Nasal metered-dose inhalers

Fomulationis) nasal spray 25 mg/metered dose inhaler with 0.25 mg/spray... 

A number of other peptide molecules are currently being explored for delivery via inhalation (6). Very recently, a much smaller peptide (leuprolide, about 9 amino acid residues) has been delivered by metered dose inhaler (MDI) in a characterized fashion to humans (7). This work revealed that about 50% of a dose deposited in the lung could be bioavailable. This value is much greater than those reported for nasal bioavailabilities of this and similar molecules (8). These results, and ours in the rat lung (9), imply that inhalation administration of some peptide and polypeptide molecules is perfectly feasible. 

Other delivery systems are transdermal patches, metered dose inhalers, nasal sprays, implantable devices, and needle-free injections. A description of needleless injection is given in Exhibit 5.16. 

Aerosol 17 (freon-free), 18 mcg/puff in 200 metered-dose inhaler 0.02% (500 mcg/vial) for nebulization Nasal spray 21, 42 mcg/spray Tiotropium (Spiriva)... 

Metered-Dose Inhalers and Nasal Aerosols Content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial bioburden, valve delivery, extractables, leachables from plastic and elastomeric components. 

Inhalation drug products include inhalation aerosols (metered dose inhalers) inhalation solutions, suspensions, and sprays (administered via nebulizers) inhalation powders (dry powder inhalers) and nasal sprays. The CMC and preclinical considerations for inhalation drug products are unique in that these drug products are intended for respiratory tract-compromised patients. This is reflected in the level of concern given to the nature of the packaging components that may come in contact with the dosage form or the patient. 

As a nasal spray, flunisolide is effective in allergic rhinitis in clinical use [32-34], and their protective effects in patients with bronchial asthma have also been studied. The efficacy and safety of a new metered-dose inhaler of flunisolide has recently been reported [35]. 

Since the introduction of metered-dose inhalers, nasal solutions have increasingly been formulated as nasal sprays. Initially, aerosol-based systems containing chloro-fluorocarbons were employed however, the Montreal Protocol put an end to this. Thereafter, mechanical pumps or actuators were employed to deliver nasal formulations as sprays. These devices, using actuators, can precisely deliver as little as 25 pL and as much as 200 pL of a formulation. However, various factors must be considered in formulating the spray these include viscosity, particle size, and surface tension, all of which may affect the accuracy of the dose administered. 

Inhalation drug products, also referred to as orally inhaled and nasal drug products (OINDPs including inhalation aerosols and solutions, nasal aerosols and sprays), have a high likelihood of packaging component-dosage form interaction,and therefore have individual USFDA guidance documents. As an example, consider the metered dose inhaler (MDI), shown... 

Metered dose inhalers (MDIs) are pharmaceutical delivery systems designed for oral or nasal use, which deliver discrete doses of aerosolized medicament to the respiratory tract. The MDI contains the active substance, dissolved or suspended in a liquefied propellant system held in a pressurized container that is sealed with a metering valve. Actuation of the valve discharges a metered dose of medicament as an aerosol spray through an actuator during oral or nasal inhalation. 

Pulmonary delivery of drugs is the administration route of choice in respiratory diseases such as chronic obstructive pulmonary disease and asthma. Different devices are available, including metered-dose inhalers, dry powder inhalers, and nebulizers, and nearly 80% of asthmatic patients worldwide use metered dose inhalers (1). Chlorofluorocarbons have been used as an aerosol propellant in metered-dose inhalers however, they deplete the ozone layer and are being replaced by more environment-friendly propellants, even though the contribution of aerosols of this type to the total global burden of chlorofluorocarbons is less than 0.5%. The first chloro-fluorocarbon-free metered-dose inhaler for asthma treatment was approved by the FDA in 1996 (2) and the European Union has set 2005 as a target date for the withdrawal of all chlorofluorocarbon-based inhalers (1). In the USA, prescriptions for chlorofluorocarbon-free medications rose from 16.4 million in 1996 to 33.8 million in 2000 (2). Most of the chlorofluorocarbon-free medications were steroids for nasal use (27.2 million). However, chlorofluorocarbon-containing medications stiU represented two-thirds of all prescriptions and increased from 63.0 to 67.6 million dispensed (2). 

