Home » Posts tagged 'Antiacne'

Tag Archives: Antiacne

ADAPALENE

January 25, 2022 11:20 am / Leave a comment

ADAPALENE

Molecular FormulaC₂₈H₂₈O₃
Average mass412.520 Da
CD 271
CD-271

CD-271, Differin, Differine106685-40-9[RN]
2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo[3.3.1.1^3,7]dec-1-ylphenyl)-
6-[3-(Adamantan-1-yl)-4-methoxyphenyl]-2-naphthoic acid
6-[4-methoxy-3-(tricyclo[3.3.1.1^3,7]dec-1-yl)phenyl]naphthalene-2-carboxylic acid AdapaleneCAS Registry Number: 106685-40-9
CAS Name: 6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid
Additional Names: 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
Manufacturers’ Codes: CD-271
Trademarks: Differin (Galderma)
Molecular Formula: C28H28O3
Molecular Weight: 412.52
Percent Composition: C 81.52%, H 6.84%, O 11.64%
Literature References: Retinoid selective for retinoic acid receptor (RAR) subtypes b and g. Prepn: B. Shroot et al.,EP199636; eidem,US4717720 (1986, 1988 both to Cent. Int. Recher. Dermatol.); and structure-activity study: B. Charpentier et al.,J. Med. Chem.38, 4993 (1995). Pilot-scale synthesis: Z. Liu, J. Xiang, Org. Process Res. Dev.10, 285 (2006). HPLC determn in plasma and tissue: R. Ruhl, H. Nau, Chromatographia45, 269 (1997). Clinical pharmacology: C. E. M. Griffiths et al.,J. Invest. Dermatol.101, 325 (1993). Clinical trial in acne: A. Shalita et al.,J. Am. Acad. Dermatol.34, 482 (1996). Reviews of pharmacology and clinical potential: B. A. Bernard, Skin Pharmacol.6, Suppl. 1, 61-69 (1993); R. N. Brogden, K. L. Goa, Drugs53, 511-519 (1997); of clinical use in acne vulgaris: J. Waugh et al.,Drugs64, 1465-1478 (2004).
Properties: White crystals from THF and ethyl acetate, mp 319-322°. pK 4.2. Stable to light.
Melting point: mp 319-322°
pKa: pK 4.2
Therap-Cat: Antiacne.
Keywords: Antiacne.

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions.^[1] Studies have found adapalene is as effective as other retinoids, while causing less irritation.^[2] It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation.^[2] It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide.^[2] Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent. ^[3]

Adapalene is a third-generation topical retinoid with anti-comedogenic, comedolytic, and anti-inflammatory properties used to treat acne vulgaris in adolescents and adults.

SYN

AU 9047961; EP 0199636; US 4717720; US 5098895; US 5183889

J Med Chem 1995,38(26),4993

Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H2SO4 yielded the adamantyl phenol (III). Subsequent alkylation of the sodium phenoxide of (III) with iodomethane produced the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), was converted to the organozincate derivative, and then subjected to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). The target carboxylic acid was finally obtained by saponification of the methyl ester (VII).

SYN

CA 2021550; EP 0409740; FR 2649976; JP 1991063246; US 5073361; US 5149631

The bromination of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (I) with Br2 in dichloromethane gives the dibromo derivative (II), which is hydrogenated with tritium gas over Pd/C in THF containing TEA to yield the bis tritiated ester (III). Finally, ester (III) is hydrolyzed with NaOH in refluxing methanol to afford the target tritiated naphthoic acid.

SYN

doi:10.1071/CH9732303c US4717720

SYN

Adapalene (CAS NO.: 106685-40-9), with its systematic name of 2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo(3.3.1.1(sup 3,7))dec-1-ylphenyl)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H₂SO₄ yields the adamantyl phenol (III). Next, subsequent alkylation of the sodium phenoxide of (III) with iodomethane produces the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), is converted to the organozincate derivative, and then subjects to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). Finally, the target carboxylic acid is obtained by saponification of the methyl ester (VII).

Synthesis Reference

Graziano Castaldi, Pietro Allegrini, Gabriele Razzetti, Mauro Ercoli, “Process for the preparation of adapalene.” U.S. Patent US20060229465, issued October 12, 2006.

US20060229465

PATENT

https://patents.google.com/patent/US8119834B2/enThe chemical name for adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, which is represented by Compound I (below):

Adapalene has been approved by the FDA as a cream, a gel, a solution and pledgets for the topical treatment of acne vulgaris and is marketed under the tradename of DIFFERIN®.U.S. Pat. No. 4,717,720 (“the ‘720 patent”) discloses benzonaphthalene derivatives, including adapalene. The ‘720 patent describes a process for preparing adapalene (i.e., according to example 9c followed by example 10) that involves two reaction steps.The first step for preparing adapalene according to the ‘720 patent involves the preparation of the methyl ester of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. According to example 9c of the ‘720 patent, 2-(1-adamantyl)-4-bromoanisole (also known as 1-(5-bromo-2-methoxyphenyl)adamantane) is converted to its organomagnesium derivative and then into its organozinc derivative. The organozinc derivative is next coupled to methyl 6-bromo-2-naphthoate by adding a catalytic amount of NiCl₂/DPPE complex (also known as [bis(diphenylphosphino) ethane]dichloronickel(II)). Upon completion of the reaction, the mixture is poured into water, extracted with dichloromethane, and then dried. The product is next isolated by column chromatography by eluting with a mixture of heptane (70%) and dichloromethane (30%). The resulting product is then recrystallized in ethyl acetate (yield: 78%).The second step for preparing adapalene according to the ‘720 patent involves hydrolyzing the product of step 1 (above). According to example 10 of the ‘720 patent, the ester obtained in Example 9c can be treated with a solution of soda in methanol followed by heating at reflux for 48 hours. The solvents are then evaporated and the resulting residue is taken up in water and acidified with concentrated HCl to neutralize the resulting adapalene sodium salt. The resulting solid is next filtered and dried under vacuum over phosphoric anhydride and then recrystallized in a mixture of tetrahydrofuran and ethyl acetate to yield adapalene (yield: 81%).The process of preparing adapalene according to the ‘720 patent is both difficult and uneconomical to conduct on an industrial scale. Regarding step 1, the use of dichloromethane is both toxic and hazardous for the environment. Additionally, purification of the intermediate product by column chromatography, followed by recrystallization, in order to obtain a crystalline product of acceptable purity is both expensive and laborious. Moreover, the step 1 process produces as a biaryllic C—C bond, and the catalytic coupling is noticeably exothermic. Regarding step 2, the synthesis of adapalene and/or its sodium salt requires a long reaction time (i.e., 48 hours) at methanol reflux and further requires a high ratio of solvent (volume) to product (mass).Additionally, according to the prior art, the manufacture of adapalene is not satisfactory for industrial implementation because the presence of high amounts of undesired by-products makes it necessary to use uneconomical purification procedures to isolate the product according to quality specifications. One significant undesired by-product produced during the Grignard reaction of step 1 in the synthesis of adapalene is 3,3′-diadamantyl-4,4′-dimethoxybiphenyl, which has not been previously described in the literature and which is represented by Compound VI (below):

The level of the by-product in a sample of adapalene, adapalene methyl ester and/or an adapalene salt can be determined using standard analytical techniques known to those of ordinary skill in the art. For example, the level can be determined by HPLC. A specific method for determining the level of this impurity is provided herein.Since the solubility of the dimeric by-product is very low in most solvents, the design of an economical industrial process that yields pure adapalene without the use of expensive chromatographic methods requires the selection of the proper solvents and conditions to inhibit formation of the by-product during the manufacturing process.Additionally, adapalene has been described as being white (see, e.g., Merck Index, 13^thed., p. 29). It has been observed that adapalene has a tendency to yellow under certain synthetic conditions or due to the quality of the starting materials used in its preparation. In this regard, color must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC.

