Formulation and characterization of nasal sprays · 2019-07-17 · AS APPEARED IN Inhalation JUNE 2012, COPYRIGHT CSC PUBLISHING Formulation and characterization of nasal sprays Introduction

AS APPEARED IN Inhalation JUNE 2012, COPYRIGHT CSC PUBLISHING www.inhalationmag.com

Formulation and characterization ofnasal sprays

IntroductionAdministration of drugs through the nose in the spraydosage form is a non-invasive method that gives rapidonset of drug action. Because the nasal spray dosageform is cost-effective, easy to use/carry and self-adminis-trable, it has high patient compliance. Therefore, nasaldrug delivery has become a popular route of drug admin-istration and has strong growth opportunity. A publishedreport indicates that the combined sale for inhalation andintranasal drug delivery products exceeded US $20 billionin 20091 and it is expected to grow.

The total surface area of the nasal cavity of an averageadult is approximately 180 cm2. It is richly vascularizedfor rapid blood flow and has microvilli in epithelialcells.2,3 Therefore, the nasal mucosal membrane haspotential advantages for quick bioavailability and fastonset of drug action. Traditionally, nasal drug deliverywas limited to treating the common cold and nasal aller-gies. Recently however, there has been growing interestin developing nasal drug delivery systems for systemicdelivery as an alternative to oral or injectable dosageforms, including small molecular weight drugs, peptides,proteins and vaccines.3,4 In addition, there have beenseveral studies since the 1970s that have suggested

intranasal drug delivery could be used to deliver drugsinto the central nervous system via the olfactory epithe-lium, bypassing the blood brain barrier.5 Only relativelyrecently have specially-designed devices emerged thatcan target the delivery of sprays or powders to theolfactory region of the nose, thereby enabling delivery ofthe drug directly to the central nervous system.5-7 Thisarticle examines nasal spray formulation parameters andexcipients and their influence on key in v itro tests.

Critical parameters affecting nasal spray formulation performance and bioavailabilityPhysical properties of formulations. Nasal spray formu-lations are broadly categorized into two types: solutionsand suspensions and each can be either aqueous or non-aqueous. When formulating aqueous nasal spray prod-ucts, it is critical to control properties such as pH,buffer capacity, osmolality and viscosity. The US FDAChemistry, Manufacturing and Controls (CMC) guid-ance on nasal sprays recommends measurement of pH,osmolality and viscosity as part of the drug productspecification.15

pH and buffer. Local pH inside the nasal cavity mayhave a direct effect on the rate and extent of absorption

Vitthal Kulkarni and Charles ShawDPT Laboratories, Ltd.

An examination ofnasal spray formulationparameters andexcipients and theirinfluence on key invitro tests.

of ionizable drugs. A study by Washington, et al.8

showed that, for a pool of healthy human volunteers,overall range of pH of the anterior part of the nosewas 5.17 to 8.13 while that of the posterior part was5.20 to 8.00, indicating that an average baseline humannasal pH is approximately 6.3. Their study showed thatSorensen’s phosphate buffer at 0.13M (pH 5.8)increased the pH of the posterior part of the nose. Themildly acidic solutions produced an increase in pH, pre-sumably due to reflux bicarbonate secretion. However,the phosphate buffer at 0.06M (pH 5.8) did not alter thepH of the posterior region of the nose, suggesting thatthe phosphate buffer of higher concentration may alterthe pH of the posterior region of the nose. Therefore,the study by Washington, et al. emphasizes the signifi-cance of controlling pH and buffer concentration ofnasal spray formulations. The pH values for severalcommercially-available nasal spray products are listed inTable 1. The pH of these products vary from approxi-mately 3.5 to 7 while an optimal range for pH of thenasal spray formulation is suggested to be 4.5 to 6.5.9

Osmolality. The data from animal models has shownincreased bioavailability for salmon calcitonin fromnasal spray formulations with an osmolality of 100 or600 mOsmol/Kg compared to isotonic formulations.10

Other studies have shown that hypotonic nasal spray for-mulations improved drug permeability through the nasalmucosa.11 Some existing marketed products have reportedosmolality in the range of 300-700 mOsmol/ Kg (seeTable 1). The FDA suggests reporting and controllingosmolality of nasal spray formulations that containtonicity agents.12

Viscosity. The FDA CMC guidance12 recommends mea-suring viscosity at release and on stability for nasal sprayformulations comprised of viscosity contributing agents,and where ingredients are used to control the viscosity of

Table 1

pH and osmolality of select nasal spray productson the market. Data compiled from: #Productliterature, ¶The National Library of Medicine

(dailymed.nlm.nih.gov) and *www.drugs.com.

