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14. Parenterals
Contents
Injections
Small volume parenterals
Large volume parenterals
Special considerations associated with
parenteral therapy
Other injectable products-pellets or
implants
Irrigation and dialysis solutions
Injections
Injections are sterile, pyrogen-free
preparations intended to be administered
parenterally.
（注射剂为用于注射给药的无菌、无热原的
制剂）
The term parenteral refers to the injectable
routes of administration.
Pyrogens are fever-producing organic
substances arising from microbial
contamination and are responsible for
many of the febrile reactions which occur
in patients following intravenous injection.
热原为来自微生物污染引起发热反应的有
机物质，是造成许多患者在静脉注射后产
生高热反应的原因。
Parenteral Routes of Administration
1) Intravenous route
Intravenously administered drugs provide
rapid action compared with other routes of
administration.
In emergency situations, the intravenous
administration of a drug may be a lifesaving procedure.
On the negative side, once a drug is
administered intravenously, it cannot be
retrieved.
Strict aseptic precautions must be taken at
all times to avoid risk of infection.
Not only are the injectable solutions sterile,
the syringes and needles used must also
be sterilized,
and the point of entrance must be
disinfected to reduce the chance of
carrying bacteria from the skin into the
blood via the needle.
Both small and large volumes of drug
solutions may be administered
intravenously.
The main hazard of intravenous infusion is
the possibility of thrombus formation
induced by the touching of the wall of the
vein by the catheter or needle.
Intravenously administered drugs
ordinarily must be in aqueous solution;
they must mix with the circulating blood
and not precipitate from solution.
Intravenously delivered fat emulsions have
gained acceptance for use as a source of
calories and essential fatty acids for
patients requiring parenteral nutrition for
extended periods of time.
Patient-controlled
analgesia
2) Intramuscular route
Intramuscular injections of drugs provide
drug effects that are less rapid, but
generally of greater duration than those
obtained from intravenous administration.
Aqueous or oleaginous solutions or
suspensions of drug substances may be
administered intramuscularly.
The Z-Track Injection technique is useful
for intramuscular injections of medications
that stain upper tissue.
3) Subcutaneous route
The subcutaneous route may be utilized
for the injection of small amounts of
medication.
Drugs that are irritating or those that are
present in thick suspension form may
produce induration（硬化）, sloughing
（蜕皮）, or abscess formation（形成囊肿）
and may be painful to the patient. Such
preparations should be considered not
suitable for subcutaneous injection.
4) Intradermal route
A number of substances may be
effectively injected into the corium（真
皮）, the more vascular layer of the
skin just beneath the epidermis.
These substances include various
agents for diagnostic determinations,
desensitization, or immunization.
常见的给药途径包括
静脉注射、
肌内注射、
皮下注射、
皮内注射，
动脉注射、脊椎腔注射、穴位注射、
腹腔注射和关节腔内注射。
Official types of injections
According to the USP, injections are
separated into five general types,
1. Drug Injection-Liquid preparations
that are drug substances or solutions
thereof.
2. Drug for Injection-Dry solids that,
upon the addition of suitable vehicles,
yield solutions conforming in all
respects to the requirements for
Injections.
3. Drug Injectable Emulsion-Liquid
preparations of drug substances
dissolved or dispersed in a suitable
emulsion medium.
4. Drug Injectable Suspension-Liquid
preparations of solids suspended in a
suitable liquid medium.
5. Drug for Injectable Suspension-Dry
solids that, upon the addition of
suitable vehicles, yield preparations
conforming in all respects to the
requirements for Injectable
Suspensions.
unstable in solution
dry powder
suspension
Insoluble in water
aqueous suspension
nonaqueous solvent
water-soluble salt
Solvents and vehicles for injections
1) Water for Injection, USP
The most frequently used solvent in the
large-scale manufacturer of injections is
Water for Injection, USP.
This water is purified by distillation or by
reverse osmosis and meets the same
standards for the presence of total solids
as does Purified Water, USP, not more
than 1mg per 100mL Water for Injection,
USP.
Although water for injection is not required
to be sterile, it must be pyrogen-free.
Water for injection should be stored in tight
containers at temperatures below or above
the range in which microbial growth occurs.
Water for injection is intended to be used
within 24 hours following its collection.
Naturally, the water should be collected in
sterile and pyrogen-free containers.
The containers are usually glass or glasslined.
2) Sterile Water for Injection, USP is water
for injection which has been sterilized and
packaged in single-dose containers of not
greater than 1-liter size.
This water may contain a slightly greater
amount of total solids than water for
injection.
This water is intended to be used as a
solvent, vehicle or diluent for alreadysterilized and packaged injectable
medications.
3) Bacteriostatic Water for Injection, USP
is sterile water for injection containing one
or more suitable antimicrobial agents.
It is packaged in pre-filled syringes or in
vials containing not more than 30 mL of
the water.
The container label must state the name
and proportion of the antimicrobial agents
present.
The water is employed as a sterile vehicle
in the preparation of small volumes of
injectable preparations.