Following the debate surrounding sampling by inertial impaction in the early 1990s, the apparatus required for propellant-driven metered-dose inhalers and dry powder inhalers has been specified by the USP [33] and EP [147]. In addition, the FDA has issued guidelines on the methods to be employed for both pulmonary and nasal delivery products [148]. 

Treatment of Migraine. Many years ago, ergotamine via metered dose inhaler was used successfully to treat migraine headache. I was made aware of this when I first became interested in medical aerosols by a senior professor of medicine who testified to its efficacy. More recently, sumatriptan nasal spray has been shown to provide significant relief of headaches [132]. 

Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers Monograph. USP 29-NF 24 The United States Pharmacopoeia and The National Formulary The Official Compendia of Standards. Rockville, MD The United States Pharmacopeial Convention, Inc, 2006 2617-2636. 

Metered-dose inhalations and nasal aerosols should be evaluated for appearance (including content, container, and the valve and its components), color, taste, assay, degradation products, assay for cosolvent (if applicable), dose content uniformity, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight), and extractables and leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-the-side orientations. 

In the US, two separate guidelines have been developed, one covering both metered dose inhalers (MDIs) and dry powder inhalers (DPIs) and one covering nasal sprays, inhalation solutions, and suspensions and inhalation sprays [22, 23], The guidance on MDIs and DPIs is however still in draft form nearly 10 years after being published for comment one of the unresolved issues is the dose content uniformity requirements which are discussed later in this chapter (Section 16.5.4). There are also other sections which would benefit from further discussion, in particular the number and nature of some of the tests that may be expected on stability. 

Nasal spray Inhalation spray Inhalation solutions and suspensions Metered dose inhaler MDI Dry powder inhaler DPI, device metered Dry powder inhaler DPI, pre-metered Not included Non-pressurized metered dose nasal spray Nasal single use sprays Non-pressurized metered dose inhaler Product for nebuhzation (single and multiple use) Pressurized metered dose nasal sprays Pressurized metered dose inhaler Dry Powder Inhaler, device metered Nasal powders, device metered Dry Powder Inhaler, pre-metered Nasal drops (single and multiple use)... 

Stability test Nonpros surized metered dose nasal spray Nasal single use sprays Non-pressurized metered dose inhaler Product for nebulization (single and multiple use)... 

Stability test Pressurized metered dose nasal spray Pressurized metered dose inhaler Dry powder inhaler and nasal powders, device metered Dry powder inhaler pre-metered... 

United States Pharmacopoeia (2008) USP 30-NF 25 Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers 601. ... 

Meter-dose inhalers which can either be dry power inhaler or metered-dose inhalers require a greater amovmt of testing because the metered valve, oral adapter, and the formulation are collectively responsible for the delivery the API to the appropriate site in the respiratory passages. Similar to aerosols and nasal sprays, very specialized tests which include leakage rate, number of dose per container (i.e., emitted dose test), particle distribution, and value delivery tests have been devised to test the suitability of the metered-dose inhalers. 

In addition to the specialized tests, there are many other tests that are similar to those used for tablets and capsules. However, complexity of the sampling procedures required to perform the tests and details of the tests are beyond the scope of this chapter. So for further information, the reader is directed to consult the general chapter in the US Pharmacopeia on Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers. ... 

Uses W/o emulsifier, wetting agent, pigment dispersant for cosmetics, pharmaceuticals (oral, topical, parenteral), food/food pkg., paints, inks, metalworldng fluids, adhesives, industrial applies. surfactant for nasal dosage and metered dose inhalers emulsifier for intramuscular pharmaceuticals food-pkg. adhesives, coatings defoamer in food-contact paper/paperboard emulsifier in m. of food-con-t3ct srticiss... 

Fluticasone propionate nasal suspension and inhalation aerosol are both available as micronized suspensions in a chlorofluorocarbon propellant that delivers 50 pg per metered spray. The total daily adult dose for fluticasone propionate is 200 pg for the nasal suspension and 880 pg for the inhalation aerosol. 

There are unique features pertaining to nasal sprays and inhalation products which make stability studies more complex and challenging. Examples include metering and spray production, energy required for spray production, the container closure system, and small doses. Critical attributes include the reproducibility (throughout the shelf-life) of the dose, the spray plume, and the particle/droplet size... 

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