Colon-specific Drug Delivery System Research Articles

Development and evaluation of colon targeted drug delivery system by using natural Polysaccharides/Polymers

Colon is being extensively investigated as a drug delivery site. This study contains comparison of the usual enteric coating polymers viz. xanthan gum, guar gum, chitosan and ethyl cellulose, as carriers for colon specific drug delivery. Lactose based metoprolol succinate tablets were prepared. These were coated with one of the coating polymers to a varying coat thickness. Tablets were prepared using polysaccharides or synthetic polymer as binders. These included xanthan gum, guar gum, chitosan and ethyl cellulose. Metoprolol Succinate was used as a model drug. The prepared tablets were enteric coated with kollicoat MAE 100 DP to give protection in the stomach. The coated tablets were tested in-vitro for their suitability as colon specific drug delivery systems. The drug release studies were carried out in simulated stomach environment (pH 1.2) for 2 h followed by small intestinal environment at pH 6.8. The dissolution data obtained from tablets demonstrates that the dissolution rate of the tablet is dependent upon the type and concentration of polysaccharide/polymer used as binder. The results demonstrate that enteric coated tablets containing 3% chitosan as a binder, showed only 12.5% drug release in the first 5 h, which is the usual upper gastrointestinal transit time, whereas, tablets prepared using guar gum as binder, were unable to protect drug release under similar conditions. Preparations with xanthan gum as a binder formed time-dependent release formulations. When used in a concentration of 5.92% in the tablets, 28% drug release was observed in the usual upper gastrointestinal tract conditions. It was also found that enteric coated preparation formulated with 8.88% of kollicoat MAE 100 DP as binder could be used to carry water insoluble drug molecules. The above study shows that chitosan could be successfully used as a binder, for colon targeting of water insoluble drugs in preference to guar gum when used in the same concentration. Additionally, formulations developed with chitosan and kollicoat MAE 100 DP would be highly site specific since drug release would be at a retarded rate till microbial degradation or polymer solubilization takes place in the colon. DOI: http://dx.doi.org/10.3329/dujps.v13i1.21874 Dhaka Univ. J. Pharm. Sci. 13(1): 105-113, 2014 (June)

MICROBIAL TRIGGERED COLON TARGETED COMPRESSION COATED TABLETS OF TENOXICAM: FORMULATION AND EVALUATION

The present investigation deals with to formulation and evaluation of colon specific drug delivery system of Tanoxicam by compression coated tablet technique. Tenoxicam, Avicel pH101, HPMC K4M, Guar gum were used as components.Tenoxicam compression coated tablets were prepared and evaluated for differential scanning colorimetry (DSC), FTIR spectroscopy and in-vitro dissolution study without rat caecal content and with rat caecal content. The results suggest that Colon specific drug delivery system of Tenoxicam compression coated tablets were formulated successfully by using natural polymer such as Guar gum in combination with different concentration of HPMC. Tablets were evaluated for drug content, hardness, thickness, friability, weight variation, in-vitro dissolution and all the results were found within the specification. As the concentration of HPMC in compression coat increased, drug release was decreased. Based on in-vitro drug release study, it was concluded that compression coated tablets with combination of 90% Guar gum and 10% HPMC could produce a successful drug targeting to the colon with minimal amount released in the stomach and small intestine for tenoxicam.

Preparation of magnetic pH-sensitive microcapsules with an alginate base as colon specific drug delivery systems through an entirely green route

The aim of this work was to prepare pH-sensitive drug carriers for colon specific drug delivery through a completely green and environmentally friendly route (without using any organic solvents, hazardous chemicals and even a harsh procedure).

Preparation and Evaluation of Newly Developed Chitosan Salt Coating Dispersions for Colon Delivery without Requiring Overcoating.