4) Sodium Chloride Injection, USP is a
sterile isotonic solution of sodium chloride
in Water for Injection.
It contains no antimicrobial agents.
The solution may be used as a sterile
vehicle in preparing solutions or
suspensions of drugs for parenteral
administration.
Sodium Chloride Injection is frequently
used as catheter or IV line flush to
maintain patency.
5) Bacteriostatic Sodium Chloride
Injection, USP is a sterile isotonic solution
of sodium chloride in Water for Injection.
It contains one or more suitable
antimicrobial agents which must be
specified on the labeling.
Sodium chloride is present at 0.9%
concentration to render the solution
isotonic.
Bacteriostatic Sodium Chloride Injection
is also used to flush a catheter or IV line to
maintain its patency.
6) Ringer’s Injection（林格氏注射液）,
USP
is a sterile solution of sodium chloride,
potassium chloride, and calcium chloride
in water for injection.
The solution is employed as a vehicle for
other drugs, or alone as an electrolyte
replenisher and fluid extender.
Nonaqueous Vehicles
The selected vehicle must be nonirritating,
non-toxic in the amounts administered,
and nonsensitizing.
The solvent’s physical and chemical
properties such as stability, viscosity,
fluidity, boiling point, miscibility with body
fluids, purity must be considered.
Among the nonaqueous solvents presently
employed in parenteral products are
fixed vegetable oils
glycerin,
polyethylene glycols,
propylene glycol,
alcohol
and a number of lesser used agents as ethyl
oleate, isopropyl myristate（十四酸异丙酯）,
and dimethylacetamide（二甲基乙酰胺）.
Added substances
Many of added substances to injection are
antibacterial preservatives,
buffers,
solubilizers,
antioxidants,
and other pharmaceutical adjuncts.
For the following preservatives, the indicated
maximum limits prevail for use in a parenteral
product unless otherwise directed:
for agents containing mercury and the cationic,
surface-active compounds, 0.01%;
for agents like chlorobutanol（氯代丁醇）,
cresol（甲酚）, and phenol（苯酚）, 0.5%;
for sulfur dioxide as an antioxidant, or for an
equivalent amount of the sulfite（亚硫酸盐）,
bissulfite, or metabisulfite of potassium or
sodium, 0.2%. （亚硫酸氢盐或钾和钠的焦亚硫酸盐）
The air within an injectable product is
frequently replaced with an inert gas, such
as nitrogen, to enhance the stability of the
product.
常用的附加剂
（1）pH调节剂 盐酸、氢氧化钠、碳酸氢钠、
枸橼酸缓冲液、酒石酸缓冲液和磷酸盐缓
冲液等。
（2）表面活性剂 聚山梨酯类（常用聚山梨
酯80）、聚氧乙烯蓖麻油、泊洛沙姆188、
卵磷脂等，作为增溶、润湿、乳化剂使用。
（3）助悬剂 PVP、明胶、甲基纤维素、羧
甲基纤维素钠等，用于混悬型注射剂。
（4）延缓氧化的附加剂
抗氧剂常用亚硫酸钠、亚硫酸氢钠、焦亚
硫酸钠、硫代硫酸钠；螯合剂常用EDTA钠
盐；惰性气体常用二氧化碳或氮气。
（5）等渗调节剂
常用氯化钠、葡萄糖。
（6）局部止痛剂
苯甲醇、三氯叔丁醇、盐酸普鲁卡因、利
多卡因。
（7）抑菌剂
用于多剂量注射剂及不经灭菌的无菌操作
制剂
静脉和脊椎注射的产品不得加抑菌剂
一次用量超过5ml的注射液应慎加
常用苯酚、甲酚、氯甲酚、苯甲醇、三氯
叔丁醇、硫柳汞等。
（8）填充剂
冷冻干燥制品中，根据具体产品的需要可
加入特定的稳定剂、填充剂，如葡萄糖、
乳糖、蔗糖、甘露醇。
（9）蛋白类药物保护剂
乳糖、蔗糖、麦芽糖、甘氨酸、人血清白
蛋白。
Methods of Sterilization
The term sterilization, as applied to
pharmaceutical preparations, means the
complete destruction of all living
organisms and their spores or their
complete removal from the preparation.
药物制剂中使用的术语“灭菌”，是指将所
有活的生物体及其孢子完全破坏或将其从
制剂中完全去除。
1.
2.
3.
4.
5.
Five general methods are used for the
sterilization of pharmaceutical products:
Steam sterilization
Dry-heat sterilization
Sterilization by filtration
Gas sterilization
Sterilization by ionizing radiation
1. Steam sterilization
Steam sterilization is conducted in an
autoclave and employs steam under
pressure.
10 pounds pressure (115.5C), for 30 minutes
15 pounds pressure (121.5C), for 20 minutes
20 pounds pressure (126.5C), for 15 minutes
The temperature at which most autoclaves
are routinely operated is usually 121C。
In general, this method of sterilization is
applicable to pharmaceutical preparations
and materials that can withstand the
required temperatures and are penetrated
by, but not adversely affected by, moisture.