ExampleStep 2: Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid-potassium Salt (i.e., Adapalene Potassium Salt)In a 2 L, five necked cylindrical reaction vessel equipped with reflux condenser, distillation kit, heat-transfer jacket, anchor impeller and purged with nitrogen, were added 48.38 g (dry equivalent amount) of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate (1.134×10⁻¹mol), wet with methanol, 2.73 g of tetrabutylammonium bromide (8.47×10⁻³mol), 18.39 g of potassium hydroxide (85% alkali content, freshly titrated. 2.79×10⁻¹mol) and 581 mL of toluene. The mixture was heated to reflux temperature, and the methanol/water was removed by distillation. The distilled mixture was replaced by pure toluene and the mixture was stirred at reflux for approximately three hours (including the time required for the distillation). The solution was then cooled to approximately 20-25° C., filtered and the resulting solid was washed with toluene.The solid was next suspended in 187 mL of tetrahydrofuran and stirred for approximately 30 minutes. Then, 375 mL of toluene was added, and the mixture was heated to reflux and maintained at that temperature for approximately 1 hour. The solution was then cooled to approximately 20-25° C., filtered, and the resulting solid washed with toluene. The toluene-wet product was then suspended in 256 mL of methanol, heated to reflux for approximately 30 minutes and cooled to 50-60° C. After cooling, 409 mL of water was added dropwise. The mixture was then again heated to reflux for approximately 15 additional minutes, cooled to room temperature and filtered. The resulting solid was washed with water to yield 50.69 g (wet) of adapalene potassium salt (1.12×10⁻¹mol, dry equivalent amount calculated from loss on drying; yield: 99.18%). Analytical data: HPLC Purity (HPLC at 272 nm): 99.86%; Impurity (i.e., 3,3′-diadamantyl-4,4′-dimethoxybiphenyl) area percent (HPLC at 272 nm): not detected; ¹H-NMR (300 MHz, CD₃OD): δ 1.83 (broad s, 6H), 2.08 (broad s, 3H), 2.21 (broad s, 6H), 3.88 (s, 3H), 7.04 (d, 1H, J=8.4 Hz), 7.56 (overlapped, 1H, J=2.4, 9.6 Hz), 7.57 (overlapped s, 1H), 7.74 (dd, 1H, J=8.7, 1.8 Hz), 7.87 (d, 1H, J=9.0 Hz), 7.97 (d, 1H, J=8.7 Hz), 8.00 (broad d, 1H, J=0.9 Hz), 8.06 (dd, 1H, 8.4, J=1.8 Hz), 8.47 (broad d, 1H, J=0.9 Hz); ¹³C-NMR (75.4 MHz, CD₃OD): δ 30.6, 38.3, 41.8, 55.5, 113.3, 125.3, 126.4, 126.6, 127.8, 128.3, 130.0, 130.4, 133.0, 134.2, 136.1, 136.3, 139.7, 141.1, 159.9, 175.4.

ExampleStep 3: Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic Acid (i.e., Adapalene)In 500 mL of methanol was added 49.59 g (1.10×10⁻¹mol, dry equivalent amount) of the wet solid obtained in Example/Step 2, and the mixture was heated to reflux for 30 minutes and cooled to approximately 40° C. Next, 33.17 g of concentrated HCl was slowly added over approximately 1 hour with gentle stirring in order to ensure homogeneity, followed by the slow addition of 248 mL of water. The resulting mixture was stirred for approximately 30 additional minutes at approximately 40° C. and then cooled to room temperature, filtered and washed with methanol. The wet solid was then suspended with 1020 mL of tetrahydrofuran and heated to reflux for approximately 10 minutes or until complete dissolution. The solution was then cooled to approximately 35° C., the solid particles were removed by filtration, and the filter was washed with tetrahydrofuran.The collected mother liquors were heated to reflux, and 654 g of tetrahydrofuran was removed by distillation. The mixture was then cooled to approximately 55-60° C. Thereafter, 650 mL of methanol was added over approximately 10 minutes, and the mixture heated to reflux for approximately 30 minutes, cooled, and filtered. The resulting solid was filtered with methanol and dried at 80° C. in a vacuum oven to yield 40.54 g of adapalene (9.83×10⁻²mol; yield: 89.29% (from adapalene potassium salt); 88.56% (from adapalene methyl ester); and 78.67% (from methyl 6-bromo-2-naphthoate)). Analytical data: HPLC Purity (HPLC at 272 nm): 100.00%; Assay: 99.99%; Residue on Ignition: 0.02%; IR: matches reference.Table 1 (below) lists the peak assignments of the X-ray powder diffractogram of the adapalene obtained and are illustrated in FIG. 1.

TABLE 1
peak	peak_position	peak_intensity	background

1	9.94547	175.32198	42.94638
2	13.18338	239.32156	48.88440
3	14.87487	234.32591	47.91444
4	15.28319	573.40082	53.73505
5	16.37472	1207.21631	69.64595
6	16.54000	882.00000	68.42529
7	17.39657	110.88804	58.39248
8	17.93203	114.02068	55.36037
9	19.44575	285.34473	113.52401
10	19.94692	569.60516	153.63921
11	22.43198	2846.14307	110.81189
12	24.02238	140.20882	85.37505
13	25.04586	925.64282	121.97974
14	25.41035	240.42351	102.81077
15	26.68556	362.45480	68.05973
16	27.71646	141.77916	72.53469
17	40.51307	133.00453	43.44914
18	46.52728	130.31587	50.16773

ExampleStep 4: Preparation of 3,3′-diadamantyl-4,4′-dimethoxybiphenylTo a 100 mL rounded bottom reaction vessel equipped with a magnetic stirrer, thermometer, reflux condenser, pressure compensated addition funnel, were added 0.15 g of 1-(5-bromo-2-methoxyphenyl)adamantane, 0.47 g of magnesium turnings and 7 mL of tetrahydrofuran. The mixture was heated to approximately 35° C., and 0.13 mL of 1,2-dibromoethane were added to the mixture. Reaction exothermy self-heated the mixture. Next, a solution of 4.85 g of 1-(5-bromo-2-methoxyphenyl)adamantane and 28 mL of tetrahydrofuran was added to the mixture dropwise. During this addition, the temperature of the mixture dropped from reflux temperature to approximately 45° C. The reaction was then stirred for approximately 45 additional minutes at approximately 45° C. and was permitted to cool to approximately 22° C. Next, 2.3 g of ZnCl₂was added to the mixture, resulting in an exothermic reaction that raised the temperature of the mixture to approximately 38° C. The mixture was then permitted to cool to approximately 22° C. and was stirred for approximately 1 hour at this temperature.Next, 0.03 g of Pd(OAc)₂and 3.5 g of 1-(5-bromo-2-methoxyphenyl) adamantane were added to the mixture, followed by 25 mL of tetrahydrofuran in order to improve agitation, and the mixture was heated at reflux for approximately 24 hours. The resulting mixture was then evaporated to dryness and poured into 103 mL of 0.015 N HCl. Next, 150 mL of dichloromethane and 100 mL of water were added to yield a mixture consisting of a solid, an aqueous layer and an organic layer. The mixture was then filtered to separate the solid, the aqueous layer was discarded, and the organic layer was washed with 200 mL of water and decanted again. This process was repeated twice on the filtered solid. The three collected organic layers were evaporated to dryness, washed in methanol, and dried to yield 2.1 g of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl (yield: 39.9%). Analytical data: Melting point: 288.1-289.1° C.; Elemental analysis: C 83.63%, H 8.73%; ¹H-NMR (300 MHz, CDCl₃): δ 1.78 (broad s, 12H), 2.08 (broad s, 6H), 2.15 (broad s, 12H), 3.86 (s, 6H), 6.92 (dm, 2H, J=8.1 Hz), 7.34 (dd, 2H, J=2.4, 8.1 Hz), 7.39 (d, 2H, J=2.4 Hz); ¹³C-NMR (75.4 MHz, CDCl₃): δ 29.2, 37.1, 37.2, 40.6, 55.1, 111.9, 125.0, 125.5, 134.0, 138.5, 157.8; MS (EI, 70 eV): m/z=484 (6), 483 (36), 412 (1,100), 410 (5), 347 (8), 135 (22), 107 (7), 93 (14), 79 (17), 67 (9), 55 (6); IR (Selected absorption bands): 2992, 2964, 2898, 2850, 1603 cm⁻¹.

