Evaluation of dibutyrylchitin as new excipient for sustained drug release

Dibutyrylchitin (DBC), a lipophilic chitin diester, has been synthesized from chitin and butyric anhydride with methanesulfonic acid as catalyst. Exhaustive esterification of free alcoholic groups of chitin was assessed by FT-IR and (1)H-NMR spectroscopy. High degree of alkyl substitution allowed DBC to acquire an almost completely lipophilic character. Tablets of paracetamol and metformin employing DBC as major excipient, in comparison with starch, microcrystalline cellulose, lactose and polyvinylpyrrolidone, were prepared and rates of drug release were checked by dissolution test assays. DBC released drug at a lower rate than that of the other tested materials. A comparison study of rate release of metformin from DBC tablets and from metformin-hydroxypropyl methylcellulose prolonged release oral formulation available on the market has been also curried out. Under the same conditions and in the presence of the same amount of loaded drug, DBC released 64% of metformin whereas hypromellose-based tablets released 87%.     

Soluble filler as a dissolution profile modulator for slightly soluble drugs in matrix tablets

The purpose of this experimental work was the development of hydrophilic–lipophilic matrix tablets for controlled release of slightly soluble drug represented here by diclofenac sodium (DS). Drug dissolution profile optimization provided by soluble filler was studied. Matrix tablets were based on cetyl alcohol as the lipophilic carrier, povidone as the gel-forming agent, and common soluble filler, that is lactose or sucrose of different particle size. Physical properties of tablets prepared by melt granulation and drug release in a phosphate buffer of pH 6.8 were evaluated. In vitro studies showed that used filler type, filler to povidone ratio and sucrose particle size influenced the drug release rate. DS dissolution profile could be changed within a wide range from about 50% per 24 hours to almost 100% in 10 hours. The release constant values confirmed that DS was released from matrices by the diffusion and anomalous transport. The influence of sucrose particle size on the drug release rate was observed. As the particle size decreased, the drug release increased significantly and its dissolution profile became more uniform. Soluble fillers participated in the pore-forming process according to their solubility and particle size. Formulations containing 100 mg of the drug, 80 mg of cetyl alcohol, 40 mg of povidone, and 80 mg of either lactose or sucrose (particle size 250–125 μm) were considered optimal for 24-hour lasting dissolution of DS.     

Immediate release of ibuprofen from Fujicalin®-based fast-dissolving self-emulsifying tablets

Background: Drug release from a solid form of self-emulsifying drug delivery system (SEDDS) has greatly been limited due to strong adsorption and physical interaction with carriers. To facilitate drug release process in the stomach, an acid-soluble powderizing carrier, Fujicalin^® was evaluated together with different disintegrants and hydrophilic lubricants. Method: Immediate-release self-emulsifying tablets (IR-SETs) of ibuprofen (IBU) was prepared with solidified SEDDS of IBU, various disintegrants, and lubricants, and drug release was evaluated to develop IR-SET that can release IBU with a similar IBU release rate to that obtained with liquid SEDDS. Results: The liquid SEDDS consisted of Capryol 90, Cremophor EL, Labrasol, and IBU at a ratio of 3:4:3:3, and was solidified with various adsorbents. The powderized SEDDS was tabletted by a direct compression. Fujicalin^®-based SEDDS tablets demonstrated remarkably higher dissolution rate of IBU compared with Neusilin^® and Neosyl^®-based SEDDS tablets. The IR-SET formula of IBU prepared with Fujicalin^® as an adsorbent, Polyplasdone^® as a disintegrant, and sodium bicarbonate as a co-disintegrant showed over 90% of initially loaded dose of IBU released within 5?min in a stimulated gastric juice (pH 1.2), exhibiting almost equivalent rate of IBU release to that shown by liquid SEDDS. The particle size analysis revealed no significant differences in droplet sizes of the microemulsions formed from liquid (116?nm) and IR-SET (110?nm). Conclusion: The novel IR-SET can be promising as a fast-releasing SEDDS tablet of IBU for fast onset of action.     

Water based silicone elastomer controlled release tablet film coating VI: The effect of tablet shape

Abstract

The silicone elastomer latex containing colloidal silica and poloyoxyethylene glycol 8,000 was shown to produce controlled released film coating on potassium chloride tablets with different shapes. The tablet shape did not affect the zero-order release characteristic of the active ingredinent from the coated tablests. With the same coating weight, the capsule shaped tablets exhibited a faster drug release rate as compared to the oval and round deep-cup shaped tablets.     

The use of liquid self-microemulsifying drug delivery systems based on peanut oil/tween 80 in the delivery of griseofulvin

Peanut oil and Tween 80 blends devoid of any cosurfactant were employed in the formulation of different batches of liquid self-microemulsifying drug delivery systems (LSMEDDS) and their suitability as vehicles for the delivery of a typical lipophilic drug-griseofulvin-was investigated. The LSMEDDS were evaluated using the following parameters: phase separation, globule size, viscosity, solubility of griseofulvin, and partition coefficient. The release profile of griseofulvin from the optimized LSMEDDS was evaluated in citrate/phosphate buffer solutions of pH 2.0, pH 6.5, and pH 7.4. The results obtained indicated that there was significantly higher (alpha 相似文献   

Evaluation of hydrophilic,hydrophobic and waxy matrix excipients for sustained release tablets of Venlafaxine hydrochloride

Objective: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets.

