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Dosage Form Design For Hormonal Products

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Dosage form design for hormonal products - a presentation done with Mrs L-M Schutte in 2011

Dosage form design for hormonal products - a presentation done with Mrs L-M Schutte in 2011


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  • 1. Dr Liesl Brown Mrs Liza-Marie Schutte Department of Pharmacy University of Limpopo (Medunsa Campus)Module 3.4: Endocrine and Reproductive Pharmacy (2011)
  • 2. Subcutaneous injectablesSubcutaneous hormonal implantsIntra-uterine devices (IUDs)CondomsSustained release implantsVaginal creams and pessariesTransdermal patches
  • 3. ByDr Liesl Brown
  • 4. 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: Examples:  Site of injection -Insulin -Choriogonadotrophin alpha (Ovidrel)  Body temperature -Chorionic gonadotrophin (Pregnyl)  Age of patient -Human menopausal gonadotrophin  Degree of massaging the injected site (Menopur)
  • 5. Difference betweenID, SC and IMadministrations
  • 6. Sites ofadministration forSC injections (male)
  • 7. Sites ofadministration forSC injections(female)
  • 8. Subcutaneous hormonal implantsDefinition: 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
  • 9. Subcutaneous hormonal implantsProgesterone only-contraceptives (not available in SA) Releases levonorgestrel over period of 5 years and Etonorgestrel (active metabolite of desogestrel) over 3 yearsTestosterone implant (male hypogonadism): adequate hormone levels up to 4-5 months
  • 10. 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)
  • 11. Implanton® (1 rodin stead of 6)Implanon, a newimplant (Progestin-onlyhormone implant -releases hormone forprevention ofpregnancy for 3 years)-uses only 1 rod and iseasier to insert andremove than Norplantimplants (not availablein SA)
  • 12. Site ofadministration forsc hormonalimplantsSix thin, flexible capsulesfilled with levonorgestrel(LNG) that are inserted justunder the skin of a woman’supper arm
  • 13. Site ofadministration andan example of theSC implants
  • 14. SC levonorgestrelimplants
  • 15. SC hormonalimplants in awoman’s upper arm
  • 16. Components of asingle rod implant
  • 17. Sustained- release implantsZoladex® 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
  • 18. Deep intramuscular contraceptiveinjectionsParenteral 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®
  • 19. Deep intramuscular contraceptiveinjections MOA:Mainly stops ovulationThickens cervical mucusRelative low costDepo-provera® Depot-medroxyprogesterone acetate Administered 12 weeklyNur-Isterate® Norethisterone enanthate Administered 8 weekly
  • 20. Deep intramuscularcontraceptive 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
  • 21. Deep intramuscular contraceptiveinjectionsAdvantages +Very effective (99 %) +Does not interfere with the process of love making +No daily pill-taking +No oestrogen side-effectsSide effects -Heavy, prolonged periods / absent periods (may be an advantage) -Headaches -Weight gain -Delayed return of fertility
  • 22. Deep intramuscular contraceptiveinjectionsContraindications for use in women: Undiagnosed abnormal vaginal bleeding Hormone- dependent cancer Migraine sufferers Liver problems or a history of thrombosis Risk factors for osteoporosis
  • 23. 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)
  • 24. 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
  • 25. 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
  • 26. An example of aMirena® IUDMirena is a new type of IUDthat gradually releases theprogestin levonorgestrel.Progestin-releasing IUDsmake menstruation lighterand less painful. Mirena hasbeen approved for 5 years ofuse in more than 100countries.
  • 27. An example of anIUD containinglevonorgestrel andcopperAn intrauterine device (IUD)is a small, plastic, T-shapeddevice that is inserted intothe uterus to preventpregnancy. IUDs containcopper or the hormonelevonorgestrel (LNg). Plasticstrings tied to the end of theIUD hang down through theopening of the uterus(cervix) into the vagina.
  • 28. An example of anIUD in the uterus
  • 29. An example of asingle cylinder IUDthat is anchored inthe fundus of theuterusFrameless IUDs, such asGyneFix, do not have theplastic T-shaped frame ofconventional IUDs. Instead,they consist of several coppercylinders tied together on astring. The device isanchored 1 centimeter deepinto the fundus of the uterus.
  • 30. 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 pregnancyA 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
  • 31. 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
  • 32. 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
  • 33. Step 1: Step 2: Collection of Compounding raw material Rubber trees (Brazil, SA Asia, West Africa) Collect sap (containing latex) Step 7: Step 3:Packaging Storage Latex = emulsion or dispersion of small rubber particles in water -Add to the shelve Latex condoms (end product) also life of latex contains: -Makes rubber less -Antifungal/antibacterial agents biodegradable -ZnO2 and sulfur (vulcanization agent) (trash rather than -K-laurate (stabilizer) Step 6: Steptoilet) 4: -Ammonia (anticoagulant) Testing Dipping -Antioxidants -Preservatives and pigments Step 5: Tumbling
  • 34. Step 1: Step 2: Collection of Compounding raw material Ingredients added that must bind to the rubber particles in the latex Step 7: Step 3:Packaging Storage Chemical additives are added to make a paste and mix this with the liquid latex Step Done: 6: -Strength Step 4: Testing -Reliability Dipping -Lower allergenic potential Step 5: Tumbling
  • 35. Step 1: Step 2: Collection of Compounding raw material Step 7: Step 3:Packaging Storage 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 6: Step 4: Testing Dipping Step 5: Tumbling
  • 36. Step 1: Step 2: Collection of Compounding raw material Belt 7: Step drags and rotates glassPackaging Step 3: Storage rods/mandrels through a series of dips into the latex compound -makes condoms thickDone: enough-Latex is evenly spread (repeat x2-3) -dries water (> water,-After each dip the latex is hot air dried so thinner condom)that:completes 6: chemical reactions and Step the Step 4: Testingensures strength and stability DippingRing of latex at the base ofStep 5: each Tumblingcondom is made
