Gastrointestinal mucoadhesive patch system

Depth of diffusion is dependent on the diffusion coefficient of both phases. Reinhart and Peppas[ 12 ] reported that the diffusion coefficient depended on the molecular weight of the polymer strand and that it decreased with increasing cross-linking density. According to the adsorption theory, after an initial contact between two surfaces, the materials adhere because of surface forces acting between the chemical structures at the two surfaces. This theory describes the force required for the separation of two surfaces after adhesion.

The fracture strength is equivalent adhesive strength through the following equation. This theory is useful for the study of bioadhesion by tensile apparatus. Mucoadhesive polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate. These groups attach to mucus or the cell membrane by various interactions such as hydrogen bonding and hydrophobic or electrostatic interactions.

These hydrophilic groups also cause polymers to swell in water and, thus, expose the maximum number of adhesive sites. An ideal polymer for a bioadhesive drug delivery system should have the following characteristics;[ 9 , 13 ]. It should preferably form a strong noncovalent bond with the mucus or epithelial cell surface. The polymer must not decompose on storage or during the shelf life of the dosage form. The cost of the polymer should not be high so that the prepared dosage form remains competitive.

Polymers that adhere to biological surfaces can be divided into three broad categories:[ 7 , 10 ]. Polymers that adhere through nonspecific, noncovalent interactions which are primarily electrostatic in nature. Polymers possessing hydrophilic functional groups that hydrogen bond with similar groups on biological substrates.

The latter polymer category includes lectins and thiolated polymers. Lectins are generally defined as proteins or glycoprotein complexes of nonimmune origin that are able to bind sugars selectively in a noncovalent manner.

Thiolated polymers, also designated thiomers, are hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone. Due to these functional groups, various features of polyacrylates and cellulose derivatives were strongly improved.

Table 1 shows the chemical structures of several bioadhesive polymers commonly used in modern drug delivery. Mucoadhesion may be affected by a number of factors, including hydrophilicity, molecular weight, cross-linking, swelling, pH, and the concentration of the active polymer.

Bioadhesive polymers possess numerous hydrophilic functional groups, such as hydroxyl and carboxyl. These groups allow hydrogen bonding with the substrate, swelling in aqueous media, thereby allowing maximal exposure of potential anchor sites. In addition, swollen polymers have the maximum distance between their chains leading to increased chain flexibility and efficient penetration of the substrate. The interpenetration of polymer molecules is favored by low-molecular-weight polymers, whereas entanglements are favored at higher molecular weights.

The optimum molecular weight for the maximum mucoadhesion depends on the type of polymer, with bioadhesive forces increasing with the molecular weight of the polymer up to , Beyond this level, there is no further gain.

Cross-link density is inversely proportional to the degree of swelling. To achieve a high degree of swelling, a lightly cross-linked polymer is favored. However, if too much moisture is present and the degree of swelling is too great, a slippy mucilage results and this can be easily removed from the substrate. Besides molecular weight or chain length, spatial conformation of a polymer is also important. Despite a high molecular weight of 19,, for dextrans, they have adhesive strength similar to that of polyethylene glycol PEG , with a molecular weight of , The helical conformation of dextran may shield many adhesively active groups, primarily responsible for adhesion, unlike PEG polymers, which have a linear conformation.

The pH at the bioadhesive to substrate interface can influence the adhesion of bioadhesives possessing ionizable groups. Many bioadhesives used in drug delivery are polyanions possessing carboxylic acid functionalities. If the local pH is above the p K of the polymer, it will be largely ionized; if the pH is below the p K of the polymer, it will be largely unionized. The approximate p K a for the poly acrylic acid family of polymers is between 4 and 5. The maximum adhesive strength of these polymers is observed around pH 4—5 and decreases gradually above a pH of 6.

A systematic investigation of the mechanisms of mucoadhesion clearly showed that the protonated carboxyl groups, rather than the ionized carboxyl groups, react with mucin molecules, presumably by the simultaneous formation of numerous hydrogen bonds. Ahuja[ 10 ] stated that there is an optimum concentration of polymer corresponding to the best mucoadhesion. In highly concentrated systems, beyond the optimum concentration the adhesive strength drops significantly.

In concentrated solutions, the coiled molecules become solvent-poor and the chains available for interpenetration are not numerous.

