Topical Agents PDF

Inorganic Pharmaceutical Chemistry: Topical Agents This chapter discusses the use of topical compounds, which are applied to body surfaces, in contrast to systemic compounds that are absorbed into the bloodstream. Topical drugs primarily act at the surface of application, but in some cases, they ma...

Inorganic Pharmaceutical Chemistry: Topical Agents This chapter discusses the use of topical compounds, which are applied to body surfaces, in contrast to systemic compounds that are absorbed into the bloodstream. Topical drugs primarily act at the surface of application, but in some cases, they may penetrate deeper tissues, leading to both beneficial and potentially harmful systemic effects, such as toxicity or allergic reactions. Some drugs, like antiseptics, can prevent deep infections by penetrating wound tissues, while others (e.g., mercury-based compounds) can be toxic if absorbed in large amounts. Topical compounds are categorized based on their action: (1) protective agents (2) antimicrobial and (3) astringent compounds. Protective Agents Protectives are substances which may be applied to the skin to protect certain areas from irritation, usually of mechanical origin. Those compounds or substances most appropriate for this purpose are insoluble and chemically inert. Insolubility is a desirable property in that this limits the absorption of the compounds through the skin, makes it difficult to wash them off, and diminishes metallic properties on tissue. Compounds which are chemically unreactive are necessary to prevent interactions between the protective substance and the tissue. In other words, ideal protectives are biologically inactive. Many protectives also act as adsorbents, efficiently absorbing moisture from the skin’s surface, which reduces mechanical friction and irritation. The effectiveness of these substances improves with smaller particle size, as finer particles offer a larger surface area for adhesion and better moisture absorption. These protectives are commonly used as powders, ointments, or suspensions, and may also help soothe irritated skin. 1 Inorganic Pharmaceutical Chemistry: Topical Agents 1- Talc (3MgO 4SiO₂ H₂O) Talc is a native, hydrous magnesium silicate, sometimes containing a small proportion of aluminum silicate. The U.S.P. describes it as a very fine, white or grayish white, crystalline powder. It is unctuous, adheres readily to the skin, and is free from grittiness. Talc is a layered silicate and is the softest mineral known. It has a smooth, greasy feeling to the touch, and in its lump form (steatite) it is known as soapstone. Talc is odorless, tasteless, and insoluble in water, dilute acids, and dilute bases. It has very low adsorptive properties. A hydrothermal method can be used to mimic the natural geological conditions under which talc forms. The reaction typically involves reacting magnesium oxide or a magnesium salt with silica in an aqueous solution at elevated temperatures and pressures. MgO + H₂O → Mg(OH)₂ 3Mg(OH)₂ + 4SiO₂ → Mg₃Si₄O₁₀(OH)₂ + H₂O Chemically, talc may consider to be a hydrated magnesium silicate having the elements illustrated by the formula represented above. The actual composition of talc is somewhat variable, containing from 28.1 to 31.2% MgO, 57 to 61.7% SiO ₂, and 3 to 7% H₂O. As a magnesium polysilicate, it is unreactive to acids and bases, and inert to most other reagents. Talc can be used as:  lubricating, protective dusting powder. It can be used to prevent irritation due to friction, and to protect areas from further irritation.  Talc is used in preparations which may be perfumed for cosmetic purposes, or medicated with antimicrobial agents, such as boric acid. 2 Inorganic Pharmaceutical Chemistry: Topical Agents 2- Zinc Oxide (ZnO; Mol. Wt. 81.37) Zinc Oxide is a very fine, odorless, amorphous, white or yellowish white powder, free from gritty particles. It gradually absorbs carbon dioxide from the air. When heated to 400° or 500°C, the oxide develops a yellow color that disappears on cooling. Zinc Oxide is insoluble in water and alcohol and will gradually absorb carbon dioxide from the air to form a basic zinc carbonate [Zn₂(OH)₂CO₃]. Chemically, zinc oxide reacts with dilute acids and aqueous solutions of ammonium compounds to form water-soluble products. When treated with dilute hydrochloric acid, the oxide forms the Lewis acid, zinc chloride. ZnO + 2HCl → ZnCl₂ + H₂O Zinc oxide can be used as:  Mild astringent and a weak antimicrobial compound. The antimicrobial- astringent action is due to the release of a small amount of zinc ion from hydrolysis in the acidic moisture on the skin  Astringent and topical protective in ointments in the treatment of skin ulcerations and other dermatological problems.  