湿热灭菌
是采用高温饱和水蒸气或沸水或流通蒸汽
进行灭菌的方法。
由于蒸气潜热大，穿透力强，因此灭菌效
率高，灭菌温度低，时间短。
（1）热压灭菌法
采用大于常压的饱和水蒸气杀灭微生物的
方法。
为热力灭菌中最有效，用途最广泛的方法。
灭菌条件为：115.5℃（67Kpa），30min；
121.5℃ （ 97Kpa ） ， 20min ； 126.5℃
（139Kpa），15min。
在规定的时间和温度内对细菌的繁殖体和
芽孢有效。
（2）流通蒸汽灭菌法
是在不密闭的容器内，用100℃流通蒸汽灭
菌的方法。
煮沸灭菌法是把灭菌物品放入沸水中煮沸
灭菌的方法。一般灭菌时间为30～60min 。
不能保证杀灭所有的芽孢，因此必要时应
加入适当的抑菌剂。本法一般用于消毒或
不耐高热制剂的灭菌。
（3）低温间歇灭菌法
将灭菌的制剂或药品，用60～80℃加热1h，
将其中的细菌繁殖体杀死，然后室温放置
24h，让其中的芽孢发育成繁殖体，再次加
热灭菌，如此加热和放置操作连续进行3～
5次，至全部芽孢消灭为止。
此法适用于必须加热灭菌又不耐高热的制
剂或药品。
应用本法灭菌的制剂或药品，必要时可加
入适当的抑菌剂，以提高灭菌效力。
2. Dry-heat sterilization
Dry-heat sterilization is usually carried
out in sterilizing ovens specifically
designed for this purpose.
The ovens may be heated either by gas
or electricity and are generally
thermostatically controlled.
160C170C for periods of
not less than 2 hours
Dry-heat sterilization is generally
employed for substances that are not
effectively sterilized by moist heat.
Such substances include
fixed oils,
glycerin,
various petroleum products such as
petrolatum, liquid petrolatum,
and paraffin
and various heat-stable powders such as
zinc oxide.
Dry-heat sterilization is also an effective
method for the sterilization of glassware
and surgical instruments.
干热灭菌法
加热主要是破坏蛋白质与核酸的氢键,导致
蛋白质变性或凝固、核酸破坏，酶失活，
从而使微生物死亡。
细菌的芽孢较繁殖体耐热，因此灭菌应以
杀灭芽孢为标准。
干热灭菌法包括火焰灭菌法和干热空气灭
菌法两种。
（1）火焰灭菌法
直接在火焰中灼烧的灭菌方法。将灭菌物
品通过火焰3～4次，每次20秒以上。
（2）干热空气灭菌法
在高温干热空气中进行灭菌的方法。干燥
状态下微生物有较强的耐热性，需高温长
时间才能达到灭菌目的。
《中国药典》2000年版规定的干热灭菌条
件为160～170℃2h以上，170～180℃1h以上，
250℃ 45min以上。
3. Sterilization by Filtration
Sterilization by filtration, which
depends upon the physical removal of
microorganisms
by adsorption on the filter medium
or by a sieving mechanism,
is used for the sterilization of heatsensitive solutions.
Commercially available filters are
produced with a variety of pore-size
specifications.
Millipore filters are made from a variety of
polymers to provide membrane
characteristics required for the filtration of
almost any liquid or gas system.
The size of the smallest particle visible to
the naked eye is about 40 m, a red blood
cell is about 6.5 m, the smallest bacteria,
about 0.2 m, and a polio virus, about
0.025 m.
The major advantages of bacterial filtration
include
its speed in the filtration of small quantities
of solution,
its ability to sterilize effectively thermolabile
materials,
the relatively inexpensive equipment
required,
the development and proliferation of
membrane filter technology,
The complete removal of living and dead
microorganisms as well as other particulate
matter from the solution.
滤过灭菌法
是指用滤过方法除去微生物的方法，是一
种机械除菌法。
一般选用孔径0.22μm或0.3μm的微孔薄膜滤
器或G6号垂熔玻璃漏斗。
主要适用于对热不稳定的药液、气体、水
等的灭菌。
4. Gas Sterilization
Some heat-sensitive and moisturesensitive materials can be sterilized much
better by exposure to ethylene oxide or
propylene oxide gas than by other means.
These gases are highly flammable when
mixed with air but can be employed safely
when properly diluted with an inert gas
such as carbon dioxide or a suitable
fluorinated hydrocarbon.
Sterilization with ethylene oxide gas
requires from 4 to 16 hours of exposure.
Ethylene oxide is thought to function as a
sterilizing agent by its interference with the
metabolism of the bacterial cell.