Although chitosan (CS) has been recognized as a good material for colon-specific drug delivery systems, an overcoating with an enteric coating polymer on the surface of CS is absolutely necessary because CS is soluble in acidic conditions before reaching the colon. In the present study, to improve its stability in the presence of acid, a newly developed CS-laurate (CS-LA) material was evaluated as a coating dispersion for the development of colon-specific drug delivery systems. Two types of CS with different molecular weights, CS250 and CS600, were used to prepare CS-LA films by the casting method. The CS250-LA films had smooth surfaces, whereas the surfaces of the CS600-LA films were rough, indicating that the CS250-LA dispersion could form a denser film than CS600-LA. Both of these CS-LA films maintained a constant shape over 22 h in a pH 1.2 HCl/NaCl buffer, where the corresponding CS films rapidly disintegrated. In addition, the CS250-LA film showed specific colon degradability in a pH 6.0 phosphate buffered solution containing 1.0% (w/v) β-glucosidase. As a result of tensile strength and elongation at the break, both CS-LA films were found to have flexible film properties. Finally, the release of acetaminophen from disks coated with CS250-LA dispersions was significantly suppressed in fluids at pH 1.2 and 6.8, whereas disks coated with CS solution rapidly released the drug in pH 1.2 fluids. Taken together, this study shows that LA modification could be a useful approach in preparing CS films with acid stability and colonic degradability properties without requiring overcoating.

Evaluation of a conducting interpenetrating network based on gum ghatti-g-poly(acrylic acid-aniline) as a colon-specific delivery system for amoxicillin trihydrate and paracetamol

Development of colon-specific drug delivery systems for amoxicillin trihydrate and paracetamol using gum ghatti based crosslinked hydrogels.

The New Progress and Outlook of Oral Colon-specific Drug Delivery System for Treating Cancer

The morbidity of colon cancer is increasingly frequent in past years. Although quite a few researches about colon targeted drugs have achieved certain results and there are quite a few drugs for treatment at present, insufficient of dosage form and function still exists. The paper will give an outlook about a kind of multi-functional colon targeted delivery system.

Oxaprozin/poly(2-hydroxyethyl acrylate/itaconic acid) hydrogels: morphological, thermal, swelling, drug release and antibacterial properties

In this study, a series of novel stimuli-sensitive hydrogels based on 2-hydroxyethyl acrylate and itaconic acid monomers were designed for the controlled release of hydrophobic drug, Oxaprozin. All samples were synthesized by the free-radical crosslinking copolymerization and characterized for structural, morphological, thermal, surface charge, swelling and antibacterial properties. In order to investigate the influence of the drug on hydrogel properties the same characterization was conducted for all Oxaprozin-loaded samples. The chemical composition of hydrogels was studied using Fourier transform infrared spectroscopy, while their morphology and thermal properties were examined by scanning electron microscopy and differential scanning calorimetry. Swelling studies, conducted in the physiological pH range from 2.20 to 8.00 and in the temperature range from 25 to 50 °C, showed that the loaded drug does not modify the pH and temperature sensitivity of the hydrogels, but reduces their swelling capacity. The in vitro drug release study conducted at pH 2.20 and 7.40 showed that all hydrogels can be tailored as colon specific drug delivery systems, and the drug release rate can be effectively controlled by IA content. In addition, the antibacterial activity of the hydrogels was determined against Escherichia coli and Staphylococcus aureus, by the zone of inhibition test. Results of our study indicate that these “smart” hydrogels, with specific morphology, surface charge, swelling capacity, drug loading efficiency and release behavior, could be designed to obtain an enhanced and site-specific controlled drug release system by simply adjusting their composition.

Preparation and Characterization of Metronidazole-Surface Imprinted Microspheres MIP-PSSS/CPVA for Colon-Specific Drug Delivery System

