Tut 3412 dosage form design for hormonal products (2011)

Dr Liesl Brown
Mrs Liza-Marie Schutte
Department of Pharmacy
University of Limpopo (Medunsa Campus)
Module 3.4: Endocrine and Reproductive Pharmacy (2011)

Subcutaneous injectables
Subcutaneous hormonal implants
Intra-uterine devices (IUDs)
Condoms
Sustained release implants
Vaginal creams and pessaries
Transdermal patches

Sub-cutaneous injectables
 Definition: SC drug administration = where drugs are injected into the
subcutaneous layer of the skin. This is the easiest and least painful of
injection to administer
 Injected into loose connective and adipose tissue immediately
underneath the skin (drug absorption slower and < predictable
compared to IM route)
 Volume injected: not exceeding 1 ml
 Injection sites:
 Abdomen, upper back, upper arms, lateral upper hips
 Route used when drugs can not be taken orally (drugs more rapidly and
predictably absorbed compared to the oral route)
 Drug distribution – affected by:
 Site of injection
 Body temperature
 Age of patient
 Degree of massaging the injected site
Examples:
-Insulin
-Choriogonadotrophin alpha (Ovidrel)
-Chorionic gonadotrophin (Pregnyl)
-Human menopausal gonadotrophin
(Menopur)

Difference between
ID, SC and IM
administrations

Sites of
administration for
SC injections (male)

Sites of
administration for
SC injections
(female)

Definition: Implants: solid dosage form which is inserted under the skin
by a small surgical insertion e.g. HRT/contraceptive
• Very small pellets (dense tablet, normally spherical) composed of drug
substance only
• 2-3mm in diameter
• Prepared in aseptic manner to be sterile
• Inserted into body tissues by surgical procedures
• In tissue they are very slowly absorbed over a period of months

Progesterone only-contraceptives (not available
in SA)
Releases levonorgestrel over period of 5 years
and
Etonorgestrel (active metabolite of desogestrel) over 3 years
Testosterone implant (male hypogonadism):
adequate hormone levels up to 4-5 months

Norplant Implants (not available in SA)
 Set of 6 small, plastic capsules (size: matchstick)
 Placed under woman’s upper arm skin
 Contains a progestin (slow release) and no oestrogen
 Efficacy: 5 years or longer
 MOA:
 Thicken cervical mucus (makes it difficult for sperm to pass through)
 Stops ovulation in ½ menses cycles (after 1 year of use)
 Will not work in disrupting an existing pregnancy
 Advantages:
+ Effective 24 hours after insertion
+ Fertility returns immediately after capsules are removed
+ Increased sexual enjoyment (no interruptions)
 Disadvantages:
- Pain upon insertion
- Client cannot start/stop use on her own
- Discomfort (upon and after insertion and removal)

Implanton® (1 rod
in stead of 6)
Implanon, a new
implant (Progestin-only
hormone implant -
releases hormone for
prevention of
pregnancy for 3 years)
-uses only 1 rod and is
easier to insert and
remove than Norplant
implants (not available
in SA)

Site of
administration for
sc hormonal
implants
Six thin, flexible capsules
filled with levonorgestrel
(LNG) that are inserted just
under the skin of a woman’s
upper arm

Site of
administration and
an example of the
SC implants

SC hormonal
implants in a
woman’s upper arm

Components of a
single rod implant

Sustained- release implants
Zoladex® implant
 Contains goserelin acetate a synthetic analogue of LHRH
 Thus it acts as a potent inhibitor of pituitary gonadotropin
secretion
 Used in males for prostate cancer
 10.8 mg implant: release continues over 12 weeks
 3.6 mg implant: 28 days

Deep intramuscular contraceptive
injections
Parenteral contraceptives: Progesterone-only
contraceptives (POPs)
Medroxyprogesterone acetate (DMPA), administered 12
weekly, e.g. Depo-Provera®
or
 Norethisterone enanthate (DNET-EN), administered 8
weekly, e.g. Nur-Isterate®

injections
 MOA:
Mainly stops ovulation
Thickens cervical mucus
Relative low cost
Depo-provera®
 Depot-medroxyprogesterone acetate
 Administered 12 weekly
Nur-Isterate®
 Norethisterone enanthate
 Administered 8 weekly

