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Pulmonary drug delivery system Currently, over 20 drug substances are marketed as inhalation aerosol product for local pulmonary effect and about the same number of drugs are in different stage of clinical development pulmonary drug delivery systems: 1: Disease of respiratory tract for asthma, 2: For systemic delivery via the drug Unique advantages of pulmonary rout high permeability large absorptive surface area of lungs(approximately 70-140 m2 in adult humans having extremely thin absorptive mucosal membrane) good blood supply low enzymatic activity rapid absorption of drug capacity for overcoming first-pass metabolism Advantages of pulmonary delivery Advantages of pulmonary rout for systemic delivery Improved efficiency Reduced unwanted systemic side effect Large surface area for absorption Tine alveolar epithelium permitting rapid absorption Absence of first pass metabolism Rapid onset of action Human airways 1: conduction region: The drug transport is limited due to smaller surface area and lower regional blood flow. this region removes up to 90% of delivered drug particles 2: respiratory region for more than 95% of the lung’s surface area directly connected to the systemic circulation via the pulmonary circulation Bronchial circulation Only alveolar region and respiratory bronchioles are supplied by the pulmonary circulation Blood flow to the larger airways is via the systemic circulation (0.1 % cardiac output)(bronchial circulation) limitations of pulmonary rout for systemic delivery 1: oropharyngeal deposition gives local side effect 2: Patients may have difficulty using pulmonary drug delivery device correctly 3: Inefficiencies of available inhalation devices that deposit only 1015% of the emitted dose in the lung 4: Drug absorption may be limited by the physical barrier of the mucus layer 5: Various factors affect the reproducibility on drug delivery on the lung, including physiological and pharmaceutical barrier Lung deposition of particles Deposition of drug/aerosol in the airways depends on four factors: 1: The physic-chemical properties of drug 2: The formulation 3:The delivery device 4: Physiological factor(breathing pattern and clinical status) Definition of aerodynamic diameter and fine particle fraction The particle size of aerosol is usually standardized by calculation of its “aerodynamic diameter” to deliver particle to different are of lung it depends on size, shape, and density of the particulate system Da= Dp √ρ Fine particle fraction (FPF) The fraction of particles of particles that can achieve deposition in the lower respiratory tract Particles between 0.1-1 µm remain suspended, these particles tend to be exhaled rather than deposited maximum deposition is obtained in the pulmonary region for particles approximately 3µm in size Lung deposition occurs mainly by 3 mechanisms 1 1: Inertial impaction Particles >5µm and particularly > 10 µm are deposited by this mechanism 2: Gravitational sedimentation 2 Particles 1-5 µm are deposited by this mechanism U= ρgd2/18ŋ 3 3: Brownian motion Smaller than 0.5 µm Dp=CKT/3πdŋ >5 µ 1-5 µ ≤1 µ Alton pharmaceutics Pulmonary drug delivery Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications 2003 Blackwell Publishing Ltd Br J Clin Pharmacol, 56 588–599 Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications Br J Clin Pharmacol 56 600–612 Physiological factors affect deposition in the air way 1: Respiratory flow rate (RFR) Low flow rate reduce impaction in larger airways 2: Tidal volume Volume of air inhaled in one breath 3: Breath holding Prolonged breath hold allow greater time for sedimentation and diffusion to occur in the peripheral airway Increasing the time between the end of inspiration and the start of exhalation increases the time for sedimentation to occur 4: Disease statute Bronchial obstruction result in localized deposition in larger airway Health care providers should ensure that their patients can and will use these device correctly Lung clearance mechanism Once deposited in the lung, inhaled drugs are either: 1: cleared from the lungs, 2: absorbed into systemic circulation 3: degraded via drug metabolism Lung clearance mechanism mucociliary clearance Drugs deposited in the conducting airways Drugs deposited in the alveolar region absorption into the bronchial circulation absorbed into the pulmonary circulation phagocytosed by alveolar macrophages All metabolizing enzymes found in the liver are found to a lesser extent in the lung Lung clearance mechanism Challenges in pulmonary drug delivery Low efficiency of inhalation system Less drug mass per puff Poor formulation stability for drug Improper dosing reproducibility Lung clearance Formulating and delivering therapeutic inhalation aerosols It is the optimization of the whole system