7. 2023-07-10 7
Hutera
기존 탈모치료제인 ‘두타스테리드’ 약물을 탑재한 개량 신약
두피 국소도포에 따른 기존 경구용 치료제의 부작용을 최소화
약물의 전달 효과 극대화하여 기존치료제의 복약 순응도를 개선
DDS 기술인 나노-마이크로버블 기술 적용
약물을 LNP을 봉입 → 적은 양으로도 모낭에 전달될 수 있도록 제형 설계
LNP에 약물을 탑재한 마이크로버블은 초음파 자극에 의해 두피에 미세 구멍을
뚫고 탈모치료 약물을 진피에 위치한 모낭 세포까지 전달
미세구멍이라 전혀 통증이 없으며 단 3분만에 효과적으로 치료물질을 전달
Biomaterials에 논문 보고를 통한 검증 완료
효과적인 모낭 세포 침투 효과를 확인
14. 2023-07-10 14
진피 투과 효과
파란 막대 : 표피층에 전달된 약물의 양
주황색 막대 : 진피층에 전달에 약물의 양
두피의 모낭은 진피에 위치 → 주황색막대 수치 중요
경구투여에 비해 약 20배 높은 진피 약물전달 효율
혈중 농도
경구용 투여 약물 대비 1% 수준의 낮은 혈중 농
→ 체내 DHT 생성에 최소한의 영향
→ 부작용 최소화 [간, 환 등에 존재하는 환원효소(5α –reductase) 영향 최소화
→ 부작용이 거의 없음 증명
효능 시험 통해 인체 용법/용량 추정
매주 1~2회 도포, 단 3분의 처치 → 경구투여약물의 복약순응도를 대폭 개선 예측
Animal Efficacy Test III
34. 2023-07-10 34
Mechanism of Action
Tyrvaya is believed to activate a pathway originating in the nose that is responsible
for tear film production, signaling the body to produce more natural tears
48. 2023-07-10 48
Episil
스웨덴 Camurus : FluidCrytal 기술 적용
FDA : ‘항암 화학요법 또는 방사선치료에 의해 유발 구강 병변 통증관리와 완화
에피실 6가지 주요 성분인
글리세롤 디올리에이트 /포스파티딜콜린 /에탄올 /PG / Tween80 /페퍼민트 오일
상처 부위에 사용 시 소량의 수성 유체를 흡수하여 겔로 변형
→구강 내 물리적인 보호막을 형성하여 창상 보호
생성된 물리적인 보호막은 외부 접촉으로부터 환부 보호
52. 2023-07-10 52
iLet Bionic Pancreas : History of development
FDA : Beta Bionics사 자동 인공 췌장 iLet Bionic Pancreas 승인
iLet Bionic Pancreas
-6세 이상 1형 당뇨병 적응증으로 승인된 연속혈당측정기(CGM)와 함께 구동되는
소프트웨어시스템
Beta Bionics iLet ACE pump + iLet 투약 결정 소프트웨어 장착
기존 인공췌장(closed-loop system)
환자가 인슐린 양과 시간 입력
iLet Bionic Pancreas는 처음에만 체중을 입력
→혈당 정보를 학습해 환자에게 맞는 인슐린 양이 자동으로 투여
iLet Bionic Pancreas 유효성 : NEJM(2021.09)
13주 동안 표준치료군과 비교군을 비교 연구
평균 당화혈색소(A1C)를 7.9% 에서 7.3%로 감소( CI : -0.6~-0.3, P<0.001)
평균 목표혈당범위(70~180mg/dL) 시간
표준치료군 : 11% 증가 → 하루에 2.6시간에 해당 수치
고혈당(180mg/dL 이상)과 중증 고혈당(250mg/dL 이상) 유지시간 현저하게 감소
53. 2023-07-10 53
iLet Bionic Pancreas
A bionic pancreas—a wearable, pocket-sized, automated insulin delivery device—that was first
developed in a Boston University lab has been cleared by FDA
The iLet Bionic Pancreas is now commercially available, bringing fresh hope to the almost two
million Americans with type 1 diabetes
The approval is a massive milestone in a two-decade—and deeply personal—journey
Invented 20 years ago in the lab of Ed Damiano, a BU College of Engineering professor of
biomedical engineering, the bionic pancreas combines an insulin infusion pump with
algorithm-controlled dosing decision software
Damiano was inspired to develop the system by his son, who was diagnosed with type 1
diabetes when he was just 11 months old
When paired with a Bluetooth-enabled glucose monitor, the iLet can deliver tailored insulin
doses every five minutes, based on calculations of current and past glucose levels and the
body’s reaction to past insulin deliveries
Small enough to be clipped on a bra strap or thrown in a pocket, the iLet means patients will
no longer have to constantly measure their glucose levels and calculate, with help from their
doctor, their correct insulin dose—a 24/7 endeavor
The iLet was cleared for people aged six years and older with type 1 diabetes
54. 2023-07-10 54
iLet Bionic Pancreas
For most of his son’s early life, Damiano and his partner would wake every few hours in the
night, checking their son’s blood sugar levels, giving him insulin or juice to control the numbers
In people with type 1 diabetes, the pancreas doesn’t produce enough insulin—an essential
hormone for converting and storing sugars
The chronic condition carries a host of complications, from heart disease to eye damage
There’s no cure
Back in 2013, nearly a decade into the bionic pancreas’ development, Damiano talked with
Bostonia about the fear and panic of those nighttime checks—which often started with making
sure his son was still warm, still breathing
“Sleeping is the scariest part of all this,” he told Bostonia
“It’s what put this project on a high-speed rail
It’s a very scary prospect that blood sugars could go low at night
When you’re sleeping, you’re checked out—you don’t want to check out permanently”
55. 2023-07-10 55
iLet Bionic Pancreas
In 2015, Damiano cofounded Beta Bionics, a public benefit corporation, to advance the
technology; four years later, the company raised $126 million to push the device through the final
stages of its development
Given the iLet’s origins—and Damiano’s very personal motivation for ensuring its success—the
FDA’s approval came on a fitting date
“This milestone is particularly poignant to me as the news of FDA clearance coincided with the
24th birthday of my son, David, who developed type 1 diabetes as an infant, just over 23 years
ago,” says Damiano, founder and executive chairman at Beta Bionics
David graduated summa cum laude from BU in 2021, double majoring in history and
international relations. He’s now a researcher at a documentary and feature film production
company.
“Sleeping is the scariest part of all this,” he told Bostonia
“It’s what put this project on a high-speed rail
It’s a very scary prospect that blood sugars could go low at night
When you’re sleeping, you’re checked out—you don’t want to check out permanently”
63. 2023-07-10 63
A body-worn sensor (left) transmits glucose levels
via Bluetooth every 5 minutes to the iLet Bionic
Pancreas (lower right)
Algorithms on the iLet compute the insulin dose,
and the iLet's pumping mechanism administers it
through tubing and an infusion set (right of navel)
The infusion set contains a tiny cannula that
inserts just under the skin, and insulin is infused
through the cannula into the subcutaneous tissue
(not intravenously)
This closed-loop sequence repeats every 5 minutes,
or 288 times a day
iLet Bionic Pancreas
68. 2023-07-10 68
팩펜트 나잘스프레이 국내 출시
다양한 컨디션에 있는 암환자들의 돌발성 암성통증 관리에 맞춤형 치료옵션
팩펜트 나잘스프레이 100 mcg과 400 mcg 출시 (2020년 9월)
PecSysTM technology
Pectin (gelling agent)가 비강점막 내 칼슘이온과 작용
→ 점막에 부착되어 약물의 흘러내림(dripping) 개선
→ 펜타닐이 빠르게 흡수되면서도 최고 혈중 농도를 감소
→ 부작용의 위험 감소
기존 타사 나잘 스프레이 대비 용기(device)가 혁신적으로 개선
투여가 용이하도록 날개형 헤드
시험분무 후 사용 시점을 시각적으로 확인
투여 시 클릭소리와 함께 횟수가 표시
→약물 투여 확인가능 →약물 오남용 위험 줄임
75. 2023-07-10 75
활동성 간질 환자 : 수 천만 명
발작 증세 초기에 빠르게 대처할 수 약물 필요
FDA : 3D 프린팅 기술로 제조된 빠르게 용해/흡수 작용하는 약물(Spritam®, Aprecia
Pharmaceuticals)허가
간질 환자들은 발작 시 빠르게 약물을 통해 진정시켜야 주어야 하는데 정제 는 크고
삼키기가 어려워서 간질 환자에게 적합하지 않음
3D 프린팅 기술로 고용량 (최대 1000mg)의 약물(levetiracetam)이 입 안에서 빠르게
(몇 초 안에) 녹아 투여되도록 제조
기존의 molding 기술 또는compression기술로 제조되지 않고, 적층(layer-by-layer)
방식으로 제조된 다공성의 약물 제형
가루형태의 약물을 powder jet 3D print로 분사
→액체 바인더 방울를 통해 가루 형태의 약물을 뭉치게 하여 얇은 박막을 형성
→원하는 만큼의 약물을 추가적으로 적층 하여 프린트
Spiritam
76. 2023-07-10 76
SPRITAM is an oral prescription flash-dispersing medication that is approved for the treatment of
certain types of epileptic seizures
SPRITAM is the first and only medicine made using 3D printing
You may find that SPRITAM is surprisingly easy to take
SPRITAM, administered with a sip of water, was shown to have equivalent rate and extent of
absorption to KEPPRA® (levetiracetam) immediate release tablets
SPRITAM is a different form of levetiracetam
Levetiracetam is a medication that patients with epilepsy and their healthcare providers have
relied on for more than 15 years
A different form of levetiracetam, a trusted medicine for epilepsy
Spiritam
81. 2023-07-10 81
Advantages of Power-Liquid 3DP Manufacturing
for Fast Melt Technology
Rapid dispersion at high loads
Powder-liquid 3DP overcomes the limitations of existing ODT technologies to produce a
high dose fast melt pharmaceutical product that disperses in seconds with a sip of liquid
Through thoughtful selection of materials and parameters for the 3DP manufacturing
process, dosage forms are designed and built with a porous structure that allows quick
ingress of liquid, which then breaks the particle-to-particle connections created during
the 3DP process
This loss of structure results in rapid dispersion in the mouth within seconds when
taken with a sip of liquid, even at high dose loads
Versatile taste masking
Powder-liquid 3DP enables a wide range of taste masking options, such as direct
masking with sweeteners and flavors, creating chemical complexes to bind the API and
using particle-level coating or encapsulation to sequester the active ingredient while it is
in the mouth
82. 2023-07-10 82
Advantages of Power-Liquid 3DP Manufacturing
for Fast Melt Technology
Broad application
3DP technology has significant flexibility in the range of materials it can accommodate
and will have an important impact on the fast-melt pharmaceutical market
Other features may be added to complement the fast-melt functionality, such as inclusion
of multiple active ingredients or extended-release of API over time
Flexibility in product development
3DP technology offers the innovation of an automated process that does not require any
molding or tooling for production, with designed placement of liquid droplets throughout
the structure according to a blueprint for each strength of product
This approach enables flexibility during product development, particularly for the
refinement of the product dimensions and for the degree of binding and porosity
The following table provides a comparison of currently available fast melt technologies
based on key performance criteria
84. 2023-07-10 84
WHAT IS ZIPDOSE TECHNOLOGY?
