Dosage form design for hormonal products (2011)
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Dosage form design for hormonal products (2011)

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Dosage form design for hormonal products

Dosage form design for hormonal products

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    Dosage form design for hormonal products (2011) Dosage form design for hormonal products (2011) Presentation Transcript

    • Dr Liesl BrownMrs Liza-Marie SchutteDepartment of PharmacyUniversity of Limpopo (Medunsa Campus)Module 3.4: Endocrine and Reproductive Pharmacy (2011)
    • Subcutaneous injectablesSubcutaneous hormonal implantsIntra-uterine devices (IUDs)CondomsSustained release implantsVaginal creams and pessariesTransdermal patches
    • ByDr Liesl Brown
    • Sub-cutaneous injectables Definition: SC drug administration = where drugs are injected into thesubcutaneous layer of the skin. This is the easiest and least painful ofinjection to administer Injected into loose connective and adipose tissue immediatelyunderneath the skin (drug absorption slower and < predictablecompared 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 andpredictably absorbed compared to the oral route) Drug distribution – affected by: Site of injection Body temperature Age of patient Degree of massaging the injected siteExamples:-Insulin-Choriogonadotrophin alpha (Ovidrel)-Chorionic gonadotrophin (Pregnyl)-Human menopausal gonadotrophin(Menopur)
    • Difference betweenID, SC and IMadministrations
    • Sites ofadministration forSC injections (male)
    • Sites ofadministration forSC injections(female)
    • Subcutaneous hormonal implantsDefinition: Implants: solid dosage form which is inserted under the skinby a small surgical insertion e.g. HRT/contraceptive• Very small pellets (dense tablet, normally spherical) composed of drugsubstance 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 implantsProgesterone only-contraceptives (not availablein SA)Releases levonorgestrel over period of 5 yearsandEtonorgestrel (active metabolite of desogestrel) over 3 yearsTestosterone 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 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)
    • Site ofadministration forsc hormonalimplantsSix thin, flexible capsulesfilled with levonorgestrel(LNG) that are inserted justunder the skin of a woman’supper arm
    • Site ofadministration andan example of theSC implants
    • SC levonorgestrelimplants
    • SC hormonalimplants in awoman’s upper arm
    • Components of asingle rod implant
    • Sustained- release implantsZoladex® implant Contains goserelin acetate a synthetic analogue of LHRH Thus it acts as a potent inhibitor of pituitary gonadotropinsecretion Used in males for prostate cancer 10.8 mg implant: release continues over 12 weeks 3.6 mg implant: 28 days
    • Deep intramuscular contraceptiveinjectionsParenteral contraceptives: Progesterone-onlycontraceptives (POPs)Medroxyprogesterone acetate (DMPA), administered 12weekly, e.g. Depo-Provera®or Norethisterone enanthate (DNET-EN), administered 8weekly, e.g. Nur-Isterate®
    • Deep intramuscular contraceptiveinjections MOA:Mainly stops ovulationThickens cervical mucusRelative low costDepo-provera® Depot-medroxyprogesterone acetate Administered 12 weeklyNur-Isterate® Norethisterone enanthate Administered 8 weekly
    • 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 fromthe slow absorption of the drug from the injection site as a result ofthe slow dissolution of the drug from this depot Concentrations achieved within 24 hours of administration issufficiently high to provide almost immediate protection againstpregnancy 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 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 anadvantage) -Headaches -Weight gain -Delayed return of fertility
    • 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
    • Intrauterine device (IUD) Definition: Is a form of birth control that involves an object placed in theuterus to prevent fertilization of the egg by sperm, inhibit tubular transportand 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 cervixinto the vagina (use string to check if IUD is in place and also to removeIUD - 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 theIUD 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 eithersingle 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 theIUD The progesterone/progestogen is surrounded by a silica membrane which resultsin 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 afertilised egg to implant/grow) Hormone: progesterone (levonorgestrel): reduces menstrual bleeding and cramping
    • 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.
    • 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.
    • An example of anIUD in the uterus
    • 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.
    • Other dosage forms: Condoms Definition:A male condom is a sheath, or covering, made oflatex/(polyurethane/lamb cecum) materials, made to fit over a man’serect penis to prevent his sperm of being expelled into an orifice ofanother person (e.g. vagina), thereby preventing pregnancyA female condom is a latex/polyurethane sheath or covering, which isplaced into the vagina to prevent sperm from entering a woman’svagina/uterus, thus preventing pregnancy MOA: Cover the cervix or the penis to block sperm from entering the cervicalcanal
    • 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 oflamb cecum Manufacturing stays the same since Schmid 1st manufacturedcondoms 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:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialRubber trees (Brazil, SA Asia, West Africa)Collect sap (containing latex)Latex = emulsion or dispersion of smallrubber particles in waterLatex condoms (end product) alsocontains:-Antifungal/antibacterial agents-ZnO2 and sulfur (vulcanization agent)-K-laurate (stabilizer)-Ammonia (anticoagulant)-Antioxidants-Preservatives and pigments-Add to the shelvelife of latex-Makes rubber lessbiodegradable(trash rather thantoilet)
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialIngredients added that must bind tothe rubber particles in the latexChemical additives are added tomake a paste and mix this with theliquid latexDone: -Strength-Reliability-Lower allergenic potential