including drug formulation, and device for successful development of inhalation therapies There are currently four main types of aerosol generating 1: conventional pressurized aerosols 2: pressurized metered-dose inhalers (MDI) 3: dry powder inhalers (DPI) 4: nebulizers. conventional pressurized aerosols Space sprays Surface spray Aerated spray Inhalation aerosols drug is either dissolved or suspended in liquid propellant(s) together with other excipients, including surfactants, and presented in a pressurized container محاسن آیروسل ها مقدار مورد نیاز دارو برای هربار مصرف به راحتی می تواند از ظروف برداشته شود بدون اینکه باقیمانده آلوده شود فراورده از اکسیژن هواونور محفوظ بوده وهمین طور استریل بودن فراورده باقی نگه داشته می شود استعمال یکنواخت دارو روی موضع بدون تماس با سطح پوست هیچ گونه تحریک زایی مکانیکی وجود نخواهد داشت تبخیر سریع پروپالنت یک احساس مطلوب خنک وتازه ای پروپالنت عبارت است از یک یا مخلوط چند گاز مایع شدنی یا مایع نشدنی کمپرس پذیر پروپالنت دونقش دارد: منبع ایجاد فشار درسیستم نقش حالل انواع پروپالنت ها: گازهای مایع شدنی کلرو فلوروکربن ها گازهای کمپرس شده ای که به حالت مایع درنمی اید کربن دی اکساید نیتروژن ونیتروس اکساید chlorofluorocarbons HFA-134 and HFA-227 are nonozone depleting, non-Flammable HFAs, which are now used as alternatives to CFC-12 انواع سیستم های آیروسل ها سیستم ها ی دوفازی سیستم های سه فازی درتهیه آیروسل ها ممکن است مخلوطی ازگازهای مایع شدنی استفاده گردد: رسیدن به یک فشاربخار مطلوب تهیه یک حالل مناسب برای انحالل دارو فشارنسبی درفرموالسیون آیروسل ها فشار را می توان با نوع ومقدار پروپالنت تنظیم نمود فشاربخار مخلوطی از پروپالنت ها توسط قانون رایولت بیان می شود P = p a + pb Pa= Xa P○a فشار بخار مخلوط 60به 40پروپان وایزوبوتان چقدر است 10.23 0.69+0.69/1.36 )0.69+1.36(/1.36 1/36=60/44.1 = *72.98=110 0.69=40/58 *30.40 Metered dose inhalers این سیستم ها دوز مورد نظر را اندازه گیری و تنظیم می نماید مقداری از فراورده که الزم است به بیرون رانده شود به وسیله یک محفظه که حجم آن مشخص است تنظیم می شود حجم این محفظه می تواند بین 25تا 150 میکرولیترباشد این نوع سیستم ها به دودسته تقسیم می شوند نوع ایستاده نوع معکوس Advantages of MDI Low cost Many doses (up to 200) are stored in small canister Dose delivery is reproducible Protect drugs from oxidative degradation and microbiological contamination disadvantages of MDI high velocity (30 m/s) They are inefficient at drug delivery Propellants may not evaporate sufficiently (5 s after actuation) Cold-freon effect disadvantages of MDI failure to remove the protective cap covering the mouthpiece failure to inhale slowly and deeply inadequate breath-holding following inhalation poor inhalation/actuation synchronization Correct use by patients is vital for effective drug deposition and therapeutic action. pMDI should be actuated during the course of a slow, deep inhalation, followed by a period of breath-holding. Advantages of spacer no co-ordination requirement No cold-Freon effect Reduced oropharyngeal deposition Increased lung drug deposition in the Novel technology in MDI Breath-actuated MDI increase lung drug deposition from 7.2% to 20.8% Do not help stop inhaling at the moment of actuation (cold-freon) The oropharyngeal dose remains the same as for the MDI device Autohaler AUTOHALER syncroner عملیات پرکردن آیروسل ها :1پرکردن تحت سرما سیستم های آبی را به این روش نمی توان به ظرف آیروسل منتقل کرد :پرکردن تحت فشار پروپالنت کمتری درپروسه پرکردن به هدر می رود خطر آلودگی بارطوبت وجود ندارد Dry powder inhalers (DPI) ADVANTAGES: Elimination the co-ordination difficulties associated with MDI Elimination CFC-containing MDIs DPI can also deliver larger drug doses than MDIs DPI are very portable Patient friendly Easy to use and do not require spacers Dry powder inhalers DISADVANTAGES Deagregation of particles and aerolization depend on the patient ability to inhale Increase inhaled air velocity increases the deagregation of particle, but increase inertial impaction DPI are less efficient at drug delivery than MDI the effectiveness of DPI depends on : 1: The properties of the powder formulation Reducing Da agglomeration Reduce particle density Increasing particle shape factor reduce Dg increase particle cohesive force reduce aerolization greater introduce porosity using needle shape particle 2: The design of device 3: patient respiratory air flow Increasing the IFR from 35 l/min to 60 l/min thrugh Turbuhaler increased the total lung dose of terbutaline from 14.8 to 27.7 DPI formulations For topical respiratory drug For systemic delivery PZ: less than 3 micron that adhere to larger carrier particles such as lactose or as drug only agglomerate The purpose of adding carriers: PZ:2-5 micron 1: To reduce strongly cohesive agglomerate 2: Increase the flow ability of powder prior to aerolisation Performance of existing DPI There are three main types of DPI systems: 1; The single unite dose inhaler 2: Multi unite device deliver individual