Preparation of codeine-resinate and chlorpheniramine-resinate sustained-release suspension and its pharmacokinetic evaluation in beagle dogs

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60°C, the outlet air temperature was 32-38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

Preparation and in vitro release of dual-drug resinate complexes containing codeine and chlorpheniramine

Objective: To develop the dual-drug resinate complexes containing codeine and chlorpheniramine with a novel batch processing, characterize the dual-drug resinate complexes, and study its drug release behavior in vitro. Methods: A procedure of simultaneous dual-drug loading using combination solutions composed of different proportions of codeine phosphate and chlorpheniramine maleate was performed to achieve the specific resinate, and the dual-drug loading content was determined by high-performance liquid chromatography method. The dual-drug resinate complexes were characterized by a scanning electron microscope, and the formation mechanisms were confirmed with X-ray diffraction analyses and differential scanning calorimetric analyses. The release behavior of the two drugs from the dual-drug resinate complexes in vitro was studied in the media simulating in vivo environments (simulated gastric fluid: pH = 1.2 HCl, simulated in vivo ionic strength: 0.15 M NaCl, and simulated intestinal fluid: pH = 6.8 buffer solution containing KH2PO4–NaOH). Results: Scanning electron microscopic analyses proved that the dual-drug resinate complexes had the same appearance and characters as the initiative ion exchange resins (IERs). Via X-ray diffraction and differential scanning calorimetric analyses, it is found that the two drugs in dual-drug resinate complexes were combined with IERs by chemical bond. The drug-resinate complex, like IER, was in amorphous state. More than 90% of codeine phosphate was released in 15 minutes in three different media, whereas little amount of chlorpheniramine maleate was released in all the release time in the medium pH = 1.2 HCl, and the release equilibrium time was about 5 minutes, only 40% was released in the medium 0.15 M NaCl, and the equilibrium time was 40 minutes, and about 90% was released in the medium pH = 6.8 KH2PO4–NaOH. The increased ionic strength generally accelerated the release of the two drugs from the dual-drug resinate complexes. Conclusion: The dual-drug resinate complexes were formed through the reaction between the drugs and the IERs by chemical bond. The release behavior of the drug from the dual-drug resinate complexes in vitro was mainly correlated with the drug molecular structure, the eluting ionic strength, composition, and ionic strength of the release media. The novel dual-drug resinate complexes could be used to deliver two drugs in one therapeutic dose.     

Effect of Process Variables on Drug Release from Microparticles Containing A Drug-Resin Complex

Abstract

Microparticles consisting of dextromethorphan-resin complex (resinate) coated with a cellulose derivative were prepared by a modified emulsion-solvent evaporation method. Adjustment of the release rate was achieved by varying resinate (core) to polymer (coat) ratio or by using additives. Higher ratios of resinate to polymer gave faster release of the drug. Polyethylene glycol (PEG) 4000 also increased the release rate. Increasing core to coat ratio also increased average particle size. Placing the emulsifying agent in different phases of the emulsion in the fabrication process also affected the particle size distribution. The microparticles showed good sustained release of the drug     

Evaluation of sustained release aqueous suspensions containing microencapsulated drug-resin complexes

Abstract

Cellulose Acetate Butyrate coated resinates released chlorpheniramine faster if the microcapsules were hydrated by suspension prior to release studies when compared to dry, unsuspended microcapsules. Contrasting a sulfonic acid resinate with a carboxylic acid resinate showed a reduced rate of release for chlorpheniramine from both coated and uncoated sulfonic acid resinates. Microcapsules of smaller diameter released chlorpheniramine faster than larger coated resinates of a similar batch. Microcapsules prepared under identical conditions released pseudoephedrine, diphenhydramine, and chlorpheniramine at different rates, with pseudoephedrine being released the fastest and chlorpheniramine the slowest. Aging of aqueous suspensions containing the coated resinates at room and elevated temperatures resulted in drug release profiles which were within experimental error.     

