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.     

Development and characterization of mucoadhesive microspheres bearing salbutamol for nasal delivery

Mucoadhesive drug delivery systems are those that provide intimate contact of the drug with the mucosa for an extended period of time. In our present work, mucoadhesive chitosan microspheres were prepared by emulsion solvent method. Formulations were characterized for various physicochemical attributes, shape, surface morphology, size, and size distribution, drug payload, swelling ability, and mucoadhesion. The effect of drug, citric acid, and permeation enhancer concentration on the physicochemical properties was studied. Crosslinked chitosan microspheres showed very good mucoadhesion, which was decreased on increasing the drug concentration and citric acid concentration, and slightly improved upon incorporation of permeation enhancer. The in vitro drug release and in vitro drug permeability through mucous membrane were performed, and slow release/permeation was noted with chitosan citrate complexed microspheres compared with noncomplexed chitosan microspheres. The in vivo performance of mucoadhesive microspheres formulations showed prolonged and controlled release of salbutamol as compared with oral administration of conventional dosage form.     

Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder

Purpose

Purpose of the present study was the development of a mucoadhesive nanoparticulate drug delivery system for local use in intravesical therapy of interstitial cystitis, since only a small fraction of drug actually reaches the affected site by conventional treatment of bladder diseases via systemic administration.

Methods

Chitosan-thioglycolic acid (chitosan-TGA) nanoparticles (NP) and unmodified chitosan NP were formed via ionic gelation with tripolyphosphate (TPP). Trimethoprim (TMP) was incorporated during the preparation process of NP. Thereafter, the mucoadhesive properties of NP were determined in porcine urinary bladders and the release of TMP among simulated conditions with artificial urine was evaluated.

Results

The particles size ranged from 183 nm to 266 nm with a positive zeta potential of +7 to +13 mV. Under optimized conditions the encapsulation efficiency of TMP was 37%. The adhesion of prehydrated chitosan-TGA NP on the urinary bladder mucosa under continuous urine voiding was 14-fold higher in comparison to unmodified chitosan NP. Release studies indicated a more sustained TMP release from covalently cross linked particles in comparison to unmodified chitosan-TPP NP over a period of 3 h in artificial urine at 37 °C.

Conclusion

Utilizing the method described here, chitosan-TGA NP might be a useful tool for local intravesical drug delivery in the urinary bladder.     

黏膜黏附材料在阴道给药中的应用

黏膜黏附材料使阴道黏膜给药系统更具有局部浓度高,作用时间长,减少给药次数和总量等优点.本文在讨论黏膜黏附机制的基础上,综述了聚丙烯酸类、纤维素类及壳聚糖等各种黏附材料在阴道给药中的应用及安全性评价.     

Mucoadhesive polymeric platforms for controlled drug delivery

The process of mucoadhesion involving a polymeric drug delivery platform is a complex one that includes wetting, adsorption and interpenetration of polymer chains amongst various other processes. The success and degree of mucoadhesion bonding is influenced by various polymer-based properties such as the degree of cross-linking, chain length and the presence of various functional groupings. The attractiveness of mucosal-targeted controlled drug delivery of active pharmaceutical ingredients (APIs), has led formulation scientists to engineer numerous polymeric systems for such tasks. Formulation scientists have at their disposal a range of in vitro and in vivo mucoadhesion testing setups in order to select candidate adhesive drug delivery platforms. As such, mucoadhesive systems have found wide use throughout many mucosal covered organelles for API delivery for local or systemic effect. Evolution of such mucoadhesive formulations has transgressed from first-generation charged hydrophilic polymer networks to more specific second-generation systems based on lectin, thiol and various other adhesive functional groups.     

Subjective effects of additional doses of buprenorphine in patients on buprenorphine maintenance

OBJECTIVES: Buprenorphine has considerable abuse potential. Patients who are maintained on buprenorphine (for opioid dependence) further use additional doses besides its maintenance dose. Subjective effects of the additional doses of buprenorphine in patients on buprenorphine maintenance patients is focused in this study. METHODS: Nineteen subjects who were maintained on buprenorphine 4mg, s/l per day for at least 1month were admitted and given three additional doses of buprenorphine 2mg, s/l at the interval of 2h each and subjective effects were assessed with the help of standard tools after 2h of each dose and the next day also. Drug was given in a cumulative dose design in the inpatient unit of a de-addiction centre. RESULTS: Dysphoria and sleepiness increased while euphoria and drug liking decreased with additional doses of buprenorphine. These changes were statistically significant and were highest at maximum cumulative dose of 10mg. CONCLUSION: Results suggest that abuse liability of buprenorphine in these subjects is low in higher doses. However, these findings need to be replicated in this group of patients to make a comment on clinical implication.     

