Estradiol benzoate butyrate

Estradiol benzoate butyrate
Clinical data
Trade namesNeolutin N, Redimen, Soluna, Unijab (all combinations)
Other namesEBB; 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 classEstrogen; Estrogen ester
Identifiers
IUPAC name
  • [(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 InfoCard100.057.989
Edit this at Wikidata
Chemical and physical data
FormulaC29H34O4
Molar mass446.587 g·mol−1
3D model (JSmol)
SMILES
  • 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
  • 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.[1][2] It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive.[1][2] EBB is not available for medical use alone.[3] The medication, in combination with DHPA, is given by injection into muscle once a month.[1][2]

Side effects of EBB include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[4] EBB is a synthetic estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[5][6] It is an estrogen ester and a prodrug of estradiol in the body.[6][5] Because of this, it is considered to be a natural and bioidentical form of estrogen.[6]

EBB was first described in 1938.[7] It was developed for use as a form of birth control in the 1970s[8][1] and was introduced for medical use for this indication by the 1980s.[9][10] The medication is used in combination with DHPA as a combined injectable contraceptive in Peru and Singapore.[11][12]

Medical uses

EBB is used in combination with DHPA as a once-a-month combined injectable contraceptive to prevent pregnancy in women.[1][11][12][2][13]

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.[11][12]

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.[1][14]

Pharmacology

Estradiol, the active form of EBB.

Pharmacodynamics

EBB is an estradiol ester, or a prodrug of estradiol.[6][5] As such, it is an estrogen, or an agonist of the estrogen receptors.[6][5] 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.[6]

The estrogenic potency of oral ethinylestradiol is approximately 30-fold higher than that of parenteral EBB.[1] 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.[1]

Potencies and durations of natural estrogens by intramuscular injection
EstrogenFormDose (mg)Duration by dose (mg)
EPDCICD
EstradiolAq. soln. ?–<1 d
Oil soln.40–60–1–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ?–1 ≈ 30 d
Estradiol benzoateOil 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 dipropionateOil soln.25–30–5 ≈ 5–8 d
Estradiol valerateOil soln.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrateOil soln. ?1010 ≈ 21 d
Estradiol cypionateOil soln.20–30–5 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthateOil soln. ?5–1010 ≈ 20–30 d
Estradiol dienanthateOil soln. ?–7.5 ≈ >40 d
Estradiol undecylateOil soln. ?–10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphateAq. soln.40–60–40 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
EstroneOil soln. ?–1–2 ≈ 2–3 d
Aq. susp. ?–0.1–2 ≈ 2–7 d
EstriolOil soln. ?–1–2 ≈ 1–4 d
Polyestriol phosphateAq. 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.[1][2][15] Its duration is shorter than that of estradiol enantate.[1][2] A preliminary study of the duration of EBB relative to other estradiol esters was conducted in 1952.[16]

Chemistry

EBB is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) and C17β butyrate (butanoate) diester of estradiol.[17] 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.[17]

The experimental octanol/water partition coefficient (logP) of EBB is 6.3.[18]

Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight		Relative
E2 contentb		log Pc
Position(s)Moiet(ies)TypeLengtha
Estradiol
––––1.001.004.0
Estradiol acetate
C3Ethanoic acidStraight-chain fatty acid21.150.874.2
Estradiol benzoate
C3Benzenecarboxylic acidAromatic fatty acid– (~4–5)1.380.724.7
Estradiol dipropionate
C3, C17βPropanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.9
Estradiol valerate
C17βPentanoic acidStraight-chain fatty acid51.310.765.6–6.3
Estradiol benzoate butyrate
C3, C17βBenzoic acid, butyric acidMixed fatty acid– (~6, 2)1.640.616.3
Estradiol cypionate
C17βCyclopentylpropanoic acidAromatic fatty acid– (~6)1.460.696.9
Estradiol enanthate
C17βHeptanoic acidStraight-chain fatty acid71.410.716.7–7.3
Estradiol dienanthate
C3, C17βHeptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–10.4
Estradiol undecylate
C17βUndecanoic acidStraight-chain fatty acid111.620.629.2–9.8
Estradiol stearate
C17βOctadecanoic acidStraight-chain fatty acid181.980.5112.2–12.4
Estradiol distearate
C3, C17βOctadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
C3Sulfuric acidWater-soluble conjugate–1.290.770.3–3.8
Estradiol glucuronide
C17βGlucuronic acidWater-soluble conjugate–1.650.612.1–2.7
Estramustine phosphated
C3, C17βNormustine, phosphoric acidWater-soluble conjugate–1.910.522.9–5.0
Polyestradiol phosphatee
C3–C17βPhosphoric acidWater-soluble conjugate–1.23f0.81f2.9g
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.[7][19][20][21] It was developed in combination with DHPA as a combined injectable contraceptive in the 1970s.[8][1][22][23][24][25] The combination was marketed for use as a combined injectable contraceptive in Peru by 1987.[9][10]

Society and culture

Brand names

EBB is marketed in combination with DHPA under the brand names Neolutin N, Redimen, Soluna, and Unijab.[1][11][12][26][27][28][29] It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.[1][2][13][8][30]