Deep intramuscular
contraceptive injections
 Medroxyprogesterone acetate is insoluble in water
 If administered IM a depot or reservoir of the drug is formed
 The long apparent half-life and long duration of action result from
the slow absorption of the drug from the injection site as a result of
the slow dissolution of the drug from this depot
 Concentrations achieved within 24 hours of administration is
sufficiently high to provide almost immediate protection against
pregnancy
 The concentration of drug increases for approximately three weeks
 Peak concentration of 1 to 7 ng/ml is reached
 Concentration drops to 0.2 ng/ml 5-6 months after administration
 Up to 6 months may be required for fertility to return

injections
Advantages
 +Very effective (99 %)
 +Does not interfere with the process of love making
 +No daily pill-taking
 +No oestrogen side-effects
Side effects
 -Heavy, prolonged periods / absent periods (may be an
advantage)
 -Headaches
 -Weight gain
 -Delayed return of fertility

injections
Contraindications for use in women:
 Undiagnosed abnormal vaginal bleeding
 Hormone- dependent cancer
 Migraine sufferers
 Liver problems or a history of thrombosis
 Risk factors for osteoporosis

Intrauterine device (IUD)
 Definition: Is a form of birth control that involves an object placed in the
uterus to prevent fertilization of the egg by sperm, inhibit tubular transport
and prevent implantation of the blastocyst into the endometrium
 Long term
 Small, safe and highly effective
 Small, T-shaped device wrapped in copper/contains hormones
 Inserted into the vagina (dr)
 Plastic string tied to the end of the device hangs down through the cervix
into the vagina (use string to check if IUD is in place and also to remove
IUD - dr)
 Types:
 Inert/unmedicated (um-IUD) (USA, aka IUDs)
 Hormonally based/medicated (m-IUD) (UK aka IU system)
 Type 1: PE plastic with progesterone/progestogen attached to the stalk of the
IUD
 Type 2: PE plastic and reservoir of progesterone/progestogen (levonorgestrel)

 Inert/unmedicated (um-IUD) (USA, aka IUDs)
 Made of plastic (polyethylene, PE)
 PE plastic and copper
 PE plastic and a copper base surrounding the PE plastic (copper can be either
single sleeves or wound onto IUD
 Effective, 3-5 (??10) years
 MOA: Copper is toxic to sperm
 Fallopian tubes produce fluid (WBCs, copper ions, enzymes and prostaglandins)
that kills sperm

 Hormonally based/medicated (m-IUD) (UK aka IU system)
 Type 1: PE plastic with progesterone/progestogen attached to the stalk of the
IUD
 The progesterone/progestogen is surrounded by a silica membrane which results
in a controlled rate of release of the progesterogen/progestogen
 Effective: 5 years
 Type 2: PE plastic and reservoir of progesterone/progestogen (levonorgestrel)
 Mirena®
 Effective : 5 years
 MOA: prevents fertilisation of the egg
 Prevents fertilisation by damaging/killing sperm
 Makes the mucus thick and sticky (sperm cannot get to uterus)
 Thick growth of the endometrium (results in a lining that is a poor place for a
fertilised egg to implant/grow)
 Hormone: progesterone (levonorgestrel): reduces menstrual bleeding and cramping

An example of a
Mirena® IUD
Mirena is a new type of IUD
that gradually releases the
progestin levonorgestrel.
Progestin-releasing IUDs
make menstruation lighter
and less painful. Mirena has
been approved for 5 years of
use in more than 100
countries.

An example of an
IUD containing
levonorgestrel and
copper
An intrauterine device (IUD)
is a small, plastic, T-shaped
device that is inserted into
the uterus to prevent
pregnancy. IUDs contain
copper or the hormone
levonorgestrel (LNg). Plastic
strings tied to the end of the
IUD hang down through the
opening of the uterus
(cervix) into the vagina.

An example of an
IUD in the uterus

An example of a
single cylinder IUD
that is anchored in
the fundus of the
uterus
Frameless IUDs, such as
GyneFix, do not have the
plastic T-shaped frame of
conventional IUDs. Instead,
they consist of several copper
cylinders tied together on a
string. The device is
anchored 1 centimeter deep
into the fundus of the uterus.

