Sustained Release Suppository of Sodium Diclofenac: use of Water Absorbable Polymer

Abstract

The investigation on the usefulness of water absorbable polymer (Poys® SA-20) for the preparation of sustained release suppository was performed. To prepare the sustained release suppository, sodium diclofenac solution is absorbed into the sphere polymer, and the particles of the polymer after dryness are suspended in the melted triglyceride suppository base, followed by solidification. The sustained release of sodium diclofenac from the suppository was confirmed by the in vitro release study with slow release of sodium diclofenac and by the in vivo absorption study in dogs with an avoidance of transient high plasma diclofenac concentration and a prolong of plasma diclofenac concentration.     

Sustained Release of Diclofenac from Polymer-Containing Suppository and the Mechanism Involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.     

Sustained release of diclofenac from polymer-containing suppository and the mechanism involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro–in vivo correlation was observed for these products.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro-in vivo correlation was observed for these products.     

Comparative study of drug release from pellets coated with HPMC or Surelease

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.     

Studies on Controlled-Release Formulations of Diclofenac Sodium

The effects of various polymers on the release of diclofenac sodium from their matrices have been evaluated. In vitro release profiles of diclofenac sodium from ethylcellulose and hydroxypropylmethylcellulose (HPMC) K4M matrices showed that decreasing the concentration of ethylcellulose and increasing the concentration of HPMC K4M resulted in an increase in the release rate of diclofenac sodium. An increase in the amount of lactose in matrix resulted in an increase in the release rate of diclofenac sodium. It is suggested that the use of ethylcellulose or Precirol containing relatively large percentage concentrations of lactose in matrices will not provide zero-order release of diclofenac sodium from matrices. The best-fit release kinetics with the highest correlation coefficients was achieved with the Higuchi's plot followed by the zero-order. A straight line relationship was established bemeen the T_50% and the ratio of HPMC K4M to diclofenac sodium.     

Physicochemical characterization of diclofenac sodium-loaded poloxamer gel as a rectal delivery system with fast absorption

Rectal poloxamer gel systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and were mucoadhesive to the rectal tissues without leakage after the dose. However, a poloxamer gel containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a poloxamer gel using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength, and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers, and sodium chloride were investigated. Furthermore, the pharmacokinetic study of diclofenac sodium delivered by the poloxamer gel was performed. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. The poloxamer gels with less than 1.0% sodium chloride, in which the drug was not precipitated, were inserted into the rectum without difficulty and leakage, and were retained in the rectum of rats for at least 6 hr. Furthermore, poloxamer gel gave significantly higher initial plasma concentrations and faster T_max of diclofenac sodium than did solid suppository, indicating that drug from poloxamer gel could be absorbed faster than that from the solid one in rats. Our results suggested that a rectal poloxamer gel system with sodium chloride and poloxamers was a more physically stable, convenient, and effective rectal dosage form for diclofenac sodium.     

Studies on Controlled-Release Formulations of Diclofenac Sodium

Abstract

The effects of various polymers on the release of diclofenac sodium from their matrices have been evaluated. In vitro release profiles of diclofenac sodium from ethylcellulose and hydroxypropylmethylcellulose (HPMC) K4M matrices showed that decreasing the concentration of ethylcellulose and increasing the concentration of HPMC K4M resulted in an increase in the release rate of diclofenac sodium. An increase in the amount of lactose in matrix resulted in an increase in the release rate of diclofenac sodium. It is suggested that the use of ethylcellulose or Precirol containing relatively large percentage concentrations of lactose in matrices will not provide zero-order release of diclofenac sodium from matrices. The best-fit release kinetics with the highest correlation coefficients was achieved with the Higuchi's plot followed by the zero-order. A straight line relationship was established bemeen the T_50% and the ratio of HPMC K4M to diclofenac sodium.     