The Effect of Curing on Drug Release and Morphological Properties of Ethylcellulose Pseudolatex-Coated Beads

Abstract

Drug-containing nonpareil beads were coated in a fluidized bed with a commercial ethylcellulose pseudolatex, Aquacoat. The drug release was investigated as a function of curing conditions (curing time and temperature) for a hydrophilic and lipophilic drug (chlorpheniramine maleate and ibuprofen) at different levels of plasticizer (triethyl citrate). Curing of coated beads at elevated temperatures immediately after the coating process significantly changed the drug release pattern. Both a retardation and an enhancement in drug release were seen, with the extent being dependent on the type of drug and curing conditions. With chlorpheniramine maleate, a drug with low affinity for the ethylcellulose coating, a curing step was necessary at intermediate plasticizer levels to obtain good film formation and a limiting drug release pattern, while the use of higher plasticizer levels eliminated the need for a curing step. With ibuprofen, a lipophilic drug with high solubility in the ethylcellulose coating, drug crystals were apparent on the bead surface after curing. Curing of ibuprofen beads as a function of time initially decreased but then substantially increased the drug release as a result of drug diffusion across the ethylcellulose membrane with subsequent crystallization on the bead surface. An intermediate seal coat reduced the diffusion of the drug into the ethylcellulose coating.     

Taste masking of azithromycin by resin complex and sustained release through interpenetrating polymer network with functionalized biopolymers

Abstract

Objective: The objective was to evaluate taste masking of azithromycin (AZI) by ion exchange resins (IERs) and the formation of covalent semi interpenetrating polymer network (IPN) beads using chitosan (CS) and sodium carboxylated agarose (SCAG) for sustained release of drug.

Methods: Methacrylic acid (MAA)-based IERs were prepared by suspension polymerization method. Drug release complexes (DRCs) were prepared by different drug:resin ratios i.e. 1:1, 1:2 and 1:4. The resultant DRCs were characterized using DSC, FTIR, PXRD, in vivo and in vitro taste masking, and in vitro drug release at gastric pH. IPN beads were prepared by entrapping DRCs with bio polymers and cross linked with trisodium citrate (NaCIT), and further cross-linked with glutaraldehyde (GA) for sustained release of AZI.

Results: In vitro and in vivo taste masking studies showed that MD1:4 DRC formulation was optimal. The release of AZI from DRC was found to be very fast at gastric pH i.e. 97.37?±?1.02% within 45?min. The formation of IPN beads was confirmed by FTIR. The release of drug from IPN beads at gastric and intestinal pH was found to be “<28% and <60%”, respectively. The release kinetics showed Fickian diffusion profile for ionically cross-linked beads and zero-order release mechanism for GA cross-linking beads.

Conclusions: DRCs can be effectively used for taste masking and newly formulated IPN beads demonstrated sustained release of AZI.     

Dissolution Controlled Drug Release from Agarose Beads

Abstract

A simple method was used for loading ibuprofen or indomethacin into agarose beads to obtain sustained release. Placebo beads were prepared by a dropwise addition of a hot aqueous agarose solution into a beaker of chilled mineral oil and water. Prior to loading, the aqueous component in the beads was replaced by repeated soakings in ethanol. Loading was accomplished at room temperature using ethanolic drug solutions. Upon drying, the beads shrank to about a third of their original size. The surface morphology of dried placebo and loaded beads was studied using electron microscopy. The release time at 37° C and pH 7.5 increased with drug loading and at 50% loading the release time was 4 hours for indomethacin and 6 hours for ibuprofen. Release of chlorpheniramine from dried and swollen beads was examined to elucidate the release mechanism. From dissolution studies it was concluded that the delay due to swelling is less than 10 minutes, chlorpheniramine release from swollen beads was primarily diffusion controlled, and the release mechanism for indomethacin and ibuprofen has three components: i) swelling of the beads, ii) dissolution of crystallized drug, and iii) diffusion of dissolved drug from the beads.     

The Effect of Curing on Drug Release and Morphological Properties of Ethylcellulose Pseudolatex-Coated Beads

Drug-containing nonpareil beads were coated in a fluidized bed with a commercial ethylcellulose pseudolatex, Aquacoat. The drug release was investigated as a function of curing conditions (curing time and temperature) for a hydrophilic and lipophilic drug (chlorpheniramine maleate and ibuprofen) at different levels of plasticizer (triethyl citrate). Curing of coated beads at elevated temperatures immediately after the coating process significantly changed the drug release pattern. Both a retardation and an enhancement in drug release were seen, with the extent being dependent on the type of drug and curing conditions. With chlorpheniramine maleate, a drug with low affinity for the ethylcellulose coating, a curing step was necessary at intermediate plasticizer levels to obtain good film formation and a limiting drug release pattern, while the use of higher plasticizer levels eliminated the need for a curing step. With ibuprofen, a lipophilic drug with high solubility in the ethylcellulose coating, drug crystals were apparent on the bead surface after curing. Curing of ibuprofen beads as a function of time initially decreased but then substantially increased the drug release as a result of drug diffusion across the ethylcellulose membrane with subsequent crystallization on the bead surface. An intermediate seal coat reduced the diffusion of the drug into the ethylcellulose coating.     