This result seems to be of interest only for more or less liquid mucoadhesive formulations. Author demonstrated increased adhesion when water was limited in the system due to an increase in the elasticity, caused by the complex formation between drug and the polymer. While in the presence of large quantities of water, the complex precipitated out, leading to a slight decrease in the adhesive character.

Mucoadhesion may be affected by the initial force of application. The rate of mucus turnover can be affected by disease states and also by the presence of a bioadhesive device. The evaluation of bioadhesive properties is fundamental to the development of novel bioadhesive delivery systems. These tests are also important to screen large number of materials and their mechanisms.

Numerous methods have been developed for studying mucoadhesion. Since no standard apparatus is available for testing bioadhesive strength, an inevitable lack of uniformity between test methods has arisen. Nevertheless, three main testing modes are recognized — tensile test, shear strength, and peel strength. But during the shear stress, the direction of the forces is reoriented so that it acts along the joint interface. In both tensile and shear modes, an equal pressure is distributed over the contact area.

The peel test is based on the calculation of energy required to detach the patch from the substrate. The peel test is of limited use in most bioadhesive systems. However, it is of value when the bioadhesive system is formulated as a patch. In tensile and shear experiments, the stress is uniformly distributed over the adhesive joint, whereas in the peel strength stress is focused at the edge of the joint.

Thus tensile and shear measure the mechanical properties of the system, whereas peel strength measures the resistant of the peeling force. Review of the literature confirmed that the most common technique used for the measurement of bioadhesion test is tensile strength method.

McCarron et al. The texture analyzer, operating in tensile test mode and coupled with a sliding lower platform, was also used to determine peel strength of similar formulations [ Figure 4 ].

Simplified representation of a typical test set-up used to determine peel strength of bioadhesive films. Rheological techniques that study the flow and deformation of materials may be useful in predicting the mucoadhesive ability of a polymeric formulation. A simple rheological approach for polymer solutions and gels was first suggested by Hassan and Gallo.

It was shown that a polymer gel and mucin solution mixture exhibited larger rheological responsethan the sum of the values of polymer and mucin. However, a wide variation in results is found in the literature that utilize rheological methods for mucoadhesion determination, which may be attributable to differences in mucin type and concentration,[ 38 , 39 ] as well as polymer concentrations.

In vivo aspects of mucoadhesive testing have recently been reported to monitor the mucoadhesion on tissue surface such as the GIT or the buccal cavity.

However, there are only a limited number of in vivo studies reported in the literature in vitro work because of the time, cost, and ethical constrains. The most common in vivo techniques to monitor mucoadhesion include GI transit times of bioadhesive-coated particles and drug release from in situ bioadhesive devices. A 51Cr-labeled bioadhesive was inserted at selected time intervals; the GITs were removed. The GIT of the rat was then cut into 20 equal segments and the radioactivity was measured.

Davis[ 43 ] investigated the noninvasive in vivo technique to determine the transit of mucoadhesive agent. Therefore, in this study a formulation was used containing a gamma-emitting radionuclide.

The release characteristics and the position polymer could be examined by gamma scintigraphy. In recent times, magnetic resonance imaging MRI is another noninvasive technique that is widely used.

Mucosa or the mucus membrane is the moist tissue that lines organs and body cavities such as mouth, gut, rectum, genital area, nose, and eye lid. Anatomical differences of the mucus membrane at varying body locations are given in Table 2. Mucoadhesive drug delivery systems in the past have been formulated as powders, compacts, sprays, semisolids, or films.

For example, compacts have been used for drug delivery to the oral cavity,[ 51 ] and powders and nanoparticles have been used to facilitate drug administration to the nasal mucosa. Details of the mucoadhesive dosage forms are given in Table 3. Recently, there has been a growing interest in alternative delivery system designs. Buccal films have been suggested as a means of offering greater flexibility and comfort than adhesive tablets. In addition, films may circumvent the problem of the relatively short residence time of oral gels.

Drug delivery through the oral mucosa has gained significant attention due to its convenient accessibility. The buccal and sublingual routes are considered as the most commonly used rotes.

The nonkeratinized epithelium in the oral cavity, such as the soft palate, the mouth floor, the ventral side of the tongue, and the buccal mucosa, offers a relatively permeable barrier for drug transport. Local drug therapy is used to treat disease states like aphthous ulceration gingivitis, periodontal disease, and xerostoma. Different dosage designs include adhesive gels, tablets, films, patches, ointments, mouth washes, and pastes.

