In vitro/in vivo studies on a buccal bioadhesive tablet formulation of carbamazepine

A buccoadhesive controlled-release system for delivery of carbamazepine (CBZ) was prepared by compression of hydroxypropyl methylcellulose (HPMC) and carbomer, incorporating a penetration enhancer, sodium glycodeoxycholate (GDC). The release behaviour of systems containing CBZ and various amounts of the two polymers with and without GDC was found to be non-Fickian. Formation of an interpolymer complex between HPMC and carbomer was confirmed in acidic medium by turbidity, viscosity and FT-IR measurements. Addition of the drug to the buccoadhesive formulation reduced the adhesion force significantly (p < 0.1). GDC did not have any effect on bioadhesion. Permeability of bovine buccal mucosa to CBZ was determined using Ussing diffusion chambers [1]. In vivo interaction between the tablet and tissue was examined histologically as well as by scoring mucosal irritation. Histological changes observed in the buccal epithelium after 4 h contact with the tablets containing GDC recovered completely within 24 h after removal. No measurable plasma level of CBZ was obtained either in the absence or presence of GDC.     

Transbuccal delivery of 2',3'-dideoxycytidine: in vitro permeation study and histological investigation.

Permeation of 2',3'-dideoxycytidine (ddC), an ionic compound, through buccal mucosa was investigated in this in vitro study to identify the major permeation barrier within the epithelium of buccal mucosa and explore the feasibility of transbuccal delivery of ddC. In vitro permeation of ddC across porcine buccal mucosa was conducted in isotonic McIlvaine buffer solution (IMB) using in-line flow through diffusion cells at 37 degrees C. Sodium glycodeoxycholate (GDC) was used as the permeation enhancer in the permeation enhancement studies. Light microscopy was used in the histological studies of buccal tissue. The steady-state flux of ddC permeating through buccal mucosa increased linearly (R(2)=0.96, P<0.05) as the donor concentration of ddC was increased from 1 to 20 mg/ml. The permeabilities for the full thickness buccal mucosa, the epithelium, and the connective tissue were determined to be 1.75+/-0.74x10(-7), 2.90+/-1.86x10(-7), and 3.49+/-1.19x10(-6) cm/s, respectively. The permeability of ddC was significantly (P<0.05) enhanced by GDC at a concentration of 4 mM. The histological study revealed that the thickness of epithelium was greatly reduced after buccal tissues were immersed in IMB for 12 and 24 h but the basal lamina remained intact even after 24 h. A bilayer diffusion model was established to quantitatively describe the contributions of the epithelium and the connective tissue to the permeation barrier. In conclusion, ddC permeated through buccal mucosa by passive diffusion over the range of concentrations examined. The basal lamina layer within the epithelium of buccal mucosa acted as an important barrier to the permeation of ddC. GDC effectively enhanced the buccal permeability of ddC. The transbuccal delivery is a potential route for the administration of ddC.     

Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel

Summary The salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel have been compared. The bioadhesive tablet consisted of a mixture of thermally modified starch and 5% polyacrylic acid.Although the amount of drug administered via the bioadhesive tablet was sixfold lower than when the gel was used, the salivary miconazole levels were higher and remained above the MIC value ofCandida albicans for more than 10 hours. The mean adhesion time of the tablet was 586 min.The bioadhesive tablet appears to be a promising drug delivery system for the buccal administration of drugs for local therapy.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

The use of mucoadhesive polymers in buccal drug delivery

Buccal delivery of the desired drug using mucoadhesive polymers has been the subject of interest since the early 1980s. Advantages associated with buccal drug delivery have rendered this route of administration useful for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. Starting with a review of the oral mucosa, mechanism of drug permeation, and characteristics of the desired polymers, this article then proceeds to cover the theories behind the adhesion of bioadhesive polymers to the mucosal epithelium. Additionally, we focus on the new generation of mucoadhesive polymers such as thiolated polymers, followed by the recent mucoadhesive formulations for buccal drug delivery.     

