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Hormone Delivery Options
Tori Hudson, N.D.
Hormone Delivery Options
IWHIM April 2013
Tori Hudson, N.D.
Professor, NCNM/Bastyr U
Medical Director, A Woman’s Time
Program Director, Institute of Women’s Health and Integrative
Medicine
www.drtorihudson.com
www.instituteofwomenshealth.com
Delivery Methods
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Oral-capsules, tablets
Sublingual-drops, tablets, lozenges
Transdermal-creams, gels, patches
Intravaginal – creams, tablets,ring
Vulva- creams,ointments
Nasal sprays
Injections
Sub Q pellets
• Advantages
– Most common dosage form
– Generally least expensive
– Compliance
• Ease of use
– Storage
– Beyond Use Date
• Disadvantages
– First Pass metabolism
• Of special importance to hormones
– Subject drug to gastric pH
– Gut requires active transport of molecule
– Pediatric, Geriatric patients may have a hard
time swallowing capsules
• Size of capsules
• Can be made with inert ingredients
– Fewer excipients
• Cellulose, lactose, silica, etc.
– Gelatin or Cellulose based capsule
– Can be used vaginally as well
• Oil based vehicle
– Multiple APIs (Active Pharmaceutical
Ingredients)
– Sustained Release capsules
• Methylcellulose based matrix for release
• There is no oral capsule of unesterified
Testosterone available
– Bioavailability ~3.5%
• Oral administration does not increase circulating
testosterone levels
• Extensive first pass metabolism
– Absorbed through the gut, but plasma levels do not rise
– Use of Testosterone Esthers increases
bioavailability
• Undecanoate
• Journal of Andrology, Vol. 27, No. 1, January/February
2006
– Oral Testosterone in Oil: Pharmacokinetic Effects of 5 alpha
Reduction by Finasteride or Dutasteride and Food Intake in Men.
JOHN K. AMORY, STEPHANIE T. PAGE AND WILLIAM J.
BREMNER
• Increases serum concentrations of free testosterone by
solubilizing in oil
• Addition of 5-alpha reductase to capsule doubled serum
levels of testosterone
• Oral progesterone
– Rapid clearance and poor bioavailability
– Micronization of progesterone increases
serum levels of circulating progesterone
• From negligible to normal levels
– After administration, metabolized to over 30
metabolites
• Of varying activity
• Commercial product
– Prometrium 100mg, 200mg oil capsules
• Peanut oil
– Serum levels achieved with oral dosing
• Increased Bioavailability by micronization
(reduction of particle size)
• Solubulization in an oil matrix
• Oral administration does increase serum levels
• Vaginal Use also increases serum levels
– Though onset was delayed, AUC was similar.
• Bioavailability ~2 to 10%
– Low absorption
– Extensive First Pass metabolism
– High conversions to estrone & metabolites
• 5:1 ratio of estrone:estradiol
• Conjugates of up to 50% of estradiol present in
blood after PO administration
• Converts to estrone sulfate & other metabolites of
unknown activity
• Rapid rise in blood levels to max in 1-3 hrs
• Metabolites are circulating in high
concentrations and serve as a hormonally
inert reservoir from which estradiol is
continuously delivered
• Second peak hours later
• ~12hrs blood levels remain
• Changes in lipid profile
– Decreases LDL
– Increases HDL
– Increases triglyceride levels
• Increase in atherogenicity of LDL during
oral estradiol administration
– Increase in oxidized LDL
• Increase in serum amyloid A
– Associated with inflammation
• C-reactive protein
– Increase production of CRP by liver
