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Estradiol benzoate butyrate
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    Estradiol benzoate butyrate

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    Estradiol benzoate butyrate
    Estradiol butyrate benzoate.svg
    Estradiol benzoate butyrate molecule ball.png
    Clinical data
    Trade names Neolutin N, Redimen, Soluna, Unijab (all combinations)
    Other names EBB; Estradiol 3-benzoate 17β-n-butyrate; Estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate
    Routes of
    administration
    Intramuscular injection
    Drug class Estrogen; Estrogen ester
    Identifiers
    • [(8R,9S,13S,14S,17S)-17-butanoyloxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.057.989
    Chemical and physical data
    Formula C29H34O4
    Molar mass 446.587 g·mol−1
    3D model (JSmol)
    • CCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5)C
    • InChI=1S/C29H34O4/c1-3-7-27(30)33-26-15-14-25-24-12-10-20-18-21(32-28(31)19-8-5-4-6-9-19)11-13-22(20)23(24)16-17-29(25,26)2/h4-6,8-9,11,13,18,23-26H,3,7,10,12,14-17H2,1-2H3/t23-,24-,25+,26+,29+/m1/s1
    • Key:MKYFGNOOEKZNPW-ZRJUGLEFSA-N

    Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.

    Side effects of EBB include breast tenderness, breast enlargement, nausea, headache, and fluid retention. EBB is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.

    EBB was first described in 1938. It was developed for use as a form of birth control in the 1970s and was introduced for medical use for this indication by the 1980s. The medication is used in combination with DHPA as a combined injectable contraceptive in Peru and Singapore.

    Medical uses

    EBB is used in combination with DHPA as a once-a-month combined injectable contraceptive to prevent pregnancy in women.

    Available forms

    The combination of EBB and DHPA contains 10 mg estradiol benzoate butyrate (EBB), an estrogen, and 150 mg algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA), a progestin.

    Side effects

    The combination of EBB and DHPA is said to be associated with poor control of menstrual bleeding when used as a once-a-month combined injectable contraceptive.

    Pharmacology

    Estradiol, the active form of EBB.

    Pharmacodynamics

    EBB is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. EBB is of about 64% higher molecular weight than estradiol due to the presence of its C3 benzoate and C17β butyrate esters. Because EBB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.

    The estrogenic potency of oral ethinylestradiol is approximately 30-fold higher than that of parenteral EBB. In accordance, 50 μg/day oral ethinylestradiol has been reported to be about 3 times stronger in estrogenic effect than once-a-month injections of 10 mg EBB.

    Potencies and durations of natural estrogens by intramuscular injection
    Estrogen Form Dose (mg) Duration by dose (mg)
    EPD CICD
    Estradiol Aq. soln. ? <1 d
    Oil soln. 40–60 1–2 ≈ 1–2 d
    Aq. susp. ? 3.5 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
    Microsph. ? 1 ≈ 30 d
    Estradiol benzoate Oil soln. 25–35 1.66 ≈ 2–3 d; 5 ≈ 3–6 d
    Aq. susp. 20 10 ≈ 16–21 d
    Emulsion ? 10 ≈ 14–21 d
    Estradiol dipropionate Oil soln. 25–30 5 ≈ 5–8 d
    Estradiol valerate Oil soln. 20–30 5 5 ≈ 7–8 d; 10 ≈ 10–14 d;
    40 ≈ 14–21 d; 100 ≈ 21–28 d
    Estradiol benz. butyrate Oil soln. ? 10 10 ≈ 21 d
    Estradiol cypionate Oil soln. 20–30 5 ≈ 11–14 d
    Aq. susp. ? 5 5 ≈ 14–24 d
    Estradiol enanthate Oil soln. ? 5–10 10 ≈ 20–30 d
    Estradiol dienanthate Oil soln. ? 7.5 ≈ >40 d
    Estradiol undecylate Oil soln. ? 10–20 ≈ 40–60 d;
    25–50 ≈ 60–120 d
    Polyestradiol phosphate Aq. soln. 40–60 40 ≈ 30 d; 80 ≈ 60 d;
    160 ≈ 120 d
    Estrone Oil soln. ? 1–2 ≈ 2–3 d
    Aq. susp. ? 0.1–2 ≈ 2–7 d
    Estriol Oil soln. ? 1–2 ≈ 1–4 d
    Polyestriol phosphate Aq. soln. ? 50 ≈ 30 d; 80 ≈ 60 d
    Notes and sources
    Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

