Drug Administration 13 rug solution Jet nebulizer <35 00 Transdermal delivery system (DS) Tme A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3) LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 13 A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3), and percutaneous (4) application With and without fracture ring Often with preservative Sterile, iso-osmolar Ampule 1 – 20 ml Cartridge ampule 2 ml Multiple-dose vial 50 – 100 ml, always with preservative Infusion solution 500 – 1000 ml Propellant gas Drug solution Jet nebulizer Suppository Vaginal tablet Backing layer Drug reservoir Adhesive coat Transdermal delivery system (TDS) Time 12 24 h Ointment TDS 4 Paste Ointment Powder 1 3 2 Drug release 35 ºC Melting point 35 ºC Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
14 Drug Administratio Drug Administration by Inhalation mucociliary transport functions to re- halation in the form of an aerosol ortion of the drug aerosol(-%) (p applied to the bronchial mucosa and, just a fraction of this amount penetrate 2), a gas, or a mist permits drugs to gains access to the respiratory tract and t, to the alve the muc branes. This route is chosen for drugs in- the aerosol undergoes mucociliary tended to affect bronchial smooth mus- transport to the laryngopharynx and is cle or the consistency of bronchial m swallowed. The advantage of inhalatie cus. Furthermore, gaseous or volati .e, 0is fully igen stered by inhala- ploited by using drugs that are poorly tion with the goal of alveolar absorption absorbed from the intestine(isoprotere. lyn) or are su aesthetics, p. 218). Aerosols formed when a drug solution or micron- lomethasone dipropionate, budesonide, ized powder is converted into a mist or flunisolide, flutica Even when the swallowed portion conventional sprays(e. g, ne lizer). the air blast required for aerosol form, administration by th as the advantage that drug con- p. Alternatively, the drug is delin ions at the bronchi will be higher than in other organs aged in a pressurized canister equipped The efficiency of mucociliary trans- dose is discharged. During use, the in- motion and the viscosit haler(spray dispenser) is held directly mucus. Both factors in front of the mouth and actuated at pathologically (e.g, in the start of inspiration. The effective. bronchitis)or can be adversely affected ness of delivery depends on the position by drugs(atropine, antihistamines of the device in front of the mouth, the size of aerosol particles, and the coordi- nation between opening of the spray alve and inspiration. The size of aeros particles determines the speed at which ence the depth of penetration into he respiratory tract. Particles opharyngeal cavity; those having dia- meters between 10 and 60um will be an reach the alveoli, but they rill be largely exhaled because of the ndency to impact rug deposited on the mucous lin- g of the bronchial epithelium is partly absorbed and partly transported with Bronchial mucus travels upwards due he epithelial cilia. Physiologically LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration by Inhalation Inhalation in the form of an aerosol (p. 12), a gas, or a mist permits drugs to be applied to the bronchial mucosa and, to a lesser extent, to the alveolar membranes. This route is chosen for drugs intended to affect bronchial smooth muscle or the consistency of bronchial mucus. Furthermore, gaseous or volatile agents can be administered by inhalation with the goal of alveolar absorption and systemic effects (e.g., inhalational anesthetics, p. 218). Aerosols are formed when a drug solution or micronized powder is converted into a mist or dust, respectively. In conventional sprays (e.g., nebulizer), the air blast required for aerosol formation is generated by the stroke of a pump. Alternatively, the drug is delivered from a solution or powder packaged in a pressurized canister equipped with a valve through which a metered dose is discharged. During use, the inhaler (spray dispenser) is held directly in front of the mouth and actuated at the start of inspiration. The effectiveness of delivery depends on the position of the device in front of the mouth, the size of aerosol particles, and the coordination between opening of the spray valve and inspiration. The size of aerosol particles determines the speed at which they are swept along by inhaled air, hence the depth of penetration into the respiratory tract. Particles > 100 µm in diameter are trapped in the oropharyngeal cavity; those having diameters between 10 and 60µm will be deposited on the