Bacterial protein synthesis

Adapalene 0.1% with clindamycin phosphate 1.2% (ADA + CLNP) and the fixed-dose combination of clindamycin phosphate with benzoyl peroxide 3% (CLNP/BPO 3%) are strongly recommended as first-line topical therapies for the early treatment of acne vulgaris in Japan. This phase IV, multicenter study was conducted to compare the early efficacy and safety of CLNP/BPO 3% with the Japanese standard topical regimen of ADA + CLNP. A total of 351 patients were randomized to receive either CLNP/BPO 3% or ADA + CLNP once daily for 12 weeks. The primary endpoint was the percent reduction from baseline in total lesion count at week 2. Secondary endpoints included percent changes in total, inflammatory, and non-inflammatory lesion counts; Investigator's Static Global Assessment score; quality of life assessed by Skindex-16; and patient preference. Local tolerability and adverse events were also monitored. At week 2, CLNP/BPO 3% demonstrated a significantly greater percent reduction in total lesion count compared with ADA + CLNP, and this superiority persisted through week 4. Over the 2- to 12-week period, CLNP/BPO 3% was superior in reducing inflammatory lesions, though not non-inflammatory lesions. Additionally, CLNP/BPO 3% showed greater improvements in patient quality of life and Investigator's Static Global Assessment scores, and received higher patient preference ratings. Both treatments were well tolerated; however, adverse drug reactions occurred more frequently in the ADA + CLNP group (37%) than in the CLNP/BPO 3% group (17%). In conclusion, CLNP/BPO 3% demonstrated superior early efficacy and a more favorable safety profile compared with ADA + CLNP for the treatment of acne vulgaris in Japan. [2]

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A single-center, single-arm, open-label study was conducted to evaluate the efficacy and safety of a novel thermosetting bioadhesive vaginal gel containing 2% clindamycin phosphate for the treatment of bacterial vaginosis. Thirty patients diagnosed with bacterial vaginosis based on Amsel criteria were enrolled; a subset of ten patients also underwent Nugent score assessment. Eligible participants received a single 5 g dose of 2% clindamycin phosphate vaginal gel via a prefilled applicator. Patients returned for follow-up visits 7–14 days post-dose and again 21–30 days post-dose. Two patients were excluded from the cure rate analysis. Among the 28 evaluable patients, 24 (86%) achieved clinical cure at the first follow-up visit following a single dose. Of the seven evaluable patients in the Nugent-scored subset, four (57%) achieved bacteriologic cure and four (57%) demonstrated therapeutic response. Among the 24 women who were cured at the first follow-up visit based on Amsel criteria, 23 (96%) remained cured at the final visit. In the Nugent-scored subset, seven of nine evaluable patients (78%) had a Nugent score ≤ 3 at the final visit, and six of nine (67%) were considered therapeutically cured. No adverse reactions, including local tolerability issues, were reported throughout the study. These findings support further clinical evaluation of 2% clindamycin phosphate vaginal gel for bacterial vaginosis. [3]

The investigational product was a thermosetting bioadhesive vaginal gel containing 2.0% clindamycin phosphate (expressed as the free base). The formulation consisted of Poloxamer 407, xanthan gum, citric acid, sodium citrate, and benzyl alcohol in purified water. The gel was manufactured in compliance with current Good Manufacturing Practices and filled into pre-filled vaginal applicators, each delivering a single 5.0 g dose. [3]
A single-center, open-label clinical study was conducted at OB/GYN Associates of Montgomery (Montgomery, AL, USA) to evaluate the gel's efficacy and safety in patients with bacterial vaginosis. As clindamycin phosphate is an approved active ingredient for intravaginal use, and all excipients are components of existing vaginal products, the study was exempt from Institutional Review Board approval. Written informed consent was obtained from all participants prior to enrollment. [3]
A total of 30 women, aged 17 to 51 years and self-identifying as Caucasian or African American, were enrolled. Eligibility was assessed through patient history, pelvic examination, and fulfillment of all four Amsel criteria: (1) presence of a thin, homogeneous, off-white vaginal discharge with minimal or absent pruritus and vulvovaginal inflammation; (2) vaginal pH > 4.5; (3) presence of clue cells comprising >20% of total epithelial cells on saline wet mount microscopy; and (4) a positive whiff test (fishy odor upon addition of 10% potassium hydroxide to vaginal discharge). In the last ten enrolled subjects, vaginal smears were also evaluated using the Nugent scoring system, which quantifies bacterial morphotypes on Gram-stained slides. [3]
Eligible patients received a single dose of the 2% clindamycin phosphate vaginal gel at the enrollment visit (Visit 1). Participants returned for follow-up visits approximately 7–14 days (Visit 2) and 21–30 days (Visit 3) after gel administration. At each follow-up visit, pelvic examination was repeated, and all four Amsel criteria were reassessed. Patients were also queried regarding comfort and tolerability following the initial treatment. For the subset of ten subjects, Nugent scores were re-evaluated at Visits 2 and 3.

