Hydroxyprogesterone caproate.svg

17-Hydroxyprogesterone caproate

[(8R,9S,10R,13S,14S,17R)-17-Acetyl-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] hexanoate
Molecular Weight: 428.6041 g/mol
Molecular Formula: C₂₇H₄₀O₄

Pregn-4-ene-3,20-dione,17-hydroxy-, hexanoate (7CI,8CI);Progesterone, 17-hydroxy-, hexanoate (6CI);Hexanoic acid, ester with 17-hydroxypregn-4-ene-3,20-dione (8CI);17a-Caproyloxypregn-4-ene-3,20-dione;17a-Hydroxypregn-4-ene-3,20-dionecaproate;17a-Hydroxypregn-4-ene-3,20-dionehexanoate;17a-Hydroxyprogesteronecaproate;17a-Hydroxyprogesteronen-caproate;Delalutin;Depo-proluton;Hormofort;Pregn-4-ene-3,20-dione,17-[(1-oxohexyl)oxy]-;NSC 17592;Neolutin;Primolut Depot;Procyte Depo;Proge;Syngynon;Teralutil;

FDA grants orphan drug status for Lipocine’s LPCN 1107 to prevent preterm birth
Specialty pharmaceutical firm Lipocine has received orphan drug designation from the US Food and Drug Administration (FDA) for its LPCN 1107 to prevent preterm birth (PTB).

http://www.pharmaceutical-technology.com/news/newsfda-grants-orphan-drug-status-lipocines-lpcn-1107-prevent-preterm-birth-4592067?WT.mc_id=DN_News

LPCN 1107 is an oral product candidate of 17-alpha hydroxyprogesterone caproate under development for the indication of prevention of recurrent preterm birth. LPCN 1107 has the potential to become the first oral HPC product for the prevention of preterm birth in women with a prior history of at least one preterm birth. Potential benefits of our oral product candidate relative to current injectable products include the elimination of pain and site reactions associated with weekly injections, elimination of weekly doctor visits or visits from the nurse, and elimination of interference/disruption of personal, family or professional activities associated with weekly visits.

Preterm Birth (PTB) is defined as delivery of less than 37 weeks of gestation. PTB occurs in ~12% of all US births. PTB remains the leading cause of perinatal mortality and morbidity, accounting for as many as 75% of perinatal deaths.

The expense associated with PTB involves not only the immediate cost of the preterm baby being treated in the hospital ICU setting, but includes the long term treatment costs for disabilities for the life of the child. Current total PTB related economic impact on the US health system far exceeds $26 billion, an estimated cost in 2006.

Behrman RE et al. in: Behrman RE, Butler AS, eds. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: The National Academies Press; 2006:329-354.

There is a significant unmet need for a ‘patient friendly’ product for the prevention of PTB. The only FDA approved product for the prevention of PTB must be given by an intra-muscular injection each week for a total of 18-22 injections.

LPCN 1107: A Novel Oral Alternative

LPCN 1107 Product Attributes:

Designed for oral administration twice daily of hydroxyprogesterone caproate (same active as in the only FDA approvd injectable product for the prevention of recurrent PTB).
Eliminates site reaction and pain at the site of injection
Eliminates regular doctor office visits or visits from the nurse (weekly visits for 16 – 20 weeks)
Significant absorption upon oral dosing of LPCN 1107 in healthy non-pregnant women
Good dose response demonstrated in healthy non-pregnant women
LPCN 1107 was well tolerated in single dose study
LPCN 1107 may be eligible for orphan drug designation

LPCN 1107, Lipocine’s oral hydroxyprogesterone caproate (HPC) product candidate has the potential to become the first oral HPC product for the prevention of preterm birth in women with a prior history of at least one preterm birth. Potential benefits of our oral product candidate relative to current once-a-week intramuscular (IM) injectable product include the elimination of pain and site reactions associated with weekly injections, elimination of weekly doctor visits or visits from the nurse, and elimination of interference/disruption of personal, family or professional activities associated with weekly visits. Lipocine has successfully completed a Phase 1 study under a US IND designed to determine the pharmacokinetics and bioavailability of LPCN 1107 relative to an IM HPC, as well as safety and tolerability, in healthy non-pregnant female volunteers.

17α-Hydroxyprogesterone caproate is a synthetic, steroidal progestin that is similar to medroxyprogesterone acetate andmegestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid).

17α-Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999.

The US FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention ofpreterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Synthesis

Hydroxyprogesterone caproate can be prepared by the following sequence:^[13]

It is made from 16-dehydropregnenolone acetate (16-DPA),^[14] product of the Marker degradation.

Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F.; J. Amer. Chem. Soc. 1956, 78, 816.

……………………………….

PATENT

http://www.google.com/patents/CN104017041A?cl=en

method of synthesizing progesterone caproate, comprising the steps of:

[0006] Step one to 17 α- hydroxy progesterone as a raw material, and n-hexyl acid in pyridine and p-toluene sulfonic acid catalysis by esterification reaction mixture esterified, the reaction is as follows

Step two, to the mixture of step one described esterified in an alcohol solution of acid catalysis to give progesterone caproate

Ketone crude reaction is as follows:

Step one to obtain a mixture containing progesterone caproate ester compound of step two the mixture is esterified in an alcohol solution of acid catalysis to give progesterone caproate crude. The reaction process of the present invention avoids the costly esterification agent n-hexyl anhydride used materials costs and recovery costs are significantly reduced.

Example 1

17 a – hydroxy progesterone 20g, n-caproic acid 40ml, topiramate 唳 16ml, p-toluenesulfonic acid 1.6g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 3 hours TLC sampling The reaction was monitored. The reaction is as follows:

[0016] 17 a – hydroxy progesterone concentration treatment made after completion of the reaction, as a method for the enrichment process concentrated under reduced pressure and toluene, pyridine, and the unfinished batch reaction of n-hexanoic acid.

After the end of the [0017] concentrated in the three-necked flask was added 100mL ethanol, 3ml of concentrated hydrochloric acid was heated to reflux alcohol solution 2 hours, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. The reaction is as follows:

cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 24g, crude yield of 120%.Progesterone caproate crude was purified with ethanol to give progesterone caproate boutique 19.Sg, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.5% of the total yield of 99.0% o

Example 2

17 α – hydroxy progesterone 20g, n-caproic acid 50ml, topiramate 唳 30ml, p-toluenesulfonic acid 3g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 3 hours TLC monitoring sampling reaction. 17 α – hydroxy progesterone concentration treatment made after completion of the reaction, as the concentration treatment method evaporated toluene, pyridine and n-hexyl Unreacted acid.

After the end of the [0022] concentrated in the three-necked flask was added 100mL ethanol, 5ml of concentrated hydrochloric acid was heated to reflux alcohol solution I hour, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23.5g, crude yield of 117.5%. Progesterone caproate crude was purified with ethanol to give progesterone caproate boutique 19.2g, progesterone caproate Collectibles yield based on the crude progesterone caproate 81.7%, the total yield was 96.0%.

Example 3

17 α – hydroxy progesterone 20g, n-caproic acid 60ml, topiramate 唳 40ml, p-toluenesulfonic acid 4g, toluene 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 2.5 hours TLC monitoring sampling reaction. 17 α – hydroxy progesterone concentration treatment made after completion of the reaction, as the concentration treatment method evaporated toluene, pyridine and n-hexyl Unreacted acid.

After the end of the [0025] concentrated in the three-necked flask was added 100mL ethanol, 8ml of concentrated hydrochloric acid was heated to reflux alcohol solution 40 minutes, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23g, crude yield of 115%. Progesterone caproate crude was purified with ethanol to give progesterone caproate fine 19g, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.6% of the total yield of 95.0%.

Example 4

17 α – hydroxy progesterone 20g, n-caproic acid 60ml, topiramate 唳 40ml, p-toluenesulfonic acid 4g, benzene, 300ml, 500ml three-necked flask were put, the reaction temperature was raised to between 110 ~ 120 ° C 2.5 hours TLC monitoring sampling reaction. 17 α- hydroxy progesterone concentration treatment made after completion of the reaction, as a method for the enrichment process concentrated under reduced pressure benzene, pyridine and non-completion of the reaction of n-hexanoic acid.

After the end of the [0028] concentrated in the three-necked flask was added 100mL of methanol, 8ml of concentrated sulfuric acid was heated to reflux alcohol solution 40 minutes, the reaction was monitored sampling TLC, complete hydrolysis of the diester into progesterone caproate stop the reaction. Cooled to below 5 ° C, filtered and dried to obtain crude progesterone caproate 23g, crude yield of 115%. Progesterone caproate crude was purified with ethanol to give progesterone caproate fine 19g, progesterone caproate Collectibles yield based on the crude progesterone caproate 82.6% of the total yield of 95.0%.

