Glucocorticoid receptor [1,5,6]

- Effect on collagen synthesis: In human skin, Hydrocortisone butyrate (applied topically) inhibits collagen synthesis. Compared with hydrocortisone, it shows a stronger inhibitory effect. After topical application, the incorporation of 14C-proline into skin collagen is reduced, indicating decreased collagen production [5]
- Vasoconstrictive activity: In a vasoconstriction assay, topical application of Hydrocortisone butyrate (as a cream or ointment) exhibits stronger vasoconstrictive activity than hydrocortisone. The vasoconstrictive effect is evaluated by the degree of blanching of the skin, with Hydrocortisone butyrate inducing more pronounced and longer-lasting blanching [6]
- Clinical efficacy in dermatological conditions: Hydrocortisone butyrate (topical formulation) is effective in treating various inflammatory skin disorders, including eczema and dermatitis. It reduces redness, swelling, and itching associated with these conditions [1]

- For vasoconstriction assay: Hydrocortisone butyrate is formulated into creams or ointments. These formulations are applied topically to the skin of human subjects (or animal models). The skin is observed at specific time points (e.g., 2, 4, 6, 24 hours) to assess the degree of blanching, which reflects vasoconstrictive activity. Comparisons are made with hydrocortisone formulations [6]
- For collagen synthesis study: Hydrocortisone butyrate is applied topically to human skin. After a specified period, 14C-proline is administered, and skin biopsies are taken. The incorporation of 14C-proline into collagen is measured to evaluate collagen synthesis inhibition [5]

Absorption, Distribution and Excretion
Topical corticosteroids are absorbed through normal, intact skin. Skin inflammation and/or other conditions can increase percutaneous absorption. Corticosteroids are primarily metabolized in the liver and then excreted via the kidneys. Some topical corticosteroids and their metabolites are also excreted via bile. Metabolism/Metabolites Primarily metabolized in the liver via CYP3A4. Biological Half-Life 6-8 hours

Allergic contact dermatitis: Topical application of hydrocortisone butyrate can induce allergic contact dermatitis in some individuals, manifesting as papular rashes similar to papular rosacea [8]
protein binding
95%

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26133 rat oral LD50 >3 gm/kg Oyo Yakuri. Pharmacometrics., 8(991), 1974
26133 rat intraperitoneal injection LD50 >3 gm/kg Behavioral: altered motor activity (specific determination); gastrointestinal tract: hypermotility, diarrhea; kidney, ureter and bladder: hematuria Oyo Yakuri. Pharmacometrics, 8(991), 1974
26133 rat subcutaneous injection LD50 >3 g/kg Behavioral: altered motor activity (specific determination); gastrointestinal tract: hypermotility, diarrhea; kidney, ureter and bladder: hematuria Oyo Yakuri. Pharmacometrics, 8(991), 1974
26133 Oral LD50 in mice >3 g/kg Oyo Yakuri. Pharmacometrics, 8(991), 1974
26133 Intraperitoneal LD50 in mice 1550 mg/kg Behavioral: somnolence (overall activity inhibition); kidneys, ureters and bladder: hematuria; skin and its appendages (skin); hair: other Oyo Yakuri. Pharmacometrics., 8(991), 1974

[1]. Hydrocortisone 17-butyrate: a new topical corticosteroid preliminary report. Drugs, 1976, 12(4), 249–257.
[2]. Statistical design for formulation optimization of hydrocortisone butyrate-loaded PLGA nanoparticles. AAPS PharmSciTech. 2014 Jun;15(3):569-87.
[3]. Development of the hydrocortisone butyrate qualitative determination method. Ceska Slov Farm. Fall 2014;63(6):275.
[4]. Nanoparticle-Based Topical Ophthalmic Gel Formulation for Sustained Release of Hydrocortisone Butyrate. AAPS PharmSciTech. 2016 Apr;17(2):294-306.
[5]. Comparison of the effect of hydrocortisone, hydrocortisone-17-butyrate and betamethasone on collagen synthesis in human skin in vivo. Acta Derm Venereol. 1995 Jul;75(4):269-71.
[6]. Comparison of activity of different topical corticosteroid creams and ointments using a vasoconstriction assay: superiority of hydrocortisone butyrate over hydrocortisone]. J Dtsch Dermatol Ges. 2005 May;3(5):348-53.
[7]. Kinetics of decomposition and formulation of hydrocortisone butyrate in semiaqueous and gel systems. J Pharm Sci. 1983 Jul;72(7):776-81.
[8]. Allergic contact dermatitis induced by topical hydrocortisone-17-butyrate mimicking papular rosacea. Dermatitis. 2012 Mar-Apr;23(2):95-6.

