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Novel Dosage Forms
And Drug Delivery
Technologies
Main Contents
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1. Introduction
2.Topical Administration
3.Oral Administration
4.Vaginal Administration
5.Ophthalmics
6.Parenteral Administration
7.Peglated Dosage Forms
8.Fusion Protein
9.Implants
10.Other Novel Delivery Systems
2
Introduction
• This chapter discusses novel drug delivery
systems that are modifications of those
previously presented, are relatively new
on the market, or do not fit into
categories in previous chapters.
• They may be relatively new, use new or
relativel new delivery systems, or use
unique delivery systems or unique devices
before, during, or after administration.
3
Introduction
• Changes are coming about as new
technologies are developed and reduce
the limitations of existing therapies.
• In some cases, the new drugs require new
delivery systems because the traditional
systems are inefficient or ineffective;
this may be true especially of some of the
recombinant DNA and gene therapies of
the future.
4
Benefits:
•
•
•
•
A) improvement of patients’ compliance;
B) improved outcomes;
C) reduction of adverse effects;
D) improvement of patients’ acceptance of
the treatment;
• E) avoidance of costly interventions such as
laboratory services;
• F) allowing patients to receive medication as
outpatients
• G) a reduction in the overall use of medicinal
resources.
5
Therapeutic benefits
• Optimization of the duration of
action of the drug;
• Decreasing dosage frequency,
• Controlling the site of release,
• Maintaining constant drug level
6
Safety benefits
• Reducing adverse affects,
• Decreasing the number of
concomitant medications patient must
take,
• Decreasing the need for
interventions
• Reducing the number of emergency
department visits
7
Economic benefits
• Simplifying administration regiments;
• Enhancing patients’ compliance
• An overall reduction of health care
costs
8
Introduction
• The therapeutic efficacy of selected
products can be enhanced and in
some cases the toxicity can be
decreased by incorporating novel
drug delivery technologies.
9
Introduction
• With these novel dosage forms and
drug delivery technologies, some
therapies may become very site
specific; and more controlled drug
delivery systems will be available in
the very near future.
10
11
Mechanisms
• Physical mechanisms, also referred to
as controlled drug delivery systems,
including：
• Osmosis, diffusion,
• erosion, dissolution,
• and eletrotransport
12
Mechanisms
Biochemical mechanisms, including:
Monoclonal antibodies,
Gene therapy and vector systems,
Polymer drug abducts
Liposomes
13
Composition
• New drug delivery systems base on
polymer technologies.
• The polymers rang from naturally
derived substances, such as gelatin
and sugars, to the more
• complex polymers.
14
Composition
• For example, degradable bonds can
be used to attach an active drug to a
synthetic or naturally occurring
polymer—this is usually called
Bioconjugates.
15
Bioconjugates
16
Composition
• Upon delivery to the target site and
in the presence of certain enzymes
or through hydrolysis or a
comparable mechanism the
bioconjugates can be cleaved,
releasing the active drug at a specific
site of action.
17
Potential problems of the
polymers based systems
• A) Their high molecular weight may cause
them to be very slowly excreted from the
body,
• B) Because of their size, permeability
through various membranes may be slow
• C) Immunologic or toxic reactions may
occur
• D) Since they are complex, they may be
labor intensive and expensive to develop.
19
2.Topical Administration
• Novel topical systems, also called
transdermal drug delivery systems
are patches involves percutaneous
absorption.
20
Barriers for
transdermal delivery
21
Iontophoresis
• Iontophoresis (IP) is an
electrochemical method that
enhances the transport of some
solute molecules by creating a
potential gradient through the skin
with an applied electrical current or
voltage.
22
23
Iontophoresis
24
1. An adhesive patch contains
a thin electrode and the
drug-containing gel in
contact with the skin;
2. The battery-powered
microcontroller activates
the electrode with a mild
current repelling the drug
into the skin;
3. Depending on the dose and
energy, the drug can act
either locally or can be
carried into the
bloodstream.
图 离子导入示意图
26
Advantages of IP
• (a) Control of the delivery rates by variations of
current density, pulsed voltage, drug
concentration, and ionic strength
• (b) Eliminating gastrointestinal incompatibility,
erratic absorption, and first-pass metabolism
• (c) Reducing side effects and variation among
patients
• (d) Avoiding the risks of infection, inflammation,
and fibrosis associated with continuous injection
or infusion
• (e) Enhancing compliance with a convenient and
noninvasive therapeutic regimen.
27
补充内容
Macroflux® technology
• Macroflux® technology（微针技术）
incorporates a titanium microprojection
array affixed to a polymeric adhesive
back .
• When the patch is applied to the skin,
the drug-coated microprojections
penetrate through the skin's barrier
layer into the epidermis.
28
Macroflux® technology
• Drug is absorbed by the microcapillaries
for systemic distribution.
• The rate of absorption is promoted by the
high local drug concentration around the
microprojections and the large surface
area provided by the patch array.
