Troubles ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS .


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2. Foundation. Metered Dose Inhalers (MDIs)Pressurized framework Contains melted gas (propellant)Propellant suspends drug substance Provides energySurfactant - balance out suspension formulationCo-solvents - detailing aidDispense micrograms to milligrams API per actuationSmall exact volume conveyed (25 - 100 mL) .
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Drug store Compounding Advisory Committee July 13-14, 2000 DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS Brian Rogers, Ph.D. Office of New Drug Chemistry Center for Drug Evaluation and Research Food and Drug Administration Rockville, Maryland

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Background Metered Dose Inhalers (MDIs) Pressurized framework Contains condensed gas (charge) Propellant suspends sedate substance Provides vitality Surfactant - balance out suspension detailing Co-solvents - plan help Dispense micrograms to milligrams API per activation Small exact volume conveyed (25 - 100 m L)

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Background Metered Dose Inhalers (MDIs) Sequence of occasions: Formulation removed from valve Liquefied gas vaporizes Propelling and scattering drug substance Dispersed medication substance portrayal Particle measure appropriation (PSD) Dose content circulation (dosage content consistency)

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Background Dry Powder Inhalers (DPIs) Contains micronized tranquilize substance with or without transporter Lactose - most basic bearer Energy provided by: Patient motivation Compressed gas Motor-driven impeller Current outlines Pre-metered Device-metered

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Background DPI Current Designs INHALATION POWDERS (DPIs) Patient-Driven or Power-Assisted DEVICE-METERED DOSE PRE-METERED DOSE DIRECT TRANSFER SINGLE DOSE MULTIPLE DOSE

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Background Dry Powder Inhalers (DPIs) Further associations - sedate substance, bearers, and segments of the compartment/conclusion framework. Gravitational Fluid element Electrostatic Van der Waals Capillary powers Responsible for contrasts in fluidization practices

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Background General Concepts for MDIs and DPIs Aerodynamic molecule estimate - Affects affidavit Smaller particles - more prominent aviation route entrance Patients require fine particles (< 5  m) Effective molecule sizes - limit run Larger particles Systemic presentation just No clinical advantage Classical BE and BA are typically not pertinent Dose too little for blood examination BE studies obstructed 85 - 90% of dosage consumed through GI tract

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Difficulties in Compounding Drug Delivery System Dosing and execution Design Reproducibility Performance attributes Affects wellbeing and viability Formulation similarity Metering valve Canister lining - consumption of fundamental metal Drug retention into plastic segments Swelling Leaching

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MDI COMPONENTS - Canister and Actuators

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MDI COMPONENTS - Metering Valve

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Difficulties in Compounding Drug Delivery System Actuator work Generates vaporized particles Directs tuft Influences speed Controls pharmaceutical conveyed Controls molecule measure dissemination Valve work Measure detailing Provide watertight seal

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DISKUS DPI CROSS-SECTION

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Difficulties in Compounding Drug Delivery System Sophisticated and complex Crucial to sedate dosing precision and reproducibility Direct impact on strength, virtue, and quality Indirectly influences security and adequacy

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Difficulties in Compounding Drug Formulation and Consistency Mixture of micronized or solubilized tranquilize substance in lattice of sleek excipient material, fuel, and conceivably a co-dissolvable Composition and physical synthetic properties of every segment is pivotal to execution. Creation has coordinate impact on degree of agglomeration and suspension soundness

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Difficulties in Compounding Drug Formulation and Consistency Important medication substance properties: molecule estimate dispersion molecule morphology solvates and hydrates clathrates morphic shapes indistinct character dissolvability profile dampness as well as remaining dissolvable substance microbial quality pH profile (pKa) particular pivot All of the above properties must be controlled amid generation

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Difficulties in Compounding Drug Formulation and Consistency Important parts of detailing fluid stage: Propellant, co-dissolvable, surfactant personality, fixation, and quality Relative extents of unpredictable segments impact weight Polarity, surface strain, and thickness are basic properties

