An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits

Abstract Background Metformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile. Results Metformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution. Conclusions Metformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.

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Potential of Sustained Release Microparticles of Metformin in Veterinary Medicine: An in Vivo Pharmacokinetic Study of Metformin Microparticles as Oral Sustained Release Formulation in Rabbits.

10.21203/rs.3.rs-80177/v1 ◽

2020 ◽

Author(s):

Sihem Bouriche ◽

Angela Alonso-García ◽

Carlos M Cárceles-Rodríguez ◽

Farouk Rezgui ◽

Emilio Fernández-Varón

Keyword(s):

Veterinary Medicine ◽

Sustained Release ◽

Pharmacokinetic Study ◽

Half Life ◽

Physicochemical Characterization ◽

Absolute Bioavailability ◽

Poly Lactic Acid ◽

Metformin Hydrochloride ◽

Sustained Release Formulation

Abstract Background: Metformin hydrochloride a biguanide derivative has been widely used in the treatment of type 2 diabetes in humans. In veterinary medicine, metformin has been increasing his potential in different species as equids for insulin dysregulation, dogs and cats with diabetes. It is a highly soluble hydrophilic drug, shows incomplete absorption from the gastrointestinal tract and the absolute bioavailability is 40-60 % with a short biological half-life of 1.5-1.6 h in humans. In this study, to improve its efficacy a sustained-release microparticles of metformin was developed by loading within poly lactic acid (PLA) polymer followed by an in vivo pharmacokinetics study in rabbits. Results: Pharmacokinetic study in rabbits showed the sustained-release characteristic from the prepared microparticles with delayed time to reach maximum concentrations Tmax, decreased Cmax, increased Mean Residence Time (MRT) and half-life compared to the pure drug solution. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonds and that the drug was transformed to an amorphous state. Conclusions: The The pharmacokinetics parameters resulted in delayed Tmax, increased MRT and t1/2, decreased Cmax of metformin from microparticles that show promise for prolonged/sustained release of metformin after oral administration in different animal species affected by insulin disorders. PLA microparticles provided sustained release of the drug, and these systems can be useful as drug carriers for hydrophilic drugs in long term disease treatment such as diabetes.

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Abstract #64: A Comparative Pharmacokinetic Study of Metformin Hydrochloride Oral Solution (100 mg/mL) in Healthy Adult Male Patients Under Fasting, Low-Fat, and High-fat Meal Conditions

Endocrine Practice ◽

10.1016/s1530-891x(20)46341-4 ◽

2004 ◽

Vol 10 ◽

pp. 23

Author(s):

Kiran Marthak

Keyword(s):

Adult Male ◽

Pharmacokinetic Study ◽

Healthy Adult ◽

Oral Solution ◽

Metformin Hydrochloride ◽

High Fat ◽

Comparative Pharmacokinetic ◽

Healthy Adult Male ◽

Male Patients ◽

Fat Meal

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Formulation and Evaluation of Itopride Hydrochloride Floating Beads for Gastroretentive Delivery

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2013.6.4.10 ◽

2013 ◽

Vol 6 (4) ◽

pp. 2269-2280

Author(s):

Nagratna Dhople ◽

P N Dandag ◽

A P Gadad ◽

C K Pandey ◽

Masthiholimath V S

Keyword(s):

Sustained Release ◽

In Vitro Release ◽

Entrapment Efficiency ◽

Sustained Release Formulation ◽

Prokinetic Drug ◽

Drug Entrapment Efficiency ◽

Itopride Hydrochloride ◽

Vitro Release

A gastroretentive sustained release system of itopride hydrochloride was formulated to increase the gastric residence time and modulate its release behavior. Itopride hydrochloride is a prokinetic drug used in the treatment of gastroeosophageal reflux disease, Non-ulcer dyspepsia and as an antiemetic. Hence, itopride hydrochloride beads were prepared by emulsion gelation method by employing low methoxy pectin and sodium alginate as sustained release polymers in three different ratios alone and in combination and sunflower oil was used to enable floating property to the beads. The effect of variation in polymer and their concentration was investigated. The beads were evaluated for production yield, particle size, swelling index, density measurement, buoyancy, drug content, drug entrapment efficiency, in vitro release characteristics and release kinetic study. Based on drug entrapment efficiency, buoyancy, swelling and in vitro release, F9 was selected as the optimized formulation. F9 was further subjected to surface morphology by SEM, in vitro release comparison with marketed formulation, in vivo floating study in rabbits and stability study for 90 days. In vitro release follows zero order and fitted in Korsmeyer peppas model (Non-Fickian release). Therefore, the rate of drug release is due to the combined effect of drug diffusion and polymer swelling. The in vivo X-ray studies revealed that the beads were floating in the rabbit stomach up to 10 hours. Thus, it was concluded that the sustained release formulation containing itopride hydrochloride was found to improve patient compliance, minimize the side effects and decrease the frequency of administration.

