A long acting ophthalmic gel formulations of atenolol

The main aim of pharmacotherapeutics, is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. In this study a trial was made to formulate atenolol, which is a beta-adrenergic blocker in a topical ophthalmic gel. Two polymers were used in this study, carboxymethylcellulose and sodium alginate in different concentrations. Atenolol was used in concentrations 0.5, 1, and 1.5% w/v. The in vitro release study was carried out. The results showed that the release rate of atenolol from gel preparations decreased as an inverse function of polymer concentration, while the release rate of the drug increased as the initial concentration increased. The data of drug release from the two polymers in different concentrations was plotted against the square root of time, and the diffusion coefficients (D), were calculated from the slope of the equation.

Intra-ocular pressure (IOP) measurements of the rabbit's eye treated with 1% w/v atenolol solution, and 1% w/v atenolol in two gel formulations with different concentrations of the polymer were determined. The two gel formulations showed that these polymers extended the duration of pressure reducing effect to 8 hr, when compared with atenolol solution. Area above the curve (AAC), maximum response, maximum time of response (t_max), and the duration of action were calculated.

The overall results of this study indicated that the gel formulations of atenolol could be used for the development of a long-acting ophthalmic formulation.     

Effect of Excipient and Processing Variables on Adhesive Properties and Release Profile of Pentoxifylline From Mucoadhesive Tablets

ABSTRACT

The bioavailability and onset of action of drugs with high first-pass metabolism can be significantly improved by administration via the sublingual route. The objective of this study was to evaluate the effect of polymer type and tablet compaction parameters on the adhesive properties and drug release profile from mucoadhesive sublingual tablet formulations. Pentoxifylline was selected as the model drug because it has poor oral bioavailability due to extensive first-pass metabolism. Two polymers known to possess mucoadhesive properties, carbomer and hydroxypropyl methyl cellulose (HPMC), were used to prepare the formulations. Tablets were prepared by using direct compression technique and evaluated for in vitro dissolution, drug-excipient interactions, and adhesive properties. In general, there was a decrease in the rate of drug release with an increase in the concentration of polymers. No drug-excipient interactions were evident from differential scanning calorimetry or high-performance liquid chromatography analysis. For the formulations containing HPMC, the force of mucoadhesion increased with an increase in the concentration of polymer; however, for carbomer formulations, no such correlation was observed. Force of mucoadhesion decreased as a function of hydration time in both of the polymers.     

Effect of excipient and processing variables on adhesive properties and release profile of pentoxifylline from mucoadhesive tablets

The bioavailability and onset of action of drugs with high first-pass metabolism can be significantly improved by administration via the sublingual route. The objective of this study was to evaluate the effect of polymer type and tablet compaction parameters on the adhesive properties and drug release profile from mucoadhesive sublingual tablet formulations. Pentoxifylline was selected as the model drug because it has poor oral bioavailability due to extensive first-pass metabolism. Two polymers known to possess mucoadhesive properties, carbomer and hydroxypropyl methyl cellulose (HPMC), were used to prepare the formulations. Tablets were prepared by using direct compression technique and evaluated for in vitro dissolution, drug-excipient interactions, and adhesive properties. In general, there was a decrease in the rate of drug release with an increase in the concentration of polymers. No drug-excipient interactions were evident from differential scanning calorimetry or high-performance liquid chromatography analysis. For the formulations containing HPMC, the force of mucoadhesion increased with an increase in the concentration of polymer; however, for carbomer formulations, no such correlation was observed. Force of mucoadhesion decreased as a function of hydration time in both of the polymers.     

Formulation and in vitro evaluation of a thermoreversible mucoadhesive nasal gel of itopride hydrochloride

Itopride hydrochloride (ITO HCl) is a prokinetic agent, used in the treatment of gastrointestinal motility disorders. The aim of the study was to develop stable mucoadhesive thermoreversible nasal gel to avoid first pass effect. ITO HCl was incorporated into the blends of thermoreversible polymers like poloxamer 407 and various mucoadhesive polymers in different concentrations to increase the contact of the formulations with nasal mucosa. The compatibility between the drug and the suggested polymers was studied by Fourier transform infrared and differential scanning calorimetry (DSC). The formulations were evaluated for clarity, pH, gelation temperature, mucoadhesive strength, gel strength, viscosity, and drug content. In addition, the in vitro drug release and the dissolution efficiency (DE)% were measured. The optimized formulations that showed the highest dissolution efficiency% (DE%) in saline phosphate buffer of pH 6.4 at 35?±?0.5?°C were chosen for stability testing at temperatures of 4?±?2 and 25?±?2?°C/60?±?5% RH. It was found that F1 and F17 that contain 18% w/v poloxamer 407 and 0.5% w/v of hydroxypropylmethyl cellulose K4M or methyl cellulose (MC), respectively, showed higher stability results as indicated by their higher t₉₀ values (days).     

Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: rheology, in vitro drug release, and in vivo resident property

To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of such in situ gel ophthalmic formulations, were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. It was also shown that the drug concentration had no obvious effect on drug release. The release rates of drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount increased by 4-fold and 1.2-fold for in situ gel compared with eye drops. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. The results showed that the Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery.     

Rheological,mechanical, and bioadhesive behavior of hydrogels to optimize skin delivery systems

Background: Hydrogels are widely used for cutaneous formulations; thereby comparing the bioadhesive properties of polymers with a view to prolong the residence time of topical drugs on the skin would be very useful to design novel topical drug delivery systems.

Aim: The objective of this study was to correlate data from rheological studies and texture profile analysis, with bioadhesion on the skin.

Methods: Polyacrylic acid polymers used were carbomer homopolymer type A (C971) and type B (C974), and polycarbophil (PP) dispersed in water at various concentrations (0.1, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0%, w/v). Rheological, texture, and bioadhesive properties were determined to compare the hydrogels.

Results: Rheological analysis showed that all samples exhibited pseudoplastic behavior with thixotropy. Texture profile analysis showed that compressibility, hardness, and adhesiveness of the hydrogels were dependent on the polymer concentration, and the cohesion values were high. Bioadhesion of C974 and PP at 0.5 and 2% was of the same magnitude, while all samples of C971 had lower values. The bioadhesion of 5% C974 was the highest, while that 5% PP was lower, possibly because PP showed the greatest hardness and this rigidity may decrease the interaction of the polymer with the skin.

Conclusion: A comprehensive comparative rheological and textural analyses of several polymers for topical systems were undertaken in terms of their bioadhesion. Therefore, it is possible to conclude that these polymers can be used for optimization of drug delivery systems on the skin.     

Effect of hydrophilic and hydrophobic polymers on permeation of S-amlodipine besylate through intercalated polymeric transdermal matrix: 3(2) designing,optimization and characterization

Objective: Innovation in material science has made it possible to fabricate a pharmaceutical material of modifiable characteristics and utility, in delivering therapeutics at a sustained/controlled rate. The objective of this study is to design and optimize the controlled release transdermal films of S-Amlodipine besylate by intercalating hydrophilic and hydrophobic polymers.

Methods: 3(2) factorial design and response surface methodology was utilized to prepare formulations by intercalating the varied concentration of polymers(A) and penetration enhancer(B) in solvent. The effect of these independent factors on drug release and flux was investigated to substantiate the ex-vivo, stability and histological findings of the study.

Results: FTIR, DSC revealed the compatibility of drug with polymers; however, the semicrystallinity in drug was observed under PXRD. SEM micrographs showed homogeneous dispersion and entanglement of drug throughout the matrix. Results from the permeation study suggested the significant effect of factors on the ex vivo permeation of drug. It was observed that drug release was found to be increased with an increase in hydrophilic polymer concentration and PE. The formulations having polymers (EC:PVPK-30) at 7:3 showed maximum drug release with highest flux (102.60?±?1.12?µg/cm²/h) and permeability coefficient (32.78?±?1.38?cm/h). Significant effect of PE on lipid and protein framework of the skin was also observed which is responsible for increased permeation. The optimized formulation was found to be stable and showed no-sign of localized reactions, indicating safety and compatibility with the skin.

Conclusion: Thus, results indicated that the prepared intercalated transdermal matrix can be a promising nonoral carrier to deliver effective amounts of drug.     

Formulation and ex vivo–in vivo evaluation of pH-triggered brimonidine tartrate in situ gel for the glaucoma treatment using application of 32 factorial design

Context: Short residence time, poor bioavailability and poor permeability are the major problems for conventional eye drops treatment.

Objective: The aim of this article is to develop, optimize and ex vivo–in vivo investigation of brimonidine tartrate in situ gel as compared to marketed eye drops for the treatment of glaucoma.

Materials and methods: The effect of independent variables, namely concentrations of polymers, on various dependent variables like viscosity at physiological pH and in vitro drug release were studied by using 3² factorial design. Further the optimized formulation was characterized for ex vivo and in vivo study.