制药工业上用的杀菌气体，多用环氧乙烷。
环氧乙烷的杀菌作用是基于其烷化剂的性
质，使菌体蛋白的-COOH，-NH2，-SH，-OH
中的H被-CH2-CH2-OH所置换，对细菌代谢产
生不可逆的损害。
环氧乙烷可用于塑料容器、对热敏感的固
体药物、纸或塑料包装的药物、橡胶制品、
注射筒及注射针头等的灭菌。
环氧乙烷具可燃性，当与空气混合，空气
含量达3.0%（V/V）时即可发生爆炸。
因此，一般用12%的环氧乙烷与88%氟氯烷
烃的混合气或10%环氧乙烷与90%二氧化碳
混合气。
保持一定时间后，抽真空排除环氧乙烷，
然后通无菌空气完全排除环氧乙烷。
对操作室内的灭菌，常用甲醛蒸气。
每立方米空间用40%甲醛溶液30ml，
室内相对湿度宜高，以增进甲醛的灭菌效
果。
5. Sterilization by ionizing radiation
Techniques are available for the
sterilization of some types of
pharmaceuticals by gamma rays and by
cathode rays（阴极射线）,
but the application of such techniques is
limited because of the highly specialized
equipment required and the effects of
irradiation on products and their containers.
（1）紫外线灭菌法
是指用紫外线照射灭菌的方法。
用于灭菌的紫外线波长为200～300nm，最
强为254nm。
紫外线直线传播，较易穿透清洁空气或洁
净的水，故仅适用于空气或表面灭菌。
（2）辐射灭菌法
辐射灭菌是指用γ射线灭菌的方法。γ射线通
常可由60Co产生。
灭菌剂量一般为2.5×104Gy。
适用于热敏物料和制剂，如维生素、抗生
素、激素、生物制品、中药材和中药制剂、
药用包装材料和高分子材料。
（3）微波灭菌法
是指用微波照射后产生的热能杀灭微生物
的方法。
微波是指频率300MHz～300kMHz的电磁波。
适用于液体和固体物料。
物理灭菌法
灭菌法
干热灭菌法
湿热灭菌法
射线灭菌法
滤过灭菌法
气体灭菌法
化学灭菌法
化学药剂杀菌法
无菌操作法
Validation of Sterility
Pharmaceutical preparations required
to be sterile must undergo tests to
confirm the absence of
microorganisms.
A biologic indicator is a characterized
preparation of specific microorganisms
resistant to a particular sterilization
process.
Biologic indicator are generally of two
main forms.
In one, spores are added to a carrier,
such as a strip of filter paper, packaged
to maintain physical integrity while
allowing the sterilization effect.
In the other, the spores are added to
representative units of the product
being sterilized, with assessment of
sterilization nased on these samples.
Steam and ethylene oxide
sterilization
Dry heat
Ionizing radiation
Spores of
Bacillus stearothermophilus
（芽孢杆菌）
Spores of
Bacillus subtilis（枯草杆菌）
Spores of B. pumilus,
B. stearothermophilus,
B. subtilis
The effectiveness of thermal sterilization has
been quantified through the determination
and calculation of F value to express the time
of thermal death.
Thermal death time is defined as the time
required to kill a particular organism under
specified conditions.
The F0 at a particular temperature other than
121C is the time in minutes required to
provide lethality equivalent to that provided
at 121C for a stated time.
F0=D121(LogA-LogB)
where
D121 is the time required for a one-log
reduction in the microbial population
exposed to a temperature of 121C,
A is the initial microbial population, and
B is the number of microorganisms that
survive after a defined heating time.
Pyrogens and pyrogen testing
One of the more common means of
removing pyrogens is by oxidizing
them to easily eliminated gases or to
nonvolatile solids, both of which are
easily separated from water by
fractional distillation.
Potassium permanganate is usually
employed as the oxidizing agent, with
its efficiency increased by addition of a
small amount of barium hydroxide
serving to impart alkalinity to the
solution and to make nonvolatile
barium salts of any acidic compounds
that may be present.
Pyrogen test
The USP Pyrogen Test utilizes healthy
rabbits that have been properly maintained
in terms of environment and diet prior to
performance of the test.
Limulus amebocyte lysate (LAL) test for
the presence of bacterial endotoxins.
The USP Bacterial Endotoxins Test
utilizes LAL and is considered generally
more sensitive to endotoxin than the rabbit
test.
The Industrial Preparation of
Parenteral Products
In manufacturing plants the area in
which parenteral products are made is
maintained
bacteria free by use of ultraviolet lights;
a filtered air supply;
sterile manufacturing equipment, such
as flasks, connecting tubes, and filters,
and sterilized work clothing.
filtered through
a membrane
tested for sterility
and pyrogens
transferred
sterilized
suspension
ball mill
micronizer
colloid mill
sterilize separately the
individual components
注射剂的制备
注射剂的生产过程：
1. 原辅料的准备
2. 配制
3. 灌封
4. 灭菌
5. 质检
6. 包装
注射剂的生产
安瓿或玻璃瓶洗前处理
原料
装
配液
蒸馏水或去离子水
粗滤
清洗
精滤
蒸馏
干燥灭菌
封口
冷却
灭菌
注射用水
洁净区
灯检
控制区
印字
包
Packaging, Labeling, and Storage of
Injections
Containers for injections, including the
closures, must not interact physically or
chemically with the preparation so as to
alter its strength or efficacy.
