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Int J Pharm ; 629: 122380, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36368608


As a drug advances through the late stages of clinical development, formulation changes are common to meet clinical, manufacturing, and/or business needs. Since some formulation changes may alter in vivo drug absorption, it is critical to understand the impact of these changes on in vivo PK performances to support the transition between pre- and post-change formulations and ensure the drug's efficacy and safety. While clinical RBA/BE studies are time-consuming and expensive, other formulation bridging approaches that bring opportunities to expedite drug development by waiving clinical formulation bridging studies are summarized. This review discussed the current formulation bridging options based on in vitro dissolution, physiologically-based biopharmaceutics modeling (PBBM), in vitro - in vivo correlation (IVIVC), and risk-based assessment during the early and late stages of clinical development. By increasing the understanding of the opportunities and challenges associated with different formulation bridging approaches, this review helps with the selection/design of formulation bridging studies in a phase appropriate manner for formulation change during product development.

Biofarmácia , Desenvolvimento de Medicamentos , Solubilidade , Modelos Biológicos , Equivalência Terapêutica
Int J Pharm ; 628: 122284, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36244561


Wildlife medicine is a specialised division of veterinary medicine that is concerned with patients that are physiologically very diverse with similarly diverse life histories. The medicines to be delivered to wildlife parallel those used in other areas of veterinary medicine and human medicine, however species-specific information on drug administration is lacking for wildlife species. Currently there are numerous threats of extinction to wildlife globally due to climate change and habitat destruction. The COVID-19 pandemic has also made us acutely aware of the important link between human health and wildlife health and how zoonotic diseases can cause devastating impacts globally. Consequently, the ability to effectively treat this group of animals with therapeutic compounds is becoming increasingly more critical. Importantly, delivery of therapeutics to wildlife is a particular challenge that must be overcome. The objective is to highlight the area of wildlife therapeutics as an emerging field by presenting case studies to illustrate the opportunities for engagement of pharmaceutical scientists in this fascinating frontier of research. The case studies included are avian malaria in yellow-eyed penguins, transmissible cancers in Tasmanian devils, and the vaccination of wildlife for the control of SARS-Cov-2 transmission.

Animais Selvagens , COVID-19 , Animais , Humanos , SARS-CoV-2 , Pandemias , Biofarmácia
Pharm Dev Technol ; 27(7): 816-828, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36062973


This study focuses on the dry milling of biopharmaceutical classification system (BCS) class II molecules. These molecules have a limited bioavailability because of their low aqueous solubility, poor water wettability and low dissolution rate. In order to improve these properties, indomethacin (IND) and niflumic acid (NIF) were milled using two different types of equipment: Pulverisette 0® and CryoMill®. Milled samples were characterized and compared to commercial molecules. IND shows a modified solid state, like surface crystallinity reduction and an increase in water vapor adsorption from to 2- up to 5-fold due to milling processes. The obtained solubility data resulted in an improvement in solubility up to 1.2-fold and an increase in initial dissolution kinetics: 2% of dissolved drug for original crystals against 25% for milled samples. For NIF no crystallinity reduction, no change of surface properties and no solubility improvement after milling were noticed. In addition, milled particles seemed more agglomerated resulting in no changes in dissolution rate compared to the original drug. IND solubility and dissolution enhancement can be attributed to the modification of surface area, drug crystallinity reduction, and water sorption increase due to specific behavior related to the drug crystal disorder induced by milling process.

Produtos Biológicos , Biofarmácia , Indometacina/química , Ácido Niflúmico , Vapor
J Pharm Sci ; 111(12): 3251-3260, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36058256