Assessment of test methods evaluating mucoadhesive polymers and dosage forms: An overview

Oral mucoadhesive preparations have gained increasing importance in the last decades, by reason of numerous advantages like easy application, discrete handling and no swallowing of the drug product. Pharmacopoeial methods to study mucoadhesion are not available so far, despite the new monograph for oromucosal preparations is valid since the European Pharmacopoeia 7.4 (2012) including a chapter on mucoadhesive preparations.Several mucoadhesion test methods are reviewed concerning the applicability for various polymers, different drug dosage forms and comparability of experimental set-ups. Different test methods and experimental set-ups lead to huge differences regarding the results.     

Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents

The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications.     

Formulation of sublingual promethazine hydrochloride tablets for rapid relief of motion sickness

The delivery of antihistaminic agents via the oral route is problematic, especially for elderly patients. This study aimed to develop a sublingual formulation of promethazine hydrochloride by direct compression, and to mask its intensely bitter taste. Promethazine hydrochloride (PMZ) sublingual tablets prepared by direct compression were optimized using Box-Behnken full factorial design. The effect of a taste-masking agent (Eudragit E 100, X1), superdisintegrant (crospovidone; CPV, X2) and lubricant (sodium stearyl fumarate; SSF, X3) on sublingual tablets’ attributes (responses, Y) was optimized. The prepared sublingual tablets were characterized for hardness (Y1), disintegration time (Y2), initial dissolution rate (IDR; Y3) and dissolution efficiency after 30 min (Dissolution Efficiency (DE); Y4). The obtained results showed a significant positive effect of the three independent factors on tablet hardness (P < 0.05), and the interactive effect of Eudragit E 100 and CPV on tablet hardness was significant. Disintegration time was mainly affected by Eudragit E 100 and CPV concentrations. Moreover, IDR was employed to assess the taste masking effect, lower values were obtained at higher Eudragit E 100 concentration despite it was statistically insignificant (p > 0.05). Optimized formulation that was suggested by the software was composed of: Eudragit E 100 (X1) = 2.5% w/w, CPV (X2) = 4.13% w/w, and SSF (X3) = 1.0% w/w. The observed values of the optimized formula were found to be close to the predicted optimized values. The Differential Scanning Calorimetric (DSC) studies indicated no interaction between PMZ and tablet excipients.     

Coated dosage forms for colon-specific drug delivery

Coating materials used in the manufacture of colon-specific solid oral dosage forms include polymers with a pH-dependent solubility that rely on the difference in pH between the small and the distal large intestine (pH-controlled release), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion that take advantage of the constant small intestinal transit time (time-controlled release), polymers that are degradable by the microbial enzymes in the colon (enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase of the luminal pressure in the colon caused by peristaltic waves (pressure-controlled release). This review gives an overview of coated dosage forms that have been developed to achieve colon specificity.     

Positively charged gelatin microspheres as gastric mucoadhesive drug delivery system for eradication of H. pylori

Gastric mucoadhesive drug delivery systems are very promising for eradication of Helicobacter pylori (H. pylori), a spiral bacterium that resides in the gastric mucus layer and at the mucus- epithelial cell interface. New positively charged biodegradable microspheres were prepared using aminated gelatin by surfactantfree emulsification in olive oil, followed by a cross-linking reaction with glutaraldehyde. The amino group contents of the modified gelatin and the microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. With the increase of glutaraldehyde concentration, the amino group content of the microspheres decreased accordingly. The influence of glutaraldehyde concentration, cross-linking reaction time, drug-loading patterns, and type of release media on the in vitro release characteristics of amoxicillin from the microspheres was investigated. Amoxicillin release rate from the modified gelatin microspheres was significantly reduced compared with that from gelatin microspheres. Furthermore, the release was decreased with the increase of glutaraldehyde concentration and/or cross-linking time. On the other hand, a faster release was observed in a lower pH release medium and/or using a lower pH solution for amoxicillin loading. The gastric mucoadhesive properties of the microspheres were evaluated using RITC-labeled microspheres in an isolated rat stomach. The gastric mucoadhesion of the modified gelatin microspheres was markedly improved compared with that of gelatin microspheres. The modified gelatin microsphere proves to be a possible candidate delivery system for the effective eradication of H. pylori.     

Biopharmaceutical evaluation of transnasal,sublingual, and buccal disk dosage forms of butorphanol

A series of three-way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist-antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non-compartmental pharmacokinetic analysis. The elimination half-life of butorphanol was about 3–5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.     