doses from pre-metered replaceable blisters 3: Multiple dose reservoir inhaler The single unite dose inhaler Spinhaler Rotaheler Handihaler Rotacap Revolizer Needs a sequence steps that may not be easy for children and elderly people The capsule may not always protect the formulation against atmosphere humidity Spinhaler and rotahaler very low resistance while rotacape needs high flow rate Multi unite device deliver individual doses from pre-metered blisters Diskus inhaler containing 60 doses It is not refillable and the mouthpiece is not userfriendly The production cost is high Diskus (accuhaler) low to moderate resistance multi unite dose device Multiple dose reservoir inhaler Turbuhaler is the highest resistance device (60 l/min) Easyhaler Clickhaler Less independent of flow rate compared to that of turbuhaler active device Active device with an inspiration actuated integrated energy source such as compressed gas motor driven impeller or electronic vibration are under investigation Respiratory force independent useful for aged people Exubera insulin delivery used compressed air Aspirair (not yet approved) employs an air flow sensor triggered compressed air energy and a vortex chamber Recent innovation in DPIs There are two generation approaches to improve the effectiveness of DPI 1: develop better device Better powder NEXT a multi unit device accurate dose metering and protection the drug from environment easy to use and cost effective Twincer moisture sensitive high powder dose Microdse a breath actuated and piezo-electronic device Characteristics of an ideal DPI device Simple to use, convenient to carry, contains multiple dose, protect the drug from moisture and has indicator of doses remaining Dose delivery which is accurate and uniform over a wide range of IFR Optimal particle size of drug for deep lung delivery Minimum adhesion between drug formulation and device Product stability Cost-effectiveness Presently, over 20 DPI devices are available in market and more than 25 are in development nebulizers There are two basic types of nebulizers: Jet nebulizerss Compressed gas (air or oxygen) passed through a narrow orifice creating an area of low pressure Ultrasonic nebulizers Uses piezoelecteric crystal vibrating at high frequency (13 MHz) Provide large dose with very little patient co-ordination Time consuming and inefficient with large amount of drug wastage(50% loss with continuously operated nebulizer) Only 10% of the dose actually deposited in the lung Viscosity, ionic strength, osmolarity, ph, and surface tension may prevent the nebulization Inhaled drug formulation Drug formulation plays an important rule for efficient inhalation medication 1: to have a drug that is pharmacologically active 2: efficiently deliver to the lung 3: remain in the lung until the desired pharmacological effect occurs Principle of dry powder inhaler design Dry powder inhaler formulations The effective dispersion of drug particles depends on: 1: Cystalinity and polymorphism 2: Morphology 3: Surface area 4: Moisture content and hygroscopicity 5: Particle size and size distribution 6: Density 7: Adhesion/cohesion force Crystalinity and polymorphism Most drugs are crystalline On third of all drugs are known to display polymorphism With different properties such as stability, solubility It is possible to generate noncrystaline solid Amorphous materials have higher Gibbs free energy Crystaline particles are typically nonsphercal, low energy surface, and stable, but they have high particle density and tend to pack more tightly Moisture content and hygroscopicity Hygroscopic drugs present a greater risk of physical and chemical instability Hygroscopic growth can be prevented by coating the drug particles with hydrophobic film However, no such approach has been successfully implanted in market Aerodynamic diameterand dynamic shap factor X: the ratio of the actual resistance force experinced by the non spherical falling particle to the resistance force experience by a shere having the same volume Fine particle fraction: percantage of An ideal respiratory dry powder formulation should: An ideal respiratory dry powder formulation should have: 1: Narrow aerodynamic particle size range 2: Low surface energy 3: Non-spherical morphology 4: Low density or high porosity 5: High physical and chemical stability Carrier particles Lactose is commonly used The crystallinity of lactose carrier plays an important role in the aerosol performance of DPI formulation Amorphous lactose carrier exhibit strong adhesive interaction with drug molecules low inhalation efficiency Conventional α-lactose monohydrate ≥ spray-dried amorphous lactose Another problem of amorphous carrier humidity Reduce the amorphous content or increasing the crystalinity of the lactose recrystalization and higher relative Carrier particles