The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices.

The present invention provides compositions comprising an anti-angiogenic factor, and a polymeric carrier. Representative examples of anti-angiogenic factors include Anti-Invasive Factor, Retinoic acids and derivatives thereof, and paclitaxel. Also provided are methods for embolizing blood vessels, and eliminating biliary, urethral, esophageal, and tracheal/bronchial obstructions.

Anti-angiogenic compositions and methods of use

Protein release from gelatin matrices

Controlled release from biodegradable polymers is a novel approach to replace daily painful injections of protein drugs A major obstacle to development of these polymers is the need to retain the structure and biological activity of encapsulated proteins during months of incubation under physiological conditions We encapsulated bovine serum albumin (BSA) in injectable poly(DL-lactide- co-glycolide) (PLGA) 50/50 cylindrical implants and determined the mechanism of BSA instability Simulations of the polymer microclimate revealed that moisture and acidic pH (<3) triggered unfolding of encapsulated BSA, resulting in peptide bond hydrolysis and noncovalent aggregation To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polyester, we coincorporated into the polymer an antacid, Mg(OH)2, which increased microclimate pH and prevented BSA structural losses and aggregation for over one month We successfully applied this stabilization approach in both cylinder- and microsphere-injectable configurations and for delivery of angiogenic basic fibroblast growth factor and bone-regenerating bone morphogenetic protein-2

Stabilization of proteins encapsulated in injectable poly (lactide-co-glycolide)

Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing l-analogue amino acids with d-amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG2,40 K conjugate of INF-α-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.

Strategies to improve plasma half life time of peptide and protein drugs

To obtain a three-month release injection of leuprorelin acetate, microspheres were prepared with copoly(DL-lactic/glycolic acid) or poly(DL-lactic acid) (PLA) using an in-water drying method, and drug release was evaluated. The content of water-soluble oligomers in the polymers was found to strongly affect the initial burst, and reducing the content to less than 0.1% was necessary to keep the first-day release below 10%. Drug loading of more than 15% also increased the initial drug release; the acceptable maximum loading was 12%. Elevation of the glass transition temperature of the microspheres was observed with an increase in drug loading. This suggests formation of a rigid structure, possibly with arrangement of the polymer around the drug cores like in a micelle. This structure provides a hydrophobic barrier against diffusion of the hydrophilic peptide, resulting in high trapping efficiency and long-term sustained release dependent on polymer erosion. The microspheres prepared with PLA having a m.w. of 12,000 to 18,000 provided linear sustained release and persistent serum levels of the drug in rats for over 3 months.

Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers

Introduction: Ramelteon (TAK-375) is an MT 1 /MT 2 receptor agonist being studied for the treatment of insomnia and circadian rhythm sleep disorders. We compared the behavioral effects of ramelteon and exogenous melatonin in freely moving cats. Methods: Ramelteon and melatonin were each suspended in a 0.5% (weight per volume) methylcellulose solution and administered orally to freely moving cats. In the control trial, each cat was given vehicle. Each dose of ramelteon or melatonin was compared with the vehicle control in a crossover design. Electroencephalogram, electromyogram, and electrooculogram recordings were assessed. Results: Ramelteon significantly decreased wakefulness at doses of 0.001, 0.01, and 0.1 mg/kg, increased slow-wave sleep at doses of 0.001, 0.01, and 0.1 mg/kg, and increased rapid eye movement sleep at a dose of 0.1 mg/kg, compared with the vehicle controls, as assessed by analysis of variance. The effects of ramelteon lasted for up to 6 hours when evaluated by reduction of wakefulness. Exogenous melatonin (0.01-1 mg/kg) significantly increased slow-wave sleep, but the effect was weaker than that of ramelteon and lasted for only 2 hours. The lowest doses of ramelteon (0.0001 mg/kg) and melatonin (0.001 mg/kg) had no significant effect on sleep-wakefulness stage. Conclusions: Ramelteon was more effective than exogenous melatonin in promoting and maintaining sleep in freely moving cats. Based on its unique mechanism of action, ramelteon should be studied further to evaluate its potential for the treatment of sleep disorders.

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The sleep-promoting action of ramelteon (TAK-375) in freely moving cats.

The pharmacological effects of leuprorelin three-month depot microspheres were investigated in rats and dogs. After s.c. and i.m. injection, the microspheres provided similar linear drug release and sustained serum drug levels for 3 months. Persistent suppression of serum LH, FSH (in rats) and testosterone (in rats and dogs) for over 16 weeks was achieved when the microspheres were given at a dose of 100 (rat) and 25.6 (dog) micrograms/kg/day. These hormone release responses upon periodic challenge tests revealed that a single injection of the microspheres caused dramatic suppression of the function of the pituitary-gonadal system for 15 weeks in rats. The growth of the genital organs was also suppressed dose-dependently by injection of the microspheres over 3 months; the strongest suppression was achieved at a dose of 100 micrograms/kg/day. This three-month depot formulation is expected to be more convenient than the one-month depot with improved patient compliance and therapeutic effects.

Sustained suppression of the pituitary-gonadal axis by leuprorelin three-month depot microspheres in rats and dogs

Persistent suppression of the pituitary‐gonadal system in female rats by three‐month depot injectable microspheres of leuprorelin acetate

PROBLEM TO BE SOLVED: To obtain a controlled release preparation which can be stored long term at room temperature by suppressing the coagulation of a microsphere by adding a specific amount of saccharide and heating when frozen drying the microsphere of a medicine using an in vivo degradable polymer SOLUTION: This preparation is obtained by frozen drying a microsphere obtained from a water in oil type emulsion containing a solution of a bioactive peptide, an inner water phase, and polylactic acid having approximately 5000-25000 of weight average molecular weight, as oil phase, after adding approximately 2-60wt% of saccharide Then heated at the temperature approximately 20 degC higher than the glass transition temperature of the microsphere for about 24-120 hours The peptides of the formula [R1 is His, Tyr, etc, R2 is Tyr, etc, R3 is Gly, etc, R4 is Leu, etc, R5 is Gly-NH-R6 (R6 is H, an alkyl), etc] or its salt is preferable as the bioactive peptide D-mannitol, sodium alginate, fructose, dextrin, dextran, sucrose, sorbitol, etc, is preferred as saccharide

Yayoi Doken

Papers

Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers

The sleep-promoting action of ramelteon (TAK-375) in freely moving cats.

Sustained suppression of the pituitary-gonadal axis by leuprorelin three-month depot microspheres in rats and dogs

Persistent suppression of the pituitary‐gonadal system in female rats by three‐month depot injectable microspheres of leuprorelin acetate

Production of controlled release preparation for injection