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.
The EMA and US FDA say they agree on how pharmaceutical firms should include quality-by-design (QbD) elements in drug approval and manufacturing change applications, citing a recently completed pilot collaboration.
Chemical Exchange Saturation Transfer (CEST) approach is a novel tool within magnetic resonance imaging (MRI) that allows visualization of molecules possessing exchangeable protons with water. Many molecules, employed as excipients for the formulation of finished drug products, are endowed with hydroxyl, amine or amide protons, thus can be exploitable as MRI-CEST contrast agents. Their high safety profiles allow them to be injected at very high doses. Here we investigated the MRI-CEST properties of several excipients (ascorbic acid, sucrose, N-acetyl-d-glucosamine, meglumine and 2-pyrrolidone) and tested them as tumor-detecting agents in two different murine tumor models (breast and melanoma cancers). All the investigated molecules showed remarkable CEST contrast upon i.v. administration in the range 1–3 ppm according to the type of mobile proton groups. A marked increase of CEST contrast was observed in tumor regions up to 30 min post injection. The combination of marked tumor contrast enhancement and lack of toxicity make these molecules potential candidates for the diagnosis of tumors within the MRI-CEST approach.
Areas covered: The review firstly presents a systematic analysis of the trends in development of particle delivery systems using spray drying. This is followed by exploring the mechanisms governing particle formation and the transformations undergone in the various process stages. The next section highlights the particle design factors including those of different equipment configurations and feed/process attributes. Finally, the review summarises the current industrial approaches for scale-up of pharmaceutical spray drying.
Expert opinion: The spray drying process provides the ability to directly design particles of the desired functionality. This is of great benefit for the pharmaceutical sector especially as product specifications are becoming more encompassing and exacting. One of the biggest barriers to the spray dried product translation remains one of scale-up/scale-down. A shift from the trial and error approaches of the past to fundamental model-based particle design approaches helps to enhance control over product properties. To this end, process innovations and advanced manufacturing technologies are also particularly welcomed.
Ceftriaxone, a third generation cephalosporin, has a wide antibacterial spectrum that has good CNS penetration, which makes it potentially suitable for initial treatment of severe neonatal pediatric infections providing suitable formulation. We evaluated its physicochemical and technical characteristics to assess its potential for development as a non-parenteral dosage form. As ceftriaxone is marked only for injectable use, these data are not available. Using HPLC and Karl Fischer titration, sensitivity of ceftriaxone to water, feasibility and impact of pharmaceutical processes and compatibility with common pharmaceutical excipients were assessed. X-ray diffraction studies gave deeper insight into the mechanisms involved in degradation. Chemometrical analysis of near infrared spectra enabled classification of ceftriaxone powder according to exposure conditions or processes applied. The results showed that ceftriaxone was not highly hygroscopic, could be processed in all climatic zones, but should be packaged protected against humidity. Controlling water presence in formulation was shown critical, as ceftriaxone degraded in the presence of water content above 2.4% w/w. To improve flowability, a critical parameter for dry dosage form development, granulation (wet and dry techniques, providing complete drying and moderate force compaction respectively) was shown feasible. Compression with moderate forces was possible, but grinding and high compression forces significantly affected long term ceftriaxone stability and should be avoided. Based on these results, development of ceftriaxone non-parenteral solid or liquid non-aqueous forms appears feasible.
In recent years, a novel low molecular weight hypromellose (hypromellose 2906, VLV hypromellose) was developed to improve tablet-coating process and lower costs in the pharmaceutical industry. Such VLV hypromellose imparted economic, environmental, and performance benefits to the coating process and final products. However, there were still some concerns about this polymer in regard to weak mechanical strength of films and resultant stability issues of film coatings on tablets. In this study, a tablet-coating formulation was optimized using Box–Behnken design via blending conventional hypromellose with VLV hypromellose to achieve balanced coating performance in terms of highly productive coating, no sticking issues under mild coating conditions, and robust tablet film coatings in an accelerated stability study. By addition of only 5 wt% of conventional hypromellose (3.35 wt% HPMC E50 and 1.65 wt% HPMC E3), the film elongation and toughness index of optimized VLV hypromellose formulation increased by 154% and 372%, respectively, while the solution viscosity was still suitable for spray coating. The results of the following tablet-coating trials and stability study revealed that the stability and quality of tablet film coatings were significantly improved using this optimized VLV hypromellose-coating formulation, while a highly productive coating process and mild coating conditions without “sticking” issues were maintained simultaneously to the utmost extent.
The aim of the present investigation is to produce rapidly disintegrating laminar extrudates for delivering ibuprofen in the mouth of paediatric patients. is laminar shape is particularly convenient for drug delivering in the mouth and can be easily cut in cut in di erent sizes allowing for a convenient adjustment of the drug dose depending on the age of the patient. Due to the fact that in paediatric formulations, the selection of the excipients is always a challenging issue and the reduction of their amount is always highly desirable, in this study to select the most appropriate composition to achieve a rapid disintegration and simultaneously permit a high amount of ibuprofen in the system, an experimental design for mixtures was employed and the disintegration time in simulated saliva was used as experimental response. In addition, a er solid state analyses to check possible insurgence of drug-excipients interactions, laminar extrudates were characterised in terms of mechanical properties and in vitro dissolution performances. Extrudates with the desired uniform laminar shape, constant thickness (2 mm) and a very high content of drug (82% wt) were produced. ese products exhibited a short disintegration time. e dose for a patient of 6-12 years corresponded to a length of extrudate between 1-1.5 cm, perfectly compatible with a formulation orodispersible thin laminar extrudate intended for a paediatric patient (Figure 1).
A colon-specific capsule with alginate beads containing a self-microemulsifying drug delivery system (SMEDDS) was developed and evaluated. The SMEDDS technique was used to improve the solubility of curcumin (Cur). After encapsulating the Cur-loaded SMEDDS, the alginate beads were placed inside an impermeable capsule body. A konjac glucomannan/lactose/hydroxypropyl methylcellulose (KG/Lac/HPMC) plug tablet was then prepared and placed in the mouth of the capsule. The capsule demonstrated a pulsatile drug-release profile with a specific lag time and subsequent sustained-release phase. The lag time was modified by changing the type of HPMC and the ratio of KG/Lac/HPMC. In addition, 0.5% β-mannase solution and 5% rat cecal solution were used to simulate the colon fluid, significantly decreasing the lag time of the capsule. The results show that the capsule has potential for use in colon-specific drug delivery and exhibits a sustained-release characteristic.
Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. Dry coating using high-intensity vibratory mixing is employed to reduce API cohesion and granular Bond number as well as agglomeration as predicted by contact models, hence improve blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~ 10 μm), a model API, was dry coated with nano-silica R972P (20 nm), and mixed with Avicel 102. The amount of silica was varied from 0 to 2.74 wt%, corresponding to theoretical surface area coverage (SAC) from 0 to 100% respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1.0 wt% silica was adequate for API property enhancement; further corroborated by improved CU for 5 wt% API blends. Excellent CU was achieved for 3, 5 and 10 wt% API loaded blends, where 30 min of mixing was found to be acceptable for all three. The CU with dry coated mAPAP was significantly lower and within the acceptable range as compared to control blends without silica, as well as those with silica added during blending. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. Compared to theoretical predictions, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.
The aim was to develop immediate-release carbamazepine tablets consisting of self-emulsified drug delivery system (SEDDS) by using the melt granulation technique, application of Quality by design. The first set of screening experiments investigated the influence of six parameters (meltable binder type; amounts of meltable binder, carbamazepine and crospovidone; carrier type, and compression force) on carbamazepine release rate from tablets, using fractional factorial experimental design. In the second set of experiments, amounts of meltable binder and Cremophor® RH40 were varied according to the central composite design. The optimal formulation which showed the fastest release rate (more than 80% in first 30 min) was identified (compression force of 8 kN, 20% of Labrafil® 2130CS, 10% of Cremophor® RH40, 30% of carbamazepine, 5% of crospovidone NP and Neusilin® UFL2 used as the carrier). Different analytical techniques (DSC, PXRD, FT-IR, Raman spectroscopy) confirmed the maintenance of carbamazepine in its therapeutically active polymorph form III in the optimal formulation. Raman spectroscopy was used to demonstrate the stability of the optimal formulation during the two months stability study (25°С, RH 40%). It can be concluded that melt granulation technique can be used in development of solid-SEDDS with immediate-release of the drug.
Pharma is approaching continuous manufacturing with caution. However, equipped with fresh technical experience, plus decades of process design and control science across chemical synthesis and manufacture, pharma’s confidence is growing in continuous manufacturing’s cost, quality and risk-controlling benefits and its potential application to a broader range of oral solid dose processing environments.
