INTERNATIONALE PHARMACEUTICA SCIENCIA

| April-June 2012 | Vol. 2 | Issue 2 | Available online http://www.ipharmsciencia.com ISSN 2231-5896 2012 IPS
REVIEW ARTICLE

Review on: Pharmaceutical Aerosol

ABSTRACT
Pulmonary drug delivery system is a needle free technique. The origin of inhaled therapies seen in back 4000 years ago to India, where people smoked the leaves of the Atropa belladonna plant to suppress cough. In the 19th and early 20th centuries, asthmatics smoked asthma cigarettes that contained stramonium powder mixed with tobacco to treat the symptoms of their disease. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variation in inhalation techniques can affect the quantity of a drug delivered to the lungs. Pulmonary drug delivery remains the preferred route for administration of various drugs. It is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various diseases. Due advancement in application nowadays Pulmonary drug delivery is useful to treat Diabetes, angina pectoris, cancer , bone disorders , migraine, tuberculosis, acute lung injury and others. In this article, we summarize the outline of this dosage form. Keywords: Unani system; Anxiety; Izterabe Nafsani

Mr. Hitesh. G. Pokar*, Dr. K. R. Patel, Dr. N. M. Patel Department of Industrial Pharmacy Shri B. M. Shah College of Pharmaceutical Education and Research, Modasa,Gujarat-383315 Date of Submission: 02-5-2012 Date of Acceptance: 17-06-2012 Conflict of interest: Nil Source of support: None

Introduction: Packaging of therapeutic active ingredients in a pressurized system. Aerosols are depends on the power of compressed or liquefied gas to expel the contents from containers. A dose can be removed without contamination of materials. Stability is enhanced for these substances adversely affected by oxygen and or moisture. When sterility is an important factor, it can be maintained while a dose is being dispensed. The medication can be delivered directly to the affected area in a desired form, such as spray, steam, quick breaking foam or stable foam. Irritation produced by the mechanical application of topical medication is reduced or eliminated. Ease of convenience of application. Application of medication in thin layer. Components of aerosols: Propellant: It is responsible for developing the power pressure within the container and also expel the product when the valve is opened and in the
Address for correspondence

atomization or foam production of the product. # For oral and inhalation Fluorinated hydrocarbons Di-chloro di-fluro methane (propellant 12) Di-chloro tetra-fluro ethane (propellant 114) # Topical preparation Propane Butane Isobutane # Compound gases Nitrogen Carbon di-oxide Nitrous oxide Containers: They must be stand at pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 1300 F.The containers are generally made up of glass or metal. But brittleness restricts the use of glass. If the pressure is less than 25psig and propellant content is less than 15% then glass can be used. Glass should be coated with plastic coating in two layers if pressure is less than or equal to 33psig. Epoxy and vinyl resins can be used as linings. Vinyl resins can form strong lining but
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Pokar Hitesh. G 16/Bombay society, T. B. Road Vijapur-382870, District-Mehsana Email:- hiteshpokar1990@gmail.com

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol it will get damaged by steam. But epoxy resins can be used as they are resistant to steam. A vinyl coating on which the epoxy coating is most suitable for products having less PH. Choice of the material is depend on- Pressure of the system, whether product is aqueous or not, PH of the product, physicochemical properties of preparation. A. Metals 1. Tinplated steel: It is used for most aerosol as it is light inexpensive and durable. It is steel that has been plated on both side with tin. Tin plated steel containers are of two types(a) Two pieces container body, consisting of adrawn cylinder, the base of the container, is held in place with double seam. (b) The three piece container has aside seam the base being attached as for two piece container, the top has a 1 inch opening and is joined to body by double seaming. 2. Aluminium : Aluminium containers are more resistant to corrosion than tin-plated steel. Aluminium container are made by an extrusion process and hence have no seam. Aluminium is subjected to corrosion by water and alcohol. 3. Stainless steel: It is resistant to corrosion and no coating is required. It can withstand high pressure. However they are expensive. B. Glass Glass containers are often coated with plastics. The coating gives protection from impact. Glass has advantage of being transparent so contents can be viewed. Glass is virtually inert. C. Plastic Types of inhalers: Dry powder inhalers:
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Not widely used for aerosol container. Polyethylene tetra phthalate (PET) container as used for some non pharmaceutical products. Valves: Valves delivers the drug in desored form. They also provide proper amount of medication.there are two types of valves are available which are continuous spray valve and metering valve. Dispersing of potent medication at proper dispersion/ spray approximately 50 to 150 mg 10 % of liquid materials at one time use of same valve.

