Injectable Formulation Research Articles

PLGA-based long-acting injectable (LAI) formulations.

PLGA-based long-acting injectable (LAI) formulations.

Efficacy and safety results of a multi-center phase I study of utidelone capsule, a novel oral microtubule inhibitor, in advanced solid tumor patients.

3030 Background: Utidelone is a novel microtubule inhibitor, whose injectable formulation (UTD1) has been approved for advanced breast cancer in China since 2021. Attempts to develop oral microtubule inhibitor have not made significant progress; no oral microtubule inhibitors have been approved in the United States to date. Utidelone is insusceptible to P-glycoprotein-mediated efflux, thereby optimizing it for oral administration on an intermittent schedule. Utidelone capsule (UTD2) can significantly improve medication compliance and the convenience of clinical application. This is the first-in-human study of UTD2, and the trial has been completed with final results presented here. Methods: Eligible patients were aged ≥18, with an ECOG PS of 0-1, life expectancy ≥12weeks, pathologically confirmed advanced solid tumor refractory to prior standard therapies. Patients were treated with UTD2 monotherapy. The starting dose was 5-day 25 mg/m 2 /d for 2 patients, with planned escalation to 5-day 50, 75, 100 mg/m 2 /d and 7-day 70 mg/m 2 /d for 2, 6, 3 and 2 patients, repectively in a 21-day cycle. The primary objective was to determine DLT and the MTD. Secondary objectives included efficacy, PK profile and RP2D. Results: 18 advanced solid tumor patients were enrolled (3 didn’t complete DLT observation) with median age of 60.8 years (range 29.0-81.0), 9 females and 9 males. All patients had received prior treatment in advanced settings with maximal 9 lines. Two DLTs of Grade 3 and Grade 4 diarrhea occurred, one at 5-day 100 mg/m 2 /d and one at 7-day 70 mg/m 2 /d. Considering the total dose per cycle for both cohorts were similar, the MTD was determined to be 5-day 75 mg/m 2 /d via SMC. 11 patients were evaluated for efficacy with an outcome of 1 CR (ovarian cancer), 1 PR (ovarian cancer), 7 SD (testicular Sertoli cell tumor, NSCLC*2, pancreatic adenocarcinoma*2, appendiceal adenocarcinoma and soft tissue sarcoma), with the longest DoT of 12 cycles. The ORR was 18.2% and the CBR was 81.8%. PK results showed that the characteristics of utidelone were consistent with a two-compartment model. Compared to single-dose administration, there was no accumulation of utidelone in plasma upon multi-dose. The most frequent TEAEs were Grade 1/2, including diarrhea, fatigue, nausea, peripheral sensory neuropathy, vomiting, and decreased appetite (≥20% incidence rate), which recovered with supportive treatments. The ≥Grade 3 TRAE included diarrhea (27.8%) and fatigue (5.6%). Conclusions: This completed study demonstrates encouraging anti-tumor activity with manageable safety of UTD2 in patients with heavily pre-treated advanced solid tumors. The results support continuing development of UTD2 for the upcoming phase II/III studies for gastric and ovarian cancers. Clinical trial information: NCT05681000 .

Cannabidiol-loaded-injectable depot formulation for the treatment of triple-negative breast cancer: design, development, in-vitro and in-ovo evaluation of its anticancer activity.

Cannabidiol-loaded-injectable depot formulation for the treatment of triple-negative breast cancer: design, development, in-vitro and in-ovo evaluation of its anticancer activity.

Identification and characterization of related substances in DTX-AI via LC-QTOF-HRMS.

Identification and characterization of related substances in DTX-AI via LC-QTOF-HRMS.

Real-world outcomes and practice patterns among patients with schizophrenia when switched from oral antipsychotics to long-acting injectable formulations after hospitalization.

Real-world outcomes and practice patterns among patients with schizophrenia when switched from oral antipsychotics to long-acting injectable formulations after hospitalization.

Development and evaluation of a model characterizing the release characteristics of a new letrozole long-acting injectable formulation.

Development and evaluation of a model characterizing the release characteristics of a new letrozole long-acting injectable formulation.