Until now adhesive tablets have been the most commonly used dosage forms for buccal drug delivery. Tablets can be applied to different regions of oral cavity, such as cheeks, lips, gums, and palate. Unlike conventional tablets, buccal tablets allow drinking, eating, and speaking without any major discomfort.

Perioli[ 83 ] studied the influence of compression force on tablet behavior and drug release rate for mucoadhesive buccal tablets.

Tablets were prepared by using hydroxyethyl cellulose HEC and carbopol in a ratio as matrix-forming polymers at varying compression forces. Compression forces did not significantly affect the water penetration and polymer chain stretching; however, mucoadhesion performance and drug release were influenced by compression force. Increase in compression force resulted in a decreased in vitro and in vivo drug release while giving the best in vivo mucoadhesive and hydration time.

Moreover, it was observed that tablets prepared with the lowest force gave the best results, in comparison with tablets prepared with highest forces causing pain during in vivo application, needing to be detached by human volunteers. Shermer[ 84 ] evaluated the efficacy and tolerability of a mucoadhesive patch compared with a pain-relieving oral solution for the treatment of aphthous stomatitis.

The mucoadhesive patch was found to be more effective than the oral solution in terms of healing time and pain intensity after 12 and 24 h. Local adverse effects 1 h after the treatment were significantly less frequent among the mucoadhesive patch patients compared with the oral solution patients.

Donnelly[ 29 ] reported on a mucoadhesive patch containing TBO as a potential delivery system for use in photodynamic antimicrobial chemotherapy PACT of oropharyngeal candidiasis. The authors concluded that short application times of TBO-containing mucoadhesive patches should allow the treatment of recently acquired oropharyngeal candidiasis, caused solely by planktonic cells.

Longer patch application times may be required for persistent disease where biofilms are implicated. Periodontitis is an inflammatory disease of the oral cavity, which results in the destruction of the supporting structures of the teeth.

Such systems may be formulated to exhibit requisitory flow properties and hence may be easily administered into the periodontal pocket using a syringe , mucoadhesive properties ensuring prolonged retention within the pocket , and sustained release of therapeutic agent within this environment. Mucosal delivery of drugs via the buccal route is still very challenging in spite of extensive clinical studies.

Here, we are underlining several formulations which are in clinical trials or commercial products. The 3M company has developed a buccal patch system which consists of a matrix patch containing drug, mucoadhesive polymers, and polymeric elastomers surrounded by a backing material.

Their buprenorphine patch is capable of delivering the drug for a period up to 12 h, with good patient comfort reported. Oralin, a novel liquid aerosol formulation Generex Biotechnology , has been developed and it is now in clinical phase II trials.

Levels of drug in the mouth are noticeably increased compared with conventional formulations. This oral aerosol formulation is rapidly absorbed through the buccal mucosal epithelium, and it provides the plasma insulin levels necessary to control postprandial glucose rise in diabetic patients.

This novel, pain-free, oral insulin formulation has a number of advantages, including rapid absorption, user-friendly administration technique, precise dosing control comparable to injection within one unit , and bolus delivery of drug. The area of the normal human nasal mucosa is approximately cm 2 , a highly dense vascular network and relatively permeable membrane structure; all these factors make nasal cavity interesting.

Among the advantages are rapid uptake and avoiding first-pass hepatic metabolism. In addition, bioadhesive application of liquids, semisolids, and solids can significantly increase retention time. Nasal delivery of protein and peptide therapeutics can be compromised by the brief residence time at this mucosal surface. Some bioadhesive polymers have been suggested to extend residence time and improve protein uptake across the nasal mucosa. McInnes[ 92 ] quantified nasal residence of bioadhesive formulations using gamma scintigraphy and investigated absorption of insulin.

Coucke[ 93 ] studied viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR G adjuvant was made in vivo in a rabbit model. The authors concluded that the use of bioadhesive carriers based on starch and poly acrylic acid facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.

Functionalized mucoadhesive polymers, such as polycarbophil, hyaluronan, and amberlite resin, have been developed and the characterization and safety aspects of nasal drug products extensively studied. Recently, mucosal vaccines have been introduced in immunization to induce a systemic immune response. Addition of mucoadhesive polymer to the vaccine formulation increases the affinity for mucus membranes and may enhance the stability of the preparation.

