Monolithic osmotic tablet system for nifedipine delivery.

The monolithic osmotic tablet system, which is composed of a monolithic tablet coated with cellulose acetate (CA) membrane drilled with two orifices on both side surfaces, has been described. The influences of tablet formulation variables including molecular weight (MW) and amount of polyethylene oxide (PEO), amount of potassium chloride (KCl), and amount of rice starch as well as nifedipine loading have been investigated. The optimal tablet formulation and the osmotic-suspending co-controlled delivery mechanisms have been proposed. Orifice size and membrane variables including nature and amount of plasticizers as well as thickness on drug release have also been studied. The in vitro release profiles of the optimal system have been evaluated in various release media and different agitation rates, and compared with commercialized conventional capsule and push-pull osmotic tablet. It was found that PEO with MW of 300000 g/mol was suitable to be thickening agent, both amount of KCl and amount of PEO had comparable and profoundly positive effects, while nifedipine loading had a strikingly negative influence on drug release. It could be found that the optimal orifice size was in the range of 0.25-1.41 mm. It has also been observed that hydrophilic plasticizer polyethylene glycol (PEG) improved drug release, whereas hydrophobic plasticizer triacetin depressed drug release when they were incorporated in CA membrane. The monolithic osmotic tablet system was found to be able to deliver nifedipine at the rate of approximate zero-order up to 24 h, independent of both environmental media and agitation rate, and substantially comparable with the push-pull osmotic tablet. The monolithic osmotic tablet system was simple to be prepared as exempting from push layer and simplifying in the orifice drilling compared with the push-pull osmotic tablet. The monolithic osmotic tablet system may be used in drug controlled delivery field, especially suitable for water-insoluble drugs.     

Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the “magic bullets” concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know‐how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products.     

Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: preparation and in vitro characterization.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. Multiple unit systems avoid the 'all-or-none' gastric emptying nature of single-unit systems. A controlled release system designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microspheres by the emulsion solvent diffusion technique consisting of (i) calcium silicate (FLR) as porous carrier; (ii) repaglinide, an oral hypoglycemic agent; and (iii) Eudragit S as polymer. The effect of various formulation and process variables on the internal and external particle morphology, micromeritic properties, in vitro floating behavior, physical state of the incorporated drug, drug loading and in vitro drug release were studied. The microparticles were found to be regular in shape and highly porous. The release rate was determined in simulated gastro-intestinal fluids at 37 degrees C. The formulation demonstrated favorable in vitro floating and release characteristics. The drug encapsulation efficiency was high. Incorporation of FLR in the microspheres proved to be an effective method to achieve the desired release behavior and buoyancy. The designed system, combining excellent buoyant ability and suitable drug release pattern, could possibly be advantageous in terms of increased bioavailability of repaglinide.     

Critical factors in the release of drugs from sustained release hydrophilic matrices

Hydrophilic matrix systems are one of the most interesting drug delivery systems, and they are currently some of the most widely used to control the release rate of drugs. There are too much factors involved in drug release from hydrophilic matrix systems. The most important factors to be taken into account when developing a formulation based on hydrophilic matrices are the percentage, solubility and drug particle size; the type of polymer, the percentage incorporated, its degree of viscosity and the polymer particle size. Also important are the drug/polymer ratio and the amount of water entering the matrix. Other factors have been shown to be involved in the release of drugs, such as the percentage and mixtures of polymers and the dimensions of the matrix. The compression force is important among the formulation factors to the extent that it determines the amount of air trapped in the matrix. Knowledge of these factors involved in the release of the drugs is crucial for the optimal development of formulations based on hydrophilic systems.     

Microspheres for controlled release drug delivery

Controlled release drug delivery employs drug-encapsulating devices from which therapeutic agents may be released at controlled rates for long periods of time, ranging from days to months. Such systems offer numerous advantages over traditional methods of drug delivery, including tailoring of drug release rates, protection of fragile drugs and increased patient comfort and compliance. Polymeric microspheres are ideal vehicles for many controlled delivery applications due to their ability to encapsulate a variety of drugs, biocompatibility, high bioavailability and sustained drug release characteristics. Research discussed in this review is focused on improving large-scale manufacturing, maintaining drug stability and enhancing control of drug release rates. This paper describes methods of microparticle fabrication and the major factors controlling the release rates of encapsulated drugs. Furthermore, recent advances in the use of polymer microsphere-based systems for delivery of single-shot vaccines, plasmid DNA and therapeutic proteins are discussed, as well as some future directions of microsphere research.     