Microsponge is a polymeric drug delivery system composed of spherical particles ranged in micron size and loaded with active pharmaceutical ingredient. Microsponges have maximum residency on the skin and slow release rate. Resiquimod is a candidate drug to be entrapped in microsponge drug delivery system. Formulation of resiquimod loaded microsponges was done using oil in water emulsion solvent evaporation method. The method had two phases, organic and aqueous phase. Three types of solvent were used in organic phase along with four volumes. Dichloromethane (DCM), chloroform and ethyl acetate (EA) were the solvent in organic phase with the volumes were used 1, 2.5, 5, 10 mL. Different formulations of microsponges using different volumes of solvents were prepared. From twelve microsponges formulations, three were chosen to be incorporated in aqueous gel. Microsponges prepared by 2.5 mL of DCM, 1 mL of chloroform or 5 mL of EA were selected and coded as F1, F2 and F3. Microsponges were evaluated for % entrapment efficiency (EE), average particle size (PS), span value (SV), and % production yield (PY). For determination of % EE and quantification of resiquimod in skin and percutaneous penetration samples, two reversed phase high performance liquid chromatographic methods were developed and validated. Differential scanning calorimetry (DSC) was used to evaluate the physical nature of resiquimod in microsponges. For both unincorporated and incorporated microsponges in gels, field emission scanning electron microscopy (FESEM) and Fourier transform infrared spectroscopy (FTIR) were used. The release and drug disposition from microsponges gels were evaluated by Franz diffusion cells using human skin. The highest % EE was 47.05 ± 1.88 and observed at 1 mL of chloroform. In contrast, the lowest % EE 12.7 ± 3.9 resulted from using 10 mL of EA. The range of PS was from 38 ± 9.96 to 2.44 ± 1.14. The SV for all of formulations was less than 2, which was an indication of monodispersity of PS. The percent of PY ranged from 79.02 ± 0.97 to 28.84 ± 3.35 for 1 mL DCM and 10 mL of EA. The FESEM results showed that there were no crystals on the surface of any microsponges as well as integrity and sphericity were preserved when incorporated in gel. DSC results of microsponges suggested amorphous nature of entrapped resiquimod in microsponges. Whereas, FTIR spectrums of loaded microsponges against non-loaded suggested no chemical interaction between resiquimod and ethylcellulose polymer. While FTIR results of lyophilized loaded and non-loaded microsponges gels suggested no chemical interaction between microsponges and gel excipients. F1 formulation had 7 times lower flux 2.97 ± 0.25 µg/cm2/hr compared to resiquimod control gel 20.55 ± 8.86 µg/cm2/hr while F2 and F3 had no flux. Results of quantified resiquimod in SC were 0.56 ± 0.26, 0.55 ± 0.30, 0.51 ± 0.30 and 1.04 ± 0.17 µg/cm2 for F1, F2, F3 and control gel respectively. On the other hand, quantified resiquimod in epidermis plus dermis were 0.88 ± 0.30, 0.36 ± 0.12, 0.16 ± 0.05 and 0.17 ± 0.05 µg/cm2 for F1, F2, F3 and control gel respectively. Resiquimod loaded microsponges in gel resulted localization of resiquimod in skin layers and minimal flux.
Personalized medicine is an important treatment approach for diseases like cancer with high intrasubject variability. In this framework, printing is one of the most promising methods since it permits dose and geometry adjustment of the final product. With this study, a combination product consisting of anticancer (paclitaxel) and antiviral (cidofovir) drugs was manufactured by inkjet printing onto adhesive film for local treatment of cervical cancers as a result of HPV infection. Furthermore, solubility problem of paclitaxel was overcome by maintaining this poorly soluble drug in a cyclodextrin inclusion complex and release of cidofovir was controlled by encapsulation in polycaprolactone nanoparticles. In vitro characterization studies of printed film formulations were performed and cell culture studies showed that drug loaded film formulation was effective on human cervical adenocarcinoma cells.
Our study suggests that inkjet printing technology can be utilized in the development of antiviral/anticancer combination dosage forms for mucosal application. The drug amount in the delivery system can be accurately controlled and modified. Moreover, prolonged drug release time can be obtained. Printing of anticancer and antiviral drugs on film seem to be a potential approach for HPV-related cervical cancer treatment and a good candidate for further studies.
Reducing the promiscuous tropism of native adenovirus by using fiberless adenovirus is advantageous towards its use as a gene therapy vector or vaccine component. The removal of the fiber protein on native adenovirus abrogates several undesirable interactions; however, this approach decreases the particle’s physical stability. In order to create stable fiberless adenovirus for pharmaceutical use, the effects of temperature and pH on the particle’s stability profile must be addressed. Our results indicate that the stability of fiberless adenovirus is increased when it is stored in mildly acidic conditions around pH 6. The stability of fiberless adenovirus can be further enhanced by employing excipients. Excipient screening results indicate that the non-ionic surfactant Pluronic F-68 and the amino acid glycine are potential stabilizers because of their ability to increase the thermal transition temperature of the virus particle and promote retention of biological activity after exposure to prolonged thermal stress. Our data indicate that the instability of fiberless adenovirus can be ameliorated by storing the virus in the appropriate environment and it should be possible to further optimize the virus so that it can be used as a biopharmaceutical.
Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30 μm to 350 μm (particle size d90) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170 μm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool.
The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier-drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier-drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with α-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D < 10.0 μm) excipient fraction from 1.84 to 8.70% v/v increased the respirable drug fraction in the excipient-drug mixture from 56.42 to 67.80% v/v (p < 0.05). The results suggest that low concentrations of fine excipient particles bind to active sites on and fill deep crevices in coarse carrier particles. As the concentration of fine excipient particles increases beyond that saturating active sites, they fill the spaces between and adhere to the surfaces of coarse carrier particles, creating projections and micropores. They thereby promote deagglomeration of drug particles during carrier-drug mixing. The findings pave the way for a comprehensive understanding of contributions of fine excipient materials to the performance of carrier-based dry powder inhalation mixtures.
Children are not small adults, but rather a distinct and heterogeneous patient group with specific therapeutic needs. Child development entails dynamic processes inherent to growth from birth into adulthood, and children face a scope of diseases different than those of adults. Accordingly, safe and effective paediatric pharmacotherapy requires medicines adjusted to the needs, acceptability and preferences (of each subpopulation) of children. Moreover, child-specific antibiotics are one key public health area of interest, due to their potential to fight bacterial infections that are among leading causes of death in early life. Despite recent progress, more work lies ahead, and so the aim of the present thesis was to document advancements with respect to priority medicines for children, and conduct additional research on age-appropriate formulations and use of antibiotics in children across different settings.
The adoption of the EU Paediatric Regulation has lead to a fundamental change of culture, as the incentives and regulatory requirements have induced companies to screen new adult products for their potential paediatric value. Due to the modest impact on high priority and unmet paediatric needs (e.g. oncology, pain, neonatal morbidity), a number of corrective measures have now been taken, so that medicines for children are developed independently from adult indications. We observed shifting trends toward oral solid formulations with a focus on innovative flexible, multiparticulate and dispersible preparations. Their advantages include a provision of easy, safe and convenient dose delivery and - in terms of resource-limited settings - superior stability in hot climate zones, easier transport and storage, as well as a reduction in problems with confidentiality and social stigma. However, our research suggests that more age-appropriate antibiotics that facilitate the treatment of children exist globally than currently included on the World Health Organization Model List for Essential Medicines for Children. Hence, it is important to create a global platform to provide the information about the benefits, shortcomings and availability of age-appropriate formulations for children, and advocate for their rational use.
Then again, the rational use of medicines in children has been inadequately studied. Our study on trends in prescribing patterns for acute childhood infections in primary care in developing and transitional countries showed a mixed progress with most of the treatment aspects of infections remaining sub-optimal over time. In high-income countries prescribing is often not rational either, as we found incorrect use of newer broad spectrum antibiotics and/or inappropriate use of antibiotics for viral infections. Moreover, we investigated a specific form of irrational use of antibiotics, self-medication, by patients in Macedonia. This entails either getting antibiotics at the pharmacy without a prescription or using leftover antibiotics from previous treatments. We found that interventions had a small effect on self-medication of children, but not their parents, and the effect disappeared later. Thus, solutions need to focus on multifaceted and multilevel interventions that define local barriers, and integrate the promotion of the rational use of antibiotics for children within health systems.
Excipients serve a critical role in the production of final dosage forms for drug products and biologics. They facilitate the manufacturing process (e.g., anticaking agents) and protect, support, and enhance stability. They may also improve bioavailability. In addition, excipients help maintain the safety, or function, of the product during storage and use.
No longer characterized as inert accompaniments to an active pharmaceutical ingredient (API), excipients are the target of an intensified push for more stringent quality management, placing new requirements on both suppliers and users. Regulating excipient quality, however, is no small task. The global market is expected to exceed $5 billion by 2020 — with a growth rate of 6.0% from 2014 to 2020 (1). Thousands of different excipients are available, and only a small percentage of them are manufactured solely for pharmaceutical use.
For many years, there have been clearly defined GMP requirements for APIs, including EU GMP Part II, 21 CFR Part 11 and ICH Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients. But, until recently, well-defined and stringent GMP requirements for excipients did not exist.
How to Optimize Fluid Bed Processing Technology: Part of the Expertise in Pharmaceutical Process Technology Series addresses the important components of fluid bed granulation, providing answers to problems that commonly arise and using numerous practical examples and case studies as reference. This book covers the theoretical concepts involved in fluidization, also providing a description of the choice and functionality of equipment. Additional chapters feature key aspects of the technology, including formulation requirements, process variables, process scale-up, troubleshooting, new development, safety, and process evaluation.
Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice, Second Edition illustrates how to develop high-quality, safe, and effective pharmaceutical products by discussing the latest techniques, tools, and scientific advances in preformulation investigation, formulation, process design, characterization, scale-up, and production operations. This book covers the essential principles of physical pharmacy, biopharmaceutics, and industrial pharmacy, and their application to the research and development process of oral dosage forms. Chapters have been added, combined, deleted, and completely revised as necessary to produce a comprehensive, well-organized, valuable reference for industry professionals and academics engaged in all aspects of the development process.