Protein particle formation during peristaltic pumping of biopharmaceuticals is due to protein film formation on the inner tubing surface followed by rupture of the film by the roller movement. Protein adsorption can be prevented by addition of surfactants as well as by increasing the hydrophilicity of the inner surface. Attempts based on covalent surface coating were mechanically not stable against the stress of roller movement. We successfully incorporated surface segregating smart polymers based on a polydimethylsiloxane (PDMS) backbone and polyethylene glycol (PEG) side blocks in the tubing wall matrix. For this we applied an easy, reproducible and cost-effective process based on soaking of tubing in toluene containing the PDMS-PEG copolymer. With this tubing modification we could drastically reduce protein particle formation during peristaltic pumping of a monoclonal antibody and human growth hormone (HGH) formulation in silicone and thermoplastic elastomer-based tubing. The modification did not impact the tubing integrity during pumping while hydrophilicity was increased and protein adsorption was prevented. Free PDMS-PEG copolymer might have an additional stabilizing effect, but less than 50 ppm of the PDMS-PEG copolymer leached from the modified tubing during 1 h of pumping in the experimental setup. In summary, we present a new method for the modification of tubings which reduces protein adsorption and particle formation during any operation involving peristaltic pumping, e.g. transfer, filling, or tangential flow filtration.

Biofarmácia , Hormônio do Crescimento Humano , Humanos , Peristaltismo , Dimetilpolisiloxanos , Polietilenoglicóis , Polímeros
J Pharm Sci ; 111(12): 3397-3410, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36096285


Product DRL is a generic IR tablet formulation with BCS Class-III API, available in two strengths: 50mg & 100mg. The reference and test formulations have salt-A & salt-B of API but both products were bioequivalent based on the in vivo bioequivalence study conducted for higher strength 100mg. While leveraging the generic product to different market, the reference product from other market showed slower release than generic formulation resulting in f2<50 in pH 6.8 for both 50mg and 100mg, because of which waiver for BE study couldn't be granted. To support f2 mismatch at 100mg, 50mg and to facilitate biowaiver of 50mg, a Gastroplus® PBBM model was developed & validated. Virtual bioequivalence trials were performed using the slower dissolution profile of other market reference. It was demonstrated that despite slower dissolution, bioequivalence was achieved for test product against other market reference for 50mg & 100mg strengths. Additionally, dissolution safe space was created using virtual dissolution profiles, which indicated that when >85% released up to 60 min there is no impact on bioequivalence. Overall, for molecules with permeability controlled absorption (i.e. BCS-III), very rapid dissolution criteria can be relaxed by defining dissolution safe space thereby enabling more waivers in future.

Biofarmácia , Biofarmácia/métodos , Solubilidade , Equivalência Terapêutica , Comprimidos/química , Permeabilidade
Mol Pharm ; 19(9): 3005-3006, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35983990

Pharm. care Esp ; 24(4): 6-22, ago 2022. tab, ^eanexo
Artigo em Espanhol | IBECS | ID: ibc-207456


Introducción: El servicio profesional farmacéutico asistencial de administración de medicamentos inyectables, tradicionalmente, se ha ofertado en farmacias comunitarias costarricenses. El objetivo de este estudio es describir la conceptualización y principales características del servicio profesio-nal farmacéutico asistencial de administración de inyectables en Costa Rica.Método: Estudio exploratorio y descriptivo realiza-do en 35 farmacias comunitarias del área metropo-litana de Costa Rica. Los datos se obtuvieron, me-diante encuesta presencial al regente farmacéutico, haciendo uso de un cuestionario diseñado para este fin y en cumplimiento de principios éticos.Resultados: Un 97,14% de las farmacias comu-nitarias entrevistadas ofrecen el servicio, mayori-tariamente demandado por parte de pacientes y conformes al protocolo específico del Colegio de Farmacéuticos de Costa Rica. Como parte de este servicio se administran medicamentos inyectables, derivados de los servicios de dispensación de me-dicamentos con receta y de indicación farmacéu-tica. Destacan medicamentos AINE administrados por vía intramuscular. Además, se destaca la rela-ción con el servicio farmacéutico en inmunización.Conclusiones: Se evidencia la importancia del servicio de administración de inyectables para el sistema sanitario costarricense y el desarrollo de los servicios farmacéuticos.(AU)

