Assignment on :

Targeted Drug Delivery Systems &

IntraUterine Drug Delivery

Submitted To:

Vaish Institute of Pharmaceutical Education &

Research,Rohtak

Sub- Practice School (BP- 706)

By: NAKUL SINGH

Regn. No: 20-VIR-33

University Roll No. : 254285

Under the supervision of

Mrs. Alka Agrawal Jain

Assistant professor

(Pharmaceutical Chemistry)

PT. B.D. SHARMA UNIVERSITY OF HEALTH SCIENCES

ROHTAK
 B. PHARMA {SEMESTER-VII}

2021-2024

PT. BD SHARMA UNIVERSITY OF HEALTH SCIENCE,

ROHTAK

CERTIFICATE

This is certified that the project entitled “Target Drug Delivery System &
Intrauterine Drug Delivery ”

Submitted by Mr. NAKUL SINGH in partial fulfillment of the requirement for the
award of the bachelor degree in pharmacy at VAISH INSTIUTE OF
PHARMACEUTICAL SCIENCES, ROHTAK (HARYANA) affiliated to PT. BD
SHARMA UNIVERSITY OF HEALTH SCIENCE, ROHTAK (HARYANA) is an
authentic work carried out by him under guidance and support.
 ACKNOWLEDGEMENT

I would like to express my gratitude and sincere thanks to my mentors

MRS. ALKA AGRAWAL JAIN and for the guidance, support, encourage-
ment, and cooperation during my project work.

I further extend my sincere gratitude to all my teacher, parents, and

friends for their kind cooperation and support during my project
work.

Thank you
 DECLARATION

This work done on the project entitled “ Target Drug Delivery System &
Intrauterine Drug Delivery”

Submitted in partial fulfillment of the requirement for the award of

the bachelor degree in pharmacy at VAISH INSTITUTE OF
PHARMACEUTICAL SCIENCE,ROHTAK (HARYANA) affiliated to PT. BD
SHARMA UNIVERSITY OF HEALTH SCIENCE, ROHTAK (HARYANA) is
an authentic record of my work.

NAKUL SINGH
 Table of Contents

Targeted Drug Delivery Systems

TDDS Introduction
Reasons for Site specific delivery of drugs
OBJECTIVES
IDEAL CHARACTERISTICS
Advantages and Disadvantages
Biological processes and events involved in drug targeting
Cellular Uptake and Processing
Transport across the epithelial barrier
Extravasation
Lymphatic Uptake
APPROACHES TO DRUG TARGETING
Applications of Drug Targeting
INTRAUTERINE DRUG DELIVERY SYSTEM
IUD Introduction
Advantages and Disadvantages
DEVELOPMENT OF IUDS
Non-hormonal IUDs/Copper-Medicated IUDs
MECHANISM OF ANTIFERTILITY ACTION OF COPPER
Hormonal IUDs
Non-Medicated IUDs
APPLICATION
 Targeted Drug Delivery Systems

Introduction

It is a special form of drug delivery system where the pharmacologically

active agent or medicament is selectively targeted or delivered only to its
site of action or absorption and not to the non-target organs or tissues or
cells.
The drug may be delivered:
To the capillary bed of the active sites,
To the specific type of cell (or) even an intracellular region. Ex- tumour cells
but not to normal cells,
To a specific organ (or) tissues by complexing with the carrier that recognizes
the target

Reasons for Site specific delivery of drugs

Pharmaceutical
Drug instability in conventional dosage form
Solubility
Biopharmaceutical
Low absorption
High-membrane bounding
Biological instability
Pharmacokinetic / Pharmacodynamic
Short half-life
Large volume of distribution
Low specificity
Clinical
 Low therapeutic index.

OBJECTIVES
• To achieve a desired pharmacological response at a selected sites without
undesirable interaction at other sites, there by the drug have a specific action
with minimum side effects & better therapeutic index.

• Ex- in cancer chemotherapy and in enzyme replacement therapy.

IDEAL CHARACTERISTICS

Targeted drug delivery system should be-

HOW??

Biochemically inert (non-toxic)

Non-immunogenic.
Both physically and chemically stable in vivo and in vitro.
Restrict drug distribution to target cells or tissues or organs
Should have uniform capillary distribution.
Controllable and predicate rate of drug release.
Drug release does not effect the drug action.
Therapeutic amount of drug release.
Minimal drug leakage during transit.
Carriers used must be bio-degradable or readily eliminated from the body
without any problem and no carrier induced modulation of diseased state.
The preparation of the delivery system should be easy or reasonably simple,
reproductive and cost effective.

