifugation by an additional rotation of the samples during centrifugation, resulting in a very fast and powerful movement of the samples inside the vials, which − in combination with milling beads − result in effective milling. DC-nanomilling was compared to conventional wet ball milling and results in same or even smaller particle sizes. Also drug concentrations up to 40% can be processed. The process is fast (typical 90 min) and the temperature can be controlled. DC-nanomilling appears to be very gentle, experiments showed no change of the crystal structure during milling. Since batch sizes are very small (100–1000 mg) and since 40 sample vials can be processed in parallel, DC is ideal for the screening of suitable polymer/surfactant combinations. Fenofibrate was used to investigate DC-nanomilling for formulation screening by applying a DoE-approach. The presented data also show that the results of DC-nanomilling experiments are highly comparable to the results obtained by common agitator mills.

More

Read More

Recent advances in oral delivery of macromolecular drugs and benefits of polymer conjugation

Abstract

Oral administration of drugs is a two-edged sword – on one hand it is a non-invasive and easy-to-handle administration of drugs, on the other hand macromolecular pharmaceutical compounds cannot easily cross the epithelial barrier to reach systemic circulation or they could be inactivated in the gastrointestinal tract. Due the latter's nature with pH variations and proteolytic enzymes which digest and degrade external compounds, in particular peptides and proteins, oral delivery of macromolecular substances is an ongoing challenge in the field of pharmaceutical research. Several avenues of overcoming these drawbacks have been evaluated in the past, among them the promising approach of conjugation to natural and synthetic polymers. Polymers provide protection under harsh gastrointestinal conditions, may further enhance macromolecular drug absorption and pharmacological activity, and thus augment therapeutic efficiency. This short review highlights state-of-the-art developments in the field of oral macromolecule delivery and the benefit of polymer conjugation. We focus on a main review period from 2012–2017, and critically discuss latest developments for macromolecule engineering.

More

Read More 0 Comments

Improving tadalafil dissolution via surfactant-enriched tablets approach: Statistical optimization, characterization, and pharmacokinetic assessment

Abstract

Tadalafil suffers from poor aqueous solubility that could lead to fluctuating blood levels and unreproducible effect. Thus, this work aimed at improving tadalafil dissolution utilizing the approach of surfactant-enriched tablets. The feasibility of minimizing various surfactants quantities was investigated by establishing the ratio of the surfactant to drug that is required for drug solubilization in micellar solutions. Based on the computed ratios, Tween was precluded from formulation studies due to its poor solubilizing capacity towards the drug. 23 factorial design was employed to assess the impact of formulation attributes on tablets' characteristics. Based on the statistical analysis and the desirability function approach, tablet formulation F6 prepared using CTAB, Avicel PH 102, and 5% Ac-Di-Sol was selected as the optimum formulation. The selected formulation showed adequate stability after storage at 40 °C and 75% R.H. for twelve weeks. Pharmacokinetic study revealed that the selected surfactant-enriched tablet formulation F6 showed enhanced bioavailability compared to the market product Cialis®.

More

Read More

Continuous Manufacturing of Pharmaceuticals - Book

A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals

As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.

This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles. 

  • Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
  • Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
  • Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
  • Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products

Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.

