challenges and considerations in the development and ...€¦ · 02/04/2019 · siepmann &...
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Challenges and considerations in the development and validation of in vitro drug release testing for intravaginal ringsKarl Malcolm
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Manuscript to be submitted to the International Journal of Pharmaceutics
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Contento Vaginal ringso The human vaginao Methods for in vitro release testingo In vitro-in vivo correlations (IVIVC)o Challenges
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Vaginal ringshttp://www.google.com/patents/US3545439
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Vaginal rings
1960 1970 1980 1990 2000 2010
First patent
2020
Nuvaring®
Estring®
Sweden
UK
US
US & Europe
FiledPatented
Femring®U
K & US
Annovera®
Ornibel®Progering®
Fertiring®
Chile
DapivirineEU
S. America
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Femring® Nuvaring® Estring®6
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Thank you for listening!‘Nuala with the Hula’
A famous Belfast landmark
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Vaginal ringsMcBride et al., Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 T inhibitor 5P12-RANTES, Journal of Controlled Release 298 (2019) 1–11
Drug molecules
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Vaginal ringsRegulatory considerationso Single entity combination products / as defined in 21 CFR
3.2(e)
o Drug + device
o “For drug delivery vaginal rings, primary mode of action relates to the ‘drug’ component
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Vaginal ringsDrug product specification tests Product quality tests Product performance tests
Appearance and Description In vitro release testing
Identification
Assay (drug content)Impurities / Related substances / Degradation productsUniformity of dosage unit (ring weight)
Content uniformity
Microbial limits
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Vaginal ringsMechanical testing
International Journal of Pharmaceutics 559 (2019) 182–191
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Contento Vaginal ringso The human vaginao Methods for in vitro release testingo In vitro-in vivo correlationso Challenges
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The human vagina
Barnhart et al., Baseline dimensions of the human vagina, Human Reproduction 2006;21:1618–22
Mucosa Surface area (cm2)
oral 200
gastrointestinal 350,000
skin 20,000
vaginal 90
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The human vagina
Owen DH, Katz DF, A vaginal fluid simulant, Contraception, 1999;59(2):91-95.
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The human vaginao Composition of vaginal fluid
• salts, proteins, carbohydrates, low molecular weight organic compounds, lactic acid, acetic acid, glycerol, urea, glucose
o Quantity of vaginal fluid• 0.5–0.75 g fluid present at any one time• 6 g /day production
o Vaginal pH• 3.5 – 4.5 in healthy, non-menstruating, premenopausal women• >4.5 in healthy, post-menopausal women
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The human vaginaVaginal fluid simulantComponent Concentration (g/L)
NaCl 3.51KOH 1.40Ca(OH)2 0.222bovine serum albumin 0.018lactic acid 2.00
acetic acid 1.00
glycerol 0.16urea 0.4glucose 5.0
Adjust to pH 4.2
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The human vagina
stratified squamous
stratifiedsquamous
simplecolumnar
Histology
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The human vaginaDrug absorption
c
Tissue
Fluid
1. dissolution2. diffusion3. partitioning4. diffusion5. partitioning6. diffusion
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Contento Vaginal ringso The human vaginao Methods for in vitro release testingo In vitro-in vivo correlationso Challenges
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In vitro release testingFactors: Drug / drug product • ring type (e.g. matrix, reservoir, pod,
insert, exposed core, etc.)• overall ring dimensions• core length (for reservoir rings)• membrane thickness (for reservoir
rings)• drug type• drug solubility in the ring polymer• drug diffusivity in the ring polymer• initial drug loading (for matrix rings)• drug particle size distribution
• salt form of drug• polymorphic form of drug• co-formulation / drug-drug interactions• polymer type and grade• cure temperature and time (for silicone
elastomer)• molding/extrusion temperature
(thermoplastics)• formulation excipients• drug photosensitivity• ring storage / storage conditions
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In vitro release testingFactors: Testing parameters • type of test (shake-flask vs. flow-
through)• type of agitation (orbital vs. linear
shaking)• composition of release medium• pH of release medium• volume of release medium• sink vs non-sink conditions• sampling frequency and interval
• frequency of medium replacement• rate of stirring• rate and diameter of orbital shaking• temperature of release medium /
prewarming of medium• position of ring in flask (suspended or
lying flat)• type of flask / shape of flask (affects
fluid dynamics around the ring)
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In vitro release testingo Ring typeso Release testing equipment o Release medium typeo Release medium volumeo Shaking speedso Release medium sampling schedules
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Ring type / Matrix rings• solid crystalline drug dispersed
throughout ring volume• manufacture via one-step injection
molding process• Fertiring®, Progering®, dapivirine ring
In vitro release testing
