Development of Nasal Dosage Forms
Mohanned Jallad
R&D Formulation Manager-(B.Sc./MSc)-EU/EMEA/ SFDA/ JFDA/ GCC Oral Solid- Oral Liquid/Suspension-lyophilized Sterile -Liquid sterile-Nasal Liquid/ Suspension-Topical Liquid & Semi-solid-Suppository & Ovules
Abstract
The anatomy and physiology of the nasal cavity provide unique advantages for accessing targets for local, systemic, and potentially central nervous system drug delivery. the advantages and the challenges that must be overcome to reach these targets.
Introduction
Preservative-free nasal spray drug products represent a small portion of the overall drug delivery market. However, the desire to remove preservatives from formulations driven by concerns over potential damage from long-term use coupled with innovations in device technology has allowed Pharma companies to consider preservative-free nasal sprays as a viable option. In this article, an overview of nasal cavity physiology will be presented along with a review of locally and systemically acting drug products. Current formulation and manufacturing strategies are discussed .
Introduction on intranasal administration
Nasal sprays or drops are widely used and therefor easy-to-use and cost-effective solutions are already available for liquid or for dry powder formulated drug products. Also the basic requirements for the development of nasal sprays are well known. An important point when a development for nasal administration is considered: the product should have no unpleasant smell and should not be irritating or influence the sense of smell. There should be also no safety concern, if a dose is unintentionally shot into the eyes.
For most nasal spray pumps the dispensed volume per actuation is set between 50 and 140 μl, and an administered volume of 100 μl per nostril is optimum in adults. Higher volumes are prone to drip out immediately. So the anticipated dose should fit into a volume of roughly 100-200 μl when both nostrils are sprayed. Standard spray pumps will deposit most of the sprayed dose into the anterior region of the nasal cavity (see?Fig. 1) . Surface tension of the droplets and mucus layer will cause the immediate spread of the spray. Afterwards mucociliary clearance will distribute the liquid layer within the nasal cavity. Since the nasal mucus layer is continuously renewed and discarded into the throat, the nasal residence time of the administered drug depends on how fast it dissolves within the mucus layer and penetrates into the mucosa
Fig .1 . Intranasal structure
If a nasal spray is considered, authorities will require a lot of data to describe the nasal spray pump and its performance as part of the container closure system . Most of these required parameters are used for quality control purposes. For nasal deposition efficiency, the spray plume angle and administration angle are critical factors, while many other spray parameters, including droplet particle size, have relatively minor influences on deposition within the nasal cavity .
Formulation development
Nasal drug formulations are broadly categorized into several types including solutions, suspensions, powders or gels. A key factor in selecting the type of nasal formulation to be developed is whether the therapy is intended for local or systemic application.
Depending on the application, factors such drug absorption rate from the nasal mucosa into the systemic blood circulation and residence time in the nasal cavity become key elements in the formulation development process.
Taking as examples spray solutions and suspension type formulations, the following factors should be considered during nasal formulation development:
Drug, particles:?consideration should be given to the desired therapeutic concentration for each dose, keeping in mind whether the total dose to the nasal cavity will be one (single nostril delivery) or two (one delivery into each nostril). For aqueous solutions and suspensions the typical dosing volume ranges are 50-140μl and for solution or suspension in pressurized metered dose inhalers (pMDIs) the typical delivery volumes are in the range of 25μl. The primary particle size of the API in suspension formulations also needs to be considered with regard to the droplet size delivered during dosing and any impact it may have on the dissolution of the particles once deposited in the nasal cavity.
pH/buffers:?the pH inside the nasal cavity can influence the rate and extent of absorption of ionizable drugs. The average baseline human nasal pH is reported to be around 6.3 and the pH of several commercially available nasal spray products are in the range of 3.5 to 7.0, and the optimal range for pH of these nasal formulations is suggested to be 4.5 to 6.5 [14]. The pH of the formulation can also affect the stability of the drug product during its shelf life so this also needs to be considered during development.
Osmolality:?Studies have shown that hypotonic nasal spray formulations improve drug permeability through the nasal mucosa and some marketed products report osmolality in the range 300-700mOsmol/K.
Viscosity/surface tension:?the majority of commercially marketed products contain agents that modify the viscosity and surface tension of the formulations, they are included in order to manage factors such as thinning and thixotropic behavior and are key elements in the performance of the dispensed product such as drop particle size, spray angles and also influence the residence time of the product once delivered, in the nasal cavity.
The nose is a very effective filter and most particles and droplets will be caught within the nasal cavity. Only particles less than 10 μm median aerodynamic diameter, so called fine particles, can reach the lower airways during nasal breathing. Most spray pumps will generate an aerosol with a mean particle size from 40-100 μm during the fully developed phase which is recognized as fine mist. Such an aerosol will deposit well in the nasal cavity.