Link to Book

Read More

In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding

Abstract

Twin-screw wet granulation is gaining increasing interest within the pharmaceutical industry for the continuous manufacturing of solid oral dosage forms. However, limited prior fundamental physical understanding has been generated relating to the granule formation mechanisms and kinetics along the internal compartmental length of a twin-screw granulator barrel, and about how process settings, barrel screw configuration and formulation properties such as particle size, density and surface properties influence these mechanisms. One of the main reasons for this limited understanding is that experimental data is generally only collected at the exit of the twin-screw granulator barrel although the granule formation occurs spatially along the internal length of the barrel. The purpose of this study is to analyze the twin-screw wet granulation process using both hydrophilic and hydrophobic formulations, manufactured under different process settings such as liquid-to-solid ratio, mass throughput and screw speed, in such a way that the mechanisms occurring in the individual granulator barrel compartments (i.e., the wetting and different conveying and kneading compartments) and their impact upon granule formation are understood. To achieve this, a unique experimental setup was developed allowing granule characteristic data-collection such as size, shape, liquid and porosity distribution at the different compartments along the length of the granulator barrel. Moreover, granule characteristic information per granule size class was determined. The experimental results indicated that liquid-to-solid ratio is the most important factor dictating the formation of the granules and their corresponding properties, by regulating the degree of aggregation and breakage in the different compartments along the internal length of the twin-screw granulator barrel. Collecting appropriate and detailed experimental data about granule formation along the internal length of the granulator barrel is thus crucial for gaining fundamental physical understanding of the twin-screw wet granulation process.

More

Read More

Brain targeting efficiency of antimigrain drug loaded mucoadhesive intranasal nanoemulsion

Abstract

Zolmitriptan (ZT) is a well-tolerated drug in migraine treatment suffering from low bioavailability due to low amount of the drug that reaches the brain after oral and nasal delivery. Development of new nasal mucoadhesive nanoemulsion formulation for zolmitriptan may success in delivering the drug directly from the nose to the brain to achieve rapid onset of action and high drug concentration in the brain which is required for treatment of acute migraine. ZT mucoadhesive nanoemulsion were prepared and characterized for drug content, zeta potential, particle size, morphology, residence time and permeation through the nasal mucosa. The selected formula was tested in-vivo in mice for its pharmacokinetics in comparison with intravenous and nasal solution of zolmitriptan. Results showed that addition of chitosan as mucoadhesive agent in 0.3% concentration to the nanoemulsion enhanced its residence time and zetapotential with no significant effect on the globule size. All tested formulations showed higher permeability coefficients than the zolmitriptan solution through the nasal mucosa. In-vivo studies showed that the mucoadhesive nanoemulsion formulation of zolmitriptan has higher AUC0-8 and shorter Tmax in the brain than the intravenous or the nasal solution. This was related to the small globule size and higher permeability of the formulation.

More

Read More

Effect of polymer type on the surface energy of acetaminophen solid dispersions prepared by melt method

Abstract

Many newly developed active pharmaceutical ingredients (APIs) have very low solubility in aqueous media. The preparation of solid dispersions (SDs) is one way of avoiding this problem. However, compound wettability and thus solubility are influenced by surface energy. In this study, we used inverse gas chromatography (IGC) to evaluate the surface energies of prepared SDs, and compared them with those obtained for physical mixtures (PMs). SDs containing different weight ratios of crystalline acetaminophen and one of three polymers (Kollidon® 12 PF, Kollidon® VA 64 or Soluplus®) were prepared by the melt-quenching of corresponding PMs. In all cases, as the polymer content increased, the surface energy decreased significantly. For the SDs and PMs containing Soluplus®, this decrease in surface energy showed the same non-linear trend. In the cases of Kollidon® 12 PF and Kollidon® VA 64, the trend was linear, with the SDs showing a steeper decrease in surface energy than the corresponding PMs. Typically, such decreases are ascribed to the dissolution of the crystalline structure of an API. Our results suggest that in the case of the Kollidons, the steeper decrease is caused by another mechanism, namely, strong API-Kollidon interaction leading to the less wettable surface of SDs.

