Need for alternate, nonoral routes to the systemic circulation

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Chapter: Pharmaceutical Drugs and Dosage: Organ-specific drug delivery

Delivery of drugs via the absorptive mucosa in various easily accessible body cavities, such as the buccal, nasal, ocular, sublingual, rectal, and vagi-nal mucosae are pursued when it offers advantages over peroral administra-tion for systemic drug delivery.


Need for alternate, nonoral routes to the systemic circulation

Delivery of drugs via the absorptive mucosa in various easily accessible body cavities, such as the buccal, nasal, ocular, sublingual, rectal, and vagi-nal mucosae are pursued when it offers advantages over peroral administra-tion for systemic drug delivery, since the preferred route of administration for pharmaceutical product has been oral ingestion. The need for alternate routes of drug delivery into the systemic circulation originates with the challenges involved in the systemic delivery of drugs administered orally.

As a drug passes through the (GI) tract, it encounters different envi-ronments with respect to pH, enzymes, electrolytes, fluidity, and surface features, all of which can influence drug absorption. There is a great vari-ation in the pH across the GI tract, which runs from the mouth to the anus. The interdigestive migration of a drug or a dosage form is governed by GI motility, wherein the drug is exposed to different pHs at different time periods. The stomach has an acidic pH varying from 2 to 4. The acidic pH in the stomach increases up to a pH of 5.5 in the duodenum. The pH then increases progressively from the duodenum to the small intestine (a pH of 6–7) and reaches a pH of 7–8 in the distal ileum. After the ileoce-cal junction, the pH falls sharply to 5.6 and then climbs up to neutrality during transit through the colon. Due to the pH variation in the GI tract, pH-sensitive polymers have been historically utilized as an enteric coating material. Enteric-coated products featuring pH-sensitive polymers include tablets, capsules, and pellets and are designed to keep an active substance intact in the stomach and tend to release it to the upper intestine.

Apart from the pH, mucosal layer plays an important role in drug absorp-tion from the lumen of the GI tract. Small intestine has a large epithelial surface area, which consists of mucosa, villi, and microvilli. Drug must first diffuse through the unstirred aqueous layer, the mucus layer, and the glyco-calyx (which is the coating of the mucus layer) to reach the microvilli, which is the apical cell membrane. The tight junction between the cell membranes of adjacent epithelial cells acts as a major barrier to the intercellular passage of drug molecules from the intestinal lumen to the lamina propria.

The low oral bioavailability of peptide and protein drugs is primarily due to their large molecular size and vulnerability to proteolytic degradation in the GI tract. Most protein and peptide drugs are susceptible to rapid degradation by digestive enzymes. Furthermore, most peptide and protein drugs are rather hydrophilic, and thus are poorly partitioned into the epithelial cell membranes, leading to their absorption across the GI tract through passive diffusion.

Various delivery systems have been proposed to increase drug absorption from the colon and ileum and minimize exposure of the drug to proteolytic enzymes. Enteric coatings that delay drug release for a sufficient period of time have been used to target both the ileum and colon. In addition, encap-sulation into polymeric materials that are degraded by the human colonic microflora has been proposed as a method to increase drug absorption from the intestine. Coadministration of enzyme inhibitors and absorp-tion enhancers have shown some promise. Encapsulation into erodible or biodegradable nanoparticles have been explained as a way of protecting drugs from enzymatic degradation. Submicron size particles are absorbed through transcytosis by both enterocytes and M cells, which are epithelial cells of the mucosa-associated lymphoid tissues.

For systemic action of drugs, the oral route has been the preferred route of administration. When administered by the oral route, however, many therapeutic agents are subjected to extensive presystemic elimination by GI degradation and/or hepatic metabolism.

Several nonoral routes of drug delivery have been utilized to provide ade-quate drug concentrations in the systemic circulation, in addition to local-ized drug treatment. These include the rectal, vaginal, and the transdermal routes of drug administration.