– May also have decrease in IGF-1 (antiinflammatory)
• Activated Protein C
– Thrombin Inhibitor decreased by oral estrogen
– May be involved in increased CVD events
• Antithrombin III
– Decreased by oral estrogen, increases risk of
VTEs
• HOWEVER
– Multiple studies show that risk of CVD is not
elevated
• Exception is first year of treatment
• Still considered cardioprotective if used without
progestins
– Bone density increased with oral estrogen use
• Troche
– Dot, square troche
• RDT tablets
– Tablet triturate
• Oil based sublingual drops
– Glycerin/ethanol
– Medium Chain Triglyceride/EtOH
– Oil only
• Polyethylene Glycol Base (PEG)
– polymerized ethylene oxide
• Available over a wide range of molecular weights from 300 g/
mol to 10,000,000 g/mol
• Contains
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Sodium Saccharine
Acesulfame Potassium
Stevia
Can be made in many flavors
• Or without flavors
– Magnasweet
• Hides bitterness, glycerizza derivative (proprietary
ingredients)
• RDTs
– PEG based
• Contains
– Acesulfame Potassium, stevia
• Tablet Triturates
– Lactose base
– Low dose only
• More time consuming process to make
– Increases costs
• Gly/Eth and MCT oil solutions
– Alcohol based
– Have maximum solubility's for solutions
• Testosterone in MCT/Eth
• Biest in Gly/Eth
• Progesterone in MCT
• Sublingual Oils
– Suspensions except at very low dose
– Oil filled Capsules
• Advantages
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Rapid absorption
Decrease first pass metabolism
Bypasses gastric system
Removal of dosage form if needed
• Troches
• Disadvantages
– Interference with saliva testing
• Pocketing of hormones in salivary glands
– Still will be oral administration from swallowing
dose
– Taste
• Rapid, burst-like absorption into the
systemic circulation
– Yielding high E2 levels that fall rapidly over
the first 6 hours.
• BID dosing results in steady state levels
– E2 levels 10% higher than after PO
– Bioavailability ~5x higher
– E2 to E1 ratio 3:1
• Fewer estrone metabolites in circulation
• Testosterone, Progesterone and Estradiol
show blood levels after SL administration
– Approx 10min and still observed after 3 hrs.
• In sesame oil only
– No other penetration enhancers used
• Depot hormone injections
– Many commercial available products
– Estradiol Valerate, Testosterone Cypionate,
Testosterone Propionate
• Ester forms of hormones
• Long acting
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Weekly dosing
Bi weekly dosing
Monthly
Sustained action
• Causes supratherapeutic dose at first
• Followed by slow decline of circulating
hormone levels
• Depots in the lipid layers of the injection site
– Secondary depots in adipose tissue may develop
as well
• Especially with estradiol
• Length of fatty acid chain determines
duration of activity
– Decrease in serum levels over time
• Contain
– Benzyl Benzoate
• solvent
– Benzyl Alcohol
• Preservative
– Vehicle
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Sesame oil
Cottonseed oil
Castor oil
Ethyl Oleate
– Can be made preservative free
• Estradiol Valerate
– Dose slowly absorbed after depot injection
• Peak after 2 days
– Every 4 weeks dosing
• 100% bioavailable
• E2:E1 ratio 2:1
• Adverse events
– Thrombolytic events
• Cypionate or Enanthate
– Half life ~ 8 days
– Potent androgen
• Can lead to dose dependent adverse events
• Dose can significantly drop off near end of half life
– Roller coaster effect
• Effective in increasing free Testosterone levels in
hypogonadal males.