More

Read More 0 Comments

Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation

Abstract

This study investigated comparative impact of different binder addition methods (pouring, dripping, spraying), binders and diluents on resulting granule and tablet attributes via high shear wet granulation. Lactose monohydrate and mannitol as diluents, and hydroxypropyl methylcellulose (HPMC E5) and polyvinylpyrrolidone (PVP K30) as binders were used. Granules were characterized for morphology, bulk-density, tapped-density, flow, size, segregation-potential and friability. To determine granule friability, procedure described in European Pharmacopoeia was slightly modified to reduce manual-variations and obtain appreciable discrimination between the formulations. Binder-diluent affinity was assessed by measuring contact angles of diluent-dispersion droplets on binder films over a period of time. All blends were pressed at the same compression force and resulting tablets were characterized for pharmacotechnical properties. Results revealed that the binder addition methods altered granule-shape, which predominantly governed the granule flow. The binder addition by spraying increased fines, blend segregation-potential, granule friability, tablet tensile-strength and tablet disintegration-time; binder addition by pouring showed an opposite impact. Mannitol granules exhibited lower bulk density, superior flow, lower segregation-potential and higher friability than their lactose counterparts. Amongst binders, PVP produced more friable granules compared to HPMC. The high polydispersity-index of polymer-binder induced non-homogeneity facilitating the blend segregation-potential. Due to higher affinity, HPMC was suitable binder for mannitol, and PVP for lactose to promote granule growth. The binder-diluent affinity dominated viscosity and surface tension of binder solution to improve granule size. Increase in granule size decreased granule-friability, which subsequently decreased tablet hardness, tensile-strength and disintegration-time. Mannitol produced harder tablets, and lactose tablets disintegrated faster by all binders and binder addition methods.

More

Read More

Challenges and Strategies to Facilitate Formulation Development of Pediatric Drug Products: Safety Qualification of Excipients

Abstract

A public workshop entitled “Challenges and strategies to facilitate formulation development of pediatric drug products” focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case-study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk-based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement.

More

Read More 0 Comments

Development of a novel ocular insert with slow release properties loaded with sodium fluorescein

INTRODUCTION

Eye drops have been the most popular and best accepted dosage form for ocular delivery of drugs. However, conventional eye drops have well known disadvantages such as low ocular availability due to defence mechanisms of the eye. Frequent instillation is recommended or even required in order to reach therapeutic levels of the drug at the site of action. Many attempts have been made over several decades to increase the ocular availability and hence improve the efficacy of topically applied drugs. This has led to the emergence of new drug delivery devices with common ambitions, including decreasing the instillation frequency, prolonging the residence time of the drug applied and thus improving patient compliance.

Link to Original

Read More 0 Comments

Going Natural: Using polymers from nature for gastroresistant applications

Abstract

Nutraceuticals provide an additional health or medicinal benefit besides their nutritional value and are therefore marketed for the prevention and treatment of certain conditions. Nutraceuticals contain natural ingredients, usually presented in the form of functional foods or as dietary supplements. Many of the ingredients are susceptible to degradation by gastric acid or can provoke nauseatic feelings or induce vomiting on oral administration. Gastroresistant coatings, widely researched and used in pharmaceuticals, employ enteric polymers which are not regarded as natural ingredients or do not possess GRAS (generally regarded as safe) status by the regulatory bodies, thus cannot be used for nutraceutical products. Consequently, most nutraceuticals are not formulated as gastroresistant and can therefore lack efficacy or are well tolerated. This manuscript provides a critical review of natural substances employed in producing gastroresistant products, their shortcomings, and potential industrial applications. It also identifies current gaps in our knowledge to encourage further research in this area.

Original Link

Read More 0 Comments

Increased drug load and polymer compatibility of bilayered orodispersible films

Abstract

The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (> 1 mg per ODF) when using the solvent casting method.The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose–carbomer 974P (SCS) was investigated.

Results and conclusions

We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS.An increased casting height did not result in a proportionally increased enalapril load.The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced.Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC.

More

Read More 0 Comments

Design, Preparation and Evaluation of HPMC-Based PAA or SA Freeze-Dried Scaffolds for Vaginal Delivery of Fluconazole

Purpose

Aim of this work was preparation of bioadhesive gel formulations based on Hydroxypropyl methylcellulose (HPMC), Poly(acrylic acid) (PAA) or Sodium alginate (SA) loaded with anise/fluconazole β-cyclodextrin inclusion complexes in 1:2 and 1:3 ratios intended for vaginal applications.

