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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5937_Библиотеки_им_академика_М_И_Перельмана.pdf
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Contents
12.4 Suppository Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
12.4.1 Suppository Base Considerations . . . . . . . . . . . . . . . . . . . 188
12.4.2 Oleaginous Bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
12.4.3 Water-Soluble Bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
12.4.4 Other Excipients Used in Suppository Dosage Forms . . . . 192
12.4.5 Particle Size and Particle Settling During
the Preparation of Suppositories . . . . . . . . . . . . . . . . . . . . 193
12.4.6 Drug Release from a Suppository Base
and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
12.4.7 Storage and Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
12.5 Suppository Manufacture/Production . . . . . . . . . . . . . . . . . . . . . . 194
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
13 Pulmonary Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
13.2 Lung Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
13.3 Mechanisms of Particle Deposition . . . . . . . . . . . . . . . . . . . . . . . . 199
13.3.1 Particle Clearance and Dissolution . . . . . . . . . . . . . . . . . . 200
13.3.2 Inuence of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
13.4 Nebulizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
13.4.1 Jet Nebulizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
13.4.2 Ultrasonic Nebulizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
13.4.3 Vibrating Mesh Nebulizers . . . . . . . . . . . . . . . . . . . . . . . . 203
13.4.4 Nebulizer Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
13.5 Pressurized Metered Dose Inhalers . . . . . . . . . . . . . . . . . . . . . . . . 204
13.5.1 Device Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
13.5.2 Formulation Considerations of pMDIs . . . . . . . . . . . . . . . 207
13.5.3 Propellants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
13.5.4 Other Excipients Used in pMDIs . . . . . . . . . . . . . . . . . . . . 208
13.6 Dry Powder Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
13.6.1 Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
13.6.2 Mechanisms of Aerosolization (Particle Fluidization
and Redispersion). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
13.6.3 Device Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
13.6.4 Device Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
13.7 Analytical Methods for Pulmonary Drug Delivery Systems . . . . . 212
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
14 Nasal Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
14.2 Barriers for Nasal Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . 216
14.3 Excipients Used in Nasal Formulations . . . . . . . . . . . . . . . . . . . . . 217
14.4 Methods and Devices for Nasal Administration . . . . . . . . . . . . . . 218
14.5 Nasal Device Performance Testing . . . . . . . . . . . . . . . . . . . . . . . . 219
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Contents
15 Drug Product Design and Delivery of Biologics . . . . . . . . . . . . . . . . . . 221
15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
15.2 Production of Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
15.3 Formulation of Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
15.4 Devices for Administration of Biological Products
and Performance Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
15.5 Characterization and Performance Testing of Biologics . . . . . . . . 228
15.6 Biosimilars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Futher Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
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About the Authors
Ashlee D. Brunaugh is an assistant professor at the University of Michigan
College of Pharmacy in the Department of Pharmaceutical Sciences. She is also the
President/CEO of CloXero Therapeutics Inc and a scientic advisor for Via
Therapeutics LLC. Dr. Brunaugh holds both a Pharm.D. and a Ph.D. degree in
Pharmaceutical Sciences from the University of Texas at Austin. Upon completing
her education, she worked as a senior scientist and later Director of Strategy and
Operations at Via Therapeutics, a pharmaceutical start-up located in Austin, TX,
focused on the bridging of novel drug delivery systems from the preclinical to clinical stages of development. In 2021, she joined the faculty at the University of
Michigan. Dr. Brunaugh’s research is focused on the elucidation of the underlying
mechanisms for respiratory disease progression to determine appropriate therapeutic targets and develop novel formulation and drug delivery approaches to improve
patient outcomes. In addition to her research experience, Dr. Brunaugh is a registered pharmacist and has experience practicing in hospital, community, and clinical
trial settings. She has several years of experience in teaching pharmaceutical science courses at the undergraduate and graduate level, including the development
and implementation of a ipped-classroom basic pharmaceutics course with Drs.
Smyth and Williams at the University of Texas at Austin College of Pharmacy.
DanielMoraga-Espinoza is a pharmacist from Universidad de Valparaíso, Chile
(2010), and completed a Ph.D. in Molecular Pharmaceutics and Drug Delivery
(MPDD) at the University of Texas at Austin, USA (2018). Presently, Dr. MoragaEspinoza holds the position of Assistant Professor at Universidad de Valparaíso,
serves as an adjunct professor at the University of Texas at Austin, and works as an
associate researcher at the Chilean Pharmacopeia Research Center. His primary
research focus lies in the eld of drug delivery into the lungs and the nasal cavity
through controlled release systems. He has published multiple research articles,
reviews, book chapters, and patent applications. Additionally, he is member of the
editorial boards of the scientic journals Drug Development and Industrial
Pharmacy (DDIP) (2018) and AAPS PharmSciTech journal (2018). Dr. Moraga was
the recipient of the Grant FONDECYT de iniciación 11190987 for young
xiii
xiv
About the Authors
researchers, honored as one of the leading research innovators by BRAIN Chile
(2023), and serves as a regulatory consultant for the Chilean regulatory agency,
contributing to the development of guidelines for the evaluation of orally and nasally
inhaled drug products.