Introduction: The professional pharmaceutical care service of injectable drug administration has traditionally been offered in Costa Rican commu-nity pharmacies. The objective of this study is to describe the conceptualization and main charac-teristics of the professional pharmaceutical assis-tance service of injectable drug administration in Costa Rica.Methods: Exploratory and descriptive study was carried out in 35 community pharmacies in the metropolitan area of Costa Rica. Data were ob-tained by means of a face-to-face survey of the pharmacist regent, using a questionnaire designed for this purpose and in compliance with ethical principles.Results: 97.14% of the community pharmacies interviewed offer the service, mostly demanded by patients and in accordance with the specific pro-tocol of the College of Pharmacists of Costa Rica. As part of this service, injectable drugs are admin-istered, as well as drugs derived from prescription drug dispensing services and those with pharma-ceutical indications. NSAIDs administered intra-muscularly stand out. In addition, the relationship with the pharmaceutical service in immunization is highlighted.Conclusions: The importance of the injectable administration service for the Costa Rican health system and the development of pharmaceutical services is evidenced.(AU)

Assistência Farmacêutica , Serviços Comunitários de Farmácia , Injeções Intramusculares , Biofarmácia , Costa Rica
Pharm. care Esp ; 24(4): 23-42, ago 2022. tab
Artigo em Espanhol | IBECS | ID: ibc-207457


Introducción: la visibilidad de las Enfermedades Raras a nivel multidisciplinar y su humanización, son uno de los retos planteados en la Agenda 2030 de Naciones Unidas. El farmacéutico comunitario necesita renovarse y promover habilidades, como técnicas de atención farmacéutica individualizada, imprescindibles para el apoyo de estos pacientes. El objetivo de esta investigación es identificar las necesidades socio-sanitarias de las familias perte-necientes a asociaciones de enfermedades raras que acude a la farmacia comunitaria en España.Método: Estudio observacional y transversal me-diante cuestionario digital enviado a usuarios de la Asociación de Enfermedades Raras D ́genes, a través de la Asociación y de los Colegios Oficiales de Farmacéuticos, n=253.Resultados: las enfermedades raras se distribuyen por todo el territorio con una alta dispersión. La mayoría de pacientes o familiares suelen visitar la farmacia comunitaria más de dos veces al mes. Estas familias suelen confiar en su farmacia desde hace más de tres años y no encuentran dificultades para obtener su tratamiento. El perfil de los pacien-tes que acuden a la farmacia es muy heterogéneo, pero la mayoría de familiares afirman conocer y centrarse únicamente en sus necesidades sociosa-nitarias. En relación a sus niveles de satisfacción, el recibimiento, la discreción en el trato, el tiempo de atención y la despedida son los factores mejor valorados.Conclusiones: El profesional farmacéutico debe poseer, habilidades científicas y técnicas, necesita promover valores como empatía, habilidades socia-les o capacidad de escucha, para poder prestar una atención farmacéutica personalizada a familias con enfermedades raras y conseguir humanizar la farmacia comunitaria del siglo XXI.(AU)

Introduction: the visibility of Rare Diseases at a multidisciplinary level and their humanization are one of the challenges set out in the 2030 Agenda of the United Nations. Community pharmacists need to renew themselves and promote skills, such as in-dividualized pharmaceutical care techniques, which are essential for the support of these patients. The aim of this research is to identify the socio-health needs of families belonging to rare disease asso-ciations who go to the community pharmacy in Spain.Method: Observational and transversal study by a digital questionnaire to users of the Association of Rare Diseases D'genes, through the Associa-tion and the Official Associations of Pharmacists, n=253.Results: Rare diseases are distributed throughout the territory with a high dispersion. Most patients or relatives usually visit the community pharmacy more than twice a month. These families usually trust their pharmacy for more than three years and do not encounter difficulties in obtaining their treatment. The profile of the patients who visit the pharmacy is very heterogeneous, but the majority of family members claim to know and focus only on their social and health needs. In relation to their levels of satisfaction, the reception, discretion in treatment, time of attention and farewell are the best valued factors.Conclusions: The professional pharmacist must possess, scientific and technical skills, needs to promote values such as empathy, social skills or listening skills, to be able to provide personalized pharmaceutical care to families with rare diseases and manage to humanize the community pharma-cy of the 21st century.(AU)

Humanos , Farmácias , Doenças Raras , Assistência ao Paciente , Farmacêuticos , Biofarmácia
AAPS PharmSciTech ; 23(6): 203, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882674


Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results-RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators.