Methods

Freeze-drying method was effectively utilized and superporous morphology was obtained. The superporous morphology of the lyophilized gels, dynamic water vapor sorption measurements, drug release kinetics studies and their antimicrobial activities are presented.

Results

HPMC content influences especially the sorption/desorption behaviour of HPMC-based PAA gels and the morphology of the gel formulations with fluconazole/β-cyclodextrin inclusion complexes, due to the interactions among the gel networks absorbing water molecules. It was found that fluconazole release kinetics correspond to quasi-Fickian, Fickian diffusion and non-Fickian mechanisms for the studied hydrogels. The tested vaginal formulations with β-cyclodextrin inclusion complexes exhibited selectivity toward S. aureus ATCC 25923 and all tested Candida strains in comparison with the gel formulation without β-cyclodextrin.

Conclusions

The fluconazole/β cyclodextrin inclusion complexes ensure a controlled release of fluconazole over a few days, the highest amount of drug release (92%) being observed after 43 h. These bioadhesive gel formulations could be very promising topical alternative for treatment of vaginal fungal infections.

More

0 Comments

Excipient-mediated alteration in drug bioavailability in the rat model depends on the sex of the animal

Abstract

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate(metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p < 0.05) the bioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (p < 0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp.

More

Read More 0 Comments

Limited Influence of Excipients in Extemporaneous Compounded Suspensions

Objective: The objective of this study was to identify whether compounding oral suspensions with SyrSpend SF based on tablets or capsules is a suitable alternative for using raw pharmaceutical materials. Methods: Suspensions based on 5 different tablets and capsules were studied in SyrSpend SF. The summary of product characteristics of these different tablets and capsules were obtained from the manufacturer. Our hypothesis was that, if the maximum beyond-use date of the study was reached, the excipient did not seem to have an influence on the stability of the active pharmaceutical ingredient (API) within the studied time frame. Results: All excipients used in flecainide acetate, labetalol HCl, and tiagabine HCl tablets as well as in celecoxib and oseltamivir capsules did not seem to influence the beyond-use date of the overall suspension based on SyrSpend SF. Conclusion: Although using raw materials as API sources is preferred, oral suspensions with SyrSpend SF prepared from crushed tablets or opened capsules could be a possible alternative. Based on this study, a wide range of different excipients does not seem to impact the beyond-use date of different APIs compounded in SyrSpend SF.

Original Link

Read More 0 Comments

Review – An update on the use of oral phospholipid excipients

Abstract

The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously. Nevertheless the present number of oral products using these excipients as essential excipient is very limited. This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. In addition, phospholipid excipients are multifunctional biodegradable, non-toxic excipients, which can be used in oral dosage forms as wetting agents, emulsifier, solubilizer and matrix forming excipients. Especially natural phospholipid excipients, made from renewable sources, may be considered as environmentally friendly excipients and as a viable alternative to synthetic phospholipid and non-phospholipid analogues. This review describes 1) essential physico-chemical properties of oral phospholipid excipients 2) the fate of orally administered phospholipids with respect to absorption and metabolism in the GI tract 3) the main dosage forms used for oral administration containing phospholipids. These elements are critically assessed and areas of future research of interest for the use of oral phospholipid excipients are summarized.

Original Link

Read More 0 Comments

Drug solubility in lipid nanocarriers: Influence of lipid matrix and available interfacial area