In this paper, the use of molecular surface imprinted polymers (MIPs) in designing colon-specific drug delivery systems was investigated. MIPs were prepared on crosslinked polyvinyl alcohol microspheres (CPVA) with sodium 4-styrene sulfonate (SSS) as functional monomer, Metronidazole (MTZ) as template and N,N’-Methylene bisacrylamide (MBA) as crosslinking agent by utilizing cerium salt-hydroxyl group redox initiation system, obtaining MTZ molecular surface imprinted microspheres MIP-PSSS/CPVA. The MIP-PSSS/CPVA microspheres were further characterized by scanning electron microscope and batch binding method. Because there is strong electrostatic interactions between MTZ and monomer SSS, the MTZ molecular surface imprinting is quite successful, and the imprinted microspheres MIP-PSSS/CPVA possess high recognition selectivity and excellent combining affinity. The experimental results show that at pH 1, the MIP-PSSS/CPVA microspheres exhibit very strong binding ability for MTZ, and the binding capacity reaches up to 115 mg/g. The in vitro release of the MTZ-loaded MIP-PSSS/CPVA is highly pH-dependent and time-delayed. The release behavior shows that the drugs do not release in simulated gastric fluid (pH = 1), the drug release is small while in the simulated small intestinal fluid (pH = 6.8), an abrupt release will be firstly produced and then drug release is sustained and slowed in the simulated colon fluid (pH = 7.4), displaying excellent colon-specific drug delivery behavior.

Preparation and characterization of cross-linked microspheres C(Dex-g-PSSS) and their drug-carrying and colon-specific drug delivery properties

The graft polymer Dex-g-PSSS was obtained through poly(sodium 4-styrene sulfonate) (PSSS) grafted on dextran(Dex) by using the cerium salt–hydroxyl group redox initiation system. The cross-linked microspheres C(Dex-g-PSSS) were synthesized by suspension polymerization with epichlorohydrin as the cross-linking agent. The chemical structure and physicochemical characteristics of C(Dex-g-PSSS) microspheres were represented by infrared spectroscopy (FTIR), optical microscope, and zeta potential analysis. The aim of the study is to constitute a colon-specific drug delivery system via molecular design, using C(Dex-g-PSSS) microspheres as the drug-carrying material and taking 5-fluorouracil (5-FU) as the model drug. The drug-carrying ability and mechanism of the cross-linked microspheres C(Dex-g-PSSS) for 5-FU were investigated. Finally, in vitro release tests for the drug-carrying microspheres were conducted. The experimental results show that in the medium with pH 2, the cross-linked microspheres C(Dex-g-PSSS) exhibit a strong adsorption ability for 5-FU because of strong electrostatic interactions and have an adsorption capacity of 154 ± 7.5 mg/g, displaying high drug-carrying efficiency. The in vitro release behavior of the drug-carrying microspheres is highly dependent on pH and dextranase. In the medium with pH 2, the drug-carrying microspheres do not release the drug and in the medium with pH 1, they release a little, whereas in the medium with pH 7.4, a sudden delivery phenomenon of the drug will occur, and in the presence of dextranase, a more sudden delivery phenomenon of the drug will occur, displaying an excellent colon-specific drug delivery behavior.

Preparation of novel pH‐sensitive nanocomposites based on ionic‐liquid modified montmorillonite for colon specific drug delivery system

An ionic liquid monomer, 3‐methyl‐1‐[2‐(2‐methyl‐acryloxy)‐ethyl]‐imidazolium chloride, was synthesized through the quaternization of N‐methylimidazole and 2‐chloroethyl methacrylate. This ionic liquid monomer intercalated into the montmorillonite layers and subsequently copolymerized with methacrylic acid. The organic–inorganic composite was characterized by FTIR, XRD, SEM, and EDX to study their structure and properties. Naproxen as a model drug was entrapped in these pH‐sensitive positively charged nano carriers and the in vitro release profiles were established separately in both enzyme‐free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4) respectively. It was observed that the drug release percentages in SIF were higher; hence the prepared nanocomposite could be considered as a suitable carrier for colon specific drug delivery. POLYM. COMPOS., 182–187, 2016. © 2014 Society of Plastics Engineers

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion–spheronization

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett–Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box–Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.