ZipDose® Technology is a drug-formulation platform designed to produce rapidly
disintegrating forms of highly prescribed medications
It is the first and only platform that uses 3D printing to make medications
91. 2023-07-10
Illustration of the fentanyl Separated System
with Enhanced Controller and drug unit
(A)Controller and drug unit prior to assembly
(B) Assembled fentanyl SSEC system
(C) Fentanyl SSEC user interface
SSEC: Separated system with enhanced
controller
95. 2023-07-10
Dosage
IONSYS (see Figure 1A) is for use only after patients have been titrated to an acceptable level of
analgesia using another opioid analgesic
Apply one IONSYS to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest
or upper outer arm ONLY
IONSYS provides a 40 mcg dose of fentanyl per activation
It is important to instruct patients how to operate IONSYS to self-administer doses of fentanyl as
needed to manage their acute, short-term, postoperative pain
Allow only the patient to self-administer doses of IONSYS. Each on-demand dose is delivered over
a 10-minute period
To initiate administration of IONSYS, the patient must press and release the button twice within 3
seconds
One single audible beep indicates the start of delivery of each dose
The green light will start blinking rapidly and the digital display will alternate between a walking
circle and the number of doses delivered
When the 10-minute dose is complete, the green light will blink at a slow rate and the display will
show the number of doses delivered (see Figure 1B)
96. 2023-07-10
A maximum of six 40-mcg doses per hour can be administered by IONSYS
The maximum amount of fentanyl that can be administered from a single IONSYS over
24 hours is 3.2 mg (eighty 40-mcg doses)
Each IONSYS operates up to 24 hours or 80 doses, whichever comes first
Use one IONSYS at a time for up to 24 hours or 80 doses, whichever comes first
IONSYS may be used for a maximum of 3 days (72 hours) of therapy for acute
postoperative pain, with each subsequent IONSYS applied to a different skin site
After the 24 hours have elapsed, or 80 doses have been delivered, IONSYS will not deliver
any additional doses
The light and audible beep will not function
The digital display will continue to show the number of doses delivered for an additional
12 hours
If the patient tries to initiate a dose, IONSYS will ignore the dose request
Dosage
98. 2023-07-10
Preparation Of Patient Site
Choose healthy, unbroken skin on the upper outer arm or chest ONLY
IONSYS may only be applied to one of the three sites shown in Figure 2
Administration sites - Illustration
Clip excessive hair if necessary. Do not shave as this may irritate skin
Clean the site with alcohol and let it dry. Do not use soaps, lotions, or other agents
99. 2023-07-10
Open the tray by peeling back the tray lid (see Figure 3a)
Remove the foil (drug) pouch and the Controller
Open the pouch containing the Drug Unit starting at the pre-cut notch and then carefully
tearing along the top of the pouch
Remove the Drug Unit from the pouch and place on a hard, flat surface
Align the matching shapes of the Controller and the Drug Unit (see Figure 3b)
Press on both ends of the device to ensure that the snaps at both ends are fully engaged
(see Figure 3c)
You should hear one or two clicks when the snaps are fully engaged (see Figure 3d)
Once assembled, the digital display of the Controller will complete a short self-test during
which there will be one audible beep, the red light will blink once, and the digital display
will flash the number “88”
At the end of the self-test, the display will show the number “0” and a green light will
blink at a slow rate to indicate IONSYS is ready for application (see Figure 3e)
Assembly Of IONSYS
116. Adlarity Vs Donesiv
아이큐어가 세계 최초로 도네페질 패치허가 이후 Corium 개발 치매 패치제 미국에서 허가
아이큐어도 미국 임상 허가 / 코리움 허가에 따라 두 회사 격차 벌어짐
일주일간 효능 유지
2022.04 미국 임상 1상 허가 → 미국 허가 시점 2025년 예측→ 허가 시점 격차 3년
아이큐어 제품은 주 2회 부착으로 코리움 제품과 차이
Patch Size
아이큐어 : 25 ㎠ / 50 ㎠ Vs 코리움 : 94 ㎠ /180 ㎠
사이즈가 커질수록 부착된 패치가 울거나 할 수 있어 사용상의 문제가 발생 할 수 있음
1주일 부착 제품의 편의성은 높을 수 있지만, 피부 안정성이 떨어질 가능성 예측
121. Microneedle Patch – Attractive Delivery Solution
Avoids first-pass effect associated with oral dosage forms
Effective alternative to injection without needlestick injury and needle phobia
Eliminates cold chain storage and distribution
Convenience of self-administration
Increases patient compliance
122. Zosano Microneedle Patch System – Key Feature
Drug-coated solid microneedles
Unit dose patch applied with a reusable applicator
Single step therapeutic drug delivery
Short patch wear time (30 min)
Band-Aid like patch removal and disposal
Rapid drug delivery
Room Temperature stability
Low bioburden manufacturing
128. Treatment of Acute Migraine: Unmet Need
A leading cause of disability
Est. 36 MM Americans affected
Ranks among the top ten causes of disability worldwide
Triptans as first-line acute treatment for moderate-to-severe migraine
Currently available dosage forms less optimal
Oral tablet/Orally disintegrating tablet
: slow absorption exacerbated by migraine related nausea, vomiting, gastroparesis
Nasal sprays
: absorption not fast enough, significant portion absorbed through the
gut, poor palatability
SC injectables
129. Why Zolmitriptan Microneedle Patch?
Effective alternative to SC injection
Circumvents absorption issues of oral route due to migraine related symptoms
No unpleasant taste or smell like nasal sprays
Zolmitriptan
Approved in the US
No injectables available
A potent triptan with dosages well-suited topatch size and manufacturing capability
135. Pivotal Study Results – Primary End Points
Figure 1. Primary Endpoints
Proportion of patients who were (A) pain-free or (B) free of their most bothersome other symptom at 2 hours post-dose
138. Conclusion
Zosano microneedle patch delivery technology presents better alternative to oral
and parenteral routes
Suitable for diverse therapeutic compounds both small and large
Capable of rapid systemic delivery with fast onset and high bioavailability
Well accepted by patients
Room temperature stability
Scalable manufacturing
139. Zosano goes bankrupt after FDA rejects migraine
drug delivery patch
After working to find a strategic alternative in the wake of the FDA’s refusal to review
its submission, the transdermal drug delivery specialist has now filed for paperwork for
Chapter 11 bankruptcy
California-based Zosano has worked in recent years to win approval for a patch that
uses microneedles to deliver the selective serotonin receptor agonist zolmitriptan
through the skin
By delivering the drug transdermally, rather than via the typical oral route, Zosano
sought to accelerate absorption and thereby improve the treatment of migraine
However, the company received a frosty reception from the FDA
The agency issued a complete response letter in 2020 and then refused to review
Zosano’s resubmission earlier this year
Zosano responded by making two rounds of layoffs and suspending the program
The cuts bought Zosano time as it sought to find a financial or strategic alternative
Having seen its cash reserves dip below $10 million last month, Zosano is now out of
time
The lack of a company-saving deal has led Zosano to the bankruptcy court
144. 2023-07-10 144
ROPERMA® : KEY BENEFITS
1. Enteris BioPharma is a pioneer in the formulation of BCS III & IV compounds, including small molecules
and peptidomimetics that suffer from challenging solubility and permeability characteristics resulting in
poor oral bioavailability
2. ProPerma® oral formulation technology utilizes several patented oral bioavailability enhancement
techniques, using a variety of conventional pharmaceutical formulation methods and pharmaceutical