29
Macroflux® 是一种新兴的透
皮给药技术…
具有长约 200µm的钛制微针头，
携带药物微针头
可以穿透角质层
角质层 (10-15 µm)
表皮层 (50-150 µm)
真皮层
30
Macroflux® 系统用于控释贴剂
的使用和药物输送
携带药物的Macroflux® 贴片
通过安装器贴置Macroflux®
片: 加压
贴片支撑环
贴片
安装器
贴置后
31
Macroflux® 贴片敷用人体皮肤后的
研究证明了它具有良好的耐受性和疗效
毛
治疗前
治疗后
褪色的亚甲基蓝
Macroflux® technology
• Macroflux ® transdermal patch
technology has been developed to
deliver biopharmaceutical drugs in a
controlled, reproducible manner that
optimizes bioavailability and efficacy
without significant discomfort for
the patient.
33
• Dr. Peter Daddona is Vice
President of Biological Sciences
and Macroflux® Research and
Development at ALZA
Corporation in Mountain View,
California.
•He also has an appointment as Consulting
Associate Professor of Dermatology at Stanford
University.
34
3.Oral administration
• (1) Chewable Dispersible Tablets（咀嚼分
散片）
• (2) Mucoadhesive System（粘附给药系统）
• (3) Osmotic Pump（渗透泵）
• (4) Oral inhalation（经口腔吸入剂）
35
3(1) Chewable Dispersible Tablets
• Lamotrigine(拉莫三嗪)咀嚼分散片
• 虽然有普通拉莫三嗪口服片剂，咀嚼分
散片因其可以吞服、咀嚼或溶解在水中，
而极大地增加了病人（儿童）的顺应性。
36
Advantages
• 咀嚼分散片同时具有其他片剂、胶囊、颗粒
剂、干混悬剂、干糖浆剂的全部优点。
◇ 直接吞服（具有片剂及胶囊的优点）
◇ 含服（具有含片的优点）
◇ 咀嚼服用（具有口嚼片及口腔崩解片的
优点）
◇ 投入温水、牛奶或果汁中，搅拌成混悬
状态后服用（三分钟内即可全部崩解，具有
颗粒剂、干糖浆剂及冲剂的优点）
37
Formulation
• Chewable Dispersible Tablets具有崩解快
（3min内）、分散状态佳、药物溶出迅
速；起效快的特点。
• 高效崩解剂；
• 水溶性辅料；
• 高效矫味剂和矫臭剂
38
Cetirizine Chewable
Dispersible Tablets
•
•
•
•
•
•
•
•
•
polyvinylpyrrolidone ( PVP,聚乙烯吡咯烷酮)
mannitol(甘露醇)
Lactose(乳糖)
microcrystalline cellulose(微晶纤维素)
amylum pregelatinisatum (预胶化淀粉)
magnesium stearate(硬脂酸镁)
AsPartame (阿斯巴甜)
苹果酸(malic acid)
为主要辅料制备盐酸西替利嗪咀嚼分散片
39
3(2) Mucoadhesive System
• Columbia公司于2003年6月
20日宣布，它的Striant(睾酮
颊系统,testosterone buc
cal system)粘膜粘着剂(CⅢ)
获FDA批准，用于男性内源睾
酮缺失或缺乏，包括性腺机能
减退。
40
testosterone buccal
system
• 这是迄今第一个用于睾酮替代治疗(TRT)
的经颊(牙龈表面)治疗药。
• testosterone大小如同一片阿司匹林，
可快速黏附在牙龈与上唇交接处，能够
在12小时内向口腔黏膜缓慢释出睾酮。
41
testosterone
•处方中使用了粘附性辅料
•carbomer 934P(卡波姆)，
•Polycarbophil(聚卡波非),
•Hypromellose(羟丙甲纤维素)
42
• 其他包括
• anhydrous lactose（无水乳糖）,
• lactose monohydrate（乳糖一水合物）,
• magnestium stearate（硬脂酸镁）,
• colloidal silicon dioxide (胶体二氧化硅),
• Starch（淀粉） and
• talc（滑石粉）
43
Carbopol polymers
• Carbopol
polymers
are polymers of
acrylic acid(丙烯酸)
cross-linked with
Polyalkenyl ethers
or divinyl glycol.
44
Carbopol polymers are offered as
fluffy, white, dry powders (100%
effective).
• The carboxyl groups provided by the
acrylic acid backbone of the polymer are
responsible for many of the product
benefits.
• Carbopol polymers have an average
equivalent weight of 76 per carboxyl
group
45
General Structure of Carbopol Polymers
46
Carbopol polymers
• Carbomers readily absorb water, get
hydrated and swell.
• In addition to its hydrophilic nature,
its cross-linked structure and its
essentially insolubility in water makes
Carbopol a potential candidate for
use in controlled release drug
delivery system
47
3(3) Osmotic Pump
• ALZET® Osmotic Pumps
are miniature, infusion
pumps for the continuous
dosing of laboratory
animals as small as mice
and young rats.
• These mini-pumps provide
researchers with a
convenient and reliable
method for controlled
agent delivery in vivo.