Examples of these include intranasal vaccines against influenza, diphtheria, and tetanus. Pilot studies involving the use of a nasal morphine—chitosan formulation for the treatment of breakthrough pain in 14 cancer patients suggested that this system was acceptable, well-tolerated, and may lead to rapid onset of pain relief.

Tzachev[ 96 ] has compared a mucoadhesive solution formulation of xylometazoline with commercially available decongestatnt solution in 20 human subjects with perennial allergic rhinitis. The author concluded that the mucoadhesive formulation exhibited a significantly more prolonged clinical effect than the nonmucoadhesive product.

Drug administration to the eye is a challenge because there are several mechanisms tear production, tear flow, and blinking that protect the eye from the harmful agents. Conventional delivery methods are not ideal. Solutions and suspensions are readily washed from the cornea and ointments alter the tear refractive index and blur vision; so it is a target to prolong the residence time by mucoadhesion.

Sensoy[ 97 ] aimed to prepare bioadhesive sulfacetamide sodium microspheres to increase residence time on the ocular surface and to enhance treatment efficacy of ocular keratitis.

Microspheres were fabricated by a spray-drying method using a mixture of polymers, such as pectin, polycarbophil, and HPMC at different ratios.

Author concluded that a sulfacetamide sodium—loaded polycarbophil microsphere formulation with a polymer:drug ratio of was found to be the most suitable for ocular application and used in in vivo studies on New Zealand male rabbit eyes with keratitis caused by Pseudomonas aeruginosa and Staphylococcus aureus. Gene transfer is considered to be a promising alternative for the treatment of several chronic diseases that affect the ocular surface. De la Fuente[ 98 ] investigated the efficacy and mechanism of action of a bioadhesive DNA nanocarrier made of hyaluronan HA and chitosan CS , specifically designed for topical ophthalmic gene therapy.

The author concluded that on topical administration to rabbits, the nanoparticles entered the corneal and conjunctival epithelial cells and got assimilated by the cells. More importantly, the nanoparticles provided an efficient delivery of the associated plasmid DNA inside the cells, reaching significant transfection levels.

Many clinical studies have been performed on mucoadhesive ocular dosage forms. Ocular films applied behind the eye lid were found to prolong retention time and precision of dosing.

It has been shown that the addition of mucoadhesive polymers to ocular films reduced film movement across the eye, minimizing ocular irritation and burning sensations. The vagina is a fibrovascular tube connecting the uterus to the outer surface of the body. The vaginal epithelium consists of a stratified squamous epithelium and lamina propia. Dosage forms used for vaginal route are solutions, gels, suspensions, suppositories, creams, and tablets and all have short residence time. These formulations may contain drug or, quite simply, act in conjunction with moisturizing agents as a control for vaginal dryness.

Alam[ ] developed an acid-buffering bioadhesive vaginal clotrimazole antifungal and metronidazole antiprotozoal and antibacterial tablets for the treatment of genitourinary tract infections. From bioadhesion experiment and release studies, it was found that polycarbophil and sodium carboxymethyl cellulose was a good combination for an acid-buffering bioadhesive vaginal tablet.

From ex vivo retention studies, it was found that the bioadhesive polymers held the tablet for more than 24 h inside the vagina. The in vitro spreadability of the swelled tablet was comparable to the marketed gel. Cevher[ ] aimed to prepare clomiphene citrate CLM gel formulations for the local treatment of human papilloma virus infections.

Author concluded that gels containing CP-Cys showed the highest adhesiveness and mucoadhesion. A significant decrease was observed in drug release from gel formulations as the polymer concentration increased. Recent advances in polymeric technology have increased the potential of vaginal gels. Vaginal gels are semisolid polymeric matrices comprising small amounts of solid, dispersed in relatively large amounts of liquid and have been used in systems for microbicides, contraceptives, labor inducers, and other substances.

Several clinical trials are in underway on microbicidal gels. Microbicidal gels are intended to improve mucosal permeation rate of microbicides for the prevention of sexually transmitted diseases. Various clinical trials of contraceptive gels are also ongoing, with a view to determine their effectiveness. Janssen Pharmaceutica conducted phase III clinical trial of mucoadhesive systems based on itraconazole vaginal cream containing cyclodextrins and other ingredients.

The rectum is part of the colon, it is 10 cm in length, and has surface area cm 2. The function of the rectum is mostly concerned with removing water. Surface area without villi gives it a relatively small surface area for drug absorption. Drugs that are liable to extensive first-pass metabolism can benefit greatly if delivered to the rectal area, especially if they are targeted to areas close to the anus.