Zinc oxide is the primary ingredient in Calamine. 3- Calamine (ZnO Fe₂O₃) Calamine is zinc oxide with a small proportion of ferric oxide. The presence of the ferric oxide (Fe₂O₃) gives the substance a pink color. The material is a fine powder, odorless, and practically tasteless. It is insoluble in water, but almost completely soluble in mineral acids. 3 Inorganic Pharmaceutical Chemistry: Topical Agents The term calamine, besides being applied to the official product, is also used to describe the impure, naturally occurring zinc carbonate. The official Calamine is obtained by calcination (powdered by heating) of the natural ore. The calcined product is then passed through a 100-mesh sieve to obtain the finely powdered material necessary for good cohesive and adhesive (adhering to skin) properties.  Thermal Decomposition of Zinc Carbonate: ZnCO₃ → heat ZnO + CO₂  Calamine Formation: ZnO + Fe₂O₃ → ZnO⋅xFe₂O₃ (Calamine) Calamine is a topical protective. It is used in dusting powders, ointments, and lotions (Calamine Lotion, U.S.P.) where it is applied to the skin for its soothing, adsorbent, protective properties. Antimicrobial Agents These are the chemicals, and their preparations used for the prevention and/or reduction of infection caused by microorganisms. The terminology of antimicrobial agents include:  Antiseptic: A substance that kills or inhibits the growth of microorganisms, usually applied to living tissues (e.g., skin) to prevent infection.  Germicide: A substance that kills microorganisms outright. This term includes agents like bactericides (kills bacteria), fungicides (kills fungi), and amebicides (kills protozoa).  -stat (e.g., bacteriostat): Refers to agents that do not kill microorganisms but inhibit their growth. For example, a bacteriostat stops bacteria from multiplying. 4 Inorganic Pharmaceutical Chemistry: Topical Agents  Disinfectant: A chemical used to kill microorganisms on inanimate objects, such as instruments or surfaces, but not safe for use on living tissue.  Sterilization: A process (often using heat or chemicals) that completely removes or kills all microorganisms from an object, making it free of any life. The mechanisms of action of inorganic antimicrobial agents can be divided into three general categories: oxidation, halogenation, and protein precipitation. I- Oxidation: those compounds are generally nonmetals and certain types of anions. Most common among these are hydrogen peroxide, metal peroxides, permanganates, halogens (i.e., chlorine and iodine), and certain oxo-halogen anions. The effective oxidative action of these compounds involves the reducing groups present in most proteins, e.g., the sulfhydryl (-SH) group in cysteine. An illustration of the reaction between the oxidizing antiseptic and a sulfhydryl- containing protein is shown in Fig1. Based on the concept that the protein has a specific function in the microorganism, e.g., enzyme, the formation of the disulfide bridge (Fig1-B) will alter the conformation (shape) of the protein and thereby alter its function. II- Halogenation: This is a reaction occurring with antiseptics of the hypohalite type and hypochlorite, OCl⁻. It is expected that a similar reaction can take place 5 Inorganic Pharmaceutical Chemistry: Topical Agents under appropriate conditions with the peptide linkage between the amino acid groups comprising the protein molecule. This reaction is ultimately destructive to the function of specific proteins because the substitution of the chlorine atom for the hydrogen produces changes in the forces (hydrogen bonding) responsible for the proper conformation of the protein molecule. III- Protein Precipitation: This type of mechanism involves the interaction of proteins with