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The absolute bioavailability of an oral sustained-release formulation of desvenlafaxine succinate in healthy subjects

Clinical Pharmacology & Therapeutics ◽

10.1016/j.clpt.2004.12.071 ◽

2005 ◽

Vol 77 (2) ◽

pp. P47-P47 ◽

Cited By ~ 6

Author(s):

V PARKER ◽

L RICHARDS ◽

A NICHOLS ◽

J BEHRLE ◽

R FRUNCILLO

Keyword(s):

Sustained Release ◽

Healthy Subjects ◽

Absolute Bioavailability ◽

Release Formulation ◽

Sustained Release Formulation ◽

The Absolute

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In vitro and in vivo Studies of a New Sustained Release Formulation of Morphine

Arzneimittelforschung ◽

10.1055/s-0031-1296566 ◽

2011 ◽

Vol 58 (12) ◽

pp. 647-652

Author(s):

Amparo Araíco ◽

Francisca Torres-Molina ◽

Anas Saadeddin ◽

Jaime Cárcel-Trullols ◽

Josefa Alvarez-Fuentes ◽

...

Keyword(s):

Sustained Release ◽

In Vivo Studies ◽

Release Formulation ◽

Sustained Release Formulation

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Formulation Development and Evaluation of Sustained Release Matrix Tablets of Guaiphenesin

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2016.9.3.7 ◽

2016 ◽

Vol 9 (3) ◽

pp. 3312-3316

Author(s):

Ganesh D. Basarkar ◽

Ketan H. Shah ◽

Madhuri B. Sonawane

Keyword(s):

Drug Release ◽

Sustained Release ◽

Rice Bran ◽

Half Life ◽

Water Soluble ◽

Matrix Tablet ◽

Formulation Development ◽

Sustained Release Formulation ◽

Rice Bran Wax ◽

Melt Granulation

In this study we sought to formulate and evaluate sustained release matrix tablet of guaiphenesin by melt granulation technology. The sustained release tablets were prepared by melt granulation technique using rice bran wax as a drug retardant and dibasic calcium phosphate (DCP) as a channelling agent. Guaiphenesin is an expectorant and has a short plasma half-life of one hour. Because of high frequency of administration and short biological half-life, guaiphenesin was considered as model drug. Sustained release formulation that would maintain plasma levels for 12 hours is sufficient for twice daily dosing of guaiphenesin. The compatibility of drug and wax was examined by differential scanning calorimetry (DSC). The effect of waxes at different (drug: wax) concentrations on the release profile of drug from matrix formulation were studied. Drug release was studied at pH 1.2 for 2 hour and pH 6.8 for 10 hours. A significant retardation in the drug release was observed by increasing the wax concentration. The drug release study revealed that wax concentration of 30% to be optimum. Dissolution study showed 99% drug release within 12 hrs. Kinetic modelling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. These results suggest that the rice bran wax has good release retardant property for highly water-soluble drug such as guaiphenesin.

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Pharmacokinetics of Immediate and Sustained Release Cephalexin Administered by Different Routes to Llamas (Lama glama)

Advances in Pharmacological Sciences ◽

10.1155/2016/4621039 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Verónica Kreil ◽

Luis Ambros ◽

Ana Paula Prados ◽

Lisa Tarragona ◽

Agustina Monfrinotti ◽

...

Keyword(s):

Sustained Release ◽

Immediate Release ◽

Effective Dosage ◽

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Release Formulation ◽

Sustained Release Formulation ◽

E Coli ◽

Routes Of Administration ◽

Elimination Half

We investigate the pharmacokinetics of two different cephalexin formulations administered to llamas by the intravenous (IV), intramuscular (IM), and subcutaneous (SC) routes, the minimum inhibitory concentration (MIC) of cephalexin against someEscherichia coliand staphylococci isolated from llamas, and we apply the PK/PD modelling approach, so that effective dosage recommendations for this species could be made. Six llamas received immediate (10 mg/kg, IV, IM, and SC) and sustained (8 mg/kg IM, SC) release cephalexin. Pharmacokinetic parameters were calculated by noncompartmental approach. Immediate release SC administration produced a significantly longer elimination half-life as compared with the IV and IM administration (1.3±0.2versus0.6±0.1and0.6±0.1 h, resp.) and higher mean absorption time as compared with the IM administration (1.7±0.5versus0.6±0.4 h). Absolute bioavailability was in the range of 72–89% for both formulations and routes of administration. Cephalexin MIC90values against staphylococci andE. coliwere 1.0 and 8.0 μg/mL, respectively. Our results show that the immediate release formulation (10 mg/kg) would be effective for treating staphylococcal infections administered every 8 h (IM) or 12 h (SC), whereas the sustained release formulation (8 mg/kg) would require the IM or SC administration every 12 or 24 h, respectively.

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