Other dosage forms: Condoms
 Definition:
A male condom is a sheath, or covering, made of
latex/(polyurethane/lamb cecum) materials, made to fit over a man’s
erect penis to prevent his sperm of being expelled into an orifice of
another person (e.g. vagina), thereby preventing pregnancy
A female condom is a latex/polyurethane sheath or covering, which is
placed into the vagina to prevent sperm from entering a woman’s
vagina/uterus, thus preventing pregnancy
 MOA: Cover the cervix or the penis to block sperm from entering the cervical
canal

Other dosage forms: Condoms
 Advantages:
 +Prevents STIs and HIV/AIDS
 +Easily obtainable and comes in a variety of sizes and types
 +Enables males to take responsibility in preventing pregnancy and STIs
 +Easy to use
 +Immediately effective
 Disadvantages:
 -Latex and lubricant allergy
 -Interruption in love making process
 -Male erection needed
 -Embarrassment (purchase, use, put on/take off)
 Efficacy: 10 - 15 pregnancies per 100 women per year as typically used

Manufacturing of condoms
 Lamb cecum (‘skin’ condoms)
 New Zealand – raises large numbers of sheep – primary sources of
lamb cecum
 Manufacturing stays the same since Schmid 1st manufactured
condoms
 Cecums are washed, defatted and salted
 Polyurethane condoms
 Female (expensive: $3 vs $0.64 for male condom)
 Male condoms (new advances, 1994)
 Just as strong as latex (female condom 40x stronger than latex)
 1/10 as thick as latex condom
 Recommended for latex sensitive persons
 Latex condoms

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Rubber trees (Brazil, SA Asia, West Africa)
Collect sap (containing latex)
Latex = emulsion or dispersion of small
rubber particles in water
Latex condoms (end product) also
contains:
-Antifungal/antibacterial agents
-ZnO2 and sulfur (vulcanization agent)
-K-laurate (stabilizer)
-Ammonia (anticoagulant)
-Antioxidants
-Preservatives and pigments
-Add to the shelve
life of latex
-Makes rubber less
biodegradable
(trash rather than
toilet)

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Ingredients added that must bind to
the rubber particles in the latex
Chemical additives are added to
make a paste and mix this with the
liquid latex
Done: -Strength
-Reliability
-Lower allergenic potential

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Content is then loaded into drums
for 7 days
-vulcanized (heated) chemically to
strengthen rubber bonds
-so that the O2 (in the mixture (can
escape)

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Belt drags and rotates glass
rods/mandrels through a series of
dips into the latex compound
Done:
-Latex is evenly spread (repeat x2-3)
-After each dip the latex is hot air dried so
that:
completes the chemical reactions and
ensures strength and stability
Ring of latex at the base of each
condom is made
-makes condoms thick
enough
-dries water (> water,
thinner condom)

A continuous line of clean
glass formers are dipped into
the latex, where they become
coated. The formers are
rotated to ensure the latex is
evenly spread.
After drying, the formers are
dipped for a second time.

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Mandrels travel through a tunnel oven
-vulcanize the condoms
Condoms are removed and washed
Placed in a special tumble drier
Remove
-odours
-allergens
-pathogens
Condoms
coated with
talc/cornstarch,
silica or
magnesium
carbonate
-prevent it
sticking
together
-easier to unroll

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Tested after several days
Batches are made and tested
1. Inflation test 2. Water leakage
test

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
1. Inflation test
Most important test because
it tests the elasticity and burst
strenght
(NB: determines a parameter
of the condom’s ability not to tear during sex)
Stretched beyond 1.5 cubic feet (size of a watermelon)
International latex standard: 18 litres

Inflation tests measure how
much air a condom can hold
-- and how far it can stretch -
- before it breaks.

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
2. Water leakage test
Condoms are filled with 300 ml
of water and inspected for pin-
sized holes by rolling it over blotter
paper
as well as electronically
-mandrel is mounted on a stainless steel charged
mandrel
-mandrel is then passed over a soft conductive brush
If there is pinholes, a circuit will be established and the
machine will reject the condom

Water leakage test –
condoms are filled with 300
ml of water and inspected for
pin-sized holes

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Condoms that have passed the tests
rolled
Lubricant/spermacide added by a meter pump (last
step)
Condom sandwiched between 2 layers of laminated foil
Top wrap is added to the foiling process
Put on conveyor belt - exterior packaging (box)
Lubricated condoms - silicone
Spermicidally lubricated condoms -
nonoxynol-9 (N9), in the lubricant
!! amount of N9 used in condoms
- little effect during sexual activity
-Since it can cause vaginal
irritation - make s disease transfer
more likely, it can
do more harm than good