excipients
3. The technology delivers valuable formulation exclusivity through its robust IP protection in the U.S.
4. We do not offer a single off-the-shelf technology but work collaboratively with our partners to develop
formulations that are specifically bespoke and optimized for our partners’API
5. Manufacturing process is a highly scalable and straight forward procedure that uses methods such as dry
blend and direct compression, to produce dosage forms that readily satisfy in-process controls and release
testing
6. Formulation technologies have and continues to prove itself as a safe, effective technology that has been
reduced to practice in over 15 clinical studies
145. 2023-07-10 145
MECHANISM FOR ORAL DRUG DELIVERY
ORAL SMALL MOLECULE DELIVERY CHALLENGES
Solubility or dissolution with limited absorption
Poor permeability due to interaction with efflux transporters or other mechanisms
151. 2023-07-10 151
Peptelligence Overview
Formulation technology that enables oral delivery of many peptide and small molecules that
have poor permeability across the gut
Peptides are generally not bioavailable with oral administration as they are degraded in the
digestive tract
Applicable to New Molecular Entities as well as reformulations of existing molecules
Combines two key active excipients that solubilize API and enhance cross membrane transport
Over 1,500 patients have been dosed with drugs that utilize the technology with no serious side
effects related to Peptelligence
Patent protected through 2036 with 56 issued U.S. and foreign patents, as well as 15 pending
U.S. and foreign patent applications
Current Enteris team members authored key patents and are actively expanding patent
portfolio
155. 2023-07-10 155
Internal Pipeline Summary
Enteris has applied the Peptelligence technology to off-patent molecules that are not available in
oral formulations to create proprietary, patentprotected reformulation products
In 2017 and 2018 Enteris incurred $1.4mm and $0.5mm of incremental spend on internal product
clinical development
161. 2023-07-10 161
Considerations in the developability of peptides
for oral administration
Considerations in the developability of peptides for oral administration when formulated together
with transient permeation enhancers
162. 2023-07-10 162
Introduction I
Enormous efforts have been made over the past few decades to realize the
therapeutic efficacy of protein and peptide drugs (PPDs)
Owing to their excellent specificity and biocompatibility, PPDs can achieve ideal
therapeutic effects at relatively low doses
Since the isolation of insulin in 1922, the use of PPDs as therapeutic agents has been
considered as an attractive approach to combat various diseases
Recent developments in the biotechnology and pharmaceutical sciences have made
it possible to produce potential therapeutic PPDs in commercial quantities
By far, over 240 PPDs has been approved by FDA and a variety of potential drug
candidates in clinical trials
Though parenteral administration is the most commonly employed administration
route for PPDs, it often associates with poor patient compliance
Compared to parental administration, oral drug delivery routes are advantageous
in terms of patient compliance, safety, long-term dosing and manufacturing costs
Further, oral administration is used for both local and systemic delivery of a wide
range of drug molecules, from small molecules to biomacromolecules
163. 2023-07-10 163
Introduction II
However, oral delivery of macromolecules (such as PPDs) is particularly
challenging due to their physicochemical properties and the involving barriers in
the gastrointestinal tract (GIT)
The major strategies to deliver PPDs orally with improved the therapeutic efficacy
can be categorized into non-targeting and targeting delivery, including chemical
modification and drug delivery systems for PPDs to avoid enzymatic degradation
and reduce off-target drug distribution
Targeting different GIT area can be achieved by exploiting its physiological features
and combining the PPDs with suitable drug formulations
Moreover, the presence of numerous types of intestinal cells, such as enterocytes,
M cells, goblet cells and Paneth cells interspersed throughout the GIT provides
various targets and allows for the design of a broad array of passive or active
targeting delivery systems
164. 2023-07-10 164
Introduction III
In this review, we summarize major barriers for oral delivery of PPDs, and the
state-of-the-art formulation approaches for promoting the oral bioavailability of
PPDs
Intestinal cell targeting strategies are presented with an emphasis on examples that
showed great potential for clinical applications
Additionally, multifunctional biomaterials which can be used to prepare oral carrier
systems as well as to modulate the mucosal immune response are also discussed
166. 2023-07-10 166
Physical and biochemical barriers and
mechanism of intestinal drug absorption ( I )
The absorption of orally administered PPDs from the GIT into the systemic circulation
is limited by various factors
These include the release of drugs from the carrier systems and pass on their way to
the target receptors within the harsh intestinal environment
Ingested PPDs first encounter digestive enzymes in our oral cavity, including amylase
and lipase in the saliva
The second enzymatic barrier is the intensive acidic environment and the presence of
pepsin and cathepsin that degrades most of the PPDs in stomach
Gastric pH might alter the ionization of the PPDs causing change of structure or
function of the drug
Moreover, trypsin and α-chymotrypsin are the major proteolytic enzymes in the
intestinal lumen
167. 2023-07-10 167
Physical and biochemical barriers and
mechanism of intestinal drug absorption( II )
Figure shows the mucus layer covering GIT epithelial membrane is considered as the
first physical barrier
Mucin is the main component which is a highly glucosylated glycoprotein
The backbone consists repeating sequences of serine, proline and threonine residues
The O-linked oligosaccharide side chains are generally terminated in L- fructose,
sulfonic acid or sialic acid
Therefore, the intestinal mucus layer shows negatively charged
Second physical barrier, the layer of epithelial cells connecting with tight junctions,
which forming a seal wall for the drug permeation
Furthermore, PPDs being metabolized by the enterocytes cytochrome P450 3A4
(CYP3A4) enzyme and being pumped out via P-gp efflux protein, as well as the post-
absorptive clearance are other involving barriers for oral drug delivery
168. 2023-07-10 168
Physical and biochemical barriers and
mechanism of intestinal drug absorption( III )
The two major mechanism of drugs permeate through the intestinal mucosa are the
passive diffusion via the transcellular or paracellular pathway , and the carrier-
mediated transport including active transport and facilitated diffusion
The permeation mechanism for a particular drug depends on its physiochemical
properties such as molar mass, polarity, lipophilicity and hydrophilicity
Lipophilic, non-ionized form of drugs generally have higher permeability, while the
ionized, hydrophilic drugs tend to penetrate over epithelium via paracellular pathway ,
and the hydrogen-bonding capability of the drugs dictated by the number of hydrogen
bond donors and acceptors usually no more 10 and 5, respectively
Carrier-mediated transport is energy dependent, and has notable features of substrate
specificity and saturability
It requires the interaction of drugs with a protein carrier often in the apical side of the
intestinal membrane
169. 2023-07-10 169
A diagram of transport pathways of protein and peptide
compounds over the intestinal mucosal epithelial membrane
170. 2023-07-10 170
Biochemical and physical barriers for oral drug delivery,
and the structure of intestinal mucosa with major intestinal cell types
171. 2023-07-10 171
The overview of main formulation strategies for oral delivery of PPDs, including chemical
modification, addition of effective agents, drug carrier systems and medical devices
Formulation strategies for oral delivery of PPDs
174. 2023-07-10 174
Strategies to enhance oral bioavailability of PPDs ( I )
Chemical modification
The oral bioavailability of PPDs is often hampered by their physicochemical
characteristics, such as hydrophilicity, large molecular weight and sensitivity to
enzymes and pH
To alter the physiochemical properties of PPDs, chemical modifications strategies,
including lipidization, cationization, PEGylation and prodrug formation have been
applied
175. 2023-07-10 175
Chemical modification
Rapidly and completely transported drugs are generally lipophilic and distribute
readily into the epithelial cell membranes of GIT
The overall polarity of a drug molecule can be reduced by adding a non-polar or
removal of a polar group to increase the lipophilicity, which leads to a higher
concentration gradient for facilitating the diffusion of drugs over the intestinal mucosa
However, lipidization can reduce the water solubility of original drug
A typical drawback of lipidization is reduced receptor affinity
One example is the leu-enkephalin peptide which is chemically modified by a
reversible aqueous lipidization method with a dimethylmaleic anhydride analog
This resultant drug was stable in various pH phosphate buffers and showed greater
stability against enzymatic degradation
The study demonstrated the lipidization may be an enabling strategy which can be
used to enhance oral absorption
Lipidization I
176. 2023-07-10 176
Chemical modification
Nobex Corporation added a hydrophilic PEG chain (protection from enzymatic
degradation) and a lipophilic alkyl chain to insulin for oral administration
Phase III results announced that it failed to meet the target endpoint, and recent
iterations of PEG conjugation technique which include C10 and bile salts, presumably
to promote peptide drug permeation