Tania F.Bahamondez-Canas is a pharmacist from Universidad de Valparaiso,
Chile (2010), and holds a Ph.D. from the University of Texas at Austin, USA (2018).
She is an associate professor at Universidad de Valparaiso, Chile, an academic position sponsored by the Chilean Agency of Research and Development (ANID) with
the grant PAI 77190010 (2019). She is also an adjunct professor of the Ph.D. program in Molecular Pharmaceutics and Drug Delivery at the University of Texas at
Austin, USA.She has teaching experience in various programs from the College of
Pharmacy of Universidad de Valparaíso, including undergraduate pharmacy, master's, and continuing education programs. She is the Director of the Chilean
Pharmacopeia Research Center (CIFAR) at Universidad de Valparaíso and PI of the
Antimicrobial Pharmaceutics laboratory focusing on novel drug delivery systems to
effectively ght bacterial biolm infections. She has published multiple research
articles, reviews, book chapters, and patent applications. Her work on biolm infections and tissue engineering in chronic wounds was funded by the ANID grants for
young researchers FONDECYT 11190348 (2019) and applied sciences FONDEF
ID19I10028 (2019) and FONDEF ID21I10153 (2021), and was recently awarded
by the Chilean regulatory agency (ISP).
HughD.C.Smyth is the Alcon Centennial Professor, with tenure, in the Division
of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of
Texas at Austin. Dr. Smyth oversees multidisciplinary laboratory funded by NIH,
FDA, and industry that focuses on engineering new drug delivery systems with an
emphasis on drug delivery to the airways. He has over 350 published works. Dr.
Smyth is editor of four books and is an inventor on numerous patents or patent
applications. He has a Pharmacy and a Ph.D. degree from the University of Otago,
New Zealand. Dr. Smyth has worked as a practicing pharmacist and a scientist in
industry and has received training in several academic settings. He has been faculty
at the University of North Carolina at Chapel Hill and the University of New
Mexico. He was the American Association of Pharmaceutical Scientists (AAPS)
New Investigator award winner for Pharmaceutics and Pharmaceutical Technologies
in 2007. He also received the PhRMA Foundation New Investigator Award in pharmaceutics in 2007. He gave the DDL Annual Lecture in 2022. He was the Editor-inChief of Drug Development and Industrial Pharmacy from 2014 to 2022. Dr. Smyth
has started several companies resulting from technologies discovered in his laboratory which are now advancing these technologies for clinical use.
RobertO. Williams Bill Williams is the Johnson & Johnson Centennial Chair
and Professor of Pharmaceutics and the Division Head of Molecular Pharmaceutics
and Drug Delivery at the College of Pharmacy, University of Texas at Austin. He
earned a B.S. in Biology from Texas A&M University, a B.S. in Pharmacy from the
About the Authors
xv
University of Texas at Austin, and Doctor of Philosophy in Pharmaceutics in 1986
from the University of Texas at Austin. Dr. Williams was elected Fellow of the
American Association of Pharmaceutical Scientists in 2006, Fellow of the American
Institute of Medical and Biological Engineering in 2008, and Fellow of the National
Academy of Inventors in 2019. He was named the Inventor of the Year by the
University of Texas at Austin in 2017. He has been a member of the American
Association of Pharmaceutical Scientists (AAPS) since its inception, as well as
other professional societies including the American Association of Colleges of
Pharmacy. He is the co-founder of several pharmaceutical companies. He has published over 500 peer-reviewed research articles, reviews, abstracts, and book chapters and co-edited four books in the eld of pharmaceutical technology and drug
delivery, including Formulating Poorly Water-Soluble Drugs, Third Edition (AAPS
and Springer). He is an inventor on over 60 patents and patent applications. Dr.
Williams is the Editor-in-Chief of AAPS PharmSciTech since 2014. He is on the
Editorial Advisory Board of Journal of Drug Delivery Science and Technology, and
he serves as a reviewer for numerous other journals.
Chapter 1
Essential Pharmaceutics intheFlipped
Classroom
Abstract This chapter provides a guide on how to implement a ipped classroom
model into a pharmaceutics course. Course design, daily class organization, strategies for student success, and how to implement prereading materials (specically
this text) are discussed in detail.