Buccal drug delivery

Buccal formulations have been developed to allow prolonged localised therapy and enhanced systemic delivery. The buccal mucosa, however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for biopharmaceutical products (proteins and oligonucleotides) arising from the recent advances in genomics and proteomics. The buccal route is typically used for extended drug delivery, so formulations that can be attached to the buccal mucosa are favoured. The bioadhesive polymers used in buccal drug delivery to retain a formulation are typically hydrophilic macro-molecules containing numerous hydrogen bonding groups. Newer second-generation bioadhesives have been developed and these include modified or new polymers that allow enhanced adhesion and/or drug delivery, in addition to site-specific ligands such as lectins. Over the last 20 years a wide range of formulations has been developed for buccal drug delivery (tablet, patch, liquids and semisolids) but comparatively few have found their way onto the market. Currently, this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. In particular, patient acceptability and the successful systemic delivery of large molecules (proteins, oligonucleotides and polysaccharides) via this route remains both a significant opportunity and challenge, and new/improved technologies may be required to address these.     

Buccal drug delivery

Buccal formulations have been developed to allow prolonged localised therapy and enhanced systemic delivery. The buccal mucosa, however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for biopharmaceutical products (proteins and oligonucleotides) arising from the recent advances in genomics and proteomics. The buccal route is typically used for extended drug delivery, so formulations that can be attached to the buccal mucosa are favoured. The bioadhesive polymers used in buccal drug delivery to retain a formulation are typically hydrophilic macro-molecules containing numerous hydrogen bonding groups. Newer second-generation bioadhesives have been developed and these include modified or new polymers that allow enhanced adhesion and/or drug delivery, in addition to site-specific ligands such as lectins. Over the last 20 years a wide range of formulations has been developed for buccal drug delivery (tablet, patch, liquids and semisolids) but comparatively few have found their way onto the market. Currently, this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. In particular, patient acceptability and the successful systemic delivery of large molecules (proteins, oligonucleotides and polysaccharides) via this route remains both a significant opportunity and challenge, and new/improved technologies may be required to address these.     

In Vivo Buccal Delivery of the Peptide Drug Buserelin with Glycodeoxycholate as an Absorption Enhancer in Pigs

Purpose. To study the potential of buccal delivery of the peptide drug in pigs. Methods. Intravenous administration and buccal delivery without and with 10 mM sodium glycodeoxycholate (GDC) as absorption enhancer were investigated as a randomised cross-over study in six pigs. The buccal delivery device consisted of an application chamber with a solution of buserelin and was attached to the buccal mucosa for 4 hours using an adhesive patch. Results. Buccal administration of buserelin resulted in rapidly reached steady state plasma levels. The absolute bioavailability of the peptide after buccal delivery for 4 hours could be increased from 1.0 ± 0.3 to 5.3 ± 1.1% (mean ± S.D.) by co-administration of 10 mM GDC (0.45% w/v)). Conclusions. The results of this study demonstrate that buccal administration with the use of absorption enhancers is a useful approach for the delivery of peptide drugs such as buserelin.     

Cyclodextrin-containing poly(ethyleneoxide) tablets for the delivery of poorly soluble drugs: potential as buccal delivery system

The aim of this work was to develop a tablet for the buccal delivery of the poorly soluble drug carvedilol (CAR), based on poly(ethyleneoxide) (PEO) as bioadhesive sustained-release platform and hydroxypropyl-beta-cyclodextrin (HPbetaCD) as modulator of drug release. As first, PEO tablets loaded with CAR/HPbetaCD binary systems with different dissolution properties were tested for CAR and HPbetaCD release features and compared to PEO tablets containing only CAR. When the drug was incorporated as CAR/HPbetaCD freeze-dried product, all CAR content was released from the tablet in about 10 h, displaying a constant release regimen after a transient. The effect of HPbetaCD incorporation on the release mechanism, was rationalized on the basis of the interplay of different physical phenomena: erosion and swelling of the tablet, drug dissolution, drug counter-diffusion and complex formation. In the second part of the study, the potential of HPbetaCD-containing PEO tablets as buccal delivery system for CAR was tested. It was found that the incorporation of HPbetaCD in the tablet did not alter significantly its good adhesion properties. The feasibility of buccal administration of CAR was assessed by permeation experiments on pig excised mucosa. The amount of CAR permeated from PEO tablet was higher in the case of HPbetaCD-containing tablets, the maximum value being obtained for CAR/HPbetaCD freeze-dried system. Our results demonstrate that, when the tablet is employed as transmucosal system, the role of drug dissolution enhancement in the hydrated tablet is much more relevant than in solution for increasing the delivery rate.     

Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels.