C10 elevates intestinal membrane fluidity via interaction with protein and lipids on the
membrane, and it permeate over through both transcellular and paracellular pathways
Lipidization II
177. 2023-07-10 177
Chemical modification
Cationic drugs are more permeable over the intestinal mucosa compared with anionic
drugs, it is due to the negatively charged glycoproteins and glycosphingolipids on the
intestinal cell membrane
Hence, formulating a cationic drug is postulated to elevate the drug permeability
However, peptide cationization may lead to increased immunogenicity, which will
result in faster removal of the drug from the body and hence loss of activity
Moreover, its non-specific targeting in terms of tissue uptake, and potential toxicity
found in the kidney and liver limits its therapeutic clinical use
Cationization I
178. 2023-07-10 178
Chemical modification
Studies have showed that PPDs can be cationized by chemical conjugation demon-
strated efficient intracellular delivery via adsorptive-mediated endocytosis
Futami et al. demonstrated the negatively charged mammalian cell membrane
consisting glycoproteins and glycosphingolipids, cationization of these proteins
elevated their ability for intestinal drug permeation
Moreover, the recent developed sophisticated protein chemistry, controlled chemical
modifications, such as substitutions, PEGylation and acylation, could significantly
reduce side effects
Strategies to avoid protein misfolding and aggregation during storage are benefit in
protein fibrillation
This in turn to prevent unforeseen side effects in drug delivery
Thus, cationization has proven to be a great tool for oral PPDs delivery
Cationization II
179. 2023-07-10 179
Chemical modification
Generally, PEGylation is the covalent attachment of polyethylene glycol (PEG) to
PPDs and elevate their half-lives due to steric hindrance against proteolytic enzymes
The increase in the molecular mass can improve both pharmacokinetic and
pharmacodynamic properties of PPDs
However, PEG may lead to size enlargement, increased viscosity, or reduce cell affinity
and limits the biological activity
Moreover, the non-biodegradable PEG materials might trigger adverse effects
PEGylation
180. 2023-07-10 180
Chemical modification
A prodrug is a chemical derivative of a main drug, it usually has greater stability,
solubility, lipophilicity and intestinal permeability
It converts to an active drug in vivo usually undergoes transformation either by a
chemical or an enzymatic reaction
Esterification of hydroxyl, amino acid, or carboxylic acid containing drugs can
increase lipophilicity, thus improve intestinal drug permeation
However, the highly lipid-soluble drugs may bind to plasma protein, and limit free
drugs in the plasma
Especially for PPDs, modification of PPDs maybe diminishes their specific receptors
binding, since the plasma protein may occupy certain portion of the available PPDs
In some cases, during its activation stage, the prodrug might consume a vital cell
constituent leading to its depletion
Prodrug formation
182. 2023-07-10 182
Addition of effective agents
Absorption enhancers are usually one of a varied class of chemical moieties, they are
used to improve drug absorption by facilitating intestinal cells permeation
Generally, absorption enhancers alter the structural integrity of the epithelium or by
simply promoting drug diffusion across the intestinal mucosa
The associated mechanisms of action which include
: changing membrane fluidity or mucus viscosity, and/or opening tight junctions,
generally governed by passive diffusion and modeled by Fick’s first law of diffusion
Absorption enhancers I
183. 2023-07-10 183
Addition of effective agents
The commonly used absorption enhancers are surfactants, fatty acids, chelators,
glycerides, bile salts, salicylates, chitosan and cholesterol
They normally increase the solubility and bioadhesion of the drug or drug carrier
system which allows more drug amount to be retained at the absorption site and
resulting in greater drug oral bioavailability
However, it was found some absorption enhancers such as claudins, EDTA, sodium
cholate, sodium dodecyl sulfate may cause the disruption of membrane integrity and
systemic toxicity
The constant tight junction opening can cause mucosal damage and may also transport
toxic molecules across the intestinal membrane
Absorption enhancers II
184. 2023-07-10 184
Addition of effective agents
Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a promising absorption
enhancer can enhance passive permeation of polar charged drug molecules through
the intestinal epithelium
This is noteworthy in view of the very low tendency of a polar drug to permeate over
the lipophilic intestinal epithelial membrane
Several PPDs including calcitonin, insulin and heparin were conjugated with SNAC to
promote the intestinal drug permeation
Semaglutide utilized this technique is in clinical trials, that has shown protection
against gastric enzymes and enhanced hydrophobicity to promote the peptide drug
permeate over the intestine
Additionally, SNAC has not been reported to be associated with significant disruption
of the tight junctions, change in membrane fluidity, thus the low toxicity is beneficial
for later clinical studies
Absorption enhancers III
185. 2023-07-10 185
Addition of effective agents
Another effective permeation enhancer, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-
caprylic acid) (5-CNAC) is the leading examples of Eligen® technology from
Emisphere
It was reported that 5-CNAC can deliver macromolecules (> 150 kDa), enhances
transcellular absorption without disrupting intestinal integrity
Karsdal et al. incorporated 5-CNAC with calcitonin for oral administration
5-CNAC interacts with calcitonin forming an insoluble entity at low pH in stomach,
once it reaches small intestine at higher pH, the complex dissolves and facilitates
intestinal drug uptake, resulting in systemic exposure of intact peptide
Currently there are ongoing trials for oral Eligen®- calcitonin for the treatment of
osteoporosis
Moreover, Novo Nordisk’s oral semaglutide which now has been marketed as tablet
Oral form of semaglutides, as glucagon-like peptide-1 (GLP-1) analogues, also utilizes
Emisphere Technologies’ proprietary Eligen® Technology
Absorption enhancers IV
186. 2023-07-10 186
Addition of effective agents
PPDs are usually formulated with enteric coating to prevent their degradation in the
acidic environment
Once the enteric coating reaches the intestine, the increase in pH leads in dissolution of
the coating and release the drugs, as was illustrated for an oral calcitonin form that
has been tested in clinical trials
Moreover, Intestinal and pancreatic enzymes are also able to degrade PPDs in the
neutral to basic environment in the small intestine
The use of citric acid in the oral PPDs formulation results in a decrease in pH,
inhibiting degradation by the peptidases
Lei et al. have demonstrated that co-administration of citric acid reduced the activity
of intestinal tryptic enzymes and resulted in higher oral bioavailability of calcitonin
However, the major concern is the distortion of physiological pH
Other limitations involve the long-term drug stability and the incompatibility upon
dilution
Modulation of pH
187. 2023-07-10 187
Addition of effective agents
Direct inhibiting proteolytic enzyme by using an enzyme inhibitor is another way to
circumvent intestinal enzyme activities
Proteolytic enzyme inhibitors such as aprotinin (inhibitor of trypsin and
chymotrypsin), leupeptin (inhibitor for plasmin, trypsin, papain), chicken ovomucoid
(trypsininhibitor) and FK448 (chymotrypsin inhibitor)
These proteolytic enzyme inhibitors are usuallyco-formulated with PPDs to prevent
enzymatic degradation in intestinal mucosa
However, it was also reported that the safety of using enzyme inhibitors is a major
concern
The excess use of this excipients may restrict certain therapeutic effects or trigger
undesirable pharmacological activities
The most clinically advanced enzyme inhibition example is an oral insulin formulation
known as ORMD-0801 consisting soybean trypsin inhibitor and a chelating agent that
scavenges calcium
This treatment showed a significant 24.4% reduction in the frequencies of glucose
readings >200 mg/dL, and a significant mean 16.6% decrease in glucose AUC
Proteolytic enzyme inhibitor
188. 2023-07-10 188
Addition of effective agents
Mucolytic agents, also called mucus penetrating agents, which are able to facilitate the
permeation of the drugs across the mucus barrier and elevate oral bioavailability of
PPDs
In the reported preclinical studies, the use of PEG allows to promote mucus
penetration
Liu et al. have developed a novel self-assembled nanoparticle composed of insulin and
trimethyl chitosan, and a dissociable mucolytic agent
The mucolytic agent modified nanoparticles exhibited free Brownian motion and
facilitate drug permeation over intestinal mucosa
In diabetic rats, the mucolytic agent modified nanoparticles generated a prominent
hypoglycemic response and showed an bioavailability of 2.8-fold higher than that of
unmodified nanoparticles
While mucus-penetrating strategies continue to be extensively investigated, the efficacy
and safety have not yet been validated in large clinical trials
Mucolytic agents
189. 2023-07-10 189
Addition of effective agents
Cell-penetrating peptides (CPPs) are usually derived from viruses that are efficient at
cell entry or membrane translocation, non-viral proteins or smaller molecules
normally interact with membrane glycosaminoglycans, promoting PPDs to enter
intestinal epithelial cells via endocytic pathways
However, the use of CPPs to elevate the oral bioavailability of PDDs has not yet been
validated in the clinic
Recently, CPPs such as HIV-1 Tat, penetration and oligoarginine are commonly used
for oral delivery of various drugs
However, inherent limitations were involved, including poor stability, toxicity and
endosomal entrapment.