Availability

The combination of EBB and DHPA is available only in Peru and Singapore.[11][12]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 Toppozada M (1977). "The clinical use of monthly injectable contraceptive preparations". Obstet Gynecol Surv. 32 (6): 335–47. doi:10.1097/00006254-197706000-00001. PMID 865726.
  2. 1 2 3 4 5 6 7 Mokhtar K. Toppozada (1983). "Monthly Injectable Contraceptives". In Alfredo Goldsmith; Mokhtar Toppozada (eds.). Long-Acting Contraception. pp. 93–103. OCLC 35018604.
  3. ↑ "Estradiol: Uses, Dosage & Side Effects".
  4. ↑ Amit K. Ghosh (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
  5. 1 2 3 4 Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  6. 1 2 3 4 5 6 Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.
  7. 1 2 Miescher K, Scholz C, Tschopp E (April 1938). "The activation of female sex hormones: alpha-Oestradiol and its di-esters". Biochem. J. 32 (4): 725–32. doi:10.1042/bj0320725. PMC 1264097. PMID 16746680.
  8. 1 2 3 Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848.
  9. 1 2 Bonnema, Jorien; Dalebout, Joanneke A. (1992). "The abuse of high dose estrogen/progestin combination drugs in delay of menstruation: The assumptions and practices of doctors, midwives and pharmacists in a peruvian city". Social Science & Medicine. 34 (3): 281–289. doi:10.1016/0277-9536(92)90270-Z. ISSN 0277-9536. PMID 1557669.
  10. 1 2 Thomas, David B.; Molina, Ramiro; Cuevas, Hector Rodriguez; Ray, Roberta M.; Riotton, Gustave; Dabancens, Alfredo; Benavides, Socorro; Martinez, Luis; Salas, Oriana; Pallet, Jose A.; Lopez, Jorge (1989). "Monthly injectable steroid contraceptives and cervical carcinoma". American Journal of Epidemiology. 130 (2): 237–247. doi:10.1093/oxfordjournals.aje.a115330. ISSN 1476-6256. PMID 2665476.
  11. 1 2 3 4 5 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 433, 467. ISBN 978-92-832-1291-1.
  12. 1 2 3 4 5 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN 978-92-832-1272-0.
  13. 1 2 Elsayed Saad Eldin Hafez (1980). Human reproduction: conception and contraception. Harper and Row. ISBN 978-0-06-141066-6.
  14. ↑ Toppozada, Mokhtar K. (1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. ISSN 0010-7824. PMID 8013216.
  15. ↑ Ralph I. Dorfman (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 36–. ISBN 978-1-4832-7299-3.
  16. ↑ Ferin J (January 1952). "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". J. Clin. Endocrinol. Metab. 12 (1): 28–35. doi:10.1210/jcem-12-1-28. PMID 14907837.
  17. 1 2 Edith Josephy; F. Radt (1946). Elsevier's Encyclopaedia of Organic Chemistry: Tetracyclic and higher-cyclic compounds. Elsevier. pp. 99, 680.
  18. ↑ "Β-Estradiol-3-benzoate 17-N-butyrate | C29H34O4 | ChemSpider".
  19. ↑ Korenchevsky V, Burbank R, Hall K (March 1939). "The action of the dipropionate and benzoate-butyrate of oestradiol on ovariectomized rats". Biochem. J. 33 (3): 366–71. doi:10.1042/bj0330366. PMC 1264384. PMID 16746921.
  20. ↑ Sir Norman Lockyer (1938). Nature. Macmillan Journals Limited. p. 292. The oestradiol benzoate butyrate and dipropionate were supplied by Dr. Miescher (of Ciba Ltd.) who recently described their prolonged effects in rats8.
  21. ↑ American journal of cancer. 1940. Note: Our thanks are due to Doctor Karl Miescher of Messrs. Ciba in Basel, Switzerland, for a liberal supply of different esters of estradiol used in this work.
  22. ↑ Minucci D, Arreghini G, Rabasso A (1973). "Modificazioni endometriali durante trattamento con l'associazione di diidrossiprogesterone acetofenide ed estradiolo-3-benzoato-17-n-butirrato" [Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate]. Riv Ostet Ginecol Prat Med Perinat (in Italian). 54 (10): 497–505. PMID 4807299.
  23. ↑ Cittadini E, Catalano G (1973). "L'impiego di una nuova associazione: diidrossiprogesterone acetofenide ed estradiolo-3-benzoato-17 isobutirrato in ginecologia" [Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology]. Riv Ostet Ginecol Prat Med Perinat (in Italian). 54 (10): 506–12. PMID 4620236.
  24. ↑ Selvaggi L, Putignano G (December 1975). "La risposta dei recettori periferici alla somministrazione parenterale dell'associazione diidrossiprogesterone acetofenide estradiolo-3-benzoato-17n-butirrato. Nota preventiva" [Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note]. Minerva Ginecol (in Italian). 27 (12): 961–3. PMID 778679.
  25. ↑ Cappello F (December 1975). "L'impiego per via parenterale di un estroprogestinico come inibitore dell'ovulazione in una unica somministrazione mensile" [Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration]. Minerva Ginecol (in Italian). 27 (12): 964–8. PMID 778680.
  26. ↑ "Farmaco SOLUNA 150 + 10 registrado en Perú".
  27. ↑ "Unijab Dosage & Drug Information | MIMS Singapore".
  28. ↑ http://www.corporacionmisalud.com/sistema/vademecum/PLM/productos/32499.htm
  29. ↑ https://www.drugs.com/international/soluna.html
  30. ↑ Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.
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