If the container is made of glass, it must
be clear and colorless or of a light amber
color to permit the inspection of its
contents.
Single-dose containers may be ampuls or
single-dose vials.
Preparations intended for intraspinal（脊
柱内）, intracisternal（脑内）, or peridural
（硬膜外） administration must be
packaged only in single-dose containers.
Multiple-dose containers are affixed with
rubber closures to permit the penetration
of a hypodermic needle without the
removal or destruction of the closure.
Multiple-dose injectables are required to
contain added antibacterial preservatives.
Multiple-dose containers are not permitted
to allow the withdrawal of greater than 30
mL in order to limit the number of
penetrations made into the closure and
thus protect against loss of sterility.
The usual multiple-dose container
contains about ten usual doses of the
injection, but quantity may vary greatly
with the individual preparation and
manufacturer.
1)
2)
3)
4)
5)
6)
The labels on containers of parenteral
products must state:
the name of the preparation;
the content of drug;
the route of administration;
a statement of storage conditions and an
expiration date;
the name of the manufacturer and
distributor;
an identifying lot number.
Most injections prepared from chemically
pure medicinal agents are stable at room
temperature and may be stored without
special concern or conditions.
However, most biological products-insulin
injection and the various vaccines, toxoids,
toxins, and related products-are usually
stored under refrigeration.
本章要求
1.掌握灭菌与灭菌技术的原理、应用及基本
概念。
2.了解注射剂的分类、特点、质量要求，常
用溶剂和附加剂，常用设备。
3.掌握注射剂制备工艺过程及其基本理论、
基本概念和常用术语。
4.掌握热原的概念、性质、组成、污染途径
及除去方法。
Small volume parenterals
Premixed intravenous delivery systems
have simplified delivery for small-volume
parenterals in particular.
Advantages:
These ready-to-use systems is that they
require little or no manipulation to make
them patient specific.
These systems is extended stability dating
and reduced wastage.
Disadvantages:
The down side of these ready-to use small
parenteral products is that they do not
offer flexibility in changing the volume or
concentration of the product.
The ready-to use products is that some
manufacturers’ premixed products require
thawing.
Among the most used of the small volume
injections are the various insulin
preparations.
Insulin Injection (Regular)
Insulin injection is a sterile aqueous
solution of insulin.
The first insulin developed for clinical
use was amorphous.
This type has since been replaced by a
purer zinc-insulin crystalline product
that produces a clear aqueous solution.
The neutral product is more stable than
the acidic product.
Human Insulin
Biosynthetic human insulin was the
first recombinant DNA drug product to
receive approval from FDA.
It is produced by using a special nondisease-forming laboratory strain of
Escherichia coli and recombinant DNA
technology.
recombined plasmid
DNA coding
bacteria
cultured by
fermentation
freed, purified
Human insulin
A and B chains
of human insulin
linked by the specific
disulfide bridges
The insulin produced is chemically ,
physically, and immunologically equivalent
to insulin derived from the human
pancreas.
The biosynthetic insulin is free of
contamination with E. coli peptides, and, is
also free of the pancreatic peptides that
are present as impurities in insulin
preparations derived from animal
pancreatic extraction.
Pharmacokinetic studies in some normal
subjects and clinical observations in
patients indicate that formulations of
human insulin
have a slightly faster onset of action
and a slightly shorter duration of action
than their purified pork insulin counterparts.
Lispro Insulin Solution
（鱼精蛋白胰岛素溶液）
Lispro insulin solution consists of zincinsulin lispro crystals dissolved in a clear
aqueous fluid.
It is created when the amino acids at
positions 28 and 29 on the insulin B-chain
are reversed.
Lispro insulin solution is rapidly absorbed
after subcutaneous administration and
demonstrates no significant differences in
absorption from abdominal, deltoid, and
femoral sites of injection.
Its bioavailability mimics that of regular
insulin.
peak serum levels earlier (0.51.5h)
shorter acting (68h)
Hypoglycemic episodes have been less
frequent with lispro insulin than with regular
insulin.
It is more effective than regular insulin in
reducing exercise-induced hypoglycemia
when exercise is performed three hours after
a meal.
Lispro insulin solution should be stored in a
refrigerator, but not in the freezer. It may be
stored at room temperature for up to 28 days.
Isophane Insulin Suspension
(NPH Insulin低精蛋白锌胰岛素混悬剂)
Isophane insulin suspension is a sterile
suspension, in an aqueous vehicle
buffered with dibasic sodium phosphate at
between pH7.1 and 7.4,
of insulin prepared from zinc-insulin
crystals modified by the addition of
protamine so that the solid phase of the
suspension consists of crystals composed
of insulin, zinc, and protamine.
Suspensions of insulin with a pH on the
alkaline side are inherently of a longer
duration of action than those preparations
that are solutions.
Insulin is most insoluble at pH7.2.
The suspension is packaged in multipledose containers having not less than 10
mL of injection.
Isophane insulin suspension is an
intermediate-acting insulin preparation
administered as required mainly as
hormonal replacement in diabetes mellitus.
