Strategies to Improve Drug Strength in Nasal Preparations: History
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Contributor:
Patrícia C. Pires
,
Márcio Rodrigues
,
Gilberto Alves
,
Adriana O. Santos

Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions.

  • drug
  • solubilizer
  • nanosystem

1. Overview of Intranasal Formulation Strategies for Drugs with Low Aqueous Solubility

Drugs could be intranasally administered simply in the form of dry powders, but the slow dissolution of poorly water-soluble drugs will be a clear limiting factor. The dissolution limitation is the same with liquid suspensions, which are perhaps the most common nasal liquid preparations for drugs with low aqueous solubility, generally intended for a local effect. Nasal sprays of lipophilic corticosteroids (such as budesonide or fluticasone propionate) are examples of such formulations. Nevertheless, the administration of these preparations leads to most of the volume being swallowed, which means that the majority of the drug is not going to have the intended local therapeutic effect. These drugs usually have a lag time of up to several days to start having a therapeutic effect. In fact, even when aiming for a local effect, better results can be obtained by solubilizing the drug. Examples include the solubilization of budesonide in nasal formulations by using Captisol®, a proprietary cyclodextrin derivative (sulfobutylether-β-cyclodextrin), or Budesolv, developed using Marinosolv®, a proprietary solubilizing technology platform based on plant derived saponins which form a micellar solution [1][2].
The development of solid dispersions can be expected to reduce the slow dissolution limitation found in dry powders and suspensions of low water solubility drugs, and examples of these are found in the scientific literature. The budesonide solid dispersion Soluplus®, prepared through freeze-drying of a polymer-drug solution, showed faster release compared to both water-based suspension and dry powder commercial products, and higher permeation across a nasal cell model [3]. Cyclodextrin derivatives can also be used in combination to prepare soluble inclusion complexes [4]. However, this research will not focus on these approaches, but rather on liquid preparations (Table 1).
Table 1. Formulation strategies for increasing drug strength of low water solubility drugs in liquid nasal preparations.
Global Strategy Formulation Strategy Drug Approximate Water
Solubility (mg/mL)		 Achieved Drug Strength 1 (mg/mL) Drug Product or
Bibliographic Reference
Use of
solubilizers		 Change in pH
(acidification)		 K-604 0.05 10.8 [5]
Midazolam 0.01 5 Midazolam injection USP
Complexation
(cyclodextrins)		 Allopregnanolone 0.001 16 [6]
Curcumin 0.006 ~3 [7]
Cosolvents and surfactants Midazolam 0.01 50 Nayzilam®
Diazepam 0.05 50–100 ValtocoTM
Nanosuspensions and incorporation into carrier nanosystems Nanosuspensions Curcumin 0.006 3.42 [8]
Polymeric nanosystems Curcumin 0.006 ~1.5 [7]
Baicalein 0.2 0.8 2 [9]
Solid lipid nanoparticles and nanostructured lipid carriers Curcumin 0.006 500 [10]
Geraniol- ursodeoxycholic acid conjugate 0.0002 ~4.5 [11]
Rimonabant 0.002 ~2 [12]
Liposomes and related vesicular nanosystems Flibanserin 0.2 10 [13]
Resveratrol 0.07 NR [14]
Nanometric emulsions 3 Curcumin 0.006 5 [15]
Polymer-coated nanometric emulsions 4 Curcumin 0.006 1.9 [16]
Drug molecule modification Salts and hydrophilic prodrugs Phenytoin (used as fosphenytoin) 0.07 34.8 (equivalent to 50 mg/mL fosphenytoin) [17]
Diazepam
(avizafone)		 0.05 Up to the equivalent of ~13.5 mg/mL of diazepam [18]
1 In the case lyophilized systems, it was considered, sometimes estimated, the strength of the liquid suspension used in vivo; 2 concentration after resuspension of the nanoparticles for nebulization (inhalation during 20 min); 3 microemulsions and nanoemulsions; 4 the one cited here was named by the authors as “amylolipid nanovesicles”; NR—not reported for the final formulation.
Alternatively to suspensions and solid dispersions, an emulsion (either liquid or semisolid) could be used, but drug retention in the vehicle/base could originate similar limitations in drug release. Alternatively, the limitations of slow dissolution/release of the drug from suspensions or emulsions could be (at least partially) solved by reducing particle or droplet size to a colloidal/nanometric range, thus increasing the specific surface area, making drug dissolution or diffusion faster. Optionally, other nanometric drug carriers can also be considered, with added functionalities, such as protecting drugs from enzymatic and chemical degradation, increasing transport through biological membranes, and overall promoting brain bioavailability [19][20][21]. Moreover, these nanosystems can have components with permeation enhancing capability, that either act by increasing the nasal membrane’s fluidity by creating temporary hydrophilic pores (due to extracting proteins from it), decreasing the viscosity of the mucous layer, or transiently altering tight junctions [22][23].