Materials and methods: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism.

Results: Dissolution data showed that commercial formulations Venlor XR^® and Venfax PR^® released the entire drug withIn 8?h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14–15?h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively.

Conclusion: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.     

Development and comparative evaluation of in vitro,in vivo properties of novel controlled release compositions of paroxetine hydrochloride hemihydrate as against Geomatrix™ platform technology

The objective of this study is to develop, in vitro and in vivo evaluation of novel approaches for controlled release of paroxetine hydrochloride hemihydrate (PHH) in comparison to patented formulation PAXIL CR^® tablets of GlaxoSmithKline (Geomatrix? technology). In one of the approaches, hydrophilic core matrix tablets containing 85% of the dose were prepared and further coated with methacrylic acid copolymer to delay the release. An immediate release coating of 15% was given as top coat. The tablets were further optionally coated using ethyl cellulose. In the second approach, hydrophobic matrix core tablets containing metharylic acid copolymer were prepared. In the third approach, PHH was granulated with enteric polymer and further hydrophobic matrix core tablets were prepared. The effect of polymer concentration, level of enteric coating on drug release was evaluated by in vitro dissolution study by varying dissolution apparatus and the rotation speeds. It was found that increase in concentration of high viscosity hydroxypropylmethylcellulose (HPMC) resulted in reduction of the release rate. The drug release was observed to be dependent on the level of enteric coating and ethyl cellulose coating, being slower at increased coating. The release mechanism of PHH followed zero-order shifting to dissolution dependent by the increase of HPMC content. The formulation was stable without change in drug release rate. In vivo study in human volunteers confirmed the similarity between test and innovator formulations. In conclusion, HPMC-based matrix tablets, which were further coated using methacrylic acid copolymer, were found to be suitable for the formulation of single layer-controlled release PHH.     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit^® RS 30D were developed and beads were produced by extrusion–spheronization. Drug beads were coated using 15% wt/wt Surelease^® or Eudragit^® NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm³ and size of 855 μm were quite close to Surelease^®-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease^®-coated beads; 5.7 ± 1.0 kP and 0.26 ± 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease^®-coated theophylline beads released drug fastest overall (t_44.2% = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease^®-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease^®-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease^® films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.     

Release Kinetics and Availability of Mebeverine Hydrochloride from Polycarbophil Loaded by Swelling

The release rate and mechanism of release of mebeverine hydrochloride were studied for commercial “Duspatalin” tablets and for different tablet formulations (F₁, F₂ & F₃) containing 20, 40 and 65% polycarbophil, respectively. The formulated granules were obtained by freeze drying of polycarbophil granules loaded with aqueous solution of the drug at 25°C by swelling of the polymer. The release of mebeverine hydrochloride from prepared tablet formulations was faster than that of Duspatalin tablets. The release rate of the drug increased as the polycarbophil content of the tablets increased. The calculated correlation coefficients for the release data fitted to various models showed that the release from Duspatalin tablets and F₂ follow first order kinetics, while release of F₁ approaches that of zero order. The release mechanism from F₃ could not be determined. DSC thermograms showed that there is an interaction between the drug and the polymer in aqueous medium, but not in the solid state.

The in-vivo guinea-pig studies revealed that mebeverine hydrochloride was released and absorbed from the tested formula (F₃), depressed the agonists-induced contractions 2 hrs after treatment but not after 4 hrs indicating rapid absorption and metabolism. The percentage inhibitions ranged from 40–85%. The treatment seems to antagonise barium chloride (BaCl₂)-induced contractions more than those induced by carbochol.     

Formulation Design of an HPMC-Based Sustained Release Tablet for Pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0–t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Dissolution Study of Prolonged Release Morphine Tablets Using Hydrophilic Matrices

This study presents the results of “in vitro” dissolution of prolonged release morphine tablets using hydroxypropylmethylcellulose. Tablets with four different doses were elaborated and the liberation from these formulated tablets was compared with that of the only commercial pharmaceutical preparation of this type registered in the Spanish Pharmaceutical Market.

The results of the dissolution tests show that the drug was gradually released in all cases and tablets had released from 60 to 90% of its contents after 8 hours.

In the comparative study, the commercial tablets showed the fastest release. In both cases the release rate was lower when artificial intestinal fluids were used as the dissolution medium.     

The effect of carboxymethyl chitin on sustained drug release of aspirin tablet

Carboxymethyl chitin (CM-chitin) was prepared at room temperature and characterized using ¹H NMR, FTIR and elemental analysis methods. The prepared CM-chitin was then used as a hydrophilic matrix for the preparation of the aspirin sustained release tablets via the wet granulation technique. The aspirin release profiles of the prepared tablets in a simulated gastric fluid and simulated intestinal fluid, respectively, were studied with the rotating-basket dissolution method. The results showed that the aspirin release rate in simulated gastric fluid was lower than that in simulated intestinal fluid. Thus, CM-chitin proved to be a pH-sensitive hydrophilic matrix.     

