Advance In Oral Drug Delivery

Published Date: 02 Nov 2017

1. Introduction

1.1. Advance in oral drug delivery

Oral route is one of the most and appropriate route for the delivery of pharmaceutical active ingredients in various perspectives such as ease of administration; patient compliance as well as patient acceptance and cost-effectiveness (Lee and Yang, 2001). Though, it has high acceptability, it possesses some limitations: (Lee and Yang, 2001; Patel et al., 2011)

Low bioavailability

Some drugs which are taken through this route are going through liver first pass metabolism. In such cases, it undergoes extensively metabolised before reaching to systematic circulation. On the account of it, they have lesser bioavailability.

Delayed onset of action

Adverse reaction

There should have to conscious about delivering of locally irritating or sensitizing drugs. For example, some drugs are gastro-toxic, causing damage to the mucosal lining of stomach.

Drug degradation of pharmaceutical active ingredients.

Some of drugs are very prone to degrade in stomach pH. Such acid sensitive drugs must need to take through different ways, such as enteric coated formulation or change in route administration.

To overwhelm from aforementioned drawbacks of conventional oral drug delivery, transmucosal route is superior to deliver drugs. There are various mucosas such as nasal, vaginal, rectal, ocular and oral mucosa can be utilized for drug delivery. Amongst aforesaid mucosa, oral mucosa has gained particular attention due to its patient compliance aspect; less susceptibility to potential allergens than other mucosa (Patel et al., 2011). The advantages and disadvantages of oral mucosa for delivery of drug are described in table 1.

Oral mucosa exists at the oral cavity which includes lips, cheek, tongue, hard palate, soft palate and floor of the mouth (Madhav et al., 2009). In adult, total surface of oral mucosa is approximately 200 cm2 (Paderni et al., 2012). Three types of oral mucosa are existed which includes lining mucosa (occur at buccal mucosa and floor of the mouth), specialized mucosa (occur at dorsal surface of tongue), and masticatory mucosa (occur at hard palate and gingiva region) (Patel et al., 2011).

Table 1.

The advantages and disadvantages related in utilisation of oral mucosa as a site for drug delivery (Hearnden et al., 2012; Paderni et al., 2012)

Advantages

Disadvantages

Accessible

Epithelium-permeability barrier

Self administrable

Involuntary scavenging activity of saliva

Oral mucosa repairs rapidly

Relative small surface area compare to skin

Highly hydrated environment to dissolve drug

Sustained delivery possible

Avoid hepatic first pass effect

High blood supply

Fast systemic delivery possible

Enhancement of bioavailability is possible

Oral mucosa is made up of three different anatomical as well as functional layers (see in Fig.1.). It comprises of epithelium, followed by lamina propria and innermost sub mucosal layer (Paderni et al., 2012). Epithelium is present up to one-third part of mucosa. It is major barrier for the transfer of the chemical entity into blood vessel (Sohi et al., 2010). Lamina propria helps to provide the nutrients to the epithelium whereas sub mucosa is rich in blood supply (Squier and Kremer, 2001; Sohi et al., 2010).

Within the oral mucosal cavity, drug can be delivered for two different perspectives: (i) local delivery and (ii) systemic delivery (Patel et al., 2012). Local delivery of medicament is used to treat oral mucosal disease which is one of the most common disease (Paderni et al., 2012) whereas systemic drug delivery is used to treat systemic disease such as migraine, pain. High drug concentration in systemic circulation can achieve through systemic delivery of medicaments (Madhav et al., 2009). There are various sites for delivery of drug through oral mucosa which embraces of sublingual, buccal, gingival and palatal. All the sites are differing in epithelium structure composition as well as its thickness (mentioned in table 2).

Mucus

Epithelium

Basal lamina

Lamina propria

Sub mucosa

Fig. 1. Anatomy of the oral mucosa (Squier and Kremer, 2001).

Table 2

Various features of oral mucosal site (Sohi et al., 2010)

Sites of oral mucosa

Structure

Epithelium thickness (µM)

Turn over time (days)

Permeability

Residence time

Buccal

NK

500-600

5-7

Intermediate

Intermediate

Sublingual

NK

100-200

20

Very good

Poor

Gingival

K

200

Poor

Intermediate

Palatal

K

250

24

Poor

Very good

NK= Non-keratinized; K= Keratinized; µM= micrometre

Amongst aforesaid sites, palatal as well as gingival mucosa is less suitable compared to sublingual mucosa and buccal mucosa due to its keratinized epithelium (Madhav et al., 2009).

1.2. Sublingual drug delivery

Buccal and sublingual route is ideal route of drug delivery through oral mucosa. Sublingual delivery means place the dosage beneath the tongue. It is used to produce quick onset of action; whereas buccal route is used to produce sustained action. It is superior to buccal route in the following aspects (Madhav et al., 2009; Patel et al., 2012):

Characteristic of epithelium

Epithelium is major barrier in orotransmucosal drug delivery. In case of sublingual site, the thickness of epithelium is lower than buccal site (see in table 2). It leads to accelerate the transportation of pharmaceutical ingredients.

Vascularity

More number of blood vessels is available at sublingual site compared to buccal mucosa. It leads to produce quick absorption of drug which ultimately leads to enhance bioavailability as well as quick action.

Saliva plays vital role in passage of drug via sublingual site due to major salivary gland is located at the sublingual site (Sudhakar et al., 2006).The active medicament is diluted by saliva. Saliva leads to cause salivary scavenging activity. As a result of this, dosage form cannot be located in site of oral mucosa. It is one of the reasons for involuntary swallowing of dosage form (Hoogstraate et al., 2001; Madhav et al., 2009).