PATENT

https://patents.google.com/patent/WO2008126104A2/en

The compound 6-[3-(l – Adamantyl) – 4 – methoxy phenyl] – 2 – naphthoic acid of Formula – I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula – 1Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as ‘720) describe the preparation of compound of Formula – I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme – 1 below:

Scheme – 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoate a penultimate step for preparation of Adapalene using Friedel – Crafts alkylation by reacting 1 – acetoxy adamantane with methyl – 6 – (4 – hydroxyphenyl) – 2 – naphthoate in presence of cone. Sulfuric acid in solvent n – heptane.Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 – adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd – Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 – (dicyclohexyl – phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.Some of the drawbacks of the prior art processes include:- The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 – 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula – I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.

Examples:Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

PATENT

https://pubs.acs.org/doi/10.1021/op050223f

Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H₂SO₄ to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate by the catalysis of both PdCl₂(PPh₃)₂ and ZnCl₂ in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal’s content within acceptable limits; (5) the use of toluene to simplify the original chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.

6-(3-(1-Adamantyl)-4-methoxyphenyl)-2-naphthoic Acid (Adapalene, 1). Compound 7 (213 g, 0.5 mol) was treated with 2 N NaOH solution (8 L) in methanol under reflux for 8 h. After evaporation of methanol (7 L) and addition of water (1.5 L), the mixture was acidified until pH 1 with 6 N HCl and filtrated through Celite. The residue was washed with water (3 × 5 L), and recrystallized twice in THF (194 g/2 L/time) to give pure (99% HPLC) 1 (177 g, 85%), mp 320-322 °C.1 H NMR (400 MHz, DMSO-d6) δ 1.77 (6 H,s, H on 1-adamantyl), 2.07 (3 H, s, H on 1-adamantyl), 2.14 (6 H, s, H on 1-adamantyl), 3.87 (3 H, s, H on ArOCH3), 7.12 (1 H, d, J ) 8.4 Hz, 5-phenyl H), 7.58 (1 H, d, J ) 2.0 Hz, 2-phenyl H), 7.65 (1 H, dd, J ) 8.4 Hz, J ) 2.0 Hz, 6-phenyl H), 7.89 (1 H, d, J ) 8.8 Hz, 7-naphthyl H), 7.98 (1 H, d, J ) 8.8 Hz, 4-naphthyl H), 8.08 (1 H, d, J ) 8.8 Hz, 8-naphthyl H), 8.15 (1 H, d, J ) 8.8 Hz, 3-naphthyl H), 8.22 (1 H, s, 5-naphthyl H), 8.60 (1 H, s, 1-naphthyl H), 13.05 (1 H, s, -COOH); 13C NMR (100 MHz, DMSO-d6) δ 28.32, 36.47, 40.09, 55.28, 112.68, 123.99, 124.99, 125.38, 125.68, 125.85, 127.55, 128.25, 129.72, 130.13, 130.83, 131.46, 135.38, 138.00, 140.13, 158.53, 167.34.

PATENT

https://patents.google.com/patent/US7345189B2/en

Adapalene, namely 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, having the following chemical formula:

is disclosed in U.S. Pat. No. 4,717,720 and used in dermatology, in particular for the treatment of acne vulgaris and psoriasis.According to U.S. Pat. No. 4,717,720 the synthesis is carried out by a coupling reaction between a magnesium, lithium or zinc derivative of a compound of formula (A) and a compound of formula (B), wherein X and Y are Cl, Br, F or I; R is hydrogen or alkyl; and Ad is 1-adamantyl

in an anhydrous solvent, in the presence of a metal transition or a complex thereof as a catalyst.A number of alternative synthetic approaches have been suggested in order to reduce the preparation costs. Surprisingly, particularly advantageous proved the alternative synthesis of the invention, which makes use of easily-available, low-cost 6-hydroxy-2-naphthoic acid alkyl esters as intermediates, and provides good yields.EXAMPLE 1Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester [adapalene methyl ester]A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added to the mixture, which is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7-g; 24.4 mmol), water (0.88 g; 48.8 mmol) and THF (50 ml). The mixture is heated under reflux for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, adjusting pH to a value below 7 with acetic acid. After cooling to a temperature of 15° C., the resulting product is filtered, thereby obtaining crystalline adapalene methyl ester (8.5 g; 20.08 mmol) in 82% yield.¹H NMR: (300 MHz, DMSO), δ 8.6 (s, 1H), δ 8.3-7.8 (m, 6H), δ 7.7-7.5 (m, 2H), δ 7.1 (d, 1H), δ 3.9 (s, 3H), δ 3.85 (s, 3H), δ 2 (m, 9H), δ 1.7 (m, 6H).EXAMPLE 2Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid sodium salt [adapalene sodium salt]A round-bottom flask is loaded with adapalene methyl ester (7 g; 16.41 mmol), THF (42 ml), water (7 ml) and a 50% w/w sodium hydroxide aqueous solution (1.44 g; 18.05 mmol). The mixture is refluxed for 6 hours, then added with water (133 ml) and THF is distilled off to a residual content of approx. 5% w/w, heated to a temperature of about 80° C. until complete dissolution of the solid, then cooled to 15° C. The crystallized product is filtered and dried under vacuum in a static dryer at a temperature of 50° C., thereby obtaining adapalene sodium salt (6.7 g; 15.42 mmol) in 94% yield.EXAMPLE 3Synthesis of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid [adapalene]A round-bottom flask is loaded with adapalene sodium salt (6.7 g; 15.42 mmol), THF (40 ml) and water (7 ml) and the mixture is refluxed until complete dissolution of the solid. The resulting solution is dropped into a 3% w/w acetic acid aqueous solution, keeping the temperature above 60-70° C., to precipitate adapalene acid (6.3 g; 15.27 mmol), which is filtered and dried under vacuum at a temperature of 50-60° C. The yield is 95%.EXAMPLE 4Synthesis of adapalene methyl esterA round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (10.53 g; 585.3 mmol) and THF (50 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9 g; 21.2 mmol) in 86% yield.EXAMPLE 5Synthesis of adapalene methyl esterA round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (15 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50° C. and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium carbonate (6.75 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (8.11 g; 450.5 mmol) and THF (30 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C., added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15° C., the resulting product is filtered, thereby obtaining adapalene methyl ester (9.37 g; 21.96 mmol) in 90% yield.EXAMPLE 6Synthesis of adapalene methyl esterA round-bottom flask is loaded with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), THF (70 ml), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7 g; 24.4 mmol), nickel chloride complexed with tri(cyclohexyl)phosphine (0.83 g; 1.2 mmol) and tri(cyclohexyl)phosphine (1.37 g; 4.88 mmol). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55° C. and added with water, then cooled to 15° C. The resulting product is filtered, thereby obtaining adapalene methyl ester (8.1 g; 19.0 mmol) in 78% yield.