A physically cross-linked palmitoyl glycol chitosan hydrogel has been evaluated as a controlled release system for the delivery of hydrophobic drugs via the buccal route. Samples of palmitoyl glycol chitosan (GCP) with diminishing hydrophobicity (GCP12>GCP11>GCP21) were synthesized, characterized by (1)H nuclear magnetic resonance and hydrogels prepared by freeze-drying an aqueous dispersion of the polymer in the presence of a model hydrophobic drug denbufylline and in some cases the soluble detergent sodium glycodeoxycholate (GDC). GDC was employed as a penetration enhancer. Gels were analysed for hydration, erosion, mucoadhesion and imaged by scanning electron microscopy. The buccal absorption of denbufylline from GCP12, denbufylline, GDC (20:12:1.5) formulations was also investigated in the rabbit model with Carbopol 974NF (CP), denbufylline, GDC (60:36:4) tablets used as controls. Denbufylline reduced the porosity, erosion and hydration of the gels while GDC increased the hydration and erosion. All gels were mucoadhesive but less so than the control CP tablets. Denbufylline was detected 0.5 h after dosing with the GCP12 formulation and delivery was sustained for at least 5 h after dosing. In comparison delivery from the CP tablets was not sustained and was first detected 1 h after dosing.     

Evaluation of buccal methyl-beta-cyclodextrin toxicity on human oral epithelial cell culture model

Cyclodextrins, especially methylated beta-cyclodextrins offer several advantages for drug delivery which include improved drug solubilization, protection against physicochemical and enzymatic degradation, as well as a potential for absorption improvement. However, little or no data are available for their use as drug penetration enhancer via the buccal route. This study focuses on the toxicity of randomly methylated beta-cyclodextrin (RAMEB) on buccal mucosa using a reconstituted human oral epithelium model composed of TR 146 cells. Toxicity of RAMEB on TR 146 cells was evaluated by measuring cell viability (MTT assay) and membrane damages followed by LDH release after single and repeated exposures to RAMEB solutions. Inflammatory effects of RAMEB are also considered by measuring expression of interleukin-1alpha and are supported by histological examination. The present results indicate that 10% RAMEB results in cytotoxic and inflammatory effects depending on time exposure, whereas 2% and 5% RAMEB do not induce tissue damages even after 5 days of repeated exposures. Therefore, the highly water-soluble RAMEB is thought to be a safe candidate as an excipient for buccal mucosal drug delivery.     

Mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines, and rat jejunum

The influence of the molecular weight on mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid (1878, 693 and 202 kDa) has been evaluated. The mucoadhesive properties were investigated using buccal and vaginal porcine mucosa by means of a tensile stress method and using rat jejunum by means of an inclined plane method. The mucoadhesive performances observed using animal tissues were compared with the mucoadhesive properties observed using submaxillary or gastric mucin dispersions. The penetration enhancement properties were investigated using porcine buccal epithelium membrane or vaginal tissue and a cell monolayer (Caco-2 cell line). Chitosan hydrochloride, already described as a penetration enhancer towards buccal and vaginal mucosae and Caco-2 cell monolayers, was used as reference. Aciclovir (acyclovir), a poorly soluble and absorbable drug, commonly used in the treatment of Herpes simplex virus (type I and II), was used as the model drug. Unlike chitosan hydrochloride, which does not show any mucoadhesive potential at pH close to neutrality (buccal and intestinal), all hyaluronic acid grades show mucoadhesive properties in all the environments considered (buccal, vaginal and intestinal). In all cases, a decrease in molecular weight of hyaluronic acid produced an increase in the mucoadhesive performance. The hyaluronic acid with the lowest molecular weight (202 kD) exhibited the best penetration enhancement properties, that, depending on the substrate under consideration, was either comparable with or even better than chitosan hydrochloride. Therefore, this grade would be the most promising for buccal, vaginal and intestinal delivery of aciclovir.     

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis

Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.     

Evaluation of bioadhesive buccal tablets containing triamcinolone acetonide in healthy volunteers

The behaviour of bioadhesive buccal tablets prepared from different ratios of poly(acrylic acid-2,5-dimethyl-1,5-hexadiene) (PADH) and hydroxypropylmethylcellulose (HPMC) with and without triamcinolone acetonide (TAA) has been investigated in the buccal cavities of healthy human volunteers. The results indicate that tablets with a higher ratio of PADH swell faster, causing the disintegration of the tablets and consequently give rise to more rapid release of drug. The inclusion of higher percentages of HPMC provides more prolonged release of drug through its properties of gelling and slow dissolution. However, adhesion of the tablet is reduced in the excessive flow of saliva and there is also a tendency for the tablet to be dislodged from the mucosa. The tablet with a PADH/HPMC ratio of 50:50 seems to provide a suitable compromise for good bioadhesion and prolonged release of drug.     