Existing market products pH Osmolality(mOsmol/Kg) or Osmolarity (mOsmol/L)

Flonase (Fluticasone 5-7 Not available

propionate nasal spray)#

Imitrex (Sumatriptan 5.5 372 or 742 mOsmol/Kg for

nasal spray)# 5 or 20 mg dose respectively

Zomig (Zolmitriptan 5 420-470 mOsmol/L

nasal spray)¶

Butorphanol nasal spray* 5 Not available

Desmopressin nasal spray* 3.5-6 Not available

the product. Eccleston, et al.13 has reported rheologicalinvestigation of four marketed nasal sprays: Beconase(GlaxoSmithKline), Nasacort (Sanofi-Aventis), Flixonase(GlaxoSmithKline) and Nasonex (Merck). The productsthey investigated exhibited shear thinning, thixotropicbehavior. Their study suggested that high viscosity, ratherthan thixotropy, was the controlling factor for prolongedresidence time of the spray in the nasal cavity.

Excipient selection. As mentioned previously, both pHand tonicity of the formula may have a significant influ-ence on performance. In addition to buffer salts, severaltypes of excipients are required for a stable nasal sprayformulation. These include solvents and co-solvents tokeep the active pharmaceutical ingredient (API) in thedissolved state, as well as preservatives for non-sterileproducts. If the formulation is a suspension or emul-sion, surfactants and/or emulsifying agents, stabilizersand suitable oil-phase components are required. If vehi-cles such as liposomes or nanoparticles are used toencapsulate the API, then lipids and vehicle componentsalso form part of the excipients. Although there are ahost of surfactants, emulsifying agents, solvents, co-sol-vents and oils available, only a limited number of excipi-ents are listed in the US Food and Drug Administration(FDA) Inactive Ingredients Guide (IIG) for nasal sprayproducts. Table 2 lists some key excipients and their IIGdosage limits, as reported in the FDA IIG database fornasal spray formulations.

Improving residence time in the nasal cavity. By increas-ing the residence time of the medication on the nasalmucosal membrane, the chance of drug absorptionthrough the nasal mucosa is improved.9 (This is chal-lenging, however, because as part of normal nasal func-tion, foreign particles are removed naturally as quicklyas possible.) A common approach is increasing the vis-cosity of the formulation by incorporating viscosity-enhancing agents, which can also act as muco-adhesives.However, it has been reported that high viscosityimpacts droplet size distribution, resulting in altereddeposition in the nasal cavity.14 Kulkarni, et al.15 havereported that formulations with hydroxyethylcellulose(HEC) as a muco-adhesive and gelling agent formedlarge droplets and, above a certain concentration ofHEC, the plume was distorted.

Use of penetration enhancers. Chemical compoundsthat increase the penetration of drugs through the skinare known as penetration enhancers. Commonly-recog-nized categories of penetration enhancers are solvents,co-solvents, ionic and some non-ionic surfactants, andsome fatty acids, including oleic acid. Some commonpenetration enhancers for mucosal membranes, includ-ing polymeric materials, are reported.16 Certain lipids areknown to be penetration enhancers for topical formula-tions. A study of a nasal spray comprised of desmo-pressin encapsulated in liposomes has been reported.17

a non-aqueous (dry) beclomethasone dipropionate nasalspray for the treatment of seasonal allergic rhinitis(SAR) and perennial allergic rhinitis (PAR) which is for-mulated with a hydrofluoroalkane propellant.22

Characterization of nasal sprays Commonly, the FDA CMC guidance12 on nasal sprays isfollowed when generating product development docu-mentation. The guidance document recommends sev-eral analytical tests, including mean delivered dose (shotweight), dose content uniformity and characterization ofthe spray plumes for spray pattern, plume geometry anddroplet size distribution. These tests are aimed at ensur-ing the “sameness” of the dose throughout the life ofthe product and from batch to batch. For determinationof dose weight, dose content uniformity and plumecharacteristics, the FDA recommends use of an auto-

The results showed an increased permeation of drugfrom the liposomal formulation compared to the solu-tion of the drug alone, suggesting that liposomeshelped the drug to penetrate the mucosal membrane.