Bicarbonatos , Biofarmácia , Biofarmácia/métodos , Tampões (Química) , Química Farmacêutica/métodos , Concentração de Íons de Hidrogênio , Ibuprofeno , Fosfatos , Solubilidade , Comprimidos
AAPS PharmSciTech ; 23(6): 185, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35778639


Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro-in vivo correlation and to predict the oral bioavailability. The level C in vitro-in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro-in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process.

Biofarmácia , Modelos Biológicos , Animais , Simulação por Computador , Preparações Farmacêuticas , Solubilidade
J Pharm Sci ; 111(11): 3064-3074, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35787368


Donepezil hydrochloride (DH) is the most used anti-Alzheimer's disease drug, however, its classification according to the Biopharmaceutics Classification System (BCS) is not clear in the literature. BCS is one of the accepted criteria used to grant biowaiver (waiver of in vivo bioequivalence studies) of new drug products. So, the purpose of this work was to elucidate the BCS classification of DH and to raise the discussion about the possibility of biowaiver for new medicines containing it. The polymorphic form was previously identified as form III of DH. The drug showed high solubility in the entire pH range evaluated (1.2 to 6.8, at 37 °C) with a pH-dependent solubility profile. The effective permeability (Peff) values obtained with different DH concentrations, using in situ closed-loop perfusion model were statistically similar (p > 0.05), even when compared to high permeability control used (ketoprofen), demonstrating that DH has high permeability which, associated with its high solubility, allows to classify DH as BCS class 1. Relevant data to evaluate for granting a biowaiver for new medicines were also reviewed from the literature. Based on information reunited new immediate-release drug products containing DH should be eligible for BCS-based biowaiver.

Biofarmácia , Cetoprofeno , Donepezila , Permeabilidade , Solubilidade , Equivalência Terapêutica
J Pharm Sci ; 111(11): 3075-3087, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35830941


A dissolution-permeation system has potential to provide insight into the kinetic contributions of dissolution and permeation to overall drug absorption. The goals of the study were to characterize a dissolution-hollow fiber membrane (D-HFM) system and compare its resulting in vitro drug permeation constants (Kp') to in vivo clinical permeation constants (kp), for four drugs in various Biopharmaceutics Classification System (BCS) classes. Model predictions for D-HFM were made based on derived mixing tank (MT) and complete radial (CRM) flow models and independent measurement of membrane permeability. Experimental D-HFM studies included donor flow rate and donor volume sensitivity studies, and drug permeation profile studies. Additionally, for the four drugs, Kp'from D-HFM system was compared to (kp) from literature, as well as Kp' values from side-by-side diffusion cell and dissolution/Caco-2 system. Results show progressive D-HFM system development as a dissolution-permeation tool. Results indicated that D-HFM models using MT or CRM provided close agreement between predicted and observed drug permeation profiles. Drug permeation in D-HFM system was volume dependent, as predicted. Favorably, more drug permeated through the D-HFM system (10-20% in 60 min) compared to side-by-side diffusion cell (1%) and dissolution/Caco-2 system (0.1%). Kp' from D-HFM system was also closer to in vivo kp; the two other in vitro models showed lower Kp'. Overall, studies reflect that HFM module has potential to incorporate drug permeation into the in vitro assessment of in vivo tablet and capsule performance.

Biofarmácia , Absorção Intestinal , Biofarmácia/métodos , Células CACO-2 , Humanos , Permeabilidade , Solubilidade , Comprimidos
Lima; Perú. Ministerio de Salud; Jul. 2022. 58 p. Ilus.
Monografia em Espanhol | MINSAPERÚ | ID: biblio-1381899


El documento contiene los criterios técnicos y las condiciones sanitarias, mínimas y obligatorias, que deben cumplir las farmacias, boticas y las farmacias de los establecimientos de salud, pública y privadas, relacionados a los servicios de almacenamiento, dispensación, farmacovigilancia y, de ser el caso, de seguimiento farmacoterapéutico y de distribución y transporte

Biofarmácia , Registros , Boas Práticas de Distribuição