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Journal of Pharmaceutical Sciences May 2024Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying...
Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying mechanism and probable root causes are not well characterized. Mostly, the phenomenon is attributed to the presence of crystallizing excipients, such as mannitol in the formulation, while other potential factors are often underestimated or not well studied. In this work we document a systematic multipronged approach to characterize and identify potential root cause(s) of vial breakage during lyophilization. Factors associated with formulation, product configuration, primary container and production process stress conditions were identified and their impact on vial breakage was studied in both lab and manufacturing scale conditions. Studies included: 1) strain gauge and lyophilization analysis for stress on glass vials with different formulation conditions and fill volumes, 2) manufacturing fill-finish process risk assessment (ex. loading and frictive force impact on the vials), and 3) glass vial design and ruggedness (ex. glass compression resistance or burst strength testing). Importantly, no single factor could be independently related to the extent of vial breakage observed during production. However, a combination of formulation, fill volume, and vial weakening processes encountered during at-scale production, such as vial handling, shelf loading and unloading, were identified to be the most probable root causes for the low levels of vial breakage observed. The work sheds light on an often-encountered problem in the pharmaceutical industry and the results presented in this paper argue against the simplistic root-cause explanations reported in literature. The work also provides insight into the possibility of implementing mitigative approaches to minimize or eliminate vial breakage associated with lyophilized drug products.
Topics: Drug Packaging; Chemistry, Pharmaceutical; Drug Industry; Freeze Drying; Glass; Technology, Pharmaceutical
PubMed: 38103690
DOI: 10.1016/j.xphs.2023.12.010 -
International Journal of Pharmaceutics May 2024Oral suspension is the most preferred dosage form for the paediatric population because of the difficulties related to solid medications, such as the swallowing... (Review)
Review
Oral suspension is the most preferred dosage form for the paediatric population because of the difficulties related to solid medications, such as the swallowing limitations, bitter taste, and poor oral bioavailability, which can cause serious impairment to attain a successful treatment. Given the importance of successful therapies, there is a need for safe and effective commercially-available paediatric oral suspension and their characterization. For the latter, it is important to identify safe excipients and preservatives. The paediatric group is a diverse category which includes infants and teenagers, with major pharmacokinetics and pharmacodynamics differences, mainly because of physiological and behavioral variations. Therefore, finding a single formulation for paediatric population remains a challenge, as well asthe formulation of stable-in-time suspension. In addition, drug's dissolving characteristic and permeation, are the main determinants for oral absorption, which are closely related to drug release kinetics from the pharmaceutical form. In this context, drug release profile is an important and limiting step in oral bioavailability, particularly for BCS class II drugs; thus, it is possible to increase bioavailability and minimize adverse effects by changing the release rate of such drugs. This review covers all the aspects for paediatric oral suspension development, and analyses the considerations for excipients selection as a crucial task for effectively choosing a safe and effective pharmaceutical form and correctly dosing paediatric patients.
Topics: Humans; Suspensions; Administration, Oral; Child; Excipients; Biological Availability; Drug Compounding; Adolescent; Drug Liberation; Chemistry, Pharmaceutical; Infant; Pharmaceutical Preparations
PubMed: 38688428
DOI: 10.1016/j.ijpharm.2024.124169 -
Contact Lens & Anterior Eye : the... Aug 2023To investigate and evaluate the chromatic dispersion of various hydrogel and silicon hydrogel contact lens materials.
PURPOSE
To investigate and evaluate the chromatic dispersion of various hydrogel and silicon hydrogel contact lens materials.
METHODS
Eighteen different soft contact lens materials with high and low water content in lens power of -1.00 DS were measured by one operator at temperature of 20 °C ± 0.5° soaked in ISO standard phosphate-buffered saline (PBS) and in their respective packaging solutions (PS). An analogue Abbe refractometer (Model Zuzi 320, AUXILAB, S.L., Navarra, Spain) was used for refractive index (RI) measurements at 5 different wavelengths. All contact lenses were presented in a random and masked order to the operator. The Bland-Altman method with 95 % limits of agreement (LoA) and coefficient of repeatability (CoR) was used to characterise the repeatability of refractive index measurements. The Abbe numbers for each material were calculated by entering the measured and interpolated refractive indices into the Abbe number equation. One-way ANOVA analysis was used to test if there were significant differences between the 5 different wavelengths (470 nm-680 nm) within each material. An unpaired t-test was used to determine if there were differences in refractive index or dispersion between packaging solution and PBS results.