Novel RP-HPLC method for quantification of peramivir and its impurity (1H-1,2,4-triazole-1-carboximidamide) in bulk and injectable preparations

This study presents a novel and robust reversed-phase high-performance liquid chromatography (RP-HPLC) method for the quantification of peramivir and its process-related impurity, 1H-1,2,4-triazole-1-carboximidamide, in bulk drug substances and injectable formulations. Chromatographic separation was achieved using an Agilent Eclipse-XDB C18 column and a mobile phase consisting of potassium dihydrogen phosphate buffer (pH 3.2) and acetonitrile in a 50:50 (v/v) ratio, at a flow rate of 1.0 mL/min. Detection was performed using a photodiode array (PDA) detector at 260 nm. The method was validated according to ICH Q2(R2) guidelines for specificity, linearity, limits of detection (LOD) and quantification (LOQ), system suitability, precision, accuracy, robustness, and stability. Results demonstrated that the method is precise, reproducible, and reliable for simultaneous estimation of peramivir and its impurity, offering significant utility for pharmaceutical quality control and research purposes.

Assessment of the Curative Anti-Glycation Properties of a Novel Injectable Formulation Combining Dual-Weight Hyaluronic Acid (Low- and Mid/High-Molecular Weight) with Trehalose on Human Skin Ex Vivo.

Glycation influences skin aging through non-enzymatic reactions between reducing sugars and proteins, forming advanced glycation end-products (AGEs) that accelerate skin deterioration. This study evaluates the curative anti-glycation effects of an injectable formulation combining dual-molecular-weight hyaluronic acid (low and mid/high) with trehalose in methylglyoxal-induced glycation in human skin explants. Thirty-six human skin explants were allocated across five experimental groups in a 12-day study. Glycation was induced using methylglyoxal (500 μM) on days 1 and 4, followed by curative product administration on day 5. CML (Nε-(carboxymethyl)lysine) immunohistochemistry was performed to assess glycation levels in the reticular dermis at days 6, 8, and 12, with quantitative analysis conducted through standardized image analysis. The formulation significantly reduced CML formation by 60% on day 6 compared to untreated controls (p < 0.001). Under methylglyoxal-induced glycation stress the product showed sustained curative effects, with CML reductions of 69% on day 6 (p = 0.008), 68% on day 8 (p = 0.012), and 61% on day 12 (p = 0.033) compared to methylglyoxal treatment alone. Cell viability remained unaffected throughout the study period across all experimental conditions. The tested injectable formulation exhibits significant and sustained curative anti-glycation properties in human skin explants for 12 days, effectively counteracting methylglyoxal-induced glycation damage without affecting cell viability. These findings advance anti-aging skin interventions, offering a novel approach to address glycation-induced skin damage with potential applications in clinical dermatology and aesthetic medicine.

Unveiling the Future: Opportunities in Long-Acting Injectable Drug Development for Veterinary Care.

Long-acting injectable (LAI) formulations have revolutionized veterinary pharmaceuticals by improving patient compliance, minimizing dosage frequency, and improving therapeutic efficacy. These formulations utilize advanced drug delivery technologies, including microspheres, liposomes, oil solutions/suspensions, in situ-forming gels, and implants to achieve extended drug release. Biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL) have been approved by the USFDA and are widely employed in the development of various LAIs, offering controlled drug release and minimizing the side effects. Various classes of veterinary medicines, including non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and reproductive hormones, have been successfully formulated as LAIs. Some remarkable LAI products, such as ProHeart® (moxidectin), Excede® (ceftiofur), and POSILACTM (recombinant bovine somatotropin), show clinical relevance and commercial success. This review provides comprehensive information on the formulation strategies currently being used and the emerging technologies in LAIs for veterinary purposes. Additionally, challenges in characterization, in vitro testing, in vitro in vivo correlation (IVIVC), and safety concerns regarding biocompatibility are discussed, along with the prospects for next-generation LAIs. Continued advancement in the field of LAI in veterinary medicine is essential for improving animal health.