FORMULATION AND EVALUATION OF A COLON DRUG DELIVERY SYSTEM CONTAINING DIFLUNISAL

Oral drug delivery is the most desirable and preferred method of administering therapeutic agents for providing both systemic and local effects in various parts of the gastrointestinal tract. Recently, greater emphasis has been placed on controlling the site and/or rate of drug release from oral formulations to improve treatment efficacy and patient compliance. Many novel oral drug therapeutic systems have been invented like fast release, targeted release and colon specific drug delivery systems etc.. During the last decade there has been an interest in developing site specific formulations for targeting to the colon. The delivery of drugs to the colon has a number of therapeutic implications in the field of drug delivery. Localized delivery of the drugs in the colon is possible only when the drug is protected from the hostile environment of upper GIT. The various approaches that can be exploited to target the release of drug to colon include prodrugs, coating with pH sensitive polymers, coating with biodegradable, timed release systems, osmotic and bioadhesive polymers. In the present study, solid dispersions of pH-dependent, time dependent and combined pH- and time-dependent systems were formulated using Eudragit RS100, Eudragit S100, Eudragit L100 and ethylcellulose, with different drug-to-polymer ratios. They were evaluated for their in-vitro release characteristics in an attempt to develop a colon-specific delivery system containing Diflunisal. Release studies of Diflunisal and Diflunisal solid dispersion systems with different polymers were employed using Release apparatus, USP (paddle type) (copley, England) showed that, the combination of pH- and time-dependent systems provided better results than the pH-dependent or the time dependent system alone. Using Eudragit S100 and Eudragit RS100 with Diflunisalin a ratio 2:3:1, respectively for preparing a solid dispersion used for developing a colon-specific delivery system of Diflunisal was the most successful formula. This formula released 0.22±0.03% of the drug included in it in the stomach pH and 26.29±0.91% of the drug in the intestine pH and 77.59±1.79% of the drug in the colon pH.

Carboxymethylcellulose–tetrahydrocurcumin conjugates for colon-specific delivery of a novel anti-cancer agent, 4-amino tetrahydrocurcumin

Several curcumin derivatives are now becoming increasingly of interest because of their bioactive attributes, especially their action as antioxidants and anti-carcinogenic activities. Tetrahydrocurcumin (THC), an active metabolite of curcumin, was selected to be a proper starting material for the work presented here as it is stable in physiological pH and has the typical pharmacological properties of curcumin. We have now reported that novel synthesized water-soluble polymeric macromolecule prodrugs can specifically deliver the drug to the colon. To study the drug loading and drug release, THC was conjugated with a hydrophilic polymer, carboxymethylcellulose (CMC) with the degree of substitution (DS) values of 0.7 and 1.2. THC was also attached to two different spacers including p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH) via an azo bond that was cleaved by the azoreductase activities of colonic bacteria. The novel active molecule, 4-amino-THC, was readily released from the conjugates in the colon (>62% within 24h) with only very small amounts released in the upper GI tract (<12% over 12h). The polymer conjugates showed chemical stability at various pH values along the gastrointestinal tract and increased water solubility of up to 5mg/mL. 4-Amino-THC demonstrated cytotoxic ability against the human colon adenocarcinoma cell lines (HT-29) with an IC50 of 28.67±1.01μg/mL, and even greater selectivity (∼4 folds) to inhibit HT-29 cells than to normal human colon epithelial cell lines while curcumin was a non-selective agent against both cell lines. Our study has demonstrated that the use of THC–CMC conjugates may be a promising colon-specific drug delivery system with its sustained release in the colon to be an effective treatment for colonic cancer.

Shape, optimization and in vitro evaluation of colon-specific multi-particulate system based on low-methoxy amidated pectin and polycarbophil

Natural polysaccharides are widely used for development of colon-specific drug delivery systems. The present study was carried out to develop multi-particulate calcium pectinate (Ca-pectinate) formulations for colon-targeted delivery of lornoxicam. The formulations were developed using a combination of polycarbophil and low-methoxy amidated pectin. The beads were prepared using an ionotropic gelation technique. The effects of the polycarbophil and low-methoxy amidated pectin concentrations on the beads characteristics, encapsulation efficiency, swelling study and drug release performance were investigated. The optimized formulation was evaluated for its morphological characteristics. The in vitro drug release of the optimized formulation over a period of 12 h was 96.78 ± 1.35 %. The concentration of the polycarbophil was a decisive factor in sustaining drug release in the colon. The study revealed that optimized Ca-pectinate beads prepared with polycarbophil can efficiently encapsulate lornoxicam. It also showed that these beads can potentially be used for colon-specific delivery of lornoxicam.