48
ALZET® Osmotic Pumps
• Alzet渗透压泵（又称植入式渗透压缓释
泵、Alzet Osmotic Pumps）是ALZA公
司于二十世纪七十年代发明的一种用于
体内药物缓释的工具。ALZA公司是一
家著名的药物研发公司，由其研发的
Alzet植入式胶囊渗透压泵一开始是用于
公司内部和相关科研机构做药物测试用
的
49
ALZET® Osmotic
Pumps
• 但是不久之后，由于渗透压泵卓越的性
能和简便的使用方法，市场上对这种植
入式胶囊渗透压泵逐渐有了需求，于是
ALZA于1977年将这种产品作为一种生
物医学研究的工具投放了市场。
50
ALZET® Osmotic Pumps
51
ALZET® Osmotic Pumps
52
ALZET® MINI-OSMOTIC PUMP
MODEL 2006
• The ALZET mini-osmotic pump Model
2006 delivers solutions continuously
for 42 days without the need for
external connections or frequent
handling of animals.
• This product is for use in
experimental animals only.
53
The development of miniature
implantable osmotic pumps in the
mid-1970s was a major breakthrough
to deliver wide range of drugs and
hormones, including peptides at
constant and programmed rate in
mice, rat and larger animals.
54
These implants provide a convective stream
of drug solution that can be directed
through suitable catheter connections to
sites in the animal remote from itself.
Most recently the implantable pumps for
human use are developed to delivery the
drug for targeting or systemic application.
55
3(4) Oral Inhalation
• Advair Diskus
• (氟替卡松和沙美特罗吸入剂<平喘药>)
Advair inhalation is used to prevent
asthma attacks.
• It is used only to prevent asthma attacks,
not to treat an attack already in progress
since it does not work fast enough to give
relief during an attack.
56
Advair Diskus
• Advair is a mixture two drugs Fluticasone
and Salmeterol(丙酸氟替卡松及沙美特罗 )
• Fluticasone is a corticosteroid and prevents
the release of substances in the body that
cause inflammation.
• Salmeterol is a beta2-adrenergic
bronchodilator, which works by relaxing
muscles in the airways to improve breathing.
57
• ADVAIR may help if you have Chronic
obstructive pulmonary disease ( COPD,
老年慢性阻塞性肺病), including chronic
bronchitis(支气管炎), emphysema(肺气
肿), or both.
• ADVAIR helps significantly improve lung
function so you can breathe better.
• ADVAIR is different from most medications
because it contains both an anti-inflammatory
and a long-acting bronchodilator(支气管扩张药)
working together to help you breathe better.
58
Advair Diskus
59
Advair Diskus
60
How to use
• 1. Open.
• Hold the DISKUS in
one hand and put the
thumb of your other
hand on the
thumbgrip. Push your
thumb away from you
as far as it will go
until the mouthpiece
appears and snaps
into position.
61
How to use
• 2. Click.
• Hold the DISKUS in a
level, flat position with
the mouthpiece toward
you. Slide the lever away
from you as far as it will
go until it clicks. The
DISKUS is now ready to
use. Every time the lever
is pushed back, a dose is
ready to be inhaled. This
is shown by a decrease in
numbers on the dose
counter.
62
How to use
• 3.Inhale.
• Put the mouthpiece to
your lips. Breathe in
quickly and deeply
through the DISKUS. Do
not breathe in through
your nose. Remove the
DISKUS from your
mouth. Hold your breath
for about 10 seconds, or
for as long as is
comfortable. Breathe
out slowly.
63
3.Inhale.
• Before inhaling your
dose from the
DISKUS, breathe
out (exhale) fully
while holding the
DISKUS level and
away from your
mouth. Remember,
never breathe out
into the DISKUS
mouthpiece.
64
How to use
• 4. CLOSE the DISKUS
• when you are finished taking a dose so
that the DISKUS will be ready for you to
take your next dose. Put your thumb on
the thumbgrip and slide the thumbgrip
back toward you as far as it will go. The
DISKUS will click shut. The lever will
automatically return to its original
position. The DISKUS is now ready for
you to take your next scheduled dose, due
in about 12 hours.
65
概述
•
EXUBERA®
补充内容
EXUBERA® (insulin human
[rDNA origin]) Inhalation Powder is
approved in both the U.S. and the EU
for adults with type 1 and type 2
diabetes on Jan.27,2006.
• Nektar developed the inhaler and the
powder insulin formulation for Exubera®.
Pfizer, is responsible for marketing and
promoting Exubera® worldwide.
66
•
•
Exubera® is a rapid-acting,
dry powder human insulin that
is inhaled through the mouth into the
lungs prior to eating, using the
handheld Exubera® Inhaler.
• The Exubera® Inhaler weighs four
ounces and, when closed, is about the
size of an eyeglass case.
67
•
The unique Exubera® Inhaler
produces a cloud of insulin powder
(＜5μm) in a clear chamber visible to
the patient.
•
This insulin powder is designed
to pass rapidly into the bloodstream
to regulate the body’s blood sugar
levels.
68
• The insulin dry powder is packaged
into a single-dose bliser containing
1 or 3 mg, with a 1 mg blister
corresponding to ～3 units of insulin.