Advantages and Disadvantages

ADVANTAGES

Control of drug delivery on to a particular site or vicinity with

predetermined or expected release kinetics.
Drug administration protocols may be simplified.
 Toxicity is reduced by delivering a drug to its target site, there by reducing
harmful systemic effects.
Drug can be administered in a smaller dose to produce the desire effect.
Avoidance of hepatic first pass metabolism.
Enhancement of the absorption of target molecules such as peptides and
particulates.
Dose is less compared to conventional drug delivery system.
No peak and valley plasma concentration.
Selective targeting toinfections cells that compare to normal cells.

DISADVANTAGES

Expensive
Technical skill required
Stability issues both
Chemical and physical biological as well

Biological processes and events involved in drug targeting

Cellular Uptake and Processing
Transport across the epithelial barrier
Extravasation
Lymphatic Uptake
Cellular Uptake and Processing

Following administration low molar mass drugs can enter into or pass
through various cells by simple diffusion
process. Targeted drug delivery usually have macro molecular assemblies
hence cannot enter by such simple process.
Hence take up by a process called ENDOCYTOSIS
Steps involved :
Internalization of the plasma membrane
Concomitant with engulfment of extracellular material
Transport across the epithelial barrier

The oral buccal nasal vaginal and rectal cavities are internally lined with one
or epithelial cells more layers of
Depending on the position and function in the body epithelial cells can be
varied forms
Three layer physiology:
Epithelial
Lamia propria
Basal lamina
Low molar mass drugs cross the above by passive difussion carrier mediated
systems ans selective and non-selective

Extravasation

Many diseases result from the dysfunction of cells located outside the
cardiovascular system thus for a drug to exert its therapeutic effects it must
exit from the central circulation this process of trans vascular exchange is
called Extravasation which is governed by blood capillary walls
Factors that control permeability of capillaries
Structure of the capillary wall
Pathological condition
Lymphatic Uptake

Following extravasation drug molecules can either reabsorb into the blood
stream directly or enter into the lymphatic system and return with the
lymph to the blood circulation
Also drugs administered by subcutaneous intracellular transdermal
peritoneal routes can reach the systemic circulation by lymphatic system.
APPROACHES TO DRUG TARGETING

An ideal targeted drug delivery approach would not only increase therapeutic
efficacy of drugs but also decrease the toxicity associated with drug to allow
lower doses of the drug to be used in therapy.

The approaches of drug targeting may be classified into two broad categories

1. chemical modification

2. carrier mediated

1. Chemical Modification

This involves chemical modification of the parent compound to a derivative,

which is activated only at the target site. This involves chemical transformation
of the active drug into inactive derivative, which when administered, will
undergo several preditable enzymatic transformations principally at its site of
action. The most common approach of drug targeting by chemical modification
is the prodrugs.
2. Carrier Mediated Approach

This approach utilizes carriers such as liposomes, microspheres nanoparticles,

etc., and macromolecules to direct the drug to its site of action.

1) Passive Targeting: This utilizes the natural distribution of the carrier system
through which it approaches the intended cell lines. The ability of the
reticuloendothelial cells of the liver and spleen to recognize some colloidal
carriers like liposomes make them ideal delivery systems for passive targeting of
drugs to these compartments. This involve macrophage cells of the
reticuloendothelial system (RES) e.g. AIDS, leishmaniosis, candidiasis etc.

2) Active Targeting: The normal distribution pattern of the delivery system is

modified in active targeting by using some exogenous means so that it can be
identified by a particular cell line.

First Order Targeting: This involves the targeting of the delivery system to the
capillary bed of the target site, organ or tissue e.g., liver, eyes, etc.

Second Order Targeting: The selective delivery of drugs to specific cell is called
second order targeting, e.g. tumor cells of liver.

Third Order Targeting: This type of targeting involves drug delivery to

intracellular sites of target cells, e.g. mitochondrial drug targeting

3) Inverse Targeting: In this type of targeting attempts are made to avoid

passive uptake of colloidal carrier by RES (Reticulo Endothelial Systems) and
hence the process is referred to as inverse targeting.

4) Physical Targeting: In this type of targeting some characteristics of

environment changes like pH, temperature, light intensity, electric field, ionic
strength small and even specific stimuli like glucose concentration are used to
localize the drug carrier to predetermined site.

5) Dual Targeting: In this targeting approach carrier molecule itself have their
own therapeutic activity and thus increase the therapeutic effect of drug..