  • 37. A continuous line of cleanglass formers are dipped intothe latex, where they becomecoated. The formers arerotated to ensure the latex isevenly spread.After drying, the formers aredipped for a second time.
  • 38. Step 1: Step 2: Collection of raw material Compounding Remove -odours Mandrels travel through a tunnel oven -allergens -vulcanize the condoms -pathogens Step 7: Condoms are removed and washed Step 3:Packaging Storage Condoms Placed in a special tumble drier coated with talc/cornstarch, silica or magnesium Step 6: Step 4: carbonate Testing Dipping -prevent it sticking Step 5: together Tumbling -easier to unroll
  • 39. Step 1: Tested after several days Step 2: Collection of Compounding raw material Batches are made and tested 1. Inflation test 2. Water leakage Step 7: test Step 3:Packaging Storage Step 6: Step 4: Testing Dipping Step 5: Tumbling
  • 40. Step 1: Tested after several days Step 2: Collection of Compounding raw material Batches are made and tested 1. Inflation test Step 7: Step 3:Packaging Most important test because Storage 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) Step 6: Step 4: Testing International latex standard: 18 litres Dipping Step 5: Tumbling
  • 41. Inflation tests measure howmuch air a condom can hold-- and how far it can stretch -- before it breaks.
  • 42. Step 1: Tested after several days Step 2: Collection of Compounding raw material Batches are made and tested 2. Water leakage test Step 7: Step 3:Packaging Condoms are filled with 300 ml Storage 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 Step 6: mandrel Step 4: Testing -mandrel is then passed over a soft conductive brush Dipping If there is pinholes, a circuit will be established and the Step 5: machine will reject the condom Tumbling
  • 43. Water leakage test –condoms are filled with 300ml of water and inspected forpin-sized holes
  • 44. Step 1: Condoms that have passed the tests Step 2: Collection of Compounding raw material rolled Lubricant/spermacide added by a meter pump (last Step 7: step) Step 3: Packaging Storage Condom sandwiched between 2 layers of laminated foil Top wrap is added to the foiling process Put on conveyor belt - exterior packaging (box) Step 6: Step 4: Testing Dipping !! amount of N9 used in condoms - little effect during sexual activity Step 5: -Since it can cause vaginalLubricated condoms - silicone Tumbling irritation - make s disease transferSpermicidally lubricated condoms - more likely, it cannonoxynol-9 (N9), in the lubricant do more harm than good
  • 45. Step 1: Condoms that have passed the tests Step 2: Collection of Compounding raw material rolled Lubricant/spermacide added by a meter pump (last step) Step 7: Step 3:Packaging Condom sandwiched between 2 layers of laminated foil Storage Top wrap is added to the foiling process Packaging done: -air out Put on conveyor belt -UV light out -exterior packaging (box) -square better Step 6: Step 4: Testing Dipping than triangular (less damage) Step 5: Expiry date: 5 Tumbling years
  • 46. Step 1: Step 2: Collection of Compounding raw material Step 7: Step 3:Packaging Storage Durex:-Water leak testing: Sample of over 2,000,000 condoms per month-Air inflation test: International latex standard: 18 L. Durex min. latexstandard: 22 L. Typically Durex condoms will expand to 40 L. Sample ofca. 500,000 condoms per month Step 6: Step 4:If the condoms fail on any of the tests the entire batch – Testing Dipping which can be up to 432,000 condoms - is discarded! Step 5: Tumbling
  • 47. This is when any lubricantand flavoring that’s going tobe used is injected into thefoil at the same time.
  • 48. Testing of a malepolyurethanecondomAt a manufacturing plant inColombia, a technician teststhe Unique brandpolyurethane condom.Polyurethane condoms havea longer shelf life than latexcondoms.
  • 49. 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
  • 50. 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
  • 51. 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
  • 52. 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
  • 53. 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
  • 54. The female condom
  • 55. The female condom
  • 56. 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.
  • 57. Either of you can put thecondom on the erect penis.Just make sure you put thecondom on before you haveany sexual activity. This helpsto prevent an unplannedpregnancy and the possibilityof catching sexuallytransmitted infections.
  • 58. Check the roll is on theoutside. If it’s on the inside,the condom is inside out.Squeeze the teat end of thecondom so there’s no airtrapped inside.
  • 59. Still squeezing the teat, putthe condom on top of thepenis and roll it down withyour other hand. If it starts toroll back up during sex, justroll it back down againstraight away. If it comes off,stop and put a new condomon.
  • 60. Soon after ejaculation, andwhile the penis is still erect,the condom should be heldfirmly in place at the base ofthe penis before withdrawal.Then just take it off, wrap itin a tissue and put it in thebin. Please don’t flush itdown the toilet.
  • 61. ByMrs Liza-Marie Schutte
  • 62. 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)
  • 63. 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)
  • 64. Vaginal creams and pessaries (cont)Canesten® VC and pessaries Use to control vaginal infections Contains clotrimazole
  • 65. 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.
  • 66. Vaginal creams and pessaries (cont)Cyclogest® pessary Progesterone 200mg For corpus luteum insufficiency Dosage: insert 200mg pessary daily; may be increased to 400mg BD
  • 67. Vaginal creams and pessaries (cont)Orthoforms® Pessaries use for contraception
  • 68. 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.
  • 69. 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
  • 70. 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
  • 71. Transdermal patches (cont)
  • 72. 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
  • 73. 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 ProgramWebsites 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#