Use of xanthan and its binary blends with synthetic polymers to design controlled release formulations of buccoadhesive nystatin tablets

Various buccoadhesive nystatin tablets formulations containing xanthan, carbopols (934P, 971P, 974P), PVP K30 or PEG 6000 or their binary blends were prepared. The powders were compressed into tablets at a constant compression pressure. Drug release behaviour, swelling and erosion indices and strength of bioadhesion in vitro to a biological membrane were investigated. The interaction between nystatin and polymers was investigated by DSC and FT-IR. Tablets containing the different types of carbopol alone consistently showed an initial burst release of drug, whereas this was not observed for matrices containing xanthan or xanthan-carbopol. The presence of PEG in xanthan-containing formulations induced an increase in dissolution rate; however, in the absence of xanthan the amount of drug release from a PEG matrix was reduced to < 15% over 8?h dissolution. The presence of PVP increased the dissolution rate of nystatin due to the relative hydrophilicity of PVP. The presence of calcium ions induced a more rigid gel in the xanthan matrix as a result of interaction between the polymer and calcium ions. Xanthan can be used in potential mucoadhesive formulations containing nystatin to produce a controlled release of the drug and the outcomes of this work may provide a suitable strategy for matrix selection to provide more efficacious treatment alternatives for candidiasis and other disease processes for significant patient populations.     

Influence of hydroxypropyl-beta-cyclodextrin complexation on piroxicam release from buccoadhesive tablets.

Interaction of piroxicam (PX) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was investigated in solution and in the solid state. Solubility studies demonstrated the formation of the PX-HPbetaCD inclusion complex with 1:1 stoichiometry. Equimolecular PX-HPbetaCD solid systems were prepared and characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffractometry. Modification of the release of a sparingly water-soluble drug, PX, from hydrophilic matrices using cyclodextrin complexation was evaluated. The buccoadhesive controlled release tablets for the delivery of PX were prepared by direct compression of hydroxypropylmethyl cellulose (HPMC) and Carbopol 940 (C940), which showed superior bioadhesion properties compared to HPMC. The tablets were evaluated for their dissolution, swelling and mucoadhesive properties. The in vitro release results demonstrated that matrix tablets containing the PX-HPbetaCD solid complex displayed faster PX release compared to those containing a physical mixture or "free" drug. Differences in release rates of PX from the tablets could be attributed to the presence of the polymers and to cyclodextrin complexation. The effect of the polymers on PX release can affect the drug solubility (complexation) and polymer water uptake (swelling). Higher polymer water uptake may result in higher drug solubility and diffusivity in a hydrated polymeric environment. Drug complexation affected also its diffusivity through the semipermeable membrane.     

The relationship between mucoadhesive polymers and surface coating in tablets for the controlled colonic delivery of a poorly water-soluble drug

BackgroundThe mucoadhesive polymers play an important role in targeted and controlled drug delivery.ObjectivesThis study aimed to investigate the drug release behaviour and interpret the role of mucoadhesive polymers involved in the coating layer of mucoadhesive tablets for the sustained release of a poorly water-soluble drug.MethodsA solid dispersion of prednisolone and zein was used in the core tablets created with two mucoadhesive polymers, which included Carbopol 940 and hydroxypropyl methylcellulose K4M. In addition, the properties of a single-layer coating, created from the combination of zein and Kollicoat MAE 100P to delay release through the upper parts of the gastrointestinal tract, were investigated in the presence of the above mucoadhesive polymers; these properties included drug dissolution, mucoadhesion, surface morphology, swelling and erosion.ResultsThe mucoadhesive polymer concentrations and types were integrated not only into the core tablets through a swelling/erosion mechanism but also into the surface polymer coatings for controlled drug release. HPMC was preferred in the formulations due to the ability to form pores on the surface coating, allowing water uptake so that the coating could control drug release for a later stage via a swelling/erosion mechanism.ConclusionThe proposed mechanism determined in this project could be beneficial in the selection of polymers for applications targeting the colon with coated mucoadhesive tablets. Open in a separate windowGraphical abstract     