Malcolm et al., Microbicide vaginal rings: Technological challenges and clinical development, Advanced Drug Delivery Reviews 103 (2016) 33–56
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Ring type / Matrix ringsIn vitro release testing
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Ring type / Matrix rings / MetronidazoleIn vitro release testing
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Matrix rings / Release kineticsIn vitro release testing
Classical Higuchi
Simplified Higuchi
General form
𝑀𝑀𝑡𝑡
𝐴𝐴= 𝐷𝐷𝐶𝐶𝑠𝑠 2𝐶𝐶0–𝐶𝐶𝑠𝑠 𝑡𝑡
𝑀𝑀𝑡𝑡
𝐴𝐴= 𝐷𝐷𝐶𝐶𝑠𝑠 2𝐶𝐶0 𝑡𝑡
𝑀𝑀𝑡𝑡 = 𝑘𝑘 𝑡𝑡
𝑀𝑀𝑡𝑡 – cumulative releaseA – ring surface areaD – drug diffusion coefficientCs – drug solubility in polymerC0 – initial drug conc. in ringt – time
*
* assumes C0 ≫ CsSiepmann & Peppas, Higuchi equation: Derivation, applications, use and
misuse, International Journal of Pharmaceutics 418 (2011) 6–12
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Ring type / Reservoir rings• Estring®, Nuvaring®, Femring®, Ornibel®
• solid or dissolved drug dispersed throughout core only
• multi-step injection molding for silicone elastomer rings
• co-extrusion for thermoplastic rings
In vitro release testing28
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Ring type / Reservoir ringsIn vitro release testing
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Ring type / Reservoir rings / MPTsIn vitro release testing
Boyd et al., International Journal of Pharmaceutics 511 (2016) 619 –629
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Reservoir rings / Release kineticsIn vitro release testing
Crank’s equation
Chien’s equation
General form
𝑀𝑀𝑡𝑡 – cumulative releaseA – ring surface areaD – drug diffusion coefficientCs – drug solubility in polymerL – length of coreb – cross-sectional radius ringa – cross-sectional radius coreh – sheath thicknesst – time
𝑀𝑀𝑡𝑡 =2𝜋𝜋𝐶𝐶𝑠𝑠𝐷𝐷𝐷𝐷𝑙𝑙𝑙𝑙 �𝑏𝑏 𝑎𝑎
𝑡𝑡
𝑀𝑀𝑡𝑡 = 𝑘𝑘𝑡𝑡
𝑀𝑀𝑡𝑡 =𝐶𝐶𝑠𝑠𝐷𝐷𝐴𝐴ℎ
𝑡𝑡
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Release testing equipmentIn vitro release testing
Fig. 2. Different type of shaking incubators commonly used for in vitro release testing of vaginal rings. A – a benchtop shaking incubator; B – a floor-standing top-opening orbital shaking incubator; C – stackable orbital shaking incubators; D – flasks containing suspended rings, and stored in an orbital shaking incubator.
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Release medium typeIn vitro release testing
Ring Medium
Fertiring® isotonic saline
Estring® 0.9% saline
Progering® isotonic saline
Nuvaring® water
Femring® 0.9% saline
Ornibel® pH 4.2 acetate buffer +0.05% Solutol HS 15
Annovera® water
dapivirine 1:1 isopropanol/water
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Release medium volumeIn vitro release testing
Ring Medium Volume (mL)
Fertiring® isotonic saline 250
Estring® 0.9% saline 250
Progering® isotonic saline 250
Nuvaring® water 200
Femring® 0.9% saline 500
Ornibel® pH 4.2 acetate buffer +0.05% Solutol HS 15 100
Annovera® water 400
Dapivirine 1:1 isopropanol/water 100
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Shaking speedsIn vitro release testing
Ring Medium Volume (mL) Shaking speed
Fertiring® isotonic saline 250 NA
Estring® 0.9% saline 250 60/130 rpm
Progering® isotonic saline 250 NA
Nuvaring® water 200 750 rpm
Femring® 0.9% saline 500 NA
Ornibel® pH 4.2 acetate buffer +0.05% Solutol HS 15 100 60 rpm
Annovera® water 400 100 opm
Dapivirine 1:1 isopropanol/water 100 60 rpm
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In vitro release testing
Fig. 3. Sealed glass flasks for in vitro release testing of drug-releasing vaginal rings. A – ring allowed to rest on bottom of flask containing 100 mL of release medium. B – ring suspended by a nylon thread in glass flask containing 200 mL release medium. The nylon string can be seen in the space between the release medium and the blue screw-top lid.
Flat vs. suspended rings
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In vitro release testing37
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Contento Vaginal ringso The human vaginao Methods for in vitro release testingo In vitro-in vivo correlationso Challenges
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In vitro-in vivo correlation
CORRELATION
In vivo data
In vivo data
MEASURED
In vitro data
PREDICTED
In vivo data
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% absorbed in vivo vs % dissolved in vitro
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In vitro-in vivo correlationScarcity of IVIVCs for vaginal ringso Require validation step based on clinical studies, which
are expensive and typically require multiple developed formulations showing different release profiles in multiple media
o Other drug dosage forms are generally more lucrative than vaginal rings financial incentive to develop IVIVC (e.g. line extensions)
o Non-compendial methods / poor water solubility / long duration of release / non-biorelevant release media
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IVIVCMatrix rings
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IVIVCReservoir rings
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IVIVCOther
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Contento Vaginal ringso The human vaginao Methods for in vitro release testingo In vitro-in vivo correlationso Challenges
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Challengeso No compendial apparatus or methods
o Considerable variation in in vitro release testing methods
o Difficulty in selection of release medium for very poorly water soluble drugs
o Difficulty in developing in vitro release methods to match in vivo performance
o Few reports describing accelerated in vitro release test methods
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Thank you for listening!