Furthermore, addition of bioadhesive polymer the migration distance in the rectum decreased. Kim[ ] aimed to develop a thermoreversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen.

Cyclodextrin derivatives, such as alpha-, beta-, gamma-cyclodextrin, and hydroxypropyl-beta-cyclodextrin HP-beta-CD , were used to enhance the aqueous solubility of flurbiprofen. The authors concluded that HP-beta-CD could be a preferable solubility enhancer for the development of liquid suppositories containing poorly water-soluble drugs. A novel bioadhesive cervical patch containing 5-fluorouracil for the treatment of cervical intraepithelial neoplasia CIN was described by Woolfson.

The film, which was mechanically stable on storage under ambient conditions, was bonded directly to a backing layer formed from thermally cured poly vinyl chloride emulsion. Release of 5-fluorouracil from the bioadhesive layer into an aqueous sink was rapid but was controlled down to an undetectable level through the backing layer.

Despite the relatively hydrophilic nature of 5-fluorouracil, substantial drug release through human cervical tissue samples was observed over approximately 20 h.

Donnelly[ ] described the design, physicochemical characterization, and clinical evaluation of bioadhesive drug delivery systems for photodynamic therapy of difficult-to-manage vulval neoplasias and dysplasias.

Aminolevulic acid ALA is commonly delivered to the vulva using creams or solutions, which are covered with an occlusive dressing. Such dressings are poor at staying in place at the vulva, where shear forces are high in mobile patients. To overcome the problems, the authors produced a bioadhesive patch by a novel laminating procedure. Oral route is undoubtedly most favored route of administration, but hepatic first-pass metabolism, degradation of drug during absorption, mucus covering GI epithilia, and high turnover of mucus are serious concerns of oral route.

In recent years, the gastrointestinal tract GIT delivery emerged as a most important route of administration. Bioadhesive retentive system involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the GIT. Using bioadhesive would be achieved increase GI transit time and increase in bioavailability. Ahmed[ ] studied gastric retention formulations GRFs made of naturally occurring carbohydrate polymers and containing riboflavin in vitro for swelling and dissolution characteristics as well as in fasting dogs for gastric retention.

The bioavailability of riboflavin, from the GRFs was studied in fasted healthy humans and compared to an immediate release formulation. It was found that when the GRFs were dried and immersed in gastric juice, they swelled rapidly and released their drug payload in a zero-order fashion for a period of 24 h.

In vivo studies in dogs showed that a rectangular shaped GRF stayed in the stomach of fasted dogs for more than 9 h, then disintegrated and reached the colon in 24 h.

Considering pharmacokinetic parameters of human subjects under fasting conditions, bioavailability of riboflavin from a large size GRF was more than triple of that measured after administration of an immediate release formulation. Salman[ ] aimed to develop polymeric nanoparticulate carriers with bioadhesive properties and to evaluate their adjuvant potential for oral vaccination. The affinity of nanoparticles to the gut mucosa was studied in orally inoculated rats.

The authors concluded that thiamine-coated nanoparticles showed promise as particulate vectors for oral vaccination and immunotherapy. The mucoadhesive dosage forms offer prolonged contact at the site of administration, low enzymatic activity, and patient compliance.

The formulation of mucoadhesive drug delivery system depends on the selection of suitable polymer with excellent mucosal adhesive properties and biocompatibility. Now researchers are looking beyond traditional polymers, in particular next-generation mucoadhesive polymers lectins, thiols, etc.

However, these novel mucoadhesive formulations require much more work, to deliver clinically for the treatment of both topical and systemic diseases. Source of Support: Nil. Conflict of Interest: None declared.

National Center for Biotechnology Information , U. J Pharm Bioallied Sci. Ryan F. Author information Article notes Copyright and License information Disclaimer. Address for correspondence: Dr. Donnelly, E-mail: ku. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC. Abstract Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Keywords: Mucoadhesion, mucoadhesive drug delivery systems, mucoadhesive materials.

Bioadhesion and Mucoadhesion The term bioadhesion can be defined as the state in which two materials, at least one biological in nature, are held together for an extended period of time by interfacial forces. Theories of Mucoadhesion Various theories exist to explain at least some of the experimental observations made during the bioadhesion process. Wetting Theory of Mucoadhesion The wetting theory is perhaps the oldest established theory of adhesion.