To date, nearly all drugs for intranasal administration are liquids and just some recreational drugs are used as powders. Of course dry powder preparations can be used without the need for reconstitution to a liquid. The particle size should be in the same range as droplets from a nasal spray and fine particles should be minimized to avoid pulmonary deposition. The size and structure of the particles must be a compromise between safe administration (no fine particles, good deposition) and fast speed of dissolution of the particles within the mucus layer . Powders for nasal administration will most likely need protection from moisture uptake though the moisture sensitivity may be formulation-dependent. Long term use of powder formulations may result in mucosal irritation and chronic use should be considered with caution, but single administration should be of much lower risk.
Table1.Examples of key nasal formulation excipients and their inactive ingredient guidance (IIG) dosing levels
Other excipients:?in addition to buffer salts several types of excipients may be required in order to develop a stable nasal spray formulation. These include solvents and co-solvents to keep the active pharmaceutical ingredient (API) in the dissolved or suspended state, as well as preservatives for non-sterile products. If the formulation is a suspension or emulsion, surfactants and/or emulsifying agents, stabilizers and suitable oil-phase components may be required. Although there are numerous surfactants, emulsifying agents, solvents, co-solvents, oils and preservatives available, only a limited number of excipients are listed in the US FDA inactive ingredient guide (IIG) for nasal products.?
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Controlling residence time in the nasal cavity:?increasing the residence time of the drug, once delivered on the nasal mucosa, can be beneficial especially for local applications and can aid drug absorption through the nasal mucosa. One approach is too increase the viscosity of the formulation but this should be balanced against any impact on droplet size distribution during delivery into the nasal cavity .
Penetration enhancers:?these agents increase the penetration of drugs through the nasal mucosa. Typical penetration enhancing agents are solvents, co-solvents, ionic and some non-ionic surfactants, selected fatty acids, including oleic acid and certain lipids and cyclodextrin .
Powder and gel nasal formulations:?in formulating nasal powders the key elements to manage are controlling the primary particle size of the API as well as the excipients to get efficient nasal deposition, and selecting a system that provides acceptable protection of the powder during storage and efficient delivery to the nasal cavity during dosing. For nasal gel applications the formulations can be relatively simple and key elements will be stability and shelf-life and the selection of the dispensing system used to deliver the gel to the nasal cavity.
Performance parameters
Nasal drug product performance characterization is driven by regulatory requirements which allow for successful approval and marketing of these products. The most stringent regulatory standards for nasal drug products are issued in the USA and in Europe . During the development process information has to be documented on many factors in order to construct a regulatory dossier.
Once approved and marketed these products have to be routinely controlled in order to assure ongoing performance and quality and the typical regulatory expectations for marketed nasal product specifications and testing . The rationale behind these performance characterization tests are related to factors such as dosing accuracy, shelf life, product robustness and user safety, the key ones being as follows:
Priming, re-priming:?most nasal spray pumps need to be primed in order to fill the dosing chambers before use and to assure full dosing of the product. In addition, some pumps do not retain the dose in the metering chamber when stored for longer periods, i.e. 7 days, 1 month etc. and may need to be re-primed before use after a specified period of non-use which will be defined in the patient leaflet.
Dose weight through life:?this test assures that the pump delivers the prescribed dose consistently throughout the use-life of the product, usually beginning middle and end of use. Regulatory requirements exist in most markets for limits on dosing accuracy and these can be found by referring to each country specific regulatory dosing limit specifications for nasal products.
Leakage:?this assures that the product integrity is maintained throughout its proposed shelf life and that the contents are not lost during storage at various environmental conditions. The ICH stability test conditions are the key reference with regard to stability testing.
Dimensional/metrology measurements:?these assure that the spray pump meets specified critical quality dimensions in order to assure that the nasal product functions efficiently and meets the key performance tests assuring consistent quality.
Particle size distribution:?this can refer to the primary particle size specification of the API itself in suspensions or to the droplet (liquid solution) or particle (powder) size distribution of the delivered spray. Specifications need to be put in place for this key parameter and the justified limits registered in the regulatory submissions as it is closely related to nasal deposition efficiency.
Spray pattern:?this is another test to assure consistent quality of the delivered nasal spray and characterizes parameters such as angle and plume shape.
Extractables/leachables: this test assures the safety of the product and specifically measures and controls the potential chemical contaminants which may come from the packaging or container closure system into the formulation and therefore be potentially toxic for the patients, if ingested.
Particulates: this test characterizes the contamination of the nasal formulation by any foreign particulates and is related to the overall safety of the product.
Microbial limits: specification and tests exist to measure and characterize this parameter, for preserved nasal formulations this will usually mean measuring the levels of preservatives, e.g. benzalkonium chloride in the product and during its proposed shelf life. The units of measurement are usually colony forming units (CFU’s). For non-preserved nasal products the characterization tests are somewhat more complicated and include challenge testing with contaminated bacterial environments to assure the integrity of the system for protection against microbial contamination. Special drug delivery systems are needed in order to use non-preserved nasal formulations.
Robustness: here a number of different test are applied including dropping the whole packaging, exposure to vibration, simulation of shipping and transportation. These characterization tests are meant to assess the robustness of the product to normal transport and day to day use.
Refrences :