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Appendix 1Detailed information on marketed vaginal ring products
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Indication
Durationof use
Material &dimensions
contraceptive for breastfeeding women
silicone elastomer56 mm x 9.0 mmmatrix-type
API
3 months continuous use
Name progesterone
Loading 2074 mg
Release rate ~10mg/day
Serum levels 10–20 nmol/L
Progering®
Silesia / Andromaco1998 / 2010 (Chile, Peru, LA)
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Indication
Durationof use
Material &dimensions
progesterone supplementation in the luteal phase; IVF
silicone elastomer60 mm x 9.0 mmmatrix-type
API
3 months continuous use
Name progesterone
Loading 1000 mg
Release rate ~10 mg/day (in vitro)
Fertiring®
Silesia / Pop. Council1993 (Chile, Ecuador)
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Estring®
Pfizer1993 (Sweden) / 1996 (USA)
Indication
Durationof use
Material &dimensions
estrogen replacement therapy; local symptoms of menopause
silicone elastomer (addition cure)55 mm x 9.0 mm; 2.0 mm corereservoir-type
API
3 months continuous use
Name 17β-estradiol
Loading 2 mg
Release rate 7.5 μg/day
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Nuvaring®
Organon / Merck2001 (Netherlands, EU, USA)
Indication
Durationof use
Material &dimensions
hormonal contraception(98–99% ovulation inhibition)
poly(ethylene-co-vinyl acetate) (EVA) 54 mm x 4.0 mmreservoir-type
APIs
21 days continuous use each month
Name etonogestrelLoading 11.7 mgRelease rate 120 μg/day
Name ethinyl estradiolLoading 2.7 mgRelease rate 15 μg/day53
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Ornibel® / Myring™Insud Pharma / Exeltis2018 (EU)
Indication
Durationof use
Material &dimensions
hormonal contraception(98–99% ovulation inhibition)
polyurethane sheath and 28% EVA copolymer core / 54 mm x 4.0 mmreservoir-type
APIs
21 days continuous use each month
Name etonogestrelLoading 11.0 mgRelease rate 120 μg/day
Name ethinyl estradiolLoading 3.47 mgRelease rate 15 μg/day54
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Femring®
Galen / WC / Actavis2001 (UK) / 2003 (USA)
Indication
Durationof use
Material &dimensions
estrogen replacement therapy; local and systemic symptoms of menopause
silicone elastomer (condensation cure)56 mm x 7.6 mm; 2.0 mm corereservoir-type
API
3 months continuous use
Name 17β-estradiol-3-acetate
Loading 12.4 / 24.8 mg
Release rate 50 / 100 μg/day
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Annovera®
Population Council2018
Indication
Durationof use
Material &dimensions
hormonal contraceptive
silicone elastomer (add. & cond. cure)58 mm x 8.4 mmreservoir-type (2 cores)
API
21 days continuous use each month
Name nestoroneLoading 103 mgRelease rate 150 μg/day
Name ethinyl estradiolLoading 17.4 mgRelease rate 15 μg/day56
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Dapivirine
IPM2017 (pending)
Indication
Durationof use
Material &dimensions
vaginal microbicide; prevention of sexual transmission of HIV
silicone elastomer (addition cure)54 mm x 7.6 mmmatrix-type
API
28-day continuous use
Name dapivirine
Loading 25 mg
Release rate IPW2600–180 μg/day
Release rate SVF 350–100 μg/day
Released in vivo ~4 mg 57
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The human vaginaHistology
Tissue Type of epithelium
vaginal stratified squamous, nonkeratinized ectocervix stratified squamous, nonkeratinized endocervix columnar, single layer
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Appendix 2Conditions and assumptions for use of the Higuchi equations to model drug release from matrix-type vaginal rings.
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Higuchi equation / ConditionsIn vitro release testing1. Drug transport through the ring is rate limiting, whereas drug transport within the
vaginal fluid is rapid. 2. The vaginal tissue acts like a “perfect sink”: The drug concentration in this
compartment can be considered to be negligible. 3. The initial drug concentration in the ring is much higher than the solubility of the
drug in the ring. 4. The drug is finely dispersed within the ointment base. 5. The drug is initially homogeneously distributed throughout the ring. 6. The dissolution of drug particles within the ring is rapid compared to the diffusion
of dissolved drug molecules within the ring. 7. The diffusion coefficient of the drug within the ring is constant and does not
depend on time or the position within the ring. 8. The ring does not swell or dissolve during drug release.
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Appendix 3Extra slides
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In vivoIn vitro release testing
Tissue
c
Fluid
c
Fluid
In vitro
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