Hydrocortisone butyrate is a more potent topical corticosteroid than hydrocortisone. Its mechanism of action is through binding to glucocorticoid receptors, exerting anti-inflammatory, immunosuppressive, and antiproliferative effects [1,5,6]. Hydrocortisone butyrate is formulated into various topical preparations, such as creams, ointments, and gels. Nanoparticle-based formulations (e.g., PLGA nanoparticles, ophthalmic gels) have been developed to improve its sustained-release and targeted delivery [2,4]. Stability studies have shown that hydrocortisone butyrate decomposes in semi-aqueous and gel systems, and its stability is affected by factors such as pH and temperature. Formulation optimization is needed to improve its stability [7]. A qualitative assay for hydrocortisone butyrate has been developed for the quality control and identification of the drug in formulations [3]. 17-Butyrate cortisol is formed by the esterification of cortisol with butyrate at the 17-hydroxyl group. It is both a dermatological drug and a drug allergen. It is a cortisol ester, butyrate, and primary α-hydroxy ketone. Hydrocortisone butyrate is the butyrate form of hydrocortisone, a synthetic glucocorticoid receptor agonist with anti-inflammatory, antipruritic, and vasoconstrictive effects. Upon binding to and activation of glucocorticoid receptors, it activates lipocortin, thereby inhibiting cytosolic phospholipase A2. Deficiency of phospholipase A2 prevents the release of arachidonic acid (a precursor to the inflammatory mediators prostaglandins and leukotrienes) from the cell membrane. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, leading to dephosphorylation and inactivation of the Jun N-terminal kinase, directly inhibiting c-Jun-mediated transcription. Finally, the transcriptional activity of nuclear factor (NF)-κB is blocked, thereby inhibiting the transcription of cyclooxygenase 2, which is essential for prostaglandin production. Pharmacological Indications: For the relief of inflammatory and pruritus symptoms in corticosteroid-responsive dermatitis. It is also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addison's disease). It is also used to treat a variety of immune and allergic diseases, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease.

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Mechanism of Action
Hydrocortisone binds to cytoplasmic glucocorticoid receptors. After binding to the receptor, the newly formed receptor-ligand complex translocates to the cell nucleus and binds to multiple glucocorticoid response elements (GREs) in the promoter regions of target genes. The DNA-bound receptor then interacts with basic transcription factors, leading to increased expression of specific target genes. The anti-inflammatory effects of corticosteroids are thought to be related to lipocortin, a phospholipase A2 inhibitory protein that controls the biosynthesis of prostaglandins and leukotrienes by inhibiting arachidonic acid. Specifically, glucocorticoids induce the synthesis of lipocortin-1 (annexin-1), which binds to the cell membrane, preventing phospholipase A2 from contacting its substrate arachidonic acid. This leads to a decrease in arachidic acid production. The expression of cyclooxygenases (COX-1 and COX-2) is also inhibited, thereby enhancing the aforementioned effects. In other words, both major products of inflammation—prostaglandins and leukotrienes—are suppressed by glucocorticoids. Glucocorticoids can also stimulate lipocortin-1 to escape into the extracellular space. Lipocortictin-1 binds to leukocyte membrane receptors, inhibiting various inflammatory responses, including epithelial cell adhesion, migration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mast cells. Furthermore, glucocorticoids suppress the immune system through mechanisms including decreased lymphatic system function, reduced immunoglobulin and complement concentrations, lymphopenia, and interference with antigen-antibody binding.

C25H36O6

432.55

432.251

C, 69.42; H, 8.39; O, 22.19

13609-67-1

Hydrocortisone acetate; 50-03-3; Hydrocortisone; 50-23-7; Hydrocortisone phosphate; 3863-59-0

26133

White to off-white solid powder

1.2±0.1 g/cm3

585.6±50.0 °C at 760 mmHg

212 °C

194.0±23.6 °C

0.0±3.7 mmHg at 25°C

1.565

2.81

2

6

6

31

817

7

C[C@@]12[C@](C(CO)=O)(OC(CCC)=O)CC[C@@]1([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3([H])[C@@H](O)C2)=O

BMCQMVFGOVHVNG-TUFAYURCSA-N

InChI=1S/C25H36O6/c1-4-5-21(30)31-25(20(29)14-26)11-9-18-17-7-6-15-12-16(27)8-10-23(15,2)22(17)19(28)13-24(18,25)3/h12,17-19,22,26,28H,4-11,13-14H2,1-3H3/t17-,18-,19-,22+,23-,24-,25-/m0/s1

[(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] butanoate

H.17B; Locoid; Alfason; hydrocortisone butyrate; Hydrocortisone 17-butyrate; Cortisol 17-butyrate; Hydrocortisone-17-butyrate; 13609-67-1; Locoid; Hydrocortisone-17alpha-butyrate; Locoid Lipocream; Hydrocortisone butyrate; Hydrocortisone 17-butyrate; Locoid lipocream

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~87 mg/mL (~201.1 mM)
Ethanol: ~15 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)