Transbuccal delivery of chlorpheniramine maleate from mucoadhesive buccal patches

This article describes buccal permeation of chlorpheniramine maleate (CPM) and its transbuccal delivery using mucoadhesive buccal patches. Permeation of CPM was calculated in vitro using porcine buccal membrane and in vivo in healthy humans. Buccal formulations were developed with hydroxyethylcellulose (HEC) and evaluated for in vitro release, moisture absorption, mechanical properties, and bioadhesion, and optimized formulation was subjected for bioavailability studies in healthy human volunteers. In vitro flux of CPM was calculated to be 0.14 ± 0.03 mg.h^-1.cm^-2 and buccal absorption also was demonstrated in vivo in human volunteers. In vitro drug release and moisture absorbed were governed by HEC content and formulations exhibited good tensile and mucoadhesive properties. Bioavailability from optimized buccal patch was 1.46 times higher than the oral dosage form and the results showed statistically significant difference.     

Evaluation of microcrystalline chitosans for gastro-retentive drug delivery

In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M_w) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t_max) were noted, but the amounts of furosemide absorbed (AUC_0–∞ and C_max) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC_0–∞ (3050 μg l⁻¹ h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M_w. With MCCh of 240 kDa M_w AUC_0–∞ was 1890 μg l⁻¹ h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its “absorption window” before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.     

Development of novel mucoadhesive pellets of metformin hydrochloride

Mucoadhesive polymer-coated pellets containing metformin hydrochloride were prepared by the powder-layering technique using a centrifugal fluidizing (CF)-granulator. Four high-viscosity polymers were applied to make the pellets: 1) hydroxymethylcellulose (HPMC), 2) sodium alginate (Na-Alg), 3) HPMC/Carbopol, and 4) sodium carboxylmethylcellulose (Na-CMC). The physical crushing test, mucoadhesive test, zeta-potential test, in vitro release study and observation of gastroretention state of the dosage form were performed to investigate the pellets. The strong adhesive interaction between the Na-CMC-coated pellets and the mucin disc was obtained by mucoadhesive test. Na-Alg was most effective among the polymers used in changing the value of zeta potential of the mucin solution by the interaction between a polymer and a mucin particle. Results from drug dissolution study showed that over 95% of the drug from all the four pellets was released before 2 h, while Na-CMC- and Na-Alg-coated pellets showed a moderate sustained-release in SGF (simulated gastric fluid) and SIF (simulated intestine fluid), respectively. In conclusion, Na-CMC and Na-Alg seem to be promising candidates for mucoadhesive formulation and further studies to improve the sustained-release property are underway for achieving the ultimate goal of once-a-day formulation of metformin hydrochloride.     

Design and fungicidal activity of mucoadhesive lactoferrin tablets for the treatment of oropharyngeal candidosis

Lactoferrin (Lf) is a potential drug candidate for the treatment of oropharyngeal Candida infections. However, for an effective therapeutic treatment an appropriate dosage form is required. Therefore a mucoadhesive tablet for buccal application was developed. Tablets of sufficient strength could be produced on high speed tabletting machines, but they could only be obtained when the protein contained at least 7% moisture. The tablet contained sodium alginate both for its release-controlling properties as well as for its mucoadhesive properties. Furthermore, phosphate buffer was added to keep the pH of the saliva in the mouth within the range of 6.5 to 7.5. In this pH range, Lf has shown to have its highest activity against Candida growth inhibition. The tablet formulation containing Lf had the same antifungal properties as compared with Lf alone, because in most cases identical inhibitory concentrations were observed against several clinical isolates of Candida albicans and Candida glabrata . In human volunteers the tablets, containing 250 mg Lf and placed in each pouch, were able to keep the Lf concentration in the saliva at effective levels for at least 2 hr, while the pH of the saliva remained within the desired range. We concluded that the developed mucoadhesive tablet can improve the therapeutic efficacy of Lf and that it is suitable for further clinical research.     

Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms

Approximately 40% of new chemical entities exhibit poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low bioavailability. Self-emulsifying drug delivery systems (SEDDS) are usually used to improve the bioavailability of hydrophobic drugs. Conventional SEDDS, however, are mostly prepared in a liquid form, which can produce some disadvantages. Accordingly, solid SEDDS (S-SEDDS), prepared by solidification of liquid/semisolid self-emulsifying (SE) ingredients into powders, have gained popularity. This article gives an overview of the recent advances in the study of S-SEDDS, especially the related solidification techniques and the development of solid SE dosage forms. Finally, the existing problems and the possible future research directions in this field are pointed out.     

药物剂型和药物传输系统的发展综述

近年来,现代药剂学发展迅速,新剂型和药物传输系统展现了广阔的发展前景。发展新剂型和新给药系统可以获得短期内成效,使药品差异化,提高制药企业研发及产业化水平。在有限的资源分配下,我国唯有发展制剂创新才能缩小同发达国家的差距。本文就现代药剂学的发展进行综述,重点探讨剂型和给药系统的相关理论和应用,介绍了药剂学的最新研究进展,并总结未来发展可能遇到的挑战和机遇。