Development and in vitro evaluation of a mucoadhesive vaginal delivery system for nystatin

The purpose of the present study was to design and evaluate a novel vaginal delivery system for nystatin based on mucoadhesive polymers. L-Cysteine and cysteamine, respectively, were covalently attached to poly(acrylic acid), and the two different thiolated polymers were evaluated in vitro regarding their swelling behavior, mucoadhesive properties and release behavior. Tablets comprising these thiolated polymers and nystatin demonstrated a high stability in vaginal fluid simulant pH 4.2 and an increase in weight by swelling whereas control tablets comprising unmodified poly(acrylic acid) disintegrated and dissolved. The mucoadhesion time of tablets on freshly excised bovine vaginal mucosa on a rotating cylinder and the total work of adhesion of gels and tablets increased significantly due to the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The drug nystatin was released more slowly out of thiomer tablets and gels than out of PAA control tablets and gels. Therefore these thiolated polymers are promising delivery systems for nystatin providing a prolonged residence time and a sustained drug release in vitro under physiological relevant conditions.     

Effect of Different Polymer Concentration on Drug Release Rate and Physicochemical Properties of Mucoadhesive Gastroretentive Tablets

Mucoadhesive tablets have emerged as potential candidates for gastroretentive drug delivery providing controlled release along with prolonged gastric residence time. Gastroretentive mucoadhesive tablets could result in increased bioavailability due to prolonged gastric residence time. A hydrophilic matrix system was developed as mucoadhesion is achievable on appropriate wetting and swelling of the polymers used. The polymers were so chosen so as to provide a balance between swelling, mucoadhesion and drug release. The polymers chosen were hydroxypropyl methylcellulose K4M, chitosan, and Carbopol 934. The concentrations of these polymers used has a great impact on the physicochemical properties of the resulting formulation. The tablets were formulated using wet granulation method and tranexamic acid was used as the model drug. The prepared tablets were characterized for size, shape, appearance, hardness, friability, weight variation, swelling, mucoadhesion and in vitro drug release. Several batches of tablets were prepared by varying the ratio of hydroxypropyl methylcellulose K4M and Chitosan. The batches having a greater ratio of chitosan showed higher rate of swelling, greater erosion, less mucoadhesion and faster release rate of the drug whereas the batches having greater ratio of hydroxypropyl methylcellulose K4M showed lesser rate of swelling, less erosion, better mucoadhesion and a smaller drug release rate. The level of carbopol was kept constant in all the batches.     

Egg shell membrane as a substrate for optimizing in vitro transbuccal delivery of glipizide

Buccoadhesive gels for transbuccal delivery of glipizide were prepared using different bio-adhesive polymers. The gels were prepared by solution polymerization technique. An apparatus simulating the in vivo conditions of the mouth was designed in order to assess in vitro drug release kinetics of these gels. The gels were also evaluated for spreadability, buccoadhesive strength, swelling index, and viscosity. Maximum buccoadhesive strength was observed for formulation, F8 with good sustained release behavior, whereas viscosity and swelling index was highest for the formulation, F5 but with minimum buccoadhesive strength. The drug release kinetics followed Higuchi model with release mechanism being Fickian diffusion.     

In vitro controlled release of sodium ferulate from Compritol 888 ATO-based matrix tablets

A controlled release matrix formulation for freely water-soluble drug of sodium ferulate (SF) was designed and developed to achieve a 24h release profile. Using Compritol 888 ATO as an inert matrix-forming agent to control the release of SF, formulation granules containing the physical mixtures or solid dispersions were investigated. The matrix tablets for these formulations were prepared by direct compression and their in vitro release tests were carried out. The solid dispersion based tablets were found to be more effective than those compressed from physical mixtures in retarding the release of SF. Drug release from the matrix tablets containing physical mixtures nearly completed within 12h, while that from the solid dispersion formulations lasted for over 24h. Images of the tablet surface and cross-section were characterized by scanning electron microscopy to show the formed pores and channels in the matrices. These might provide the release pathway for the inner embedded drugs. Drug released fast from the matrix tablets with the release-enhancer of lactose. The addition of surfactants was also found to increase the release rate of SF effectively. Moreover, the co-mixing of polyethylene glycol 6000 (PEG 6000) in the waxy matrices played a meaningful role in controlling the drug release for 24h. The drug release from the novel formulation might be attributed to the diffusion-controlled mechanism.     