Fig.1: Valve components Actuator: The actuator or adaptor which is fitted to the aerosol valve stem is a device which on depression or any other required movement opens the valve and directs the spray to the desired area. The design of the actuator which incorporates an orifice of varying size and shape and expansion chamber is very important in influencing the physical characteristics of the spray or foam, particularly in the case of inhalation aerosols, where the active ingredient(s) must be delivered in the proper particle size range. A proportion of the active ingredient(s) is usually deposited on the inner surface of the actuator; the amount available is therefore less than the amount released by actuation of the valve.different types of actuators like Spray actuators, Foam actuators, Solid steam actuators actuators are used. Special

Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol Unit-Dose Devices: Single-dose powder inhalers are devices in which a powder-containing capsule is placed in a holder. The capsule is opened within the device and the powder is inhaled. The capsule residue must be discarded after use and a new capsule inserted for the next dose. An asthma attack and requires immediate delivery of drug (Disadvantage) Multi dose Devices: The development of multi dose DPIs was pioneered by A. B. Draco (now a division of Astra Zeneca) with their Turbuhaler. This device is truly a metered-dose powder delivery system. The drug is contained within a storage reservoir and can be dispensed into the dosing chamber by a simple back-and forth twisting action on the base of the unit.The device is capable of working at moderate flow rates and also delivers carrier-free particles.However, one of the drawbacks of the Turbuhaler has been the fact that it has a highly variable delivery at different flow rates. To address issues associated with a need for multiple dosing and consistent performance, Glaxo developed the Diskhaler , which was used to deliver a range of drugs, including salbutamol and beclomethasone. This device uses a circular disk that contains either four or eight powder doses on a single disk. This typically would be treatment for one to two days. The doses are maintained in separate aluminum blister reservoirs until just before inspiration. On priming the device, the aluminum blister is pierced, and the contents of the pouch are dropped into the dosing chamber. This product had limited commercial success and was superseded in the late 90s by the Diskuse. This device is a true multi dose device, having 60 doses in a foil foil aluminum strip that is opened only at the point just prior to patient inspiration. Consistent performance and broad patient acceptance has allowed the Diskuse to become the gold standard of multi dose powder delivery devices. Dry powder formulations either contain the active drug alone or have a carrier powder (e.g., lactose) mixed with the drug. The drug particles must be of sufficiently small aerodynamic diameter to make it to and deposit on the airways. Metered dose inhaler:
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To increased interest in modifying metered dose inhalers (MDIs) to minimize the number of administration error and to improve the drug delivery of aerosols particles into the drug delivery system of the nasal passageways and respiratory tract. The MDI device consists of a canister, and actuator, and sometimes a spacer. The canister itself consists of a metering dose valve with an actuating stem. The formulation resides within the canister and is made up of the drug, a liquefied gas propellant, and often stabilizing excipients. Actuation of the device releases a single metered dose of liquid propellant that contains the medication.The volatile propellant breaks up into droplets which then evaporate, creating an aerosol containing micronized drug that is inhaled into the lungs.The dose delivered by an MDI can be analyzed using a microscope, or preferable an automated image analyzer. A bronchodilator MDI was examined using the PSA300 image analysis system.