metallic ions having large charge/radius ratios or strong electrostatic fields. This property is available in transition metal cations, e.g., Cu(II), Ag(I), and Zn(II). Aluminum(III), due to its charge and small ionic radius, is also an effective protein precipitant. The nature of the interaction is one of complexation in which the various polar groups on the protein act as ligands (see Fig2). The complexation of the metal results in a radical change in the properties of the protein or protein precipitant. The interaction of metal ions with protein is nonspecific, and at sufficient concentration will react with host as well as microbial protein. The presence of the metal "ties up" important functional groups at the active site on the enzyme. 6 Inorganic Pharmaceutical Chemistry: Topical Agents 1- Hydrogen Peroxide Solution (H₂O₂; Mol. Wt. 34.02) Hydrogen Peroxide Solution is a clear, colorless liquid which may be odorless or may have an odor resembling that of ozone. The solution will usually deteriorate upon standing or upon agitation, and rapidly decomposes when in contact with many oxidizing or reducing substances. It is unstable on prolonged exposure to light and may decompose suddenly when rapidly heated. Chemically, hydrogen peroxide may be stable in solutions of high purity; however, small amounts of contaminants, e.g., divalent and polyvalent ions of chromium, iron, copper, mercury, etc., will catalyze the decomposition of unstabilized solutions. Hydrogen peroxide solutions may be stabilized with acids, complexing agents, or adsorbents. Depending upon the chemical environment, hydrogen peroxide will react as either an oxidizing or reducing agent. The oxidation state of oxygen in the peroxide ion, (O-O)²⁻, is -1. When hydrogen peroxide functions as an oxidizing agent it forms two oxide ions, O²⁻, requiring two electrons, and resulting in a change of the oxidation state of the oxygen to -2. (O2) −2 ⟶ 2O −2 + 2e− 7 Inorganic Pharmaceutical Chemistry: Topical Agents This type of reaction is most efficient in acidic media to produce water H2O2 + 2H+ + 2e− ⟶ 2H2O The reducing actions of hydrogen peroxide result in the evolution of molecular oxygen. This involves the release of two electrons and a change from the peroxide ion to an oxidation state of zero. (O2)−2 ⟶ O2 + 2e− The primary use of Hydrogen Peroxide Solution is:  As a mild oxidizing antiseptic. This action is produced when the solution encounters open or abraded tissue, exposing the chemical to the enzyme, catalase. This enzyme catalyzes the decomposition of H₂O₂ to water and oxygen.  When diluted with one part of water, it can be used as a gargle or mouthwash in the treatment of bacterial infections of the throat and mouth.  Half-strength solutions may also be used as a vaginal douche. 2- Sodium hypochlorite Solution It is a clear, pale greenish-yellow liquid having an odor of chlorine. The solution is affected by light. Common household bleach is usually a 4.5 to 5.0% solution of sodium hypochlorite. The Diluted Sodium Hypochlorite Solution is prepared by diluting the original sodium hypochlorite solution with five times its volume of purified water. The pH is then adjusted to 8.3 or lower using a 5% sodium bicarbonate solution until no color change occurs with phenolphthalein. This adjusted solution is recognized as the only hypochlorite preparation approved for use as an antibacterial on tissues. 8 Inorganic Pharmaceutical Chemistry: Topical Agents The alkalinity and oxidizing action of this solution is too strong for use on tissues. In addition, the solution dissolves blood clots and delays healing. Solutions of sodium hypochlorite are strong oxidizing agents, as can be shown by the liberation of free iodine from solutions of potassium iodide. 2KI + NaClO + H2O ⟶ 2KOH + NaCl + I2 The antibacterial properties of sodium hypochlorite solutions are due in part to the liberation of chlorine and to the oxidizing action produced by the liberation of oxygen by forming hypochlorous acid when reacted with water. NaOCl + H2O ⟶ HOCl + NaOH In Diluted Sodium Hypochlorite Solution, the pH is reduced through the addition of sodium bicarbonate solution. This has the effect of reducing the caustic action of the highly alkaline solution on tissues and of increasing the effective concentration of hypochlorous acid. The bicarbonate acts to reduce the hydroxide ion concentration according to the reaction shown: HCO3− + OH− ⟷ CO32− + H2O The primary uses for hypochlorite solutions:  Sodium Hypochlorite Solution is useful as a disinfectant and laundry bleach.  