Chemistry:Estradiol benzoate butyrate

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Short description: Chemical compound
Estradiol benzoate butyrate
Estradiol butyrate benzoate.svg
Estradiol benzoate butyrate molecule ball.png
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
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC29H34O4
Molar mass446.587 g·mol−1
3D model (JSmol)

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 an 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]

v · d · e Potencies and durations of natural estrogens by intramuscular injection
Estrogen Form Major brand names EPD CIC-D Duration
Estradiol Oil solution – 40–60 mg – 1–2 mg ≈ 1–2 days
Aqueous suspension Aquadiol, Diogyn, Progynon, Mego-E ? 3.5 mg 0.5–2 mg ≈ 2–7 days; 3.5 mg ≈ >5 days
Microspheres Juvenum-E, Juvenum ? – 1 mg ≈ 30 days
Estradiol benzoate Oil solution Progynon-B 25–35 mg – 1.66 mg ≈ 2–3 days; 5 mg ≈ 3–6 days
Aqueous suspension Agofollin-Depot, Ovocyclin M 20 mg – 10 mg ≈ 16–21 days
Emulsion Menformon-Emulsion, Di-Pro-Emulsion ? – 10 mg ≈ 14–21 days
Estradiol dipropionate Oil solution Agofollin, Di-Ovocylin, Progynon DP 25–30 mg – 5 mg ≈ 5–8 days
Estradiol valerate Oil solution Delestrogen, Progynon Depot, Mesigyna 20–30 mg 5 mg 5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days;
40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days
Estradiol benzoate butyrate Oil solution Redimen, Soluna, Unijab ? 10 mg 10 mg ≈ 21 days
Estradiol cypionate Oil solution Depo-Estradiol, Depofemin 20–30 mg – 5 mg ≈ 11–14 days
Aqueous suspension Cyclofem, Lunelle ? 5 mg 5 mg ≈ 14–24 days
Estradiol enanthate Oil solution Perlutal, Topasel, Yectames ? 5–10 mg 10 mg ≈ 20–30 days
Estradiol dienanthate Oil solution Climacteron, Lactimex, Lactostat ? – 7.5 mg ≈ >40 days
Estradiol undecylate Oil solution Delestrec, Progynon Depot 100 ? – 10–20 mg ≈ 40–60 days;
25–50 mg ≈ 60–120 days
Polyestradiol phosphate Aqueous solution Estradurin 40–60 mg – 40 mg ≈ 30 days; 80 mg ≈ 60 days;
160 mg ≈ 120 days
Estrone Oil solution Estrone, Kestrin, Theelin ? – 1–2 mg ≈ 2–3 days
Aqueous suspension Estrone Aq. Susp., Kestrone, Theelin Aq. ? – 0.1–2 mg ≈ 2–7 days
Estriol Oil solution – ? – 1–2 mg ≈ 1–4 days
Polyestriol phosphate Aqueous solution Gynäsan, Klimadurin, Triodurin ? – 50 mg ≈ 30 days; 80 mg ≈ 60 days
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/day (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]


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] It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.[1][2][13][8][29]