Notes

SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012
Meirs et al. NEJM 2003
Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
Keirse, MJNC; Progesterone (2004). “déjà vu” or “still to be seen”?.”. Birth 31: 3.
Johnson, JWC; Austin, KL; Jones, GS; Davis, GH; King, TM (1975). “Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor”. NEJM 293 (14): 675.doi:10.1056/nejm197510022931401.
Yemini, M; Borenstein, R; Dreazen et al. (1985). “Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate”. Am J Obstet Gynecol 151 (5): 574–7. doi:10.1016/0002-9378(85)90141-3.
Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
Advisory Committees: CDER 2006 Meeting Documents
Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
Hauth, JC; Gilstrap, LC; Brekken, AL; Hauth, JM (1983). “The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population”. Am J Obstet Gynecol 146 (2): 187.
Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F. (1956). “Steroids. LXXIII. The Direct Oppenauer Oxidation of Steroidal Formate Esters. A New Synthesis of 17α-Hydroxyprogesterone”. J. Amer. Chem. Soc. 78 (4): 816. doi:10.1021/ja01585a030.
Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). “A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate”. Organic Process Research & Development 7 (3): 306.doi:10.1021/op0200625.
Armstrong J (May 2011). “Unintended consequences — the cost of preventing preterm births after FDA approval of a branded version of 17OHP”. N. Engl. J. Med. 364 (18): 1689–91.doi:10.1056/NEJMp1102796. PMID 21410391.

Sources

FDA Reproductive Health Drugs Advisory Committee. August 29, 2006 Meeting to discuss NDA 21-945 Gestiva (Adeza Biomedical)
17α-hydroxyprogesterone caproate injection, 250 mg/mL, for the proposed indication: prevention of preterm delivery in women with a history of a prior preterm delivery.
Adeza Biomedical (October 23, 2006) Receives FDA Approvable Letter For Gestiva
Adeza gets orphan drug designation for Gestiva (January 31, 2007)
Cytyc Acquires Adeza Biomedical Corporation (April 3, 2007)
Adeza’s name changed to Cytyc Prenatal Products Corp.

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KODAIKANAL, TAMILNADU, INDIA

Kodaikanal – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Kodaikanal

Kodaikanal is a city in the hills of the Dindigul district in the state of Tamil Nadu, India. Its name in the Tamil language means “The Gift of the Forest”. Kodaikanal …

‎History of Kodaikanal – ‎Kodaikanal taluk – ‎Kodaikanal block – ‎Category:Kodaikanal

Map of kodaikanal .

CUISINE OF TAMILNADU

Cuisine of Tamil Nadu

Like all other South Indian states, Tamil Nadu is also known for a wide variety of delicious food both for the vegetarians as well as the non-vegetarians. Grains, lentils, rice and vegetables are the main ingredients of the traditional foods of Tamil Nadu. Spices add flavor and give a distinctive taste to the Tamil cuisines. Some of the most common and popular dishes of the region are idly, dosai, vada, pongal and Uppuma. Coconut chutney and sambhar invariably form a part of most of the Tamil dishes.

The typical Tamil breakfast includes dosai, which is a pancake made from a batter of rice, idly (steamed rice cakes) and lentils (crisp fried on a pan), vada (deep fried doughnuts prepared from a batter of lentils), pongal (a mash of rice and lentils boiled together and seasoned with cashew nuts, ghee, pepper and cummin seed), uppuma (cooked semolina seasoned in oil with mustard, pepper, cummin seed and dry lentils). These are the main local dishes but there are several variations that are eaten with coconut chutney and mulaga podi.For lunch and the main course, the food consists of boiled rice, which is served with an assortment of vegetable dishes, sambar, chutneys, rasam (a hot broth prepared from tamarind juice and pepper) and curd. On the other hand, the non-vegetarian lunch and dinner include curries and dishes cooked with chicken, mutton or fish. Crispy Papad/Papar and appalam form an important part of a typical Tamil meal.Filter coffee is a famous and popular beverage of the people of Tamil Nadu in general and Chennai in particular. It is interesting to note that making of filter coffee is like a ritual as the coffee beans are first roasted and then powdered. After the grinding work is over, the powder is put into a filter set and then boiling water is added to prepare the decoction, which is allowed to set for about 15-18 minutes. The decoction is ready and can be added to milk with sugar according to taste. The coffee is poured from one container to another in quick succession so that the ideal frothy cup of filter coffee is ready.

Chettinad Cuisine

Chettinad cuisine is one of the spiciest and most aromatic in India. The name Chettinad cuisine comes from the place of its origin, Chettinad. Chettinad cuisine and delicacy is a specialty of Tamil Nadu and is a delight for non-vegetarian food lovers. The Chettinad cuisine consists of several variations of mutton, fish, and chicken items. The Chettinad Pepper Chicken is a specialty of all the non-vegetarian dishes. Dishes like biryani and paya are popular Tamil style of Mughali food. Paya is a type of spiced trotters broth and is usually eaten with either parathas or appam.