epithelium of the bronchial tract. Particles < 2 µm in diameter can reach the alveoli, but they will be largely exhaled because of their low tendency to impact on the alveolar epithelium. Drug deposited on the mucous lining of the bronchial epithelium is partly absorbed and partly transported with bronchial mucus towards the larynx. Bronchial mucus travels upwards due to the orally directed undulatory beat of the epithelial cilia. Physiologically, this mucociliary transport functions to remove inspired dust particles. Thus, only a portion of the drug aerosol (~ 10 %) gains access to the respiratory tract and just a fraction of this amount penetrates the mucosa, whereas the remainder of the aerosol undergoes mucociliary transport to the laryngopharynx and is swallowed. The advantage of inhalation (i.e., localized application) is fully exploited by using drugs that are poorly absorbed from the intestine (isoproterenol, ipratropium, cromolyn) or are subject to first-pass elimination (p. 42; beclomethasone dipropionate, budesonide, flunisolide, fluticasone dipropionate). Even when the swallowed portion of an inhaled drug is absorbed in unchanged form, administration by this route has the advantage that drug concentrations at the bronchi will be higher than in other organs. The efficiency of mucociliary transport depends on the force of kinociliary motion and the viscosity of bronchial mucus. Both factors can be altered pathologically (e.g., in smoker’s cough, bronchitis) or can be adversely affected by drugs (atropine, antihistamines). 14 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Administration 15 as poss Low systemic burden LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 15 A. Application by inhalation Depth of penetration of inhaled aerosolized drug solution Nasopharynx Trachea-bronchi Bronchioli, alveoli Drug swept up is swallowed Mucociliary transport Ciliated epithelium Low systemic burden As complete presystemic elimination as possible As little enteral absorption as possible 100 µm 10 µm 1 µm 1 cm/min Larynx 10% 90% Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
16 Drug Administratio emulsion of an oil in water formed with Pharmaceutical preparations applied to the aid of an emulsifier; it may also be ter skin are intended either considered an oil-in-water emulsion of for drugs that are to be absorbed lipophilic base adhere to the skin as he skin or, if appropriate, into the water-repellent coating. They do no clude)outward passage of water from Skin Protection(A) the skin. The skin is protected from dry- Protective agents are of several kinds to ing, and its hydration and elasticity in- ifferent requirements according crease. to skin condition (dry, low in oil, Diminished evaporation of water happed vs moist, oily, elastic), and the ming of the occluded sk philic agents wash off easily posure to water, regular use of alcohol- ontaining disinfectants Ip. 290] Evaporation of water is fel Distinctions among protective agents are based upon consistency, phy- cochemical properties(lipophilic. drophilic), and the presence of addi-(D)must leave its pharmaceutical pr Dusting Powders are sprinkled on- fect is desired (e.g glucocorticoid oint to the intact skin and consist of talc, ment), or be able to penetrate it, if a magnesium stearate, silicon dioxide systemic action is intended (transder (silica), or starch. They adhere to the mal delivery system, e. g nitroglycerin kin, forming a low-friction film that atch, p. 120). The tendency for the d tenuates mechanical irritation Powders ave the drug vehicle(v) is higher exert a drying(evaporative)effect. the more the drug and vehicle differ Lipophilic ointment(oil lipophilicity(high cy: hydr consists of a lipophilic base(paraffin( ic D and lipophilic V, and vice versa) petroleum jelly, wool fat [lanolin)) and cause the skin represents a closed lipo- ay contain up to 10% powder materi- philic barrier (p. 22), only lipophil als, such as zinc oxide, titanium oxide, drugs are absorbed. Hydrophilic drugs arch, or a mixture of these Emulsify- fail even to penetrate the outer ski ng ointments are made of paraffins and when applied in a lipophilic vehicle. an emulsifying wax, and are miscible This formulation can be meaningful ith wate when high drug concentrations are Paste(oil paste) is an ointment quired at the skin surface(e.g,neomy- ore than 10% pulv tions) Lipophilic(oily )cream is an emul- sion of water in oil, easier to spread than oil paste or oil ointments. Hydrogel and water-soluble oint- ment achieve their consistency by