In the human organism, the circadian regulation of carbohydrates metabolism is essential for the glucose homeostasis and energy balance. Unbalances in glucose and insulin tissue and blood levels have been linked to a variety of metabolic disorders such as obesity, meta- bolic syndrome, cardiovascular diseases and type 2 diabetes. Melatonin, the pineal hor- mone, is the key mediator molecule for the integration between the cyclic environment and the circadian distribution of physiological and behavioral processes and for the optimiza- tion of energy balance and body weight regulation, events that are crucial for a healthy organism. This chapter reviews the interplay between melatonin modulatory physiological e ects, glucose homeostasis and metabolic balance, from the endocrinology perspective. The tremendous e ect of melatonin in the regulation of metabolic processes is observed from the chronobiology perspective, considering melatonin as a major synchronizer of the circadian internal order of the physiological processes involved in energy metabolism.
Optimized orally disintegrating tablets (ODTs) containing furosemide (FUR) were prepared by direct compression method. Two factors, three levels (32) full factorial design was used to optimize the effect of taste masking agent (Eudragit E100; X1) and superdisintegarant; croscarmellose sodium (CCS; X2) on tablet properties. A composite was prepared by mixing ethanolic solution of FUR and Eudragit E100 with mannitol prior to mixing with other tablet ingredients. The prepared ODTs were characterized for their FUR content, hardness, friability and wetting time. The optimized ODT formulation (F1) was evaluated in term of palatability parameters and the in vivo disintegration. The manufactured ODTs were complying with the pharmacopeia guidelines regarding hardness, friability, weight variation and content. Eudragit E100 had a very slightly enhancing effect on tablets disintegration. However, the effects of both Eudragit E100 (X1) and CCS (X2) on ODTs disintegration time (Y1) were insignificant (p>0.05). Moreover, X1 exhibited antagonistic effect on the dissolution after 5 and 30 min (D5 and D30, respectively), but only its effect on D30 is significant (p =0.0004). Furthermore, the optimized ODTs formula showed good to acceptable taste in term of palatability, and in vivo disintegration time of this formula was about 10 s.
The individualization of solid dosage forms to realize a flexible therapy for all patient groups is a topic which increasingly gains importance in pharmaceutical research. The goal of this study was to develop a nanoparticulate, instant orodispersible film (iODF) powder which can easily be reconstituted in water to cast ODFs containing an individualized concentration of an active pharmaceutical ingredient (API). It was shown that the processing of the film casing mass to iODF powders by spray drying provides the same advantageous film properties, particles sizes redispersed from the ODF and dissolution profiles as compared to the common production route. Due to the realization of nanoparticle loads up to 50 wt.-% in the iODF powders, high API loads (11.8 mg cm-2) are achieved in final ODFs. The powders are well storable at different temperatures for at least three months and do not change their crystalline state during storage. Furthermore, dissolution of a defined amount of API from ODFs was found to be the fastest with the highest drug loads in the films.
The aim of this thesis was to develop drug encapsulation in chitosan nanoparticles for der- mal patch formulations. The thesis project included the optimization of preparation protocols of drug capsulated nanoparticles by using a model drug and a variety of synthetic routes. Subsequently, the model drug was replaced by the local anesthetic drug, lidocaine. In addi- tion, one part of the project was to develop a thin polymer film which incorporates lidocaine- encapsulated chitosan nanoparticles. Ph.D. Didem Sen Karaman from Åbo Akademi Uni- versity acted as a supervisor and an expert during this thesis project. The thesis was com- missioned by the Pharmaceutical Sciences Laboratory at Åbo Akademi University.
Nanotechnology refers to technology that utilizes nanosized materials with a diameter of 1- 100 nanometers of materials. Nanoparticles have specific properties, based on their large surface area / mass ratio and specific physicochemical properties. When the material is processed to nanoscale, the chemical, physical and biological properties are either signifi- cantly better or completely different as compared to conventional materials.
Chitosan is a natural biopolymer which can be used in drug delivery due to its many good properties. For example, it is non-toxic, biodegradable and has bactericidal and growth-in- hibiting effects. Lidocaine is a widely used drug for local anesthesia. Its effect is based on the fact that it is nonionic, which means it can easily pass through the cell membrane. Lido- caine has the ability to close sodium channels of nerve cells and thus prevent the transmis- sion of nerve impulses.
Thin polymer films are being developed for use in drug delivery. They have a number of advantages, including the possibility of designing different drug dosing on the natural poly- mer matrix. In addition, a thin polymer film which incorporates drug-encapsulated nanopar- ticles modify the release rate of the drug, reduce toxicity and enhance the therapeutic effi- ciency.
The obtained results revealed that encapsulation of lidocaine into chitosan nanoparticles improves the release of drug compared to free lidocaine in the patch formulation. In addition, the flux of drug from the film is higher when the formulation contains nanoparticles. However, the results showed that the nanoparticles’ incorporation route in the patches must be im- proved.
Objective: The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in presence or absence of hydrophilic polymers, as a tool for enhnaced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets. Significance: This strategy provide simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential. Method: Aerosil was dispersed in ethanolic solution of flurbiprofen in presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analysis. Results: The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution. Conclusion: Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.
The purpose of this study is to demonstrate that the flow function (FFc) of pharmaceutical powders, as measured by rotational shear cell, is predominantly governed by cohesion, but not friction coefficients. Driven by an earlier report showing an inverse correlation between FFc and the cohesion divided by the corresponding pre-consolidation stress [Wang et al. 2016. Powder Tech. 294:105-112], we performed analysis on a large dataset containing 1130 measurements from a ring shear tester, and identified a near-perfect inverse correlation between the FFc and cohesion. Conversely, no correlation was found between FFc and friction angles. We also conducted theoretical analysis and estimated such correlations based on Mohr-Coulomb failure model. We discovered that the correlation between FFc and cohesion can sustain as long as the angle of internal friction at incipient flow is not significantly larger than the angle of internal friction at steady-state flow, a condition covering almost all pharmaceutical powders. The outcome of this study bears significance in pharmaceutical development. Because the cohesion value is strongly influenced by the inter-particle cohesive forces, this study effectively shows that it is more efficient to improve the pharmaceutical powder flow by lowering the inter-particle cohesive forces than by lowering the inter-particle frictions.
Review question/objective: The objective of this review is to identify the experiences of nurses in administering oral medications to residents of aged care facilities with swallowing difficulties.
More specifically, the review question is:
What problems do nurses experience when administering oral medicines to people with swallowing difficulties living in aged care facilities?
Risk Assessment Tool for Excipients (RATE) has
been designed and validated by MPI. RATE is a tool designed to provide a platform to enable the recording of the risk assessments performed for excipients, in order to comply with the EU
The tool offers a mechanism for reviewing risks and scoring these in order to determine the overall risk level associated with the excipient and the manufacturer and the GMP control requirement.
Do you use multiple manufacturers of an excipient? Do you use excipients in different formulations? What if the excipient has different functions and volumes in the different formulations? RATE will help you to determine what approach should be taken where.
The RATE software will provide a structure to performing the following elements of the assessment process:
• Assessment of each of the excipients, from each manufacturer in each formulation, to ascertain the worst case use of each material on site against the criteria outlined in the guideline. This will create the Excipient Risk Profile.
• Assessment of each materials individual Excipient Risk Profile to determine the appropriate GMP that should be applied to its manufacture.
• Determination of the approach that will be taken to assessing the Excipient Manufacturers compliance to the required GMP.
• Assessment of the outcome of the compliance assessment to determine the overall Excipient Manufacturer’s risk profile against the criteria outlined in the guideline. This will create the Excipient Manufacturers Risk Profile.
For further information on McGee Pharma International’s Risk Assessment Tool for Excipients (RATE) and to request a demonstration, contact us at +353 1 846 47 42 or firstname.lastname@example.org.
Polymers are essential tools in the research and development of new therapeutic devices. The diversity and flexibility of these materials have generated high expectations in the composition of new materials with extraordinary abilities, especially in the design of new systems for the modified release of pharmaceutically active ingredients. The natural polymer rosin features moisture protection and pH-dependent behavior (i.e., it is sensitive to pH > 7.0), suggesting its possible use in pharmaceutical systems. The synthetic polymer Eudragit® RS PO is a low-permeability material, the disintegration of which depends on the time of residence in the gastrointestinal tract. The present study developed a polymeric material with desirable physicochemical characteristics and synergistic effects that resulted from the inherent properties of the associated polymers. Isolated films were obtained by solvent evaporation and subjected to a water vapor transmission test, scanning electron microscopy, calorimetry, Fourier transform-infrared (FT-IR) spectroscopy, micro-Raman spectroscopy, and mechanical analysis. The new polymeric material was macroscopically continuous and homogeneous, was appropriately flexible, had low water permeability, was vulnerable in alkaline environments, and was thermally stable, maintaining an unchanged structure up to temperatures of ∼400°C. The new material also presented potentially suitable characteristics for application in film coatings for oral solids, suggesting that it is capable of carrying therapeutic substances to distal regions of the gastrointestinal tract. These findings indicate that this new material may be added to the list of functional excipients.
The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity, and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2, and Seroquel® XR tablets were found to be influenced by the pH, buffer capacity, and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro-in vivo correlations.
We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%–0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.
Different drug delivery systems have been developed for peptides and proteins, with special interest on those that allow sustained parenteral release; they can prolong protein circulation, resulting in better therapeutic results and higher patient compliance. However, many of the manufacturing methods used involve conditions that can be detrimental for these molecules, such as the use of organic solvents, pH gradients, reduced pressure or heat. Besides, obtaining the desired formulation performance might be difficult since the dissolution profile might be far from optimal, or because the integrity of these bio-macromolecules cannot be preserved within the matrix. Thus, the development of these systems has followed a complex and challenging route, which have resulted in long development periods and few commercialized products. Therefore, gathering additional understanding of these systems and defining key parameters that impact the performance of them, is important to accelerate and assist the development of parenteral sustained release systems.