To overcome this limitation, the enteric capsules can be used to avoid acidic and
enzymatic degradation, thus promoting stability, and the sustain drug release of the
CPPs modified formulation lower the toxicity of the CPPs to the intestinal mucosa
Cell-penetrating peptides
191. 2023-07-10 191
Drug carrier systems
Microparticles (size varying 1-100 µm) with high surface to volume ratio and greater
intimate contact of the drugs with the intestinal epithelial layer, prolong gastric
resident time, thus lead to higher drug absorption and oral bioavailability
For example, microparticles have shown that encapsulation of PPDs for oral
administration and achieved a sustained biological activity
Surface modification of microparticles can be achieved by conjugation, coating or
crosslinking
For example, collagen microparticles modified by photochemical crosslinking , and silk
fibroin coated polylactide-co-glycolide acid (PLGA) and alginate microparticles have
been used to further prolong the release of the peptide drug
Several other new microparticulate systems have been developed recently
Such as temperature-responsive microspheres, dynamic hydrogel microspheres and
glucose-responsive microspheres
However, the general limitations involve the polymer/drug miscibility, excipients
compatibility for the system as well as the physical and chemical instability upon
storage
Microparticulate carrier systems
192. 2023-07-10 192
Drug carrier systems
Hydrogels generally contain water phase, a crosslinked polymer and a drug
component
Usually they can respond to environmental changes to alter network structure,
mechanical strength and swelling manner
Generally, hydrogels remain insoluble even imbibe great amounts of biological
fluids, therefore they appear to stabilize the embedded PPDs, protecting the PPDs
from degradation in the harsh GI environment
In addition, the PPD loaded hydrogel is able to prolong retention time within specific
gut regions thus elevate the drug absorption
However, hydrogels for oral delivery of PPDs have not made significant progress
towards the clinical trials
However, the main limitation of oral hydrogel is the physical and/or chemical
instability issues, fast hydrogel disintegration may occur while it contacts with large
amount of gut fluid after oral administration
Hydrogels
193. 2023-07-10 193
Drug carrier systems
Nanoparticulate carrier systems, usually with particle size of less than 1 µm, such as
polymeric or lipid nanoparticles, nanoemulsions and niosomes for oral drug delivery
are of interest owing to the great benefit in promoting drug stability, provide a
sustained drug release profile and elevate drug absorption over intestinal wall
In general, smaller particles of less than 500 nm are usually undergoes endocytosis and
shows greater intestinal drug permeation than larger particles
During the process of endocytosis, the plasma membrane invaginates and pinches off
to form enclosed vesicles and enter systemic circulation
Additionally, reducing the versicle size results in larger surface area, thus enhancing
dissolution rate and solubility of PPDs
However, limitations of nanoparticulate carrier systems are associated with limited
drug loading and high particle aggregation due to thermodynamic instability, and
scale-up difficulty for manufacturing
However, the safety and biocompatibility of the polymeric materials and applicability
of scaling up in manufacturing still remain a challenge
Nanoparticulate carrier systems
194. 2023-07-10 194
Drug carrier systems
Many publications have proposed the potential of gold nanoparticles (GNPs) for
biomedical applications
The small size and multi-valence arrangement around the gold core elevates the
capacity to improve drug biodistribution and hence effectiveness and safety
However, the GNPs that has entered clinical trials is CYT-6091 (Aurimune) is the only
GNPs that have entered clinical trial currently
They are gold core particles incorporating TNF-α (a cytokine) and showed a particle
size of 27 nm approximately. Studies demonstrated that incorporating TNF-α onto the
gold platform improved systemic tolerability
In phase I studies, the safety profile showed the GNPs were well tolerated for patients
with advanced cancer
Ultrasmall GNPs, with size of only 2–3 nm, have also showed great potential in a wide
variety of therapeutic applications
It was demonstrated that ultrasmall GNPs with size around 2 nm have a relatively
longer plasma half-life, improved tissue penetration compared with larger
counterparts
Gold nanoparticle technology
195. 2023-07-10 195
Drug carrier systems
Microemulsion is an isotropic, transparent and thermodynamically stable system
which consists of water, oil and surfactant, usually with a co-surfactant
Droplet size is normally less than 200 nm.
Structurally, they are divided into three phases:
water-in-oil (W/O), oil-in-water (O/W) and bicontinuous microemulsion
Surfactants with a hydrophilic lipophilic balance (HLB) value greater than 12 are
hydrophilic and predominantly forming O/W emulsions, while surfactants with HLB
values less than 12 are favor in formation of W/O emulsion
Surfactants generally lower the surface tension to promote the drug solubility and
opening tight junctions momentarily to enhance drug permeability
Moreover, surfactants having HLB greater than 20 usually require the addition of co-
surfactants
However, some surfactants may cause some degree of toxicity, thus the amount of
surfactant used requires careful consideration
Other limitations include the disintegration of the system due to dilution in the gut,
and in vivo instability below the critical micelle concentration
Microemulsion
196. 2023-07-10 196
Drug carrier systems
Ionic liquids as low melting salts with melting point <100°C, often formulated to
enhance the dissolution of poorly soluble drugs, as well as to promote drug permeation
through physiological barriers
In general, ionic liquids interact with various hydrophilic and hydrophobic amino
acids of a protein through an intricate balance of hydrogen bonds,disulfide bonds,
ionic interactions and hydrophobic effects
When mix with water or body fluid, a more complex interplay between ions occurs,
which can result in formation of microemulsions or micelles
Ionic liquid
197. 2023-07-10 197
Drug carrier systems
Liposomes are generally composed of one or more phospholipid membrane bilayers
surrounding aqueous inner phase with sizes from 15 nm to 10 µm
Liposomes can be divided into six types based on their size and structures
Lipophilic drugs are embedded in the phospholipid layers while hydrophilic molecules
are encapsulated in the aqueous inner core
This nature of liposomes that can carry both water soluble and lipid soluble drugs is
called amphiphilic
However, the major limitations involve poor stability, drug leakage of liposomes and
short shelf life
The intact liposomes are difficult to permeate over the lipophilic intestinal epithelium,
thus lower the oral bioavailability, especially for BCS class Ⅲ drug
Liposomes
198. 2023-07-10 198
Liposomes
A) Basic liposome structure
B) Different model membranes of liposomes
SUVs: small unilamellar vesicles; LUVs: large unilamellar vesicles; MLVs: multilamellar vesicles
MVVs: multivesicular vesicles; OLVs: oligolamellar vesicles; GUVs: giant unilamellar vesicles
200. 2023-07-10 200
Medical devices
The inherent attractiveness of microneedle-based delivery strategy demonstrates the
great suitability for various PPDs delivery, even with large molecular weight
Prausnitz et al. have utilized microneedle technology for oral drug delivery
They placed a 0.5-cm2 drug loaded microneedle patch onto the arms connected to a
base, and called this device a luminal unfolding microneedle injector (LUMI)
Once the oral administered device reached the intestine, the polymeric material
holding the spring was dissolved, led to actuation that pushed the LUMI out, pressing
the microneedle patches against the intestinal wall, allowing the drugs directly
penetrate the intestinal epithelium
The Rani Therapeutics company has developed a related technology that deployed oral
microneedles that has been carried out in a clinical trial currently, using octreotide as
a model drug
Moreover, up to 0.3 mg of drug can be loaded into LUMI, which is sufficient for many
potent PPDs
Biodegradable microneedle-based delivery system
201. 2023-07-10 201
Medical devices
Recently, it has been reported the preclinical studies of two oral microneedle devices, a
poly(methacrylic acid-co-ethyl acrylate) and PEG based microneedle device for oral
insulin delivery
The microneedle capsule was designed to dissolve at pH levels encountered in the small
intestine
The results showed the insulin levels instantly increased and the blood glucose was
reduced within 30 min, with an oral bioavailability of over 10%
Biodegradable microneedle-based delivery system
202. 2023-07-10 202
Medical devices
An ingestible self-orienting system is a recent invented device that physically inserts a
drug-loaded millipost through the GI mucosa with promising bioavailability
Inspired by the self-orienting leopard tortoise, Abramson et al. have developed an
ingestible self-orienting millimeter-scale applicator (SOMA) that tends to position itself
to engage with GIT, designed to resist external forces such as fluid flow, peristaltic
motion upon reaching a stable point on the GIT wall
It then deploys milliposts fabricated from drugs directly through the intestinal mucosa
while avoiding perforation
This SOMA device has demonstrated promising efficacy to deliver insulin orally and
could be used to deliver other PPDs orally
However, the drawback involves the deliverable dose is constrained by the formulation,
volume and stability of the millipost
By increasing the size of millipost can elevate drug loading but might compromise the
intestinal mucosa and trigger perforation risk
Furthermore, the long-term chronic effects brought by daily gastric injections shall be
evaluated
Still, the SOMA represents a great platform for oral delivery of PPDs
Ingestible self-orienting system
203. 2023-07-10 203
The ingestible self-orienting millimeter-scale applicator after oral administration, and the
device could autonomously position itself to the intestinal mucosa
Ingestible self-orienting system
204. 2023-07-10 204
Medical devices
Intestinal patches consist polymeric matrix embedding drugs, usually with a stabilizer
They can adhere to the intestinal wall and positioning the drugs directly to the
intestinal epithelium, and meanwhile protecting the drugs from local enzymatic
degradation
Recently, Banerjee et al. have fabricated an insulin loaded mucoadhesive oral patches
integrated with iontophoretic circuit and surgically placed in the intestine
It was found the iontophoresis could disrupt the tight junctions of intestinal epithelium
and facilitate insulin transport via paracellular pathway, without impairment of the
intestinal mucosa
However, clinical proof of oral patch technology has not yet been forthcoming
Intestinal mucoadhesive patches
205. 2023-07-10 205
Strategies to enhance oral bioavailability of PPDs
; Formulation technology with combinational strategies
206. 2023-07-10 206
Transient Permeation Enhancer (TPE)
TPE had been used for oral delivery of octreotide
TPE is an oily suspension of octreotide that consists a permeation enhancer that can
transiently modify the integrity of intestinal epithelium by opening the tight junction
It also consists polysorbate-80, allow to alter the thickness of intestinal mucus, thus
further promote the intestinal drug uptake
Moreover, several peptides have been incorporated into TPE® including teriparatide,
leuprolide, insulin and octreotide
However, a main concern in application of TPE®, the intestinal tight junction opening
that cause toxicity, or the use of food emulsifiers or other excipients might initiate
autoimmune disease
Currently, Phase I studies of octreotide capsules resulted in an oral bioavailability of
about 0.7% and primary endpoints were achieved in two Phase III studies
The oral octreotide dose required to achieve these endpoints was over 200 times that of
the 0.1 mg subcutaneous injection, which demonstrated a big achievement of this
promising oral form
207. 2023-07-10 207
Gastrointestinal Permeation Enhancement Technology(GIPET)
GIPET is an oral solid dose technology can effectively increase oral absorption of a
variety of low permeability PPDs
This strategy focuses on the use of medium chain fatty acid or its variants coupled with
salts, resulting in greater hydrophobicity and penetration characteristics that open
epithelial tight junction
This technology is low cost and safe, which has great advanced to the clinic
GIPET consists three major enteric coated formats
GIPET I, is an enteric coated tablet with drug in selected weight ratios
GIPET II, is a microemulsion form encapsulated within an enteric coated gel capsule.