Diluted Sodium Hypochlorite Solution, N.F. XIII, has been used in the past as an antiseptic on pus-forming (suppurating) wounds. It has the disadvantages of dissolving certain types of sutures, and of dissolving blood clots and prolonging clotting time.  The solution may also be used as a foot bath in the prevention of various fungal infections (athlete’s foot, etc.). 9 Inorganic Pharmaceutical Chemistry: Topical Agents  The antibacterial effectiveness may be increased by acidifying the solution at the time of use, thereby further increasing the concentration of HOCl. 3- Iodine Solution Both Iodine Solution and Iodine Tincture contain the same concentrations of ingredients, they differ only in the nature of the solvent, i.e., Iodine Solution is aqueous, having been prepared with purified water, and Iodine Tincture contains approximately 50% alcohol as the final solvent. Both solutions are transparent, have a reddish-brown color, and have the characteristic odor of iodine. Iodine Tincture also has the odor of alcohol. The active antimicrobial agent common to both preparations is iodine. The most notable chemical property of iodine in aqueous solution is that of a mild oxidizing agent. It is believed that the oxidizing action is mediated through the formation of hypoiodous acid [HIO]. I2 + H2O ⇌ HI + HIO ⟶ HI + (O) It will oxidize iron to form ferrous iodide. Fe + I2 ⟶ FeI2 For this reason, metal spatulas should not be used to handle iodine, and balance pans should be protected against pitting by using weighing papers. Iodine is a very active element and is, therefore, easily inactivated by organic materials in the gastrointestinal tract. Most of the toxicity due to the ingestion of large quantities of iodine is a result of the corrosive action of the element on the gastrointestinal tract, producing abdominal pain, gastroenteritis, and possibly bloody diarrhea. The treatment usually involves gastric lavage with a soluble starch solution or administration of a 5% sodium thiosulfate solution. The starch 10 Inorganic Pharmaceutical Chemistry: Topical Agents solution forms a complex with the iodine (purple color), thus aiding in its removal from the stomach. 2Na2S2O3 + I2 ⟶ Na2S4O6 + 2NaI The primary uses of iodine solutions:  Iodine Tincture and Iodine Solution are probably the most effective topical antiseptic agents available. There is some indication that Iodine Tincture may be more suitable for this purpose, since the alcohol seems to improve the penetration of the iodine.  Iodine Solution is preferred for application to wounds because the alcohol in the Tincture is very irritating to open tissue.  Iodine Tincture may be used to disinfect drinking water.  Povidone-Iodine is a member of a class of compounds referred to as Iodophors, these are complexes of iodine, with carrier organic molecules serving as a solubilizing agent. These complexes slowly liberate iodine in solution. The major advantage to their use is the lack of tissue irritation, which makes them useful for application to sensitive areas and mucous membranes. 4- Silver Nitrate (AgNO₃; Mol. Wt. 169.87) Silver Nitrate occurs as colorless or white crystals which become gray or grayish black on exposure to light in the presence of organic matter. It is very soluble in water, sparingly soluble in alcohol, and freely soluble in boiling alcohol. Solutions of silver nitrate in concentrations between 0.5 and 1.0% are used as antibacterial agents. The chemistry and pharmacological action of these preparations are essentially those of the silver ion. The only salts of silver are those 11 Inorganic Pharmaceutical Chemistry: Topical Agents of the monovalent cation [Ag(I)]. This ion is readily obtained from metallic silver through treatment with an oxidizing acid, e.g., cold dilute nitric acid. 3Ag + 4HNO₃ → 3AgNO₃ + NO↑ + 2H₂O The protein precipitant action of silver ion is not selective; it will precipitate both bacterial