Novel Dosage Forms And Drug Delivery Technologies

2

Main Contents

• 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

3

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.

4

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.

5

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.

6

Therapeutic benefits

• Optimization of the duration of action of the drug;

• Decreasing dosage frequency, • Controlling the site of release, • Maintaining constant drug level

7

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

8

Economic benefits

• Simplifying administration regiments;

• Enhancing patients’ compliance• An overall reduction of health care

costs

9

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.

10

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.

11

12

Mechanisms

• Physical mechanisms, also referred to as controlled drug delivery systems, including ：

• Osmosis, diffusion,• erosion, dissolution,• and eletrotransport

13

Mechanisms

Biochemical mechanisms, including:Monoclonal antibodies,Gene therapy and vector systems,Polymer drug abductsLiposomes

14

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.

15

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.

16

Bioconjugates

17

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.

19

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.

20

2.Topical Administration

• Novel topical systems, also called transdermal drug delivery systems are patches involves percutaneous absorption.

21

Barriers for transdermal delivery

22

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.

23

24

Iontophoresis

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.

26

图 离子导入示意图

27

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.

28

Macroflux® technology• Macroflux® technology （微针技术） inco

rporates 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.

补充内容

29

• 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.

Macroflux® technology

30

Macroflux® 是一种新兴的透皮给药技术…

具有长约 200µm 的钛制微针头， 可以穿透角质层

表皮层 (50-150 µm)

真皮层

角质层 (10-15 µm)

携带药物微针头

31

Macroflux® 系统用于控释贴剂的使用和药物输送

贴置后

贴片安装器

通过安装器贴置 Macroflux® 片: 加压

贴片支撑环携带药物的 Macroflux® 贴片

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

治疗前 治疗后 褪色的亚甲基蓝

毛

33

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.

34

• 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.

35

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）

36

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。

37

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）

38

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

39

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

40

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。

41

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。

42

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 )

43

• 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）

44

Carbopol polymers

• Carbopol polymers

are polymers of acrylic acid( 丙烯酸 )cross-linked withPolyalkenyl ethers or divinyl glycol.

45

Carbopol polymers are offered as fluffy, white, dry powders (100% effective).

• The carboxyl groups provided by the acrylic acid backbone of the polymer areresponsible for many of the product benefits.

• Carbopol polymers have an average equivalent weight of 76 per carboxyl group

46

General Structure of Carbopol Polymers

47

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

48

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.

49

• 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

ALZET® Osmotic Pumps

50

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。

51

ALZET® Osmotic Pumps

52

ALZET® Osmotic Pumps

53

ALZET® MINI-OSMOTIC PUMPMODEL 2006

• The ALZET mini-osmotic pump Model2006 delivers solutions continuously for 42 days without the need forexternal connections or frequent handling of animals.• This product is for use in

experimental animals only.

54

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.

55

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.

56

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.

57

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.

58

• 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.

59

Advair Diskus

60

Advair Diskus

61

How to use

• 1. Open. • Hold the DISKUS in o

ne 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.

62

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.

63

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.

64

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.

65

How to use

• 4. CLOSE the DISKUS • when you are finished taking a dose so tha

t 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.

66

概述

• 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.

EXUBERA® 补充内容

67

• 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.

68

• 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.

69

• 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.

70

Exubera

71Inhaled device produced by Nektar Therapeutics

72

Exubera

73

74

The AIR Inhaled Insulin System By Eli Lilly

• (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.

77

Technosphere® Insulin Technology by Mannkind (the inhaler folded closed)

78

• The MedTone inhaler (A) with the TI capsule

• Similar insulin exposure results in reduced glucose exposure with TI in a meal-challenge study conducted in patients with type 2 diabetes.

80

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.

81

Generex Oral-lyn™

82

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.

83

Vaginal Administration

•The continuous release and local absorption of drug minimizes systemic toxicity that may result from oral peak-and-valley drug administration.

84

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.

85

• 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.

ESTRING®(estradiol vaginal ring)

86

ESTRING®(estradiol vaginal ring)

87

ESTRING®(estradiol vaginal ring)

88

Intrauterine Progesterone Drug Delivery System

The Intrauterine Device (IUD ，宫内节育器 ) is

a small plastic T-shaped device t

hat contains hormones.

It must be inserted by a doctor.

89

90

Intrauterine Progesterone Drug Delivery System

91

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.

92

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.

93

5(1) Ophthalmic Gels

• Ophthalmic Gels （眼用凝胶剂） are the novel preparations that use the viscosity-increasing agents to increase corneal contact time.

examples

Pilocarpine -Carbopol 940Timolol maleate- gellan gum (Gelrite)

94

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

95

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.