Release of naltrexone on buccal mucosa: permeation studies, histological aspects and matrix system design.

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.     

Fentanyl buccal tablet: in breakthrough pain in opioid-tolerant patients with cancer

The fentanyl buccal tablet (FBT) is a new formulation of fentanyl that uses an effervescent drug delivery system to enhance penetration across the buccal mucosa for the treatment of breakthrough pain in opioid-tolerant patients with cancer. Fentanyl is rapidly absorbed from FBT across the buccal mucosa and into the bloodstream. Fentanyl is more rapidly absorbed and bioavailability is higher from FBT than from the oral transmucosal fentanyl citrate formulation. In a well designed phase III trial in opioid-tolerant patients with cancer, a single dose of FBT 100-800 microg provided clinically significant improvements in pain intensity from 15 to 60 minutes after the dose. Single FBT doses of 100-800 microg were generally well tolerated; the majority of adverse events were mild to moderate in nature and typical of those associated with opioids.     

New absorption promoter for the buccal delivery: preparation and characterization of lysalbinic acid

Drug delivery across the buccal mucosa is convenient and safe transport method. The efficiency of the buccal system of peptide delivery is, however, not yet satisfactory. To improve the buccal transport new absorption promoters should be developed to be sufficiently active and at the same time causing no side effects like irritation or unpleasant taste. We have found that lysalbinic acid, a product of the alkaline hydrolysis of egg albumin and a mild detergent, meets those requirements. The preparation and some physicochemical properties of lysalbinic acid are described. Hamster cheek pouch was used as a model for the penetration process studies lysalbinic acid was shown to increase significantly an oral mucosa permeability for alpha-interferon and insulin. So this substance of the natural origin can be applied as an absorption enhancer for the buccal delivery of peptide drugs.     

磷酸盐缓冲介质促进胰岛素透口腔黏膜渗透作用机制研究

目的　研究磷酸盐缓冲介质 (PBS)对胰岛素 (Ins)透口腔黏膜渗透扩散的作用。方法　采用离体猪口腔黏膜固定在Valia ChienChambers双室扩散池中进行体外渗透试验和原子力显微镜扫描成像研究口腔黏膜上皮细胞表面形貌。结果　 50mmol·L- 1PBS对 1g·L- 1Ins的透口腔黏膜渗透扩散有显著的促进作用 ;猪口腔黏膜表面凹槽平均孔径为2 5± 0 3nm。结论　PBS通过磷酸根离子对含锌胰岛素的脱锌作用加速了胰岛素由六聚体转化为单体或二聚体的解聚平衡移动过程 ,从而增加了Ins的跨口腔黏膜通透性。提示PBS对胰岛素透口腔黏膜渗透有一定的促进作用     

Hypoglycaemic effect of a novel insulin buccal formulation on rabbits.

Transmucosal delivery is a suitable route for insulin non-injection administration. In this study, the hypoglycaemic effect of INSULIN BUCCAL SPRAY (IBS), a formulation with soybean lecithin and propanediol combined as absorption enhancer for insulin on diabetic rabbits and rats, were investigated. The hypoglycaemic rate was calculated and the pharmacodynamics and pharmacokinetics of the formulation in rabbits were studied. The results show that when the diabetic rabbits were administrated with IBS in dosages of 0.5, 1.5 and 4.5Ukg(-1), the blood glucose level decreased significantly compared with that of the control group and the hypoglycaemic effect lasted over 5h. The blood glucose decreasing rates are 22.4, 48.1 and 53.5%, respectively. The average bioavailability of IBS by buccal delivery versus subcutaneous injection is 29.2%. Meanwhile, the diabetic rats were administrated with IBS in dosages of 1.0, 3.0 and 9.0Ukg(-1), the blood glucose level decreased significantly compared with that of the control group and the hypoglycaemic effect lasted over 4h. The blood glucose decreasing rates are 24.6, 47.5 and 59.6%, respectively. Furthermore, the penetration of fluorescein isothiocyanate (FITC)-labelled insulin through rabbit buccal mucosa was investigated by scanning the distribution of the fluorescent probe in the epithelium using confocal laser scanning microscopy. The results revealed that FITC-insulin can pass through the buccal mucosa promoted by the enhancer and the passage of insulin across the epithelium includes both intracellular and paracellular routes. From the rabbit and rat experimental results showed that IBS is an effective buccal delivery system, which is promising for clinical trial and the future clinical application.