Design of novel antifungal mucoadhesive films. Part II. Formulation and in vitro biopharmaceutical evaluation

This paper deals with the formulation of the mucoadhesive films containing nystatin. The design and formulation of the films were based on the mucoadhesive properties of carbomer 934P (CB) and carboxymethycellulose (NaCMC), and also on the plasticizer properties of polyethyleneglycol 400 (PEG400). A surfactant (ascorbyl palmitate, ASC16) was added to the system to aid in nystatin dispersion. Addition of these last two components produced a significant improvement in physical-mechanical properties (flexibility and strength) as well as an increase in the nystatin release rate. X-ray powder diffraction (XRPD) and scanning electronic microscopy (SEM) were used to evaluate the morphological changes in the films while PEG400 and ASC16 were added to the formulations. Furthermore, the in vitro nystatin profile release was determined.     

Badam gum: a natural polymer in mucoadhesive drug delivery. Design,optimization, and biopharmaceutical evaluation of badam gum-based metoprolol succinate buccoadhesive tablets

Context: Applicability of natural polymers in pharmaceutical drug delivery.

Objective: The objective of the present investigation was to evaluate the applicability of badam gum (BG) obtained from Terminalia catappa LINN, belongs to the family combretaceae as a buccoadhesive polymer using metoprolol succinate as a model drug.

Methods: Tablets were prepared by wet granulation technique. Compression coating technique was employed for the preparation of unidirectional release buccal tablets using cellulose acetate as an impermeable backing layer.

Results: Muco/buccoadhesive properties of the BG were increased with the increase in the concentration of polymer which was evident form the detachment force measurement, ex vivo residence time, and swelling studies. MBG 2 was found to be the optimized formulation based on drug dissolution studies and bioadhesion studies. FTIR and DSC studies performed on the optimized formulation indicated no drug–polymer interaction. MBG 2 was found to be stable after accelerated stability testing for 6 months as per ICH guidelines. Pharmacokinetic studies of the optimized formulation were performed in six healthy human volunteers in comparison with that of the commercial extended release oral tablet GUDPRESS XL-25 by estimating pharmacokinetic parameters and mean residence time (MRT). It was found that there is a significant increase in the bioavailability of metoprolol succinate from BG formulation which was evident from the high AUC and MRT values compared with the commercial formulation.

Conclusion: The above results clearly indicated that badam gum can be used as a mucoadhesive polymer for buccal drug delivery.     

多西环素口腔贴片的体内外特性

目的研制一种局部使用的用于治疗牙周炎的缓释多西环素口腔贴片,并比较其黏附性及体内外释放趋势。方法采用卡伯姆、羟丙基甲基纤维素和乳糖作为辅料与多西环素混合压制成片。在体外测定片剂的粘力和释放度,在体内测定健康志愿者口腔内黏附时间和不同时间的释药量。结果平均粘力167 g;口腔内黏附时间270 min。片剂在不同释放介质中释放速度不同,在水中的释放趋势与口腔内释放较一致,4 h释放约60%。结论本品黏附性强、缓释性好,体内体外释放具有相关性,是一种治疗牙周炎的新剂型。     

Analysis of macromolecular changes and drug release from hydrophilic matrix systems