Rectal drug delivery

Rectal administration provides rapid absorption of many drugs and is an alternative when oral administration is inconvenient because of inability to swallow or because of GI side effects such as nausea, vomiting, and irritation. More importantly, rectal drug administration has the advantage of minimizing or avoiding hepatic first-pass metabolism. The rectal bio-availability of lidocaine in human is 65%, as compared to an oral bioavail-ability of 30%. Rectal route is used to administer diazepam to children who are suffering from epilepsy and in whom it is difficult to establish intravenous access. However, rectal administration of drugs is inconvenient and has irregular drug absorption. Moreover, rectal administration should be avoided in immunosuppressed patients in whom even minimal trauma could lead to the formation of an abscess.


Vaginal drug delivery

Vaginal epithelium is permeable to a wide range of substances including steroids, prostaglandins, antibiotics, estrogens, and spermicidal agents. Most steroids are readily absorbed by vaginal epithelium, leading to their higher bioavailability compared to their oral administration because of a reduced first-pass metabolism. For drugs with high membrane perme-ability, vaginal absorption is determined by permeability of the aqueous diffusion layer, whereas for drugs with low membrane permeability, such as testosterone and hydrocortisone, vaginal absorption is determined by membrane permeability. Vaginal ointments and creams contain drugs such as anti-infectives, estrogenic hormone substrates, and contraceptive agents. Contraceptive creams contain spermicidal agents and are used just prior to sexual intercourse.


Transdermal drug delivery

Transdermal patches deliver drugs through the skin. Percutaneous absorp-tion of a drug generally results from direct penetration of the drug through the stratum corneum, deeper epidermal tissues, and the dermis. When the drug reaches the vascularized dermal layer, it becomes available for absorp-tion into the general circulation. Among the factors influencing percutane-ous absorption are the physicochemical properties of the drug, including its molecular weight, solubility, partition coefficient, nature of the vehicle, and condition of the skin. Chemical permeation enhancers, iontophoresis, or both are often used to enhance the percutaneous absorption of a drug.

In general, patches are composed of three key compartments: (1) a pro-tective seal that forms the external surface and protects it from damage, (2) a compartment that holds the medication itself and has an adhesive backing to hold the entire patch on the skin surface, and (3) a release liner that protects the adhesive layer during storage and is removed just prior to application.

Most patches belong to one of two general types—the reservoir system and the matrix system. The reservoir system incorporates the drug in a com-partment of the patch, which is separated from the adhesion surface. Drug transport from the patch to the skin is channelized and controlled through a rate-limiting surface layer. The matrix system, on the other hand, incor-porates the drug uniformly across the patch in a polymer matrix. Diffusion of the drug through the polymer matrix and the bioadhesive properties of the polymer determines the rate of drug absorption.

Marketed transdermal patches are exemplified by Estraderm® (estradiol), Testoderm® (testosterone), Alora® (estradiol), Androderm® (testosterone), and Transderm-Scop® (scopolamine). Nicoderm® is a nicotine patch, which releases nicotine over 16 h, continuously suppressing the smoker’s craving for a cigarette. In addition, occlusive dressings are available, which have low water vapor permeability. These dressings help prevent water loss from the skin surface, resulting in increased hydration of the stratum corneum.


Buccal and sublingual drug delivery

The buccal and sublingual mucosae in the oral cavity provide an excellent alternative over oral tablets for certain drugs. Oral transmucosal absorp-tion is generally rapid because of the rich vascular supply to the mucosa. These routes provide improved delivery for certain drugs that are inactivated by first-pass intestinal/hepatic metabolism or by proteolytic enzymes in the GI tract.

The sublingual mucosa is relatively permeable, and is suitable for delivery of low molecular weight lipophilic drugs when a rapid onset of action with infrequent dosing is required. Sublingual DDSs are generally of two differ-ent designs: (a) rapidly disintegrating tablets and (b) soft gelatin capsules filled with a drug in solution. Such systems create a very high drug con-centration in the sublingual region before they are systemically absorbed across the mucosa. Therefore, rapidly disintegrating sublingual tablets are frequently used for prompt relief from an acute angina attack.