The vagina as a route for systemic drug delivery.

Exhaustive efforts have been made toward the administration of drugs, via alternative routes, that are poorly absorbed after the oral administration. The vagina as a route of drug delivery has been known since ancient times. In recent years, the vaginal route has been rediscovered as a potential route for systemic delivery of peptides and other therapeutically important macromolecules. However, successful delivery of drugs through the vagina remains a challenge, primarily due to the poor absorption across the vaginal epithelium. The rate and extent of drug absorption after intravaginal administration may vary depending on formulation factors, vaginal physiology, age of the patient and menstrual cycle. Suppositories, creams, gels, tablets and vaginal rings are commonly used vaginal drug delivery systems. The purpose of this communication is to provide the reader with a summary of advances made in the field of vaginal drug delivery. This report, therefore, summarizes various vaginal drug delivery systems with an introduction to vaginal physiology and factors affecting drug absorption from the vaginal route.     

Investigations on the drug releasing mechanism from an asymmetric membrane-coated capsule with an in situ formed delivery orifice.

Asymmetric membrane-coated capsules with in situ formation of a delivery orifice were examined for their improved osmotic effects. The release mechanisms were investigated for drugs with both moderate to high water solubility and those with poor water solubility. The capsule wall membrane was produced by a phase-inversion process, in which an asymmetric membrane was formed on stainless steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quenching solution. In situ formation of a delivery orifice in the thin membrane was proven by visualization of a jet stream of chlorophyll being released from the capsule. The release mechanism for drugs with moderate to high water solubility was mainly controlled by the osmotic effect, which is a function of the drug's solubility. Permeability across the asymmetric membrane of the capsule was determined to be 4.28 x 10(-6) cm(2)/h-atm at 37 degrees C for drugs with water solubilities in a moderate to high range. Accordingly, the poorly water-soluble drug, nifedipine, was unable to create enough of an osmotic effect to activate drug release. Solubilization either by the addition of the solubility enhancer, SLS, or by a solid dispersion with HPMC could increase the solubility of nifedipine to a sufficient extent to activate drug release. It was found that the suspending ability induced by the viscous nature of HPMC further interacted with SLS to synergistically increase the maximal percent release and the release rate of nifedipine. The osmotic effect of this suspension ability was proposed as the underlying mechanism responsible for the release of poorly water-soluble drugs, i.e. nifedipine, from this system.     

Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome.

Colon-specific drug delivery systems (CDDSs) can be used to improve the bioavailability of protein and peptide drugs through the oral route. A novel formulation for oral administration using coated calcium alginate gel beads-entrapped liposome and bee venom peptide as a model drug has been investigated for colon-specific drug delivery in vitro. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released completely in the physiological environment of the stomach and small intestine. The release rate of bee venom from the coated calcium alginate gel beads-entrapped liposome was dependent on the concentration of calcium and sodium alginate, the amount of bee venom in the liposome, as well as the coating. Furthermore, a human gamma-scintigraphy technique was used in vivo to determine drug delivery more precisely. The colonic arrival time of the tablets was found to be 4-5 h. The results clearly demonstrated that the coated calcium alginate gel beads-entrapped liposome is a potential system for colon-specific drug delivery.     

Pharmacokinetic approach to the rational design of controlled or sustained release formulations

There is an ever-increasing realization that controlled drug delivery can provide many advantages in drug therapy. Guidelines are provided to answer three basic questions in the development of controlled-release (CR) or sustained-release (SR) formulations: (a) is a CR or SR formulation necessary for a drug product, (b) what should be the release rate for a zero-order product and rate constant for release for a first-order product, and (c) what dose should the formulation contain? Although these pharmacokinetic guidelines are simple and straightforward, they assume ideal conditions for drug release and absorption. Pharmacokinetic simulations are provided for CR or SR formulations with zero- or first-order release characteristics. Three-dimensional diagrams are also provided to illustrate the inter-relationships among the ratio of maximum to minimum plasma concentrations, the drug release rate from the CR or SR formulation, the oral clearance of the drug after an oral solution formulation and the dose. The simulations suggest that utilization of classical pharmacokinetic principles can lead to a prospective approach to the rational design of controlled or sustained release formulations.     