Evaluation of sustained release aqueous suspensions containing microencapsulated drug-resin complexes

Cellulose Acetate Butyrate coated resinates released chlorpheniramine faster if the microcapsules were hydrated by suspension prior to release studies when compared to dry, unsuspended microcapsules. Contrasting a sulfonic acid resinate with a carboxylic acid resinate showed a reduced rate of release for chlorpheniramine from both coated and uncoated sulfonic acid resinates. Microcapsules of smaller diameter released chlorpheniramine faster than larger coated resinates of a similar batch. Microcapsules prepared under identical conditions released pseudoephedrine, diphenhydramine, and chlorpheniramine at different rates, with pseudoephedrine being released the fastest and chlorpheniramine the slowest. Aging of aqueous suspensions containing the coated resinates at room and elevated temperatures resulted in drug release profiles which were within experimental error.     

Influence of Formulation and Other Factors on the Release of Chlorpheniramine Mateate from Polymer Coated Beads

Abstract

Controlled release beads containing chlorpheniramine maleate, coated with Eudragit RL and RS, were prepared using the Wurster process. The effect of membrane thickness, polymer ratio of the coating material, agitation speed and pH of the dissolution medium on drug release were investigated using the USP dissolution basket method. The in vitro release of drug was described adequately by a previously published equation. The release rate constant (K) was dependent on the membrane thickness, the polymer ratio and pH of the dissolution medium. On the other hand, agitation speed used in this study did not have any influence on the release of the drug.     

Cyclodextrin Complex Osmotic Tablet for Glipizide Delivery

ABSTRACT

Poorly soluble glipizide was selected as the model drug to prepare osmotic pump tablets (OPT) with proper accessorial material after it was made an inclusion complex by kneading method in order to increase solubility. Polyethylene glycol 4000 (PEG4000) and cellulose acetate (CA) were selected as the coating materials, and acetone–water (95:5) co-solvent was employed as the coating medium. The effects of the osmotic promoting agent, diameter of the drug-releasing orifice, coating composition, and coat weight on the drug release profile were investigated. The drug release profile of the optimal formulation was compared with a commercialized push–pull osmotic tablet. The results indicated that glipizide–cyclodextrin inclusion complex OPT had excellent zero-order release characteristics in vitro.     

Studies on in vitro release of CPM from semi-interpenetrating polymer network (IPN) composed of chitosan and glutamic acid

Interpenetrating polymer network (IPN) beads consisting of chitosan-glutamic acid were prepared for in vitro study of controlled release of chlorpheniramine maleate (CPM). A viscous solution of chitosan-glutamic acid was prepared in 2% acetic acid solution, extruded as droplets through a syringe to alkalimethanol solution and the precipitated beads were crosslinked using glutaraldehyde solution. Swelling and drug release studies were carried out. Transport of release medium through the semi-IPN depended upon its pH and extent of crosslinking. The structural and morphological studies of beads were carried out by using a scanning electron microscope (SEM). The larger surface area of beads as well as their ease of handling makes them ideal agents of controlled release.     

Reformulation of a codeine phosphate liquid controlled-release product

Background: Ion-exchange resins have been successfully used to create drug formulations providing controlled drug release that are easy to swallow, are sufficiently stable, and have good taste-masking characteristics. The objective of the present study was to replace the ion-exchange resin in a proven delayed release codeine preparation with a new resin able to provide the beneficial properties of the original formulations without the need for Eudragit coating to comply with modern manufacturing regulations. Methods: Nine cationic exchangers with different particle meshes, form, and pore structures were optimally loaded with codeine and their respective in vitro codeine release profiles were compared using the USP XXIII paddle method. Results: The most favorable release profiles were obtained with Amberlite IR 69 F and with Dowex 50 × 8?100. The former was used to prepare the formulated drug–resin complexes as it was available in a pharmaceutically pure form. Both, the cough syrup and concentrate formulations exhibited drug release profiles equivalent to the nonformulated drug–resin complex. These profiles as well as initial free codeine levels, the purity, and the identity were moreover maintained for a storage period of at least 6 months. Conclusion: The in vitro dissolution profiles demonstrated that the use of ion exchanger is most suitable for the development of sustained release codeine formulations.     