means of different gel-forming agents glycol). Lotions are aq sions of water-insoluble and solid con- LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Dermatologic Agents Pharmaceutical preparations applied to the outer skin are intended either to provide skin care and protection from noxious influences (A), or to serve as a vehicle for drugs that are to be absorbed into the skin or, if appropriate, into the general circulation (B). Skin Protection (A) Protective agents are of several kinds to meet different requirements according to skin condition (dry, low in oil, chapped vs moist, oily, elastic), and the type of noxious stimuli (prolonged exposure to water, regular use of alcoholcontaining disinfectants [p. 290], intense solar irradiation). Distinctions among protective agents are based upon consistency, physicochemical properties (lipophilic, hydrophilic), and the presence of additives. Dusting Powders are sprinkled onto the intact skin and consist of talc, magnesium stearate, silicon dioxide (silica), or starch. They adhere to the skin, forming a low-friction film that attenuates mechanical irritation. Powders exert a drying (evaporative) effect. Lipophilic ointment (oil ointment) consists of a lipophilic base (paraffin oil, petroleum jelly, wool fat [lanolin]) and may contain up to 10 % powder materials, such as zinc oxide, titanium oxide, starch, or a mixture of these. Emulsifying ointments are made of paraffins and an emulsifying wax, and are miscible with water. Paste (oil paste) is an ointment containing more than 10 % pulverized constituents. Lipophilic (oily) cream is an emulsion of water in oil, easier to spread than oil paste or oil ointments. Hydrogel and water-soluble ointment achieve their consistency by means of different gel-forming agents (gelatin, methylcellulose, polyethylene glycol). Lotions are aqueous suspensions of water-insoluble and solid constituents. Hydrophilic (aqueous) cream is an emulsion of an oil in water formed with the aid of an emulsifier; it may also be considered an oil-in-water emulsion of an emulsifying ointment. All dermatologic agents having a lipophilic base adhere to the skin as a water-repellent coating. They do not wash off and they also prevent (occlude) outward passage of water from the skin. The skin is protected from drying, and its hydration and elasticity increase. Diminished evaporation of water results in warming of the occluded skin area. Hydrophilic agents wash off easily and do not impede transcutaneous output of water. Evaporation of water is felt as a cooling effect. Dermatologic Agents as Vehicles (B) In order to reach its site of action, a drug (D) must leave its pharmaceutical preparation and enter the skin, if a local effect is desired (e.g., glucocorticoid ointment), or be able to penetrate it, if a systemic action is intended (transdermal delivery system, e.g., nitroglycerin patch, p. 120). The tendency for the drug to leave the drug vehicle (V) is higher the more the drug and vehicle differ in lipophilicity (high tendency: hydrophilic D and lipophilic V, and vice versa). Because the skin represents a closed lipophilic barrier (p. 22), only lipophilic drugs are absorbed. Hydrophilic drugs fail even to penetrate the outer skin when applied in a lipophilic vehicle. This formulation can be meaningful when high drug concentrations are required at the skin surface (e.g., neomycin ointment for bacterial skin infections). 16 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Administration 17 solution tincture Oily paste KH Semi-solid F Hydrogel Cream Suspen- Emulsion Lipophilic Hydrophilic Gel wate Occlusive Permeable impossible possible 合 Dry, non-oily skin Oily, moist skin A Dermatologicals as skin protectants in hydrophilic ∴:∷∷ Subcutaneous fat tissue als as drug vehicles LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 17 Semi-solid Solid Liquid Dermatologicals B. Dermatologicals as drug vehicles Powder Paste Oily paste Ointment Lipophilic ointment Hydrophilic ointment Lipophilic cream Hydrophilic cream Cream Solution Aqueous solution Alcoholic tincture Hydrogel Suspension Emulsion Fat, oil Oil in water Water in oil Gel, water Occlusive Permeable, coolant impossible possible Dry, non-oily skin Oily, moist skin Lipophilic drug in hydrophilic base Lipophilic drug in lipophilic base Hydrophilic drug in lipophilic base Hydrophilic drug in hydrophilic base Stratum corneum Epithelium Subcutaneous fat tissue Lotion A. Dermatologicals as skin protectants Perspiration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license