RESULTS
Nelfilcon A (Dailies Aqua Comfort Plus) soaked in PS showed the best repeatability of all 18 examined soft contact lenses across all wavelengths with an average refractive index of 1.3848 for all 6 contact lenses with a standard deviation of 0.00064. The 95 % limits of agreement were between 1.3835 and 1.3860. The mean coefficient of repeatability for nelfilcon A was 0.00125. For contact lenses soaked in ISO Standard PBS comfilcon A (Biofinity) had the best repeatability. The average refractive index of all 6 contact lenses was 1.4041 with a standard deviation of 0.00031 and a coefficient of repeatability of 0.00060. The 95 % limits of agreement were between 1.4035 and 1.4047. The analysis with One-way ANOVA with multiple comparisons involving Holm-Sidak post-hoc, showed that there are significant differences (p < 0.001, F = 376.2 between wavelengths and F = 1559 between different refractive indices) in the refractive index of most common lens materials across the visible wavelength range. Based on unpaired t-test, there is no significant difference (p > 0.05) in the Abbe numbers of the tested lens materials whether they have been placed in the packaging solution or in standard PBS (p > 0.05, 95 % CI = -4.8070 to 5.8680, t = 0.2054). The Abbe numbers for the calculated contact lenses soaked in PS ranged between 43.7 and 89.9. For contact lenses stored in PBS the range was between 46.3 and 81.6.
CONCLUSION
There is a good repeatability between repeated RI measurements taken from the same lens and from the same material. The significant differences between the refractive indices across the 5 different wavelengths showed the presence of chromatic dispersion in the 18 evaluated soft contact lens materials. Furthermore, it could be shown that there is no significant difference in dispersion whether the contact lenses are soaked in standard PBS or in their respective packaging solutions. With no other published data available as a reference, absolute accuracy of the calculated Abbe numbers remains to be confirmed, however, this study did confirm that significant chromatic dispersion exists in soft contact lens materials.
Topics: Humans; Contact Lenses, Hydrophilic; Hydrogels; Refractometry; Excipients; Spain
PubMed: 37244801
DOI: 10.1016/j.clae.2023.101864 -
Carbohydrate Polymers Jul 2023Hydroxypropyl methylcellulose (HPMC) is an important polymeric excipient. Its versatility in terms of molecular weights and viscosity grades is the basis for its wide... (Review)
Review
Hydroxypropyl methylcellulose (HPMC) is an important polymeric excipient. Its versatility in terms of molecular weights and viscosity grades is the basis for its wide and successful application in the pharmaceutical industry. Low viscosity grades of HPMC (like E3 and E5) have been used as physical modifiers for pharmaceutical powders in recent years due to their unique physicochemical and biological properties (e.g., low surface tension, high T, strong hydrogen bonding ability, etc.). Such modification is the co-processing of HPMC with a drug/excipient to create composite particles (CPs) for the purpose of providing synergistic effects of functional improvement as well as of masking undesirable properties of the powder (e.g., flowability, compressibility, compactibility, solubility, stability, etc.). Therefore, given its irreplaceability and tremendous opportunities for future developments, this review summarized and updated studies on improving the functional properties of drugs and/or excipients by forming CPs with low-viscosity HPMC, analyzed and exploited the improvement mechanisms (e.g., improved surface properties, increased polarity, hydrogen bonding, etc.) for the further development of novel co-processed pharmaceutical powders containing HPMC. It also provides an outlook on the future applications of HPMC, aiming to provide a reference on the crucial role of HPMC in various areas for interested readers.
Topics: Powders; Hypromellose Derivatives; Viscosity; Excipients; Surface Properties; Methylcellulose; Solubility
PubMed: 37028868
DOI: 10.1016/j.carbpol.2023.120731 -
Journal of Controlled Release :... Oct 2023This review highlights the importance of controlling the digestion process of orally administered lipid-based delivery systems (LBDS) and their performance. Oral LBDS... (Review)
Review
This review highlights the importance of controlling the digestion process of orally administered lipid-based delivery systems (LBDS) and their performance. Oral LBDS are prone to digestion via pancreatic lipase in the small intestine. Rapid or uncontrolled digestion may cause the loss of delivery system integrity, its structural changes, reduced solubilization capacity and physical stability issues. All these events can lead to uncontrolled drug release from the digested LBDS into the gastrointestinal environment, exposing the incorporated drug to precipitation or degradation by luminal proteases. To prevent this, the digestion rate of orally administered LBDS can be estimated by appropriate choice of the formulation type, excipient combinations and their ratios. In addition, in vitro digestion models like pH-stat are useful tools to evaluate the formulation digestion rate. Controlling digestion can be achieved by conventional lipase inhibitors like orlistat, sterically hindering of lipase adsorption on the delivery system surface with polyethylene glycol (PEG) chains, lipase desorption or saturation of the interface with surfactants as well as formulating LBDS with ester-free excipients. Recent in vivo studies demonstrated that digestion inhibition lead to altered pharmacokinetic profiles, where C and T were reduced in spite of same AUC compared to control or even improved oral bioavailability.