Catharanthus roseus: A Multipurpose Plant with their Morphology and Dosage Form

Catharanthus roseus (L.) G. Don, Frequently known as Madagascar periwinkle, is a medicinal plant of significant therapeutic importance. Belonging to the Apocynaceae family, it is well-known for producing valuable alkaloids such as vincristine and vinblastine, which are extensively used in cancer chemotherapy. Traditionally, the plant has been used to treat ailments such as diabetes, hypertension, and microbial infections. Pharmacologically, it exhibits anticancer, antidiabetic, antimicrobial, and antioxidant activities. The plant is characterized morphologically by its glossy green leaves, pink or white flowers, and slender stems. Various dosage forms including extracts, tablets, and injectable formulations have been developed from its active constituents. Despite its medicinal benefits, C. roseus may cause side effects such as nausea, hair loss, and myelosuppression, especially when used in high doses or for prolonged periods. The diverse chemical constituents and pharmacological potential of C. roseus make it a critical plant in both traditional and modern medicine.

Quantitative 1H and 13C NMR and Chemometric Assessment of 13C NMR Data: Application to Anabolic Steroid Formulations.

This study investigates the potential of 1H and 13C NMR for the characterization and classification of anabolic androgenic steroids (AASs) in various formulations. First, twenty AAS formulations, including tablets, capsules, and injectable solutions, were analyzed using 1H NMR for the qualitative identification and quantification of active compounds. The results revealed discrepancies between the labeled and detected substances in several samples, highlighting issues related to product mislabeling and potential health risks. Then, twelve oil-based injectable formulations were examined using 13C NMR, demonstrating its effectiveness in differentiating and quantifying closely related steroid structures that cannot be discriminated with 1H NMR. A chemometric approach from 13C NMR data, based on a principal component analysis (PCA) and hierarchical cluster analysis (HCA), enabled the classification of samples and the identification of key active ingredients.

Study of Folate-Modified Carboxymethyl Chitosan-Sinomenine-Curcumin Nanopolymer for Targeted Treatment of Rheumatoid Arthritis.

Sinomenine hydrochloride (SH) has been clinically utilized for many years to treat rheumatoid arthritis (RA) in both oral and injectable forms. However, its low bioavailability, poor targeting, high dosage requirements, and side effects, present significant challenges. This study developed folic acid-carboxymethyl chitosan-modified sinomenine-curcumin nanopolymers (named SCNP) for the targeted treatment of RA, to reduce dosage and side effects. The design of SCNP employs folic acid (FA) as a targeting moiety, facilitating specific binding to the folate receptor (FR) on the surface of macrophages and enabling internalization into activated macrophages via endocytosis, thereby achieving targeted delivery to sites of inflammation. In a rat and cell model of RA, SCNP was found to decrease reactive oxygen species (ROS) and pro-inflammatory factors while increasing the anti-inflammatory factor IL-10 through the NF-κB/NLRP3 pathway. These findings indicate that SCNP has the potential to lower drug dosage, enhance therapeutic efficacy, and minimize side effects such as diarrhea and rash, thereby highlighting its promise as an inflammation-targeting nanopolymer.

Prevalence of Bisphosphonate and Denosumab Use in Elderly Care Facilities: Implications for the Management of Medication-Related Osteonecrosis of the Jaw.

Our group is investigating the contribution of pharmacists in reducing medication-related osteonecrosis of the jaw (MRONJ) associated with bisphosphonates (BPs) and denosumab (Dmab). Recently, our group encountered a case of MRONJ occurring in an elderly care setting. The aim of this study was therefore to investigate the actual use of BP and Dmab and the incidence of MRONJ in elderly care facilities. We also discussed measures for the prevention and early detection of MRONJ by dentists and pharmacists associated with these facilities. A cross-sectional survey across four elderly care facilities (including the one where the case occurred) was conducted to determine the prevalence of BP and Dmab use and related factors, as well as the incidence of MRONJ. Among 327 residents, 9.8% (32) were receiving BP or Dmab therapy (84.4% oral, 15.6% injectable). The encountered MRONJ case was the only one identified, occurring in a resident using injectable BP. In these elderly facilities, 9.8% of residents used BPs or Dmab, with 15.6% receiving injectable formulations. One MRONJ case occurred with injectable BP use, suggesting the potential for sporadic MRONJ in elderly care. As BP/Dmab use is likely to increase, pharmacist intervention for prescription review and training for visiting dentists are considered effective strategies for MRONJ prevention and early detection.