Abstract

Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most screening methods for the identification of a suitable lipid-based formulation fail to elucidate the role interfacial effects play for drug solubility in disperse systems. In a novel screening approach called passive drug loading, different preformed lipid nanocarrier dispersions are incubated with drug powder. Afterwards, undissolved drug is filtered off and the amount of solubilized drug is determined. The aim of this study was to identify parameters for drug solubility in pure lipids as well as for drug loading to the lipid-water interface of lipid nanoparticles. Using passive loading, the solubility of eight poorly water-soluble drugs in seven lipid nanocarriers varying in particle size or lipid matrix was investigated. Drug solubility in the nanocarriers did not follow any apparent trend and different drugs dissolved best in different carriers. Drugs with a melting point below approximately 150 °C displayed distinctly better solubility than higher melting drugs. Additionally, relating the specific lipid nanocarrier surface area to the drug solubility allowed drawing conclusions on the drug localization. Fenofibrate, dibucaine and, less distinct also clotrimazole, which all melt below 150 °C, were predominantly located in the lipid droplet core of the nanoparticles. In contrast, the five remaining drugs (betamethasone valerate, flufenamic acid, itraconazole, ketoconazole, mefenamic acid) were also located at the lipid-water interface to different, but substantial degrees. The ability to account for drug loading to the lipid-water interface is thus a major advantage of passive loading.

Link to article (payable)

Read More 0 Comments

3D printing of pharmaceuticals: patent and regulatory challenges

0 Comments

Aqueous Polymer Dispersion Coating Used for Osmotic Pump Tablets: Membrane Property Investigation and IVIVC Evaluation

Abstract

The objective of this study was to investigate the fundamental properties of propranolol hydrochloride osmotic pump tablets coated by aqueous polymer dispersion, simultaneously exploring the in vitro and in vivo correlation of the tablet. The physicochemical properties and parameters of aqueous polymer dispersion membranes (SEM, water uptake, and water vapor transmission coefficient) were investigated. In addition, the release behavior and the in vitro release and in vivo absorption profiles of the tablets coated by aqueous polymer dispersion were investigated by comparing with propranolol hydrochloride osmotic pump tablets coated by an organic solvent. Results showed that the similarity factor (f2) between cellulose acetate-coated tablet and Eudragit-coated tablet was 78.1, and f2 between cellulose acetate-coated tablet and Kollicoat-coated tablet was 77.6. The linear IVIVC of Eudragit-coated and Kollicoat-coated osmotic pump tablets was determined, which confirmed excellent correlation between the absorption in vivo and the drug release in vitro. Consequently, the membrane coated by aqueous polymer dispersion or organic solvent has similar in vitro release rates of controlled release. Also, compared with organic solvent coating, aqueous polymer dispersion has numerous advantages, such as reduced toxicity and no environmental damage. Therefore, the aqueous polymer dispersion technology has enormous potential as a replacement of organic solvent coating.

More

0 Comments

Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation

Abstract

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The effects of barrel temperature, binder type, powder feed rate, and screw speed on granule properties (size and strength) and torque value in twin screw granulation were investigated. Due to the high content of hydrophilic model drug, the granules prepared at a higher temperature with HPMC binding solution had the narrower size distribution and greater strength than the granules prepared with distilled water as a binding solution. After continuous drying and milling steps, the granules (continuous process) satisfied the fundamental purpose of granulation with size and flowability, despite different shape compared with the granules (batch process). Furthermore, there were no significant differences between two granulation processes in tablet properties, such as tablet hardness and in vitro release. The considerations and strategies used in this study to transfer from a batch to continuous process can be applied to other existing formulations based on high shear granulation to enable rapid process transfer in the pharmaceutical industry.

More

Read More

Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations

Abstract

The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.

More

Excipient of medication the probable cause of urticaria in a boy with autism

Introduction

Beneficence and non-maleficence: these classic ethical principles often contradict when atypical antipsychotics are prescribed to children. Expedient effects on development should be weighed carefully against harmful side effects, especially metabolic complications. Prescribing antipsychotic medication requires thorough monitoring of effects and side effects.

During this process, health professionals are often tempted to assign every inter-current symptom to the drug prescribed. However, sometimes this reasoning is false and thereby the decision to stop the medication. Effective treatment may be withheld based on erroneous reasoning, and this situation is sometimes avoidable.

Link to the original

Read More 0 Comments