96

How to use Ophthalmic Gels

Wash hands thoroughly. Apply the correct amount of Pilopine HS® Gel to the edge of your index finger.

97

• Pull down lower eyelid with middle finger of other hand to form a pouch. Gently roll the strip of gel into the eye pouch.

How to use Ophthalmic Gels

98

How to use Ophthalmic Gels

• Gently squeeze the lower eyelid and pull it slightly away from your face.

99

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.

100

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

101

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.

102

Structure of Gellan

103

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.

104

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.

105

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.

106

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.

107

• 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

108

109

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.

110

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.

111

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.

112

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.

113

How to use

114

• 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.

115

• 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.

116

• 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.

117

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.

118

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.

119

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 FDA-approved.

120

121

6. Parenteral Administration

• Long-Acting Parenteral Systems• (1) crystal or amorphous drug forms having prol

onged dissolution characteristics;• (2) solutions or suspensions of drug in slowly abs

orbed carriers or vehicles;• (3) large particles of drug in suspension• (4) slowly eroding microspheres of drug

Examples of proprietary extended action parenteral productsProducts 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 (TAP Pharmaceuticals)

Sterile lyophilized microspheres; mixed with diluent, fom IM injection suspension q3-4mo

123

Liposomes• Liposomes( 脂质体 ) are composed of small vesic

les 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 water-soluble drugs in the aqueous spaces, and lipid-soluble drugs can be incorporated into the membranes.

124

Liposomes

125

Transmission electron photomicrographs of liposomes

126

127

Liposomes

• Liposomes can be administered parenterally, topically, by inhalation, and possibly by other routes of administration.

• Current products are administered parenterally.

128

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.

129

The category of liposomes

• single unilamellar vesicles, SUV• large unilamellar vesicles, LUV• multilamellar vesicles, MLV• Multivesicular vesicles, MVV

130

The category of liposomes

131

The components of liposomes

• Phospholipid and cholesterol are usually combined to form liposomes.

Phospholipid

Lecithin （ phosphatidylcholine ）

Dipalmitoylphosphatidylcholine (DPPC, 二棕榈酰磷脂酰胆碱 )

Dimyristoylphosphatidylcholine. (DMPC, 二肉豆蔻酰磷脂酰胆碱 )

132

The general formula of lipid

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

133

134

135

cholesterol

136

The arrangement of lipid and

cholesterol

137

The bilayer of the liposomes

138The formation of liposomes

139

LiposomesMicelles

140

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.

141

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.

142

stealth liposomes

143

144

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 site-specific and targeted drug delivery

• (2) Liposomes can be used for both hydrophilic and lipophilic drugs without chemical modification

145

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.

146

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.

147

148

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.

149

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.

150

ABELCET ® is provided as a sterile, opaque suspension in 20 mL glass, single-use 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

151

DaunoXome

Daunorubicin citrate liposome injection

152

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.

153

• 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.

154

Stealth liposomes -Doxil

155

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.

156

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.

157

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

158

Fusion Protein: Special Handing

• Ontak is a recombinant DNA-derived 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).

Ontak （白介素融合毒素）

159

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.

160

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.

161

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

162

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.

163

164

左炔诺孕酮植入剂左炔诺孕酮植入剂

• 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。

165

•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。

左炔诺孕酮植入剂左炔诺孕酮植入剂

166

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.

167

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.

168

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.

169

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。

170

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

171

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

172

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

                        

173

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

174

5. Securing the Wafers• Anchor wafers with ½-inch-

wide strips of Surgicel® (oxidized cellulose), starting at bottom of cavity and moving up Keep Surgicel® strips 1 layer deep: do not create large mass

175

6. Ensure watertight dural closure• Take extra care to decreas

e 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

176

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

177

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

178

Zoladex Implant

• Goserelin acetate is dispersed in a matrix consisting of D,L-lactic 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

179

• 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.

180

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).

181

Other novel delivery systems

• DEFINITY® is a vial of Perflutren• ( 全氟丙烷 <超声造影药 >) • Lipid Microspheres for preparing and i

njectable suspension.

182

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

183

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.

184

EpiPen

185

Autoinjection

186

Humlin N Pen

187

Safe-Needle Systems

189

Safe-Needle Systems

• Lovenox

190

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。

191

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 medic

ation and the corneal surface • 4. The category of Long-Acting Parenteral Systems? • 5. What is liposomes? The advantages and the disadvan

tages of liposomes• 6. What is Implant? What is Zoladex Implant?

192

193