Development and characterization of a novel peroral peptide drug delivery system.

Novel drug delivery systems were developed for peroral administration of peptide and protein drugs for site specific mechanical fixation at the gut wall and with specific release patterns. These so-called shuttle systems were designed by using superporous hydrogels (SPH) and SPH composite (SPHC) as the conveyor of a core which contained the model compound N-alpha-benzoyl-L-arginine ethylester (BAEE). Two different types of shuttle systems were evaluated: (a) core inside the shuttle system, and (b) core attached to the surface of shuttle system. Each of these systems was made of two parts: (1) the conveyor system made of SPHC which is used for keeping the dosage form at specific site(s) of the GI tract by mechanical interaction of the dosage form with the intestinal membranes, and (2) the core containing the active ingredient and incorporated in the conveyor system. The effect of formulation composition of the core on the release profile of BAEE was investigated by changing the type and amount of excipients in the formulations. In addition, the effect of various enteric-coat layers on the release profile and dissolving of the dosage form was investigated. The systems were also characterized for trypsin inactivation and Ca(2+) binding. The release profile of BAEE from the core formulation consisting of PEG 6000 microparticles or small tablets showed the desired burst release. When these core formulations were incorporated into the conveyor system made of SPH and SPHC, a suitable time-controlled release profile was obtained. Changing the type, concentration and thickness of the enteric-coat layer influenced the starting time of BAEE release from the dosage form, which indicates the necessary lag time for dissolving of the dosage form at any desired specific site of drug absorption in the intestine. Both SPH and SPHC were found to partly inhibit the activity of trypsin, due to two mechanisms: Ca(2+) binding and entrapment of the enzyme in these polymers. In conclusion, the presently developed delivery systems demonstrate suitable in vitro characteristics with an appropriate time-controlled release profile, making these systems very promising for effective peroral delivery of peptide and protein drugs.     

A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS.

Paclitaxel (Taxol) is one of the best antineoplastic drugs found from nature in the past decades. Like many other anticancer drugs, there are difficulties in its clinical administration due to its poor solubility. Therefore an adjuvant called Cremophor EL has to be employed, but this has been found to cause serious side-effects. However, nanoparticles of biodegradable polymers can provide an ideal solution to the adjuvant problem and realise a controlled and targeted delivery of the drug with better efficacy and fewer side-effects. The present research proposes a novel formulation for fabrication of nanoparticles of biodegradable polymers containing d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) to replace the current method of clinical administration and, with further modification, to provide an innovative solution for oral chemotherapy. In the modified solvent extraction/evaporation technique employed in this research, the emulsifier/stabiliser/additive and the matrix material can play a key role in determining the morphological, physicochemical and pharmaceutical properties of the produced nanoparticles. We found that vitamin E TPGS could be a novel surfactant as well as a matrix material when blended with other biodegradable polymers. The nanoparticles composed of various formulations and manufactured under various conditions were characterised by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) for surface chemistry and differential scanning calorimetry (DSC) for thermogram properties. The drug encapsulation efficiency (EE) and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was concluded that vitamin E TPGS has great advantages for the manufacture of polymeric nanoparticles for controlled release of paclitaxel and other anti-cancer drugs. Nanoparticles of nanometer size with narrow distribution can be obtained. A drug encapsulation efficiency as high as 100% can be achieved and the release kinetics can be controlled.     

3He ion-beam analysis of water uptake and drug delivery.