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Difficulties in Compounding Drug Formulation and Consistency Factors unfavorably influencing definition physical steadiness: Preferential cooperation of suspended medication substance with holder segments Settling and creaming coming about because of differential densities Less homogeneous suspension - conflicting measurement conveyance and molecule measure dissemination Beginning-to end-of-canister fluctuation Canister-to-canister inconstancy Batch-to-group changeability Properties of fluid stage should be enhanced to limit the above impacts

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Difficulties in Compounding Drug Formulation and Consistency Formulation segments Require extremely watchful control of contaminations and debasement items Minor change in focus or dosage - substantial change in toxicological properties Montreal Protocol - CFC Propellants Formulation of MDIs and DPIs Complex arrangement and high general many-sided quality Require devoted assembling environment Product-to-item consistency Critical for dosing exactness Difficult to accomplish Necessary for keeping up security and viability

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Difficulties in Compounding Complexity of Compounding Multiple, muddled and interrelated strides Significant potential for blunder Formulation Container and conclusion framework plan and execution attributes Internal temperature control Monitor and control outside ecological conditions Manufacturing parameters Assay of gather Pressure filling In-line warming Aging

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Difficulties in Compounding Complexity of Compounding Errors - high potential to antagonistically influence wellbeing and additionally adequacy Careful control basic for: Dosing reproducibility Performance Stability Bioavailability

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Difficulties in Compounding Facilities and Equipment Complex definition and compartment and conclusion framework Stringent natural controls required Air cleanliness Humidity Temperature High temperatures or moistness Disruptive to molecule measure circulation Resulted in reviews of business items Sophisticated hardware required Crimper Pressure filler Propellant pump Precise item filler

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Difficulties in Compounding Training required for generation and quality confirmation Special plan prerequisites Critical traits of compartment and conclusion framework Lack of appropriate preparing in figuring necessities may influence all parts of item execution Inadequate preparing in quality affirmation will counteract convenient discovery of detailing mistakes.

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Difficulties in Compounding Testing Examples of complex tests important to guarantee item quality: Particle measure dissemination Moisture content Leak rate Leachables Microbial cutoff points

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Difficulties in Compounding Testing Particle estimate circulation - Cascade impactor More basic for MDIs and DPIs Not exclusively dictated by introductory medication substance particles Change in PSD Decrease in adequacy Increase in systemic presentation Critical autonomous factors - complex Formulation Valve Mouthpiece Inability to meet molecule estimate appropriation details has brought about item reviews

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Difficulties in Compounding Testing Moisture Content Most basic for MDI suspension definitions and for DPIs Strict limits expected to counteract changes Particle estimate dispersion Morphic frame Crystal development and accumulation Leak Rate Affects inner canister weight Influences execution of actuator and valve Delivery of the best possible dosage to the patient Leakage may impact plan creation Change molecule estimate conveyance or potentially dosage content consistency Failure to meet determinations have brought about item reviews

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Difficulties in Compounding Testing Leachables Compounds removed into plan from Elastomers Plastic segments Requires ID and quantitation Concentration profile set up Make clear undisclosed changes

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Difficulties in Compounding Testing Microbial Limits Total oxygen consuming tally Total yeast and shape check Freedom from pathogens Additional testing is essential for item advancement Ensure plan does not bolster microbial development Microbial quality is kept up all through the lapse dating period

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Conclusion Because of the above intricate and fundamental criteria for aggravating, MDI and DPI tranquilize items show self evident challenges in this attempt These troubles would likely adversy affect the wellbeing and viability of such medication items.

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Conclusion Difficulties in intensifying outcome from the accompanying attributes and necessities: Sophisticated medication conveyance frameworks Require broad improvement Dosing precision (dosage consistency and molecule estimate dispersion) Reproducibility of conveyed measurement Product-to-item consistency basic - hard to accomplish Reproducible bioavailability - hard to accomplish Sophisticated plan required Compounding of MDI and DPI items - complex Sophisticated offices and gear required specialized preparing basic Difficult to perform testing required

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