Involuntary swallowing of dosage form is also taking place owing to continuous production of mucus. Mucus is intercellular ground substance which is present at the epithelial cell of buccal mucosa. The mucus layer has short turnover rate. On account of this, dosage form cannot be resided at site of application (Hoogstraate et al., 2001; Patel et al., 2011).

To circumvent the residence problem of dosage form, mucoadhesive polymers are extensively used (Desai and Kumar, 2004; Ahn et al., 2002; Perioli et al., 2004). They could be natural (gelatin, sodium alginate, gaur gum, chitosan) or synthetic and semisynthetic (hydroxyl propyl methyl cellulose, carbopol, sodium carboxymethyl cellulose, synthetic derivatives of chitosan) (Samani et al., 2005). Amongst the other polymers, chitosan and its derivatives has considered interest in research field due to its biocompatibility, bio adhesive property, antifungal property and biodegradability (M.N.V. Ravi Kumar, 2000). Chitosan can also act as permeation enhancer by direct fluidizing effect on organized intercellular lipid lamellae (Sohi et al., 2010; Schnurch and Dunnhaupt, 2012).

1.3. Duloxetine Hydrochloride (DXH)

Duloxetine Hydrochloride (DXH) is manufactured by Eli Lily researchers. It has gained approval from U.S. Food and Drug Administration (FDA) for treatment of major depressive disorder in august, 2004. It is also approved for the treatment of diabetic neuropathy in September 2004 by U.S.FDA (Deepak and Kumar, 2011). It is dual inhibitor of serotonin as well as norepinephrine reuptake (Lantz et al., 2003; Hunziker et al., 2005). It has low affinity to other receptors such as serotonergic, cholinergic, histaminic and dopaminergic cause lesser risk of adverse effects which is usually observed in older antidepressant (Hunziker et al., 2005).

DXH is being extensively metabolised by cytochrome enzyme system into inactive metabolite (Mehta et al., 2011). The enzymes responsible for its metabolism are CYP2D6 and CYP1A2 which are predominantly present in liver (Hunziker et al., 2005; Mehta et al., 2011). The pharmacokinetic properties of duloxetine are: bioavailability (50%); tmax (6 hour with lag time 2 hour); volume of distribution (1943 L) (Hunziker et al., 2005; Deepak and Kumar, 2011; Lantz et al., 2003). The Cmax value is found to be 23.5, 93.640 and 158.02 ng/ml for 20, 40 and 60 mg dose, respectively (Lantz et al., 2003).

DXH encompasses aryl ether linkage, which leads to make it as an acid sensitive. By reason of this, it freely reacts in the gastric environment (Baertschi, 2005). Since the absorption site of DXH is intestine, it is mainly available in enteric coated formulation which is commonly used approach to protect acid sensitive drug from acidic environment of stomach (Persicaner and Sareen, 2008).

According to Biopharmaceutical Classification System (BCS), DXH comes under BCS class II drug- low solubility and high permeability (Vyas et al., 2009). Dissolution is the rate limiting step for such class of drugs due to its limited solubility (Kocbek et al., 2006). Different methodologies are available to overwhelm solubility issue such as solid dispersions (Modi and Tayade, 2006), reduction of particle size (Naseema et al., 2004), self-emulsifying drug delivery systems (Gursoy and Benita, 2004), liquisolid technology (Spireas et al., 1998) and inclusion complex by cyclodextrin derivatives (Naseema et al., 2004).

Amongst aforesaid techniques, inclusion complex by Cyclodextrins (CDs) have established cumulative interest in the pharmaceutical field because of their ability to favourably modify physical, chemical and biological properties of a number of hydrophobic drug molecules (Mosher and Thompson, 2002). Worldwide, 35 different drugs are presently marketed as solid or solution based cyclodextrins (CDs) complex preparation. In these pharmaceutical products, CDs are predominantly used as complexing agents to accelerate the aqueous solubility of less water soluble drugs such as (BCS class-II and BCS class-IV) to improve their bioavailability (Brewster and Loftsson, 2007).

1.4. Inclusion complex by cyclodextrin

Cyclodextrins are cyclic oligosaccharides, acquired from starch (Brewster and Loftsson, 1996). It contains hydrophilic outer surface as well as hydrophobic central cavity. Natural occurring cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin entailing of six, seven and eight glucopyranose units, respectively (Loftsson and Fee, 2003). Amongst the various natural CDs, the β-cyclodextrin (β-CD) appears more functional as a complexing agent owing to its cavity dimension, low cost, higher productive rate and other properties (Uekama et al., 1998). β-CD is also available in various pharmacopoeias such as US Pharmacopoeia (USP 23/NF 18, 1995) as well as in European Pharmacopoeia (3rd ed. 1997). It is not absorb too much extant through upper intestinal tract after oral administration. Thus, It is probably best suited cyclodextrin in human (E.M. Martin del valle, 2003).

In addition to above, the molecular weight of β-CD is much lower than their semi synthetic derivatives such as hydroxy propyl β–cyclodextrin (HPβ-CD). This leads to decrease the bulk of formulation, which is a major impediment in case of HPβ-CD (Loftsson et al., 1999). The major drawback of β-CD is its low solubility as well as low complexing ability. Therefore, different tactics have been undertaken to improve its performance (Loftsson, 2002).

Among the possible different tactics, the addition of suitable auxiliary hydrophilic polymers can significantly increase the β-CD solubility and its complexing ability by multicomponent complex formation. At the same time, hydrophilic polymers tend to increase the intrinsic solubility of the drug as well as the stability constant of the complex (Loftsson and Brewster, 1996).