Rheological investigation and its correlation with permeability coefficient of drug loaded carbopol gel: influence of absorption enhancers

Context: The present study was planned to investigate the effect of absorption enhancers on the microstructure of Losartan potassium gel and hence its influence on the diffusion of Losartan potassium across nasal mucosa.

Method: Losartan potassium loaded carbopol gel (1% w/v) with and without absorption enhancers was prepared. Polyethylene glycol (PEG) 4000 and ethanol were used as absorption enhancers. Microstructural elucidation of prepared gels was done using shear rheology. Ex vivo drug release studies were performed on the prepared gels.

Results: It was observed that the absorption enhancers PEG 4000 and ethanol altered the gel microstructure. The prepared gels were viscoelastic in nature suggesting their suitability for topical application. Permeability coefficient of Losartan potassium loaded into gels was found to be inversely proportional to the storage modulus. Thus increase in storage modulus lead to slow drug diffusion.

Conclusion: The current study emphasizes on the fact that selection of polymeric carrier for nasal drug delivery and/or absorption enhancer strongly influence the microstructure of the gel and hence the pharmaceutical performance of the formulation.     

Development and physicochemical characterization of clindamycin resinate for taste masking in pediatrics

Purpose: To evaluate the physicochemical characteristics of clindamycin HCl in a complex form (resinate) with ion exchange resin (IER) (Amberlite IRP69).

Methods: Drug–resin complex was prepared by simple aqueous binding method. Drug binding study was carried out at different drug and resin concentrations. Several physicochemical characterization studies were conducted to evaluate the resinate complex. These studies included flow properties, in vitro drug release in SGF and SIF, DSC, TGA, mass spectroscopy and XPRD evaluations. In addition, stability study of resinate complex was conducted at 25?and 40?°C for up to 1 month.

Results: Clindamycin and Amberlite IRP69 have formed a complex (resinate) and have shown good flow properties, good thermal properties and chemical stability (short term over 4 weeks) at 25 and 40?°C. Clindamycin release profiles from resinate in SGF and SIF have shown immediate release characteristics and release in simulated saliva has shown dependence on water volume.

Conclusion: The clindamycin stable complex with IER (Amberlite IRP69) has the potential for further development as a compatible pediatric liquid formulation (suspension) or a fast disintegrating tablet.     

Controlled release multiple layer coatings

Purpose: In a fluid-bed coating machine, the coating solutions are normally sprayed using a manually controlled peristaltic pump. This study provides a process where two or more coating solutions can be sprayed consecutively using two or more syringe pumps controlled by a computer, to form multiple layers. In this process, the spraying parameters can be controlled easily from a computer. Methods: Propranolol HCl was used as a model drug. Nine different drug-loaded controlled release coated beads were prepared by using a combination of ethylcellulose and/or chitosan solutions. The pulse-coated beads were prepared by changing the spray rate and/or volume of the polymer solutions. Results: There was a fourfold increase (18 versus 75 minutes) in lag time when the same amount of ethylcellulose (4 g) was dissolved in 100 mL of ethanol instead of 160 mL. When the same amount of drug and ethylcellulose solution was applied on the acrylic coated beads as multiple layers coating, the lag time decreased to only 6 minutes. Similarly, the 50% drug release time also decreased significantly. Conclusion: An overall comparison of the dissolution profiles showed that drug release from these coated beads was changed significantly when the sequence of the drug and polymer layers was changed.     