PubMed: 37579977
DOI: 10.1016/j.jconrel.2023.08.024 -
PloS One 2023This crossover randomized controlled trial (RCT) investigated differences in short-term entero-endocrine response to a mixed-meal tolerance test preceded by nutrient... (Randomized Controlled Trial)
Randomized Controlled Trial
The entero-endocrine response following a mixed-meal tolerance test with a non-nutritive pre-load in participants with pre-diabetes and type 2 diabetes: A crossover randomized controlled trial proof of concept study.
INTRODUCTION
This crossover randomized controlled trial (RCT) investigated differences in short-term entero-endocrine response to a mixed-meal tolerance test preceded by nutrient sensing between participants with pre-diabetes (pre-T2D) and type 2 diabetes (T2D). Additionally, differences in gut and oral microbiome composition between participants with a high and low entero-endocrine response were investigated.
RESEARCH DESIGN AND METHODS
Ten participants with pre-T2D and ten with T2D underwent three test days with pre-loads consisting of either swallowing water (control), or rinsing with a non-nutritive sweetener solution, or swallowing the sweetener solution before a mixed-meal tolerance test. Blood glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, glucose, insulin and peptide YY (PYY) were determined at t = -20, 0, 15, 30, 60, 120 and 240 minutes. The composition of the oral and gut microbiome at baseline were also determined.
RESULTS
The entero-endocrine response differed by pre-loads, e.g. a lower PYY response after swallowing the non-nutritive sweetener (-3585.2pg/mL [95% CI: -6440.6; -729.8]; p = 0.01). But it also differed by T2D status, e.g. a higher glucose, glucagon and PYY response was found in participants with T2D, compared to those with pre-T2D. Evidence for associations between the oral and gut microbiome composition and the entero-endocrine response was limited. Still, the level of entero-endocrine response was associated with several oral microbiome measures. Higher oral anterior α-diversity was associated with a lower PYY response (e.g. Inverse Simpson index -1357pg/mL [95% CI -2378; -336; 1.24]), and higher oral posterior α-diversitywith a higher GIP response (e.g. Inverse Simpson index 6773pg/mL [95% CI 132; 13414]) in models adjusted for sex, age and T2D status.
CONCLUSIONS
Non-nutritive pre-loads influence the entero-endocrine response to a mixed-meal, and this effect varies based on (pre-)T2D status. The entero-endocrine response is likely not associated with the gut microbiome, and there is limited evidence for association with the α-diversity of the oral microbiome composition.
TRIAL REGISTRATION
Trial register: Netherlands Trial Register NTR7212, accessible through International Clinical Trials Registry Platform: ICTRP Search Portal (who.int).
Topics: Humans; Child, Preschool; Prediabetic State; Glucagon; Non-Nutritive Sweeteners; Proof of Concept Study; Diabetes Mellitus, Type 2; Excipients; Gastric Inhibitory Polypeptide; Glucose
PubMed: 37624823
DOI: 10.1371/journal.pone.0290261 -
Expert Opinion on Drug Delivery Apr 2024Novel injectables possess applications in both local and systemic therapeutics delivery. The advancement in utilized materials for the construction of complex... (Review)
Review
INTRODUCTION
Novel injectables possess applications in both local and systemic therapeutics delivery. The advancement in utilized materials for the construction of complex injectables has tremendously upgraded their safety and efficacy.
AREAS COVERED
This review focuses on various strategies to produce novel injectables, including oily dispersions, in situ forming implants, injectable suspensions, microspheres, liposomes, and antibody-drug conjugates. We herein present a detailed description of complex injectable technologies and their related drug formulations permitted for clinical use by the United States Food and Drug Administration (USFDA). The excipients used, their purpose and the challenges faced during manufacturing such formulations have been critically discussed.
EXPERT OPINION
Novel injectables can deliver therapeutic agents in a controlled way at the desired site. However, several challenges persist with respect to their genericization. Astronomical costs incurred by innovator companies during product development, complexity of the product itself, supply limitations with respect to raw materials, intricate manufacturing processes, patent evergreening, product life-cycle extensions, relatively few and protracted generic approvals contribute to the exorbitant prices and access crunch. Moreover, regulatory guidance are grossly underdeveloped and significant efforts have to be directed toward development of effective characterization techniques.