The influence of water-soluble and insoluble excipients on dynamics of hydration, front movement, erosion, and drug release from hydrophilic matrix tablets containing water-soluble drug was studied. Tablets were manufactured by direct compression, and their un-constrained swelling behavior and gel strength were assessed with a texture analyzer. Dissolution was performed using USP 26 apparatus II modified by insertion of a mesh to prevent sticking of tablets to the bottom of the vessel and to allow free three-dimensional matrix swelling. Significant release differences between tablet batches were observed and this was consistent with changes in swelling rate, gel thickness, and swelling front movement within the tablets. Matrices containing approximately 30% drug load and water-soluble lactose, demonstrated more pronounced swelling front movement and hence drug release relative to the matrix tablets containing dicalcium phosphate dihydrate. The observed differences in release were verified by calculating the similarity and difference factors. The interdependence of front movement and mass erosion in relation to excipient types on progression of swelling front movement and alteration of water penetration, erosion, and drug release are explained. It is concluded that unlike in conventional dosage forms inclusion of excipients in hydrophilic controlled-release tablets containing water-soluble drugs should be carefully analyzed as their various physico-chemical properties may have significant implications on swelling dynamics, front movement, drug release kinetics, and consequently in vivo performance.     

Buccoadhesive gels of glibenclamide: A means for achieving enhanced bioavailability

The aim of the present study was to formulate and evaluate buccoadhesive gels of model drug, glibenclamide indented as an alternate route of drug delivery to have enhanced bioavailability. The buccoadhesive gels were prepared by solution polymerization technique containing Hydroxy Propyl Methyl Cellulose (HPMC, E15 LV) and Carbopol (CP, 934P). An apparatus, simulating the in-vivo conditions of the mouth was designed in order to assess in-vitro release kinetics of the prepared gels. The gels were also evaluated for buccoadhesive strength, hydration, and swelling index, and viscosity. In-vivo evaluation for pharmacodynamic and pharmacokinetic properties of the optimized gel was done in rabbits. The drug release of buccoadhesive gels through rabbit buccal mucosa increased significantly (p?<?0.05) by the use of penetration enhancers. The release kinetics followed Higuchi model with release mechanism being Fickian diffusion. In-vivo results of the optimized gel (2% CP: 2% HPMC) revealed that the gel successfully prevented severe hypoglycemia, showed sustained action, and enhanced relative bioavailability with and without penetration enhancers as compared to the marketed formulation. The buccoadhesive gels could possibly be a means for alternative dosage form in avoiding first pass metabolism and ensuring enhanced bioavailability for glibenclamide.     

Development of mucoadhesive dosage forms of buprenorphine for sublingual drug delivery

The development of mucoadhesive formulations of buprenorphine for intended sublingual usage in the treatment of drug addiction is described. The formulations include mucoadhesive polymer films, with or without plasticizers, and mucoadhesive polymer tablets, with or without excipients that enhance drug release and/or improve tablet compaction properties. The mucoadhesive polymers studied include carbomers such as Carbopol 934P, Carbopol 974P, and the polycarbophil Noveon AA-1, with excipients chosen from pregelatinized starch, lactose, glycerol, propylene glycol, and various molecular weights of polyethylene glycol. The development of plasticizer-containing mucoadhesive polymer films was feasible; however, these films failed to release their entire drug content within a reasonable period. Thus, they were not determined suitable for sublingual usage because of possible loss by ingestion during routine meal intakes. The mucoadhesive strength of tablet formulations containing Noveon AA-1 appears to be slightly superior to the Carbopol-containing tablets. However, the Carbopol 974P formulations exhibited superior drug dissolution profiles while providing adequate mucoadhesive strength. The tablet formulations containing Carbopol 974P as mucoadhesive polymer, lactose as drug release enhancer, and PEG 3350 as compaction enhancer exhibited the best results. Overall, the mucoadhesive tablet formulations exhibited superior results compared with the mucoadhesive film formulations.     