Isophane Insulin Suspension and Insulin
Injection
In years past, patients needing a more
rapid onset of insulin and the intermediate
duration of activity approximately one day.
A premixed formulation of isophane insulin
suspension and insulin injection became
available.
70/30 combination and 50/50 combination
Insulin Zinc Suspension
Insulin for Insulin Zinc Suspension is
modified by the addition of zinc chloride so
that the suspended particles consist of a
mixture of crystalline and amorphous
insulin in a ratio of approximately 7 parts
of crystals to 3 parts of amorphous
material.
The sterile suspension is in an aqueous
vehicle buffered to pH7.2 to 7.5 with
sodium acetate.
The suspension contains about 0.7%
sodium chloride for tonicity and 0.10%
methylparaben for preservation.
The expiration date of the suspension is
24 months after the immediately container
was filled.
The suspension must be stored in a
refrigerator with freezing being avoided.
Extended Insulin Zinc Suspension
Extended insulin zinc suspension is a
sterile suspension of zinc insulin crystals
in an aqueous medium buffered to
between pH7.2 and 7.5 with sodium
acetate.
This preparation is classified as a longacting insulin preparation.
Prompt Insulin Zinc Suspension
The sterile suspension of insulin in prompt
Insulin Zinc Suspension is modified by the
addition of zinc chloride so that the solid
phase of the suspension is amorphous.
This is a rapid-acting insulin preparation.
It must be stored in a refrigerator and not
permitted to freeze.
Insulin Infusion Pumps
Insulin infusion
pumps are
portable, batteryoperated, and
programmable
unit are available.
These systems utilize microcomputers to
regulate the flow of insulin from a syringe
attached to a catheter connected to a 27to 28-gauge needle inserted in the patient.
The insulin may be delivered
subcutaneously, intravenously, or
intraperitoneally.
Insulin infusion pumps allow patients to
achieve and maintain blood glucose at
near-normal levels on a constant basis.
Large volume parenterals (LVPs)
LVPs are usually administered by
intravenously infusion to replenish body
fluids, electrolytes, or to provide nutrition.
They are usually administered in volumes
of 100 mL to liter amounts and more per
day by slow intravenous infusion with or
without controlled-rate infusion systems.
These solutions must not contain
bacteriostatic agents or other
pharmaceutical additives.
They are packaged in large single-dose
containers.
Large volume parenteral solutions are
employed in maintenance therapy
for the patient entering or recovering from
surgery,
or for the patient who is unconscious and
unable to obtain fluids, electrolytes, and
nutrition orally.
The solutions may also be utilized in
replacement therapy in patients who have
suffered a heavy loss of fluid and
electrolytes.
输液的质量要求
1、无菌
2、无热原
3、澄明度
4、等渗、偏等渗
5、不加抑菌剂
Maintenance Therapy
maintained on parenteral
fluids for several days
water,dextrose,
sodium and potassium
unable to take oral nutrition
or fluids for 3 to 6 days
solutions of higher
caloric content
oral feeding must be deferred
for periods of weeks or longer
total nutrient
admixtures (TNA)
TNA
for patients undergoing chemotherapy
gastrointestinal patients
anorexic patients（厌食）
When using TNA, the pharmacist must consider
the order of substrate mixing,
differentiate between various brands of substrate
and their physical-chemical properties,
determine the type of plastic bag system that is
most appropriate to use,
determine whether the TNA should be filtered prior
to infusion,
determine how the product should be stored,
and assess any potential complications that might
arise with the use of this method of administering
nutritional products.
Replacement Therapy
Crohn’s disease
AIDS
burn patients
experiencing trauma
Water Requirement
The normal daily requirement of water for
adults is about 25 to 40 mL/kg of body
weight, or an average of about 2000 mL
per square meter of body surface area.
<10kg: 100mL/kg/day
10-20kg: 1000mL plus 50mL/kg/day for
weight over 10 kg
>20 kg to maximum of 80 kg: 1500 mL
plus 20 mL/kg/day for weight over 20 kg
The parenteral administration of water is
generally as a solution with dextrose or
electrolytes in which the solution has
sufficient tonicity to protect the red blood
cells from hemolyzing.
Electrolyte requirement
Potassium, the primary intracellular cation,
is particulary important for normal cardiac
and skeletal muscle function.
The usual daily intake of potassium is
about 100 mEq and the usual daily loss is
about 40 mEq.
Potassium
Excessive perspiration
Repeated enemas
Trauma
Uncontrolled diabetes
Diseases of the intestinal tract
Surgical operations
Use medications as thiazide and loop diuretics
In cases of severe potassium deficiency,
electrolyte replacement through the
intravenous administration of potassium is
usually employed.
The most commonly used concentration of
potassium chloride for continuous infusion,
IV maintenance therapy is between 2040mEq/L.
Sodium, the principal extracellular cation,
is vital to maintain normal extracellular
fluids.
Average daily intake of sodium is 135 to
170 mEq.