3He ion-beam analysis utilises a micronuclear reaction analysis (of deuterium and carbon) and microparticle induced X-ray emission (in this case silicon and chlorine), to determine an elemental map of the surface of a sample. This study used D(2)O to model the behaviour of water in poly(tetrahydrofurfuryl methacrylate-polyethyl methacrylate) and chlorhexidine diacetate doped silicone elastomers. The poly(tetrahydrofurfuryl methacrylate-polyethyl methacrylate) systems demonstrated an initial Fickian absorption process (diffusion coefficient 1.1 x 10(-11) m(2)s(-1)) which indicated the 2-stage nature of the polymer's absorption kinetics. The doped silicone samples demonstrated an osmotic mechanism for the controlled release of drugs, with correlation between the D(2)O and the chlorhexidine diacetate inclusions increasing during the experiment. The technique proved valuable in the analysis of delivery polymers and will undoubtedly have further applications in the development of drug delivery systems.     

Controlled delivery of nanosuspensions from osmotic pumps: zero order and non-zero order kinetics

Nanosuspensions have gained great interest in the last decade as a formulation tool for poorly soluble drugs. By decreasing particle sizes nanosuspensions enhance dissolution rate and bioavailability of the active pharmaceutical ingredient. Micro-osmotic pumps are widely used in experimental pharmacology and offer a tool of interest for the sustained release of nanosuspensions via the intraperitoneal or subcutaneous application site. The purpose of the present study was to investigate in-vitro the influence of (1) nanosuspension viscosity, (2) pump orifice position and (3) formulation osmolality on the delivery behavior of formulations in implantable osmotic systems. Therefore fenofibrate nanosuspension, methylene blue and fluorescein sodium solutions were chosen as model formulations. They were released in water or isotonic saline solution and drug/dye concentrations were determined by HPLC/UV. Release of nanosuspension particles in low viscous formulations resulted in a burst whereas increasing the viscosity led to the expected zero order delivery. Pumps with upward-positioned orifices released the nanosuspension in a zero order manner. Within the release of dyes, constant delivery could be ensured up to an osmolality of 486 mO sm/kg; above this value premature release of formulation was observed. The results indicate the requirement of in-vitro experiments prior to in-vivo animal testing for determining the release profiles of osmotic pumps.     

Osmotic drug delivery using swellable-core technology.

Swellable-core technology (SCT) formulations that used osmotic pressure and polymer swelling to deliver drugs to the GI tract in a reliable and reproducible manner were studied. The SCT formulations consisted of a core tablet containing the drug and a water-swellable component, and one or more delivery ports. The in vitro and in vivo performance of two model drugs, tenidap and sildenafil, formulated in four different SCT core configurations: homogeneous-core (single layer), tablet-in-tablet (TNT), bilayer, and trilayer core, were evaluated. In vitro dissolution studies showed that the drug-release rate was relatively independent of the core configuration but the extent of release was somewhat lower for the homogeneous-core formulation, particularly under non-sink conditions. The drug-release rate was slower with increasing coating thickness and decreasing coating permeability, and was relatively independent of the drug loading and the number and size of the delivery ports. The drug-release rates were similar for the two model drugs despite significant differences in their physicochemical properties. Tablet-recovery and pharmacokinetic studies conducted in beagle dogs showed that the in vivo release of drug from SCT formulations was comparable to the in vitro drug release.     

Oral drug delivery with nanoparticles into the gastrointestinal mucosa

The oral route of protein and peptide drugs has been a popular method of drug delivery in recent years, although it is often a challenge to achieve effective drug release and minimize the barrier functions of the gastrointestinal tract. Gastrointestinal mucosa can capture and remove harmful substances; similarly, it can limit the absorption of drugs. Many drugs are effectively captured by the mucus and rapidly removed, making it difficult to control the release of drugs in the gastrointestinal tract. The use of drug carrier systems can overcome the mucosal barrier and significantly improve bioavailability. Nanoparticle drug carriers can protect the drug from degradation, transporting it to a predetermined location in the gastrointestinal tract to achieve more efficient and sustained drug delivery. It is becoming clearer that the characteristics of nanoparticles, such as particle size, charge, and hydrophobicity, are related to permeability of the mucosal barrier. This review focuses on the latest research progress of nanoparticles to penetrate the mucosal barrier, including the delivery methods of nanoparticles on the surface of gastrointestinal mucosa, and aims to summarize how successful oral nanoparticle delivery systems can overcome this biological barrier in the human body. In addition, the in vitro model based on gastrointestinal mucus is an important tool for drug research and development. Here, we discuss different types of drug delivery systems and their advantages and disadvantages in design and potential applications. Similarly, we reviewed and summarized various methods for evaluating oral nanoparticles in in vitro and in vivo models.     