Mesalazine–probiotics beads for acetic acid experimental colitis: formulation and characterization of a promising new therapeutic strategy for ulcerative colitis

Background: Acetic acid ulcerative colitis (UC) is an experimental condition created due to intra-rectal administration of acetic acid which causes inflammation and ulceration in the lining of colon and rectum. In such condition, the colon cannot absorb liquid from the stools, resulting in larger volume of watery stools. Mesalazine is mainly used for the treatment of UC but suffers from the drawback of having poor bioavailability. UC is also characterized by alteration in colonic microflora. The present work was focused on delivering mesalazine along with probiotic, which would facilitate to refurbish customary growth of microflora. Mesalazine and probiotic were encapsulated in pectin beads with an aim to protect the drug from gastric environment and target to colonic region.Methods: Pectin beads were prepared, formulation process was optimized for polymer concentration, drug concentration, cross-linking agent concentration. Formulation was characterized for surface morphology, in vitro drug release studies, determination of viable cell count, in vivo ulcer protective studies and stability studies.Results: Average particle diameter of beads was ∼1.44–1.72 mm. Drug entrapment efficiency was found to be optimal (78–79%). A sustained release of drug was observed for 5 h; nearly 60% of drug was released at the end of 10 h. Microbiological studies of probiotic showed best cell viability. In acetic acid induced UC model, Mesalazine–probiotic beads-treated group showed significant (p < 0.01) ulcer protection index with respect to free drug-treated group.Conclusion: In conclusion, mesalazine–probiotic loaded beads may serve as a useful colon specific drug delivery system for treatment of colitis.

Formulation of indomethacin colon targeted delivery systems using polysaccharides as carriers by applying liquisolid technique.

The present study aimed at the formulation of matrix tablets for colon-specific drug delivery (CSDD) system of indomethacin (IDM) by applying liquisolid (LS) technique. A CSDD system based on time-dependent polymethacrylates and enzyme degradable polysaccharides was established. Eudragit RL 100 (E-RL 100) was employed as time-dependent polymer, whereas bacterial degradable polysaccharides were presented as LS systems loaded with the drug. Indomethacin-loaded LS systems were prepared using different polysaccharides, namely, guar gum (GG), pectin (PEC), and chitosan (CH), as carriers separately or in mixtures of different ratios of 1 : 3, 1 : 1, and 3 : 1. Liquisolid systems that displayed promising results concerning drug release rate in both pH 1.2 and pH 6.8 were compressed into tablets after the addition of the calculated amount of E-RL 100 and lubrication with magnesium stearate and talc in the ratio of 1 : 9. It was found that E-RL 100 improved the flowability and compressibility of all LS formulations. The release data revealed that all formulations succeeded to sustain drug release over a period of 24 hours. Stability study indicated that PEC-based LS system as well as its matrix tablets was stable over the period of storage (one year) and could provide a minimum shelf life of two years.

Colonic Drug Delivery Systems Based on Natural Polysaccharides and their Evaluation

Natural polysaccharides are found in abundance, are inexpensive, safe and available in a variety of structures which can easily be modified chemically and biochemically. A number of natural gums and mucilages along with their chemically modified forms have been evaluated as controlled drug delivery devices. They are reported to be capable of providing the desired drug release profiles and in some cases, have shown comparable drug release properties with currently available sustained release products in the market. Colon specific drug delivery based on natural polysaccharides has highly been acclaimed in recent years. A colon specific drug delivery system should prevent drug release in the stomach as well as the small intestine. Several polysaccharides have been reported to be capable of preventing drug release in the upper GI tract while being susceptible to enzymatic degradation by colonic bacterial enzymes. A wide range of natural or modified polysaccharides has been investigated for peroral delivery of drugs to the colon. As the release of drug from these polysaccharides based systems is independent of pH and gastric emptying time these polysaccharides based systems are considered the most effective and preferable means for colonic drug delivery in terms of target specificity.