Nevertheless, there is no doubt that the simplest and most direct way to deliver the drug readily available for absorption is to formulate it in an aqueous solution. Classical ways to increase drugs’ water solubility are well known and include strategies related to the modification of the chemical entity itself or strategies dependent on formulation excipients. Modification of the drug molecule itself includes salt formation (which can be useful when the chemical entity has an ionizable moiety) and hydrophilic prodrug development (molecule with an additional moiety that has to be metabolized in order to exhibit pharmacological activity), both of which can result in not only higher aqueous solubility but also increased chemical stability [24]. As for strategies concerning formulation excipients, these include pH control (useful with weak acidic or basic drugs), the use of organic solvents (either the change of the solvent to an oil or, preferentially, the use of water-miscible organic solvents in mixture with water), the use of hydrophilic surfactants (above the critical micellar concentration), and the preparation of soluble complexes. In addition, a combination of these strategies can also be employed.
The issue of the formulation having a short residence time in the nasal cavity, and therefore decreasing the time available for drug absorption to occur (and consequently bioavailability), can also be tackled by adding certain components to either nanocarriers or solutions. The inclusion of a mucoadhesive polymer, such as pectin, chitosan, sodium alginate, or certain cellulose derivatives, will help these formulations interact with the nasal mucosa, and thereby retaining the preparation in the nasal cavity for a longer period of time. The use of polymers that increase a formulation’s viscosity (viscosifiers), such as cellulose derivatives, or gelling polymers, such as poloxamers, can also be an efficient strategy in increasing the retention time in the nasal mucosa [19][22][25][26].
In order to help define formulation parameters, including in the case of nanoformulations, bio/chemoinformatics (in silico) tools can be used, with some recent studies having done a good job predicting nose-to-brain transport of antibiotics for the treatment of meningitis, or even for combating COVID-19 [19][27]. Nevertheless, this research will focus on the experimental approach.
Examples, benefits and limitations of all the mentioned experimental strategies (water-solubilization and colloidal liquid dispersions) in the context of nasal preparations, in particular aiming for nose-to-brain drug delivery, are discussed in the subsequent sections, and summarized in Table 2. Frequently, different strategies can be found combined.
Table 2. Advantages and limitations of formulation strategies for increasing drug strength of low water solubility drugs in liquid nasal preparations.
Global Strategy Formulation Strategy Advantages Limitations
Use of
solubilizers		 Change in pH
(acidification)		 Increased drug solubility Irritation of the nose and upper respiratory tract
Complexation
(cyclodextrins)		 Increased drug solubility, protection, and permeation Safety is dependent on the type of cyclodextrin, their concentration, and the administration route
Cosolvents and surfactants Increased drug solubility and permeation Irritation of the nose and upper respiratory tract
Nanosuspensions and incorporation into carrier nanosystems Nanosuspensions Increased drug strength, simplicity of preparation, controlled drug release, and reduced toxicity Physical instability and drug precipitation
Polymeric nanosystems Increased drug strength, controlled drug release, targeted drug delivery, and prolonged therapeutic effect Physical instability, low drug loading, and excipients not biocompatible
Solid lipid nanoparticles and nanostructured lipid carriers Increased drug strength, high safety (biocompatible), and
controlled release profile		 Physical instability and low drug loading
Liposomes and related vesicular nanosystems Increased drug strength, high safety (biocompatible), and enhanced permeation Physical instability and low drug loading
Nanometric emulsions Increased drug solubilization, easy preparation (some), and enhanced permeability Physical instability and low drug solubilization
Drug molecule modification Salts and hydrophilic prodrugs Increased drug solubility and safety Might not be enough to increase drug strength (has to be joined by other strategies)

2. Use of Excipients for Enhanced Aqueous Solubility

2.1. Adjustment of the pH

The nasal mucosa’s pH is slightly acidic (≈5–6.5), hence a neutral to slightly acidic pH is well tolerated. It would be ideal for this pH range to be sufficient to solubilize any drug molecule, but, if that were the case, the drug would probably not even be considered poorly water soluble. Some drugs require more extreme pH values for solubilization, and a pH below 4 seems to be less well tolerated, as described in the following examples.
K-604 is a selective acyl-coenzyme A:cholesterol acyltransferase-1 inhibitor that blocks cholesterol esterification, which in the brain has been linked to the clearance of amyloid beta peptides and suppression of 24(S)-hydroxycholesterol induced neuronal cell death. Hence, it can have potentially beneficial effects in several neurodegenerative disorders, such as Alzheimer’s disease, also having recently been reported as a promising strategy to treat glioblastoma [5][28]. Nevertheless, alongside having poor blood−brain barrier permeability, its poor water solubility at neutral pH (0.05 mg/mL) makes it hard to formulate at high strength. Yet, since K-604′s solubility increases at a lower pH, Shibuya et al. [5] prepared several solutions containing hydroxycarboxylic acids, either hyaluronic acid, gluconic acid or citric acid, for intranasal administration. These solutions, with pH values ranging from 3.0 to 3.8, were able to solubilize an increased amount of K-604, 10.8 mg/mL, which is 216 times higher than its solubility in purified water. In vivo intranasal administration of these solutions to mice showed enhanced drug delivery efficiency, since the obtained brain and blood area under the drug concentration vs. time curve (AUC) values were approximately between 100 and 211 times higher than those obtained with oral administration. The citric acid solution, having reached the highest brain maximum drug concentration (Cmax), was selected for repeated intranasal administration, to assess therapeutic efficacy (reduction of brain cholesteryl ester levels). However, even though the administration was performed on seven consecutive days, the brain lipid profiles showed that after the first day the brain cholesteryl ester levels had already been reduced up to 94%. Nevertheless, after the 7-day time period, histological evaluations of respiratory and olfactory epithelium of the mice in which the administration was performed showed slight disruption, which could have led to enhanced drug permeability. Hence, although this approach seemed to show high therapeutic promise, its safety profile does not seem ideal, as expected from an acidic formulation.
The development of intranasal benzodiazepine medicines for sedation and seizure control has received a substantial amount of attention. In general, clinical trials show that intranasal benzodiazepines are at least as effective in stopping seizures and preventing their recurrence as the same drugs administered through the intravenous, intramuscular, rectal, or buccal routes [29][30][31][32]. One of the biggest focuses has been on intranasal midazolam, which has a predicted intrinsic water solubility of only 0.00987 mg/mL [33]. Hence, in intravenous administration simple acidified saline solutions (pH 3–4) are used, since midazolam converts to its water-soluble form at this pH [34]. However, lacrimation, throat, and nose burning, and general discomfort are associated with the intranasal administration of these same preparations, which shows that albeit effective, there was still room for improvement regarding formulation safety [35][36].