A flexible technology for modified release of drugs: multi layered tablets.

Modified release dosage forms offer definite advantages over conventional release formulation of the same drug. Hydrophilic polymers are mainly used for preparation of matrix type controlled delivery systems. The system usually provides nonlinear release profile. The multi-layered matrix system overcomes inherent disadvantages of non-linearity associated with diffusion controlled matrix devices by providing additional release surface with time to compensate for the decreasing release rate. This technology also demonstrates a wide flexibility for various applications. In this article, we review system design, various constructions and formulation parameters of modified release dosage forms.     

Three-layer guar gum matrix tablet formulations for oral controlled delivery of highly soluble trimetazidine dihydrochloride.

The present study is carried out to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of three-layer matrix tablets. Trimetazidine dihydrochloride was chosen as a model drug because of its high water solubility. Matrix tablet granules containing 30% (M1), 40% (M2) or 50% (M3) of guar gum were prepared by the wet granulation technique using starch paste as a binder. Three-layer matrix tablets of trimetazidine dihydrochloride were prepared by compressing on either side of guar gum matrix tablet granules of trimetazidine dihydrochloride M1, M2 or M3 with 200 mg of guar gum granules containing either 65% of guar gum (T1M1, T1M2 or T1M3), 75% of guar gum (T2M1, T2M2 or T2M3) or 85% of guar gum (T3M1, T3M2 or T3M3) as release retardant layers. The three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of trimetazidine dihydrochloride released from the matrix and three-layer matrix tablets at different time intervals was estimated using a HPLC method. The three-layer guar gum matrix tablet (T3M3) provided the required release rate on par with the theoretical release rate for guar gum formulations meant for twice daily administration. The three-layer guar gum matrix tablet (T3M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. The DSC study did not show any possibility of interaction between trimetazidine dihydrochloride and guar gum/other formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as trimetazidine dihydrochloride.     

Buccal bioadhesive drug delivery--a promising option for orally less efficient drugs.

Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive presystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parenteral route of administration is the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the right dosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and permeation. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug and excipients. Advances in experimental and computational methodologies will be helpful in shortening the processing time from formulation design to clinical use. This paper aims to review the developments in the buccal adhesive drug delivery systems to provide basic principles to the young scientists, which will be useful to circumvent the difficulties associated with the formulation design.     

Implantable controlled release systems

A controlled release system utilizes a polymer matrix or pump as a rate-controlling device to deliver the drug in a fixed, predetermined pattern for a desired time period. These systems have the following advantages compared to other methods of administration: 1) plasma drug levels are continuously maintained in a therapeutically desirable range, 2) harmful side effects from systemic administration can be reduced or eliminated by local administration from a controlled release system, 3) drug administration may be improved and facilitated in underpriviledged areas where good medical supervision is not available, 4) administration of drugs that have short in vivo half lives may be greatly facilitated, 5) continuous small amounts of drug may be less painful than several large doses, 6) patient compliance may be improved, and 7) this method is relatively less expensive and less wasteful of the drug. Disadvantages include possible toxicity, need for surgery to implant the system, possible pain, and difficulty in shutting off release if necessary. Two types of diffusion-controlled systems have been developed. The reservoir is a core of drug surrounded with a polymer film. The 2nd type, the matrix, is one in which the drug is uniformly distributed through a polymer. In chemically controlled systems, the rate of drug release is regulated by a chemical reaction with the polymer. In solvent activated systems a swelling or osmotic mechanism is involved. Pharmaceutical applications have been made in ocular disease with the Ocusert, a reservoir system for glaucoma therapy and which is not widely used, and in contraception with 4 systems. These systems are: 1) subdermal implants of nonbiodegradable polymers such as Norplant, 6 capsules of 36 mg levonorgestrel; 2) subdermal implant of biodegradable polymers; 3) steroid releasing IUD; and 4) vaginal rings, which are silicone-coated. Other applications have been made in the areas of dentistry, immunization, anticoagulation, cancer, narcotic antogonists, and insulin delivery. Transdermal delivery involves placing a polymeric system containing a contact adhesive on the skin.