• The bioavailability of this product
is about 10% compared to regular
human insulin given by subcutaneous
route.
69
Exubera
70
Inhaled device produced by Nektar Therapeutics
71
Exubera
72
73
The AIR Inhaled Insulin System
By Eli Lilly
74
• (A) AIR Insulin Inhaler and AIR Insulin capsules
to demonstrate relative size.
• (B) Closeup of AIR Insulin capsules.
• Percent of maximum glucose infusion rate (GIR) versus
time after administration of 12 U of insulin lispro
• subcutaneously (SC) and 12 U-equivalent AIR Insulin.
Technosphere® Insulin
Technology by Mannkind (the
inhaler folded closed)
77
• The MedTone inhaler (A) with the TI
capsule
78
• Similar insulin exposure results in reduced
glucose exposure with TI in a meal-challenge
study conducted in patients with type 2 diabetes.
Generex Oral-lyn™
• Generex Oral-lyn™, is an insulin spray for
the treatment of Type I and Type II
diabetes. Generex Oral-lyn™ is a safe,
simple, fast, effective, and pain-free
alternative to subcutaneous injections of
prandial insulin and is conveniently
delivered to the membranes of the oral
cavity by a simple asthma-like device with
no pulmonary (lung) deposition.
80
Generex Oral-lyn™
81
4. Vaginal Administration
• Vaginal administration of drugs,
especially hormones, has several
advantages, including self-insertion
and removal, continuous drug
administration at an effective dose
level, and good patient compliance.
82
Vaginal Administration
• The continuous release and
local absorption of drug
minimizes systemic toxicity
that may result from oral
peak-and-valley drug
administration.
83
ESTRING®
(estradiol vaginal ring)
• ESTRING ® (estradiol vaginal ring)
is a slightly opaque ring with a
whitish core containing a drug
reservoir of 2 mg estradiol(雌二醇).
Estradiol, silicone polymers and
barium sulfate are combined to
form the ring.
84
ESTRING®
(estradiol vaginal ring)
• Estrogens used in therapeutics are
well absorbed through the skin,
mucous membranes, and the
gastrointestinal (GI) tract.
• The vaginal delivery of estrogens
circumvents first-pass metabolism.
85
ESTRING®
(estradiol vaginal ring)
86
ESTRING®
(estradiol vaginal ring)
87
Intrauterine Progesterone
Drug Delivery System
The Intrauterine
Device (IUD，
宫内节育器) is
a small plastic
T-shaped device
that contains
hormones.
It must be
inserted by a
doctor.
88
89
Intrauterine Progesterone
Drug Delivery System
90
5. Ophthalmics
• One of the problems associated with
the use of ophthalmic solutions is the
rapid loss of administered drug due
to the blinking of the eye and the
flushing effect of lacrimal fluids.
91
To increase the contact time
between the medication and the
corneal surface may be accomplished
• (1) through use of agents that increase
the viscosity of solutions;
• (2) by ophthalmic suspensions in which the
drug particles slowly dissolve;
• (3) by slowly dissipating ophthalmic
ointment;
• (4) or by the use of ophthalmic inserts.
92
5(1) Ophthalmic Gels
• Ophthalmic Gels（眼用凝胶剂） are the
novel preparations that use the viscosityincreasing agents to increase corneal
contact time.
examples
Pilocarpine
-Carbopol 940
Timolol maleate
- gellan gum (Gelrite)
93
眼用凝胶剂
• 凝胶剂粘度较大，可延长药物在眼内的
滞留时间，提高生物利用度。
• 国内已研制成功氯霉素，
• 毛果芸香碱，
• 倍仁米松等
94
Pilocarpine
(Pilopine HS gel)
• PILOPINE HS® (pilocarpine
hydrochloride ophthalmic gel,毛果云香碱)
4% is a sterile topical ophthalmic aqueous
gel which contains more than 90% water
and employs CARBOPOL 940, a synthetic
high molecular weight cross-linked
polymer of acrylic acid, to impart a high
viscosity.
95
How to use Ophthalmic Gels
Wash hands
thoroughly. Apply
the correct amount
of Pilopine HS® Gel
to the edge of your
index finger.
96
How to use Ophthalmic Gels
• Pull down lower
eyelid with middle
finger of other
hand to form a
pouch. Gently roll
the strip of gel
into the eye pouch.
97
How to use Ophthalmic Gels
• Gently squeeze
the lower
eyelid and pull
it slightly away
from your face.
98
How to use Ophthalmic Gels
• Look down and
then close your
eye for a moment.
Wipe off any
excess gel with a
tissue. Repeat in
the other eye if so
directed by your
doctor. Replace
cap.
99
Timolol maleate
(Timoptic-XE )
• TIMOPTIC-XE Sterile
Ophthalmic Gel Forming
Solution is supplied as a
sterile, isotonic,
buffered, aqueous
solution of timolol
maleate in two dosage
strengths.
Timoptic XE
100
The gel forming solution contains a
purified anionic
heteropolysaccharide derived from
gellan gum.
• An aqueous solution of gellan gum, in
the presence of a cation(阳离子), has
the ability to gel.