6) Double Targeting: Temporal and spatial methodologies are combined to

target a carrier system, then targeting may be called double targeting.
Applications of Drug Targeting

Delivery of toxic drugs to tumors: Highly toxic drugs, which are too
dangerous to deliver in a systemic manner can be delivered to particular
target site without affecting the normal cells, e.g potent radionuclides,
cellular toxins, etc.
Targeting also reduces the effective dose of the drug thereby reducing the
adverse effects.
Delivery of DNA vectors to target cell types for genetic corrections
Targeting to vasculature, e.g. in cancer treatment
Targeting to neovasculature forming around tumors: e.g. pulmonary,
cardiovascular and inflammatory disease.
Targeting to pathogen infected cells
Crossing blood brain barrier for brain targeting
 INTRAUTERINE DRUG DELIVERY SYSTEM

Introduction

The uterus (womb) is a pear-shaped dynamic muscular organ that is

responsible for a variety of functions such as gestation (pregnancy),
menstruation, labor, and delivery.
The uterine drug delivery system works with a variety of medical or non-
medical devices that perform the act of contraception in the uterus
continuously for a prolonged range of time. In recent times they are mainly
used for family planning.
The device which is used in the intrauterine drug delivery system is known as
an Intrauterine device (IUD)

Advantages and Disadvantages

ADVANTAGES

Lower probability of death and risk compared to oral pills.

Doesn't alter or affect the natural hormonal balance.
Offers long-term birth control around 2-10 years.
Doesn't interfere with sexual activity or coitus or libido
Higher patient compliance in terms of dosing frequency and adherence.

DISADVANTAGES

Copper IUDs avoided in case of Wilson's disease

Hormonal IUDs not recommended for liver disease or breast cancer
Risk of expulsion within the first year
 Irregular bleeding in initial stages
Can't be used in case of pelvic infection or heavy bleeding or endometriosis.
Side effects include nausea, vomiting, headaches, or weight gain.
Can cause unwanted allergies
Risk for preterm delivery if you get pregnant with an IUD, particularly if it's
left in place.

DEVELOPMENT OF IUDS

first generation of IUDs made of silkworm gut and flexible metal wire, such
as the Grafenberg star and the Ota ring. These devices have been withdrawn
due to the complexity of the procedure to include the need for repeated
removal due to pain and bleeding, and other serious problems.
There are 2 types of IUDs

Medicated IUDS

Medicated IUDs are those IUDs that are capable of delivering

pharmacologically active antifertility agents e.g. copper-bearing IUDs,
progesterone releasing IUDs

Non-Medicated IUDs

The non-medicated IUD exerts its contraceptive action by producing a

sterile inflammatory response in the endometrium by its mechanical
interaction. They do not exert any pharmacological or therapeutic action in
the body. The non-medicated IUDs currently available for intrauterine
contraception consist of ring-shaped IUDs made of stainless steel or plastic
e.g. the Lippes Loop Saf-T-Coil or Chinese stainless steel rings.

Non-hormonal IUDs/Copper-Medicated IUDs

These are made of plastic with copper sleeves and copper wire on the
plastic, such as TCu-380A and ML Cu-375.
The effect of copper ions on the binding of steroid hormones to receptors
was investigated in the rabbit's uterus. The results showed that cupric ion
(Cu2 +) is a competitive inhibitor of steroid-receptor interactions by acting
on receptor sites by differentiating and binding to the receptor
macromolecule.
Copper wire thickness -0.2-0.4 mm
Nova T: it is similar to CuT-200, containing 200 m2 of copper. However it has
a silver core to the copper wire, flexible arms, and a large flexible loop at the
bottom to prevent cervical perforations. Nova T or Flexi T 300 IUD is about
98.7per cent effective in preventing pregnancy. Irena IUD is 99 percent
effective in preventing pregnancy
Copper-T IUD causes an increase in cervical fluid containing copper ions,
enzymes, prostaglandins, and macrophages that form a violent sperm area
and prevent it from fertilizing the egg. Oocytes and fertilized ova formation.
Potential development

1. Membrane controlled reservoir-type drug delivery system:

These drug delivery devices consist of a polymeric membrane that both

encapsulates and controls the release of contraceptive agent

Single component system: In this system the contraceptive agent is

encapsulated in its pure solid form in a capsule fabricated form bio-
compatible polymeric materials (silicon elastomers and polyethylene
polymers) The release of contraceptive agent such as progesterone follows
essentially zero-order kinetics.

Multi component system: In this system a constant drug release profile is

maintained by encapsulating a liquid medium saturated with excess drug
profiles in a rate-controlling polymeric membrane.
2. Polymer matrix diffusion controlled drug delivery devices:

This drug delivery device is prepared by homogenously dispersing the drug

particles in a crossed linked polymeric matrix.