This work focused on the development of biodegradable implants for protein delivery, using ovalbumin (OVA) as acid-labile model protein. Hot melt extrusion (HME) was selected as the manufacturing method, since it does not involve the use of solvents and the protein can be incorporated on its more stable dry state, avoiding the creation of interfaces that compromise protein stability. Nonetheless, the use of high temperatures and presence of shear forces might impact protein stability. Therefore, the feasibility of HME to prepare OVA-loaded implants was investigated. With this purpose, a mini-ram extruder (syringe-die device) was used as a rapid screening tool. Moreover, two types of biodegradable matrices (PLGA- and lipid-based) were used to assess differences on formulation performances, with special emphasis on dissolution and protein stability.
The deployment of continuous manufacturing (CM) is prompting the pharmaceutical industry to understand better the characteristics of the excipients they are using and work more closely with suppliers to assure that the materials are fit for purpose. CM is also prompting a harder look at how to open up the clearance pathway for new/modified excipients that would better serve the advanced processing needs and objectives.
The intensifying focus on excipients, as industry and regulators explore together how to take pharmaceutical manufacturing and control to the next level, was evident throughout the third FDA/Product Quality Research Institute Conference on “advancing product quality,” held in Rockville, Maryland in late March.
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9–4.3% in forced expiratory volume in 1 s (FEV1 ) and 3.7–5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01–1.79 n = 349, one study). Some participants exhibited a reduction in FEV1 (≥10–15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.
This work was carried out to explore the unknown area of converting non-woven fibres, prepared by high speed electrospinning, into a directly compressible blend by mixing with excipients. An experimental design, with independent variables of compression force and fillers fraction, was realized to investigate tabletability of electrospun material (EM) and to produce hard tablets with appropriate disintegration time. The models proved to be adequate; fitted to the results and predicted values well for the optimal tablet, which was found to be at 76.25% fillers fraction and 6 kN compression force. Besides standard characterizations, distribution of EM was investigated by Raman mapping and scanning electron microscopy revealing the propensity of EM to cover the surface of microcrystalline cellulose and not of mannitol. These analytical tools were also found to be useful at investigating the possible formation of the so-called gelling polymer network in tablets. Scanning electron microscopic pictures of tablets confirmed the maintenance of fibrous structure after compression. The moisture absorption of EM under increasing humidity was studied by dynamic vapour sorption measurement, which suggested good physical stability at 25 °C and 60% relative humidity (corroborated by modulated DSC). These results demonstrate the feasibility of a pharmaceutically acceptable downstream processing for EMs.
There is more research required to broaden the knowledge on the downstream processing of nanosuspensions into solid oral dosage forms, especially for coated nanosuspensions onto beads as carriers. This study focuses on bead layering as one approach to solidify nanosuspensions. The aim was to systematically investigate the influence of type of coating polymer (HPMC VLV vs. copovidone), bead material and bead size (sugar vs. MCC, and small vs. large) and coating thickness (50%–150% layering level) on the properties of a dried itraconazole nanosuspension. A stable itraconazole nanosuspension with a mean particle size below 200 nm was prepared and a ratio of itraconazole and coating polymer of around 1:1 was identified. XRD and DSC scans revealed that itraconazole remained mostly crystalline after the bead layering process. The fastest dissolution rate was achieved using the small bead size, sugar beads, HPMC VLV as film-forming polymer and lowest layering level, with the best formulation releasing 94.1% (±3.45% SD) within the first 5 min. A deterioration of the release profile with increasing layering level was only observed for MCC beads and was more pronounced when copovidone was used as a coating polymer. It was observed that bead layering is a suitable method to process an itraconazole nanosuspension into a solid form without compromising release.
The structural changes of crystalline atorvastatin upon high-energy ball milling at room temperature have been studied. The study investigates the effect of polyvinylpyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) polymeric matrix on stabilizing amorphous atorvastatin before and after storage under ambient and elevated humidity conditions. The materials were characterized by X-ray diffraction (XRD), Fourier transform infrared spectrophotometry (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), 19F MAS NMR spectroscopy, and dissolution testing. The results indicate that this drug has undergone a direct crystal-to-glass transformation upon milling. Stable amorphous form of atorvastatin calcium has been obtained with PVP and HPMC (in 1:1 ratios).
It seems evident that the ill-defined weltanschauung of the past decade of enabling oral, un-truncated permeability-dependent protein delivery carte-blanche, using existing excipients has produced sparse results. Existing excipients are better utilized for exploiting niches which do not require either permeation or a permeation enhancement incongruent and/or is disproportionate to the existing excipient molecules' ability.
Bilateral Effects of Excipients on Protein Stability: Preferential Interaction Type of Excipient and Surface Aromatic Hydrophobicity of Protein
Understanding the mechanism of protein-excipient interaction and illuminating the influencing factors on protein stability are key steps in the rational design of protein formulations. The objective of this study was to assess effects of preferential interaction type of excipient and surface aromatic hydrophobicity of protein on protein solution stability.
The preferential interaction between excipient and aromatic hydrophobic area of protein was investigated by solubility and fluorescence studies of amino acid derivatives in excipient solutions. We examined conformational, colloidal and mechanical stabilities of model proteins with different surface aromatic hydrophobicities, including bovine serum albumin (BSA) and ovalbumin (OVA), and then stability data were visualized by three-index empirical phase diagram.
The result showed that preferentially excluded excipients (trehalose, sucrose and sorbitol) protected protein conformation against damage, but they could accelerate mechanical stress-induced aggregation. Preferentially bound excipients (propanediol and arginine) suppressed BSA aggregation, but arginine failed to inhibit OVA aggregation, which might be attributed to the disparate conformational perturbing effects of arginine on aromatic hydrophobic regions of BSA and OVA.
These findings provided strong evidence that excipient possessed bilateral effects, and its application should be determined on different preferential interaction behaviors of excipients with protein, especially with the aromatic hydrophobic region.
Transdermal transport of high-molecular-weight and hydrophilic substances is complicated by the protective skin layer, the stratum corneum. Physical breaching of this layer using microneedles combined with penetration- enhancing properties of cubosomes was previously reported as an effective approach to transdermal drug delivery and therefore employed in this project. (Rattanapak et al. 2012) Delivering abilities of solid (600 μm), coated (500, 600, 750 μm) and hollow (450, 600 μm) MNs were compared with intradermal injection by hypodermic needle. Cubosomes were prepared from phytantriol, poloxamer 407 and propylene glycol using liquid precursor method and loaded with fluorescent ovalbumin (FL-OVA) or SIINFEKL-TAMRA (ST) peptide. Several formulations for coating of solid microneedles were prepared using various solvents and excipients to investigate quality of coatings and their ability to deliver the drug into skin. Polyvinyl alcohol (PVA) turned out to be the most efficient coating excipient providing equally spread coatings that could be delivered into skin, allowing the drug to permeate to the deeper layers of dermis. As only limited amount of drug can be coated onto the surface of MNs tips, application using NanoPass MicronJet hollow MNs was investigated and resulted in massive fluorescence proving successful delivery by 450 μm long MNs. Solid MNs used to poke through the solution previously poured onto intact skin surface also showed successful delivery. Combination of cubosomes and microneedles is a promising approach to transdermal drug delivery and transcutaneous immunization, however, there is still a need to tackle several issues e.g. irritability of materials used for preparation of formulations, stability of cubic phase, reproducible way of MNs application, preservation of protein or peptide structure during manufacture, storage and use or possible unwanted immunological effects.
The aim of the present study was to formulate and evaluate oral thin films of zolpidem tartarate.
Zolpidem tartarateis used to treat insomnia. It affects chemicals in your brain that may become unbalanced and cause sleep problems (insomnia). Zolpidem tartarate oral thin films were prepared by using solvent casting method. In this method, water soluble polymer is completely dissolved in to form uniform clear viscous solution other ingredients including API are dissolved in a small portion of aqueous solvent by using a high shear processor. This viscous solution is degassed under the vacuum to remove the air bubbles. This bubble free solution is poured into a glass mold and kept in oven at 40 o-50oC. Oral disintegrating films are prepared using three grades of polymers HPMC E5, GUAR GUM and SODIUM ALGINATE Compatibility of Zolpidem tartarate with polymers was confirmed by FT-IR studies. All the formulations were evaluated for their physical appearance, average weight and thickness, folding endurance, disintegration time, tensile strength, percentage elongation, drug content, content uniformity and in vitro drug dissolution studies. From the result, it was concluded that the fast dissolving films of Zolpidem tartarate can be made by solvent casting technique with enhanced dissolution rate and taste masking by using suitable combination of sweeteners, flavors and citric acid. The final composition optimized was drug to Guar Gum ratio of 1:1, plasticizer concentration of 15% w/w of polymer. The film had acceptable physical properties, assay and uniformity values and in vitro dissolution within 2 minutes.
This work aimed to investigate the co-grinding effects of β-cyclodextrin (β-CD) and cucurbituril (CB) on crystalline zaltoprofen (ZPF) in tablet formulation. Crystalline ZPF was prepared through anti-solvent recrystallization and fully analyzed through single-crystal X-ray diffraction. Co-ground dispersions and mono-ground ZPF were prepared using a ball grinding process. Results revealed that mono-ground ZPF slightly affected the solid state, solubility, and dissolution of crystalline ZPF. Co-ground dispersions exhibited completely amorphous states and elicited a significant reinforcing effect on drug solubility. UV-vis spectroscopy, XRPD, FT-IR, DSC, ssNMR, and molecular docking demonstrated the interactions in the amorphous product. Hardness tests on blank tablets with different β-CD and CB contents suggested the addition of β-CD or CB could enhance the compressibility of the powder mixture. Disintegration tests showed that CB could efficiently shorten the disintegrating time. Dissolution tests indicated that β-CD and CB could accelerate the drug dissolution rate via different mechanisms. Specifically, CB could accelerate the dissolution rate by improving disintegration and β-CD showed a distinct advantage in solubility enhancement. Based on the comparative study on β-CD and CB for tablet formulation combined with co-grinding, we found that CB could be considered a promising drug delivery, which acted as a disintegrant.