PATENThttps://patents.google.com/patent/WO2008126104A2/en

Formula – 1Potassium organotrifluoroborates are air and moisture-stable crystalline solids which can be stored for extended periods of time making it more industrial friendly to use on large scale production.The other advantage of the present invention is in the use of methyl ester of 6 – Bromo – 2 -naphthoic acid and isolating adapalane directly from the reaction instead of its methyl ester, the above process becomes more robust and eliminates the saponification step as reported in prior art. Also the use of readily and cheaply available Pd catalyst on carbon over the conventional and costlier Pd-catalyst with ligands offers further advantage to the current process.Examples:Example 1: Preparation of 3 – Adamantyl – 4 – methoxy phenyl potassium trifluoroborate:In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n – butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 – 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 – 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 – 5⁰C. The product, 3 – adamantyl – 4 – methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 – 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.Example 2: Preparation of 6 – [3-(l- Adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid:In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 – Adamantyl – 4 – methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 – 75°C till constant weight to get 6 – [3-(l- adamantyl) – 4 – methoxyphenyl] – 2 – naphthoic acid.The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 – 30⁰C. 500 ml of n – heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 – 5°C and maintained stirring at 0 – 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n – heptane. The pure crystalline 6 – [3-(l- adamantyl) – 4 methoxyphenyl] – 2 – naphthoic acid thus obtained was then dried till constant weight. Yield = 40 – 42 gms (68 – 72 %)

/////////////////////////////

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Medical uses

Per the recommendations of the Global Alliance on Improving Outcomes of Acne, retinoids such as adapalene are considered first-line therapy in acne treatment and are to be used either independently or in conjunction with benzoyl peroxide and/or an antimicrobial agent, like clindamycin, for maximum efficacy.^[4]^[5] Furthermore, adapalene, like other retinoids, increases the efficacy and penetration of other topical acne medications that are used in conjunction with topical retinoids as well as hastens the improvement of the post-inflammatory hyperpigmentation caused by acne.^[4] In the long term, it can be used as maintenance therapy.^[4]

Off-label uses

Adapalene has the unique ability to inhibit keratinocyte differentiation and decrease keratin deposition. This property makes adapalene an effective treatment for keratosis pilaris and callus. It may be used by men undergoing foreskin restoration to reduce excess keratin that forms a layer on the exterior of the human penis after circumcision. Other non-FDA approved indications that have been reported in the literature include treatment of warts, molluscum contagiosum, Darier disease, photoaging, pigmentary disorders, actinic keratoses and alopecia areata.^[6]

Side effects

Adapalene is known to cause mild adverse effects such as photosensitivity, irritation, redness, dryness, itching, and burning.^[2] It is common (between 1% and 10% of users)^[7] to experience a brief sensation of warmth or stinging, as well as dry skin, peeling and redness during the first 2–4 weeks of using the medication.^[4]^[8] These effects are considered mild and generally decrease over time.^[4]^[8] Any serious allergic reaction is rare.^[8] Furthermore, of the three topical retinoids, adapalene is often regarded as the most tolerable.^[6]

In pregnancy

Use of topical adapalene in pregnancy has not been well studied, but has a theoretical risk of retinoid embryopathy.^[9] Thus far, there is no evidence that the cream causes problems in the baby if used during pregnancy. Use is at the consumer’s own risk.^[10]

According to the Drugs and Lactation Database, topical adapalene has poor systemic absorption and results in low blood levels (less than 0.025 mcg/L) despite long term use, suggesting that there is low risk of harm for a nursing infant.^[11] However, it is recommended that the topical medication should not be applied to the nipple or any other area that may come into direct contact with the infant’s skin.^[11]

Interactions

Adapalene has been shown to enhance the efficacy of topical clindamycin, although adverse effects are also increased.^[12]^[13] Application of adapalene gel to the skin 3–5 minutes before application of clindamycin enhances penetration of clindamycin into the skin, which may enhance the overall efficacy of the treatment as compared to clindamycin alone.^[14]

Pharmacology

Unlike the retinoid tretinoin (Retin-A), adapalene has also been shown to retain its efficacy when applied at the same time as benzoyl peroxide due to its more stable chemical structure.^[15] Furthermore, photodegradation of the molecule is less of a concern in comparison to tretinoin and tazarotene.^[6]

Pharmacokinetics

Absorption of adapalene through the skin is low. A study with six acne patients treated once daily for five days with two grams of adapalene cream applied to 1,000 cm² (160 sq in) of skin found no quantifiable amounts, or less than 0.35 ng/mL of the drug, in the patients’ blood plasma.^[16] Controlled trials of chronic users of adapalene have found drug levels in the patients’ plasma to be 0.25 ng/mL.^[9]

Pharmacodynamics

Adapalene is highly lipophilic. When applied topically, it readily penetrates hair follicles and absorption occurs 5 minutes after topical application.^[2] After penetration into the follicle, adapalene binds to nuclear retinoic acid receptors (namely retinoic acid receptor beta and gamma).^[5]^[9] These complexes then bind to the retinoid X receptor which induces gene transcription by binding to specific DNA sites, thus modulating downstream keratinocyte proliferation and differentiation.^[2]^[9] This results in normalization of keratinocyte differentiation, allowing for decreased microcomedone formation, decreased clogging of pores, and increased exfoliation by increasing cell turnover.^[6]^[9]^[17] Adapalene is also regarded as an anti-inflammatory agent, as it suppresses the inflammatory response stimulated by the presence of Cutibacterium acnes,^[6] and inhibits both lipoxygenase activity and the oxidative metabolism of arachidonic acid into prostaglandins.^[9]

Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma when applied to epithelial cells such as those found in the skin.^[18] Its agonism of the gamma subtype is largely responsible for adapalene’s observed effects. In fact, when adapalene is applied in conjunction with a retinoic acid receptor gamma antagonist, adapalene loses clinical efficacy.^[19]

Retinization is a common temporary phenomenon reported by patients when initiating use of retinols.^[20] Within the initial period of treatment, skin can become red, irritated, dry and may burn or itch from retinol application; however, this tends to resolve within four weeks with once a day use.^[20]

History

Adapalene is a research product of Galderma Laboratories, France.^[21] Adapalene was approved in 1996 by the U.S. Food and Drug Administration (FDA) for use in the treatment of acne.^[22]

Research

A study has concluded that adapalene can be used to treat plantar warts and may help clear lesions faster than cryotherapy.^[23]

