Draw Attention Towards Mucoadhesive Buccal Drug Delivery System

1. Introduction

Considerable attention has been focused in recent years on the delivery through the oral mucosa of drugs which have a high first pass metabolism (i.e., metabolized to a large extent by the liver during the first pass there through and therefore do not enter the blood stream) or degrade in the gastrointestinal tract. Transmucosal delivery has also been considered for treatment of oral disorders and as a local anesthetic1.

Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, which presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption2. Other routes, such as nasal, ocular, pulmonary, rectal, and vaginal drug administration, have provided excellent opportunities for the delivery of a variety of compounds. However, the mucosal lining of the oral cavity offers some distinct advantages.

Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site.3

2. Advantages of Buccal Drug Delivery Systems

Advantages of buccal administration are currently recognized commercially or in the medical literature. The first known advantage is rapidity of action. Medications administered buccally enter the blood stream immediately after passage through the buccal mucosa instead of first having to be swallowed and then having to pass through a portion of the gastrointestinal tract before being absorbed. This rapidity of action is one of the reasons that one commercially available and one experimental product for pain relief have been administered via the buccal route. The first of these products contains nitroglyerin, and is available as a buccal pill that adheres to the mucosa, sold under the trademark Nitrogard. The second product contains the non-steroidal anti-inflammatory analgesic diclofenac which has been used in an experimental buccal pill that adheres to the mucosa. The second known advantage of the buccal route is to allow administration of medications which cannot normally be administered orally. Additional unique advantages of the buccal route and the medications that exploit these advantages are described below, as well as additional medications that could be administered buccally to exploit the two previously mentioned advantages of the buccal route4.

As far as the first advantage, rapidity of action, is concerned several classes of medications would have improved efficacy if administered via the buccal route. One class of medications for which rapidity of action is important and which could be placed in buccal tablets in general and the inventive buccal tablet in particular are analgesics which include aspirin, ibuprofen, fenoprofen, sulindac, salsalate, diflunisal, mecleofenamate, naproxen, nabumetone, tolmetin, diclofenac, oxaprozin, indomethacin ketoprofen, choline salicylate, piroxicam, mefenamic acid, etodolac and ketorolac.

As far as the second advantage of buccal administration, the ability to administer drugs that cannot be ingested because of drug destruction, there are several drugs which are potentially in this category. Testosterone could be placed in a buccal tablet and could then be administered via the oral route to avoid destruction via first pass metabolism. Normally such metabolism necessitates the administration of testosterone via injection or a large skin patch worn on the scrotum. However, the scrotal patch has an important potential disadvantage since scrotal skin generates an increased amount of a testosterone metabolite, 5 alpha-dihydrotestosterone that can potentially stimulate prostate hypertrophy.5

Similarly, many drugs affect liver metabolism of other drugs. This affect would be greatly attenuated by administering such drugs in buccal form. One class of drugs in this category are medications that inhibit metabolizing enzymes in the liver resulting in increased concentrations of other drugs. Another class of drugs increases metabolizing enzymes in the liver resulting in decreased concentrations of other drugs. By administering both classes of these drugs using a buccal tablet there would be less effect on the concentration of other drugs and thus the avoidance of toxic as well as sub-therapeutic drug levels. Drugs in the category of liver enzyme inhibitors which could be administered via a buccal tablet include allopurinol, ketoconazole. Drugs in the category of liver enzyme inducers which could be administered via a buccal tablet include cabamazepine, phenytoin, glutethimide, primidone, rifampin and barbiturates such as phenobarbital, pentobarbital, secobarbital,

The third of these advantages of buccal administration is that it results in much less exposure of the GI tract to a drug as opposed to oral ingestions. One of the side effects of many antibiotics is the destruction of normal GI flora resulting in diarrhea and overgrowth with dangerous organisms such as C. difficile. Antibiotics that could be incorporated in a buccal tablet, which would then have enhanced safety because of reduction in the toxic effect on gut flora, include cephlosporins such as cephalexin, cefadroxil, cefaclor, cefamandone, cefuroxime, cefprozil, cefpodoxime, loracarbef and cefixime; also penicillins including penicillin G, penicillin V, cloxacillin, dicloxacillin

The fourth of these advantages of buccal administration is that it allows drugs to be administered which would otherwise interfere with the absorption of other drugs. In particular iron supplements can be administered via a buccal tablet with the avoidance of many adverse effects on the absorption of other medications such as thyroid hormone.

The fifth of these advantages of buccal administration is that it increases the practicality of administering drugs whose absorption is adversely affected by the presence of food. Tetracyclines, in particular, could be administered buccally thus avoiding the effects of food on tetracycline administration which otherwise complicates the administration of this class of antibiotics via the oral route.

The sixth of these advantages of buccal administration is that it allows blood lipids such as cholesterol to be lowered and modified in ways not possible through the oral ingestion of medications. Lipids can be incorporated into a buccal tablet. Lipids absorbed via the buccal mucosa bypass liver metabolism and can directly interact with endogenous lipoproteins thus influencing blood lipid levels. Recently an acute lowering of cholesterol has been demonstrated by applying lecithin to the skin.6

Compared with the oral, nasal, and rectal routes for drug delivery, the buccal route presents advantages such as an efficient blood supply and relatively low enzymatic activity. Moreover, the buccal mucosa is easily accessible and acceptable to patients; it allows the patient to interrupt drug administration by simply removing the drug delivery system. On the other hand, the buccal route is characterized by some intrinsic limitations (barrier properties of the mucosa, small area available for drug absorption, short residence time of the formulation caused by physiologic-removal mechanisms), which have to be considered in the design of buccal drug delivery systems.7

3.3. Factors affecting mucoadhesion in the oral cavity

Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. A variety of factors affect the mucoadhesive properties of polymers, such as molecular weight, flexibility, hydrogen bonding capacity, cross-linking density, charge, concentration, and hydration (swelling) of a polymer, which are briefly addressed below.

3.3.1. Polymer-related factors

3.3.1.1. Molecular weight

In general, it has been shown that the bioadhesive strength of a polymer increases with molecular weights above 100,000 8. As one example, the direct correlation between the bioadhesive strength of polyoxyethylene polymers and their molecular weights, in the range of 200,000 to 7,000,000, has been shown by Tiwari et al. 9

3.3.1.2. Flexibility

Bioadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore, it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. A recent publication demonstrated the use of tethered poly(ethylene glycol)–poly(acrylic acid) hydrogels and their copolymers with improved mucoadhesive properties 10. The increased chain interpenetration was attributed to the increased structural flexibility of the polymer upon incorporation of poly(ethylene glycol). In general, mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network 11.

3.3.1.3. Hydrogen bonding capacity

Hydrogen bonding is another important factor in mucoadhesion of a polymer. Park and Robinson found that in order for mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds 12. They have also confirmed that flexibility of the polymer is important to improve this hydrogen bonding potential. Polymers such as poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid), as well as all their copolymers, are polymers with good hydrogen bonding capacity 13. avodart |trimox |epivir |cipro |viagra |levlen |strattera |zyrtec |cialis |doxycycline |
levitra |yasmin |medrol |lasix |kamagra |alavert |flovent |sinequan |imuran |keftab |
lasuna |anafranil |seroquel |chloramphenicol |ampicillin |lisinopril |cozaar |neurontin |diflucan |synthroid |
femara |zyloprim |lasuna |ponstel |actos |rhinocort |accupril |accupril |arimidex |zyban |
zyrtec |levothroid |actonel |rhinocort |cephalexin |herbolax |zerit |imuran |zelnorm |zyvox |