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Condoms that have passed the tests
rolled
Lubricant/spermacide added by a meter pump (last step)
Condom sandwiched between 2 layers of laminated foil
Top wrap is added to the foiling process
Put on conveyor belt
-exterior packaging (box)
Packaging done:
-air out
-UV light out
-square better
than triangular
(less damage)
Expiry date: 5
years

Step 2:
Compounding
Step 3:
Storage
Step 4:
Dipping
Step 5:
Tumbling
Step 6:
Testing
Step 7:
Packaging
Step 1:
Collection of
raw material
Durex:
-Water leak testing: Sample of over 2,000,000 condoms per month
-Air inflation test: International latex standard: 18 L. Durex min. latex
standard: 22 L. Typically Durex condoms will expand to 40 L. Sample of
ca. 500,000 condoms per month
If the condoms fail on any of the tests the entire batch –
which can be up to 432,000 condoms - is discarded!

This is when any lubricant
and flavoring that’s going to
be used is injected into the
foil at the same time.

Testing of a male
polyurethane
condom
At a manufacturing plant in
Colombia, a technician tests
the Unique brand
polyurethane condom.
Polyurethane condoms have
a longer shelf life than latex
condoms.

Condoms – Quality Control
 Class II Medical Devices (FDA)
 Inspection once every 2 years
 Condom dipping machines may not stop (clogged and rusted)
 Measurements:
 Length: 150-200 mm
 Width: 47-54 mm
 Thickness: 0.03-0.09 mm (most condoms range: 0.002 and 0.0024 mm)
 Weight: not > 2 g
 Tensile strength: 15 000 pounds psa
 Elongation before breakage: 625%
 Checks: cracking, molding, drying/sticking latex
 Lots will not pass:
 > 4% failure with respect to the above dimensions
 2.5% with respect to tensile strength and elongation
 0.4% due to leakage

Condoms – Quality Control
 Class II Medical Devices (FDA)
 Inspection once every 2 years
 Condom dipping machines may not stop (clogged and rusted)
 Measurements:
 Length: 150-200 mm
 Width: 47-54 mm (when laid flat)
 Thickness: 0.03-0.09 mm (most condoms range: 0.002 and 0.0024 mm)
 Weight: not > 2 g
 Tensile strength: 15 000 pounds psa
 Elongation before breakage: 625%
 Checks: cracking, molding, drying/sticking latex
 Lots will not pass:
 > 4% failure with respect to the above dimensions
 2.5% with respect to tensile strength and elongation
 0.4% due to leakage

Female condom
 The female condom is up to 95% effective. But it can sometimes slip or
split when used incorrectly
 Advantages:
 +No side effects
 +Can help protect against STIs, including HIV/AIDS
 +Can be put in anytime before sex
 Disadvantages:
 -Putting them in can interrupt sex
 -Some people claim condoms reduce sensitivity during sex
 -Not widely available

How to use a male condom
 Always follow the instructions in the condom pack.
Check the expiry date on the condom wrapper before
you use it. Tear the wrapper open from the serrated
edge and handle the condom carefully, as it can be
damaged by fingernails and sharp objects like
jewellery and body piercings.

Either of you can put the
condom on the erect penis.
Just make sure you put the
condom on before you have
any sexual activity. This helps
to prevent an unplanned
pregnancy and the possibility
of catching sexually
transmitted infections.

Check the roll is on the
outside. If it’s on the inside,
the condom is inside out.
Squeeze the teat end of the
condom so there’s no air
trapped inside.

Still squeezing the teat, put
the condom on top of the
penis and roll it down with
your other hand. If it starts to
roll back up during sex, just
roll it back down again
straight away. If it comes off,
stop and put a new condom
on.

Soon after ejaculation, and
while the penis is still erect,
the condom should be held
firmly in place at the base of
the penis before withdrawal.
Then just take it off, wrap it
in a tissue and put it in the
bin. Please don’t flush it
down the toilet.