Modified Approaches for Colon Specific Drug Delivery System: A Review

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review mainly describes the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules. Oral administration of different dosage forms is the most commonly used method due to flexibility in design of dosage form and high patient acceptance, but the gastrointestinal tract presents several formidable barriers to drug delivery. In oral colon-specific drug delivery system, colon has a large amount of lymphoma tissue (facilitates direct absorption in to the blood), negligible brush boarder membrane activity, and much less pancreatic enzymatic activity as compared with the small intestine. Colon-specific drug delivery has gained increased importance not just for the delivery of the drugs for treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides. Different approaches are designed based on prodrug formulation, pH-sensitivity, time-dependency (lag time), microbial degradation and osmotic pressure etc to formulate the different dosage forms like tablets, capsules, multiparticulates, microspheres, liposomes for colon targeting. The delivery of drugs to the colon has a number of therapeutic implications in the field of drug delivery. In the recent times, the colon specific delivery systems are also gaining importance not only for local drug delivery of drugs but also for the systemic delivery of protein and peptide drugs. This review updated the research on different approaches formulation and evaluation of colon-specific drug delivery.

Applicability of enzyme-responsive mesoporous silica supports capped with bridged silsesquioxane for colon-specific drug delivery

The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. In this study, we prepared a new capped mesoporous silica nanoparticle as a potential material for colon-specific drug delivery. This material consisted of nanoscopic mesoporous MCM-41 supports loaded with ibuprofen and capped with a bridged silsesquioxane with azo groups. X-ray diffraction, N2 sorption analysis, transmission electron microscopy, UV–vis diffusion reflectance spectroscopy, and 29Si magic angle spinning nuclear magnetic resonance were used to verify the well-ordered mesostructure and the successful grafting of bridged silsesquioxane on the surface of the mesoporous material. The material showed “zero release” in simulated gastric fluid and simulated intestinal fluid. The opening and release of cargo occurred in simulated colonic fluid with azo-reductase due to the reductive cleavage of the azo bonds. However, no release of ibuprofen was observed in phosphate-buffered saline without enzyme. These results indicated that the capped mesoporous material showed excellent behavior for colon specificity and could be a potential material for colon-specific drug delivery.

Impact of cross-linking and drying method on drug delivery performance of casein-pectin microparticles.

Pectin is a heteropolysaccharide which has been investigated for the development of colon-specific drug delivery systems. Polymers have been associated with pectin to reduce its aqueous solubility and improve the performance of drug delivery systems. Pectin-casein interaction is widely known in food research, but it has not been fully considered by pharmaceutical scientists. Thus, this study investigated the potential of casein-pectin microparticles as a drug delivery system and clarified the impact of cross-linking and drying methods on the in vitro release of indomethacin (IND) or acetaminophen (PCT) from microparticles. Microparticles were prepared by coacervation and dried by spray or spouted bed methods. Drug recovery, in vitro drug release, size, morphology, and the thermal and diffractometric properties of dried microparticles were determined. Spray-dried non-cross-linked microparticles were able to prolong IND release, and pectin was still degraded by pectinolytic enzymes. On the other hand, glutaraldehyde cross-linking prevented the enzymatic breakdown of pectin without improving IND release. Spouted bed drying reduced IND recovery from all microparticles when compared with spray drying, thus the successful spouted bed drying of microparticles depends on the chemical characteristics of both the drug and the polymer. Release data from PCT microparticles suggested that the microparticle formulation should be improved to bring about a more efficient delivery of water-soluble drugs. In conclusion, casein-pectin microparticles show great potential as a drug delivery system because casein reduces the water solubility of pectin. The drying method and cross-linking process had significant effects on the in vitro performance of these microparticles.