2.2. Cyclodextrins

Cyclodextrins are cyclic oligosaccharides with a central hydrophobic cavity that can form inclusion complexes with hydrophobic drugs. The outer hydrophilic surface, which will be in contact with the external aqueous environment, renders the complex water-soluble, increasing apparent drug solubility [7].
Allopregnanolone (or brexanolone) is a neuroactive steroid (gamma-aminobutyric acid A receptor positive modulator) approved by the FDA for the treatment of postpartum depression in adult females, under the brand name ZulressoTM. Allopregnanolone’s predicted water solubility is very low (only 0.00136 mg/mL), but with sulfobutylether-β-cyclodextrin, the solubilizing agent in Zulresso, it was possible to obtain a concentrated solution (5 mg/mL) for intravenous perfusion [37]. An adaptation of this formulation for intranasal administration, an aqueous solution containing 0.9% NaCl and a large amount of sulfobutylether-β-cyclodextrin (40%), reached a drug concentration of 16 mg/mL, and has been shown to provide rapid seizure protection [6].
Curcumin is an extensively studied natural polyphenolic compound, with many known properties, such as antioxidant and anti-inflammatory effects. These properties could be useful for the treatment of many illnesses, such as Alzheimer’s disease [38]. Nevertheless, its poor aqueous solubility (0.00575 mg/mL), high instability under physiological conditions, rapid metabolism, and fast elimination lead to low oral bioavailability and poor tissue distribution. Moreover, it also has very limited permeation through the blood–brain barrier, which further restricts its delivery to the brain [7][39]. To tackle some of these issues, Zhang et al. [7] studied the solubilization of curcumin by hydroxypropyl-β-cyclodextrin (HP-β-CD, 300 mM), which increased from ~1.5 × 10−4 mM to ~3 mM (~2000-fold). They also prepared inclusion complexes of curcumin:HP-β-CD, which were lyophilized and resuspended in water at a greater drug strength. These inclusion complexes and which performed better than chitosan-coated poly(lactic-co-glycolic acid) nanoparticles in protecting the drug from degradation at physiological pH and promoting bioavailability through the intranasal route, having reached much higher brain drug levels than plasma’s, suggesting the existence of a considerable amount of direct transport through the neuronal pathways. However, the administration volume was too large, and the obtained bioavailability was not compared to other routes, which makes it difficult to fully assess the potential of the developed formulation. Moreover, the inclusion complexes did not perform much better than a simpler similar solution, made from curcumin solubilized in DMSO first and then diluted with 0.3 M HP-β-CD.
As for safety, in general natural and modified cyclodextrins are considered safe, since they are listed as inactive ingredients and accepted as excipients in pharmaceutical products by the FDA. Nevertheless, their safety is dependent on the type of cyclodextrin, their concentration and the administration route. For intranasal administration, preclinical toxicity studies have shown that, in general, a concentration below 10% in the formulation causes low to no local irritation [40].

2.3. Cosolvents and Surfactants

As previously mentioned, intranasal benzodiazepines have shown to be at least as effective in stopping seizures and preventing their recurrence as intravenous, intramuscular, rectal, or buccal administrations of the same drugs [29][30][31][32]. Several clinical trials with intranasal administration of benzodiazepines have been undertaken, either using parenteral solutions employing cosolvents, or alternative formulations, including using a liquid surfactant as solvent (Polyoxyl 35 castor oil or Cremophor® EL, nowadays brand name Kolliphor® EL) (reviewed by Pires et al. [35]). Midazolam and diazepam innovative formulations have since reached the market. Nayzilam®, a midazolam nasal spray, developed by Proximagen, Ltd. (London, UK), received FDA approval in 2019 for the acute treatment of seizure clusters. However, the drug’s solubilization (at 50 mg/mL) was only achieved by using ethanol, polyethylene glycol-6 methyl ether, polyethylene glycol 400, and propylene glycol [41]. ValtocoTM, a diazepam formulation with drug strengths between 50 and 100 mg/mL developed by Neurelis, also reached the market in 2020 for the same indication. Valtoco’s vehicle is composed of vitamin E, ethanol, benzyl alcohol, and n-dodecyl beta-d-maltoside (Intravail®—proprietary surfactant used as permeation enhancer) [42][43][44]. Hence, drug solubilization was in both cases performed by adding high amounts of organic cosolvents and/or surfactants to the preparations. Nevertheless, organic solvents have been associated with reports of lacrimation, alteration in taste sensation, rhinorrhea, and burning and general discomfort in the nose and upper respiratory tract to different extents, depending on the exact excipients and their dose [35][36][45][46][47][48][49]. Despite favorable results regarding the approved midazolam and diazepam intranasal formulations, there seems to be scope for improvement regarding formulation tolerability. In fact, side effects could be expected to have a stronger negative impact in treatment compliance in more frequent, non-emergency, treatment regimens.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14030588

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