Results and discussion: Experimental data demonstrated that optimized in situ gel formulation (F8) showed in vitro–ex vivo sustained release profile with polymer composites carbopol 974P and HPMC K4M. After 5?h of ex vivo transcorneal permeation study, the amount recovered from the corneal surface on the donor chamber 12.40% (124 ug) and the amount collected from the receptor chamber 76.8% (760 ug) of the initial dose 1?mg. The total amount recovered from the permeation experiment was 89.2%. Bioadhesive carbopol 974P and viscosity HPMC K4M composites optimized formulation (F 8) produce greater influence on the duration of drug action and improved intraocular pressure reduction activity as compared to marketed eye drop solution in in vivo study.

Conclusion: The developed in situ gelling system as a promising ophthalmic formulation to prolong the drug lowering effect on the intraocular pressure.     

Formulation development and human in vitro-in vivo correlation for a novel, monolithic controlled-release matrix system of high load and highly water-soluble drug niacin

Novel, controlled-release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO-based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC-based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner-Nelson technique, and a level A “in vitro-in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

Novel cyclodextrin-based film formulation intended for buccal delivery of atenolol

Background: Unknown influence of cyclodextrin on the properties of the film formulation aimed for buccal application. Aim: Development and characterization of a novel bioadhesive film formulation for buccal atenolol delivery containing drug/cyclodextrin inclusion. Method: Interaction between atenolol and randomly methylated β-cyclodextrin (RAMEB) in solution was studied by phase solubility studies. The complex in solid state was prepared by the freeze-drying method and characterized by differential scanning calorimetry and Fourier-transformed infrared spectroscopy (FTIR). The drug, free or in complex form, was incorporated into polymeric films prepared by the casting method using ethylcellulose (EC), polyvinyl alcohol (PVA), and hydroxypropyl methylcellulose (HPMC). The prepared film formulations were characterized in terms of swelling, bioadhesion, and in vitro drug release. Results: The formation of a stabile inclusion complex (K_s = 783.4?±?21.6 M^?1) in 1:1 molar stoichiometry was confirmed in solution and in solid state. The swelling properties of films were predominated by the type of polymer used in the formulation. In vitro bioadhesive properties of the films were well correlated with the swelling properties of the polymers used in the formulation. Although incorporation of the drug, free or in complex form, decreased the bioadhesion of the films, PVA- and HPMC-based formulations retained suitable bioadhesive properties. Higher atenolol solubility upon complexation with RAMEB increased the drug dissolution rate under conditions designed to be similar to those on the buccal mucosa, but it has decreased the drug release rate from the PVA and HPMC film formulation, leading to a sustained drug release pattern. In the case of EC-based films, RAMEB promoted drug release. Other parameters that influenced the drug release rate were associated with the structure of the polymer used in the formulation, swelling characteristics of the films, and the interaction between atenolol and hydrophilic polymers that was demonstrated by FTIR analysis. Conclusion: Incorporation of atenolol in the form of an inclusion complex into hydrophilic films may be an appropriate strategy to prepare a suitable formulation for buccal drug delivery.     

Preparation and evaluation of in situ gelling ophthalmic drug delivery system for methazolamide

Purpose: In this study, a thermosensitive in situ gelling vehicle was prepared to increase the precorneal resident time and the bioavailability of methazolamide (MTA). Method: Poloxamer analogs were used as the gelling agents, and the in situ gel was obtained by using a cold method. The gelation temperature, rheological properties, in vitro release as well as in vivo evaluation (the elimination of MTA in aqueous humor and intraocular-lowering effect) of the optimized formulations were investigated. Results: The optimum concentrations of poloxamer analogs for the in situ gel-forming delivery system were 21% (w/w) poloxamer 407 and 10% (w/w) poloxamer P188. This formulation was able to flow freely under nonphysiological conditions and underwent sol–gel transition in the cul-de-sac upon placement into the eye. In vitro release studies demonstrated a diffusion-controlled release of MTA from the poloxamer solutions over a period of 10 hours. In vivo evaluation indicated that the poloxamer solutions had a better ability to retain drug than MTA eyedrops did. Conclusion: These results suggested that in situ gelling ophthalmic drug delivery system may hold some promise in ocular MTA delivery.     