References

^ Rolewski SL (October 2003). “Clinical review: topical retinoids”. Dermatology Nursing. 15 (5): 447–50, 459–65. PMID 14619325.
^ Jump up to:^a ^b ^c ^d ^e ^f Tolaymat, L; Zito, PM (January 2021). “Adapalene”. PMID 29494115.
^ Asai, Yuka; Baibergenova, Akerke; Dutil, Maha; Humphrey, Shannon; Hull, Peter; Lynde, Charles; Poulin, Yves; Shear, Neil H.; Tan, Jerry; Toole, John; Zip, Catherine (2 February 2016). “Management of acne: Canadian clinical practice guideline”. Canadian Medical Association Journal. 188 (2): 118–126. doi:10.1503/cmaj.140665. PMC 4732962. PMID 26573753.
^ Jump up to:^a ^b ^c ^d ^e Kolli, Sree S.; Pecone, Danielle; Pona, Adrian; Cline, Abigail; Feldman, Steven R. (2019-01-23). “Topical Retinoids in Acne Vulgaris: A Systematic Review”. American Journal of Clinical Dermatology. 20 (3): 345–365. doi:10.1007/s40257-019-00423-z. ISSN 1179-1888. PMID 30674002. S2CID 59225325.
^ Jump up to:^a ^b Xiang, Leihong Flora; Troielli, Patricia; Lozada, Vicente Torres; Tan, Jerry; Suh, Dae Hun; See, Jo-Ann; Piquero-Martin, Jaime; Perez, Montserrat; Orozco, Beatriz (2018-02-01). “Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne”. Journal of the American Academy of Dermatology. 78 (2): S1–S23.e1. doi:10.1016/j.jaad.2017.09.078. hdl:10067/1492720151162165141. ISSN 0190-9622. PMID 29127053. S2CID 31654121.
^ Jump up to:^a ^b ^c ^d ^e Tolaymat, Leila; Zito, Patrick M. (2018), “Adapalene”, StatPearls, StatPearls Publishing, PMID 29494115, retrieved 2019-03-13
^ “Differin”. Swedish Drug Formulary. Retrieved 2017-12-11.
^ Jump up to:^a ^b ^c “Adapalene Gel”. WebMD. Retrieved 2017-12-11.
^ Jump up to:^a ^b ^c ^d ^e ^f Piskin, Suleyman; Uzunali, Erol (August 2007). “A review of the use of adapalene for the treatment of acne vulgaris”. Therapeutics and Clinical Risk Management. 3 (4): 621–624. ISSN 1176-6336. PMC 2374937. PMID 18472984.
^ “FDA approves Differin Gel 0.1% for over-the-counter use to treat acne”. July 8, 2016. Retrieved 14 July 2016.
^ Jump up to:^a ^b “Adapalene”, Drugs and Lactation Database (LactMed), National Library of Medicine (US), 2006, PMID 30000483, retrieved 2019-03-13
^ Wolf JE, Kaplan D, Kraus SJ, Loven KH, Rist T, Swinyer LJ, Baker MD, Liu YS, Czernielewski J (September 2003). “Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigator-blinded study”. Journal of the American Academy of Dermatology. 49 (3 Suppl): S211-7. doi:10.1067/S0190-9622(03)01152-6. PMID 12963897.
^ Jain, GauravK; Ahmed, FarhanJ (2007). “Adapalene pretreatment increases follicular penetration of clindamycin: In vitro and in vivo studies”. Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–9. doi:10.4103/0378-6323.34010. ISSN 0378-6323. PMID 17921613.
^ Jain GK, Ahmed FJ (2007). “Adapalene pretreatment increases follicular penetration of clindamycin: in vitro and in vivo studies” (PDF). Indian Journal of Dermatology, Venereology and Leprology. 73 (5): 326–9. doi:10.4103/0378-6323.34010. PMID 17921613.
^ Martin B, Meunier C, Montels D, Watts O (October 1998). “Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation”. The British Journal of Dermatology. 139 Suppl 52: 8–11. doi:10.1046/j.1365-2133.1998.1390s2008.x. PMID 9990414. S2CID 43287596.
^ “DIFFERIN® (adapalene) Cream, 0.1% Label” (PDF). FDA. May 25, 2000. Retrieved 4 Oct 2011.
^ “DIFFERIN® (adapalene) Gel, 0.3%” (PDF). Retrieved March 12, 2019.
^ Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (2006). “Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety”. Clinical Interventions in Aging. 1 (4): 327–48. doi:10.2147/ciia.2006.1.4.327. PMC 2699641. PMID 18046911.
^ Michel S, Jomard A, Démarchez M (October 1998). “Pharmacology of adapalene”. The British Journal of Dermatology. 139 Suppl 52: 3–7. doi:10.1046/j.1365-2133.1998.1390s2003.x. PMID 9990413. S2CID 23084886.
^ Jump up to:^a ^b “Differin Gel: An Over-the-Counter Retinoid for Acne”. http://www.differin.com. Retrieved 2019-03-25.
^ US Patent 4717720A, Shroot B, Eustache J, Bernardon J-M, “Benzonaphthalene derivatives and compositions”, published 1988-01-05, issued 1988-01-05, assigned to Galderma Research and Development SNC
^ “FDA approval of DIFFERIN® (adapalene) Solution, 0.1%”. FDA. May 31, 1996. Retrieved 29 May 2017.
^ Gupta, Ramji; Gupta, Sarthak (2015). “Topical Adapalene in the Treatment of Plantar Warts; Randomized Comparative Open Trial in Comparison with Cryo-Therapy”. Indian Journal of Dermatology. 60 (1): 102. doi:10.4103/0019-5154.147835. ISSN 0019-5154. PMC 4318023. PMID 25657417.

External links

“Adapalene”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Trade names	Differin, Pimpal, Gallet, Adelene, Adeferin
AHFS/Drugs.com	Monograph
MedlinePlus	a604001
License data	US DailyMed: Adapalene
Pregnancy category	AU: D
Routes of administration	Topical
Drug class	Retinoids
ATC code	D10AD03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S3CA: ℞-onlyUK: POM (Prescription only)US: OTC / Rx-only
Pharmacokinetic data
Bioavailability	Very low^{[medical citation needed]}
Excretion	Bile
Identifiers
show IUPAC name
CAS Number	106685-40-9
PubChem CID	60164
IUPHAR/BPS	5429
DrugBank	DB00210
ChemSpider	54244
UNII	1L4806J2QF
KEGG	D01112
ChEBI	CHEBI:31174
ChEMBL	ChEMBL1265
CompTox Dashboard (EPA)	DTXSID5046481
ECHA InfoCard	100.149.379
Chemical and physical data
Formula	C₂₈H₂₈O₃
Molar mass	412.529 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(verify)

/////////////////ADAPALENE, CD 271, CD-271, ANTIACNE, Differin, Differine

COC1=C(C=C(C=C1)C1=CC2=C(C=C1)C=C(C=C2)C(O)=O)C12CC3CC(CC(C3)C1)C2

NEW DRUG APPROVALS

ONE TIME

$10.00

Isotretinoin

June 29, 2021 2:38 am / Leave a comment

Isotretinoin

Title: Isotretinoin

CAS Registry Number: 4759-48-2
CAS Name: 13-cis-Retinoic acid

Additional Names: 2-cis-vitamin A acid; neovitamin A acid

Manufacturers’ Codes: Ro-4-3780Trademarks: Accutane (Roche); Isotrex (Stiefel); Oratane (Douglas); Roaccutane (Roche)
Molecular Formula: C20H28O2Molecular Weight: 300.44Percent Composition: C 79.95%, H 9.39%, O 10.65%
Literature References: Naturally occurring metabolite of vitamin A, q.v.; inhibits sebum production. Prepn: C. D. Robeson et al.,J. Am. Chem. Soc.77, 4111 (1955). Stereoselective process: R. Lucci, EP111325; idem,US4556518 (1984, 1985 both to Hoffmann-La Roche). Toxicology and teratogenicity study: J. J. Kamm, J. Am. Acad. Dermatol.6, 652 (1982). Identification as endogenous metabolite of all-trans-retinoic acid: M. E. Cullum, M. H. Zile, J. Biol. Chem.260, 10590 (1985). HPLC determn in serum: G. Tang, R. M. Russell, J. Lipid Res.31, 175 (1990). Review of pharmacology and clinical efficacy in acne: A. R. Shalita et al.,Cutis42, Suppl. 6A, 1-19 (1988). Symposium on clinical experience: Dermatology195, Suppl. 1, 1-37 (1997).
Properties: Reddish-orange plates from isopropyl alcohol, mp 174-175°. uv max: 354 nm (e 39800). LD50 (20 day) in mice, rats (mg/kg): 904, 901 i.p.; 3389, >4000 orally (Kamm).

Melting point: mp 174-175°Absorption maximum: uv max: 354 nm (e 39800)Toxicity data: LD50 (20 day) in mice, rats (mg/kg): 904, 901 i.p.; 3389, >4000 orally (Kamm)Therap-Cat: Antiacne.Keywords: Antiacne.

Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.

The most common adverse effects are a transient worsening of acne (lasting 1–4 months), dry lips (cheilitis), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (myalgias), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. It is also associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviours. Other rare side effects include hyperostosis, and premature epiphyseal closure, have been reported to be persistent.

In the United States, a special procedure is required to obtain the pharmaceutical. In most other countries, a consent form is required which explains these risks. In other countries, such as Israel, it is prescribed like any other medicine from a dermatologist (after proper blood tests).

Women taking isotretinoin must not get pregnant during and for one month after the discontinuation of isotretinoin therapy. Sexual abstinence or effective contraception is mandatory during this period. Barrier methods by themselves (e.g., condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who become pregnant while taking isotretinoin therapy are generally counseled to have an abortion.

It was patented in 1969 and approved for medical use in 1982.^[2] It sold well, but in 2009, Roche decided to discontinue manufacturing due to diminishing market share due to the availability of the many generic versions and the settling of multiple lawsuits over side effects. It continues to be manufactured as of 2019 by Absorica, Amnesteem, Claravis, Myorisan, Sotret, and Zenatane.^[3]

Medical uses

Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments.^[4]^[5]^[6]^[7] Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring.^[8] Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age.^[9]

It is also somewhat effective for hidradenitis suppurativa and some cases of severe rosacea.^[10] It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.

Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for recalcitrant condylomata acuminata (RCA) of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.^[11]^[12]

Prescribing restrictions

Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug in utero, and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment.^[13] Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies.^[13]

In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom^[14] and Australia,^[15]^[16] isotretinoin may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious.^[17] In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.^[18]

In the United States, since March 2006 the dispensing of isotretinoin is run through a website called iPLEDGE. The FDA required the companies marketing the drug in the US, which at the time that iPLEDGE was launched were Roche, Mylan, Barr, and Ranbaxy, to put this website in place as a risk evaluation and mitigation strategy. These companies formed a group called the Isotretinoin Products Manufacturing Group, and it hired Covance to run the website.^[19]^[20] Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.^[21]^[22]

History[edit]

The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer and, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered the drug’s use as a treatment of cystic acne while studying it as a treatment for lamellar ichthyosis, and published that work. Roche resumed work on the drug. In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche’s New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. The FDA approved the application in 1982.

Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA’s advisory committee was convened and recommended stronger measures, which the FDA took and were that time unprecedented: warning blood banks not to accept blood from people taking the drug, and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to the New York Times^[77] a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the CDC argued to withdraw the drug from the market. The committee recommended to restrict physicians who could prescribe the drug and to require a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required to Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug; the program was called the “Pregnancy Prevention Program”.

A CDC report published in 2000^[78] showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the “Targeted Pregnancy Prevention Program” and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.^{[citation needed]}

In February 2002, Roche’s patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some people who took the drug.^[79] Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.^[80]

Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon.^[81] The jury, however, decided that James Marshall had a pre-existing bowel disease.^[82]

Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.^[83]

Society and culture

Brands

As of 2017 isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.^[1]

As of 2017 it was marketed as a topical combination drug with erythromycin under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.^[1]

Research

While excessive bone growth has been raised a possible side effect, a 2006 review found little evidence for this.^[84]

syn

C. D. Robeson et al., J. Am. Chem. Soc. 77, 4111 (1955). Stereoselective process: R. Lucci, EP 111325; idem, US 4556518 (1984, 1985 both to Hoffmann-La Roche). doi:10.1021/jo00349a001.

syn

J Chem Soc 1968,(16),1982-83

The reaction of vinyl-beta-ionol (I) with triphenylphosphonium bromide (II) in ethanol gives the corresponding phosphonium salt (III), which is condensed through a Wittig reaction with cis-beta-formylcrotonic acid (IV) by means of sodium ethoxide in ethanol to afford a mixture of cis-2-cis-4-vitamin A acid (V) and the desired product. Finally, compound (V) is isomerized bv irradiation with diffuse light in ether in the presence of iodine.

syn

Tetrahedron 2000,56(37),7211

The formylation of the beta-ionone (I) with methyl formate and NaOMe gives the enol (II), which by reaction with methanol and H2SO4 yields the dimethylacetal (III). The reaction of (III) with methylenetriphenylphosphorane (IV) affords the methylene compound (V), which is treated with formic acid to provide the aldehyde (VI). The condensation of (VI) with isopropylidenemalonic acid dimethyl ester (VII) by means of NaOH gives the polyenic malonic acid (VIII) as a mixture of isomers that is separated by crystallization in ethyl ether to yield the desired all-trans-isomer (IX). Finally, this malonic acid is selectively monodecarboxylated by means of refluxing 2,6-dimethylpyridine to afford the target (E,E,E,Z)-isomer.

