A Cubic-Phase Oral Drug Delivery System for Controlled Release of AG337

AG337 is a novel thymidylate synthase inhibitor possessing potent antitumorogenic activity which was designed using protein structure-based techniques. It is currently undergoing clinical trials as both N and oral formulations. Based on AG337's short in vivo half-life, an oral controlled-release formulation is desired. The feasibility of using cubic liquid crystalline phases formed from monoolein for controlled release of AG337 has been investigated in this study. AG337 (m.p. = 298®C) was triturated with glycerol and then dissolved in monoolein using mild heat. The resulting gel was liquified by further heating to 65®C, then cooled to RT to yield a clear viscous solution. Samples of the formulation were exposed to water for up to 48 hr at 25®C. Thermal analysis of this system was undertaken in order to determine the effect of hydration state on the liquid crystalline structure. The differential scanning colorimetry (DSC) profile of samples not exposed to water showed no distinct endo- or exothermic transitions. However, samples exposed to water exhibited multiple endothermic transitions from 80° to 120°C. These data demonstrate a thermal response to time-dependent water uptake in the formulation as might occur in vivo after oral dosing, due to changes in physical properties of the system. In vitro release rates of AG337 from this formulation were evaluated.     

A Cubic-Phase Oral Drug Delivery System for Controlled Release of AG337

Abstract

AG337 is a novel thymidylate synthase inhibitor possessing potent antitumorogenic activity which was designed using protein structure-based techniques. It is currently undergoing clinical trials as both N and oral formulations. Based on AG337′s short in vivo half-life, an oral controlled-release formulation is desired. The feasibility of using cubic liquid crystalline phases formed from monoolein for controlled release of AG337 has been investigated in this study. AG337 (m.p. = 298®C) was triturated with glycerol and then dissolved in monoolein using mild heat. The resulting gel was liquified by further heating to 65®C, then cooled to RT to yield a clear viscous solution. Samples of the formulation were exposed to water for up to 48 hr at 25®C. Thermal analysis of this system was undertaken in order to determine the effect of hydration state on the liquid crystalline structure. The differential scanning colorimetry (DSC) profile of samples not exposed to water showed no distinct endo- or exothermic transitions. However, samples exposed to water exhibited multiple endothermic transitions from 80° to 120°C. These data demonstrate a thermal response to time-dependent water uptake in the formulation as might occur in vivo after oral dosing, due to changes in physical properties of the system. In vitro release rates of AG337 from this formulation were evaluated.     

Controlled Drug Delivery Systems Based on Thiolated Chitosan Microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.     

Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

Buccal Drug Delivery Systems

Abstract

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Mucoadhesive Drug Delivery Systems

Pharmaceutical aspects of mucoadhesion have been the subject of great interest during recent years because mucoadhesion could be a solution for bioavailability problems that result from a too short length of stay of the pharmaceutical dosage form at the absorption site within the gastro-intestinal tract.

This paper describes some aspects of bioadhesion such as mucus structure, stages of adhesion and the theories proposed that attempt to explain the adhesion mechanism. The factors that affect the bioadhesive power of a polymer, the methods that permit the evaluation of a bioadhesive system and the methods for surface characterization of biomaterials are discussed. Finally, the various polymers used and the bioadhesive systems designed for several therapeutic purposes are presented.     

A Diffusion Controlled Drug Delivery System for Theophylline

Abstract

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.     

A Diffusion Controlled Drug Delivery System for Theophylline

The goal of achieving ideal attributes of a drug delivery system including reliability and predictability has led investigators to design controlled release (CR) systems based on the principles of microporous coatings, diffusion controlled coatings and various hydrogel type systems.

In this study, the critical role of “water content fraction” of a polymer in deciding its diffusion characteristics has been ascertained and the correlation between molecular size/shape, membrane thickness, pore radii and drug diffusion has also been demonstrated. The theoretical considerations, designing and engineering of a “barrier coated-reservoir” type of a delivery system for theophylline using poly (vinyl alcohol) [PVA] as the coating material are discussed. After realizing the desired theoretical in-vitro release profile, in-vivo studies were carried out on a dog model. The potential of poly (vinyl alcohol) as a barrier coating material in developing a CR system is interestingly observed.     

Mucoadhesive Drug Delivery Systems

Abstract

Pharmaceutical aspects of mucoadhesion have been the subject of great interest during recent years because mucoadhesion could be a solution for bioavailability problems that result from a too short length of stay of the pharmaceutical dosage form at the absorption site within the gastro-intestinal tract.

This paper describes some aspects of bioadhesion such as mucus structure, stages of adhesion and the theories proposed that attempt to explain the adhesion mechanism. The factors that affect the bioadhesive power of a polymer, the methods that permit the evaluation of a bioadhesive system and the methods for surface characterization of biomaterials are discussed. Finally, the various polymers used and the bioadhesive systems designed for several therapeutic purposes are presented.     

Mucoadhesive Drug Delivery Systems

Mucoadhesion in drug delivery systems has recently gained interest among pharmaceutical scientists as a means of promoting dosage form residence time as well as improving intimacy of contact with various absorptive membranes of the biological system. Besides acting as platforms for sustained-release dosage forms, bioadhesive polymers can themselves exert some control over the rate and amount of drug release, and thus contribute to the therapeutic advantage of such systems. This paper describes some aspects of bioadhesion such as mucus layer, mucoadhesion, and theories of bioadhesion to explain the adhesion mechanism. The factors important to mucoadhesion, the methods used to study bioadhesion, and bioadhesive polymers are described. The methods that evaluate the mucoadhesive dosage forms and finally the bioadhesive drug delivery systems designed for several therapeutic purposes are presented.     