Open in a separate window. Figure 1. A liquid bioadhesive spreading over a typical soft tissue surface. Electrostatic Theory of Mucoadhesion According to electrostatic theory, transfer of electrons occurs across the adhesive interface and adhering surface.

Diffusion Theory of Mucoadhesion Diffusion theory describes that polymeric chains from the bioadhesive interpenetrate into glycoprotein mucin chains and reach a sufficient depth within the opposite matrix to allow formation of a semipermanent bond.

Figure 2. Adsorption Theory of Mucoadhesion According to the adsorption theory, after an initial contact between two surfaces, the materials adhere because of surface forces acting between the chemical structures at the two surfaces.

Fracture Theory of Adhesion This theory describes the force required for the separation of two surfaces after adhesion. Mucoadhesive Materials Mucoadhesive polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate. It should be nonirritant. It should adhere quickly to moist tissue and possess some site specificity.

It should allow easy incorporation of the drug and offer no hindrance to its release. Polymers that adhere to biological surfaces can be divided into three broad categories:[ 7 , 10 ] Polymers that adhere through nonspecific, noncovalent interactions which are primarily electrostatic in nature Polymers possessing hydrophilic functional groups that hydrogen bond with similar groups on biological substrates Polymers that bind to specific receptor sites on the cell or mucus surface The latter polymer category includes lectins and thiolated polymers.

Table 1. Chemical structures of some bioadhesive polymers used in drug delivery. Factors Affecting Mucoadhesion Mucoadhesion may be affected by a number of factors, including hydrophilicity, molecular weight, cross-linking, swelling, pH, and the concentration of the active polymer. Hydrophilicity Bioadhesive polymers possess numerous hydrophilic functional groups, such as hydroxyl and carboxyl.

Molecular Weight The interpenetration of polymer molecules is favored by low-molecular-weight polymers, whereas entanglements are favored at higher molecular weights. Cross-linking and Swelling Cross-link density is inversely proportional to the degree of swelling. Spatial Conformation Besides molecular weight or chain length, spatial conformation of a polymer is also important. Concentration of Active Polymer Ahuja[ 10 ] stated that there is an optimum concentration of polymer corresponding to the best mucoadhesion.

Other Factors Affecting Mucoadhesion Mucoadhesion may be affected by the initial force of application. Techniques for the Determination of Mucoadhesion The evaluation of bioadhesive properties is fundamental to the development of novel bioadhesive delivery systems. Figure 3. Figure 4. Routes of Administration for Mucoadhesive-based Drug Delivery Systems Mucosa or the mucus membrane is the moist tissue that lines organs and body cavities such as mouth, gut, rectum, genital area, nose, and eye lid.

Table 3 Different types of mucoadhesive dosage forms. Oral Mucoadhesive Drug Delivery Systems Drug delivery through the oral mucosa has gained significant attention due to its convenient accessibility. Nasal Mucoadhesive Drug Delivery Systems The area of the normal human nasal mucosa is approximately cm 2 , a highly dense vascular network and relatively permeable membrane structure; all these factors make nasal cavity interesting. Ocular Mucoadhesive Drug Delivery Systems Drug administration to the eye is a challenge because there are several mechanisms tear production, tear flow, and blinking that protect the eye from the harmful agents.

Vaginal Mucoadhesive Drug Delivery Systems The vagina is a fibrovascular tube connecting the uterus to the outer surface of the body. Rectal Mucoadhesive Drug Delivery Systems The rectum is part of the colon, it is 10 cm in length, and has surface area cm 2. Cervical and Vulval Drug Delivery Systems A novel bioadhesive cervical patch containing 5-fluorouracil for the treatment of cervical intraepithelial neoplasia CIN was described by Woolfson.

Gastrointestinal Mucoadhesive Drug Delivery Systems Oral route is undoubtedly most favored route of administration, but hepatic first-pass metabolism, degradation of drug during absorption, mucus covering GI epithilia, and high turnover of mucus are serious concerns of oral route.

Conclusion The mucoadhesive dosage forms offer prolonged contact at the site of administration, low enzymatic activity, and patient compliance. References 1. Good WR. Transdermal nitro-controlled delivery of nitroglycerin via the transdermal route. Drug Dev Ind Pharm. Bioadhesion of Hydrated Chitosans: An in vitro and in vivo Study. Int J Pharm. The Contribution of anionic polymer structural features related to mucoadhesion. J Control Release. Fundamental aspects of bioadhesion.