Topical drug application has the advantage of avoiding systemic side effects. We attempted to develop a long-acting matrix-type tablet containing indomethacin (IM) with low physical stimulus and potent mucoadhesive force to treat pain caused by oral aphtha. A mixture of polyethylene glycol (PEG) and hard fat was used as the tablet base. Ethylcellulose was added to the base in an attempt to control drug release. Tablets with PEG as a base were also prepared for comparison. Polyvinyl alcohols (PVAs) with various degrees of saponification were added to increase the mucoadhesive force. From the optical microscopic observations, formulations using PEG and hard fat exhibit PEG/hard fat dispersions caused by the stabilizing effects of PVA. Although the tablets using PEG and hard fat showed sufficient adhesiveness and sustained drug release, those using PEG as the base did not. Drug release was controlled by the amount of hard fat and the saponification degree of PVA. The drug release rate was most increased in a tablet containing PVA with an intermediate degree of saponification, PEG and hard fat. From differential scanning calorimetry and powder X-ray diffraction, IM was considered to exist in the molecular phase. From the results of buccal administration of tablets to rats, highest tissue concentrations were observed in the tablet containing PVA with the intermediate degree of saponification using PEG and hard fat, and the plasma concentrations were sufficiently low in comparison.
Ribavirin (C8H12N4O5; anti-viral agent) was crystallized as two unique, phase-pure polymorphs (R-I and R-II). Calorimetrically determined isobaric heat capacities and heat of transition data were utilized to determine the solid-state transition temperature (Ttr), confirming enantiotropism, while R-I was determined to be kinetically stable at ambient temperature. Unprocessed samples of the low Tm polymorph, R-II, did not convert into R-I when held isothermally well above Ttr for 7 days. In contrast milled R-II completely transformed to R-I after 15 min at the same storage conditions, indicating that defects sustained during processing reduced the energy barrier for transformation, allowing it to occur. R-II was subjected to both cryogenic milling and impact milling at ambient temperature for various durations. Cryomilling resulted in an in situ progressive reduction of crystallinity, with complete conversion to amorphous ribavirin after 2 h. Limited molecular mobility attributable to the low milling temperature (Texp = –196 °C) likely inhibited recrystallization, allowing the amorphous solid to persist. In contrast, continuous impact milling at ambient temperature resulted in complete in situ conversion from R-II to R-I after 3 h. The data suggested rapid conversion to R-I from highly disordered regions during extended milling, facilitated by localized heat buildup that likely exceeded Tg and/or Ttr.
The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol(PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in-vitro dissolution condition, and we found the release profile fit Korsmeyer–Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations.
The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets.
The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations.
The aim of this study was to develop esomeprazole magnesium (EMZ-Mg) enteric-coated pellets and pellet-based tablets, as well as to investigate the effects of pellet size and compression method on acid tolerance, content uniformity, compressibility, and stability of preparations. This study used two types of pellet cores, namely, microcrystalline cellulose (MCC) core with a particle size of 150–300 μm and sucrose core with a particle size of 600–700 μm. Enteric-coated pellets, which consisted of a drug-free core, a drug layer, a sub-coating layer (hydroxypropyl methylcellulose, 6 cps), and an enteric-coating layer (Eudragit®L30D-55), were prepared by using a bottom-spray fluidized bed-coating technique. Pellet-based tablets were prepared by using a direct compression method or a wet granulation method. The acid tolerances of the two types of enteric-coated pellets (MCC and sucrose cores) reached up to 98% in simulated gastric fluid (pH 1.0) within 2 h, and the dissolution rates in simulated intestinal fluid (pH 6.8) reached up to 85% of the labeled amount within 15 min. When compressed into tablets, the pellets based on MCC core (smaller particle size) displayed a significantly higher acid tolerance (up to 92%) compared with the pellets based on sucrose core (larger particle size). In addition, the MCC core-based tablets (F8), especially those prepared by using a granulation method, showed higher drug content uniformity and compressibility than the sucrose core-based tablets (F10), and no lamination phenomenon was observed during compression. The crystallinity of EMZ-Mg was altered during drug layering process, and some physicochemical interactions were observed between the drug and excipients. Moreover, the two types of enteric-coated pellets showed a relatively high stability after storage under high temperature and strong light. However, they showed poor stability under high humidity, resulting in remarkable degradation of active compound. The EMZ-Mg enteric-coated pellets and pellet-based tablets were successfully developed, and reduction in pellet size and wet granulation reduced the differences in content uniformity and better protected the pellet coating from damages during compression.
This thesis is focused on investigating the scale-up of the roll compaction process by firstly considering the effect of plastic/brittle mixtures and process parameters, secondly, the impact of the change in scale on ribbon properties, and finally, the application of models to try to successfully scale the process up. Seven binary mixtures of MCC (plastic material) and mannitol (brittle behaviour) were investigated. The blends were roll compacted at different conditions of specific compaction force, gap width and roll speed determined by a design of experiments. A total of six compactors organized in three couples of different scale depending on the supplier were investigated, what means a total of three individual scale-up studies.
In the first part of the thesis, the effect of varying the fraction of plastic/brittle material (variation of the proportion of MCC) was evaluated together with the process parameters, by characterizing ribbon density and microhardnes, as well as the granule size distribution. The results showed that the ribbon relative density decreases linearly when increasing the MCC fraction. However, when plotting the microhardness or the granule properties (expressed as the percentiles D10, D50 and D90 as well as the amount of fines) against the proportion of MCC, a non-linear relationship is observed. The percolation theory was applied in order to investigate this fact deeper. As conclusion, it was proven the importance of the MCC/mannitol fraction on the product properties. In the second and main part of the thesis, 3 individual scale-up studies were performed: Gerteis, L.B. Bohle and Freund-Vectors line, classified according to the compactors’ provider. Ribbon relative density was characterized for all cases. For the Gerteis and L.B. Bohle studies, it was generally concluded that that the higher the specific compaction force, the lower the gap and content of MCC, the denser the ribbons. However, the compactors scale or its interaction with another factors was also affecting the results proportionally or inversely. MCC compacted at the L.B. Bohle machines was the exception. For the Freund-Vector line, a general tendency of the large scale to have denser ribbons was observed, although unexpected as for the same conditions, the small scale applies a higher roll force and densifies the product more. Therefore, in this second chapter, the importance of the scale and the difficulties to transfer the process has been confirmed. Finally, in the third chapter, the modelling of the roll compaction scale-up was investigated in order to successfully transfer the process between scales. After testing several approaches, it was concluded that the best one is the mechanistic model proposed by Reynolds et al. 2010, which gives good fitting and predictions.
The scalability of the roll compaction process for some couples of compactors available on the market has been investigated, by identifying the most important parameters affecting the results and adapting them through the application of a mechanistic model proposed by Reynolds et al.
Docusate sodium is a pharmaceutical grade surfactant, making it an efficient emulsifier, wetting, dispersing and solubilizing agent. Cytec offers Docusate sodium as a 100% waxy material and 85% active combined with NF grade sodium benzoate.
Historically, docusate sodium was used as a pharmaceutical grade excipient as it has proven effective in various formulations:
In addition to excellent solubilizing, wetting, dispersing and emulsifying properties, docusate sodium gives a low order of toxicity and is stable and compatible with a wide range of pharmacologically active drugs.
Docusate sodium is also as a powerful solubilizing agent, helping the formulation of poorly soluble active ingredients (APIs). Many new APIs (reported to be 40-70%) have a poor aqueous solubility leading to reduced bioavailability. Reduced bioavailability has an efficacy and financial consequence, as patients are not receiving the benefits of the medication and companies are not able to take full advantage of expensive APIs. There is also an unforeseen impact on the environment as trace quantities of these APIs might find their way into the water table.
Docusate sodium can be used to overcome this bioavailability issue by improving solubility using a variety of manufacturing techniques such as wet granulating, nano milling and hot melt extrusion (HME). Cytec can provide formulation examples of these various techniques with BCS class 2 and 4. To learn more about Cytec’s industry-leading pharmaceutical grade docusate sodium surfactant, register to receive additional information or contact us to discuss your specific pharmaceutical application with one of our Cytec Specialty Additives technical representatives.
During the early stages of drug development, a compound is often solubilised to create a liquid formulation that can be used to evaluate the pharmacokinetics, pharmacology and toxicology of a substance. Although a critical aspect in formulation development, solubility remains one of the most difficult obstacles to overcome due to many compounds possessing low aqueous solubility. Consequently, selecting the right excipient is vital to improve the solubilisation capacity of a drug.
There are several techniques available to improve solubility including, chemical modifications, physical modifications, carrier systems and solvent modifications, however, generally speaking, the most widely used approach to identify and select these excipients is a trial and error-based technique, which can be both costly and time consuming. With this in mind, there is an obvious gap for a more intelligent method to be developed and deployed to save time, money and more efficiently determine an excipient’s solubilisation capacity.
Amjad Alhalaweh PhD, formulation scientist at contract development and manufacturing organisation (CDMO) Recipharm, discusses a new throughput screening methodology that can be used to improve the efficiency of solubilising compounds by identifying and selecting one or more appropriate excipients.