• Disadvantages
– Pain on injection
– Compliance
– Long residence time of hormone
• Dose adjustments last
– Supranormal levels at onset, with sharp
decrease of levels in hormone
• “roller coaster” effect
• Estopel (25mg Estradiol USP)
• Testopel (75mg Testosterone USP)
• Surgically implanted pellets
– Long term (implantation every 3 to 6 months)
– No compliance issues
– Cost/pain associated with procedure
– No dosage adjustments without procedure
– Extrusions possible
• Testosterone Pellets
– 200mg pellet yield 1.34mg/pellet/day over 3
months
– Average re-implantation 5.8months
– Estradiol Pellets
• Dose remains constant over 6 months
• May cause accumulation of doses
• Estradiol Pellets(cont)
– E2:E1 ration 2:1
– No effect/ negligible effect on lipid profiles
• May decrease LDL levels
• 15% increase in HDL in one study
– Dose dependent increase in bone density
– Reduction in vasomotor symptoms
• Caused some recurrence 3-16 weeks after
implantation
• Creams, gels, ointments
– Many products now on the market
– Estrogen gels
– Premarin creams
– Estradiol creams
– OTC hormone creams
• Patches
– Estrogen only
– Estrogen/progestin
• Advantages
– Ease of use
– Avoids first pass metabolism
– Avoids gut metabolism
– With patches, quick removal of patch removes
therapy
– Adjustable dosages
• Disadvantages
– Dose variability
• Absorption variability
– Time, surface area, temperature, hydration of skin
– Compliance
• Includes application practices
– Drying time
• Can inadvertently dose another person
– Clothing may be contaminated as well
• Bases
– Hydro-alcohol bases
• Alcohols used to solubilize the skin to allow for
diffusion of hormone
• Penetration enhancers to deliver drug into lower
dermal layers for diffusion into circulation
• Drying to skin, may cause burning sensation
– Creams
• Moisturizing emollient based vehicles designed to
solubilize the dermis, with penetration enhancers
to allow for drug delivery
• Gels
– Semisolid colloidal dispersion
– Water based or lipid based
– Some have both hydrophilic and hydrophobic
properties
• Ointments
– Oil based vehicle, with heavy moisturizing
properties.
– Not a very “elegant” dosing form
• Creams(cont)
– Emollient Cream Base
• Oil-in-Water emulsion
– Petrolatum, Mineral Oil, water, sodium benzoate or BHT,
– Versabase
• Oil-in-water emulsion
– Elegant moisturizing cream.
– Studies available on serum levels of progesterone
delivered
– Contains penetration enhancers
• VaniCream
– Petrolatum, propylene glycol, BHT, sorbitol
– “Non-comedogenic”
– Available as a lotion as well
• NataCream
– New base from PCCA
• Designed as a more “natural” vehicle
• Based on botanical oils
• Hypoallergenic
• Gels
– Carbomer
• Water based gel with alcohol as solvent
– Pluronic Lecithin Organogel (PLO)
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Hydrophobic and hydrophilic properties
Designed to penetrate the dermis
Rapid, high absorption of API
May depot medication in lower dermal areas
• Lipoderm
– Designed to penetrate skin more effectively
than PLO
• More cosmetically elegant base
• More temperature stable than PLO
• Increased drug penetration than PLO
– 2.4x more than PLO with promethazine
• Special Populations
– Allergies
• Most common:
– Parabens (preservative)
» Substitute sodium benzoate, BHT
– Lanolin
– Dyes
– Fragrances
• Propylene glycol (penetration enhancers)
– Wetting agent in many compound preparations
– Toxic for some (?), allergic reactions
• Options exist for most patients
– VaniCream, Versabase billed as
“hypoallergenic”
– NataCream for more natural delivery
• What is the patient sensitive to?
– Note that altering base will change
therapeutics of dose form
– Topical dosage form will still need some way
to deliver drug into body
• Success depends on permeability of
hormone through the dermal layers
• Metabolism in the skin layers are low
– E2:E1 levels 1:1
– No accumulation of metabolites in the blood
with this dosage form
– Large intra-individual variations in circulating
hormone levels
Vulvo/Vaginal Delivery
• Systemic
+ ???
+ Femring
• Local
+ estrogen creams-ex/ Premarin, Estrace
compounded
+ Estring
+ DHEA ovules-compounded
+ Progesterone-Prochieve gel and compounded
+ Testosterone creams
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Pharmacokinetics and Relative Bioavailability of Testosterone
Absorption After Administration of a 1.62% Testosterone Gel to
Different Application Sites in Hypogonadal Men. Endocr Pract.
2011 Mar 31:1-28.
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Objective: To determine the pharmacokinetics, bioavailability, and safety of
a new formulation (1.62%) of testosterone gel that produces eugonadal
testosterone levels using a lower amount of gel than the currently available
1% gels.
Each application method produced average testosterone concentrations
within the eugonadal range (300-1000 ng/dL) and steady-state testosterone
concentrations were achieved after two days of gel application to either the
abdomen or upper arms/shoulders.