GIPET III,consists of drugs with fatty acid derivatives within an enteric coated gel
capsule
Currently, the Phase I and II studies have shown the safety profile of the three formats
given on a repeated basis
In addition, permeation enhancer C10, have been incorporated to increase intestinal
membrane fluidity and promote transcellular drug transport
Moreover, another feature of GIPET promotes the oral bioavailability of drugs may
relate to inhibition of P-gp efflux
208. 2023-07-10 208
Peptelligence technology
Peptelligence is a highly developed, clinically proven platform technology that enables
the oral delivery of PPDs
It protects PPDs from acid hydrolysis, enzymatic degradation, and also enhances
paracellular transport
Enteris’s Peptelligence technology focuses on two main strategies
The first is a permeation enhancer, which opens tight junctions and facilitates
paracellular transport
The second is a pH-lowering agent, lowering the local pH of the intestinal fluids in
order to reduce protease activity
Additionally, the coating of the organic acid granules forms a thin barrier that prevents
PPDs from acid degradation in the stomach
This technology was initially developed by Unigene and then Enteris Biopharma
Enteris has demonstrated positive results in several clinical studies, including phase III
oral calcitonin and phase I oral leuprolide
The results from multiple preclinical as well as early and late-stage clinical studies have
demonstrated the promising applicability of Peptelligence to the oral delivery of PPDs
209. 2023-07-10 209
Peptelligence technology
Peptelligence is a highly developed, clinically proven platform technology that enables
the oral delivery of PPDs
It protects PPDs from acid hydrolysis, enzymatic degradation, and also enhances
paracellular transport
Enteris’s Peptelligence technology focuses on two main strategies
The first is a permeation enhancer, which opens tight junctions and facilitates para
cellular transport
The second is a pH-lowering agent, lowering the local pH of the intestinal fluids in
order to reduce protease activity
Additionally, the coating of the organic acid granules forms a thin barrier that prevents
PPDs from acid degradation in the stomach
This technology was initially developed by Unigene and then Enteris Biopharma
Enteris has demonstrated positive results in several clinical studies, including phase III
oral calcitonin and phase I oral leuprolide
The results from multiple preclinical as well as early and late-stage clinical studies have
demonstrated the promising applicability of Peptelligence to the oral delivery of PPDs
210. 2023-07-10 210
ThioMatrix technology
Thiolated mucoadhesive polymers (thiomers) that are capable of forming covalent
bonds with intestinal mucus glycoproteins via thiol/disulfide exchange reactions
Thus, thiomers modified delivery system enhances the intestinal mucoadhesion,
prolongs the retention in GIT and lead to higher oral bioavailability
In addition, thiomers also exhibit enzyme inhibitory, permeation enhancing and efflux
pump inhibitory properties
However, thiomers are rather unstable in formulation form as they are subject
of thiol oxidation at pH ≥ 5 unless sealed under inert conditions
Therefore, the use of pre-activated thiol groups might be an interesting approach to
enhance its stability
ThioMatrix GmbH (Vienna, Austria) uses thiomers incorporates with reduced
glutathione, to enhance oral delivery of hydrophilic macromolecules based on
inhibition of protein tyrosine phosphatase by thiol groups
The results demonstrated the thiomeric mucoadhesive, permeation enhancing, and
efflux pump inhibition properties were promising, thus lays a great platform for oral
delivery of PPDs
211. 2023-07-10 211
Transferrin-based recombinant fusion protein technology
Transferrin (Tf) is an endogenous serum protein that transports iron to cells expressing
the Transferrin receptor (TfR) through TfR-mediated endocytosis
Studies have applied Tf to prepare drug carrier system to deliver PPDs, genes and poor
soluble drugs to the target tissues including intestinal epithelium and blood brain
barriers that abundantly express Tf receptors
Melanie et al. generated and expressed functionally active colony-stimulating factor (G-
CSF) as a recombinant fusion protein incorporated with Tf to evaluate the function of
Tf as a carrier for oral delivery of G-CSF
The results demonstrated that the Tf moiety of the fusion protein not only promoted
the drug permeation over the GI epithelium, but also protected the drug from
enzymatic degradation
Therefore, it demonstrates that a Tf-based recombinant fusion protein technology is a
promising approach for future development of orally active PPDs
212. 2023-07-10 212
Oral sCT (Ostora) technology
Oral sCT (Ostora)is built around coated citric acid vesicles in a Eudragit®-coated
capsule, and currently has completed Phase III, indicating it is a clinically advanced
oral peptide format
Briefly, it uses lauroyl carnitine chloride as the permeation enhancer to promote
intestinal drug permeation, and citric acid as a pH lowering agent, lowering pH to
reduce protease activity, as well as encapsulating within a Eudgradit® capsule to
prevent the drugs from acidic degradation in the stomach
There are other platforms with clinical trial data: TPE (Chiasma), POD™ (Oramed),
Eligen® (Emisphere), IN-105 (Biocon) and GIPET (Merrion)
What stands out about these formulations is their simplicity compared with highly
complex delivery constructs
213. 2023-07-10 213
Oramed and Orasome technology
Oramed is a carrier system used for oral delivery insulin and GLP-1, which was
developed by the Oramed Pharmaceuticals
Ormade’s oral insulin is available as ORMD-0801, it allows to protect drug from
enzymatic degradation and elevate the intestinal permeation of insulin
Ormades oral insulin was investigated for both type I and type II diabetes
It is currently under phase II clinical trial for oral insulin delivery and phase I trial for
oral GLP-I delivery (NCT02535715)
Orasome is a polymer-based liposome for oral delivery of insulin and human growth
factor, which was introduced by the Endorex Corporation
This formulation allows to protect the loaded PPDs from acidic degradation in the
stomach and protecting the drugs from the bile salts
214. 2023-07-10 214
Q-Sphera™ technology
Q-Sphera technology is a novel platform to individually print narrow size distribution
particles of approximate 30 μm to generate predictable pharmacokinetic profile
This micro-piezo technologywas developed by the MidaTech
Midatech’s Q-Sphera technology focuses on long actinginjectables using proprietary
piezo printing technology that encapsulates PPDs into polymeric microparticles with
precision properties
The piezo printing process regulates the internal pH inside microparticles and reduces
the likelihood of protein destruction
Additionally, the Q-Sphere technique does not use surfactants, toxic solvents or
biphasic mixtures, providing a promising safety profile of the technique
An example of Midatech’s Q-Sphera has utilized an advanced 3D printing technology
to fabricate a PLGA microparticle depot system
It is low cost and environmentally friendly, with an efficient high yield production and
scalable manufacture
215. 2023-07-10 215
Nano Inclusion technology
This technology allows to solubilize potent molecules that have minimal solubility at
biological pH for oral delivery
Midatech’ MidaSolve project, MTX110, utilizes the MidaSolve nanosaccharide
inclusion technology to solubilize panobinostat, allowing it to be orally administered
via a micro-catheters system
Therefore, this technology focuses on promoting drug solubility, meanwhile the
delivery system also elevates the oral drug bioavailability as well as to facilitate the
drug to cross the blood-brain-barrier
The initial Phase I study showed promising safety profile in patients
Phase II trial of safety, tolerability, recommended dose and efficacy in 19 patients are
under investigation
The study endpoint is expected to be patient survival after 12 months
216. 2023-07-10 216
Oleotec and Soctec gastro-retentive technology
Oleotec and Soctec gastro-retentive technologies were introduced by the Skyepharma
This strategy mainly focuses on promoting the drugs being absorbed in the stomach
Briefly, the technique prolongs the retention of the drugs within the stomach, and
gradually releasing the encapsulated drug without being degraded by the acidic
environment
Upon oral administrated the formulated dosage, the delivery system encapsulating
drug was activated by GIT fluid
The polymer gradually swelled and enlarged 8 and 10 times in size, which
guaranteeing its preservation in the stomach even after 6 – 8 hours of gastric emptying
and released drugs in a sustained manner
The Accordion Pill™ is a typical gastro retentive formulation composed of polymeric
films
It has a planar structure with multi-layer folded to an accordion shape, and
encapsulated within a capsule
Upon reaching the stomach, the capsule dissolves, the Accordion Pill™ unfolds and
allows to retain within the stomach for up to 12 hours
217. 2023-07-10 217
Strategies to enhance oral bioavailability of PPDs
; Formulation technology with combinational strategies
(Platform Technology)
220. 2023-07-10 220
History of development of Mycapssa
The first representative example is the adjustment of the dosing interval through glucagon-like
peptide-1 (GLP-1) receptor agonist half-life improvement
Exenatide, firseveloped in 2005, requires injection twice daily
Since then, products that are administered once daily (lixisenatide and liraglutide) and once a
week (dulaglutide, albiglutide, and semaglutide) have been developed by improving the half-life
of the peptide
More recently, a daily oral administration product (oral semaglutide, Rybelsus®) has been
developed
Furthermore, octreotide has also undergone a flow of formulation development to improve
dosing convenience. Since the endogenous hormone somatostatin has a short half-life of less than
3 min, octreotide, a synthetic somatostatin receptor ligand with an improved half-life (90–120
min), was developed in the 1980s
Octreotide was initially developed as a subcutaneous injectable formulation administered 2–3
times daily
The frequent administration caused patient discomfort, and in the 1990s, octreotide LAR
(long-acting release) product, administered once a month, was developed to improve the dosing