Excipents are chemicals added to medicines to improve their quality. Sporadic reports indicate that some may be toxic for neonates and lead to significant morbidity or death. However, there is insufficient information about the risks generated by excipient exposure because systematic surveys have not been done and studies on babies have not been ethical in the past. Recent advances allow determination of excipient levels in very small blood volumes (50 microlitre) including dry blood spot methods and estimates of excipient exposures based on only 2-4 samples per baby. Hypothesis 1: information about exposures across the EU will promote reduction of neonatal exposure to excipients by highlighting opportunities for product substitution and priorities for reformulation.|Hypothesis 2: small volume blood samples can be used to generate models of systemic excipient exposure. Our consortium comprises researchers from Estonia, France and the UK with extensive experience in all aspects of the study. We will develop a platform of techniques to assess excipient exposure including: a questionnaire and point prevalence study of neonatal excipient exposure; systematic reviews of relevant literature; dried blood spot assays for high impact excipients; a cohort study to construct population excipient kinetic models (EK, analogous to active drug pharmacokinetics or PK) for high impact excipients. This work will lead to recommendations for the European Medicines Agency and other stakeholders about assessment of excipient exposure and underpin future work to relate exposures to outcomes.|
Co-processed excipients are expected to play a key role in the production of new chemical entities (NCEs), according to BCC Research. As developing new excipients can be time-consuming and expensive from a safety perspective, manufacturers see co-processing of already approved excipients as an attractive alternative. These excipients are engineered to achieve the properties of the key components of the tableting blend in a single, highly flowable and compressible granular material.1 As a result, where there were less than a handful of co-processed excipients on the market 15 or 20 years ago, there now are more than 20 that are commercially available to formulators, and it is very likely that this number will continue to grow.
• Enables dispensing straight from the drum to the hopper
• Eliminates any need for external lubricant
• Placebos provided optimal substrates for film coating
Brussels, 6 April 2017
EXCiPACT asbl is pleased to announce their very first Japanese certification. The Croda Japan K.K. Shiga factory has just been awarded an EXCiPACT Certificate from SGS, one of EXCIPACT’s internationally-recognised Certification Bodies.
The Certificate demonstrates that the Croda Japan Shiga factory in Shiga-Ken, Japan manufactures pharmaceutical excipients according to the EXCiPACT Good Manufacturing Practice (GMP) Certification Standard. Its scope covers manufacture of pharmaceutical excipients, (functional ester
derivative, purified mineral oil, vegetable oil, wax, fatty acid and lanolin).
Objectives of the thesis
Many protein drugs exhibit short half-lives in vivo and multiple dosing schemes and frequent injections are necessary to achieve therapeutic drug levels, which results in poor patience compliance. Due to the good biocompatibility of triglycerides and silica materials, the objective of this work was to develop protein loaded microparticles for sustained release application based on triglycerides and silica (TMEOS) carriers. It included two main parts, which were lipid coating of protein carrying beads in a fluid bed coater and silica particle fabrication via spray drying.
High shear mixers are classically used for wet granulation because they provide granules with a high density and a high strength in a short granulation time. In this study, the high shear wet granulation process was employed using chlorpheniramine maleate as a model drug, since it represents an example of low dose drug employing 32 randomized full factorial design and optimized in terms of different properties using Response Surface Methodology (RSM) approach. The effect of binder concentration (X1) and dry mixing time (X2) at three levels on the granules and tablet properties was studied. Chlorpheniramine maleate tablets were prepared from the produced granules to evaluate the impact of dry mixing time and the binder concentration on the produced granules and tablet properties as well as tablet content uniformity. The results show that both evaluated variables had an impact on the produced granules and tablets as well as tablet content uniformity. The high shear mixer is found to be an efficient mixer for dry blending prior to the wet massing of a low dose drug formulation when impeller speed and chopper speed were carefully selected. The results of RSM optimization indicated that formulation containing 4.46% Binder concentration at a dry mixing time of 5 min, gave the most desirable properties for the produced granules and tablets. The observed results of the optimized formula were: Carr's Index:12.72%, Hausner Rati:1.14, angle of repose: 35.18°, hardness: 5.5 Kp, friability: 0.42%, disintegration time: 60 s, average of content uniformity: 112.18% with RSD: 4.6%, and d (0.9): 982 μ which are in consistence with the predicted results, having low values of standard error.
Phthalates are known endocrine disruptors. Not commonly recognised, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1,000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethylphthalate (DEP) and dibutylphthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low-molecular-weight phthalates and three high-molecular-weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1,000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multienzymes (24.6-32.8 mg per DDD) and mesalazine (12.5-26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate-containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.
A compound, which is a selective peroxisome proliferator activated receptor (PPAR) agonist, was investigated. The aim of the presented studies was to evaluate the potential of the further development of the compound. Fundamental physicochemical properties and stability of the compound were characterized in solution by liquid chromatography and NMR and in solid-state by various techniques. The drug itself is a poorly soluble lipophilic acid with tendency to form aggregates in solution. The neutral form was only obtained in amorphous form with a glass-transition temperature of approximately 0 °C. The intrinsic solubility at room temperature was determined to 0.03 mg/mL. Chemical stability studies of the compound in aqueous solutions showed good stability for at least two weeks at room temperature, except at pH 1, where a slight degradation was already observed after one day. The chemical stability in the amorphous solid-state was investigated during a period of three months. At 25 °C/60% relative humidity (RH) and 40 °C/75% RH no significant degradation was observed. At 80 °C, however, some degradation was observed after four weeks and approximately 3% after three months. In an accelerated photostability study, degradation of approximately 4% was observed. Attempts to identify a crystalline form of the neutral compound were unsuccessful, however, salt formation with tert-butylamine, resulted in crystalline material. Results from stability tests of the presented crystalline salt form indicated improved chemical stability at conditions whereas the amorphous neutral form degraded. However, the salt form of the drug dissociated under certain conditions. The drug was administered both per oral and intravenously, as amorphous nanosuspensions, to conscious dogs. Plasma profiles showed curves with secondary absorption peaks, indicating hepatic recirculation following both administration routes. A similar behavior was observed in rats after oral administration of a pH-adjusted solution. The observed double peaks in plasma exposure and the dissociation tendency of the salt form, were properties that contributed to make further development of the candidate drug challenging. Options for development of solid dosage forms of both amorphous and crystalline material of the compound are discussed.
Sumatriptan succinate (SS) is a drug used in the treatment of migraine headaches, but suffers from low patient compliance due to its unpalatable bitter taste. The purpose of the present work was to prepare taste-masked oro dispersible tablets (ODTs) of SS by incorporating drug loaded microspheres into tablets for use in patients experiencing difficulty in swallowing. Microspheres loaded with SS were prepared by solvent evaporation technique. Eudragit EPO, a pH-sensitive aminoalkylmethacrylate copolymer, was used for coating the drug particles, acetone as solvent for the polymer and light liquid paraffin as an encapsulating medium. Drug : polymer ratio of 1:1 was considered to be optimized formulation with a yield of 99.96%, entrapment efficiency of 61.55%, particle size ranging from 30.32 – 90.96μm and in vitro drug release of 85.06% within an hour. FTIR studies suggested absence of drug-excipient interaction. Tablets prepared by direct compression containing microspheres and effervescent agents were evaluated for pre-compression and post-compression parameters. The wetting time, in vitro dispersion time and in vitro disintegration time of the tablets were found to be 39 sec, 35 sec and 32 sec, respectively. The drug release from the tablet was about 85.44% within an hour. The SEM of final ODTs revealed that the microspheres remained intact even after compression. Stability studies indicated that the selected formulation was stable. The results obtained suggested that effective taste-masking was achieved for SS using the technique of microencapsulation and ODTs of acceptable characteristics were obtained by adding effervescent agents followed by direct compression.
Date: June 1st & 2nd, 2017
Venue: WILL BE ANNOUNCED SOON, Washington, DC
Course "Design of Experiments (DOE) for Process Development and Validation" has been pre-approved by RAPS as eligible for up to 12 credits towards a participant's RAC recertification upon full completion.
Date: June 8th & 9th, 2017
Venue: Hilton Zurich Airport Hohenbuhlstrasse 10, 8152 Opfikon-Glattbrugg, Switzerland
Course "Cosmetics Product Regulation - Four Years after its implementation" has been pre-approved by RAPS as eligible for up to 12 credits towards a participant's RAC recertification upon full completion.
The aim of this review is to draw attention on potential applications of phospholipids in drug delivery system through different sources, structure, properties and as carrier. Phospholipids have the exceptional biocompatibility and remarkable amphiphilicity characteristics that make phospholipids the major and suitable agent or excipient for the formulation and to achieve better therapeutic applications in drug delivery system. The applications of phospholipids in the drug delivery systems are enhancement of bioavailability of drugs with low aqueous solubility or low membrane penetration, an improvement or alteration the uptake and release profile of drugs, protection of sensitive active agents from degradation in the GIT tract, reduced the side effects and masking of bitter taste of drugs. These properties offer various possibilities in formulation and potential applications.
With increasing importance of continuous manufacturing, the interest in integrating dry granulation into a continuous manufacturing line is growing. Residence time distribution measurements are of importance as they provide information about duration of materials within the process. These data enable traceability and are highly beneficial for developing control strategies. A digital image analysis system was used to determine the residence time distribution of two materials with different deformation behavior (brittle, plastic) in the milling unit of dry granulation systems. A colorant was added to the material (20% w/w iron oxide), which did not affect the material properties excessively, so the milling process could be mimicked well. Experimental designs were conducted to figure out which parameters effect the mean residence time strongly. Moreover, two types of dry granulation systems were contrasted. Longer mean residence times were obtained for the oscillating mill (OM) compared to the conical mill (CM). For co-processed microcrystalline cellulose residence times of 19.8–44.4 s (OM) and 11.6–29.1 s (CM) were measured, mainly influenced by the specific compaction force, the mill speed and roll speed. For dibasic calcium phosphate anhydrate residence times from 17.7–46.4 (OM) and 5.4 − 10.2 s (CM) were measured, while here the specific compaction force, the mill speed and their interactions with the roll speed had an influence on the mean residence time.