References

^ Jump up to:^a ^b ^c “Isotretinoin international brands”. Drugs.com. Retrieved 1 June 2017.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 476. ISBN 978-3-527-60749-5.
^ “Isotretinoin (Oral Route) Description and Brand Names – Mayo Clinic”.
^ Merritt B, Burkhart CN, Morrell DS (June 2009). “Use of isotretinoin for acne vulgaris”. Pediatric Annals. 38 (6): 311–20. doi:10.3928/00904481-20090512-01. PMID 19588674.
^ Jump up to:^a ^b Layton A (May 2009). “The use of isotretinoin in acne”. Dermato-Endocrinology. 1(3): 162–9. doi:10.4161/derm.1.3.9364. PMC 2835909. PMID 20436884.
^ Jump up to:^a ^b ^c “Roaccutane 20mg Soft Capsules – Summary of Product Characteristics”. UK Electronic Medicines Compendium. 1 July 2015.
^ Jump up to:^a ^b ^c US Label (PDF) (Report). FDA. 22 October 2010 [January 2010]. Retrieved 1 June2017. See FDA Index page for NDA 018662 for updates
^ Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, Thiboutot DM, Van Voorhees AS, Beutner KA, Sieck CK, Bhushan R (April 2007). “Guidelines of care for acne vulgaris management”. Journal of the American Academy of Dermatology. 56 (4): 651–63. doi:10.1016/j.jaad.2006.08.048. PMID 17276540.
^ Jump up to:^a ^b ^c ^d “Isotretinoin (oral formulations): CMDH scientific conclusions – Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s)”(PDF). European Medicines Agency. August 2017. Retrieved 17 May 2019.
^ Jump up to:^a ^b Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006.^{[page needed]}
^ Georgala S, Katoulis AC, Georgala C, Bozi E, Mortakis A (June 2004). “Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: a randomised placebo controlled trial”. Sexually Transmitted Infections. 80 (3): 216–8. doi:10.1136/sti.2003.006841. PMC 1744851. PMID 15170007.
^ Sehgal VN, Srivastava G, Sardana K (June 2006). “Isotretinoin–unapproved indications/uses and dosage: a physician’s reference”. International Journal of Dermatology. 45 (6): 772–7. doi:10.1111/j.1365-4632.2006.02830.x. PMID 16796650.
^ Jump up to:^a ^b Choi JS, Koren G, Nulman I (March 2013). “Pregnancy and isotretinoin therapy”. Canadian Medical Association Journal. 185 (5): 411–3. doi:10.1503/cmaj.120729. PMC 3602257. PMID 23296582.
^ Joint Formulary Committee. British National Formulary (47th ed.). London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 978-0-85369-584-4.^{[page needed]}
^ “Fresh call for GPs to prescribe Roaccutane”. AustralianDoctor. 19 June 2012.
^ Specifically, doctors who are fellows of the Australasian College of Dermatologists (FACD); cf. Pharmaceutical Services Branch, Guide to poisons and therapeutic goods legislation for medical practitioners and dentists, Sydney: NSW Department of Health; 2006.^{[page needed]}
^ James M (June 1996). “Isotretinoin for severe acne”. Lancet. 347 (9017): 1749–50. doi:10.1016/S0140-6736(96)90814-4. PMID 8656912. S2CID 28756302.
^ “Acne, Isotretinoin, and Depression”. MEDSAFE (New Zealand Ministry of Health). June 2013 [June 2005]. Retrieved 7 February 2014.
^ Thiboutot, D. M.; Cockerell, C. J. (1 August 2006). “iPLEDGE: A Report from the Front Lines of Dermatologic Practice”. AMA Journal of Ethics. 8 (8): 524–528. doi:10.1001/virtualmentor.2006.8.8.pfor1-0608. ISSN 1937-7010. PMID 23234692.
^ Darves, Bonnie (March 9, 2006). “Dermatologists Frustrated With Problematic iPledge Program”. Medscape.
^ “iPledge (About iPledge)”.
^ “Isotretinoin (marketed as Accutane) Capsule Information”. U.S. Food and Drug Administration (FDA). 2018-11-03.
^ Jump up to:^a ^b ^c “Isotretinoin 20mg capsules – – (eMC)”. http://www.medicines.org.uk. Retrieved 2017-12-27.
^ “Isotretinoin 20mg capsules – – (eMC)”. http://www.medicines.org.uk. Retrieved 2018-01-10.
^ David M, Hodak E, Lowe NJ (1988). “Adverse effects of retinoids”. Medical Toxicology and Adverse Drug Experience. 3 (4): 273–88. doi:10.1007/bf03259940. PMID 3054426. S2CID 12432684.
^ DiGiovanna JJ (November 2001). “Isotretinoin effects on bone”. Journal of the American Academy of Dermatology. 45 (5): S176-82. doi:10.1067/mjd.2001.113721. PMID 11606950.
^ Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ (1984). “Isotretinoin therapy is associated with early skeletal radiographic changes”. Journal of the American Academy of Dermatology. 10 (6): 1024–9. doi:10.1016/S0190-9622(84)80329-1. PMID 6588057.
^ “Isotretinoin risks in acne treatment: Page 3 of 4”. October 2014.
^ Jump up to:^a ^b Moy A, McNamara NA, Lin MC (September 2015). “Effects of Isotretinoin on Meibomian Glands”. Optometry and Vision Science. 92 (9): 925–30. doi:10.1097/OPX.0000000000000656. PMID 26154692. S2CID 205905994.
^ Jump up to:^a ^b Lambert RW, Smith RE (March 1989). “Effects of 13-cis-retinoic acid on the hamster meibomian gland”. The Journal of Investigative Dermatology. 92 (3): 321–5. doi:10.1111/1523-1747.ep12277122. PMID 2918239.
^ Fraunfelder FT, Fraunfelder FW, Edwards R (September 2001). “Ocular side effects possibly associated with isotretinoin usage”. American Journal of Ophthalmology. 132 (3): 299–305. doi:10.1016/S0002-9394(01)01024-8. PMID 11530040.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h Brelsford M, Beute TC (September 2008). “Preventing and managing the side effects of isotretinoin”. Seminars in Cutaneous Medicine and Surgery. 27 (3): 197–206. doi:10.1016/j.sder.2008.07.002. PMID 18786498.
^ Scheinfeld N, Bangalore S (May 2006). “Facial edema induced by isotretinoin use: a case and a review of the side effects of isotretinoin”. Journal of Drugs in Dermatology. 5 (5): 467–8. PMID 16703787.
^ Jump up to:^a ^b “Updated measures for pregnancy prevention during retinoid use”. European Medicines Agency. 21 June 2018.
^ Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.^{[page needed]}
^ Leyden JJ, Del Rosso JQ, Baum EW (February 2014). “The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions”. The Journal of Clinical and Aesthetic Dermatology. 7 (2 Suppl): S3–S21. PMC 3970835. PMID 24688620.
^ BNF, edition 57^{[page needed]}
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Bremner JD, Shearer KD, McCaffery PJ (January 2012). “Retinoic acid and affective disorders: the evidence for an association”. The Journal of Clinical Psychiatry (Systematic Review). 73 (1): 37–50. doi:10.4088/JCP.10r05993. PMC 3276716. PMID 21903028.
^ Jump up to:^a ^b ^c Kontaxakis VP, Skourides D, Ferentinos P, Havaki-Kontaxaki BJ, Papadimitriou GN (January 2009). “Isotretinoin and psychopathology: a review”. Annals of General Psychiatry. 8: 2. doi:10.1186/1744-859X-8-2. PMC 2637283. PMID 19154613.
^ Jump up to:^a ^b ^c ^d Borovaya A, Olisova O, Ruzicka T, Sárdy M (September 2013). “Does isotretinoin therapy of acne cure or cause depression?”. International Journal of Dermatology. 52 (9): 1040–52. doi:10.1111/ijd.12169. PMID 23962262.
^ Jump up to:^a ^b “Interactive Drug Analysis Profile – Isotretinoin”. mhra.gov.uk. Medicines & Healthcare Products Regulatory Agency. 31 March 2017.
^ Jump up to:^a ^b Goodfield MJ, Cox NH, Bowser A, McMillan JC, Millard LG, Simpson NB, Ormerod AD (June 2010). “Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010”. The British Journal of Dermatology. 162 (6): 1172–9. doi:10.1111/j.1365-2133.2010.09836.x. PMID 21250961.
^ Jump up to:^a ^b Ludot M, Mouchabac S, Ferreri F (June 2015). “Inter-relationships between isotretinoin treatment and psychiatric disorders: Depression, bipolar disorder, anxiety, psychosis and suicide risks”. World Journal of Psychiatry. 5 (2): 222–7. doi:10.5498/wjp.v5.i2.222. PMC 4473493. PMID 26110123.
^ Wysowski DK, Pitts M, Beitz J (October 2001). “An analysis of reports of depression and suicide in patients treated with isotretinoin”. Journal of the American Academy of Dermatology. 45 (4): 515–9. doi:10.1067/mjd.2001.117730. PMID 11568740.
^ Jump up to:^a ^b Rowe C, Spelman L, Oziemski M, Ryan A, Manoharan S, Wilson P, Daubney M, Scott J (May 2014). “Isotretinoin and mental health in adolescents: Australian consensus”. The Australasian Journal of Dermatology (Review). 55 (2): 162–7. doi:10.1111/ajd.12117. PMID 24283385. S2CID 29178483.
^ Palha JA, Goodman AB (June 2006). “Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia” (PDF). Brain Research Reviews. 51(1): 61–71. doi:10.1016/j.brainresrev.2005.10.001. hdl:1822/3943. PMID 16325258. S2CID 30773986.
^ Jump up to:^a ^b ^c ^d Goodman AB (March 1994). “Retinoid dysregulation as a cause of schizophrenia”. The American Journal of Psychiatry. 151 (3): 452–3. doi:10.1176/ajp.151.3.452b. PMID 8109664.
^ Goodman AB (May 1996). “Congenital anomalies in relatives of schizophrenic probands may indicate a retinoid pathology”. Schizophrenia Research. 19 (2–3): 163–70. doi:10.1016/0920-9964(96)88523-9. PMID 8789914. S2CID 12089905.
^ Goodman AB (July 2005). “Microarray results suggest altered transport and lowered synthesis of retinoic acid in schizophrenia”. Molecular Psychiatry. 10 (7): 620–1. doi:10.1038/sj.mp.4001668. PMID 15838536.
^ Samad TA, Krezel W, Chambon P, Borrelli E (December 1997). “Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family”. Proceedings of the National Academy of Sciences of the United States of America. 94 (26): 14349–54. Bibcode:1997PNAS…9414349S. doi:10.1073/pnas.94.26.14349. PMC 24972. PMID 9405615.
^ Crockett SD, Porter CQ, Martin CF, Sandler RS, Kappelman MD (September 2010). “Isotretinoin use and the risk of inflammatory bowel disease: a case-control study”. The American Journal of Gastroenterology. 105 (9): 1986–93. doi:10.1038/ajg.2010.124. PMC 3073620. PMID 20354506.
^ Lowenstein EB, Lowenstein EJ (2011). “Isotretinoin systemic therapy and the shadow cast upon dermatology’s downtrodden hero”. Clinics in Dermatology. 29 (6): 652–61. doi:10.1016/j.clindermatol.2011.08.026. PMID 22014987.
^ “Drug Safety Update – Latest advice for medicines users – October 2017” (PDF). Medicines and Healthcare products Regulatory Agency. 3 October 2017. Retrieved 17 May2019.
^ “Pharmacovigilance Risk Assessment Committee (PRAC) – Minutes for the meeting on 3–6 July 2017” (PDF). European Medicines Agency. 1 September 2017. p. 44. Retrieved 17 May 2019.
^ Kremer I, Gaton DD, David M, Gaton E, Shapiro A (1994). “Toxic effects of systemic retinoids on meibomian glands”. Ophthalmic Research. 26 (2): 124–8. doi:10.1159/000267402. PMID 8196934.
^ Griffin JN, Pinali D, Olds K, Lu N, Appleby L, Doan L, Lane MA (November 2010). “13-Cis-retinoic acid decreases hypothalamic cell number in vitro”. Neuroscience Research. 68 (3): 185–90. doi:10.1016/j.neures.2010.08.003. PMID 20708044. S2CID 207152111.
^ Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery P (April 2004). “13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice”. Proceedings of the National Academy of Sciences of the United States of America. 101 (14): 5111–6. Bibcode:2004PNAS..101.5111C. doi:10.1073/pnas.0306336101. JSTOR 3371827. PMC 387382. PMID 15051884.
^ Sakai Y, Crandall JE, Brodsky J, McCaffery P (June 2004). “13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice”. Annals of the New York Academy of Sciences. 1021 (1): 436–40. Bibcode:2004NYASA1021..436S. doi:10.1196/annals.1308.059. PMID 15251924.
^ Nelson AM, Cong Z, Gilliland KL, Thiboutot DM (September 2011). “TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells”. The British Journal of Dermatology. 165 (3): 526–33. doi:10.1111/j.1365-2133.2011.10392.x. PMC 3166444. PMID 21564055.
^ Nelson AM, Gilliland KL, Cong Z, Thiboutot DM (October 2006). “13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes”. The Journal of Investigative Dermatology. 126 (10): 2178–89. doi:10.1038/sj.jid.5700289. PMID 16575387.
^ Wachter K (2009). “Isotretinoin’s Mechanism of Action Explored”. Skin & Allergy News. 40(11): 32. doi:10.1016/S0037-6337(09)70553-4.
^ Isotretinoin’s Mechanism of Action Elucidated Archived 2010-04-04 at the Wayback Machine. Medconnect (2009-08-28). Retrieved on 2010-11-13.
^ Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM (April 2008). “Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells”. The Journal of Clinical Investigation. 118 (4): 1468–78. doi:10.1172/JCI33869. PMC 2262030. PMID 18317594.
^ Jump up to:^a ^b Peck GL, Olsen TG, Yoder FW, Strauss JS, Downing DT, Pandya M, Butkus D, Arnaud-Battandier J (February 1979). “Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid”. The New England Journal of Medicine. 300 (7): 329–33. doi:10.1056/NEJM197902153000701. PMID 153472.
^ Shalita A (2001). “The integral role of topical and oral retinoids in the early treatment of acne”. Journal of the European Academy of Dermatology and Venereology. 15: 43–9. doi:10.1046/j.0926-9959.2001.00012.x. PMID 11843233.
^ ^{[unreliable medical source?]}Farrell LN, Strauss JS, Stranieri AM (December 1980). “The treatment of severe cystic acne with 13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multiple-dose trial”. Journal of the American Academy of Dermatology. 3 (6): 602–11. doi:10.1016/S0190-9622(80)80074-0. PMID 6451637.
^ ^{[unreliable medical source?]}Jones H, Blanc D, Cunliffe WJ (November 1980). “13-cis retinoic acid and acne”. Lancet. 2 (8203): 1048–9. doi:10.1016/S0140-6736(80)92273-4. PMID 6107678. S2CID 40877032.
^ Pendino F, Flexor M, Delhommeau F, Buet D, Lanotte M, Segal-Bendirdjian E (June 2001). “Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation”. Proceedings of the National Academy of Sciences of the United States of America. 98 (12): 6662–7. Bibcode:2001PNAS…98.6662P. doi:10.1073/pnas.111464998. JSTOR 3055868. PMC 34517. PMID 11371621.
^ Φαχαντίδης, Παναγιώτης Ε. (2007). Η επίδραση της ισοτρετινοϊνης και των αναστολέων της 5α-αναγωγάσης στις μεταλλοπρωτεάσες του συνδετικού ιστού σε ασθενείς με ακμή[The influence of isotretinoin and 5-a reductase inhibitors in metaloproteases of connective tissue in patients with ance] (in Greek). Aristotle University of Thessaloniki.^{[unreliable medical source?]}
^ Toyoda M, Nakamura M, Makino T, Kagoura M, Morohashi M (June 2002). “Sebaceous glands in acne patients express high levels of neutral endopeptidase”. Experimental Dermatology. 11 (3): 241–7. doi:10.1034/j.1600-0625.2002.110307.x. PMID 12102663. S2CID 23468315.
^ Wysowski DK, Swartz L (May 2005). “Relationship between headache and depression in users of isotretinoin”. Archives of Dermatology. 141 (5): 640–1. doi:10.1001/archderm.141.5.640. PMID 15897395.
^ Magin P, Pond D, Smith W (February 2005). “Isotretinoin, depression and suicide: a review of the evidence”. The British Journal of General Practice. 55 (511): 134–8. PMC 1463189. PMID 15720936.
^ Ng CH, Schweitzer I (February 2003). “The association between depression and isotretinoin use in acne”. The Australian and New Zealand Journal of Psychiatry. 37 (1): 78–84. doi:10.1046/j.1440-1614.2003.01111.x. PMID 12534661. S2CID 8475675.
^ Jump up to:^a ^b ^c ^d ^e “FDA information, side effects, and uses / Accutane (isotretinoin)”. U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014.
^ “FDA information, side effects, and uses / Accutane (isotretinoin) : Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74“. U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014.
^ “FDA information, side effects, and uses / Accutane (isotretinoin) : Drug Interactions“. U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014.
^ Gina Kolata for the New York Times. April 22, 1988 Anti-Acne Drug Faulted in Birth
^ CDC. January 21, 2000 Accutane®-Exposed Pregnancies — California, 1999 MMWR Weekly 49(02);28-31
^ Shari Roan (7 November 2009). “New study may deal final blow to acne drug Accutane”. LA Times.
^ “Roche Discontinues and Plans to Delist Accutane in the U.S.” (Press release). Genentech. 2009-06-29. Archived from the original on 2009-11-08. Retrieved 2010-11-12.
^ Feeley J (2011-03-11). “Roche Accutane Acne Drug Caused ‘Tragedy’ for Actor, Brian Dennehy Says”. Bloomberg.
^ Silverman E (2011-11-04). “It’s Curtains On Actor’s Accutane Lawsuit”. Pharmalot. UBM Canon.
^ Voreacos D (May 30, 2007). “Roche Found Liable in First Of 400 Suits Over Accutane”. The Washington Post. Bloomberg News. Retrieved April 30, 2012.
^ Halverstam CP, Zeichner J, Lebwohl M (2006). “Lack of significant skeletal changes after long-term, low-dose retinoid therapy: case report and review of the literature”. Journal of Cutaneous Medicine and Surgery. 10 (6): 291–9. doi:10.2310/7750.2006.00065. PMID 17241599. S2CID 36785828.