Surface roughness of lactose is also important Various techniques have been applied to smooth carrier particle surface 1: Dry coating with hydrophobic lubricant magnesium stearate 2: Wet coating with hydrophilic polymers sucrose tristearate, HPMC 3: Surface dissolution with organic solvent 70% ethanol Safety issue? Carrier particles The presence of a small amount of adhered fines (5 µm) on coarse lactose is critical for facilating particle deagregation in air turbulence generated by inhalation This can be accomplished by fluidized bed coating of micronized lactose particles with dissolved lactose in spray solution One drawback: lactos is reducing suger which make it incompatible with drugs that have primary amine group formetrol, peptids, proteins Manitol has emerged as a promising carrier Higher respirable fraction with budesonide compared with lactose Carrier particles One drawback: lactose is reducing sugar which make it incompatible with drugs that have primary amine group formetrol, peptides, proteins Manitol has emerged as a promising carrier Higher respirable fraction with budesonide compared with lactose Different techniques to produce inhalable particles 1: milling techniques 2: Spray drying technique 3: Spray freeze drying method 4: Supercritical fluid technology 5: Solvent precipitation method Milling techniques Fluid-energy mill The most useful milling technique High velocity particle-particle collisions Depends on the nitrogen pressure and powder feed rate particle down to 1µm jet mill Pin mill High peripheral speed mill pin mill A pin mill uses mechanical impact to grind material both by particle-particle and particlesolid collisions The pin mill can produce 1 micron particle but not as small as jet mill The energy consumption is lower than jet mill Ball mill Particle shap is near spherical Milling can induce electrostatic charges and generating amorphous domains on particle surface Inceasing cohesive and adhesive force The materials are also prone to chemical decomposition and water sorption In summary, although micronization is well developed for size reduction It is not sutable for fragil molecules and more complex structure such as hallow particle, nonspherical particle, composite, surface modified particles, coated and encapsulated particles Milling techniques reference Formulation strategy and use of excipients in pulmonary drug delivery, Int J pharmaceutics 2010 392 1-19 Spray drying Is a one step process that converts a liquid feed to a dry particulate Three operations of the spray drying include: atomization, drying and separation The feed can be: solution, a coarse fine suspension or a colloidal dispersion( emulsion, liposome, and nanoparticle) Open cycle: the drying gas (compressed air) is not recirculated and, is vented to the atmosphere Close cycle: the heated gas (nitrogen with less than 5% oxygen) is recirculated Spray drying Advantages This method is suitable for heat labile materials used for peptides and proteins Produced more spherical particle compared to milling with more homogeneous particle size distribution Particles from spray drying process are not always spherical and may have convoluted surface, asperities, hole, and voids. Advantages Ability to manipulate and control a variety of parameters: solvent composition, solute concentration, solution and gas feed rate, temperature and relative humidity droplet size Spray drying disadvantages Thermal stress, higher shear stress in nozzle, and peptide protein adsorption Polysorbate 20 has been used to reduce spray drying induced denaturation for human growth hormone Low yield value esp for particle below 2 micron (yeild 20-50%) Spray-dried particles from solutions are mostly amorphous, but to maintain the crystalline state suspension can be processed Large porous particles Pulmospheres® They have low particle densities, excellent dispensability Mass density 0.4 g/cm3 and geometric diameter > 20 µm They were prepared by solvent evaporation and spray drying techniques In two step process: 1: an oil in water emulsion by high-pressure homogenization using phosphatidylcoline as the surfactant and fluorocarbons serve as a blowing agent 2: spray drying of the emulsion Large porous particles Cromolyne pulmosphere have 68% compared with 24% Increase systemic bioavailability of Insulin and testosterone using this technology Large porous particles Advantages Large porous particles allow for escape from natural phagocyte clearance Reduces their tendency to aggregate and makes them more responsive to shear in an airflow path For potent, low-dose drugs these particles can be excellent delivery system Particle size, morphology and density can be controlled through the selection of the blowing agent type, and its concentration Spray-freeze drying (SFD) Spraying a solution containing the drug into vessel