In situ gelling, bioadhesive nasal inserts for extended drug delivery: in vitro characterization of a new nasal dosage form.

The purpose of this study was the preparation and characterization of sponge-like, in situ gelling inserts based on bioadhesive polymers. Hydrophilic polymers (carrageenan, Carbopol, chitosan, hydroxypropyl methylcellulose (HPMC) K15M and E5, sodium alginate, sodium carboxy methylcellulose (NaCMC), polyvinyl pyrrolidone (PVP) 90, xanthan gum) were dissolved with/without the model drug oxymetazoline HCl in demineralized water and lyophilized into small inserts. The drug release, water uptake, mechanical properties, X-ray diffraction and bioadhesion potential of the nasal inserts were investigated. A sponge-like structure of nasal inserts was formed with amorphous, but not with crystalline polymers during the freeze-drying process. The insert hardness increased with the glass transition temperature of the polymer (PVP25相似文献   

Sustained release of acetaminophen from a heterogeneous mixture of two hydrophilic non-ionic cellulose ether polymers

This study examined the release of acetaminophen (APAP) from hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) matrices. The effect of pseudoephedrine (PE) as a co-active, HPMC:HPC ratio, polymer loading, pH of the dissolution media, and compression force on APAP release were studied. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and HPC were compressed into tablets at different compression forces. APAP release from the matrix tablets was not considerably influenced by changes in HPMC:HPC ratio or compression force. The rate of drug release was significantly affected by pH of the dissolution media, total polymer loading, and the presence of PE. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP. Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45. Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.4. The drug release data showed a good fit to the Power Law Model. The mechanism of drug release is consistent with a complex behavior. The results of the tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation mechanism.     

Development of Press-Coated,Floating-Pulsatile Drug Delivery of Lisinopril

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor, primarily used for the treatment of hypertension, congestive heart failure, and heart attack. It belongs to BCS class III having a half-life of 12 hrs and 25% bioavailability. The purpose of the present work was to develop a press-coated, floating-pulsatile drug delivery system. The core tablet was formulated using the super-disintegrants crosprovidone and croscarmellose sodium. A press-coated tablet (barrier layer) contained the polymer carrageenan, xanthan gum, HPMC K4M, and HPMC K15M. The buoyant layer was optimized with HPMC K100M, sodium bicarbonate, and citric acid. The tablets were evaluated for physical characteristics, floating lag time, swelling index, FTIR, DSC, and in vitro and in vivo behavior. The 5% superdisintgrant showed good results. The FTIR and DSC study predicted no chemical interactions between the drug and excipients. The formulation containing xanthan gum showed drug retaining abilities, but failed to float. The tablet containing HPMC K15M showed a high swelling index. The lag time for the tablet coated with 200 mg carrageenan was 3±0.1 hrs with 99.99±1.5% drug release; with 140 mg HPMC K4M, the lag time was 3±0.1 hrs with 99.71±1.2% drug release; and with 120 mg HPMC K15M, the lag time was 3±0.2 hrs with 99.98±1.7% drug release. The release mechanism of the tablet followed the Korsmeyer-Peppas equation and a first-order release pattern. Floating and lag time behavior have shown good in vitro and in vivo correlations.     

Spray-dried carbamazepine-loaded chitosan and HPMC microspheres: preparation and characterisation

In this study, the potential of the spray-drying technique for preparing microspheres able to modify the release profile of carbamazepine was investigated. Low-, medium- and high-molecular-weight chitosan and hydroxypropyl methylcellulose (HPMC) in different drug-polymer ratios were used for the preparation of microspheres. The microspheres, characterized by X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC), were also studied with respect to particle size distribution, drug content and drug release. The results indicated that the entrapment efficiency (EE), as well as carbamazepine release profile, depended on polymeric composition and drug-polymer ratios of the microspheres prepared. The best entrapment efficiencies were obtained when chitosan of low-molecular-weight (CL) or HPMC were used for the microencapsulation. For all types of polymer used, the microspheres with low carbamazepine loading (6.3% w/w) showed better control of drug release than the microspheres with higher drug loadings. The HPMC microspheres showed the slowest carbamazepine release profile with no initial burst effect. Carbamazepine release profiles from ternary systems, carbamazepine-CL-HPMC microspheres, depended mostly on HPMC content and showed similar carbamazepine release profile as CL microspheres when HPMC content was low (9:1 CL-HPMC ratio, w/w). Otherwise, the carbamazepine release from CL-HPMC microspheres was remarkably faster than from either chitosan or HPMC microspheres. The release profile of carbamazepine from the microspheres was highly correlated with the crystalline changes occurring in the matrix.     