Biodegradable IPN hydrogel beads of pectin and grafted alginate for controlled delivery of diclofenac sodium

A novel diclofenac sodium (DS) loaded interpenetrating polymer network (IPN) beads of pectin and hydrolyzed polyacrylamide-graft-sodium alginate (PAAm-g-SA) was developed through ionotropic gelation and covalent cross-linking. The graft copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The grafting, alkaline hydrolysis, and characterization of beads were confirmed by Fourier transforms infrared spectroscopy. The crystalline structure of drug after encapsulation into IPN beads were evaluated by differential scanning colorimetry and X-ray diffraction analyses. DS encapsulation was up to 96.45 %. The effect of hydrolyzed graft copolymer/pectin ratios and glutaraldehyde concentration on drug release in acidic and phosphate buffer solutions were investigated. The release of drug was significantly increased with increase of pH. The release of drug depends on the extent of cross-linking. The results indicated that IPN beads of hydrolyzed PAAm-g-SA and pectin could be used for sustained release of DS.     

Development and characterization of pseudolatex based transdermal drug delivery system of diclofenac.

A transdermal drug delivery system of diclofenac was developed for prolonged and controlled release of diclofenac. The designed system essentially based on polymeric pseudolatex dispersion. The formulation variables that could effect the formulation stability vis a vis drug release were studied. To achieve the desired release rate, different combination of hydrophilic and hydrophobic polymer were used for the preparation of pseudolatex system. The designed system exhibited linear relationship between drug release (Q) V/s square root of time (t^0.5). The product having skin permeability rate 0.188 mg/h/cm was selected for the in vitro anti-inflammatory activity and in vivo evaluation. The system could maintained a constant and effective plasma level for 24 hours. The effective drug plasma concentration was monitored periodically. The study revealed that designed pseudolatex transdermal drug delivery system of diclofenac could be used successfully with improved performance and hold promise for further studies.     

Topical permeation characteristics of diclofenac sodium from NaCMC gels in comparison with conventional gel formulations.

Topical gel formulations of diclofenac sodium were prepared by using sodium carboxymethylcellulose (NaCMC), a low-toxicity cellulose polymer as a gel-forming material that is biocompatible and biodegradable. The influence of various formulation variables, such as initial drug concentrations and NaCMC concentration, and certain skin permeation enhancers on release characteristics of the diclofenac sodium from the prepared gels through a standard cellophane membrane was studied in comparison with four commercially available gel formulations of diclofenac sodium,. The cumulative amounts released and the apparent release rates were higher for the prepared gels in comparison with the commercial formulations. Skin permeation studies using abdominal rat skin revealed good improvement of skin permeation characteristics of diclofenac sodium using NaCMC gels as compared to the commercial gels. The cumulative amount permeated at 6 h (microg/cm2), steady-state flux Jss (microg/cm2 h), lag time tL (h), permeability coefficient kp (cm/s), partition coefficient k, and diffusion coefficient D (cm2/s) were determined for the prepared gels in comparison with the commercial gels. Skin permeation enhancers such as isopropyl alcohol (IPA), Tween 80, and alpha-tocopherol polyethylene glycol succinate (TPGS) exhibited little or no effect on the permeation characteristics of diclofenac sodium. Infrared (IR) spectrum and differential scanning calorimetry (DSC) studies on the pure diclofenac sodium, NaCMC, and their physical mixture at a 1:1 ratio revealed that there was no positive evidence for the interactions between the drug and NaCMC, indicating the compatibility of the drug and the vehicle. Based on experimental results, preparation of diclofenac sodium gels using NaCMC vehicle is promising.     

In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

This work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the serum drug profile following oral administration of the microcapsules and the commercial product to rabbits. The obtained serum concentration time profile of the EC microcapsules exhibited a sustained-release pattern similar to the commercial product and consistent with the in vitro results.     

Coated biodegradable casein nanospheres: a valuable tool for oral drug delivery

Abstract

Biodegradable casein nanospheres for the sustained release of bioactive molecules in the gastro-intestinal tract were prepared by precipitation polymerization using sodium methacrylate (NaMA) and N,N′-methylene bis-acrylamide (MEBA) as pH-responsive monomer and cross-linker. Three materials with different casein amount were obtained and characterized by scanning electron microscopy, dimensional analysis, water uptake, cytotoxicity and enzymatic degradation experiments. Nanospheres biodegradability was tuned by coating with polyacrylic acid. Coated and uncoated materials were investigated as delivery vehicles for diclofenac sodium salt. For un-coated samples, the release raise 100% in 30?h, while for coated specimens these values were lower than 70%, due to the diffusional constraints of polymer layer.     

In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

Abstract

This work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the serum drug profile following oral administration of the microcapsules and the commercial product to rabbits. The obtained serum concentration time profile of the EC microcapsules exhibited a sustained-release pattern similar to the commercial product and consistent with the in vitro results.     

Biopharmaceutical evaluation of diclofenac sodium controlled release tablets prepared from gum karaya--chitosan polyelectrolyte complexes

The phenomena of polymer interactions and formation of polyelectrolyte complexes (PECs) of oppositely charged polymers have been the focus of interest in fundamental and applied research. Such PECs may possess unique properties that are different from those of individual polymers. In the present study, attempts were made to prepare PECs of negative colloid gum karaya (GK) and positively charged polysaccharide chitosan (CH). The association and factors affecting the interactions between GK and CH were studied by pH and conductivity studies. The dried complexes were characterized by X-ray diffraction, Fourier transformed Infrared (FTIR) Spectroscopy, Scanning Electron Microscopy. The PECs were utilized for encapsulation of diclofenac sodium. Selected polyelectrolyte microparticles were compressed into tablets and were compared with commercial sustained release product Voveran SR?. Positive results of the study indicated the applicability of PECs in the design of oral controlled release drug delivery systems.     

Characterization of polyvinylalcohol microspheres of diclofenac sodium: application of statistical design

Microspheres of polyvinylalcohol (PVA) containing diclofenac sodium were prepared by an emulsion-chemical cross-linking method. A statistical design was used to study the variables that affect the preparation of microspheres and to study the release profile of diclofenac from the microspheres. To account for the drug content, a mass balance study of the process was performed. A high concentration of polyvinylalcohol, a high stirring speed, and a low level of glutaraldehyde were found to be important to obtain spherical and discrete microspheres. The concentration of polyvinylalcohol and the amount of heavy liquid paraffin were found to be critical factors in influencing the t₅₀ value. Almost 98% of the total diclofenac sodium added was accounted for in mass balance studies.     

Formulation and release behavior of diclofenac sodium in Compritol 888 matrix beads encapsulated in alginate

Sustained-release polymer beads containing diclofenac sodium (DNa) dispersed in Compritol 888 and encapsulated in calcium alginate shell were prepared utilizing 2³ factorial design. The effect of sodium alginate concentration, drug:Compritol 888 weight ratio and CaCl₂ concentration on drug content (%), time for 50% and 80% of the drug to be released, and mean dissolution time (MDT) were evaluated with analysis of variance (ANOVA). An increase in the level of all these factors caused retardation in the release, and t_50%, t_80%, and MDT were increased. The drug release was dependent on the pH of the release media. A formula that gives a release comparable to commercial products was prepared.     

Characterization of Polyvinylalcohol Microspheres of Diclofenac Sodium: Application of Statistical Design

Microspheres of polyvinylalcohol (PVA) containing diclofenac sodium were prepared by an emulsion-chemical cross-linking method. A statistical design was used to study the variables that affect the preparation of microspheres and to study the release profile of diclofenac from the microspheres. To account for the drug content, a mass balance study of the process was performed. A high concentration of polyvinylalcohol, a high stirring speed, and a low level of glutaraldehyde were found to be important to obtain spherical and discrete microspheres. The concentration of polyvinylalcohol and the amount of heavy liquid paraffin were found to be critical factors in influencing the t₅₀ value. Almost 98% of the total diclofenac sodium added was accounted for in mass balance studies.     

Effect of Sodium Caprate on the Absorption of Progesterone from Mixed Suppositories Administered to the Vagina of Rabbits

The promoting effect of sodium caprate (CAP) added to a progesterone mixed suppository was investigated in vitro and in vivo. The mixed suppository (S50), consisting of Witepsol W35 and ethylene-vinyl acetate copolymers (EVA40Y and EVA250); and a control suppository of Witepsol W35 (C50) were prepared by the fusion method. One or five percent of CAP was added to S50 and C50 containing 50 mg of progesterone. The release of progesterone from C50 was not influenced by the addition of CAP and there was no change in plasma level profile of progesterone after administration to the vagina of rabbits. On the other hand, S50 added with CAP showed rapid elevation of the plasma level of progesterone without any change in the sustained-release characteristics.