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

By

Dr Liesl Brown

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)

Subcutaneous hormonal implants 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

Subcutaneous hormonal implants

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 levonorgestrel 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®

Deep intramuscular contraceptive 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

Deep intramuscular contraceptive 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

Deep intramuscular contraceptive 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)

Intrauterine device (IUD) 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

Intrauterine device (IUD)

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

Tested after several days Batches are made and tested 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

Tested after several days Batches are made and tested 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

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

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

The female condom

The female condom

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.

By

Mrs Liza-Marie Schutte

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

Vaginal creams and pessaries (cont) 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.

Vaginal creams and pessaries (cont) Cyclogest® pessary

Progesterone 200mg

For corpus luteum insufficiency

Dosage: insert 200mg pessary daily; may be

increased to 400mg BD

Vaginal creams and pessaries (cont) 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

Transdermal patches (cont) 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

Transdermal patches (cont)

Transdermal patches (cont) 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#