Buccal Drug Delivery Systems

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Latex Film Matrix Systems with a Concentration Gradient for Controlled Drug Delivery

Latex film matrix systems with a nonuniform drug distribution were prepared by a coating process. In this process a drug concentration gradient in the coating dispersion was generated by the programmable pumping of the latex into a drug reservoir which contained the drug and latex. The film matrix formed by the dispersion would have a built-in drug concentration gradient as the coating process proceeded. A mathematical model was developed to describe the concentration change of the active ingredient in the coating dispersion as a function of the spraying rate of the coating dispersion, the pumping rate of the latex into the drug reservoir, and the initial drug concentration in the dispersion. The applicability of this process was demonstrated by the controlled in vitro dissolution of acetaminophen from ethylcellulose latex film matrices formed on glass beads. The release profile of the active ingredient from the systems changed as the drug concentration gradient profile in the matrix was altered, and a higher drug concentration gradient in the matrix resulted in a slower release rate and a more linear release profile. A faster drug release rate can also be achieved by incorporating a highly water soluble ingredient in the concentration gradient matrix.     

Latex Film Matrix Systems with a Concentration Gradient for Controlled Drug Delivery

Abstract

Latex film matrix systems with a nonuniform drug distribution were prepared by a coating process. In this process a drug concentration gradient in the coating dispersion was generated by the programmable pumping of the latex into a drug reservoir which contained the drug and latex. The film matrix formed by the dispersion would have a built-in drug concentration gradient as the coating process proceeded. A mathematical model was developed to describe the concentration change of the active ingredient in the coating dispersion as a function of the spraying rate of the coating dispersion, the pumping rate of the latex into the drug reservoir, and the initial drug concentration in the dispersion. The applicability of this process was demonstrated by the controlled in vitro dissolution of acetaminophen from ethylcellulose latex film matrices formed on glass beads. The release profile of the active ingredient from the systems changed as the drug concentration gradient profile in the matrix was altered, and a higher drug concentration gradient in the matrix resulted in a slower release rate and a more linear release profile. A faster drug release rate can also be achieved by incorporating a highly water soluble ingredient in the concentration gradient matrix.     

Design and in Vitro Evaluation of a Controlled Release Drug Delivery System of Sulfasomidine

A controlled release oral drug delivery system of Sulfasomidine was developed by spray congealing micropelleting technique using gelatin as the embedding matrix. The pellets were hardened by treating with Formalin-Isopropanol mixture. The in vitro release rate studies of Sulfasomidine from the micropelleted dosage form, revealed that the drug release can be prolonged upto eight hours and not more than 39% of the embedded drug released in the first hour of the in vitro dissolution study. The in vitro release patterns correlated with the reported in vivo studies. The method of formulation was optimized.     

Design and in Vitro Evaluation of a Controlled Release Drug Delivery System of Sulfasomidine

Abstract

A controlled release oral drug delivery system of Sulfasomidine was developed by spray congealing micropelleting technique using gelatin as the embedding matrix. The pellets were hardened by treating with Formalin-Isopropanol mixture. The in vitro release rate studies of Sulfasomidine from the micropelleted dosage form, revealed that the drug release can be prolonged upto eight hours and not more than 39% of the embedded drug released in the first hour of the in vitro dissolution study. The in vitro release patterns correlated with the reported in vivo studies. The method of formulation was optimized.     

Osmotically Controlled Oral Drug Delivery*

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Oral Bioadhesive Drug Delivery Systems

The oral mucosal cavity is a feasible, safe, and very attractive site for drug delivery with good acceptance by users. The mucosa is relatively permeable and robust, shows short recovery times after stress or damage, is tolerant to potential allergens, and has a rich blood supply. Moreover, oral mucosal drug delivery bypasses the first-pass effect and avoids presystemic elimination in the gastrointestinal tract. Bioadhesive systems provide intimate contact between a dosage form and the absorbing tissue, which may result in high concentration in a local area and hence high drug flux through the absorbing tissue. The efficacy of oral bioadhesive drug delivery systems is affected by the biological environment and the properties of the polymer and the drug. In the present paper, we review systematically some relevant citations regarding the environment, strategies for oral drug delivery and evaluation, and utilization of the main polymers.     

New Ophthalmic Drug Delivery Systems

One of the ways to optimize ocular drug delivery is to prolonge precorneal drug residence time. This review focusses on recent findings on the formulation effects in ocular drug bioavailability, employing polymers for the preparation of hydrogels, bioadhesive dosage forms, in situ gelling systems and colloidal systems including liposomes and nanoparticles. The results observed suggested that mucoadhesion or bioadhesion played a role in the sustained action of drugs more significantly compared to non-mucoadhesive polymers. Encapsulation of drugs in liposomes and nanoparticles was correlated to an increase of the drug concentration in the ocular tissues. However, all the results described suggest that the physico-chemical properties of the encapsulated drug have a significant influence on the effect with the carrier. The results suggest also that the superficial charge, the binding type of the drug onto the nanoparticles and the nature of the polymer were the most important factors regarding the improvement of the therapeutic response of the drug.