Guru V. Betageri

Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques

Abstract Glyburide (GLY) is an oral hypoglycemic agent that is poorly soluble in water. The present study describes the preparation of solid dispersions and lyophilization of the dispersions designed to increase the solubility. Solid dispersions of GLY were prepared using polyethylene glycol 4000 (PEG 4000), PEG 6000 and a mixture of PEG 4000 and PEG 6000 (h1 mixture). The effect of melt and solvent methods of preparation of solid dispersion on dissolution behavior was also investigated. Dissolution studies indicated a significant increase in dissolution of GLY when dispersed in PEGs. Physical mixtures containing PEGs also showed improved dissolution of GLY as compared with that of pure drug, indicating the solubilizing effect of PEGs. Solid dispersions containing GLY/PEG 6000, 1:8, showed a 14-fold increase in dissolution after 60 min (D60) and another dispersion containing GLY/PEG 4000, 1:10, showed an 8-fold increase in the phosphate buffer system. The dispersion containing six parts of the PEG mixture (PEG 4000/PEG 6000, 1:1 mixture) showed a 12-fold increase in D60 as compared with pure drug. When multi-carrier solid dispersion containing six parts of mixture was prepared by the solvent method, the D60 value was about 2-fold that of the same dispersion prepared by the melt method. The dissolution of lyophilized solid dispersions further increased the dissolution of GLY significantly.

Factors affecting microencapsulation of drugs in liposomes

Liposomes have been used as carriers for drugs, toxins, enzymes, proteins/peptides and other bioactive materials there are several liposomal formulations that are being investigated in preclinical and clinical trials. Achieving high encapsulation as well as retention of the encapsulated drug is very important in developing liposomes as drug carriers. A high drug-to-lipid ratio is likely to reduce the cost of formulations and also the risk of lipid-induced toxicity following their injection. Comparison of the encapsulation efficiency of the drug in liposomes with the therapeutic dose indicates whether, in principle, liposomes can be used as a delivery system for that drug. The optimization of the liposomal encapsulation of a drug is usually based on trial and error, rather than on a thorough investigation of the factors affecting it. To obtain optimum encapsulation of a drug into a liposomal preparation, parameters influencing both the liposome and the drug need to be carefully considered during the early stages of development. In this review, factors that affect encapsulation of drugs in liposomes such as liposome size and type, charge on the liposome surface, bilayer rigidity, method of preparation, remote loading, addition of ion pairing, and complexing agents and characteristics of the drug to be encapsulated are discussed.

Drug encapsulation and release from multilamellar and unilamellar liposomes

Abstract The concept of using liposomes as carriers for the delivery of drugs is well established, and the liposomal incorporation of various molecules, including peptides and proteins, has been described. In this study, propranolol (PPL) and atenolol (ATL) were used as model drugs to measure the encapsulation efficiency and release characteristics from multilamellar (MLV) and small unilamellar (SUV) liposomes. MLVs were prepared by hydration of thin lipid films and agitation using PPL and ATL solutions in phosphate-buffered saline (pH 7.4). Unilamellar liposomes were prepared by sonicating these MLVs. The non-encapsulated drug was separated either by centrifugation (MLV) or by size exclusion chromatography (SUV). The encapsulation of ATL and PPL was higher in small unilamellar liposomes. The encapsulation of PPL was higher than ATL in multi- as well as in unilamellar liposomes. The rate of drug efflux from liposomes was determined in vitro at 37°C and pH 7.4. The maximum release of both ATL and PPL was found with DSPC MLVs and DMPC: CHOL: DCP SUVs. The liposomal encapsulation and release of drug molecules are governed by the lipophilicity of drug molecules, type of liposomes and lipid composition.

Comparative Study of Separation of Non-encapsulated Drug from Unilamellar Liposomes by Various Methods

The purpose of this study was to compare the various methods available to separate non‐encapsulated drug from large unilamellar liposomes (LUV). Multilamellar liposomes (MLV) were prepared by thin film hydration using distearoylphosphatidylcholine:cholesterol (2:1 molar ratio). MLVs were passed through a 0.2‐μm polycarbonate membrane using an extruder to prepare LUVs. Particle size of liposome preparations was characterized using a submicron particle‐size analyser. The non‐encapsulated drug was separated by: filtering through Centrifree tubes; passing through gel (Sepharose‐4B and Sephadex G‐25M); passing through minicolumn; ficoll density gradient; protamine aggregation; or dialysis.

Formulation, Characterization, and In Vitro Release of Glyburide from Proliposomal Beads

The objective of our study was to formulate and evaluate proliposomes in the form of enteric-coated beads using glyburide as a model drug. The beads were enteric coated with Eudragit L-100 by a fluidized bed coating process using triethyl citrate as plasticizer. Content uniformity of glyburide was estimated using HPLC analysis of beads dissolved in methanol. These proliposomal beads formed liposomes on disintegration in phosphate buffered saline (pH 7.4), which was confirmed by transmission electron microscopy. The dissolution study of enteric-coated beads exhibited enhanced dissolution compared with pure drug and a marketed product. Liposomes can be successfully prepared for oral administration in the form of enteric-coated beads that may offer a stable system to produce liposomes for oral administration.