Engineering of poly(ε-caprolactone) microcarriers to modulate protein encapsulation capability and release kinetic

Drug delivery applications using biodegradable polymeric microspheres are becoming an important means of delivering therapeutic agents. The aim of this work was to modulate the microporosity of poly(ε-caprolactone) (PCL) microcarriers to control protein loading capability and release profile. PCL microparticles loaded with BSA (bovine serum albumin) have been de novo synthesized with double emulsion solvent evaporation technique transferred and adapted for different polymer concentrations (1.7 and 3% w/v) and stabilizer present in the inner aqueous phase (0.05, 0.5 and 1% w/v). SEM (scanning electron microscope) and CLSM (confocal laser scanning microscope) analysis map the drug distribution in homogeneously distributed cavities inside the microspheres with dimensions that can be modulated by varying double emulsion process parameters. The inner structure of BSA-loaded microspheres is greatly affected by the surfactant concentration in the internal aqueous phase, while a slight influence of polymer concentration in the oil phase was observed. The surfactant concentration mainly determines microspheres morphology, as well as drug release kinetics, as confirmed by our in-vitro BSA release study. Moreover, the entrapped protein remained unaltered during the protein encapsulation process, retaining its bio-activity and structure, as shown through a dedicated gel chromatographic analytical method.     

Formulation Development and Human In Vitro‐In Vivo Correlation for a Novel,Monolithic Controlled‐Release Matrix System of High Load and Highly Water‐Soluble Drug Niacin

Novel, controlled‐release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO‐based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC‐based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner‐Nelson technique, and a level A “in vitro‐in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

In Vitro and In Vivo Preparation Evaluations of Bleomycin Implants and Microspheres Prepared with DL-Poly (Lactide-Co-Glycolide)

ABSTRACT

In this investigation, poly(lactide-co-glycolide) (PLGA) gel implants and microspheric depot systems of bleomycin (BLM) were formulated and evaluated in vivo in mice bearing transplantable solid tumor (fibrosarcoma). The pharmacodynamic studies showed that both the formulations retarded tumor growth significantly (p < 0.05) when compared to the control animals (without any drug treatment). Preliminary pharmacokinetic studies illustrated controlled release of the drug into the systemic circulation to elicit the anti-neoplastic action. The gel implants showed better release characteristics and greater pharmacodynamic action when compared to the microspheres, thus demonstrating the feasibility of employing biodegradable depot polymer gel matrix for chronic cancer therapy.     

Oral Sustained Delivery of Theophylline and Cimetidine from In Situ Gelling Pectin Formulations in Rabbits

ABSTRACT

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.     

Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan

Context: Alternative strategies are being employed to develop liquid oral sustained release formulation. These included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes alginate solutions that form gels upon contact with calcium which may be administered separately or included in the alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The formed gel can break after gastric emptying leading to dose dumping.

Objective: Development of modified in situ gelling system which sustain dextromethorphan release in the stomach and intestine.

Methods: Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations were characterized with respect to flow, gelling capacity, gelling strength and drug release.

Results: Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling capacity and strength and reduced the rate of drug release compared to alginate only system. The effect was optimum in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and intestinal conditions and was comparable to that obtained from the marketed product.

Conclusion: Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.     

Spray-dried O-carboxymethyl chitosan as potential hydrophilic matrix tablet for sustained release of drug

Objective: The aim of the present investigation was to evaluate the use of spray-dried O-carboxymethyl chitosan (OCMCS) as potential hydrophilic matrix excipient for sustained release of drug.

Methods: The polymer was synthesized from chitosan, then spray-dried and characterized. Tablets with different OCMCS concentrations (80, 50, 30, 5 and 2% w/w), containing diltiazem (DTZ) as model drug, were prepared for direct compression (DC) and after the wet granulation method (WG).

Results: The spray-dried OCMCS powder was spherical, with a smooth surface and an average size of 2.2?µm. The tablets prepared for WG disintegrated in time less than 30?min. The tablets obtained for DC presented high retention of the drug, with zero order or Higuchi release kinetic. There was a direct relationship between the OCMCS concentration and the release ratio, swelling degree and water uptake behavior. DC tablets containing 80% OCMCS presented behavior as an effective swelling-control system. The DC tablets with 5% OCMCS showed a similar release profile at formulations with 30% HPMC.

Conclusion: Spray-dried OCMCS showed great potential as hydrophilic matrices for drug-sustained release.     

Release of Tolmetin from Carbomw Gel Systems

Abstract

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol? 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol? 941 gels and the slowest drug release was observed from Carbopol? 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

Ocular Preparations: The Formulation Approach

ABSTRACT

The main aim of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: the barriers that decrease the bioavailability of an ophthalmic drug; the objectives to be considered in producing optimal formulations; and the approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addition, the review attempts to give various analytical procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems.

The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aqueous suspensions; (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase solubility of various drugs, vesicular systems, and chemical delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resolution of the above-mentioned technological suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.     

The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets

Context: Mini-tablets are compact dosage forms, typically 2–3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices.

Objective: To develop ER mini-tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate.

Methods: The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCEL? K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied.

Results and Discussion: Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements.

Conclusion: This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength.