In order to appreciate the formulation of drugs it is important to state the necessary attribution of the human Gastro-intestinal (GI tract) system. Without a doubt the composition of a formulation is made around the knowledge and working of the GI tract, the physiochemical properties of formulation are depicted and manipulated so they can work to their potential at the necessary site as required. The GI tract consists of the mouth, stomach, small intestine and large intestine (Figure 1), where small intestine specifically within microvilli of enterocytes bearing most of the drug metabolism (Figure 2). The reasoning of this phenomenal can be supported by the presence of high surface area potential for absorbance of drugs.
Figure 1, various components of GI tract Figure 2, microvilli present within small intestine
It is well understood the oral route to be the most convenient and desirable route for drug administration. The commonest dosage forms include tablets, solutions and capsules due to its ease of manufacture and administration. Some compounds failed to be delivered from the oral route which gave a rise to research in to alternative routes of drug delivery. One of the main reason for this phenomenal was due to insufficient absorption of some drugs from the gastrointestinal tract which resulted in the drug not reaching to the main active sites throughout the body. In contrast paraenteral route had no such issue in terms of drugs absorption ability. More however absorption from intravenous route such as subcutaneous and intramuscular delivery provides great absorption ability. However this route has limited use due to the skins low permeability to many drugs.
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In the last three decades it has come to known the viability and usefulness of the nasal route for drug delivery. It was from the use of Propranolol on Rat Perfusion Model where it was shown nasal absorption of propranolol was comparable to that of intravenous route (Hussein et al). This report will investigate the importance of nasal route and its various formulations. It will compare individual formulations in terms of their physiochemical properties and usability.
1.1 Nasal formulation
Nasal formulations over the past decade have shown extensive use and a great interest within the pharmaceutical industry. This route has shown access to the brain to be faster and with great therapeutic effect when compared to other route such as oral, an example of this is from well known formulations of oral for pain and crisis treatments (Illum et al). The main explanation for this phenomenal is down to its unique putative pathway which favours such centrally acting drugs. In order to fully appreciate formulations which act within the nasal passages it is important to elaborate on the physiology and anatomy (figure 3).
Figure 3, vertical slice of human nasal passage (Illum et al)
The vast absorption within the nasal passage is said to take place in turbinates region. Drugs delivered to this region can cross the nasal mucosal membrane via two main pathways;
Paracellularly, between cells
Transcellularly, across cells
These two pathways are crucial factors, when considering nasal formulation of drugs. Pharmaceutical companies need to formulate their medicines and make them compatible to one of these pathways. In order to consider Paracellulary formulation, polar drugs can be formulated to pass through tight junctions within epithelium, although this is challenging to exercise as tight junctions are dynamic structures with tiny scope of entrance that of 10 Ó (McMartin C et al, Madara J L et al). The shear small size of tight junction means this pathway is less efficient for larger molecules and is dependent on molecular weight with cut off at 1000 Da (McMartin C et al). Alternatively lipophilic drugs can passively diffuse transcellularly by receptors or carrier mediation. Some of these lipophilic drugs such as propranolol can demonstrate rapid absorption when given as intranasal delivery. They can potentially reach bioavailability of nearly 100%, similar to that of intravenous injections (Hussein et al).
Drugs which are polar in nature tend to have poor nasal absorption with bioavailability little above 10%, one of these drugs is Sumatriptan. Some drugs which are peptides such as insulin have less than 1% bioavailability thus rendering it not the best formulation of choice. There are many suggestions of why polar drugs have poor transport across nasal mucosa (Hussein et al);
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A possible enzyme degradation of drug within nasal cavity, especially for protein and peptide drugs
Polar drugs tend to have larger molecular weight, giving rise to decrease rate of membrane permeability
Greater chance of drug clearance from the mucociliary mechanism within the nasal pathway, making little drug available to be absorbed
Sumatriptans nasal formulation is a good example of a drug which gets cleared by the natural mechanism of mucocilliary clearance within the nasal passage. Sumatriptan spray is formulated as a aqueous solution, which helps it to clear quickly from the nasal passage and in to gastrointestinal tract (GI) by motion of swallowing. The bioavailability of nasal spray sumatriptan is 15.8% (Moore, K.H. et al) some of this subsequently absorbed in the GI tract.
After learning about the great scope of possible drug delivery route of nasal passage, it is important to mention possible formulations available. From the given anatomy of the nose, it can therefore be appreciated the type of medicine going in to the nose will be small powder based mixture or solution.
Advantages and limitations of nasal route:
Nasal route has been extensively resear4ched within the last few decades, it has be bought in to spot light after learning of its potential benefits, some of which include;
-Doses within the nasal passage are usually small between 25-200µl, but rapid absorption is achieved because of good supply of blood to capillaries within the nasal mucosa. Also this route allows medicines to have higher bioavailability
- This route allows drugs to pass first pass metabolism, which gives scope for drugs which cannot get past this, such drug is insulin.
- Fast therapeutic onset is coupled to the previous point, as it passes first pass metabolism example of this is sumatriptan, the nasal formulations onset of action is a lot quicker than tablet formulation.
- Since it avoids going in to the Gastro-intestinal tract, it helps reduce any irritation of stomach. Although from research of sumatriptan, some of this can get down to the intestine, but however it is significantly less than the oral formulation.
- Medicines are normally very easy to take and administer and they also provide convenience to the patient. When compared to rectal route, this is far easier and more convenient way of administering medication
- Some limitations of this route include in the manufacturing and formulation for the medicine itself. Not all drugs can be administered from this route due to the small volume guide of 25-200µl only able to be delivered to the nostrils. For some drugs this is not enough, as the entire dose may not be able to be administered thus resulting in low absorption.
- Also if formulations lack aqueous solubility properties even after the addition of excipients this will not get through the mucosa.
- For medicines which are used chronically and on a regular basis. Example of this can be insulin, as patient will be delivering everyday and rest of their lives, this will not be a suitable route.
-There is also the chance of drug degradation in the nasal area, and larger particles to be swept away by the muccocilliary action of the nasal passage.
- Formulation of sustained release is not possible, this can limit some drugs which would need this dosage regimen
2.1 Physiochemical properties of formulations for nasal route
In order to appreciate the complexity of nasal drug formulations it may be easier to analyse individual physiochemical properties of such medicines and individualise how they can affect nasal drug delivery:
Drug solubility/ Dissolution rate -
Drug solubility is one of the most popular attributes which is thoroughly researched and it primarily determines absorption of a drug through biological membrane. This attribute can affect drug absorption and to some extent limit the formulation process of a product. Drug dissolution rate is important when considering particulate nasal products in suspensions and powder inhalation form. It is important for particles within the nose to be dissolved prior to absorption or else they would be cleared away by the nasal mucocilliary mechanism.
Drug size and molecular weight -
In 1987 fisher et al evaluated the effect of molecular weight and size of certain drugs for nasal absorption. These drugs were all water soluble and was studied on rats, he found 368 fold increase in molecular weight resulted in 43 fold decrease in nasal absorption for the drugs tested. From this particular study it can to an extent be concluded the importance of nasal absorption of water soluble drugs and how it can occur through aqueous channels of nasal mucosa (fisher). Figure 4,
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Figure 4, correlation between dose nasally absorbed and molecular weight.
Another study was carried out by Maitani et al, he showed inverse relationship between absorption and molecular weight on the nasal route. It is interesting to note from this report, he used an enhancer which was sodium glycocholate which to certain degree helped reach appreciable absorption (Maitani C et al). Further studies support the notion of the relationship between molecular weight and amount of drug absorbed. McMartin C et al compiled data on 32 compounds used through nasal route and absorption was recorded. Molecular weight of all his 32 compounds varied from 160 to 34000. He found a distinct relationship from these compounds, absorption showed inverse relationship with molecular weight. Furthermore where he could, he also used oral formulation to compare against nasal formulations. His data showed oral absorption decreased faster than nasal absorption in relation to molecular weight. For this phenomenon to be explained, one needs to consider the physiology and anatomy of each route. As understood from the introduction it can be explained nasal absorption is consistent due to non-specific diffusion through aqueous channels. These channels impose a size restriction thus controlling its flow. However it may be possible other mechanisms may also be involved and as many factors determine absorption within biological membranes it cannot be discounted solely (McMartin C et al) . (can go on))))))
Particle drug size in the case of nasal route delivery is very important when considering its absorption and acceptability. The size can be related to its dissolution, and needs to be controlled in order to obtain adequate dissolution within the nasal mucosa. The size of drug particles if made too large can be gritty and lead to nasal irritation. If size of particles is too small i.e. below five microns, it can be inhaled into the lungs, therefore particles are made within a range of 5-10 micron which is suitable to be deposited within the nostrils.
Partition coefficient and pKa of drug -
In order for the drug to get in to the bloodstream it needs to pass membrane cells which constitute a substantial barrier. This in turn happens through transcellular transport via concentration gradient-dependent diffusion. As previously mentioned, drugs can also enter via tight junctions a process better known as carrier-mediated transport. There are many factors which can affect this mediation, but some of the most important include partition coefficient and pKa of a drug. It is important to note that the pH of nasal mucosa is 7.39 (S Hirai et al). Both the mucosa and drug pH will affect the selection of absorption of a drug. S Hirai et al found in rats how nasal absorption of weak electrolytes such as aminopyrine and salicylic acid was highly dependent on the degree of ionisation. The results of this study did however support the pH-partition theory (S Hiral et al). Some studies have shown a direct relationship of pH and rate of absorption, K Ohwaki et al showed how absorption was much greater at pH below 4.79 within the nasal mucosa. The gradient of pH measure was from 3 to 7, pH 7 showing minimal absorption and pH 3 showing maximum absorption. The increase of absorption at pH 3 can be due to structural changes within epithelial cells (K. Ohwaki et al 1985, K. Ohwaki et al 1987, T. Ohwaki et al).
The absorption rate compared to the partition coefficient of progesterone for the nasal route has shown to be very efficient, it was compared to two other routes and shows to be the most permeable in comparison to rectal and vaginal absorptions. Figure 5 shows, comparison data of this analysis (D.C. Corbo et al);
Figure 5, black dotes indicate nasal absorption, it having highest absorption against octanol/water partition for progesterone (D.C. Corbo et al). The slope for nasal plot is also higher than the other two routes.
In the case of nasal route administration it can be said unionised species of the drug are absorbed more readily than ionised forms, this does support the pH-partition theory of drug absorption, T Sakane et al proved this by doing study of sulphisomidine in rats for nasal transport (T. Sakane et al). This theory can further be examined and some studies have shown drugs or compounds which are mostly ionised, but still have readily absorbed from the nasal route, an example is of benzoic acid. Huang et al showed how benzoic acid although being 99.9% ionised at pH 7.19 is still shown to have nasal absorption. The absorption for this compound should otherwise be negligible as 99.9% is ionised. This must mean the partition-coefficient of nasal passage is not the inclusive factor for nasal route absorption but more however it is not a major factor for determining nasal absorption, figure 6 shows this (C. Huang et al)
Figure 6, percent of absorption of benzoic acid at different pH within nasal route (Huang et al)
2.2 Formulations of nasal route
In order to produce a formulation for the nasal passage, certain characteristic of active ingredients need to be understood, as mentioned above. With this in mind the population, marketing and intent of use are some of the attributes needed to be considered when choosing the most appropriate formulation, some of these formulation are discussed as below.
The dose of these devices is normally delivered through a metered dose actuator. Aerosol propellants were initially used to administer these, but as researched showed how these can be harmful, then was replaced with mechanical actuators. Low precise volumes can be administered, as low as 25µl. Example of
These are delivered in same fashion as solution sprays, however the actuator itself can sometimes be designed around the suspension and patient, taking in to account the size of particle and morphology. Example of Fluticasone Furoate nasal suspension spray, used to decrease inflammation in the nose.
This is the ideal way of delivering a solution to the nose and is the simplest and most convenient. On contrary the problems of this formulation is ca be in delivering the required amount, as these generally be delivered as a droplet form. Example of salinex drops for use of temporary nasal congestion.
This particular formulation is a backup to many previous formulations, especially if the medicine cannot be made in to a solution due to stability or size issues as mentioned above. Medicines which tend to prefer this type of formulation are drugs which will be used locally in the nasal mucosa. Some downside of using a powder formulation is its ability to cause irritation within the nostrils. In terms of manufacturing powder formulations, it can be quite expensive to get the powder to suitable size before delivering in to the nasal route, such manufacturing will require many processes thus rendering it to be expensive.
Gels are suspensions or solutions but thickened by excipeints. They do have number of advantages over previous formulations, generally the gel form reduces the dripping to the back of the throat when placed in to the nose. Also it reduces the leaking associated with sprays or drops from the nostrils when administering. When producing gel formulation, the thickness can be a positive attribute as it can ascertain various agents without making it unstable such agents can added can be soothing agents. These agents can be added to help reduce any possible irritation which may otherwise be felt from powder formulations.
2.3 Possible excipeients used within nasal formulations
When talking about excipients, it is important to appreciate their role within a formulation. Most medicine within the market especially for nasal route will have excipients within it. Excipients have many benefits and are to some degree added to bulk the formulation, some of the vital excipients used within nasal formulations are as follows;
These help improve solubility of drugs, as mentioned above drug solubility within water is one of a major limitation within drug processing. Just like most membrane within the body, nasal mucosa membrane only allows soluble drugs to pass. It is therefore advised to have aqueous formulations for nasal formulation than non-aqueous formulations. Some solubilises are known to be co-solvents with examples of alcohols and glycols. Surfactants is another example of solubilise which is used to solubilise insoluble drugs. Depending on the drugs solubility requirement, more than one solubilise can be used.
Stability issues can be arisen from suspension or solution formulations, especially in these cases, antioxidant are used in small quantity to retain stability without causing any adverse reaction such as irritation or absorption issues.
Within the nostrils there is high chance for ph to alter and deviate due to nasal secretions. For this reason a buffer needs to be added in to formulation to keep the formulation in situ, however the quantity of volume which can be exported to the nasal area is limited, so this is an important factor when using a buffer. The range of volume which is typically administered to the nasal area can vary between 20-200 µl, this is a tiny amount when comparing to any oral formulations.
Preservatives can protect from any potential microbial contamination. This is important for this route as spray nozzle can commonly get contaminated with nasal secretions when nozzle inserted in to the nose. Some popular preservative include benzalkonium chloride
As mentioned previous, some formulations such as sprays and solutions have the potential to get back in to the throat. For these formulations in particular it is important to add flavour which will help mask any bitter taste of the medications. Adding taste masking agents will help patient compliance which in turn will make the medicine favourable.
In the case for gel or ointment formulations, these agents will help bring the medicine together. Some examples of gelling agents include methyl cellulose, polyvinyl alcohol and carboxymethyl cellulose to name a few. With these formulations it can also be understood the impact of viscosity on absorption.