Dexamethasone sodium phosphate-loaded Chitosan based delivery systems for buccal application

Chitosan (CH) was used as a biocompatible and bioadhesive polymer material to prepare solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP), a steroidal anti-inflammatory agent clinically used for treatment of different mouth diseases. Binary solid dispersions at various drug-to-polymer weight ratios were prepared by freeze-drying; their direct compression gave tablets which were characterized for the swelling behaviour and drug release in vitro. Similarly, DSP-loaded hydrogels composed of CH and glycerine were prepared and characterized. CH and DSP showed a good physical compatibility. A slow and prolonged release of the drug was observed in vitro from both kinds of systems. The swelling properties of the polymer seemed to be the main parameter affecting the drug release profile from both tablets and hydrogels at the pH value of mouth. In vivo buccal application of both the systems allowed to obtain a prolonged release of DSP, as compared with a glycerine solution of the drug. From the in vitro swelling studies and in vivo test, the 2:1 CH-DSP solid dispersion in particular can be designated for further investigation.     

Development of Mucoadhesive Dosage Forms of Buprenorphine for Sublingual Drug Delivery

The development of mucoadhesive formulations of buprenorphine for intended sublingual usage in the treatment of drug addiction is described. The formulations include mucoadhesive polymer films, with or without plasticizers, and mucoadhesive polymer tablets, with or without excipients that enhance drug release and/or improve tablet compaction properties. The mucoadhesive polymers studied include carbomers such as Carbopol 934P, Carbopol 974P, and the polycarbophil Noveon AA-1, with excipients chosen from pregelatinized starch, lactose, glycerol, propylene glycol, and various molecular weights of polyethylene glycol. The development of plasticizer-containing mucoadhesive polymer films was feasible; however, these films failed to release their entire drug content within a reasonable period. Thus, they were not determined suitable for sublingual usage because of possible loss by ingestion during routine meal intakes. The mucoadhesive strength of tablet formulations containing Noveon AA-1 appears to be slightly superior to the Carbopol-containing tablets. However, the Carbopol 974P formulations exhibited superior drug dissolution profiles while providing adequate mucoadhesive strength. The tablet formulations containing Carbopol 974P as mucoadhesive polymer, lactose as drug release enhancer, and PEG 3350 as compaction enhancer exhibited the best results. Overall, the mucoadhesive tablet formulations exhibited superior results compared with the mucoadhesive film formulations.     

Innovative formulation of nystatin particulate systems in toothpaste for candidiasis treatment

Oral candidiasis is a mycosis on the mucous membranes of the mouth but not limited to the mouth. Nystatin is one of the most frequently employed antifungal agents to treat infections and may be safely given orally as well as applied topically but its absorption through mucocutaneous membranes such as the gut and the skin is minimal. The purpose of this study is to enhance the effectiveness of nystatin using particulate system such as beads, micro- and nanoparticles of alginate incorporated into toothpaste. Those particulate systems of nystatin were prepared by extrusion/external gelation for beads and emulsification/internal gelation for micro- and nanoparticles and characterized. Small, anionic charged and monodispersed particles were successfully produced. The type of particulate system influenced all previous parameters, being microparticles the most suitable particulate system of nystatin showing the slowest release, the highest inhibitory effect of Candida albicans over a period of one year. Those results allowed the conclusion that alginate exhibits properties that enable the in vitro functionality of encapsulated nystatin and thus may provide the basis for new successful approaches for the treatment of oral antifungal infections such as oral candidiasis.     

Application of PVP/HPMC miscible blends with enhanced mucoadhesive properties for adjusting drug release in predictable pulsatile chronotherapeutics.

The aim of the present study was to prepare pulsatile release formulations consisting of two-layered tablets appropriate for preventing ischemic heart diseases. For this reason the active core was constituted by a FELO/PVP 10/90 w/w solid dispersion while for the adjustment of the drug release time the coating layer was composed of PVP/HPMC blends at different compositions, acting as a stimulus responsible layer. These blends as was found by DSC studies are miscible in the entire composition range, ensured by the interactions taking place between hydroxyl groups of HPMC and carbonyl groups of PVP. The miscibility of the system enhances the mucoadhesive properties of the blends, compared with those of pure HPMC, which is desired for such applications. The enhancement was attributed to the higher rate of wetting and flexibility of the new matrices due to the faster dissolution of the PVP macromolecules. Upon exposure of the prepared tablets to the release medium it was found that the coating layer disintegrates first, followed by the immediate release of FELO from the active core. The delaying time is based on a complicated mechanism, which is a combination of swelling and erosion of the PVP/HPMC polymer blends. Varying the PVP/HPMC blend ratios, the exact time that FELO is released during a daytime can be effectively adjusted and this ability is expressed mathematically by the equation t = 0.028 C1.5, where C is the concentration of HPMC in the blend.     