Partitioning and thermodynamics of dipyridamole in the n-octanol/buffer and liposome systems

Abstract— The thermodynamics of partitioning (K) of dipyridamole has been determined in n‐octanol/buffer and liposome‐buffer systems at pH 7·4. Dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) were used to prepare multilamellar liposomes. Partitioning of dipyridamole did not depend on the amount of n‐octanol employed, however, partitioning was dependent upon the quantity of DMPC employed to prepare liposomes. Plots of log K vs 1/T were linear in the n‐octanol and liposome systems. Partitioning was generally greater in liposomes than in the n‐octanol/buffer system. Among liposomes, the partitioning was greater in DMPC liposomes at all temperatures. The values of enthalpy (ΔH) and entropy (ΔS) were positive in both the n‐octanol and liposome systems. These values were lower in DMPC liposomes and were comparable in the n‐octanol and DPPC liposomes. Thus, the interaction of dipyridamole depends on the rigidity of lipid bilayers and liposomes constitute a more selective partitioning system than the n‐octanol/buffer system.

Encapsulation, Stability and In‐vitro Release Characteristics of Liposomal Formulations of Colchicine

The severe toxicity and low therapeutic index of colchicine limit its therapeutic use. Encapsulation in liposomes might reduce these toxic effects. The objective of this study was to determine the factors influencing encapsulation of colchicine in liposomes and to optimize the encapsulation parameters.

Trends in Drug Targeting for Cancer Treatment

AbstractVarious drug delivery and targeting systems and approaches are currently utilized for cancer chemotherapy. Many drugs being developed through biotechnology are also in various stages of clinical trials. The most common approaches with drug delivery and targeting systems have been those using stealth liposomes or microspheres. Recent efforts have been made to use stealth nanoparticles for cancer drug delivery. In the next few years, it is expected that several liposomal products will be on the market. Another approach that has been utilized for some time has been the use of antibody-directed drugs or toxins. Several immunotoxins are currently in phase III trials, and efforts are being made to potentiate their activity with different potentiators. In an effort to understand the intricacies of tumor morphology and the limitations of drug targeting, various mathematical models have been proposed that help in designing appropriate delivery systems for successful tumor targeting. This review considers a...

SIMULTANEOUS HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ANALYSIS OF ACETAMINOPHEN, SALICYLAMIDE, PHENYLTOLOXAMINE, AND RELATED PRODUCTS

A stability indicating high performance liquid chromatography method has been developed for simultaneous determination of acetaminophen, salicylamide and phenyltoloxamine. The reversed-phase method utilizes UV detection at 220 nm and a C8 column. This paper presents the data to support linearity, precision, specificity, and robustness of the method. The known potential degradation products of acetaminophen, p-aminophenol, p-nitrophenol, precursor impurity p-hydroxyacetophenone, the potential degradation product of salicylamide, salicylic acid, and precursor impurity ethylsalicylate were separated for quantitation simultaneous with parent compounds. Quantification was achieved by peak area and external standard method. This method can be employed in determining stability, assay, content uniformity, and dissolution of the combination in pharmaceutical dosage forms.

Stability of antibody-bearing liposomes containing dideoxyinosine triphosphate

Abstract Liposomes bearing surface-attached antibody were prepared to study the retention of dideoxyinosine triphosphate (ddITP). Liposomes of various lipid composition were prepared and conjugated with modified mouse monoclonal antibodies. The antibody (H-2-K k ) used in this study is for Fc-mediated targeting. Antibody specificity was measured by studying the binding of antibody-liposome conjugates to antimouse IgG-Sepharose. The binding of antibody-liposome conjugates (L-Ab) was maximum when negatively charged liposomes (DMPC: CHOL: DCP) were employed. Inclusion of cholesterol to DMPC liposomes increased the binding by 4%. The binding was least when the neutral phospholipid compositions were employed (DMPC, DPPC and DMPC: CHOL) to prepare liposomes. The retention of ddITP was measured in plain liposomes and antibody-bearing liposomes stored at 4, 25 and 37°C. The leakage was maximal in DMPC liposomes. Only 20% of ddITP was retained in DMPC liposomes stored at 4°C after a month. However, when samples were stored at 25 and 37°C the retention was 12% and 4% respectively. There was no leakage of ddITP at 4 and 25°C in liposomes prepared using DMPC: CHOL (1:1 mole ratio) and DMPC: CHOL: DCP (7:2:1 mole ratio). The retention of ddITP was significantly increased in DMPC and DPPC liposomes after conjugation with antibodies. The retention of ddITP in DMPC: CHOL and DMPC: CHOL: DCP liposomes conjugated with antibodies was comparable to plain liposomes. These results suggest that the lipid composition used in the preparation of liposomes affect the conjugation of antibodies to liposomes and also the retention of an encapsulated drug.