Studies on Formulations from a Clinical Perspective

This review highlights the author's research conducted at Mukogawa Women's University from April 2002 to March 2024. The work is categorized into following three areas: (1) Evaluation of the bitterness of oral medications using a taste sensor, (2) Development of drug delivery systems utilizing poly(lactic-co-glycolic acid) (PLGA), and (3) Clinical pharmaceutical evaluation of various injectable formulations. In section (1), the bitterness of oral medications, both alone and in combination with food or beverages, was quantitatively assessed. The taste sensor demonstrated high predictive accuracy, with a significant correlation observed between the sensor's bitter-sensitive outputs and the human taste receptor hT2R14, as documented in BitterDB. Recently, an innovative taste sensor featuring lipid/polymer membranes modified with 2,6-dihydroxybenzoic acid (2,6-DHBA), based on an allosteric mechanism, was developed to improve the detection of bitterness in non-charged compounds. In section (2), PLGA microspheres were engineered for the sustained release of prostaglandin derivatives over one month. Furthermore, polymeric micelles under 100 nm in diameter, composed of PLGA and LL-12 (a mutated fragment of human cathelicidin peptide), exhibited potent antibacterial activity and inhibited the proliferation of various cancer cells. Section (3) focuses on injectable formulations, including the development of a quantitative predictive system to evaluate the risk of insoluble particle formation when mixing ceftriaxone with calcium-containing injections. Additionally, the use of minimum inhibitory concentration (MIC) values and nomograms was explored to predict the clinical efficacy of imipenem derivatives. This research significantly contributes to enhancing the safety and efficacy of clinical treatments for patients.

An injectable in situ gel formed by ropivacaine with small lipid molecules to achieve long-term postoperative analgesia.

An injectable in situ gel formed by ropivacaine with small lipid molecules to achieve long-term postoperative analgesia.

Molecular mechanisms of andrographolide-induced kidney injury and senescence via SIRT3 inhibition.

Molecular mechanisms of andrographolide-induced kidney injury and senescence via SIRT3 inhibition.

Ocular Drug Delivery: Emerging Approaches and Advances.

Complex anatomical and physiological barriers make the eye a challenging organ to treat from a drug delivery perspective. Currently available treatment methods (topical eyedrops) for anterior segment diseases pose several limitations in terms of bioavailability and patient compliance. Conventional drug delivery methods to treat posterior segment ocular diseases are primarily intravitreal injection (IVT) of solutions. IVT is highly invasive and leads to retinal toxicity, endophthalmitis, and intraocular inflammation, frequently requiring professional administration and frequent clinical visits. Advanced drug delivery treatment strategies could improve patient compliance and convenience. Long-acting drug delivery platforms (biodegradable or nonbiodegradable) provide sustained/controlled release of drugs for at least four to six months. Smart drug delivery alternatives, for instance, in situ forming implants, are injectable formulations that form semisolid-to-solid implants in response to the various stimuli of pH, light, osmolarity, and temperature. Additionally, nanoparticulate drug delivery systems, contact lenses, electrospun patches, and microneedle-based drug delivery systems provide minimally invasive treatment options for ocular disorders. This comprehensive review focuses on advanced drug delivery options for the management of ocular disorders.

Long-acting glucose-responsive insulin with swift onset-of-action.

Long-acting glucose-responsive insulin with swift onset-of-action.

Preparation and comprehensive preclinical study of Peramivir inhalation solution: Achieving accurate drug delivery.

Preparation and comprehensive preclinical study of Peramivir inhalation solution: Achieving accurate drug delivery.

Phase 1 Study Evaluating the Pharmacokinetics, Dose Proportionality, Bioavailability, and Tolerability of Subcutaneous Levothyroxine Sodium (XP-8121).

Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food/drug interactions, and patient adherence. XP-8121 (levothyroxine for subcutaneous administration) is a ready-to-use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single-center, 2-part study aimed to characterize the PK and dose proportionality of XP-8121 SC compared to 600 μg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP-8121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open-label, crossover, fixed-sequence study (n = 30). Dose linearity was evaluated by escalating XP-8121 SC doses up to 1200 μg. Part 2 was an open-label, single-period study (n = 30) evaluating PK characteristics of a single dose of XP-8121 SC (1500 μg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline-adjusted levothyroxine concentration increased rapidly in plasma (Tmax median: 3.1 h); absorption for all XP-8121 SC doses was slower compared to 600 μg oral levothyroxine, and levels remained elevated for 4-5 days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP-8121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUCss). Overall, these data for XP-8121 provide adequate predictive performance to inform future phase 2 studies.