Use of a moist granulation technique (MGT) to develop controlled-release dosage forms of acetaminophen.

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.

The effects of formulation factors on the moist granulation technique for controlled-release tablets.

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.

Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables.

A novel in situ method for the preparation of injectable biodegradable poly(lactide-co-glycolide) (PLGA) microspheres for the controlled delivery of drugs is described here. A stable dispersion of PLGA microglobules ('premicrospheres' or 'embryonic microspheres') in a vehicle mixture on injection, comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion. The effect of the following formulation variables on the characteristics of the novel drug delivery system (NDDS) was investigated: (i) the concentrations of polyethylene glycol 400 (PEG 400), the encapsulated drug, and the hydrophilic excipient (mannitol); and (ii) the types of encapsulated drug (micromolecules and macromolecules such as protein) and vehicles (replacing triacetin and Miglyol 812 by triethyl citrate and soybean oil respectively). Also, the effect of formulation, process, and storage (15 days/4 degrees C) conditions on the physical stability of the encapsulated protein was evaluated. The in vitro drug release was enhanced with decrease in the PEG 400 concentration and increase in the drug and mannitol concentration. The drug release was retarded with increase in the molecular weight of the encapsulated drug. Substitution of triacetin by triethyl citrate and miglyol 812 by soybean oil resulted in variation in the release of the drug from the in situ formed microspheres. A preliminary investigation of the physical stability of the myoglobin revealed that the alpha-helical structure was unaffected by the formulation, process, and the storage conditions.

Evaluation and comparison of a moist granulation technique to conventional methods.

In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a moisture-absorbing substance. In the experiments described below, acetaminophen (APAP) was the model drug; polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) served as the binder and moisture-absorbing material, respectively. Water was used as the granulating fluid. Comparison of the MGT with direct compression (DC) and wet granulation (WG) methods was accomplished by sieve analysis (particle size) and density measurements. Moist granulation yielded an increase in particle size compared to direct compression; these results are comparable to those from the traditional wet granulation after drying and screening. Based only on the particle size, moist granulation appears comparable to conventional wet granulation for this formula. The moist granulation technique appears to have potential for the development of controlled-release formulations.

Controlled delivery of drugs from a novel injectable in situ formed biodegradable PLGA microsphere system.

A novel method for in situ preparation of injectable biodegradable microspheres from the copolymer, poly(lactide-co-glycolide) (PLGA), without incorporating unacceptable organic solvents is described. The delivery system is a dispersion of PLGA microglobules ('premicrospheres' or 'embryonic microspheres') in an acceptable vehicle mixture (continuous phase) and whose integrity is maintained by the use of appropriate stabilizers. A solution of PLGA, triacetin, a model protein (cytochrome c), PEG 400, and Tween 80 (oil phase 1) is added dropwise with continuous homogenization to Miglyol 812-Span 80 solution (oil phase 2), thereby inducing phase separation (coacervation) of PLGA and forming PLGA microglobules (containing cytochrome c) dispersed in the continuous phase. This novel drug delivery system (NDDS) is a dispersion and has a viscous consistency, but is sufficiently syringeable. When injected, it comes in contact with water from an aqueous buffer or physiological fluid and, as a result, the microglobules harden to form solid matrix type microparticles entrapping cytochrome c (in situ formed microspheres). Cytochrome c is then released from these microspheres in a controlled fashion. The composition, rationale, and optimization of the NDDS are described here. Various formulation variables such as the PLGA concentration and type and the substitution of the continuous phase by a fresh oil phase 2 influenced the characteristics of this system. A preliminary investigation of the reproducibility and stability of the NDDS, as well as the physical stability of the encapsulated cytochrome c, revealed that these characteristics were not adversely affected.

Comparison of various injectable protein-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices: in-situ-formed implant versus in-situ-formed microspheres versus isolated microspheres.

The purpose of this research was to prepare various injectable, protein (cytochrome c)-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices by a novel microencapsulation method and to compare their characteristics. Syringeable mixtures of polymer and protein solidified upon injection when coming in contact with water, and formed a solid matrix-type implant or microspheres (in-situ-formed implant or in-situ-formed microspheres, respectively) with cytochrome c entrapped. These devices exhibited different characteristics in terms of in vitro cytochrome c release profile, percentage cytochrome c encapsulation efficiency, and particle size. The burst effect from these devices exhibited the following trend: in-situ-formed implant > in-situ-formed microspheres > isolated microspheres. The in-situ-formed microspheres were larger in size than the isolated microspheres. Also, the isolated microspheres exhibited the slowest release of cytochrome c, whereas the in-situ-formed implant exhibited the fastest release. The microencapsulation process can produce various drug-loaded injectable biodegradable PLGA devices having different characteristics.

Studies on an oral iron chelator: 1,2-dimethyl-3-hydroxy-pyrid-4-one (DMHP). Mechanism of intestinal absorption in rabbits.

Over the last 30 years, desferrioxamine has been the only iron chelator in clinical use. This chelator is expensive and must be given by injection. A new class of chelators, namely 1-alkyl-2-methyl-3-hydroxypyrid-4-ones, have been shown to be orally effective. Using 1,2 dimethyl-3-hydroxy-pyrid-4-one (DMHP), we have carried out a study to clarify the mechanism of intestinal absorption of this new class of drug, using an in-situ system of the intestine from rabbit. The major site of DMHP absorption is in the intestine and is linear with increasing drug concentration. DMHP absorption per unit length of jejunum and ileum is similar; however, due to the larger surface area of jejunum, the absorption by ileum segment is more effective per unit surface. L-Proline, L-tryptophan (amino acids), 2-deoxyglucose, and sodium iodoacetate (metabolic inhibitors) have no effect on DMHP absorption, but L-phenylalanine, an amino acid with a 6-member carbon ring, significantly inhibits the DMHP absorption from the intestinal segment. We conclude that the mechanism of DMHP absorption in the intestine is mainly by simple passive diffusion based on the linear relationship found between drug concentration and absorption. However, the inhibitive effect of L-phenylalanine suggests that the co-existence of a facilitated uptake cannot be ruled out.