Lactose has two anomeric forms: α- and β-lactose. This study investigated the stability of solid lactose stored under high temperature and humidity conditions. Commercially available samples of α-lactose monohydrate (98% w/w α; 2% w/w β) and β-lactose (84 % w/w β; 16 % w/w α) were stored at 40 °C and 93% ± 3% relative humidity (RH) for up to one week and analyzed using proton nuclear magnetic resonance. The data show that the storage conditions can change the anomeric content and potentially affect the functionality of lactose as a pharmaceutical excipient.
A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.v. administration of a series of nanocrystals prepared with the bead milling technique and PEG-ylated with DSPE-PEG2000 and Pluronic F127, with and without polyvinylpyrrolidone K30 (PVP)/aerosol OT (AOT) as primary stabilizers. While all formulations were cleared significantly faster than expected from nanocrystal dissolution alone, purely DSPE-PEG2000 PEG-ylated particles displayed prolonged circulation time (particles elimination half-life of 9 minutes) compared to DSPE-PEG2000/PVP/AOT formulation (half-life of 3 minutes). The two Pluronic F127 stabilized formulations displayed similar half-lives (9 minutes with and without PVP/AOT, respectively). Whole tissue kinetics shows that clearance of particles could be attributed to accumulation in the liver. A separate in vivo study addressed the liver cell distribution after administration. Dissolved compound accumulated in hepatocytes only, while particles were distributed between liver sinusoidal endothelial cells and Kupffer cells. More DSPE-PEG2000/PVP/AOT stabilized particles accumulated in the liver, preferably in Kupffer cells, compared to Pluronic F127/PVP/AOT stabilized particles. The present study extends the understanding of PEG-ylation and “stealth” behaviour to also include nanocrystals.
The morphology and polymorphism of mannitol particles were controlled during spray drying with the aim of improving the aerosolization properties of inhalable dry powders. The obtained microparticles were characterized using scanning electron microscopy, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and inhaler testing with a next generation impactor. Mannitol particles of varied α-mannitol content and surface roughness were prepared via spray drying by manipulating the concentration of NH4HCO3 in the feed solution. The bubbles produced by NH4HCO3 led to the formation of spheroid particles with a rough surface. Further, the fine particle fraction was increased by the rough surface of carriers and the high α-mannitol content. Inhalable dry powders with a 29.1 ± 2.4% fine particle fraction were obtained by spray-drying using 5% mannitol (w/v)/2% NH4HCO3 (w/v) as the feed solution, proving that this technique is an effective method to engineer particles for dry powder inhalation.
We investigated the effectiveness of using Carr’s flowability index (FI) and practical angle of internal friction (Φ) as indexes for setting the target Mg-St mixing time needed for preparing tablets with the target physical properties. We used FI as a measure of flowability under non-loaded conditions, and Φ as a measure of flowability under loaded conditions for pharmaceutical powders undergoing direct compression with varying concentrations of Mg-St and mixing times. We evaluated the relationship between Mg-St mixing conditions and pharmaceutical powder flowability, analyzed the correlation between the physical properties of the tablets (i.e., tablet weight variation, drug content uniformity, hardness, friability, and disintegration time of tablets prepared using the pharmaceutical powder), and studied the effect of Mg-St mixing conditions and pharmaceutical powder flowability on tablet properties. Mg-St mixing time highly correlated with pharmaceutical powder FI (R2 = 0.883) while Mg-St concentration has low correlation with FI, and FI highly correlated with the physical properties of the tablet (R2 values: weight variation 0.509, drug content variation 0.314, hardness 0.525, friability 0.477, and disintegration time 0.346). Therefore, using pharmaceutical powder FI as an index could enable prediction of the physical properties of a tablet without the need for tableting, and setting the Mg-St mixing time by using pharmaceutical powder FI could enable preparation of tablets with the target physical properties. Thus, the FI of the intermediate product (i.e., pharmaceutical powder) is an effective index for controlling the physical properties of the finished tablet.
A strategy based on sequential design of experiments (screening, optimization and confirmation) was used to develop a tablet formulation of ibuprofen (400 mg) that is manufactured by direct compression. This formulation has a high content of ibuprofen (76%), in spite of the poor flowability of the drug substance. Sequential design of experiments proved to be an effective and efficient strategy in formulation development.
Local delivery of drugs and biopharmaceuticals for the treatment of inflammatory bowel disease remains a challenge. Innovative nanomedicines with appropriate properties raise the possibility of efficient drug targeting. Hence, the overall aim of this study was to develop and characterize a protamine-based nanosystem for topical delivery of therapeutics to inflamed intestinal mucosa following oral administration. Protamine nanocapsules with a new composition were for the first time prepared by, a self-emulsifying process, without the use of organic solvents or heat. A model lipophilic anti-inflammatory agent, cyclosporin A (CsA), was encapsulated in the oily core of these nanocarriers. The CsA-loaded formulation was isolated from the free drug by gel filtration and the entrapment efficiency was determined using reverse phase high-performance liquid chromatography (HPLC). Protamine nanocapsules had sizes within the range of 160-180 nm, with low polydispersity index (0.2) and positive surface charge, together with high entrapment efficiency (95%) and drug loading capacity (5%). The nanocapsules exhibited good stability in storage both as an aqueous suspension and as a freeze-dried powder. Nanocapsules also preserved their colloidal stability in simulated intestinal media. In vitro studies performed with the Jurkat human T lymphocyte cell line showed that CsA-loaded protamine nanocapsules are more efficient than the commercial Sandimmune Neoral® formulation at reducing IL-2 secretion (γγp<0.01). At the same time, nanocapsules showed no toxic effects on the cells. The results discussed herein indicate the feasibility of the developed nanosystem to serve as a potential carrier for cyclosporin A administration.
Ibuprofen is an oral analgesic usually processed by wet granulation. In this manuscript a new roller compaction process for ibuprofen is reported. The low melting point of ibuprofen is a critical point to be considered during processing. Melting of ibuprofen and its posterior solidification leads to a lower soluble form. The hypothesis of this work is that crystallinity of ibuprofen may be a good indicator of the quality for both raw material selection and the granules obtained during roller compaction. To test the hypothesis two batches of ibuprofen raw material with different crystallinity degree were used. Crystallinity was studied by X ray powder diffraction (XRPD), molecular modelling and differential scanning calorimetry (DSC). Ibuprofen was mixed with sodium croscarmellose and then compacted in a refrigerated roller compactor at five different compaction forces (KN) between 45 and 70 KN. Particle size, moisture content and dissolution rate of the granules were also studied. As it was expected, roller compaction decreased the crystallinity degree of ibuprofen. Interestingly, differences on the crystal morphology of the raw material batches were related to the dissolution behavior of the granules. Therefore, crystallinity characterization of the raw material is proposed as a critical requirement on roller compaction.
The objective of this study was to prepare and evaluate some physiochemical and biopharmaceutical properties of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. In the first stage of the study, the bitter taste masking microparticles were prepared by solvent evaporation and spray drying method. When compared to the bitter threshold (32.43 µg/ml) of azithromycin (AZI), the microparticles using AZI:Eudragit L100 = 1:4 and having a size distribution of 45–212 µm did significantly mask the bitter taste of AZI. Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H NMR) proved that the taste masking of microparticles resulted from the intermolecular interaction of the amine group in AZI and the carbonyl group in Eudragit L100. Differential scanning calorimeter (DSC) analysis was used to display the amorphous state of AZI in microparticles. Images obtaining from optical microscopy and scanning electron microscopy (SEM) indicated the existence of microparticles in regular cube shape with many layers. In the second stage, dispersible tablets containing microparticles (DTs-MP) were prepared by direct compression technique. Stability study was conducted to screen pH modulators for DTs-MP, and a combination of alkali agents (CaCO3:NaH2PO4, 2:1) was added into DTs-MP to create microenvironment pH of 5.0–6.0 for the tablets. The disintegration time of optimum DTs-MP was 53 ± 5.29 s and strongly depended on the kinds of lubricant and diluent. The pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of DTs-MP were improved by 2.19 and 2.02 times, respectively, compared to the reference product (Zithromax®, Pfizer).
The objective of this study was to develop Esomeprazole solid dosage form as minitablets. The effect of coating thickness and percentage of fast disintegrants on the in vitro and in vivo performance of minitablets were studied. Two formulae (A1&B1) of the same core composition with different coat thickness were prepared initially. The in vivo study of A1 and B1 versus the originator revealed that their rate of dissolution was not enough to achieve bioequivalence with respect to Cmax, in spite of achieving acceptable extent of absorption. Therefore one of the formulas (A1) was modified to C1, by keeping the same coat thickness and increasing the percentage of disintegrant to enhance drug release rate during absorption phase. This modification increased in the dissolution rate as indicated by a higher dissolution efficiency (DE) for C1 than A1 and B1. A good correlation between DE and rate of absorption for A1, B1 and C1 was observed. In vivo studies under fasting conditions carried on 22 subjects revealed that the minitablets and Nexium were bioequivalent. Fed study was conducted on 16 subjects, showed that there was a significant delaying effect of food on drug absorption from minitablets.