Non-aqueous nasal sprays. Prescription nasal sprayproducts on the market are mostly aqueous formula-tions. Although patents covering non-aqueous nasalsprays formulations containing poorly water solubledrug substances are reported,18,19 excipients such aspropylene glycol and PEG 400 are reported to causelocal irritation and hyperosmolarity.20 Also, acute dam-age to nasal mucosa by isopropyl alcohol is reported inanimal models and similar effects are suspected inhumans.21 Therefore, non-aqueous nasal spray formula-tions are suspected to have increased levels of safetyrisk, particularly in the case of chronic use. The FDAhas recently accepted a new drug application (NDA) for

Table 2

Select excipients used in nasal spray formulations; their FDA IIG (Inactive Ingredient Guidance) limits for nasal route, spray or aerosol dosages; and their functions. (Compiled from

http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm)

Ingredients IIG limit for nasal route and Function

spray or aerosol dosage, % w/w

Alcohol, 200 proof 2 Co-solvent

Anhydrous dextrose 0.5 Tonicity adjusting agent

Anhydrous trisodiumcitrate 0.0006 Buffering agent

Benzyl alcohol 0.0366 Preservative

Benzalkonium chloride 0.119 Preservative

Butylated hydroxyanisole 0.0002 Antioxidant

Butylated hydroxytoluene 0.01 Antioxidant

Cellulose microcrystalline/ 2 Suspending agent, Stabilizer

Carboxymethyl cellulose sodium

Chlorobutanol 0.5 Preservative

CMC-Na 0.15 Suspending agent

Edetate disodium 0.5 Chelator, Antioxidant synergist

Glycerin 0.233 Humectant

Hydrochloric acid Not reported pH adjusting agent

Methylparaben 0.7 Preservative

Oleic acid 0.132 Penetration enhancer

PEG 400 20 Surfactant, Co-solvent

PEG 3500 1.5 Surfactant

Phenylethyl alcohol 0.254 Preservative and/or Masking agent

Polyoxyl 400 stearate 15 Surfactant

Polysorbate 20 2.5 Surfactant

Polysorbate 80 10 Surfactant

Propylene glycol 20 Co-solvent

Propylparaben 0.3 Preservative

Sodium chloride 1.9 Tonicity agent

Sodium hydroxide 0.004 pH adjusting agent

Sulfuric acid 0.4 pH adjusting agent

mated actuator to eliminate the variability arising fromrepeated hand actuations. The actuation parametersinclude stroke length (displacement in mm the spraydevice is squeezed), velocity (or force) and accelerationof squeezing. The actuation parameters are likely to varyamong brands of devices and dose volumes (which mayrange from 25-100 µl per spray) and within patient pop-ulations (e.g. young, adult or senior). Therefore, develop-ing correct actuation parameters for a selected deviceand for the target patient population is important. Oncedeveloped, the same set of actuation parameters is usedfor characterization of the nasal spray for dose weight,dose content uniformity and plume characterization.

Spray pattern measures the ovality (ratio of maximumto minimum cross section diameter of the plume) ofthe spray at desired distances from the tip of the spraybottle (typically at 3 cm and 6 cm from the tip). Plumegeometry measures the plume angle at the origin of theplume and is determined for plume lengths of 3 cm and6 cm from the origin, at two side views (90° to eachother relative to the axis of the plume). Examples ofcharacterization of a nasal spray plume for plumegeometry (plume angle) and a spray pattern (cross sec-tion of the plume) are shown in Figure 1. Droplet sizedistribution is a critical parameter and its control is cru-cial for nasal spray products.12 Droplet size distributiondepends on both the formulation and the device. Fornasal sprays, the use of laser diffraction has become theindustry standard for determining droplet size distribu-tion. Measurement provides size distribution at D(v,0.1),D(v,0.5), and D(v,0.9) thresholds (corresponding toundersize at 10%, 50% and 90% by volume distribution,respectively). The FDA suggests reporting of the sizedistribution data at D(v,0.1), D(v,0.5), and D(v,0.9)thresholds, along with the percent of droplets (by vol-ume) under 10 µm and span [(D(v,0.9)- D(v,0.1))/D(v,0.5)]. Droplet size distribution studies are also per-formed at 3 cm and 6 cm from the nozzle of the spraybottle, to be consistent with spray pattern and plumegeometry measurements. Larger droplets will tend todrip out of the nose. Conversely, droplets smaller than10 µm may travel deeper into the nasal cavity and reachthe lungs, which is not the intended delivery site.Therefore, it is critical to maintain the population ofdroplets less than 10 µm at a minimum level. Analysis ofaerodynamic particle/droplet size by cascade impactionis also recommended for nasal inhalation products.12