interval
221. 2023-07-10 221
Dramatic dosing interval improvement, the intramuscular injectable form of octreotide LAR
required a fairly thick 19-gauge (diameter: 1.1 mm) needle, which caused pain during
administration and posed several pharmaceutical problems
In order to improve the disadvantages of the octreotide injectable administration, an octreotide
subcutaneous depot formulation (CAM2029)—with the advantages of being administered once a
month, being less painful because of a thinner needle, and its self-administration option by
subcutaneous injection—is being developed and is under going phase 3 clinical trials
Finally, in 2020, the FDA approved an oral octreotide product (Mycapssa®) that goes beyond
the limits of injectable products
History of development of Mycapssa
223. 2023-07-10 223
MYCAPSSA IS POWERED BY TPE TECHNOLOGY
Peptides and large molecule drugs are generally administered via injection because these
agents can be degraded by digestive enzymes and/or blocked from crossing the intestinal
epithelium via transcellular or paracellular routes resulting in low bioavailability and sub-
therapeutic levels in the blood
MYCAPSSA capsules are protected from
degradation by the enteric coating
TPE formulation allows octreotide to
be absorbed, intact, at therapeutic levels
224. 2023-07-10 224
Action Mechanism of Mycapssa
MYCAPSSA capsules
containing TPE have
an enteric coating,
protecting them from
enzymatic degradation in
the stomach and allowing
them to reach the small
intestine
Once in the small
intestine, coated capsule
dissolves releasing TPE
formulation
Medium chain fatty acids then
induce expansion of tight
junctions between intestinal
epithelial cells by leveraging a
naturally occurring process
which the body normally uses
to absorb nutrients through
paracellular transport
This allows octreotide
to enter blood stream at
therapeutic levels while
excluding larger structures
(≥70kDa) such as toxins,
bacteria, and viruses
225. 2023-07-10 225
PIVOTAL PHASE 3 CLINICAL TRIAL
TRIAL A UTILIZED A RIGOROUS STUDY DESIGN3
Starting dose: 40 mg (20 mg morning + 20 mg evening)
Dose titration was performed during the first 6 months of the study to a dose of 60 mg (40 mg morning + 20 mg
evening ) and up to a maximum dose of 80 mg daily (40 mg morning + 40 mg evening ) based on biochemical
results or symptoms
Patients then maintained a fixed dose until end of treatment
226. 2023-07-10 226
PIVOTAL PHASE 3 CLINICAL TRIAL
PRIMARY ENDPOINT
58% of patients receiving MYCAPSSA vs 19% of patients receiving placebo met criteria for
maintaining IGF-I response defined as an average of week 34 and 36 IGF-I ≤1.0 x ULN (p=0.0079)
227. 2023-07-10 227
PIVOTAL PHASE 3 CLINICAL TRIAL
SECONDARY ENDPOINTS
Median time to loss of response
was not met in the MYCAPSSA group
Loss of response criteria was not met in the group
receiving MYCAPSSA during the 36-week treatment
period
The group receiving placebo met median time to loss of
response with both IGF-I >1.0 x ULN and ≥1.3 x ULN
at week 16
78% of patients on MYCAPSSA
maintained GH response
Of the patients with a mean GH <2.5 ng/mL at
screening, at Week 36, 78% of patients receiving
MYCAPSSA maintained GH <2.5 ng/mL vs 30% for
patients receiving placebo (p=0.001)
75% of patients completed
treatment on MYCAPSSA
75% of patients treated with MYCAPSSA did not
require reversion to SSA injections anytime
throughout the 9 months for any reason vs 32%
of patients treated with placebo (p<0.003)
232. 2023-07-10 232
Unlike naturally occurring MCFAs, Eligen technology-based PEs are a family of
compounds developed for permeation enhancement
Eligen technology, based on PEs developed by Emisphere, has undergone a development
process
They originally targeted the oral delivery of peptides through microspheres composed of
thermally condensed α-amino acids
In that process, it was necessary to develop a hydrophobic α-amino acid with a low
molecular weight for microsphere preparation
They chose a method of derivatizing soy protein hydrolysate with phenylsulfonyl
chloride, and through this, they successfully manufactured microspheres
In subsequent permeability experiments, empty microspheres were found to enhance
the intestinal absorption of peptides loaded into microspheres
Through additional experiments, they discovered that (phenylsulfonyl)-α-amino acids
themselves had the effect of a PE, and through this, they began screening for the PE
activity of the modified α-amino acids themselves, and not through the microsphere
strategy
Eligen Technology
233. 2023-07-10 233
This initial study concluded that there is insufficient evidence that the increase in
peptide absorption occurs by classical mechanisms such as protease/peptidase inhibition
and penetration enhancement, and the research team focused on the possibility of
enhancing permeation by specific interactions between peptides and Eligen
technology
Based on the flow of these studies, it can be observed that they were not limited to α-
amino acids, but continuously screened for the difference in the permeability enhancing
effect according to the changes in the substituents of N-acylated-non-α-amino acid,
lipophilicity, etc
Subsequently, Emisphere’s research team conducted a study on the mechanism of PE
action with candidates obtained by screening (not including SNAC, the current leading
compound). They argued that their PE acts as a “carrier” for protein/peptide delivery
and that the passive/transcellular pathway is the main pathway
More specifically, their carriers stabilize the partially unfolded conformer of
protein/peptide through non-covalent bonding, which exposes the hydrophobic side
chain of protein/peptide and increases solubility in lipid membranes
Eligen Technology
235. 2023-07-10 235
Through this journey, SNAC (N-[8-(2-hydroxybenzoyl)amino] caprylate) was developed,
which also led to the development of oral semaglutide and other leading compounds
such as 5-CNAC (8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylate) and 4-CNAB
(N-(4-chlorosalicyloyl)-4-aminobutyrate)
The most advanced of these is SNAC, which has been applied in clinical trials with
insulin , heparin , ibandronate, and peptide YY3-36 (PYY3-36), and led to the successful
development of oral vitamin B12 and semaglutide products
The remaining leading compounds are 5-CNAC and 4-CNAB
The compound 5-CNAC has been applied to salmon calcitonin and has moved to phase
3 clinical trials
The compound 4-CNAB, for its part, has been applied to insulin, and phase 1 clinical
trials have been completed
SNAC (N-[8-(2-hydroxybenzoyl)amino] caprylate
236. 2023-07-10 236
SNAC (N-[8-(2-hydroxybenzoyl)amino] caprylate), also called sodium salcaprozate,
has a pKa value of 5.01 and a molecular weight of 301.31 Da
It shares structural similarity with MCFA in that it has a fatty acid moiety, but unlike
MCFA, it does not adequately demonstrate the tendency of surfactant-like action
membrane insertion/perturbation
SNAC has a salicylamide structure at the molecular terminal, in addition to the
carboxyl group of fatty acid shared with MCFA, and has a larger distribution of
hydrophilic groups
In effect, the computed topological polar surface area of SNAC is more dispersed, with
it being 40.1 Å for C10 and 89.5 Å for SNAC
In a recent in silico-based research model, the tendency of SNAC to disrupt the
membrane was calculated to be less than that of MCFA due to the presumed
salicylamide structure
Moreover, the tendency of expulsion from the membrane leaflet after insertion into the
membrane was also greater
There have been studies on SNAC, a representative material of Eligen technology-based
PEs, for the oral administration of insulin, octreotide, etc
SNAC (N-[8-(2-hydroxybenzoyl)amino] caprylate
237. 2023-07-10 237
This has led to the successful development of Rybelsus® (oral semaglutide)
Most studies on the mechanism of SNAC have agreed that it acts as a transcellular PE
Furthermore, many studies have concluded that SNAC does not exhibit surfactant-like
action and membrane perturbation tendencies, as MCFA does
The representative mechanism of SNAC is the carrier mechanism
That is, SNAC forms a non-covalent complex with a drug to increase lipophilicity and
membrane permeability, which is the mechanism claimed by Emisphere, who developed
SNAC
The PE mechanism of SNAC cannot be generalized to a single drug (a peptide) due to
the nature of the mechanism of non-covalent binding to the drug
Albeit, SNAC exposed the hydrophobic region of insulin and there were no changes in
TJ proteins or membrane integrity, represented by an LDH assay and a mannitol
transport assay in an insulin-modeled study
SNAC (N-[8-(2-hydroxybenzoyl)amino] caprylate
239. 2023-07-10 239
Schematic diagram of the mechanism of Eligen technology
Emisphere researchers have argued that small carrier molecules with hydrophobic moieties increase
lipophilicity through the formation of weak non-covalent bonds with drug molecules
243. 243
RYBELSUS® is a GLP-1 analog with 94% similarity to human GLP-1
Structural modifications of the RYBELSUS® molecule prevent degradation by DPP-4 and
prolong incretin activity
rybelsus(semaglutide)
Innovative coformulation with an absorption enhancer enables once-daily oral administration
SNAC: Sodium-N-[8-(2-hydroxybenzoyl) amino] caprylate: a small fatty-acid derivative
Following oral administration, maximum concentration of RYBELSUS® is reached after 1 hour
245. 245
Oral semaglutide must be co-formulated with the absorption enhancer SNAC in
order to be absorbed
SNAC raises the local pH, resulting in increased solubility and protection from
proteolytic degradation
SNAC promotes the absorption of semaglutide across the gastric mucosa in a time- and
concentration-dependent manner, which is totally reversible
Semaglutide could be developed as an oral tablet by combining it with an absorption
enhancer known as sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC)
In a concentration dependent manner, SNAC forms a noncovalent bond with GLP-1,
increasing lipophilicity and transcellular absorption of semaglutide through the stomach
epithelium
Additionally, in the acidic environment of the stomach, SNAC acts as a local pH buffer
for semaglutide, increasing solubility and protecting the drug from degradation
As SNAC’s activity is brief and reversible, it separates from the medication once it
reaches the bloodstream
How does rybelsus works ?
