An investigation into the influence of drug lipophilicity on the in vivo absorption profiles from subcutaneous microspheres and in situ forming depots

Deadman, Claire Michelle; Kellaway, I.W.; Yasin, M.al-muzzammil; Dickinson, Paul; Murdan, Sudaxshina

doi:10.1016/j.jconrel.2007.06.013

Cited by 16 publications

(6 citation statements)

References 13 publications

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“…Deadman et al 35 defined the initial burst release as the percent of total drug released in the first 24 hours. Different researchers evaluated the drug initial burst by estimating the amount released at the first 24–48 hours.…”

Section: Resultsmentioning

confidence: 99%

Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

Ahmed¹,

Alharby²,

El-Helw³

et al. 2016

DDDT

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This study aimed to develop an optimized depot injectable atorvastatin (ATR) biodegradable in situ gel (ISG) system with minimum initial burst using a central composite design. The factors selected were poly (d, l-lactide-co-glycolide) (PLGA) concentration (X1), molecular weight of polyethylene glycol (PEG) (X2), and PEG concentration (X3). The independent variables were the initial burst of ATR after 2 (Y1) and 24 hours (Y2). The optimized formulation was investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, and in vitro drug release in phosphate-buffered saline of pH 7.4 for 72 hours. The in vivo pharmacokinetic study of the optimized ATR-ISG and the corresponding PEG-free ATR-ISG were conducted by intramuscular injection of a single dose (2 mg/kg) of ATR in male New Zealand White rabbits. A double-blind, randomized, parallel design was used in comparison with those of the marketed ATR tablet. Statistical analysis revealed that PLGA concentration and the molecular weight of PEG have pronounced effects on both Y1 and Y2. The optimized formulation was composed of 36.10% PLGA, PEG 6000, and 15.69% PEG, and exhibited characteristic in vitro release pattern with minimal initial burst. Incorporation of PEG in the formulation causes a slight decrease in the glass transition temperature value of PLGA, leading to a slight change in Fourier transform infrared spectroscopy spectrum due to possible interaction. Moreover, scanning electron microscopy photomicrograph showed smooth surface with disappearance of the cracks which characterize the surface of PEG-free formulation. The pharmacokinetic data for the optimized depot injectable ATR-ISG showed a significant (P<0.05) decrease in maximum plasma concentration from 547.62 to 346.84 ng/mL, and increasing time to reach the maximum plasma concentration from 12 to 72 hours in comparison with the marketed tablet. The optimized ATR-ISG formulation has shown minimal initial drug burst which confirms the suitability of the ISG system in the prolongation of drug release in patients with chronic long-term therapy.

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Section: Resultsmentioning

confidence: 99%

Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

Ahmed¹,

Alharby²,

El-Helw³

et al. 2016

DDDT

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“…The added aspect of microsphere matrix erosion at the injection site may be controlled by chemical parameters, such as polymer or copolymer functionality and polymer-drug interactions, and physical properties such as molecular weight, dispersity, microsphere porosity and diameter, degree of crystallinity, glass transition temperature, hydrophilicity and drug distribution throughout the microsphere [56-58]. Despite these variables, initial burst release profiles are often seen from microsphere injections [59] with further identifiable stages of slow and sustained release and a later stage acceleration as the microsphere degrades [60, 61]. …”

Section: Technologies That Have Been Clinically Successful For La mentioning

confidence: 99%

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

119

102

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Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

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“…The initial large bonus of drug can result in tissue irritation and even systemic toxicity, also reduced the effective lifetime of implants. The delay between administration and depot formation has been regarded as the chief cause of burst release [9]. Many methods, such as quantitative ultrasound (QUS), photoacoustic (PA) imaging and UV-vis imaging, have been used to monitor the phase separation of ISFIs [10,11].…”

Section: Introductionmentioning

confidence: 99%

Effect of Polymer Permeability and Solvent Removal Rate on In Situ Forming Implants: Drug Burst Release and Microstructure

Zhang

Yang²,

Zhang³

et al. 2019

Pharmaceutics

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To explore the mechanism of drug release and depot formation of in situ forming implants (ISFIs), osthole-loaded ISFIs were prepared by dissolving polylactide, poly(lactide-co-glycolide), polycaprolactone, or poly(trimethylene carbonate) in different organic solvents, including N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and triacetin (TA). Drug release, polymer degradation, solvent removal rate and depot microstructure were examined. The burst release effect could be reduced by using solvents exhibit slow forming phase inversion and less permeable polymers. Both the drug burst release and polymer depot microstructure were closely related to the removal rate of organic solvent. Polymers with higher permeability often displayed faster drug and solvent diffusion rates. Due to high polymer-solvent affinity, some of the organic solvent remained in the depot even after the implant was completely formed. The residual of organic solvent could be predicted by solubility parameters. The ISFI showed a lower initial release in vivo than that in vitro. In summary, the effects of different polymers and solvents on drug release and depot formation in ISFI systems were extensively investigated and discussed in this article. The two main factors, polymer permeability and solvent removal rate, were involved in different stages of drug release and depot formation in ISFI systems.

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An investigation into the influence of drug lipophilicity on the in vivo absorption profiles from subcutaneous microspheres and in situ forming depots

Cited by 16 publications

References 13 publications

Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Effect of Polymer Permeability and Solvent Removal Rate on In Situ Forming Implants: Drug Burst Release and Microstructure

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