Blinding Controlled-Release Tablets for Clinical Trials

Abstract

The objective of the current study was to develop a method to blind commercially available Wellbutrin® SR 150 mg sustained-release tablets for a clinical study. Overcoating was selected as the most appropriate blinding method. Hydroxypropyl methylcellulose (Opadry® II) containing red iron oxide and titanium dioxide was applied to the Wellbutrin tablets at coating levels ranging from 0.5% to 4% weight gain. When compared against the uncoated product, no significant differences in drug release were noted over an 8-hr period. Matching placebo tablets, prepared using specially designed tablet tooling, were coated with the same cellulosic polymer that was used for the active. The coated active and placebo tablets were virtually indistinguishable. To test the applicability of this overcoating technique for blinding other controlled release products, the same procedure was used to coat Glucotrol® XL 5 mg tablets and Theo-Dur 200 mg tablets. The debossing on the Theo-Dur tablets and the laser-drilled hole on the surface of the Glucotrol tablets prevented blinding. The Theo-Dur tablets were mechanically weak and not able to withstand the coating process. Dissolution testing revealed significantly higher amounts of drug were released from the blinded Glucotrol tablets compared to the unblinded product at the 12 hr time point. The findings from this study suggest that overcoating with pigmented hydroxypropyl methylcellulose may not be useful for blinding all controlled-release tablets.     

Water based silicone elastomer controlled release tablet film coating VI: The effect of tablet shape

The silicone elastomer latex containing colloidal silica and poloyoxyethylene glycol 8,000 was shown to produce controlled released film coating on potassium chloride tablets with different shapes. The tablet shape did not affect the zero-order release characteristic of the active ingredinent from the coated tablests. With the same coating weight, the capsule shaped tablets exhibited a faster drug release rate as compared to the oval and round deep-cup shaped tablets.     

In-Vitro Release and In-Vivo Availability of Chloro-Quine Phosphate Formulated Suppositories

Abstract

Chloroquine phosphate suppositories were formulated using witepsol H15 as a model base. The physicomechanical properties of the prepared suppositories were studied. In-vitro drug release as well as in-vivo availability were determined and compared with those from commercial tablets containing the same dose of the drug (250 mg). In addition, the effect of pH of the different segments of GIT on the partition coefficient of the drug was tested

Results revealed that formulated suppositories exhibit good mechanical properties as well as high release characteristics. Volunteers received suppositories showed urine peak level after 2 hrs while with those administered the tablets the peak was reached after 3 hrs. The total amounts released were 60% and 48% from the administered dose in case of suppositories and tablets respectively. The higher bioavailability of the medicament after rectal therapy is explained on the basis of the partition coefficient data. The obtained values were 0.667, 0.941 and 5.333 at pH 1.2, 6.8 and 7.4 respectively. Volunteers used the formulated suppositories did not suffer from any GI irritation which is accompanying the oral administration of the drug. The proposed formula had no irritating effect on the rectum     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

Sustained-release from Layered Matrix System Comprising Chitosan and Xanthan Gum

ABSTRACT

Sustained-release tablets of propranolol HCl were prepared by direct compression using chitosan and xanthan gum as matrix materials. The effective prolongation of drug release in acidic environment was achieved for matrix containing chitosan together with xanthan gum which prolonged the drug release more extensive than that containing single polymer. Increasing lactose into matrix could adjust the drug release characteristic by enhancing the drug released. Component containing chitosan and xanthan gum at ratio 1:1 and lactose 75% w/w was selected for preparing the layered matrix by tabletting. Increasing the amount of matrix in barrier or in middle layer resulted in prolongation of drug release. From the investigation of drug release from one planar surface, the lag time for drug release through barrier layer was apparently longer as the amount of barrier was enhanced. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi's and zero order) was performed to study the drug release mechanism. Layering with polymeric matrix could prolong the drug release and could shift the release pattern approach to zero order. The drug release from chitosan-xanthan gum three-layer tablet was pH dependent due to the difference in charge density in different environmental pH. FT-IR and DSC studies exhibited the charge interaction between of NH₃⁺ of chitosan molecule and COO^? of acetate or pyruvate groups of xanthan gum molecule. The SEM images revealed the formation of the loose membranous but porous film that was due to the gel layer formed by the polymer relaxation upon absorption of dissolution medium. The decreased rate of polymer dissolution resulting from the decreased rate of solvent penetration was accompanied by a decrease in drug diffusion due to ionic interaction between chitosan and xanthan gum. This was suggested that the utilization of chitosan and xanthan gum could give rise to layered matrix tablet exhibiting sustained drug release.     

Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine

ABSTRACT

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Formulation and In Vitro Studies of a Fixed-Dose Combination of a Bilayer Matrix Tablet Containing Metformin HCl as Sustained Release and Glipizide as Immediate Release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the . The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.