Pharmacokinetics of a novel liquid controlled release codeine formulation

Codeine is an important opioid anti-tussive agent whose short half-life (2.9?±?0.7?h) requires that it be administered at 4-h intervals when formulated as a simple aqueous solution. Liquid controlled release codeine formulations such as an older Codipertussin^® formulation, which contained codeine bound to an ion exchange resin and coated with a retardant polymer, achieved an equivalent bioavailability when administered every 12?h. An accompanying paper described the development and in vitro characterization of a novel Codipertussin^® formulation containing a non-coated codeine:ion exchange resin (Amberlite IR 69 F) complex. In this study, the bioavailability of codeine from this new liquid controlled release formulation was investigated in an open label, single center, randomized, steady-state, cross-over study in healthy male volunteers. Participants received either 69.7?mg codeine as the controlled release liquid form every 12?h or 23.2?mg codeine in solution every 4?h. Controlled release from the suspension of beads protracted the apparent mean half life of codeine from 3.2?h to 8.2?h, while the mean AUC_{0–12 h} was unchanged. In vivo codeine release profiles were further derived by the numerical deconvolution method, using the data from the drug solution as weighting function for the body system. Comparison of the data obtained with the in vitro release data presented in our earlier work showed an acceptable in vitro–in vivo correlation, which was described as in vitro–in vivo relationship, indicating the power of the in vitro method to predict in vivo pharmacokinetic behavior.     

Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride

The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box–Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30?s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1?min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.     

Formulation and evaluation of meloxicam oral disintegrating tablet with dissolution enhanced by combination of cyclodextrin and ion exchange resins

Context: The bitter taste of drug is masked by the exchange of ionized drugs with counter ions of ion exchange resin, forming “resinate”. Cyclodextrin reduces the unpleasant taste and enhances the drug solubility by encapsulating drug molecules into its central cavity.

Objective: Oral disintegrating tablets (ODTs) using the combination of ion exchange resin and cyclodextrin was developed, to mask the bitter taste and enhance drug dissolution.

Methods: Meloxicam (MX) was selected as a model drug. Formulations containing various forms of MX (free drug, MX-loaded resin or resinate, complexes of MX and 2-hydroxypropyl-β-cyclodextrin (HPβCD) or MX/HPβCD complexes, and a mixture of resinate and MX/HPβCD complexes) were made by direct compression. The ODTs were evaluated for weight variation, thickness, diameter, hardness, friability, disintegration time, wetting time, MX content, MX release, degree of bitter taste and stability.

Results and discussion: The tablet hardness was ～3?kg/in², and the friability was <1%. Tablets formulated with resinate and the mixture of resinate and MX/HPβCD complexes disintegrated rapidly within 60?s, which is the acceptable limit for ODTs. These results were corresponded to the in vivo disintegration and wetting times. However, only tablets containing the mixture of resinate and MX/HPβCD complexes provided complete MX dissolution and successfully masked the bitter taste. In addition, this tablet was stable at least 6 months.

Conclusions: The combination of ion exchange resin and cyclodextrin could be used in ODTs to mask the bitter taste and enhance the dissolution of drugs that are weakly soluble in water.     

Design of a timed and controlled release osmotic pump system of atenolol

The objective of the article was to design a novel timed and controlled release osmotic pump (TCOP) containing atenolol as an active pharmaceutical ingredient and compare with a bilayer-core osmotic pump (BCOP) of atenolol. Different from BCOP, a modulating barrier was added to delay the drug release and obtain desired lag time (T_lag). The influences of the amount of pore-forming agent and modulating barrier, coating weight gain on the lag time (T_lag) and drug release rate (R_t) of TCOP were investigated. The central composite design-response surface methodology (RSM) was applied to optimize the formulation. Rhodamine B was added to modulating barrier to determine the release process of modulating barrier. A method used to correct the release profiles with a certain lag time by ΔT_lag and interpolating was applied to compare TCOP with BCOP. T_lag was directly proportional to the amount of modulating barrier and coating weight gain, but inversely related to the amount of pore forming agent, which were contrary to the effects on R_t. The optimal formulation including 60?mg PEO WSR N80, 3?g PEG 4000 and 6% coating weight gain could obtain a 3.59-h T_lag. According to the release of Rhodamine B, the modulating barrier was completely pushed out at ～5.0?h, longer than 3.59?h, therefore, atenolol along with remaining modulating barrier was released together between 3.59 and 5.0?h. By comparing with BCOP, the release profiles subtracting the part of lag time had no significant difference, yet R_t of TCOP presented a slight decrease.