Capping or lamination is an unsolved common problem in tablet manufacturing. Knowledge gaps remain despite an enormous amount of effort made in the past to better understand the tablet capping/lamination phenomenon. Using acetaminophen – containing formulations, we examined the potential use of a compaction simulator as a material-sparing tool to predict capping occurrence under commercial tableting conditions. Systematical analyses of the in-die compaction data led to insight on the potential mechanism of tablet capping/lamination. In general, capping strongly correlates with high in-die elastic recovery, high Poisson’s ratio, low tensile strength, and radial die-wall pressure. Such insight can be used to guide the formulation design of high quality tablet products that are free from capping problems for challenging active pharmaceutical ingredients.
Hyaluronic acid (HA) solutions effectively lubricate the ocular surface and are used for the relief of dry eye related symptoms. However, HA undergoes rapid clearance due to limited adhesion, which necessitates frequent instillation. Conversely, highly viscous artificial tear formulations with HA blur vision and interfere with blinking. Here, we developed an HA-eye drop formulation that selectively binds and retains HA for extended periods of time on the ocular surface. We synthesized a heterobifunctional polymer-peptide system with one end binding HA while the other end binding either sialic acid-containing glycosylated transmembrane molecules on the ocular surface epithelium, or type I collagen molecule within the tissue matrix. HA solution was mixed with the polymer-peptide system and tested on both ex vivo and in vivo models to determine its ability to prolong HA retention. Furthermore, rabbit ocular surface tissues treated with binding peptides and HA solutions demonstrated superior lubrication with reduced kinetic friction coefficients compared to tissues treated with conventional HA solution. The results suggest that binding peptide-based solution can keep the ocular surface enriched with HA for prolonged times as well as keep it lubricated. Therefore, this system can be further developed into a more effective treatment for dry eye patients than a standard HA eye drop.
Abstract: A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)—a poorly water-soluble immunosuppressant—was constructed in order to attain an apparent concentration–time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 °C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.
The aim of the present work was to develop and evaluate sustained release colon targeted micropellets of lornoxicam in order to achieve release of the drug at colon which could result in enhanced local absorption and thereby improved bio-availability. The present worker prepared micropellets of lornoxicam in nine batches using pure drug, DCP, PVPK-30 and different ratios of HPMCK-4M taking into account the direct pelletization technique. Resulted micropellets were illed in capsules and coated with eudragit S-100 to achieve colon targeted release. Compatibility studies were by using FTIR and TLC methods. Particle size determination of micronized lornoxicam was performed by SEM which revealed that the mean particle diameter was in the range of 104-263 μm while percentage yield was in the range of 88.4-98.4%.Various pre-formulation physiochemical parameters of formulation blends were evaluated such as bulk density, tapped density, carr’s index, hausner’s ratio and angle of repose and coating durability test for coated capsules (passed). The optimized batch was compared for its release pro le in pH 7.4 phosphate buffers and simulated colonic uid,
which were found to be 94.64% and 90.58% respectively. The actual responses were in accordance with the predicted values which showed validity of the model. There were no physical and chemical changes occurred in accelerated stability of tablets during three months study.
The focus was on the development of medicated foam for incorporation of two incompatible active agents for psoriasis treatment; i.e., lipophilic cholecalciferol, and hydrophilic salicylic acid. Emphasis was given to formulation of a propellant-free foam, with sufficient foaming properties, physical and chemical stability, and low irritancy potential to maintain relevance for later translation into clinical practice. Various excipients and concentrations were examined to achieve suitable foam stability parameters, viscoelasticity, and bubble-size, which relate to foamability and spreadability. The major positive impact on these properties was through a combination of surfactants, and by inclusion of a viscosity-modifying polymer. Incorporation of the incompatible drugs was then examined, noting the instability of cholecalciferol in an acidic environment, with the design aim to separate the drug distributions among the different foam phases. Cholecalciferol was stabilized in the emulsion-based foam, with at least a 30-fold lower degradation rate constant compared to its aqueous solution. The composition of the emulsion-based foam itself protected cholecalciferol from degradation, as well as the addition of the radical-scavenging antioxidant tocopheryl acetate to the oil phase. With the patient in mind, the irritancy potential was also examined, which was below the set limit that defines a non-irritant dermal product.
Dissolution of bicalutamide processed with polyvinylpyrrolidone by either supercritical carbon dioxide or ball milling has been investigated. Various compositions as well as process parameters were used to obtain binary systems of the drug with the carrier. Thermal analysis and powder X-ray diffractometry confirmed amorphization of bicalutamide mechanically activated by ball milling and the decrease in crystallinity of the supercritical carbon dioxide-treated drug. Both methods led to reduction of particles size what was confirmed by scanning electron microscopy and laser diffraction measurements. Moreover, the effect of micronisation was found to depend on the parameters of applied process. Fourier transform infrared spectroscopy revealed the appearance of intermolecular interactions between drug and carrier molecules that play an important role in the stabilization of amorphous form of the active compound. Changes in crystal structure combined with reduced size of particles of bicalutamide dispersed within polymer matrix were found to improve dissolution of bicalutamide by 4 to 10-fold in comparison to untreated drug. It is of particular importance as poor dissolution profiles are considered to be the major limitation in bioavailability of the drug.
Artemisinin, a natural anti-malarial agent, also possesses anti-proliferative and anti-angiogenic activity in cancer cells with very low toxicity to normal healthy cells. Drug loaded magnetic nanoparticlesby using external magnetic field could selectively accumulate the drug at the target site and thereby reduce the doses required to achieve therapeutic concentration which may otherwise produce serious side effects on healthy cells. In the present study the artemisinin magnetic nanoparticles were successfully formulated using chitosan by ionic-gelation method. The developed magnetic nanoparticles of artemisinin were smooth and spherical in natureand their size was in the range of 349 to 445 nm. The polydispersity index (PDI) and zeta potential of the formulated nanoparticles were in the range of 0.373 to 0.908 and −9.34 to −33.3 respectively. They showed 55% to 62.5% of drug encapsulation efficiency and 20% to 25% drug loading capacity. Around 62% to 78% of artemisinin was released from the artemisinin magnetic nanoparticles over the period of 48 h. On application of physiologically acceptable external magnetic field, FITC conjugated artemisinin magnetic nanoparticles showed an enhanced accumulation of nanoparticles in the 4T1 breast tumour tissues of BALB/c mice model.
Topical drug delivery systems provide localized drug action. A hydrophilic polymer such as polyvinyl alcohol is a multi-faceted excipient that can be used as a coating agent, lubricant, stability enhancer and viscosity-increasing agent. The objective of our study was to evaluate the use of polyvinyl alcohol polymer in preparing a topical gel with a diclofenac salt as the pharmaceutical active. The gel was characterized for its rheological and other properties and its effectiveness to deliver drug through dermatomed human skin compared to a similar commercially available topical gel. Topical polyvinyl alcohol based gel was prepared with propylene glycol, isopropyl alcohol, hydroxypropyl cellulose, and Transcutol® P. Formulation was tested for pH, rheology, adhesion, spreadability, skin irritation, in vitro drug distribution in skin, and permeation. The formulated topical gel delivered an average cumulative drug amount of 22.85 ± 9.41 μg/cm2 across skin and delivered 10.30 ± 9.09 μg/cm2 in the skin over 24 h. The mean cell viability value of 107.41± 40.81% rendered by in vitro skin irritation test confirmed the formulated gel to be non-irritant to human skin. In conclusion, a safe efficacious and rheologically competent polyvinyl alcohol polymer based topical diclofenac gel was developed and characterized successfully.
The aim of this study is to demonstrate the enhanced therapeutic efficacy of anticancer drugs on drug-resistant breast cancer using multicomponent microemulsions (ECG-MEs) as an oral delivery system. The etoposide-loaded ECG-MEs were composed of coix seed oil and ginsenoside Rh2 (G-Rh2), both of which possess not only the synergistic antitumor effect with etoposide, but also have excipient-like properties. Orally administrated ECG-MEs were demonstrated to be able to accumulate at the tumor site following crossing the intestines as intact vehicles into the blood circulation. The spatiotemporal controlled release characteristics of ECG-MEs brought about the efficient P-gp inhibition by the initially released G-Rh2 and the increased intracellular accumulation of the sequentially released etoposide. The combination antitumor activity of etoposide, G-Rh2 and coix seed oil using ECG-MEs was verified on the xenograft drug-resistant breast tumor mouse models. In addition, the safety evaluation studies indicated that treatment with ECG-MEs did not cause any significant toxicity in vivo. These findings suggest that ECG-MEs as an oral formulation may offer a promising strategy to treat the drug-resistant breast cancer.
Innopharma Labs EyeconTM inline particle characterisation technology enables customers to measure particle size and shape during fluidised bed granulation & coating, spheronisation and continuous fluid bed drying processes. This study examines the effectiveness of a particle characterising technology to capture particle images and to calculate particle growth during a fluidised bed spray coating process.
The objective of this study was to examine if the Eyecon has the ability to track the increase in particle growth over time as a result of the spray coating process.
Poloxamer 188, a commonly used emulsifying and solubilizing agent, was found to be the cause of crystallization of an investigational drug, AMG 579, from its amorphous solid dispersion at accelerated storage conditions. Investigation of this physical stability issue included thorough characterization of poloxamer 188 at non-ambient conditions. At 40 °C, poloxamer 188 becomes deliquescent above relative humidity of 75%. Upon returning to ambient conditions, the deliquescent poloxamer 188 loses water and re-solidifies. The reversible phase transformation of poloxamer 188 may cause physical and chemical stability issues and this risk should be assessed when selecting it as an excipient for formulation development.