Availability

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

See also

  • Estradiol benzoate butyrate/dihydroxyprogesterone acetophenide

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey 32 (6): 335–347. June 1977. doi:10.1097/00006254-197706000-00001. PMID 865726. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Monthly Injectable Contraceptives". Long-Acting Contraception. 1983. pp. 93–103. OCLC 35018604. https://scholar.google.com/scholar?cluster=14664537528797672080. 
  3. ↑ "Estradiol: Uses, Dosage & Side Effects". https://www.drugs.com/international/estradiol.html. 
  4. ↑ Mayo Clinic Internal Medicine Board Review. OUP USA. 23 September 2010. pp. 222–. ISBN 978-0-19-975569-1. https://books.google.com/books?id=LS65jBzoD40C&pg=PA222. 
  5. ↑ 5.0 5.1 5.2 5.3 "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric 8 (Suppl 1): 3–63. August 2005. doi:10.1080/13697130500148875. PMID 16112947. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens". Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Handbook of Experimental Pharmacology. 135 / 2. Springer Science & Business Media. 6 December 2012. pp. 261–322. doi:10.1007/978-3-642-60107-1_15. ISBN 978-3-642-60107-1. https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261. "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. ↑ 7.0 7.1 "The activation of female sex hormones: alpha-Oestradiol and its di-esters". The Biochemical Journal 32 (4): 725–732. April 1938. doi:10.1042/bj0320725. PMID 16746680. 
  8. ↑ 8.0 8.1 8.2 "A review of "once-a-month" combined injectable contraceptives". Journal of Obstetrics and Gynaecology 4 (Suppl 1): S1-34. 1994. doi:10.3109/01443619409027641. PMID 12290848. 
  9. ↑ 9.0 9.1 "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. February 1992. doi:10.1016/0277-9536(92)90270-Z. PMID 1557669. 
  10. ↑ 10.0 10.1 "Monthly injectable steroid contraceptives and cervical carcinoma". American Journal of Epidemiology 130 (2): 237–247. August 1989. doi:10.1093/oxfordjournals.aje.a115330. PMID 2665476. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 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. https://books.google.com/books?id=aGDU5xibtNgC&pg=PA433. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 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. IARC. p. 65. ISBN 978-92-832-1272-0. https://monographs.iarc.fr/wp-content/uploads/2018/06/mono72.pdf. 
  13. ↑ 13.0 13.1 Human reproduction: conception and contraception. Harper and Row. 1980. ISBN 978-0-06-141066-6. https://books.google.com/books?id=EblsAAAAMAAJ. 
  14. ↑ "Existing once-a-month combined injectable contraceptives". Contraception 49 (4): 293–301. April 1994. doi:10.1016/0010-7824(94)90029-9. PMID 8013216. 
  15. ↑ "Estrogens". Steroidal Activity in Experimental Animals and Man. Elsevier Science. 5 December 2016. pp. 36–. ISBN 978-1-4832-7299-3. https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA36. 
  16. ↑ "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". The Journal of Clinical Endocrinology and Metabolism 12 (1): 28–35. January 1952. doi:10.1210/jcem-12-1-28. PMID 14907837. 
  17. ↑ 17.0 17.1 Elsevier's Encyclopaedia of Organic Chemistry: Tetracyclic and higher-cyclic compounds. Elsevier. 1946. pp. 99,680. https://books.google.com/books?id=GP8hAQAAMAAJ. 
  18. ↑ "Β-Estradiol-3-benzoate 17-N-butyrate | C29H34O4 | ChemSpider". http://www.chemspider.com/Chemical-Structure.60431.html. 
  19. ↑ "The action of the dipropionate and benzoate-butyrate of oestradiol on ovariectomized rats". The Biochemical Journal 33 (3): 366–371. March 1939. doi:10.1042/bj0330366. PMID 16746921. 
  20. ↑ Nature. Macmillan Journals Limited. 1938. p. 292. https://books.google.com/books?id=xLQiAQAAMAAJ. "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. https://books.google.com/books?id=_FkXAQAAMAAJ. "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. ↑ "[Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate]" (in it). Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale 54 (10): 497–505. 1973. PMID 4807299. 
  23. ↑ "[Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology]" (in it). Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale 54 (10): 506–512. 1973. PMID 4620236. 
  24. ↑ "[Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note]" (in it). Minerva Ginecologica 27 (12): 961–963. December 1975. PMID 778679. 
  25. ↑ "[Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration]" (in it). Minerva Ginecologica 27 (12): 964–968. December 1975. PMID 778680. 
  26. ↑ "Farmaco SOLUNA 150 + 10 registrado en Perú". https://www.datosperu.org/farmaco-soluna-rs-N12759.php. 
  27. ↑ "Unijab Dosage & Drug Information | MIMS Singapore". http://www.mims.com/singapore/drug/info/unijab. 
  28. ↑ "SOLUNA". http://www.corporacionmisalud.com/sistema/vademecum/PLM/productos/32499.htm. 
  29. ↑ "Existing once-a-month combined injectable contraceptives". Contraception 49 (4): 293–301. April 1994. doi:10.1016/0010-7824(94)90029-9. PMID 8013216. 



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