and human protein. The range of activity available includes antibacterial, astringent, irritant, and corrosive, depending upon the concentration applied. Silver ion precipitation of protein involves interactions between the cation and various polar groups on the protein molecule, e.g., –SH, –NH₂, –COOH, and heterocyclic residues, e.g., histidine. When applied to tissue in a concentration of 0.1% Ag ⁺ the activity is rapidly bactericidal. Extended use of silver preparations is likely to cause a darkening of the skin due to the deposition of free silver below the epidermis. This condition is termed argyria and is essentially irreversible. The primary uses of silver nitrate products:  It is employed as an antibacterial in solutions ranging in concentration from 0.01 to 10%, recognizing that the higher concentrations present astringent and irritant properties to the tissues.  Silver Nitrate Ophthalmic Solution is a 1% solution for instillation into the eyes of newborn babies. Silver salts are quite effective against gonococcal organisms, and two drops of this solution are placed in each eye as a prophylactic measure against (ophthalmia neonatorum).  Silver nitrate is applied as of 0.5% aqueous solution in the form of a wet dressing on burned areas of patients suffering from third-degree burns. Astringents Agents 12 Inorganic Pharmaceutical Chemistry: Topical Agents Astringents are compounds that cause protein precipitation on the surface of cells, resulting in the coagulation of proteins and tissue constriction without causing deep damage. They typically act on small blood vessels (smooth muscle) and are applied topically. Astringents have limited penetration, causing a mild antimicrobial effect and restricting blood flow, but they don't result in the death of cells. Uses of Astringents:  Styptic action: Stops bleeding from small cuts by promoting blood coagulation and constricting capillaries.  Antiperspirant: Decreases the secretion of sweat.  Constricts mucous membranes: Reduces inflammation by limiting blood flow to the surface.  Topical actions: Removes unwanted tissue or restricts protein action, often used at higher concentrations as a corrosive agent. Common astringent products include aluminum, zinc, and zirconium salts. 1- Aluminum Chloride (AlCl₃·6H₂O): It acts as a Lewis acid and is very soluble in water, alcohol, and glycerin, producing an acidic solution. It is used in aqueous solutions as an astringent and mild antiseptic, with concentrations ranging from 10% to 25%. It can cause irritation to tissue due to the hydrolysis of the aluminum chloride forming hydrochloric acid (HCl). This compound was initially used as an antiperspirant but was too irritating and could damage clothing. 2- Aluminum Hydroxy chloride: This term refers to two possible compounds: monohydroxy chloride and dihydroxy chloride, which are both acidic but less soluble in water than aluminum chloride. 13 Inorganic Pharmaceutical Chemistry: Topical Agents These compounds are less irritating and are commonly used in commercial antiperspirants. They replace the more irritating aluminum chloride in products such as deodorant sprays, creams, and solutions, used in concentrations around 20%. 3- Zinc Chloride Zinc chloride solutions are acidic due to hydrolysis, which forms hydrochloric acid (HCl) and basic zinc chloride, as shown in the equation: ZnCl2 + H2O ⇌ Zn(OH)Cl +H+ + Cl− It is important to filter zinc chloride solutions through asbestos or glass wool as they can dissolve materials like paper and cotton. Zinc chloride is used to form zinc oxychloride when mixed with zinc oxide. This creates a hard mass, which is used in some dental cements. Uses of Zinc Chloride:  Astringent & Antiseptic: Zinc chloride acts as a powerful protein precipitant, making it a strong astringent and mild antiseptic.  Escharotic Action: The compound also acts as an escharotic, aiding in tissue sloughing and scar tissue formation, which helps in healing.  Nasal Spray & Sinus Treatment: In lower concentrations (0.5 to 2%), zinc chloride solutions are applied to mucous membranes or used as nasal sprays to aid sinus drainage.  Dentin Desensitizer: A 10% solution of zinc chloride is applied to teeth to act as a desensitizer of dentin. 14