Clindamycin phosphate is a water-soluble prodrug ester of the semisynthetic antibiotic clindamycin . It is designed for parenteral and topical/intravaginal administration, as it lacks intrinsic antibacterial activity until hydrolyzed in vivo to the active parent compound, clindamycin . The physicochemical properties that influence its disposition include a logP of 0.95, pKa of 6.78, molecular weight of 504.96 g/mol, and aqueous solubility of 3220 mg/L at pH 7 .

Absorption
Oral Administration
Clindamycin (as hydrochloride salt) is well absorbed following oral administration, with approximately 90% of a dose absorbed . Food does not impede absorption but may delay it . Absolute oral bioavailability is approximately 80% and is not affected by food consumption, although absorption is delayed . In AIDS patients, bioavailability has been reported to be higher (75%) compared to healthy volunteers (53%) .

Parenteral Administration
Following intramuscular injection of clindamycin phosphate, peak serum clindamycin concentrations (3.17–6.56 mg/L) are reached within 1.5–3 hours, with detectable levels observed after 20 minutes. Approximately 75% of the drug reaches the plasma as active clindamycin .
After intravenous infusion (300–1200 mg), peak clindamycin concentrations appear approximately 3 hours after the end of infusion, ranging from 5.4 mg/L (300 mg dose) to 15.87 mg/L (1200 mg dose) . Approximately 10% of the drug remains in serum after 8 hours as clindamycin phosphate .

Intravaginal Administration
Following intravaginal administration of clindamycin phosphate suppositories (100 mg clindamycin equivalent once daily for 3 days), approximately 30% (range 6–70%) of the administered dose is systemically absorbed based on AUC comparisons. Peak plasma concentrations (Cmax) average 0.27 µg/mL (range 0.03–0.67 µg/mL), occurring about 5 hours post-dose (range 1–10 hours). The mean AUC at steady state is 3.2 µg·hr/mL (range 0.42–11 µg·hr/mL) .

Intraperitoneal Administration
In continuous ambulatory peritoneal dialysis patients receiving 600 mg clindamycin phosphate intraperitoneally, dialysate clindamycin concentrations exceed the effective concentration (5 µg/mL) for up to 6 hours . Transfer of clindamycin is unidirectional from dialysate to plasma .

Distribution
Clindamycin is widely distributed throughout body tissues and fluids, with the notable exception of cerebrospinal fluid (even in the presence of inflamed meninges) . It crosses the placenta and appears in breast milk .
Protein Binding
Clindamycin is 90–93% bound to plasma proteins, primarily α₁-acid glycoprotein . The unbound fraction in plasma (fup) is 0.06 for clindamycin and 0.22 for clindamycin phosphate .
Cellular Accumulation
Clindamycin accumulates extensively in phagocytic cells:
- Intracellular:extracellular concentration ratio in neutrophils: 11–15
- In macrophages and monocytes: 23
- Localizes in cytoplasm and granules
Volume of Distribution
Volume of distribution at steady state following intravenous administration:
- Healthy volunteers: 0.79 ± 0.13 L/kg
- AIDS patients: 0.66 ± 0.12 L/kg


Metabolism
Clindamycin phosphate is a prodrug that undergoes rapid hydrolysis to active clindamycin. The hydrolysis half-life is dose-dependent: 1 minute for 300 mg to 3 minutes for 1200 mg doses .
Clindamycin is primarily metabolized in the liver . Seven metabolites have been described , including:
- Clindamycin sulfoxide (37% of urinary excreted compounds)
- N-demethyl clindamycin (6%)
- Clindamycin-N-demethyl sulfoxide (2%)
- Hydroxyl derivative (~15% of urinary compounds)
- Carboxyl derivative (~15% of urinary compounds)
Metabolic clearance (intrinsic hepatic CYP3A4): 2.21 µL/min/pmol P450; CYP3A5: 0.28 µL/min/pmol P450 .

Elimination
Half-Life
- Clindamycin elimination half-life: 2–3 hours in healthy adults
- Clindamycin phosphate half-life: 0.04–0.16 hours (2.4–9.6 minutes)
- Following intravaginal administration, apparent half-life averages 11 hours (range 4–35 hours), limited by absorption rate

Clearance
Plasma clearance of clindamycin: 0.18 L/h/kg (approximately 0.27 L/h/kg in healthy volunteers) . Clindamycin phosphate clearance: 0.40 L/h/kg .