Vaginal dosage forms
 Formulation:
 Tablets, capsules, pessaries, solutions, sprays, foams,
creams, ointments
 Due to low moisture environment (in the vagina) –
additives are used to improve e.g. disintegration of
vaginal tablets
 Bicarbonate + an organic acid which results in CO2 release
 Filler: lactose (converted by vaginal flora to lactic acid,
resulting in a pH of 4-4.5
 Vaginal pessaries
 Prepared with: glycerol-gelatin bases (tolerated well)
 PE glycols – less common (irritation)
 Fatty excipients (not used much)

Vaginal creams and pessaries
 Definition: Pessaries: solid dosage forms for vaginal
insertion. They are used for both local and systemic effects
 Administration
 Mainly used for local effects (Trichomonas/Candida)
 Some drugs are administered for systemic effects
 Some drugs have a higher BA compared to the oral route (drug
immediately enters the systemic circulation without passing the
metabolizing liver)
 Vagina well suited for absorption for systemic effects (vast network of
blood vessels)
 Few drugs are administrated via this route
 Oestrogens and prostaglandin analogues (creams or hydrogels)
 Progesterone (vaginal suppository/pessary)

Vaginal creams and pessaries (cont)
Canesten® VC and pessaries
 Use to control vaginal infections
 Contains clotrimazole

Cirone® vaginal gel
 Progesterone 90mg/application (8%)
 For infertility due to inadequate luteal phase
 Dosage: 1 application daily, starting after
documented ovulation or on day 18-21 of cycle.

Cyclogest® pessary
 Progesterone 200mg
 For corpus luteum insufficiency
 Dosage: insert 200mg pessary daily; may be
increased to 400mg BD

Orthoforms®
 Pessaries use for contraception

Transdermal patches
 Device which releases drug to the skin at a controlled
rate well below the maximum that the tissue can accept.
 Thus, the device, not the stratum corneum, controls the
rate at which drug diffuses through the skin.

Transdermal patches (cont)
Claimed advantages
 Variables influenced by gut absorption e.g. changes in pH along GI
tract, food/fluid intake, stomach emptying time and intestinal motility
are eliminated
 Drug enters systemic circulation directly, eliminating ‘first past’ effect
 Controlled, constant drug administration.
 This continuity may permit the use of drugs with short half-lives and
improve patient compliance
 Transdermal route can use drugs with low therapeutic index

Evra® contraceptive patch
• Contains norelgestromin 6 mg, ethinylestradiol
0.6mg which delivers norelgestromin 150 µg and
ethinylestradiol 20 µg in 24 hours
• Apply first patch on day 1 of
menstruation. Patch is effective
immediately
• Apply a new patch weekly for three
consecutive weeks (i.e. on days
1, 8 and 15) followed by one week
patch-free (days 22-28)
• Commence the next patch cycle after
no more than 7 patch-free days

Evorel Conti® patch for hormone replacement therapy
 Suitable for woman with a uterus
 Contains estradiol hemihydrate 3.2 mg, norethisterone
acetate 11.2 mg
 Release in 24 hours: estradiol 50µg, norethisterone
acetate 170 µg
 Apply twice weekly without interuption to clean, dry, intact
skin of the trunk below the waist (not to breasts). Do not
apply twice in succession to the same site

References
 Aulton, M.E. (editor). Pharmaceutics. The Science of Dosage form
Design. 2007. London: Churchill Livingstone
 Desai, A., Lee, M., Gibaldi’s Drug Delivery Systems in
Pharmaceutical Care. 2007. Maryland: American Society of health-
System Pharmacists
 Hatcher, R.A., et al. The Essentials of Contraceptive Technology.
2001. Baltimore: John Hopkins Population Information Program
Websites
 http://www.pharmainfo.net/reviews/development-fabrication-and-evaluation-transdermal-
drug-delivery-system-review
 http://informahealthcare.com/doi/abs/10.1081/DDC-100105179
 http://info.k4health.org/pr/m19/m19chap2.shtm
 lhttp://www.netdoctor.co.uk/sex_relationships/facts/contraceptiveinjection.htm
 http://www.rxlist.com/drug-slideshows/article.htm
 http://home.intekom.com/pharm/hmr/cyclogst.html (SA electronic package inserts)
 http://www.bing.com/images/search?q=transdermal+patch&form=QBIR#

Tut 3412 dosage form design for hormonal products (2011)

Tut 3412 dosage form design for hormonal products (2011)

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