The buccal mucosa is considerably less permeable than the sublingual area and is generally not able to provide rapid absorption properties. The buccal mucosa has an expanse of smooth muscle and relatively immobile mucosa, which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus, the buccal mucosa is suitable for sustained delivery of less permeable molecules, and perhaps peptide drugs. One of the major disadvantages associated with buccal drug delivery is the low flux that results in low drug bioavailability. Therefore, buccal DDSs usually include a penetration (permeability enhancer) to increase the flux of drugs through the mucosa. Another limitation associated with this route of administration is the poor drug retention at the site of absorp-tion. Consequently, bioadhesive polymers have been extensively employed in buccal DDSs. The duration of mucosal adhesion depends on the type and viscosity of the polymer used. Nicotine in a gum vehicle when chewed is absorbed through the buccal mucosa. Glyceryl trinitrate has been found quite effective when administered through this route.


Nasal drug delivery

Although nasal route is traditionally used for locally acting drugs, such as antihistamines and corticosteroids for allergies to reduce mucosal secre-tion, this route is getting more attention for the systemic delivery of vari-ous peptide drugs that are poorly absorbed via the oral route. The major advantages of nasal administration include the fast absorption, rapid onset of action, and avoidance of hepatic and intestinal first-pass effects.

Barriers to transnasal drug delivery

There are three major barriers to drug absorption across nasal mucosa. These are

1. Physical barrier: A drug or DDS needs to diffuse across the highly viscous mucus and permeate through the epithelial cell lining. Permeation through the epithelial cell lining could utilize either the lipoidal pathway or an aqueous pore pathway. Nasal absorption of weak electrolytes is dependent on the degree of ionization. Systemic bioavailability of nasally administered drugs is generally low.

2. Temporal barrier: Dosage forms for nasal absorption must deposit and remain in the nasal cavity long enough to allow effective absorp-tion. The DDS has limited time at the site of administration before it is cleared with the mucus due to the physiological processes of muco-ciliary clearance and renewal of mucosal secretion.

3. Enzymatic barrier: The mucus has proteolytic enzymes. Therefore, protein and peptide drugs that are sensitive to such enzymes may get degraded during the process of drug absorption.

Commonly used dosage forms administered through this route are nasal sprays and drops. The nasal spray deposits drug in the proximal part of the nasal atrium, whereas nasal drops are dispersed throughout the nasal cavity. A nasal spray requires that the particles have a diameter larger than 4 μm to be retained in the nose and to minimize their pas-sage into the lungs. Nasal sprays are commercially available for muserelin (a gonadotropin-releasing hormone agonist), desmopressin, oxytocin, and calcitonin.

Drug delivery to the brain through the nasal route

Intranasal administration has also been explored for brain-targeted drug delivery. Treatment of brain disorders presents significant challenges due to the inability of most drugs to cross the tight endothelial blood–brain bar-rier (BBB). Intranasal drug delivery has been explored for brain targeting because the brain and the nose compartments are connected through the olfactory/trigeminal neural pathway, in addition to the peripheral circula-tion. The olfactory region of the nasal cavity, however, is a relatively small region and provides a formidable epithelial cell barrier. Nonionic alkyl gly-cosides such as dodecyl maltoside, decylsucrose, dodecylsucrose, and tet-radecylmaltoside, have been used as absorption enhancers to improve drug absorption across the nasal mucosa.

Formulation factors affecting transnasal drug delivery

Several formulation factors are important to consider for drug delivery across the nasal barrier. These include the following:

1. pH: A pH of the formulation that provides the drug in the nonionic form can enhance drug absorption. Nonetheless, the formulation pH needs to be within the range of 4.5–6.5 to minimize nasal irritation.

2. Osmolality: Hypertonic saline solutions inhibit or reduce ciliary activity, thus increasing the residence time of the DDS at the site of absorption.

3. Gelling or mucoadhesive agents can increase the residence time of the DDS at the site of administration.

4. Solubilizers can increase the amount of a drug in the dissolved state within a formulation and increase the diffusible fraction of the drug.

5. Absorption enhancers can open the tight junctions of the endothelial barrier, leading to a higher rate of drug absorption especially for the large molecular weight protein and peptide drugs.

6. Viscosity, volume, and concentration determine the feasibility of a drug for delivery across the nasal mucosa. For example, if the thera-peutic dose of a drug is soluble in a volume that is much higher than what can be delivered through the transnasal route, or the viscosity of the solution is too high, a transnasal dosage form may not be feasible.

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