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialContent is then loaded into drumsfor 7 days-vulcanized (heated) chemically tostrengthen rubber bonds-so that the O2 (in the mixture (canescape)
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialBelt drags and rotates glassrods/mandrels through a series ofdips into the latex compoundDone:-Latex is evenly spread (repeat x2-3)-After each dip the latex is hot air dried sothat:completes the chemical reactions andensures strength and stabilityRing of latex at the base of eachcondom is made-makes condoms thickenough-dries water (> water,thinner condom)
    • 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.
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialMandrels travel through a tunnel oven-vulcanize the condomsCondoms are removed and washedPlaced in a special tumble drierRemove-odours-allergens-pathogensCondomscoated withtalc/cornstarch,silica ormagnesiumcarbonate-prevent itstickingtogether-easier to unroll
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialTested after several daysBatches are made and tested1. Inflation test 2. Water leakagetest
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialTested after several daysBatches are made and tested1. Inflation testMost important test becauseit tests the elasticity and burststrenght(NB: determines a parameterof 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 howmuch air a condom can hold-- and how far it can stretch -- before it breaks.
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialTested after several daysBatches are made and tested2. Water leakage testCondoms are filled with 300 mlof water and inspected for pin-sized holes by rolling it over blotterpaperas well as electronically-mandrel is mounted on a stainless steel chargedmandrel-mandrel is then passed over a soft conductive brushIf there is pinholes, a circuit will be established and themachine will reject the condom
    • Water leakage test –condoms are filled with 300ml of water and inspected forpin-sized holes
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialCondoms that have passed the testsrolledLubricant/spermacide added by a meter pump (laststep)Condom sandwiched between 2 layers of laminated foilTop wrap is added to the foiling processPut on conveyor belt - exterior packaging (box)Lubricated condoms - siliconeSpermicidally lubricated condoms -nonoxynol-9 (N9), in the lubricant!! amount of N9 used in condoms- little effect during sexual activity-Since it can cause vaginalirritation - make s disease transfermore likely, it cando more harm than good
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialCondoms that have passed the testsrolledLubricant/spermacide added by a meter pump (last step)Condom sandwiched between 2 layers of laminated foilTop wrap is added to the foiling processPut on conveyor belt-exterior packaging (box)Packaging done:-air out-UV light out-square betterthan triangular(less damage)Expiry date: 5years
    • Step 2:CompoundingStep 3:StorageStep 4:DippingStep 5:TumblingStep 6:TestingStep 7:PackagingStep 1:Collection ofraw materialDurex:-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 monthIf 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 lubricantand flavoring that’s going tobe used is injected into thefoil at the same time.
    • Testing of a malepolyurethanecondomAt a manufacturing plant inColombia, a technician teststhe Unique brandpolyurethane condom.Polyurethane condoms havea longer shelf life than latexcondoms.
    • 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 orsplit 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 beforeyou use it. Tear the wrapper open from the serratededge and handle the condom carefully, as it can bedamaged by fingernails and sharp objects likejewellery and body piercings.
    • 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.
    • 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.
    • 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.
    • 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.
    • ByMrs 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 ofvaginal 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 vaginalinsertion. 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 (drugimmediately enters the systemic circulation without passing themetabolizing liver) Vagina well suited for absorption for systemic effects (vast network ofblood 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 afterdocumented 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 beincreased to 400mg BD
    • Vaginal creams and pessaries (cont)Orthoforms® Pessaries use for contraception
    • Transdermal patches Device which releases drug to the skin at a controlledrate well below the maximum that the tissue can accept. Thus, the device, not the stratum corneum, controls therate at which drug diffuses through the skin.
    • Transdermal patches (cont)Claimed advantages Variables influenced by gut absorption e.g. changes in pH along GItract, food/fluid intake, stomach emptying time and intestinal motilityare 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 andimprove patient compliance Transdermal route can use drugs with low therapeutic index
    • Transdermal patches (cont)Evra® contraceptive patch• Contains norelgestromin 6 mg, ethinylestradiol0.6mg which delivers norelgestromin 150 µg andethinylestradiol 20 µg in 24 hours• Apply first patch on day 1 ofmenstruation. Patch is effectiveimmediately• Apply a new patch weekly for threeconsecutive weeks (i.e. on days1, 8 and 15) followed by one weekpatch-free (days 22-28)• Commence the next patch cycle afterno 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, norethisteroneacetate 11.2 mg Release in 24 hours: estradiol 50µg, norethisteroneacetate 170 µg Apply twice weekly without interuption to clean, dry, intactskin of the trunk below the waist (not to breasts). Do notapply twice in succession to the same site
    • References Aulton, M.E. (editor). Pharmaceutics. The Science of Dosage formDesign. 2007. London: Churchill Livingstone Desai, A., Lee, M., Gibaldi’s Drug Delivery Systems inPharmaceutical 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#