259. 259
Phase 2a Trial in T1D Completed
By directly targeting liver glucose, ORMD-0801 may provide tighter blood sugar regulation and control
for the ~1.6M¹ Type 1 diabetes patients in the US
; potentially reducing the need for multiple daily injections, including mealtime insulin
276. 276
Proprietary technologies and
a differentiated clinical pipeline
Midatech has developed three in-house technology platforms
Q-Sphera™ : Sustained Delivery)
MidaSolve™ : Local Delivery
MidaCore™ : Targeted Delivery
Each with its own unique mechanism to improve delivery of medications to sites of
disease
By improving bio-delivery and biodistribution of approved existing molecules, the
Group's unique platforms have the potential to make medicines better, lower technical
risks, accelerate regulatory approval and route to market, and provide newly
patentable products
The platform nature of the technologies allows the potential to develop multiple drug
assets, rather than being reliant on a limited number of programmes
To date, this de-risked approach has seen programmes MTD201 (Q-Octreotide) and
MTX110 successfully entering the clinic (Phase 1) in May 2018 and continued to make
good progress on their routes to market
In July 2019, MTX102 also completed an EU-sponsored Ph.1 diabetes vaccine trial
277. 277
Platform Technologies
Midatech has developed three in-house technology platforms (36 patent families including 120
granted patents and an additional 70 patent applications) that are focused on improving
biodistribution and bio-delivery of medications in different ways – either via sustained delivery,
targeted delivery, or direct delivery
Each technology has its own unique mechanism and has successfully entered human use in the
clinic, providing important validation of the potential for each platform
278. 278
Q-Sphera
: Microsphere Technology for Sustained Release Applications
Sustained delivery is achieved using polymer microsphere technology Q-Sphera™,
which is based on Midatech’s disruptive micro-piezo print production innovation to
individually print drug-loaded microspheres in the size range 20-50µm, at a rate of
several million spheres per second. Microsphere dimensions are consistently
monodispersed and homogenous and can be thus finely tuned to accurately customize
drug release rates
Reliable and precise encapsulation enables drug release into the body in a highly
controlled and predictable manner over a prolonged period of time, from a few weeks
to more than six months
Q-Sphera™ microspheres have improved injectability characteristics compared to
traditional manufacturing methods, requiring a much simpler, error free and shorter
reconstitution process
279. 279
Q-Sphera
: Microsphere Technology for Sustained Release Applications
The monodispersed particles avoid needle blockage and facilitate the use of smaller
gauge needles with reduced injection pain
Q-Sphera™ formulations typically yield consistent and reproducible blood and local
tissue drug concentrations within tight limits
Q-Sphera’s flexible, monodispersed formulation capabilities have been demonstrated
to offer superior homogeneity vs traditional PLGA manufacturing
Q-Sphera™ lead program is MTD201, which is seen as a superior alternative To
Sandostatin® LAR, an octapeptide used to treat acromegaly
283. 2023-07-10 283
Overview of ODT formulations
Because of its ease of swallowing, discomfort avoidance, adaptability, and, most
importantly, patient compliance, oral medication administration is preferred
Many patients find tablets and capsules difficult to swallow and many no longer
take their medications as recommended
It is estimated that 50% of the population is affected by these issues, which
leads to a higher risk of noncompliance and less effective treatment
For these reasons, tablets that may collapse in the oral cavity, have attracted big
attention
Solids dosage forms as oral tablets have the most huge place some of the
entire pharmaceutical formulations
Taste -covering is a vital steps withinside the formulation of an acceptable fast
dissolving/disintegrating tablet (FDDT)
Traditional tablet formulation generally do not solve the issue related to taste
masking, because it is supposed that the dosage from will not disintegrate until
it passes through the oral cavity
284. 2023-07-10 284
The put off the bitterness the pill can be organized through sugar coating on the
tablets
Many FDDT Technologies combine of taste masking as well
ODTs technology which make drugs dissolve or disintegrate in the oral hallow space
without any additional water intake has drawn an extraordinary deal of attention
ODTs are a solid dosage shape that provides the speedy disintegration or dissolution
of solid to offer as suspension or answer shape even when placed in the mouth under
restricted bio-fluids
Orally disintegrating capsules unknown through diverse call consisting of or
dispersible pills, shorts disintegrating pill speedy disintegrating pills, rapid or fast
dissolving pills, porous drugs mouth dissolving pills, porous drugs mouth dissolving
pills and rapimelts
European pharmacopoeia has used the term Oro dispersible tablets
This can be described as uncoated pill meant to be positioned in mouth wherein, they
disperse with no trouble inside 3 min earlier than swallowing
Overview of ODT formulations
285. 2023-07-10 285
Despite of extraordinary development in pills delivery, the oral direction stays the
right direction stays the precise direction for the managements of marketers due to
low price of therapy, ease of administration, correct dosage, self- medication, ache
avoidance, versatility, main to high levels of affected person compliance
Pills and tablets are the maximum famous dosages shape
However, one crucial downside of such dosage shape is dysphasia or problems in
swallowing
This is visible to stricken almost 35/ of the overall population
This disease is likewise related to a no of situation
Overview of ODT formulations
Children
Parkinsonism
Motion sickness
Elderly patients
Mentally disabled persons
Unavailability of water
Unconsciousness
286. 2023-07-10 286
Ideal properties of ODT’S
ODTs are being desired as superior dosage paperwork in most times over traditional
instant launch dosages bureaucracy for diverse classes of drugs
It’s far anticipated to undergo sure first -rate function that make the misdeal
ODTs fall apart or dissolve in mouth inside a completely brief time
They do not require water in administration gift desirable flavor masking residences
mouth feel, solid in environmental situations and need to now no longer leave any
residue in mouth after oral administration
ODTs now no longer require water on administration, gift applicable flavor covering
properties, have to have excessive pills loading capacity attractive mouth feel, strong in
environmental situations and have to now no longer leave any residue in mouth after
oral administration
The benefit provided with the aids of using ODTs over instant launch formula might
also additionally encompass ease of method designing and manufacturing ,unit
packaging, smooth to deal with through patients no want of water to administer
speedy disintegration of pill outcomes in brief dissolution and speedy absorption
which can cause enhanced healing performance because of extended bioavailability
287. 2023-07-10 287
Limitations of ODTs
Most of instances soluble diluents used for formulating ODTs would possibly render
hygroscopic dosage which may also result in balance issues
The pill can also additionally depart ugly flavor and /or grittiness in mouth if now
no longer formulated properly
Specialized packing is probably required for hygroscopic and mild touchy drugs
Precautions to be taken whilst administrating immediately after removing from
pack
Rapid drug therapy intervention.
After oral managements they have to go away minimum or no residue in mouth
The mouth feel should be pleasant
290. 2023-07-10 290
Advantages of ODx and unmet needs of these formulation
ODG—orodispersible granules / ODT—orodispersible tablet
OL—oral lyophilizate / ODF—orodispersible film