昂丹司琼口腔黏附片的制备及评价

目的 制备及评价盐酸昂丹司琼口腔黏附片.方法 采用相关的黏膜黏着剂卡波姆(CP934)、海藻酸钠、低黏度羧甲基纤维素钠( SCMCLV),用直接压片法压片,对黏附片的不同参数如药物含量,体外溶胀百分率、药物体外释放度和黏附力进行评价.结果 筛选出最佳配方:昂丹司琼5mg、CP934 30 mg、SCMC 165 mg、聚乙二醇-6000 40 mg,乳糖10mg、硬脂酸镁1.5 mg和阿斯巴甜2mg.结论 与昂丹司琼的普通片剂进行比较,昂丹司琼口腔黏附片体外药物释放和渗透都很好,既避免了肝脏首过效应,提高了昂丹司琼的生物利用度;又避免了昂丹司琼的苦味,更易于为患者所接受.     

Dexamethasone sodium phosphate-loaded Chitosan based delivery systems for buccal application

Chitosan (CH) was used as a biocompatible and bioadhesive polymer material to prepare solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP), a steroidal anti-inflammatory agent clinically used for treatment of different mouth diseases.

Binary solid dispersions at various drug-to-polymer weight ratios were prepared by freeze-drying; their direct compression gave tablets which were characterized for the swelling behaviour and drug release in vitro. Similarly, DSP-loaded hydrogels composed of CH and glycerine were prepared and characterized.

CH and DSP showed a good physical compatibility. A slow and prolonged release of the drug was observed in vitro from both kinds of systems. The swelling properties of the polymer seemed to be the main parameter affecting the drug release profile from both tablets and hydrogels at the pH value of mouth.

In vivo buccal application of both the systems allowed to obtain a prolonged release of DSP, as compared with a glycerine solution of the drug. From the in vitro swelling studies and in vivo test, the 2:1 CH-DSP solid dispersion in particular can be designated for further investigation.     

Investigation of excipient type and level on drug release from controlled release tablets containing HPMC

The purpose of this study was to investigate the influence of excipient type and level on the release of alprazolam formulated in controlled release matrix tablets containing hydroxypropyl methylcellulose (HPMC). Each tablet formulation contained alprazolam, HPMC (Methocel K4MP), excipients, and magnesium stearate. The soluble excipients investigated were lactose monohydrate, sucrose, and dextrose, and the insoluble excipients included dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, and calcium sulfate dihydrate. The similarity factor (f2 factor) was used to compare the dissolution profile of each formulation. The insoluble excipients, especially dicalcium phosphate dihydrate, caused the drug to be released at a slower rate and to a lesser extent than the soluble excipients. Soluble excipients created a more permeable hydrated gel layer for drug release, increased the porosity resulting in faster diffusion of drug, and increased the rate of tablet erosion. Use of binary mixtures of lactose monohydrate and dicalcium phosphate dihydrate produced release profiles of intermediate duration. Rapid drug dissolution was obtained when only 9.1% w/w of lactose monohydrate was present in the tablet formulation. Only when the dicalcium phosphate dihydrate level was sufficiently high (36.5% w/w) was the release rate and extent decreased. It was demonstrated that the type and level of excipient influenced the rate and extent of drug release from controlled release tablets containing HPMC. The release mechanism of alprazolam from each tablet formulation was described by either the Hixson-Crowell cube root kinetics equation or Peppas's equation. However, the different excipient types investigated did not influence the release mechanism of alprazolam from the final tablets.