• Upon contact with the precorneal tear
film, TIMOPTIC-XE forms a gel that is
subsequently removed by the flow of
tears.
101
Structure of Gellan
102
5(2) ophthalmic inserts
• Ophthalmic insert（眼内植入剂）
defined as sterile preparation with
solid or semisolid consisting and
whose size and sharp are especially
designed for ophthalmic application.
103
5(2) ophthalmic inserts
• Ocusert®, pilocarpine(毛果云香碱)
ocular therapeutic system is the
first product marketed by Alza
incorporation USA from this
category.
104
5(2) ophthalmic inserts
• They offer several advantages as
increase ocular residence, possibility
of releasing drug at a slow constant
rate, accurate dosing and increased
shelf life with respect to aqueous
solutions.
105
Pilocarpine Insert
• The Ocusert system, developed by Alza
Corp., contains a core reservoir consisting
of pilocarpine and alginic acid.
• The core is surrounded by a hydrophobic
ethylene/vinyl acetate (EVA) copolymer
membrane, which controls the diffusion of
pilocarpine from the insert.
106
• The mean release rate of drug from the
system over seven days, in micrograms per
hour.
• To rated releases of pilocarpine from the
OCUSERT® system, 20 and 40
micrograms per hour, for one week, are
available
107
108
How To Use Ocusert
Pilo-20 Systems Opht
• To apply the system, wash hands first.
• Tilt your head back, gaze upward and pull
down the lower eyelid to make a pouch.
• Place the system into the pouch.
• Blink a few times and roll your eye to
move the insert into place.
109
Lacrisert
• LACRISERT ® (hydroxypropyl
cellulose ophthalmic insert) is a
sterile,translucent, rod-shaped,
water soluble, ophthalmic insert made
of hydroxypropyl cellulose, for
administration into the inferior
• cul-de-sac of the eye.
110
cul-de-sac of the eye？
• The place where the conjunctiva
folds back from your eye lid to your
eye ball. If you have been told to put
ointment there, it just basically
means to put it inside your lower eye
lid.
111
INDICATIONS AND USAGE
• LACRISERT is indicated in patients
with moderate to severe dry eye
syndromes.
• LACRISERT is indicated especially in
patients who remain symptomatic
after an adequate trial of therapy
with artificial tear solutions.
112
How to use
113
• STEP 1: On a flat
surface, open
blister pocket slowly
and smoothly by
peeling back label
area. Each blister
pocket contains one
Lacrisert ophthalmic
insert.
114
• STEP 2: Open
applicator package with
label side up. Avoid
touching grooved tip of
the applicator. Pick up
applicator by the wide
end and rinse the tip
thoroughly under hot
running tap water.
Gently shake off
excess water.
115
• STEP 3: Hold
applicator with tip
facing down and with
forefinger on top to
guide and apply gentle
pressure. Lightly press
the grooved tip of the
applicator onto the
Lacrisert ophthalmic
insert and it will
adhere to the
applicator.
116
STEP 4: Look into a mirror.
Starting with the right eye,
turn your head to the right
so that the colored part of
the eye is close to your nose.
Use your free hand to grasp
the lower lid between the
thumb and index finger. Pull
the lid away from the
eyeball and create a pocket
between the white part of
the eyeball and the lid.
117
STEP 5:
Place the tip
of
the
applicator
containing Lacrisert into
the
pocket.
Avoid
touching the colored part
of the eye.
•Remove the applicator.
It is important, after
removing the applicator,
to look down, then
release the lower eyelid.
118
Novel Insert
• Another promising technology utilizes
implantable pellets, designed in layers like
an onion.
• Slowly biodegradable polymers gradually
expose and release microscopically thin
wafers of medication into the vitreous
cavity of the eye, providing 6–26 months
of therapy.
• This system has already been FDAapproved.
119
120
6. Parenteral Administration
• Long-Acting Parenteral Systems
• (1) crystal or amorphous drug forms having
prolonged dissolution characteristics;
• (2) solutions or suspensions of drug in slowly
absorbed carriers or vehicles;
• (3) large particles of drug in suspension
• (4) slowly eroding microspheres of drug
121
Examples of proprietary extended action parenteral products
Products
Contents and comments
Bicillin C-R injection
（Wyeth-Ayerst）
Contains penicillin G benzathine, penicillin G
procaine, which have low solubility, are slowly
released from IM injection sites. Hydrolyze to
penicillin G, Hydrolysis plus slow absorption results
in prolonged blood serum levels. Usual dose interval,
2-3days
Decadron-LA Sterile
Suspension (Merk)
Contains dexamethasone acetate, very insoluble ester
of dexamethasone. Repository IM injection may be
repeated as needed at 1=3 weeks.
Depo-Provera Contraceptive
Injection (Pharmacia ＆
Upjohn)
Medroxyprogesterone acetate, water-insoluble, in
aqueous suspension. Single IM dose is repeated q3mo
Abelcet Amphotericin B lipid
Complex injection
（Liposome Company）
Suspension of amphotericin B complexed with two
phospholipids administered by IV infusion qd.