Retrievable matrix device: This drug delivery system is designed for

feasibility of retrieval at termination of treatment. It can be easily fabricated
from silicone elastomers by premixing a drug in powder form with a
semisolid silicone elastomers before vulcanization at room or low
temperature or from polyethylene by dry mixing. The rate of drug release is
not constant but time dependent.
Bio-degradable matrix device: This drug delivery system is designed to
eliminate the need for retrieving at the end of treatment it can be prepared
by dissolving such a poly lactic acid, in a common organic solvent to
dryness, to produce drug dispersing biodegradable matrix devices of varying
shapes and sizes, The rate of drug-release from this type of drug delivery
system is a combination of polymer hydrolysis and drug diffusion.
MECHANISM OF ANTIFERTILITY ACTION OF COPPER

Copper is known to be cytotoxic in high concentration it enhances the

spermatocidal and spermato depressive action of an IUD.
The copper concentration in endometrial epithelium and superficial
stromata inhibits the binding of steroids of their receptors.
Cupric ion inhibits the binding of 17-B-estradiol to human endometrial
cytosol.
Cupric ions shows only little effect on sperm motility.
Copper wire was also "Blastocystocidal".
A copper bearing IUD was reported to produce significant effects like:
Increased alkaline phosphate activity in uterine fluids and endometrium
tissue.
No change of acid phosphate activity in uterine fluid but its concentration in
endometrium tissue increases.

Hormonal IUDs

Can be further characterized into progesterone containing IUD or

Levonorgestrel releasing IUD
Hormonal IUDs work by releasing a small amount of hormone i.e. either
progesterone or Levonorgestrel. The primary mechanism of action is making
the inside of the uterus fatal to sperm. They cause thinning of the
endometrial lining and potentially impair implantation. Doyle and Clewe
were the first to initiate the use of hormone-releasing IUDs. In the year 1970,
Scommegna conducted a human test using a standard IUD containing
contraceptive steroid. T-shaped progesterone releasing an IUD with a
vertical stem and a silicone capsule containing the drug appeared. It is also
covered with a polymer for slow-release discharge.
Progesterone releasing IUD

These IUDs make the cervical mucus thick so that sperm cannot enter the
uterus.
There is a change in the lining of the uterus to enhance uterine retention
which does not allow pregnancy by slowly releasing steroids
Levonorgestrel releasing IUD

These contain levonorgestrel-releasing devices.

It is an intrauterine system with sleeves containing levonorgestrel 52 mg
around its base.
It contains a polyethylene stem coated with a matrix Silastin: LNG (2: 1).
Withdrawal of 20 mcg/day and duration of at least 5 years.
Immediate release and then at a dose of 60% drug reduction reduced to
16mcg /day.
It also suppresses the endometrium and ovulation. Also, unlike other IUDs, it
can reduce the risk of (PID)
These IUDs prevent pregnancy by damaging or killing the sperm and making
the mucus thicker and sticky, so the sperm cannot enter the uterus.
It also keeps the endometrium from growing too much, making the
membrane a poor place for the fertilized egg to grow and develop.
It can reduce irregular menstrual bleeding and cramping.
Non-Medicated IUDs

IUDs contain a bioactive component.It made of non-abrasive materials such

as
stainless steel or plastic.
LIPPES LEXOP
The stainless steel (SSR) ring is a flexible ring that is to be inserted through
the cervix.
A plastic-like Lippes loop, which can be inserted into the cervix into a
cannula takes a trapezoidal shape into the uterus. It is less effective than a
copper or hormonal IUD
They use their contraceptive action by producing a sterile inflammatory
response in the endometrium by its mechanical interaction
The mechanism involves a local body reaction that causes the uterus to
become hostile to both sperm and prevents the implantation of the embryo.
These IUDs have a higher rate of contraception after pregnancy compared
to a copper or hormonal IUD.
APPLICATION

IUDs that release copper or levonorgestrel are extremely effective

contraceptives.
The LNG-IUS also reduces menorrhagia and dysmenorrhoea
The LNG-IUS is a proven alternative to hysterectomy and endometrial
ablation. Many surgical procedures are still performed without first
evaluating the LNG-IUS or other medical treatments. Not only is the LNG-IUS
highly effective in reducing MBL, but it is also well-tolerated, has a high user
satisfaction rate, and is cost-effective.
Intrauterine contraception provides contraception that is just as effective
as, and
arguably safer than, female sterilization.
Some studies have found that women with copper IUDs tend to have a lower
risk of endometrial cancer.
Some questions which may come to mind

Q1-Is it safe to have an intrauterine device during breastfeeding

A-No

Q2-If some one has pelvic inflamatory disease it may effect in IU devices

A-No

Q3- Can it prevent sexual transmitted diseases

A- No

Evaluation

Ultrasonography serves as first-line imaging for the evaluation of IUD

position in patients with pelvic pain, abnormal bleeding, or absent retrieval
strings.

The symptoms of an infection

lower abdominal pain

vaginal discharge, possibly with a foul odor
pain when urinating
painful intercourse
a fever
irregular menstruation