External links

Clinical data


Pronunciation	See note at tretinoin
Trade names	Accutane, Roaccutane, others^[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a681043
License data	US FDA: Isotretinoin
Pregnancy category	AU: X (High risk)US: X (Contraindicated)
Routes of administration	By mouth, topical
ATC code	D10AD04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Variable
Protein binding	99.9%
Metabolism	Liver
Elimination half-life	10–20 hours
Excretion	Kidney and fecal
Identifiers
IUPAC name [show]
CAS Number	4759-48-2
PubChem CID	5282379
IUPHAR/BPS	7600
DrugBank	DB00982
ChemSpider	4445539
UNII	EH28UP18IF
KEGG	D00348
ChEBI	CHEBI:6067
ChEMBL	ChEMBL547
CompTox Dashboard (EPA)	DTXSID4023177
ECHA InfoCard	100.022.996
Chemical and physical data
Formula	C₂₀H₂₈O₂
Molar mass	300.442 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide]O=C(O)\C=C(/C=C/C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
InChI [hide]InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14-Key:SHGAZHPCJJPHSC-XFYACQKRSA-N

////////////Antiacne, 13-cis-Retinoic acid, 2-cis-vitamin A acid, neovitamin A acid, Isotretinoin

NEW DRUG APPROVALS

ONE TIME

$10.00

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

New Drug Approvals

Tag Archives: Antiacne

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

DR ANTHONY MELVIN CRASTO Ph.D

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

ADAPALENE

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

Anthony Melvin Crasto Ph.D – India | LinkedIn

RESEARCHGATE

Anthony Melvin Crasto Dr. | Facebook

Medical uses

Off-label uses

Side effects

In pregnancy

Interactions

Pharmacology

Pharmacokinetics

Pharmacodynamics

History

Research

References

External links

Share this:

Isotretinoin

Medical uses

Prescribing restrictions

History[edit]

Society and culture

Brands

Research

References

External links

Share this:

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email