    Pharmacokinetics

    A single 10 mg intramuscular injection of EBB has a duration of approximately 3 weeks. Its duration is shorter than that of estradiol enantate. A preliminary study of the duration of EBB relative to other estradiol esters was conducted in 1952.

    Chemistry

    EBB is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) and C17β butyrate (butanoate) diester of estradiol. It is also known as estradiol 3-benzoate 17β-n-butyrate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate.

    The experimental octanol/water partition coefficient (logP) of EBB is 6.3.

    Structural properties of selected estradiol esters
    Estrogen Structure Ester(s) Relative
    mol. weight
    Relative
    E2 contentb
    log Pc
    Position(s) Moiet(ies) Type Lengtha
    Estradiol
    Estradiol.svg
    1.00 1.00 4.0
    Estradiol acetate
    Estradiol 3-acetate.svg
    C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 4.2
    Estradiol benzoate
    Estradiol benzoate.svg
    C3 Benzenecarboxylic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.7
    Estradiol dipropionate
    Estradiol dipropionate.svg
    C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 4.9
    Estradiol valerate
    Estradiol valerate.svg
    C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5.6–6.3
    Estradiol benzoate butyrate
    Estradiol butyrate benzoate.svg
    C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 6.3
    Estradiol cypionate
    Estradiol 17 beta-cypionate.svg
    C17β Cyclopentylpropanoic acid Aromatic fatty acid – (~6) 1.46 0.69 6.9
    Estradiol enanthate
    Estradiol enanthate.png
    C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 6.7–7.3
    Estradiol dienanthate
    Estradiol dienanthate.svg
    C3, C17β Heptanoic acid (×2) Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–10.4
    Estradiol undecylate
    Estradiol undecylate.svg
    C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 9.2–9.8
    Estradiol stearate
    Estradiol stearate structure.svg
    C17β Octadecanoic acid Straight-chain fatty acid 18 1.98 0.51 12.2–12.4
    Estradiol distearate
    Estradiol distearate.svg
    C3, C17β Octadecanoic acid (×2) Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
    Estradiol sulfate
    Estradiol sulfate.svg
    C3 Sulfuric acid Water-soluble conjugate 1.29 0.77 0.3–3.8
    Estradiol glucuronide
    Estradiol sulfate.svg
    C17β Glucuronic acid Water-soluble conjugate 1.65 0.61 2.1–2.7
    Estramustine phosphated
    Estramustine phosphate.svg
    C3, C17β Normustine, phosphoric acid Water-soluble conjugate 1.91 0.52 2.9–5.0
    Polyestradiol phosphatee
    Polyestradiol phosphate.svg
    C3–C17β Phosphoric acid Water-soluble conjugate 1.23f 0.81f 2.9g
    Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic exposure). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

    History

    EBB, along with a variety of other estradiol esters, was first described in 1938 by Karl Miescher and colleagues of Ciba in Basel, Switzerland. It was developed in combination with DHPA as a combined injectable contraceptive in the 1970s. The combination was marketed for use as a combined injectable contraceptive in Peru by 1987.

    Society and culture

    Brand names

    EBB is marketed in combination with DHPA under the brand names Neolutin N, Redimen, Soluna, and Unijab. It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.

    Availability

    The combination of EBB and DHPA is available only in Peru and Singapore.

    See also


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