Keywords Case studies · Pharmaceutical education · Flipped classroom ·
Problem-based learning · Teaching methods · Active learning · Information literacy
“Essential Pharmaceutics,” as the name implies, provides students in clinical and
research areas of the pharmaceutical sciences, including PharmD and PhD students,
with the critical concepts and knowledge foundation as a part of their pharmaceutics
training. These essential concepts are complemented by additional materials and
applications in our “ipped” pharmaceutics course, the design and implementation
of which is explained below.
The rst edition of this book was developed over several years as an accompaniment
to the ipped-classroom pharmaceutics course taught by Professors Hugh D.C. Smyth
and Robert O. (Bill) Williams III at the University of Texas at Austin College of
Pharmacy (UTCoP). Following 2years of planning and preparation, and with input
from educational and instructional experts, in the Spring of 2014, the “Pharmaceutics”
course within the UTCoP PharmD curriculum was restructured from a conventional
lecture-based content delivery to a ipped instruction, team- based, classroom model.
This second edition of Essential Pharmaceutics has now incorporated nearly 10years
of experience and valuable feedback received during the delivery of the course to over
one thousand PharmD and graduate students in the pharmaceutical sciences.
So, what does a “ipped class” mean in terms of a pharmaceutics course? In
short, it emphasizes the application of facts, foundational knowledge, information
literacy skills, and team-based learning to the solving of real-world drug delivery
and formulation science problems. Students leave our course with an understanding
of pharmaceutics that goes beyond rote memorization of facts and in parallel
develop the critical thinking and communication skills necessary to become leaders
in pharmacy practice, clinical, industry, and academic settings.
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_1
1© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
2
This textbook, Essential Pharmaceutics, provides the cornerstone of our ipped
classroom approach and provides the basis of students’ preclass readings, which
prepares them for in-class applications and in-depth utilization of these basic concepts and principles. This approach can be applied successfully in universities
around the world. In our own experience, we have found that the incorporation of
this text has been an invaluable asset in promoting student understanding of key
concepts and ensuring the success of the ipped classroom model as applied to
pharmaceutics.
1 Essential Pharmaceutics intheFlipped Classroom
1.1 Overview of“Flipped Pharmaceutics” Course Format
andStructure
Team-based learning and the development of effective communication skills are
critical components to the ipped pharmaceutics course. Prior to the beginning of
the semester, students enrolled in the pharmaceutics course are randomly assigned
to ve-member permanent teams, with whom they continue working through the
duration of the course. These teams are encouraged and expected to operate in a
format similar to a project team meeting or board meeting, in which students are
expected to respectfully acknowledge the input and differences of opinion from
other team members, challenge teammates in a professional manner, and engage in
concise and compelling communication, with the expectation that their position is
backed with facts, not opinions.
Our course is structured as a series of modules, each of which is focused on an
aspect of pharmaceutics and dosage form design. The chapters of this book are
based upon these modules and are intended to provide students with an understanding of the foundational concepts that they will need in order to successfully complete the real-world case studies assigned in the classroom. Generally, the semester
proceeds in the following manner:
1. Preclass reading assignment: Students are assigned factual-based content 1week
before attending class (referred to as the “Pre-class Reading Assignment”). The
prereading assignment consists of reading a prescribed chapter from this book
and answering specic questions on key concepts. Occasionally, other assigned
relevant peer-reviewed original research and review papers from the literature
are also included in the preclass reading assignment to supplement the book and
also introduce students to a diverse range of information sources relevant to
pharmaceutics. Accordingly, the purpose of this book is to provide the essential
facts related to dosage form design and drug delivery that provide the necessary
foundational knowledge for students to successfully engage in the in-class realworld case study assignments.
2. Readiness assessment quiz: Once the students have completed the Pre-Class
Reading Assignment, they should have acquired foundational knowledge prior
to class. Student readiness assessment quizzes are administered at the beginning
1.1 Overview of“Flipped Pharmaceutics” Course Format andStructure
of class and assess the students’ knowledge of the key concepts covered by these
preclass readings. Grades obtained by students in these assessments count
toward their nal grade, which provides an incentive to complete the prereading
assignment prior to the class.
3. Cumulative exam assessments: Instead of having two or three high-stake major
exams during the semester, we have recently implemented an innovative assessment tool. In our class, the Cumulative Exam is made up of a series of 11 individual tests covering each module (e.g., each technical chapter in this book) and
made up of questions covering only the prior week’s case studies. The Cumulative
Exam is administered by electronic exam software and is given at the beginning
of each class period. These 11 Cumulative Exams represent 100% of the student’s grade for their major exam, which the student has accumulated along the
way (Explanation: Each one of the 11 Cumulative Exams represents 9.09% of
the total Cumulative Exam, so 11×9.09%=100%). We also implemented an
alternative assessment strategy in which students can individually choose to take
an Optional Final Exam for any reason at the end of the semester, which replaces
their Cumulative Exam grade. The Optional Final Exam is cumulative and made
up of questions that cover all materials from the entire semester, including prereadings, mini-lectures, and case studies.