Topics: Humans; Drug Approval; United States Food and Drug Administration; Injections; United States; Drug Delivery Systems; Drug Development; Drug Compounding; Excipients; Pharmaceutical Preparations; Animals; Chemistry, Pharmaceutical
PubMed: 38703363
DOI: 10.1080/17425247.2024.2351987 -
Molecules (Basel, Switzerland) Sep 2023The ecotoxicological impact of pharmaceuticals has received considerable attention, primarily focusing on active pharmaceutical ingredients (APIs) while largely...
The ecotoxicological impact of pharmaceuticals has received considerable attention, primarily focusing on active pharmaceutical ingredients (APIs) while largely neglecting the potential hazards posed by pharmaceutical excipients. Therefore, we analyzed the ecotoxicity of 16 commonly used pharmaceutical excipients, as well as 26 API-excipient and excipient-excipient mixtures utilizing the Microtox test. In this way, we assessed the potential risks that pharmaceutical excipients, generally considered safe, might pose to the aquatic environment. We investigated both their individual ecotoxicity and their interactions with tablet ingredients using concentration addition (CA) and independent action (IA) models to shed light on the often-overlooked ecotoxicological consequences of these substances. The CA model gave a more accurate prediction of toxicity and should be recommended for modeling the toxicity of combinations of drugs with different effects. A challenge when studying the ecotoxicological impact of some pharmaceutical excipients is their poor water solubility, which hinders the use of standard aquatic ecotoxicity testing techniques. Therefore, we used a modification of the Microtox Basic Solid Phase protocol developed for poorly soluble substances. The results obtained suggest the high toxicity of some excipients, i.e., SLS and meglumine, and confirm the occurrence of interactions between APIs and excipients. Through this research, we hope to foster a better understanding of the ecological impact of pharmaceutical excipients, prompting the development of risk assessment strategies within the pharmaceutical industry.
Topics: Excipients; Risk Assessment; Environment; Drug Industry; Pharmaceutical Preparations
PubMed: 37764366
DOI: 10.3390/molecules28186590 -
AAPS PharmSciTech Oct 2023Neurovascular diseases are linked to the brain's blood vessels. These disorders are complicated to treat due to the strict selective characteristics of the blood-brain... (Review)
Review
Neurovascular diseases are linked to the brain's blood vessels. These disorders are complicated to treat due to the strict selective characteristics of the blood-brain barrier. Consequently, the potency of the pharmacological treatments for these conditions is immensely diminished, leading to a rise in neurovascular-associated morbidity and mortality. Carbon nanotubes are regarded as essential nanoparticles with a promise of treating neurovascular disorders. Current findings have demonstrated the effectiveness of carbon nanotubes as vehicles for ferrying drugs to the site of interest. This review accentuates the theoretical utilisation of carbon nanotubes as drug nanocarriers equipped with the penetrating capability to the blood-brain barrier for treating neurovascular disorders such as ischemic stroke. The success of the carbon nanotube system may result in the development of a new and highly relevant drug delivery procedure. This review will also cover carbon nanotube functionalisation for applications in the biomedical fields, toxicity, in vitro and in vivo drugs and biomolecule delivery, and the future outlook of carbon nanotubes.
Topics: Nanotubes, Carbon; Drug Delivery Systems; Blood-Brain Barrier; Biological Transport; Pharmaceutical Preparations; Excipients
PubMed: 37783896
DOI: 10.1208/s12249-023-02651-3 -
Pharmaceutical Development and... Oct 2023Skin disorders are preferentially treated by topical administration of medicines or cosmetics because of the possibility of local action. However, a great concern is the... (Review)
Review
Skin disorders are preferentially treated by topical administration of medicines or cosmetics because of the possibility of local action. However, a great concern is the delivery of topical actives with effective penetration through the stratum corneum to ensure the desired effect. Considering the search for a carrier system that allows the penetration/permeation of active pharmaceutical ingredients through this structure, searching for effective topical pharmaceutical forms is needed. Foams have been widely studied over the years due to their high capacity to favor the active to overcome the cutaneous barrier and because this form of presentation has ease of application and high acceptability by users. The objective of this review was to analyze the potential of foam as a topical pharmaceutical form for treating skin disorders, upon clinical cases reported in the literature. Foam presents technical advantages when compared to other conventional topical pharmaceutical forms due to its fast action, high tolerance, and safety, with reduction or total remission of adverse events. Regarding the patient, foam increased the rate of adherence to the treatment. Therefore, it is concluded that foam is an effective, secure, and stable topical presentation form for carrying active pharmaceutical ingredients and widely accepted by patients.
Topics: Humans; Pharmaceutical Preparations; Administration, Topical; Skin Diseases; Epidermis; Excipients; Administration, Cutaneous; Skin
PubMed: 37632372
DOI: 10.1080/10837450.2023.2251556