Fig.2: Metered dose inhaler Nebulisers: Solutions for nebulisation: Nebulisation involves the application of energy (either a high-velocity gas or by the use of ultrasonic systems) to a solution of a therapeutic agent and results in the formation of droplets of solution, which are then inspired by the patient through a facemask. The energy source is provided by a nebuliser (most commonly a jet or ultrasonic nebuliser). The use of nebulisers generally reserved for the treatment of is acute

conditions (e.g. acute asthma, respiratory infection) or in those patients who havedifficulties using other respiratory dosage forms. Formulation of solutions for nebulisation:

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol Vehicle: The vehicle for solutions designed for nebulisation is water for injections (nebuliser solutions are sterile). Due to the possibility of acidic solutions (pH-5) causing bronchoconstriction, the pH of nebuliser solutions is greater than 5. This may be modified via the use of buffers (e.g. citrate, phosphate). Co-solvents: Co-solvents may be used in nebuliser solutions to increase the solubility of the drug. However, as in other applications, care should be taken when selecting the concentration of these to ensure that there is no toxicity to the respiratory epithelia. Examples of co-solvents that may be used include: propylene glycol, glycerol, ethanol. Osmolality-modifying agents: The use of hypo- and hyperosmotic solutions within the respiratory tract has been linked to bronchoconstriction and therefore solutions designed for nebulisation should be formulated to be isoosmotic. As described previously (Chapter 5), modification of the osmolality of nebuliser solutions may be performed by adding the appropriate ionic concentration (e.g. sodium chloride, potassium chloride, mannitol). Miscellaneous agents: Other components that may be present in nebuliser solutions include: antioxidants (water-soluble examples; however, it should be noted that sulphites may cause brochospasm) preservatives: some multidose nebuliser solutions contain preservatives; however, the vast majority of formulations do not contain these excipients. Generally nebuliser solutions are packaged as singledose vials/ampoules and, as such, do not require the addition of preservatives. Formulation of pharmaceutical aerosols: Contains two essential components Product concentrate: Product concentrate contains ingredients or mixture of active ingredients and other such as solvents, antioxidants and surfactants. Propellant: Types of system : Solution system: It consists of the vapour and the liquid. It is also called two-phase system. No other solvent is required if the drug is soluble in the propellant. Based on the type of spray required, either propellant 12 is added or other propellants are also added. When less volatile substances are added to the system, three phase system is produced based on the amount of water present. Dried particle is obtained on the use of A-70 and wetten particles on use of A-17 and A-31. Water based system: If only water or large amount of water is present to solubilize the contents then it is called water based system. If spray form is required, then active ingredient is dispersed and other solvents should be present in the form of emulsion and propellant will be external phase. As the water is not miscible in propellant, generally three phase system results. To increase the solubility of propellants in water, ethyl alcohol can be added to the system. To produce a uniform dispersion, surfactants can be used and those surfactants which are soluble to large extent in non polar solvents and soluble to smaller extent in water are more preferred. Ester formed between glycol, glycerol and polyhydroxylic acid like oleic, palmitic stearic acids can be used as surfactants. The surfactants composition ranges between 0.5 to 2.0 and propellant composition ranges from 25 to 60%. The recent advancement is the aquasol valve. In aquasol dispenser system, the drug is dissolved in the water or the mixture of water and alcohol. Then the propellant layer is present on the top water layer. The solubility of the propellant increases as the amount of alcohol
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May be single or blend of various propellants are used.Blends of propellant used in a pharmaceutical formulation to achieve desired solubility characteristics or various surfactants are mixed to give the proper HLB value for emulsion system. Propellant gives the desired vapor pressure, solubility & particle size.parameters like physical,chemical and pharmaceutical properties of active ingredients and site of application are considered.

Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol increases and will become completely soluble if only alcohol is present. In aquasol, the vaporized propellant and product via different ducts reaches the actuator. Here the randomization takes place which gives an uniform spray. Aqueous stable foams: This consists of propellant in the range of 8 to 10% v/v. As the concentration of A-70, A-46 propellant increases, it results in drier spray. And wetter spray is produced as the concentration of propellant decreases. This is generally used for steroid antibiotics. Non aqueous stable foams: Glycols are used in the formulation of these foams and their esters are used as emulsifying agents. Quick breaking foams: Here the external phase is propellant. The product will come out as foam which soon merges to form liquid. This type of system can be applied to small area or larger surface. Cationic or anionic or non-ionic surfactants are used in the formulation. Fig.3: Aquasol aerosol Water based systems produces the dried spray. Suspension or dispersion systems: There comes a number of problems by the use of co solvent. To overcome this, suspension system is developed. In this system, in the propellant or the blend of propellants, the drug particles are suspended. Surfactants are added to reduce the settling rate. To increase the physical stability: 1. Moisture content must be monitored 2. The particles should have less solubility. 3. Add suspending agents. 4. By decreasing the density difference. 5. The particle size should be maintained less than 5 microns. Agglomerates will be formed in case of certain substances, if the number of agglomerates increases then caking results. As the temperature increases this condition will be increase. At extreme conditions, the particles will get attached to the walls. More the moisture content, more will be the agglomeration. Foam system: Here the propellant which is present in the liquid acts as internal phase. Here the ingredients include
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aqueous or non aqueous surfactant.

vehicle, propellant and

Thermal foams: These are not used much these days. These are used when the warmness is required. Intranasal aerosols: The design of the adaptor varies from the inhalation aerosols. The adaptors will be of less height and narrow, which results in the production of less number of smaller particles. It has number of advantages like contamination free, very less quantity of drug moves into the lungs, the mucosal irritation will be reduced. Manufacturing Aerosols Concentrate filler, Valve placer ,Purger and crimper, Pressure filler, Leak test tank equipments are used for large scale of production. Manufacturing procedure: It includes two steps, 1. Concentrate preparation 2. Propellant is mixed With help of the procedures that are previously accepted, the product is manufactured and then tested. The filling of aerosols in to the containers can be done by two methods namely 1. Cold filling method 2. Pressure filling method of Pharmaceutical

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol Cold filling method: Low temperature range -34*c to -40*c required.Product concentrate is chilled and added to open container followed by chilled prpellant, or the concentrate and propellant can be chilled together and mixture added to container. A valve is then crimped. Container passed through a heated test bath as a check for leakage and container strength. This method is not suitable for aqueous product or for preparations that are adversely affected by low temperatures. Pressure filling: A. Method-1 The product concentrate is added to container at room temperature. The valve crimped into place. The propellant is then added under pressure through the valve stern or through the actuator and around the sealing gaskets. B. Method-2 Under the cap method: position. A seal is formed around the shoulder of the container and using a vacuum, the valve cup is raised slightly from the can and propellant is added. The valve is then crimped into the place. This method is more prominent than cold filling method as most of the formulations cannot be cooled to very low temperatures Quality aerosols: 1. Propellents: All Propellants are accompanied by Specification sheet.
Parameter Tested by

Industrial Pharmaceutical Technical Section Academy Of Pharmaceutical Sciences. The object of this test is to determine magnitude of valve delivery & degree of uniformity between individual valves. Standard test solutions were proposed to rule out variation in valve delivery. Test Solutions:
Ingredients ( % w/w) Iso Propyl Myristate Dichloro Difluoro methane Dichloro tetrafluoro ethane Trichloro monofluoro methane Alcohol USP Specific Gravity @ 25c Test Solutions A 0.10% 49.95% 49.95% 1.384 Test Solutions B 0.10% 25.0% 25.0% 49.9% 1.092 Test Solutions C 0.10% 50.25% 24.75% 24.9% 1.388

Testing Procedure: product concentrate is Take 25 valves & placed on containers, Filled with specific test solution Actuator with 0.020 inch orifice is attached. Valve is actuated to fullest extent for 2 sec. Repeat this for total 2 individual delivery from each 25 test units.
Individual delivery wt in mg. Valve delivery per actuation in L = Specific gravity of test soln

added to the container and valve place in a

Valve Acceptance: Deliveries 54L or less 55 to 200 L Limits 15% 10%

control

for

pharmaceutical For 50 delivery: If 4 or more are outside limits: valves are rejected If 3 delivery are outside limits: another 25 valves are tested : lot is rejected if more than 1 delivery outside specification If 2 delivery from 1 valve are beyond limits : another 25 valves are tested : lot is rejected if more than 1 delivery outside specification 3. Containers:
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Identification Purity