Formulation,in vitro and in vivo evaluation of lidocaine HCl ocular inserts for topical ocular anesthesia

Topical anesthesia is a safe and cost-effective method considered as the first-choice in many procedures. The objective of the present study was to develop ocular inserts as a new form of lidocaine HCl to give a sufficient level of anesthetic. Ocuserts were prepared using HPMC and PVA in different ratios with lidocaine HCl alone and lidocaine HCl β-cyclodextrins complex. Drug polymer interactions were studied by Fourier transform infrared spectroscopic studies. The prepared ocular inserts were characterized by means of ocusert thickness, weight variation, folding endurance, surface pH, moisture absorption, drug content and in-vitro drug release. Stability study was conducted on selected formulations, and in vivo evaluation of lidocaine HCl was also carried out. The results revealed that F7 formulations containing drug β-cyclodextrins with 4 % HPMC and 2 % PVA were found to have good physical characteristics and appropriate flexibility. In addition to the highest initial and cumulative percentage of drug released in vitro. The selected F7 ocuserts retained their characteristics during the stability study. The results of in vivo study showed that the addition of β-cyclodextrins in F7 significantly increase the drug content in the aqueous humor when compared with F3 ocuserts containing lidocaine HCl alone.     

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.     

曲尼司特缓释片的制备及其释药影响因素研究

目的　制备了曲尼司特凝胶骨架片。方法　采用HPMCK4M、K15M为凝胶骨架材料 ,进行了处方研究 ;通过测定制剂体外释放度 ,评价了该缓释片处方。结果　曲尼司特缓释片体外释药符合Higuchi方程 ,其释药速率常数Kr为 0 193h-1/ 2 。影响缓释片体外释药的因素有骨架材料的种类、用量、粘合剂的种类和释药介质的pH等。结论　缓释片具有明显的缓释作用 ,可缓慢释药 12h。     

Formulation, characterization, and in vitro evaluation of bioadhesive gels containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16-18% w/w) either alone or in combination with HPMC K 15 M and Gantrez S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 x 10(-4) cm/s and 3.94 x 10(-5) cm/s, respectively, and differed significantly ( p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

Formulation and optimization of sustained release matrix tablet of metformin HCl 500 mg using response surface methodology

The aim of the current study was to design an oral sustained release matrix tablet of metformin HCl and to optimize the drug release profile using response surface methodology. Tablets were prepared by non-aqueous wet granulation method using HPMC K 15M as matrix forming polymer. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile. HPMC K 15M (X(1)) and PVP K 30 (X(2)) were taken as the independent variables. The dependent variables selected were % of drug released in 1 hr (rel(1 hr)), % of drug released in 8 hrs (rel(8 hrs)) and time to 50% drug release (t(50%)). Contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. The formulated tablets followed Higuchi drug release kinetics and diffusion was the dominant mechanism of drug release, resulting in regulated and complete release within 8 hrs. The polymer (HPMC K 15M) and binder (PVP K 30) had significant effect on the drug release from the tablets (p<0.05). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (p<0.05). Validation of optimization study, performed using 8 confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (+/-S.D.) 0.0437+/-0.3285. Besides unraveling the effect of the 2 factors on the in vitro drug release, the study helped in finding the optimum formulation with sustained drug release.     

Sustained Release of Acetaminophen from Heterogeneous Matrix Tablets: Influence of Polymer Ratio,Polymer Loading,and Co-active on Drug Release

ABSTRACT

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 lb. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total polymer loading (≥ 9.6%). Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the percentage of APAP released occurred after 18 hours. This was due to the hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to the Korsmeyer and Peppas model, and the values of the release exponents ranged from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation controlled mechanism. Overall, the results of this study indicated that PE, as a co-active in the formulation, modified the matrix, and hence retarded APAP release.     