4. In-class team based learning: Class time is then focused on the strategic applica-
tion of the pre-class reading assignments through practical, hands-on activities.
All teams are required to complete two research-based drug product design
assignments (referred to as “case studies”). Fifty-ve minutes are allotted for
each assignment, and a 55-min countdown clock helps keep the teams aware of
the time remaining. To successfully complete the assignment, groups are required
to utilize a variety of online information resources in order to answer a series of
analytical questions. During the time allotted for each case study, faculty, graduate student teaching assistants, and experienced PharmD student assistants (these
are PharmD students who already passed the course and are funded through an
Academic Assistant position) continuously interact and engage the teams to
facilitate learning (our student:instructor ratio is typically no more than 15:1). At
various points during the case study, the countdown clock is stopped and faculty
deliver two or three mini-lectures consisting of 2–3 slides each on different technical/scientic aspects of the case study, thus linking the student’s prereading
class assignments (facts) to the case study (applying facts to concepts).
3
1.2 Building theRequired Foundation forStudent Success
in“Flipped Pharmaceutics”
Implementation of our model required input and coordination with faculty across
the PharmD curriculum at the University of Texas at Austin. Incoming students to
our ipped pharmaceutics course are in the second semester of their rst year of the
4
1 Essential Pharmaceutics intheFlipped Classroom
Fig. 1.1 The ipped pharmaceutics course is strategically placed in the PharmD curriculum to
ensure students have the necessary foundational knowledge and critical thinking skills to achieve
success in class. The source for foundation facts, information literacy skills, and communication
skills is color coded according to the prerequisite courses offered in the immediately preceding
Fall semester of the PharmD rst year
PharmD program. By this point in the curriculum, students have completed a number of foundational courses that are crucial in laying the groundwork for the topics
covered in the ipped pharmaceutics course (Fig.1.1). We mapped each of these
prerequisite courses to conrm that students would have the necessary background
before beginning our ipped class. We also note that the placement of our course in
the curriculum is such that the students have not yet completed their second semester of Physiology/Pathophysiology and Pharmaceutical Biochemistry, which take
1.2 Building theRequired Foundation forStudent Success in“Flipped Pharmaceutics”
5
place concurrently with this pharmaceutics course in the spring semester of year
one of the PharmD program. We, thus, strategically structure our ipped course
content such that the students are assured to have covered a specic topic before it
is used in class (e.g., we ensure that anatomy of the eye is covered outside our
course prior to the introduction of ophthalmic drug products).
As the ipped pharmaceutics course has evolved over the past 10years, we have
come to understand that student acquisition of the necessary information literacy
skills prior to beginning our course is a key component to ensuring student success.
In-class activities require extensive utilization of primary literature, patents, databases, etc. This information is analyzed by students in teams, already armed with the
knowledge obtained from concepts provided in this book. Extensive work conducted
by PharmD/MSc student Natalia Malesa as part of her master’s thesis revealed that
integration of information literacy training in coursework prior to the start of ipped
pharmaceutics increased student performance of the course, as student perception of
their own information literacy abilities. In response to these ndings, faculty have
incorporated an introduction to these information literacy skills in the “Introduction
to Pharmacy Practice” course that students complete in the rst Fall semester of
their rst year. Through this course, students gain experience using bibliographic
databases for biomedical research, including Google Scholar, PubMed/MEDLINE,
ScienceDirect, and Web of Science. With assistance from a pharmacy subject specialist librarian, students learn optimal search strategies for these databases, such as
the utilization of Medical Subject Headings (MeSH). Students are also instructed in
how to locate tertiary resources and how to appropriately cite references. In our
ipped pharmaceutics course, we continue to build these information literacy skills
by introducing search strategies that are more specic to drug products, including
the use of patents, the US Pharmacopeia/National Formulary Online, drug substance
databases (e.g., TOXNET, Reaxys), medication package inserts, and FDA resources
including the Orange Book and the Inactive Ingredients Database. With assistance
from The University of Texas at Austin library system, we have designed a course
web portal that contains links to each of these resources, in addition to guides on
how to use each database, how to read US patents, and how to appropriately cite
references, and it is located here: https://guides.lib.utexas.edu/pharmacy/pharma-
ceutics. Students utilize these resources in class and beyond, with many students
reporting years later to us how helpful the web portal is throughout the PharmD
curriculum. Overall, the information literacy skills that are developed in ipped
pharmaceutics become invaluable to our students as they progress through the curriculum and begin work in clinical and industry settings.
1.3 Achieving Learning Objectives
Learning objectives for the ipped pharmaceutics course at UTCoP were initially
designed and are regularly updated to reect PharmD accreditation standards in the
United States. For example, learning objectives in our course were recently updated