Gas Chromatography Moisture, Halogen, Non-Volatile Residue Determination

2. Valves, Actuator, Dip-tubes Sampling is done according to standard procedure as found in Military Standards MIL-STD-105D. For metered dose aerosols test methods was developed by: Aerosol Specification Committee

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol Containers are examined for defects in lining. Q.C aspects includes degree of conductivity of electric current as measure of exposed metals. Glass containers examined for Flaws. 4. Weight Checking: Weight checking is done by periodically adding tared empty aerosol container to filling lines which after filling with concentrate are removed & weighed. Same procedure is used for checking weight of Propellants. 5. Leak Test: Leak test is done by measuring the Crimps dimension & comparing. Final testing of valve closure is done by passing filled containers through water bath. 6. Spray Testing It is done for , To clear dip tube of pure propellant & concentrate and To check for defects in valves & spray pattern. Evaluation parameters of pharmaceutical aerosols: Flame Projection: This test indicates the effect of an aerosol formulation on the extension of an open flame. Product is sprayed for 4 sec. into flame. Depending on the nature of formulation, the fame is extended, and exact length was measured with ruler. Flash point: Determined by using standard Tag Open Cap Apparatus. In which Aerosol product is chilled to temperature of - 25
0

This method is use for non aerosol, modification to accommodate liquefied gas preparation. In which A pressure tube is fitted with metal fingers and hoke valve, which allow for the introduction of liquids under pressure.The hydrometer is placed in to the glass pressure tube. Sufficient sample is introduced through the valve to cause the hydrometer to rise half way up the length of the tube. The density can be read directly. Moisture content: Karl Fischer method or Gas chromatography method has also been used Identification of propellants: Gas chromatography or I.R spectrophotometry methods are used for identification of propellants. Aerosol valve discharge rate: It is determined by taking an aerosol known weight and discharging the contents for given time using standard apparatus. By reweighing the container after time limit has expired, the change in weight per time dispensed is discharge rate.it is expressed as gram per seconds. Dosage with metered valves: Reproducibility of dosage each time the valve is dispersed. Amount of medication actually received by the patient. Reproducibility has been determined by assay technique. Another method is that, involves accurate weighing of filled container fallowed by dispersing of several doses, container can reweighed, and difference in weight divided by No. of dose, gives the average dosage. Net contents: Weight method. Filled full container, and dispensing the contents. Foam stability: Visual evaluation. Time for a given mass to penetrate the foam. Times for given rod that is inserted into the foam to fall. The use of rotational viscometers. Particle size determination: Cascade impactor : Operates on the projected through a series of nozzle and glass slides at high velocity, the large particles become impacted first on the lower velocity stages, and the smaller particles pass on and are collected at high

F and transferred to the test

apparatus. Temperature of test liquid increased slowly, and the temperature at which the vapors ignite is taken a flash point. It is calculated for flammable component, which in case of topical hydrocarbons. Vapor pressure : Determined by pressure gauge. Variation in pressure indicates the presence of air in headspace. A can punctuating Density: It is Determined by hydrometer or a pycnometer.
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device

is

available

for

accurately

measuring vapor pressure.

velocity stages. These practical ranging from 0.1 to 30

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol micron and retaining on RTI. Modification made to improve efficacy. Light scattering decay: Porush, Thiel and Young used light scattering method to determine particle size. As aerosols settle in turbulent condition , the change in light intensity of Tyndall beam is measured. Therapeutic Activity: For Inhalation Aerosols size. For Topical Aerosols Toxicity : For Inhalation Aerosols For Topical Aerosols are determined. Extractable Substances: Since pressurized inhalers and aerosols are normally formulated with organic solvents as the propellant or the vehicle, leaching and of extractables components from into the the elastomeric plastic : exposing test animals to : Irritation & Chilling effects vapor sprayed from Aerosol container. : is applied to test areas & adsorption of therapeutic ingredient is determined. : is depends on the particle Specifications and limits for individual and total extractables from different valve components may require the use of different analytical methods. Labeling: Medicinal aerosols should contain at least the following warning information on the label as in accordance with appropriate regulations. Warning Avoid inhaling. Avoid spraying into eyes or onto other mucous membranes. NOTEThe by inhalation. is statement Avoid inhaling is not The not phrase or other for mucous necessary for preparations specifically designed for use membranes necessary preparations