Excretion
Clindamycin is eliminated primarily via the hepatobiliary route :
- Urinary excretion: 8–28% of the dose is excreted in urine as active drug and metabolites
- Approximately 27% of urinary compounds is parent clindamycin
- Clindamycin phosphate accounts for only 1–2% of the administered dose in urine
- Renal filtration rate: 0.044 L/min
- Fecal excretion: Approximately 61% of the dose is recovered in feces over 168 hours (radiolabeled studies)
- Excretion is slow and occurs over many days

443385 rat LD50 intraperitoneal 745 mg/kg Iyakuhin Kenkyu. Study of Medical Supplies., 14(484), 1983
443385 rat LD50 oral 1832 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Toxicology and Applied Pharmacology., 27(308), 1974 [PMID:4137286]
443385 rat LD50 intramuscular >3500 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 25(691), 1983
443385 mouse LD50 intravenous 820 mg/kg Iyakuhin Kenkyu. Study of Medical Supplies., 14(484), 1983
443385 rat LD50 intravenous 321 mg/kg Iyakuhin Kenkyu. Study of Medical Supplies., 14(484), 1983

[1]. Clindamycin hydrochloride and clindamycin phosphate: two drugs or one? A retrospective analysis of a spontaneous reporting system. Eur J Clin Pharmacol. 2017 Feb;73(2):251-253.

[2]. Clindamycin phosphate 1.2%/benzoyl peroxide 3% fixed-dose combination gel versus topical combination therapy of adapalene 0.1% gel and clindamycin phosphate 1.2% gel in the treatment of acne vulgaris in Japanese patients: A multicenter, randomized, investigator-blind, parallel-group study. J Dermatol. 2018 Aug;45(8):951-962.

[3]. Proof of concept study of a novel bioadhesive clindamycin phosphate 2% vaginal gel to treat bacterial vaginosis. Clin. Exp. Obstet. Gynecol. 2020, 47(4), 516–518.

Currently marketed clindamycin phosphate products approved for intravaginal use in the United States include: (a) a 2% single-dose cream; (b) a 2% cream administered once daily for three or seven days; and (c) 100 mg ovules administered once daily for three days. Among these, the 2% single-dose cream shares a similar dosing regimen with the investigational product described in this study. In a head-to-head comparative trial, the 2% single-dose cream demonstrated a clinical cure rate of 64.3%, compared with 63.2% for the 2% cream administered as seven once-daily doses. In a pivotal placebo-controlled study, the 2% single-dose cream achieved a clinical cure rate of 41%, versus 19.7% in the placebo group. Another study comparing the same single-dose formulation with seven once-daily doses reported clinical cure rates of 53.4% and 54.0%, respectively. Across all these studies, clinical cure was defined as resolution of all four Amsel criteria. Of note, the current FDA guidance defines clinical cure as the resolution of three Amsel criteria (excluding pH). [3]
The commercially available 2% single-dose cream is formulated with bioadhesive and sustained-release properties. Similarly, the vaginal gel evaluated in this study incorporates a bioadhesive composition with the added feature of thermosensitive gelation, resulting in increased viscosity at body temperature compared with room temperature. In vitro characterization revealed that this vaginal gel releases clindamycin over an eight-day period and exhibits slow erosion. These properties are expected to enhance the efficacy of clindamycin by establishing a sustained drug reservoir within the vaginal cavity, allowing for prolonged drug release over time.[3]
Although this study has certain limitations—including its open-label design, small sample size, and single-center, single-investigator setting—the accumulated data suggest that this novel vaginal gel may offer efficacy comparable to, or potentially greater than, that of the approved 2% single-dose cream. The findings are consistent with a single-dose product that is simple to administer, efficacious, and likely to be well accepted by women requiring treatment for bacterial vaginosis. Collectively, these results support further clinical investigation into the efficacy and safety of this thermosetting bioadhesive clindamycin vaginal gel.

C18H35CL2N2O8PS

541.423863649368

540.1228796

64023-51-4

Clindamycin hydrochloride;21462-39-5;Clindamycin phosphate;24729-96-2

Typically exists as solid at room temperature

6

10

9

32

658

9

[C@]([H])([C@]1([H])[C@@H]([C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1)O)([C@@H](Cl)C)NC([C@H]1N(C[C@H](CCC)C1)C)=O.Cl

BXFXGYXLHQNDRT-SHSUDHJHSA-N

InChI=1S/C18H34ClN2O8PS.ClH/c1-5-6-10-7-11(21(3)8-10)17(24)20-12(9(2)19)15-13(22)14(23)16(18(28-15)31-4)29-30(25,26)27;/h9-16,18,22-23H,5-8H2,1-4H3,(H,20,24)(H2,25,26,27);1H/t9-,10+,11-,12+,13+,14-,15+,16+,18+;/m0./s1

[(2R,3R,4S,5R,6R)-6-[(1S,2S)-2-chloro-1-[[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate;hydrochloride

Clindamycin phosphate (hydrochloride); 64023-51-4; orb1982119; CLINDAMYCIN PHOSPHATE HYDROCHLORIDE;

2934.99.9001

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)

H2O: 100 mg/mL (198 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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