Lupron Depot for Suspension Sterile lyophilized microspheres; mixed with diluent,
(TAP Pharmaceuticals)
fom IM injection suspension q3-4mo
Liposomes
• Liposomes(脂质体) are composed of small
vesicles of a bilayer of phospholipid
encapsulating an aqueous space ranging from
about 0.03 to 10μm in diameter.
• They are composed of one or many lipid
membranes enclosing discrete aqueous
compartments.
• The enclosed vesicles can encapsulate watersoluble drugs in the aqueous spaces, and lipidsoluble drugs can be incorporated into the
membranes.
123
Liposomes
124
Transmission electron
photomicrographs of liposomes
125
126
Liposomes
• Liposomes can be administered
parenterally, topically, by inhalation,
and possibly by other routes of
administration.
• Current products are administered
parenterally.
127
The preparation of Liposomes
• (1) Prepare a solution of a lipid (lecithin) in an
organic solvent (acetone, chloroform) in a
beaker.
• (2) Allow the solvent to evaporate, leaving a thin
film of the lipid on the walls of the container.
• (3) Add an aqueous solution of the drug to the
beaker and place it in an ultrasonic bath. As the
lipid is displaced from the beaker walls, it forms
spheres or cylinders,trapping the aqueous
solution inside.
• (4) The liposomes can be collected, sized, and
used.
128
The category of liposomes
•
•
•
•
single unilamellar vesicles, SUV
large unilamellar vesicles, LUV
multilamellar vesicles, MLV
Multivesicular vesicles, MVV
129
The category of liposomes
130
The components of liposomes
• Phospholipid and cholesterol are
usually combined to form liposomes.
Lecithin （phosphatidylcholine）
Phospholipid
Dipalmitoylphosphatidylcholine
(DPPC,二棕榈酰磷脂酰胆碱)
Dimyristoylphosphatidylcholine.
(DMPC,二肉豆蔻酰磷脂酰胆碱)
131
磷脂结构：
The general formula of lipid
结构通式如下：
式中：R1、R2 是疏水链，R由C12～C18，可为饱和烃
链或不饱和烃链；X为亲水头，X不同，则磷脂命名不
同
132
133
134
cholesterol
135
The arrangement of lipid and cholesterol
136
The bilayer of the liposomes
137
The formation of liposomes
138
Micelles
Liposomes
139
The targeting mechanism
of liposomes
• The liposomes can be selectively absorbed
by tissues rich in reticuloendothelial cells,
such as the liver, spleen, and bone marrow.
• This can serve as a targeting mechanism,
but it also removes liposomes from the
circulation rather rapidly.
140
stealth liposomes
• To extend the half-life of liposomes in
the body, “stealth liposomes” have been
developed by coating the liposomes with
materials, such as the polymer
polyethylene glycol (PEG), enabling
liposomes to evade detection through the
components of the body’s immune system
• This extends their half-life and may also
alter their biodistribution.
141
stealth liposomes
142
143
The advantages of liposomes
• (1) Liposome-encapsulated drugs are
delivered intact to various tissues and
cells and can be released when the
liposome is destroyed, enabling sitespecific and targeted drug delivery
• (2) Liposomes can be used for both
hydrophilic and lipophilic drugs without
chemical modification
144
The advantages of liposomes
• (3) Other tissues and cells of the body
are protected from the drug until it is
released by the liposomes, decreasing the
drug’s toxicity
• (4) The size, charge and other
characteristics can be altered depending
on the drug and the intended use of the
product.
145
The disadvantages of liposomes
• Disadvantages of liposomes include their
tendency to be taken up by cells of the
reticuloendothelial system(RES) and the
slow release of the drug when the
liposomes are taken up by phagocytes
through endocytosis, fusion, surface
adsoption or lipid exchange.
146
147
Abelcet Injection
• ABELCET ® is a sterile,
pyrogen-free suspension
for intravenous infusion.
ABELCET ® consists of
amphotericin B complexed
with two phospholipids in
a 1:1 drug-to-lipid molar
ratio.
148
Abelcet Injection
• The two phospholipids,
• L--dimyristoylphosphatidylcholine (DMPC) and
• L--dimyristoylphosphatidylglycerol (DMPG),
• Are present in a 7:3 molar ratio.
• ABELCET ® is yellow and opaque in appearance,
with a pH of 5 - 7.
149
ABELCET ® is provided as a sterile,
opaque suspension in 20 mL glass, singleuse vials.
• Each 20 mL vial contains 100 mg of amphotericin
B , and each mL ofABELCET ® contains:
•
•
•
•
•
Amphotericin B USP
5.0 mg
DMPC
3.4 mg
DMPG
1.5 mg
Sodium Chloride USP
9.0 mg
Water for Injection USP, q.s. 1 mL
150
DaunoXome
Daunorubicin citrate
liposome injection
151
Each vial contains daunorubicin citrate
equivalent to 50 mg of daunorubicin base,
encapsulated in liposomes consisting of 704
mg distearoylphosphatidylcholine(DPPC)
and 168 mg cholesterol.