specifically designed for use on mucous membranes. Warning Contents under pressure. Do not puncture or incinerate container. Do not expose to heat or store at temperatures above 120 F (49 C). Keep out of reach of children. In addition to the aforementioned warnings, the label of a drug packaged in an aerosol container in which the propellant consists in whole or in part of a halocarbon or hydrocarbon shall, where required under regulations of the FDA, bear either of the following warnings: Warning Do not inhale directly; deliberate inhalation of contents can cause death. Warning Use only as directed; intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal. CONCLUSION: Drug delivery to the respiratory tract has been characterized in the past decade by an increase in knowledge of drug droplets or particle manufacture, behavior aerosol dispersion, lung deposition and clearance. Pulmonary drug delivery is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various diseases. Inhalation gives the most direct access to drug target. In the treatment of obstructive respiratory diseases, pulmonary delivery can minimize systemic side effects, provide rapid response and minimize the required dose since the drug is delivered directly to the conducting zone of the

formulation is a potentially serious problem. Thus, the composition and the quality of materials used in the manufacture of the valve components (e.g., stem, gaskets, housing, etc.) must be carefully selected and controlled. Their compatibility with formulation components should be well established so as to prevent distortion of the valve components and to minimize changes in the medication delivery, leak rate, and impurity profile of the drug product over time. The extractables profiles of a representative sample of each of the elastomeric and plastic components of the valve should be established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Extractable, which may include poly nuclear aromatics, nitrosamines, vulcanization accelerators, antioxidants, plasticizers, monomers, etc., should be identified and minimized wherever possible.

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Pokar Hitesh. G et al: Review on: Pharmaceutical Aerosol lungs .It is a needle free several techniques have been developed in the recent past, to improve the Quality of pulmonary drug delivery system without affecting their integrity. Because of advancement in applications of pulmonary drug delivery it is useful for multiple diseases. So pulmonary drug delivery is best route of administration as compare to other routes. References:
1) The theory and practice of Industrial Pharmacy by Leon Varghese page no 589 to 613 2) http://books.google.co.in/booksid=agEAAAAAMBAJ &pg=PA54&lpg=PA54&dq=aquasol+valve+from+pop ular+science&source=bl&ots=hkK_5ID__W&sig=jR HVore63lW2vhl_278ggOtPlc&hl=en&ei=AqITdnDJomHrAf 7uJnHDg&sa=X&oi=book_result&ct=result&resnum =1&ved=0CBYQ6AEwAA#v 3. 3) 4) 5) 6) 7) 8) 9) =onepage&q&f=false( accessed on march 20 th 9:53pm) The Theory & Practice Of Industrial Pharmacy by Leon Lachman, H.A.Liberman, Joseph Kanig, 3rd Edition, Varghese Pub, page no. 613-618. Remingtons The Science & Practice Of Pharmacy 3rd Edition, Volume-I, page no.1014-1015. Pceutical dosage form: Disperse system. Vol-3, pg 495-498 Pceutics : The science of Dosage Form Design, by M.E.Aulton 2nd edition pg 473-488. I.P 96, Vol-1, pg 24. USP, Vol-II, pg 1895. Specialized drug delivery systems manufacturing & production technology, by Praveen Tyle., 10) Marcel dekker, Inc., N.Y. & Basel, pg 452-471. 11) 12) 13) 14) 15) 16) 17) pharmaceutics- dosag for and design by david jones, page no: 198-199. www.kpaerofill.com/pages/sales/enquire.html www.kitz.co.jp/mfen/products/unipore.html http://www.cchs.net/health/health-info/doc www.shieldmedicare.com www.optinose.com www.medicombang-olufsen.com Lachman, Herbert Publishing A. Liberman, House, Joseph L. Kaing, and Joseph L. Kaing, Third edition,

18) www.chiesigroup.com

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