卡托普利缓释片的实验研究

采用羟丙基甲基纤维素(HPMC)凝胶制备的巯甲丙脯酸(卡托普利)缓释片,其体外释放曲线符合 Higuchi 动力学。HPMC 在片剂中含量达到30%以上才能控制巯甲丙脯酸的释放。HPMCK_4M、K_(15)M和 K100M 的粘度差异对凝胶片释放并无影响,释放介质的 pH 及压片压力对该制剂的药物释放影响不大。     

Studies in preparation and evaluation of pH-independent sustained-release matrix tablets of verapamil HCl using directly compressible Eudragits

The objective of the present study was to investigate the impact of formulation factors on the properties of a 12h modified-release formulation of verapamil HCl. A 2(3) full factorial design was employed to investigate the influence of amount of Eudragit RS PO/RL PO (X1, a matrixing agent), HPMC K4M (X2, an auxiliary matrixing agent cum binder) and PEG 4000 (X3, channelling agent cum plasticizer). The tablets were prepared by direct compression and they were evaluated for in vitro dissolution studies in 0.1 N HCl. The time required for 90% of the drug release (t90) and similarity factor (f2) were used as responses for the selection of most appropriate batches. Swelling and fluid penetration studies were carried out in 0.1 N HCl. Time required for 90% of the drug release (t90) was calculated by using an appropriate kinetic model for each batch. An ideal drug release profile (i.e., 25% in the first hour and a constant drug release thereafter) was considered as a reference release profile for calculation of f2. Multiple regression analysis was adopted to evolve refined models for t90. The required release pattern was shown by batches containing a low level of Eudragit RS PO/RL PO (30% w/w), low level of HPMC K4M (10% w/w), and high level of PEG 4000 (15% w/w). Response surface plots are shown for t90. These formulations showed slower drug release in alkaline medium (pH 7.2). Succinic acid and KH2PO4 were incorporated in the matrix in order to obtain pH-independent drug release. Swelling of tablets and fluid penetration in the matrix were found to be influenced by the selected independent variables. This study demonstrates that the desired drug release pattern can be obtained by adopting a systematic formulation approach.     

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.     

吲达帕胺缓释片的研制及释药机理考察

目的：研制吲达帕胺缓释片，并考察其释药机理。方法：以HPMC为骨架材料，以微晶纤维素、乳糖和可压性淀粉调节释放度，对吲达帕胺缓释片的影响因素进行了考察，并采用正交试验设计筛选处方。结果：吲达帕胺缓释片的组成为：HPMC K4M 37．5mg，HPMC K15M7．5mg，乳糖45．0mg，可压性淀粉37．5mg，微晶纤维素21．0mg，硬脂酸镁1．5mg，药物的释放符合零级动力学方程，释放机制为骨架溶蚀机制；释药速率受介质pH值的影响，几乎不受压片压力的影响。结论：研制的吲达帕胺缓释片体外释放符合国外同类产品的释药特性。     

Formulation,Characterization, and In Vitro Evaluation of Bioadhesive Gels Containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez® S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16–18% w/w) either alone or in combination with HPMC K 15 M and Gantrez® S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez® S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 × 10^?4 cm/s and 3.94 × 10^?5 cm/s, respectively, and differed significantly (p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