containing liquid nitrogen, oxygen, or argon Conducted at subambient temperature Has been used to formulate a significant number of thermolabile and highly potent proteins and peptides It is faced with the limitations of stresses associated with freezing and drying irreversible damage to the proteins This technique is time consuming (3 days), and safety issue and it is expensive Spray-freeze drying (SFD) SFD produced very fragile particle, which can not withstand production process of an adhesive mixture Adsorption of proteins at air-liquid interface during atomization is mainly responsible for loss of activity during spray drying and SFD 1: spray freezing into liquid 2: spray freezing with compressed co2 Supercritical fluids The particles produced via SCF are less charged compared with mechanical means They are more uniform in terms of crystalline, morphology and particle size Denaturating effects of the solvents/antisolvents used in this process is a drawback As conclusion Spray drying and supercritical fluid methods offer more flexibility and the possibility of control over morphology and size But produce amorphous materials and undesired polymorphism Milling remain the process of choice for micronizing because it is simple, more predictable, easier to scale up and less expensive List of accepted additives for DPI formulation lipids The surfactant present in the lung is composed of 90 % lipids and 10% proteins Saturated fatty acid dipalmitoylphosphatidylcholine (DPPC) 40% Unsaturated phosphatidyllcholines 35% Liposomes are the most extensively investigated systems for pulmonary delivery liposomes Cytotoxic agents, anti-asthma drugs, antimicrobial and antiviral agents Drugs for systemic action such as insulin and proteins Liposome are known to promote an increase in drug retention time and reduce cytotoxicity For amikacin The overall mean retention at 24h and 48h was 60% and 38%, respectively They are commonly delivered either in aqueous form via nebulization or in dry powder form total lung deposition 32% liposomes Liposome in the rang of 50-200 nm would avoid phagocytosis In future liposome playing a prominent role in pulmonary delivery for gen therapy, sustained release preparations and for targeting specific cell to treat intracellular infection and local tumor cells Francisella tularents reside and multiple in macrophages Liposome encapsulated ciprofloxacin survived 15 days post infection compared with100 mortality during 9 days Pulmonary delivery of liposomal formulation of antibiotic lipids Lipids coat the drug particles with hydrophobic film that protect the hygroscopic drug like tubramycine from humidity Only 5% lipid is sufficient to improve particle dispersion properties FPF 36% to 68% of effective lipid-coated formulation Lipids in general are the excipient of choice because they are mostly endogenous to the lung and can be easily methabolized or cleared List of accepted additives for DPI formulation Amino acids Recently amino acids have been shown to decrease hygroscopisity and improve surface activity and charge density of particles Glycine, alanine, leucine, isoleucine Addition of amino acids to inhalation formulation using spray drying improve in-vitro deposition profiles Amino acids can also protect proteins against thermal stress and denaturation Have been used as cryoprotectant Amino acids Addition of Leucin yeild the best results in term of aerolization 10-20 %w/w of leucin in spray-dried solutions gave optimal aerolization of powder containing peptidies Addition of leucine results in less cohesive particle due to the surfactant behavior of leucine , decrease particle size Little is known about the local toxicity and systemic absorption List of accepted additives for DPI formulation surfactants Sorbitan, polysorbate, sorbitan esters have been widely used in formulation of nebulization and MDI Their use in DPI is not widespread due to their low melting point and their semisolid or liquid state Poloxamer or phosphatidylcholine to prepare hallow particle 2% poloxamers significantly improved powder flowability Absorption enhancer Cyclodexterins (CDs) improvement in aqueous solubility, systemic absorbtion and bioavailability in vitro study safe at 1 m M Hydroxypropylated B-CD and natrul ƔCD Protease inhibitors: nafamostate mesilate, bacitracin Bail salt increase transcellular transport Administration of sodium taurocholate with insulin increase bioavailability from 2.6 to 23 Absorption enhancer More than 10 mm sodium glycocholate is harmful Bile salt may be useful in small amount Citric acid has been increased insulin absorption Citric acid is considered a safe and effective absorption enhancer for pulmonary delivery Chitosan and trimethylchitosan absorption enhancers for proteins and peptides significant pulmonary inflammation Biodegradable polymers