Excessive
sodium loss
Excessive sweating
Use of certain diuretics
diarrhea
fatigue
Muscle weakness
Apprehension （不安）
Convulsions（惊厥）
Caloric Requirements
Patients requiring parenteral fluids are
given 5% dextrose to reduce the caloric
deficit that usually occurs in patients
undergoing maintenance or
replacement therapy.
The use of dextrose also minimizes
ketosis（酮体症） and the breakdown
of protein.
Parenteral Nutrition
Parenteral nutrition is infusion of
enough basic nutrients to achieve
active tissue synthesis and growth.
It is characterized by the long-term
intravenous feeding of protein
solutions containing high
concentrations of dextrose, electrolytes,
vitamins, and in some instances insulin.
Special Considerations Associated
with Parenteral Therapy
1) Adsorption of Drugs
Numerous studies have demonstrated that
some drugs are adsorbed to the inner lining
of intravenous containers and tubing or
administration sets.
chlorpromazine
diazepam
insulin
nitroglycerin
promazine HCl
promethazine HCl
thiopental sodium
thioridazine HCl
trifluoperazine HCl
warfarin sodium
One method to minimize this is to
administer infusions through short lengths
of small-diameter tubing made of inert
plastics.
2) Handling and disposal of chemotherapeutic
agents for cancer
The basic steps should be taken to
minimize unnecessary exposure of
cytotoxic drugs:
1) Using vertical laminar flow hoods or
bacteriologic glove boxes for preparation
and reconstitution of cytotoxic drugs
2) Wearing protective gloves and mask
during product preparation
3) Handling and disposing of cytotoxic drugs
centrally using specially designed waste
containers and incineration
4) Periodic monitoring of personnel who
handle admixtures of cytotoxic drugs
5) Informing personnel handling cytotoxic
drugs of the risk to their health
6) Specialized labeling of containers to
ensure proper handling and disposal of the
cytotoxic agent
Other Injectable Products:
Pellets or Implants
Pellets or implants were
sterile, small, usually cylindrical solid
objects about 3.2 mm in diameter and 8
mm long,
prepared by compression and intended
to be implanted subcutaneously to
provide continuous release of
medication over time.
Irrigation and dialysis solutions
Solutions for irrigation of body tissues and
for dialysis are subject to the same
stringent standards as parenteral
preparations.
Irrigation solutions are intended to
bathe or wash wounds, surgical
incisions, or body tissues.
Dialysis may be defined as a process
whereby substances may be separated
from one another in solution by taking
advantage of their differing diffusibility
through membranes.
Solutions are commercially available
containing dextrose as a major source
of calories, vitamins, minerals,
electrolytes, and amino acids or
peptides as a source of nitrogen.
The solutions are made to be
hypertonic (with dextrose) to plasma to
avoid absorption of water from the
dialysis solution into the circulation.
Peritoneal dialysis solutions, allowed to
flow into the peritoneal cavity, are used
to remove toxic substances normally
excreted by the kidney.
Hemodialysis is employed to remove
toxins from the blood.
Questions
What are the official types of injections?
What are the solvents and vehicles for
injections?
How many different sterilization methods
for injection? What are the differences
among them?
15. Ophthalmic Solutions and
Suspensions
Hongxia Guo
Ph.D. in Pharmacy
Contents
Ophthalmic drug delivery
Pharmaceutic requirements
Packaging ophthalmic solutions and
suspensions
Proper administration of ophthalmic
solutions and suspensions
Ophthalmic drug delivery
infections
allergic or inflammation
elevated intraocular pressure
dry-eye
现临床应用的剂型中以滴眼液为主,上市产
品中62.4 %为溶液型, 8.7 %为混悬型；还
有少量的软膏剂,占17.4 %。
滴眼液用药后经泪液冲刷或从鼻泪管流失,
药效维持短,生物利用度低(1%～10%左右)
给药频繁；一般药典规定给药3～4 次/d ,
但实际临床应用时可多达10～20 次/d ,从
而造成诸多的副作用。
由于夜间给药不便,使得药理峰谷现象突出。
药物在眼部的吸收途径
1．角膜吸收途径
大多数药物眼部用药的吸收途径为角膜吸
收，水溶性大的药物不易透过角膜，脂溶
性大的药物比较容易透过角膜，但却不易
从角膜向眼的深层组织透过，所以在水和
脂溶性介质中均有一定溶解度的药物，有
利于药物的角膜吸收。
角膜吸收是眼局部用药的主要吸收途径。
2．非角膜吸收
非角膜吸收的部位在角膜—结膜处被局部
毛细血管吸收进入体循环，非角膜吸收是
眼用制剂发挥全身作用的主要吸收途径。
Pharmaceutic requirements
Special consideration for ophthalmic
preparations:
sterility
preservation
isotonicity
buffering
viscosity
ocular bioavailability and packaging
Sterility and Preservation
Ophthalmic solutions/suspensions could
be sterilized by
- autoclaving at 121C for 15 minutes
- bacterial filters
 To maintain sterility during patient use,
antimicrobial preservatives generally are
included in ophthalmic formulations.