Mechanisms of drug release in citrate buffered HPMC matrices

Few studies report the effects of alkalizing buffers in HPMC matrices. These agents are incorporated to provide micro-environmental buffering, protection of acid-labile ingredients, or pH-independent release of weak acid drugs. In this study, the influence of sodium citrate on the release kinetics, gel layer formation, internal gel pH and drug release mechanism was investigated in HPMC 2910 and 2208 (Methocel E4M and K4M) matrices containing 10% felbinac 39% HPMC, dextrose and sodium citrate. Matrix dissolution at pH 1.2 and pH 7.5 resulted in complex release profiles. HPMC 2910 matrices exhibited biphasic release, with citrate increasing the immediate release phase (<60 min) and reducing the extended release. HPMC 2208 matrices were accelerated, but without the loss of extended release characteristics. Studies of early gel layer formation suggested gel barrier disruption and enhanced liquid penetration. pH modification of the gel layer was transitory (<2 h) and corresponded temporally with the immediate release phase. Results suggest that in HPMC 2910 matrices, high initial citrate concentrations within the gel layer suppress particle swelling, interfere with diffusion barrier integrity, but are lost rapidly whereupon drug solubility reduces and the diffusion barrier recovers. These Hofmeister or osmotic-mediated effects are better resisted by the less methoxylated HPMC 2208.     

Formulation of biphasic release tablets containing slightly soluble drugs.

A new biphasic release system for slightly soluble drugs has been proposed. To enhance the dissolution rate, the drug was milled with a superdisintegrant. Then, double-layer tablets were prepared. One layer was formulated to release the drug in a very short time (fast-release). The other consisted of an extended-release hydroxypropylmethylcellulose (HPMC) matrix. Different HPMC concentrations (10, 16 and 22%) and viscosity grades (Methocel K4, K15 and K100M) were used to obtain different release rates of the drug from the extended-release layer, ketoprofen and praziquantel were used as slightly soluble model drugs.The in vitro dissolution tests of the prepared double-layer systems, showed the desired biphasic behaviour: the drug contained in the fast releasing layer dissolved within the first 15 min, while the drug contained in the prolonged-release layer was released at different times, depending on the formulation of the hydrophilic matrix. In particular, an increase in the percentage and viscosity grade of HPMC, in the extended release layer, leads to a decrease in the drug delivery rate and produces a wide range of different release rates from only a few hours up to 24 h.     

Accelerated fenofibrate release from spray-dried microparticles based on polymer blends

Fenofibrate-loaded microparticles based on PVP/Eudragit E or HPMC/Eudragit E blends were prepared by spray-drying. The composition of the systems (in particular the polymer/polymer blend ratio and the drug loading) was varied and the resulting key properties were determined (including drug release measurements in 0.1 M HCl, X-ray diffraction studies, solubility measurements and particle size analysis). For reasons of comparison, also the respective physical drug/polymer/polymer mixtures, microparticles based on binary drug/PVP and drug/HPMC blends, the fenofibrate powder as received and a commercially available drug product were investigated. Importantly, highly supersaturated fenofibrate solutions were created upon exposure of the different types of microparticles to the release medium, in contrast to any reference formulation. Also, the presence of co-dissolved Eudragit E led to a significant increase in fenofibrate solubility. At 10 % drug loading, all microparticles were amorphous and drug release stable during one month open storage. However, at 30 % loading, HPMC containing microparticles showed storage instability, due to drug re-crystallization.     

Hydrophilic Matrices for Controlled Drug Delivery: An Improved Mathematical Model to Predict the Resulting Drug Release Kinetics (the “sequential Layer” Model)

Purpose. The aims of this study were (i) to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics. Methods. Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively. Results. By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs. Conclusions. The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.     

Development of oral controlled-release tablet formulations based on diltiazem-carrageenan complex

Diltiazem HCl and lambda carrageenan react in distilled water to give a slightly soluble interaction product. The aim of this work was to verify the possible employment of lambda carrageenan-diltiazem (DTZ) complex in controlled-release formulations. The influence of complex particle size, compression force, pH of the dissolution medium, and tablet dimensions on drug release has been evaluated. The results confirm the suitability of the DTZ-carrageenan interaction product for controlled-release formulations. Good compaction properties allow tablets to slowly erode, with only the addition of the amount of hydroxypropyl methylcellulose (HPMC) necessary as a binding agent. The use of the finest sieve fraction results in the highest crushing strength values and in the slowest release rate, both in pH 1.2 and in pH 6.8. The force of compression does not affect the drug release for values over 16 kN. The release rate increases when the geometry of the tablet is varied so the surface/ volume ratio of the tablet is increased, suggesting a release mechanism involving surface dissolution/erosion.