It is demonstrated that protein and peptide encapsulated in nanoparticles have better absorption through GI tract as compared to their native counterpart. The factors affecting uptake include the particle size of particulate, the surface charge of the particles, the influence of surface ligands and the dynamic nature of particle interaction in the gut 1. Behrens 54 studied the interaction of nanoparticles consisting of hydrophobic polystyrene, bioadhesive chitosans and PLA-PEG with two human intestinal cell lines and compared the in vivo uptake in rats.

In one example, insulin was encapsulated in nanospheres using phase inversion nanoencapsulation. The insulin released over a period of appoximately 6 h, was shown to be orally active, and had One problem using nanoparticles is the erratic nature of nanoparticles absorption.

Liposomes are prone to the combined degrading effects of the acidic pH of the stomach, bile salts and pancreatic lipase upon oral administration. There are several reports on the intact liposomal uptake by cells in in vitro and in situ experiments 56 — The results are, however, not convincing for the oral delivery of protein with a liposomal system. Attempts have been made to improve the stability of liposomes either by incorporating polymers at the liposome surface, or by using GI-resistant lipids 1.

In vitro release of insulin, a model peptide, from liposomes in the bile salts solution was markedly reduced by coating the surface with the sugar chain portion of mucin or polyethylene glycol. Encapsulation of insulin with the sugar chain portion of mucin and that of polyethylene glycol completely suppressed the degradation of insulin in the intestinal fluid, whereas uncoated liposomes suppressed it only partially.

These results demonstrated that surface coating of liposomes with PEG or mucin gained resistance against digestion by bile salts and increased the stability in the GI tract. When insulin was orally administered to rats as a solution or non-charged liposome, no hypoglycemic effect was observed. Administration of insulin encapsulated in positively charged liposome caused the rapid decrease in the plasma glucose level that recovered to the control level within 3 h.

In contrast, PEG containing liposomes and mucin containing liposomes caused a gradual decrease in the glucose level after administration. The hypoglycemic effect by PEG-Liposome lasted for much longer duration than that of uncoated liposomes. The slow release of insulin from the surface coated liposomes achieved longer duration of oral hypoglycemic activity. Consequently, the surface coating should be the potential way to add desirable functions to the liposome for oral drug delivery Mucoadhesive polymeric systems are the most promising approach among several approaches.

Mucoadhesive properties can provide an intimate contact with the mucosa at the site of drug uptake preventing a presystemic metabolism of peptides on the way to the absorption membrane in the gastrointestinal tract. Additionally, the residence time of the delivery system at the site of drug absorption is increased. Thus, we can achieve site-specific drug delivery by the use of mucoadhesive polymeric system. Mucoadhesive polymers are able to adhere to the mucin layer on the mucosal epithelium and thus results in the increase of oral drug bioavailability of protein and peptide drugs.

These polymers decrease the drug clearance rate from the absorption site, thereby increasing the time available for absorption Most of the current synthetic bioadhesive polymers are either polyacrylic acid or cellulose derivatives. Examples of polyacrylic acid-based polymers are carbopol, polycarbophil, polyacrylic acid PAAc , polyacrylate, poly methylvinylether-co-methacrylic acid , poly 2-hydroxyethyl methacrylate , poly methacrylate , poly alkylcyanoacrylate , poly isohexylcyanoacrylate and poly isobutylcyanoacrylate.

Cellulose derivatives include carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose, and methylhydroxyethyl cellulose. In addition, seminatural bioadhesive polymers include chitosan and various gums such as guar, xanthan, poly vinylpyrrolidone , and poly vinyl alcohol. The system consists of four layered films contained in an enteric capsule. The backing layer is made of a water-insoluble polymer, ethyl cellulose EC. The surface layer is made of an enteric pH-sensitive polymer such as hydroxypropylmethylcellulose phthalate, Eudragit L or S and was coated with an adhesive layer.

The middle layer, drug-containing layer, made of cellulose membrane is attached to the EC backing layer by a heating press method. Both drug and pharmaceutical additives including an organic acid, citric acid, and a non-ionic surfactant, polyoxyethylated castor oil derivative were formulated in the middle layer.

The surface layer was attached to the middle layer by an adhesive layer made of carboxyvinyl polymer. After oral administration, the surface layer dissolves at the targeted intestinal site and adheres to the small intestinal wall, where a closed space is created on the target site of the gastrointestinal mucosa by adhering to the mucosal membrane. As a result, both the drug and the absorption enhancer coexist in the closed space and a high-concentration gradient is formed between inside the system and the enterocytes, which contributes to the enhanced absorption of proteins because most drugs are absorbed by a passive-diffusion mechanism.

As a result, the absorption enhancer makes full use of its capacity. As the GI-MAPS is a novel drug-delivery system preparation, the fabrication method is the second hurdle to overcome in the launch of an oral preparation of proteins. However, recent advances in microfabrication technology in the semiconductor industry have made it possible to produce many micron-size GI-MAPS. Several approaches to produce the micron-size GI-MAPS are described and the future of these technologies is discussed.

Carbopol polymers have been shown to inhibit luminal degradation of insulin, calcitonin, and insulin-like growth factor-I IGF-I by trypsin and chymotrypsin In contrast, cationic polymers adhere to the negatively charged mucus mainly due to electrostatic forces As both anionic and cationic mucoadhesive polymers exhibit a high buffer capacity, a demanded microclimate regarding the pH can be adjusted and maintained over numerous hours within the polymeric network On the contrary, the strong mucoadhesive properties of thiomers are believed to be based on additional covalent bonds between thiol groups of the thiomer and cysteine-rich subdomains of mucus glycoproteins This theory was confirmed by findings of mucoadhesion studies, where a higher amount of thiol groups on the polymer resulted in higher mucoadhesive properties 66 — Although thiomers show strongly improved mucoadhesive properties, the adhesion of delivery systems being based on such polymers is nevertheless limited by the natural mucus turnover.

The mucus turnover in the human intestine, for instance, was determined to be in the range of h Consequently, at least within this time period, the adhesion of the delivery system will fail.

Hussain et al. Improved intestinal absorption of 9-desglycinamide, 8-arginine vasopressin DGAVP was observed in rats in vitro as well as in vivo using the weakly cross-linked poly acrylate derivative polycarbophil dispersed in physiological saline Haas and Lehr Similarly, enhanced oral bioavailability of peptide and protein drugs was seen when these compounds were formulated with chitosan-EDTA conjugates The authors suggested that chitosan-EDTA conjugates protect peptide and protein drugs from enzymatic degradation across the GI tract.

In conclusion, Delivering proteins and peptides by the oral route is extremely challenging. The very nature of digestive system is designed to breakdown these polypeptides into amino acids prior to absorption. The low bioavailability of drugs remains to be an active area of research. Several sites in the GIT have been investigated by researchers, but no major breakthrough with broad applicability to diverse proteins and peptides has been achieved.

Considerable progress has been made over past few years in developing innovative technologies for promoting absorption across GI and numbers of these approaches are demonstrating potential in clinical studies. Chemical modification and use of mucoadhesive polymeric system for site-specific drug delivery seen to be promising candidates for protein and peptide drug delivery. National Center for Biotechnology Information , U. Indian J Pharm Sci. Patole Department of Pharmaceutical Sciences, Prin.

Author information Article notes Copyright and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Till recent, injections remained the most common means for administering therapeutic proteins and peptides because of their poor oral bioavailability.

Keywords: Therapeutic proteins and peptides, oral delivery, formulation vehicles, absorption enhancers, enzyme inhibitors, mucoadhesive polymeric system. Increases membrane permeability. Mucoadhesive polymeric system Achieve site-specific drug delivery. Improves membrane permeation. Open in a separate window. Enzyme inhibitors: The choice of protease inhibitors will depend on the structure of these therapeutic drugs, and the information on the specificity of proteases is essential to guarantee the stability of the drugs in the GI tract Absorption enhancers: In order for therapeutic agents to exert their pharmacological effects, they have to cross from the biological membranes into the systemic circulation and reach the site of action.

Formulation vehicles: A primary objective of oral delivery systems is to protect protein and peptide drugs from acid and luminal proteases in the GIT. Mucoadhesive polymeric systems: Mucoadhesive polymeric systems are the most promising approach among several approaches. Rick S. Oral protein and peptide drug delivery. Drug delivery: Principles and applications. New Jersey: Wiley Interscience; Adessi C, Sotto C. Converting a peptide into a drug: Strategies to improve stability and bioavailability.

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