152
• The liposomes encapsulating daunorubicin
are dispersed in an aqueous medium
containing
• 2,125 mg sucrose, 94 mg glycine, and 7 mg
calcium chloride dihydrate in a total
volume of 25 mL/vial.
• The pH of the dispersion is between 4.9
and 6.0.
153
Stealth liposomes
-Doxil
154
Preparation for Intravenous
Administration
• Each 10-mL vial contains 20 mg doxorubicin
HCl at a concentration of 2 mg/mL.
• Each 30-mL vial contains 50 mg doxorubicin
HCl at a concentration of 2 mg/mL.
• DOXIL doses up to 90 mg must be diluted in
250 mL of 5% Dextrose Injection, USP prior
to administration.
155
Preparation for Intravenous
Administration
• Aseptic technique must be strictly
observed since no preservative or
bacteriostatic agent is present in
DOXIL.
• Diluted DOXIL should be refrigerated
at 2°C to 8°C (36°F to 46°F) and
administered within 24 hours.
156
Pegylated Dosage Forms
• PEGylation is the process of covalent
attachment of poly(ethylene glycol)
polymer chains to another molecule,
normally a drug or therapeutic
protein.
-------------- See the last chapter
157
Fusion Protein:
Special Handing
Ontak （白介素融合毒素）
• Ontak is a recombinant DNAderived cytotoxic protein composed
of the amino acid sequences for
diphtheria toxin (白喉毒素)
fragments A and B followed by the
sequences for interleukin 2 (IL-2).
158
Ontak （白介素融合毒素）
• Ontak is a fusion protein designed to
direct the cytocidal action of
diphtheria toxin to cells that express
the IL-2 receptor.
159
Ontak
• The single-use vials (2ml)
contain 300 μg of recombinant
denileukin diftitox in a sterile
solution of 20mM citric acid
(柠檬酸), 0.05 mM
ethylenediaminetetra-acetic
acid (EDTA) and less than 1%
polysorbate 20 in water for
injection; the pH of the
solution is between 6.9 and 7.2.
160
Ontak（白介素融合毒素）
• 利用基因重组把白喉毒素A和B段基因与白介素-2基
因连接，转染大肠杆菌产生白介素-2和免疫毒素复
合物。
• 作用机制：本品是白介素-2和免疫毒素的融合剂，
可以介导白喉毒素的细胞毒作用，杀伤表达IL-2受
体的细胞。
• 包括皮肤T细胞淋巴瘤在内的某些白血病和淋巴瘤细
胞表达一种以上IL-2受体亚单位。
• 本品与细胞表面高亲和性IL-2受体结合，通过白喉
毒素作用，抑制细胞蛋白合成，导致细胞几小时内
死亡。
• 价格:1200美元/瓶
161
Implants
• Implants (植入剂) are defined as
sterile solid drug products made by
compression, melting, or sintering.
• They fenerally consist of the drug
and rate-controlling excipients.
162
163
左炔诺孕酮植入剂
• Norplant，即左炔诺孕酮植入剂，
• 1975年由ICCR研制，芬兰Leiras药厂生
产。埋置于皮下，效果可维持五年。
应用非常广泛，是最成功的植入剂。
164
左炔诺孕酮植入剂
• Norplant采用医用硅橡胶管作材料，管
长34mm，外径2.4mm，内径1.57mm，
内装左炔诺孕酮微晶(<20μm)36mg，
两端用硅橡胶粘合剂封固，在水蒸气罩
内24h使粘接，经环氧乙烷灭菌即得。
165
Gliadel Wafer Implants
• Polifeprosan 20 with
carmustine implant
(Gliadel Wafer
Implants,卡莫司汀植
入膜剂 ) is a sterile
off-white to pale
yellow wager
approximately 1.45
cm in diameter and
1mm thick.
166
Wafer implants are a new way of giving
chemotherapy for brain tumours.
The wafer is made of
gel that contains a
chemotherapy drug.
During brain surgery
to remove some or all
of a tumour, the
doctor places up to 8
wafers in the space
where the tumour was.
167
Gliadel Wafer Implants
Over the next few days, the wafers
slowly release a chemotherapy drug
called carmustine (BCNU,卡氮芥or卡
莫司汀) into this area.
The wafers dissolve between 2 to 3
weeks after they are put in.