However, during the development of new nasal drugspray formulations, cascade impaction may be necessaryin Bioavailability and Bioequivalence (BA-BE) studies todemonstrate safety of the formulation by 1) quantifyingthe mass of drug in small droplet (BA studies) and 2)showing that the mass of the drug in small droplets ofthe test product, is less than or equivalent to that of thereference product (BE studies).23

For nasal sprays, a uniform circular plume with an oval-ity ratio close to 1, D(v,0.5) of 30-70 µm, and D(v,0.9)<200 µm with a narrow span could be considered an idealplume. It is known that excipients, and their level in nasalspray formulations, influence the physical properties of theformulation, including viscosity and surface tension.These, in turn, can critically influence the spray pattern anddroplet size distribution of the product. In a previousstudy, Kulkarni, et al.15 have shown that the spray patternof a nasal formulation was not circular in the presence ofpolysorbate 80 at 0.1 and 0.5% (w/w), whereas a non-polymeric surfactant showed a uniform circular spray pat-tern with an ovality ratio close to 1. When 2% hydrox-yethylcellulose was used in the formula, the median droplet

Figure 1

Nasal spray plume characterization; plumegeometry (Panel A) and spray pattern (Panel B)

at 3 cm from the orifice of the device.

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size, D(v,0.5), was 173 µm, and D(v,0.9) was >300 µm,which is not desirable because such a formulation maytend to drip out of the nose.

ConclusionPlumes of nasal sprays are influenced by the presenceof excipients and their levels in the formulation. A nasalspray formulation that shows a uniform plume, spraydroplets that do not drip down the nose and a minimalpercentage of droplets less than 10 µm in diameter isconsidered a desirable formulation. Therefore, whenformulating nasal spray products, it is critical to choosethe appropriate excipients and maintain their optimumlevels in the formulation.

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15. Kulkarni, V., Brunotte, J., Smith, M., and Sorgi, F.“Investigating influences of various excipients of thenasal spray formulations on droplet size and spray pat-tern” poster at AAPS Annual meeting (2008)

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17. Law, S.L., Huang, K.J., and Chou, H.Y. “Preparationof desmopressin-containing liposomes for intranasaldelivery” J. Control. Rel. 70: 375-382 (2001)

18. Castle, J., Smith, A., Cheng, Y-H., and Watts, P.J.“Non-aqueous pharmaceutical application” US PatentApplication 2009/0233912 (2009)

19. Hatton, A.G., Scott, H., Hilton, J.E. “Calciummupirocin non-aqueous nasal spray for otitis media orfor recurrent acute bacterial sinusitis” US Patent6,156,792, (2000)

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21. Ohashi, Y., Nakai, Y., Koshimo, H., Esaki, Y.,Ikeoka, H., Horiguchi, S., Teramoto, K., and Nakaseko,H. “Toxicity of isopropyl alcohol exposure on the nasalmucociliary system in the guinea pig” Environ. Res.46(1): 25-38 (1988)

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23. Guidance for Industry: “Bioavailability andBioequivalence Studies for Nasal Aerosol and NasalSprays for Local Action” US FDA, Center for DrugEvaluation and Research, 2003

Vitthal K ulkarni and Charle s Shaw are Sc ientif ic Adv iso rsat DPT Labo rato rie s, Ltd., 318 Mc Cullo ugh, San Anto nio ,TX, 78215, US, Te l: +1 866 225-5378, Vit th al.K ulkarn i@d p tlab s .c o m , Charle s . Shaw @ d p tlab s . c o m ,Website : www.dptlabs. c o m .