When gel was applied to the abdomen approximately 30%-40% lower
bioavailability (AUC0-24) was observed compared to upper arms/shoulders
application.
The 1.62% testosterone gel was found to be safe and well tolerated in
hypogonadal males.
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• Serum levels of progesterone achieved by
this route of administration are much lower
than those measured in the luteal phase.
• The efficacy of transdermally administered
progesterone is contested
– Studies show blood levels, but no effect
– Study also shows blood levels, but sx
reduction
– Inadequate research to show anti- poliferative
effects of progesterone topical when used in
conjunction with oral/patch estrogens
• Estradiol Gel (0.06%)
– Commercial product
– Hydro-alcoholic gel
– ~ 10% of dose absorbed
• Absorption stops after alcohol evaporates
– Estradiol depots in the stratum corneum and
diffuses over 2-14 hrs.
• Lipid Profile
– Small decreases in triglycerides
– Small decreases in HDL, LDL
– Serum amyloid A
• No effect
• C-Reactive protein
– No effect
– Activated protein C
• Minimal effects, if any
• VTE
– ESTHER study showed topical HT therapy
had no impact on VTE risk
– Decreased effect on pro thrombolitic factors
over all compared to oral therapy
• Transdermal hormone therapy and the
risk of stroke and venous thrombosis.
Climacteric. 2010 Oct;13(5):429-32.
• The adjusted rate ratio (RR) for stroke for
current use of transdermal estrogens, with or
without a progestin, was not increased (RR
0.95; 95% confidence interval (CI) 0.75-1.20)
compared with a significant increase
associated with oral estrogen, with or without
a progestin (RR 1.28; 95% CI 1.15-1.42).
• Hepatic Enzymes
– No increase with topical therapy
• Bone Health
– Decreased effect over oral
– Dose dependent decrease in bone resorption
and increase in bone density
• Oral
– Simple dosing
– Gut absorption and first pass metabolism
– Reliable response
• Injectable and Pellet
– Long term dosing
• Topical
– Bypasses liver metabolism
– Compliance issues
– May have more favorable side effect profile
• Compounding
– Oral
• Inert ingredients
• Capsule options
• Dosing options and combinations
– Sublingual/ Buccal
• Dosing options and combinations
• Taste
– Injectable
• Preservative Free
• Vehicle change
• Topical
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Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and
safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly
injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999
Oct;84(10):3469-78.
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Shulman LP. Transdermal hormone therapy and bone health. Clin Interv Aging. 2008;3(1):51-4.
Amory JK, Page ST, Bremner WJ. Oral testosterone in oil: pharmacokinetic effects of 5alpha reduction by
finasteride or dutasteride and food intake in men. J Androl. 2006 Jan-Feb;27(1):72-8.
Egras AM, Umland EM. The role of transdermal estrogen sprays and estradiol topical emulsion in the
management of menopause-associated vasomotor symptoms. Int J Gen Med. 2010 May 26;3:147-51.
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H. Kuhl Pharmacology of estrogens and progestogens: influence of different routes of administration
CLIMACTERIC 2005;8(Suppl 1):3–63
Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier MT, Wahl D,
Emmerich J, Scarabin PY; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone
therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen
administration and progestogens: the ESTHER study. Circulation. 2007 Feb 20;115(7):840-5.
Koppper et al., Transdermal hormone therapy in postmenopausal women: A review of metabolic effects
and drug delivery technologies. Drug Des Devel Ther. 2008; 2:193-202
Hemelaar et al., Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk:
a systemic review. Fertil Steril. 2008 sep;90(3):642-72. Epup 2007 Oct 2007
Claus R, et al, Rise of testosterone, nortestosterone and 17beta-estradiol concentrations in peripheral
blood plasma of pigs after sublingual application in vivo. Food Chem Toxicol. 2007 Feb; 45(2):225-8
Kellener S. et al, Testosterone release rate and duration of action of testosterone pellet implants. Clin
Endocrinol (oxf), 2004 Apr;60(4) 420-8