168
Gliadel Wafer Implants
• Gliadel为一角硬币大小的薄膜，包含生物可降解聚
合物聚苯丙生20和7.7mg卡莫司汀（carmustine，
BCNU），卡莫司汀是治疗恶性胶质瘤的常用静脉
给药的化疗药物。当手术切除脑瘤时，在经手术创
建的空腔中可最多植入8片本品。
• 在植入处，Gliadel将缓慢溶解，直接向肿瘤部位释
放高浓度卡莫司汀，使扩撒到其它部位的药物减至
最少。
• Gliadel适应证是新诊断为高度恶性胶质瘤的患者的
手术和放疗辅助药物，也可作为多形性胶质母细胞
瘤（GBM）复发患者的手术辅助用药。
169
Six Steps to Using GLIADEL® Wafer
• 1. Preparation for Use
• Maximize resection of tumor
Send tumor specimen to
pathologist to confirm
malignant glioma
Achieve hemostasis before
implantation to eliminate
bleeding
Obtain clear irrigation fluid
170
2. Handle Wafers carefully
due to fragility and toxicity
of carmustine
• Use double surgical gloves
Use a surgical instrument
dedicated to wafer
handling
Keep wafer pouches
unopened until implantation
171
3. Opening the GLIADEL
pouch (outer surface of foil
pouch is not sterile)
• Open outer pouch: peel
folded corner in outward
motion
Do not pull downward this
may break wafer
Remove inner pouch: with
forceps, grab crimped edge,
pull upwards
Open inner pouch: gently
hold crimped edge, cut
around wafer
Remove wafer: gently grasp
with forceps, place onto
sterile field
172
4. Implanting GLIADEL
• Line resection cavity surface with
wafers
Cover entire surface of cavity using
mosaic pattern, using up to eight wafers
(7.7 mg carmustine each)
Pack wafers close without stacking;
slight overlap and halving wafers are
acceptable
If necessary, stretch surface area to
maximize exposure to wafers
Prevent wafer migration into ventricular
system and obstructive hydrocephalus by
closing any communication larger than a
wafer before implantation
Dispose of unused wafers
173
5. Securing the
Wafers
• Anchor wafers with ½-inchwide strips of Surgicel®
(oxidized cellulose),
starting at bottom of
cavity and moving up
Keep Surgicel® strips 1
layer deep: do not create
large mass
174
6. Ensure watertight
dural closure
• Take extra care to
decrease risk of CSF leaks
and infection
Suction to ensure no blood
in cavity
Irrigate resection cavity
before closure
If necessary, use a graft
of autologous,
nonsynthetic or synthetic
dura patch or substitute
175
Zoladex Implant
• Fosterelin acetate
implant(Zoladex) is a
sterile, biodegradable
product containing
goscerelin acetate(戈舍
瑞林), equivalent to
3.6mg of drug, designed
for subcutaneous
injection with continuous
release over 28days.
ZOLADEX 3.6 MG IMPLANT SYRN
176
Zoladex Implant
• 诺雷德是一种可在体内逐渐进行生物降解的
多聚缓释植入剂。
• 无菌、白色或乳白色柱形，含醋酸戈舍瑞林
（相当于3.6毫克戈舍瑞林），置于一注射
器中，单剂量给药
• 诺雷得具有几乎完全的生物利用度，每四周
用药一次
177
Zoladex Implant
• Goserelin acetate is
dispersed in a matrix
consisting of D,Llactic and glycolic
acids copolymer
(PLGA) containing less
than 2.5% acetic acid
and up to 12%
goserelin-related
substances.
ZOLADEX 10.8 MG IMPLANT SYRN
178
• It is a sterile white to
cream-colored cylinder 1
mm in diameter, preloaded
in a special single-use
syring with a 16-gauge
needle.
Zoladex (1 month): 3.6mg in a biodegradeable depot;
single-dose syringe applicator.
Zoladex LA (3 months): 10.8mg in a biodegradeable
depot; single-dose syringe applicator.
179
Zoladex Implant
• The product is administered
subcutaneously into the upper abdominal
wall using aseptic technique.
• Goserelin is used in men to treat prostate
cancer. It is used in women to treat
certain breast cancers or a certain uterus
disorder (endometriosis).
180
Other novel delivery
systems
• DEFINITY® is a vial of Perflutren
• (全氟丙烷<超声造影药>)
• Lipid Microspheres for preparing and
injectable suspension.
181
DEFINITY®
• DEFINITY® is indicated for use in
patients with suboptimal echocardiograms
to opacify the left ventricular chamber
and to improve the delineation of the left
ventricular endocardial border.
• DEFINITY® significantly improves
visualization in difficult-to-image
segments
182
Autoinjection systems
• Epipen autoinjectors are designed as
emergency supportive therapy of
allergic reactions and are not a
replacement or subsititute for
immediate medical or hospital care.
183
EpiPen
184
Autoinjection
185
Humlin N Pen
186
Safe-Needle Systems
187
Safe-Needle Systems
• Lovenox
189
FDA批准 Lovenox(R)
用于治疗最严重的心脏病
• Lovenox(R) 是一种抗血栓形成药剂中的独特
化学实体，是一种低分子肝素 (LMWH)。作
为全球最畅销的低分子肝素，Lovenox(R) 可
通过肝磷脂苄基酯的碱降解而得到，大约是
普通肝素分子大小的三分之一。Lovenox(R)
是被人们研究最为广泛的低分子肝素，15年
来治疗了96个国家的1.3亿名患者。
190
review questions
• 1. The benefits of the novel dosage forms and drug
delivery technologies
• 2. The Advantages of iontophoresis
• 3. How to increase the contact time between the
medication and the corneal surface
• 4. The category of Long-Acting Parenteral Systems?
• 5. What is liposomes? The advantages and the
disadvantages of liposomes
• 6. What is Implant? What is Zoladex Implant?
191
192
193