The preservatives used in ophthalmic
solutions/suspensions are
benzalkonium chloride（苯扎氯铵） ,
0.004-0.01%;
benzethonium chloride（氯化苄乙胺）,
0.01%;
chlorobutanol（三氯叔丁醇）, 0.5%;
phenylmercuric acetate（醋酸苯汞),
0.004%;
phenylmercuric nitrite（硝酸苯汞）, 0.004%;
thimerosal（硫酸汞）, 0.005-0.01%
Isotonicity Value
Isotonic solution: a solution that has the
same salt concentration as the normal
cells of the body and the blood.
Hypotonic, solutions with a lower osmotic
pressure than body fluids or a 0.9%
sodium chloride solution are commonly
referred to as hypotonic.
Hypertonic, solutions have a greater
osmotic pressure are termed hypertonic.
渗透压调节：
(1)冰点降低数据法:
血浆的冰点= 0.52 C
溶液的冰点 = 0.52 C，与血浆等渗
例题1：配100ml等渗NaCl溶液，需NaCl多
少？（1%NaCl，冰点= 0.58C ,血浆，冰
点= 0.52 C）
1% ：X = 0.58 ：0.52
X = 0.9g
例题2：配100ml的2%盐酸普鲁卡因溶液,
需加NaCl多少使成等渗溶液？
（ 血浆，冰点= 0.52 °C，1%盐酸普
鲁卡因，冰点= 0 .12 °C ）
W = （ 0.52  a）/ b
= （ 0.52  0.12•2 ）/ 0.58
= 0.48g
例3．欲配制下面复方多粘菌素B滴眼液，需
加入氯化钠多少克使成等渗溶液。
硫酸多粘菌素B
0.25g
硫酸新霉素
0.75g
氯化钠
适量
注射用水加至
100ml
（1%硫酸多粘菌素B的冰点下降0.05℃，1%
硫酸新霉素的冰点下降0.06℃，1%氯化钠
的冰点下降0.58℃）
W=[0.52(0.05×0.25+0.06×0.75)]/0.58
=0.80(g)
即配制复方多粘菌素B滴眼液100ml，需加
NaCl 0.80g使成等渗溶液。
Boric acid has a molecular weight of 61.8,
and thus 61.8 g in 1000 g of water should
produce a freezing point of -1.86C.
therefore:
1.86(C )/0.52(C )=61.8 (g)/x(g)
X=17.3 g
17.3 g of boric acid in 1000g of water
theoretically should produce a solution
isosmotic with tears and blood.
(2)氯化钠等渗当量法:
1g药物呈等渗效应的NaCl量（1g药物 = X
g NaCl，0.9%NaCl = 血浆渗透压）
例题：配100ml的2%盐酸普鲁卡因溶液，需
加NaCl多少使成等渗溶液？（1g盐酸普鲁
卡因= 0.18 g NaCl，0.9%NaCl = 血浆渗
透压）
X = 0.9% •100 （100•2% ）0.18
= 0.9  0.36
= 0.54 g
Buffering
The aims for adjusting the pH of an
ophthalmic preparation:
for greater comfort to the eye;
to render the formulation more stable;
to enhance the aqueous solubility of the
drug;
to enhance the drug’s bioavailability;
to maximize preservative efficacy.
The pH of normal tears is considered to be
about 7.4.
For maximum comfort, an ophthalmic
solution should have the same pH as the
lacrimal fluid.
A compromise pH is generally selected for
solution and maintained by buffers to
permit the greatest activity while
maintaining stability.
Viscosity and Thickening Agents
Viscosity for ophthalmic solutions is
considered optimal in the range of 15 to 25
cps.
In the preparation of ophthalmic solutions,
a suitable grade of methylcellulose or
other thickening agent (hydroxypropyl
methylcellulose, polyvinyl alcohol) is
frequently added to increase the viscosity.
Ocular Bioavailability
There are physiologic factors which can
Tears contain
affect a drug’s ocular bioavailability,
0.6-2.0% of
including
protein
protein binding,
Tears
contain
drug metabolism
enzymes
lacrimal drainage
滴眼剂的质量要求：
1、pH：5-9，
眼耐受性、溶解度、稳定性、药效
2、渗透压：
0.6-1.5% NaCl
3、无菌：
外伤---绝对无菌，
单剂量包装，
不加抑菌剂
无外伤：无致病菌、加抑菌剂
4、澄明度：较注射剂低，
5、粘度：MC
延长停留时间，
增加药效，
减少刺激
6、稳定性
Packaging ophthalmic solutions
and suspensions
Soft plastic containers
2, 2.5, 5, 10, 15, 30 mL
Proper Administration of Ophthalmic
Solutions and Suspensions
wash hands thoroughly
inspect for color and clarity
be shaken thoroughly prior
to administration
(ophthalmic suspensions)
not to touch the dropper to
the eye, eyelid or any other
surface
本章要求
掌握眼用制剂的质量要求
掌握等渗的基本概念和计算
Questions
How to sterilize ophthalmic
solutions/suspensions?
Why is the pH of an ophthalmic preparation
adjusted and buffered and how?