Special topics

• Preservatives


  Used to prevent microbial contamination
• Ideal characteristics of preservatives

  • Effective at low concentrations against all possible microorganisms (should be applicable for human use)
  • Nontoxic
  • Compatible with other constituents used in the preparation
  • Stable for the shelf-life of the preparation
• Para-hydroxybenzoic acid derivatives


  Esters of p-hydroxybenzoic acid (parabens) have distinct antifungal properties (contains hydroxyl group in para position of benzoic acid)
• Parabens


  • Low toxicity in humans (undergoes rapid hydrolysis inside the body and quickly conjugated, thereby, readily excreted)
  • Useful as preservative in liquid dosage forms (syrup, solution, elixir)
  • Preservative activity increases with molecular weight
• Parabens


  • Methylparaben
  • Propylparaben
  • Butylparaben
  • Ethylparaben
• Methylparaben


  • Methyl p-hydroxybenzoate
  • Most effective against molds
• Propylparaben


  • Propyl p-hydroxybenzoate
  • Most effective against yeasts
  • More oil-soluble, preferred for oils and fats
• Ethylparaben


  Ethyl p-hydroxybenzoate
• Chlorobutanol


  • Trichloro-2-methyl-2-propanol
  • Employed as a bacteriostatic agent in pharmaceuticals for injection, ophthalmic use, and intranasal administration
  • Antifungal: preservative at 0.5% concentration which can produce long-term stability with other ingredients
  • Antimicrobial: 0.05% in water
  • Can be used as sedative, hypnotic, and weak local anesthetic (similar with chloral hydrate – anesthesia or euthanasia of invertebrates or fishes)
• Benzyl alcohol


  • Benzene ring with methanol or a methyl with hydroxyl group
  • Preferred IUPAC name: Phenylmethanol or phenylcarbinol in some literatures
  • Commonly used as a preservative in vials of injectable drugs in concentrations of 1% to 4% in water or saline solution
• Phenylethyl alcohol


  • Contains a phenyl group attached to an ethanol or a phenylethyl group attached to an –OH
  • Occurs naturally in rose oil and pine needle oil
  • Used primarily in perfumery, some ingredients of flavors, additive in cigarettes or primarily as preservative in soaps due to its stability in basic condition or environment
• Benzoic acid


  • Preservative in foods and pharmaceutical products at low pH (dependent on the pH of the food and preparation of pharmaceuticals)
  • Inhibits the growth of molds, yeasts, and some bacteria
• Sodium benzoate


  • Salt of benzoic acid
  • Produced by reacting or neutralizing sodium hydroxide with benzoic acid
  • Preservative in acidic liquid preparations in which benzoic acid is released (vinegar, carbonated drinks, fruit juices)
  • If converted into benzoic acid, it can be a bacteriostatic and fungistatic, but then again, sodium benzoate does not occur naturally. Nevertheless, it can be found in some of the fruits and vegetables, particularly berries like cranberry and bilberry
  • Other sources can be sea foods like prawns while for dairy products, can be milk, cheese or yogurt
• Sorbic acid


  • 2, 4-hexadienoic acid
  • Sorbus aucuparia (Rowan tree)
  • Effective antifungal preservative
  • Used to preserve syrups, elixirs, ointments, and lotions
  • Its salts (generally preferred due to their water solubility) such as sodium sorbate, potassium sorbate, and calcium sorbate are also acting as antimicrobial agents (below pH 6.5)
  • Food and drinks: used to prevent the growth of molds, yeasts, and fungi
  • Used in concentrations of 0.025% to 0.1%
• Tuberculosis is a disease that has been known from the earliest recorded history
• Tuberculosis was discovered by Dr. Robert Koch, who announced that the disease was caused by a bacterium called Mycobacterium tuberculosis


  March 24, 1882
• In 1882, tuberculosis killed 1 out of every 7 people living in the US and in the Europe
• Designated as the World TB Day (day designated to educate the public about the impact of TB around the world and its control and elimination)

  1982, March 24
• Sulfonilamide (for Guinea pigs only) was the first breakthrough in treating tuberculosis
• Streptomycin was discovered to aid and to control the disease
• Mycobacterium tuberculosis


  • Causative agent of tuberculosis
  • Mode of transmission: person to person through air (cough)
  • Leading cause of mortality worldwide
• Isoniazid (INH)


  • Isonicotinic acid hydrazide
  • MOA: Inhibits the synthesis of mycolic acid, an importance of the cell walls of mycobacterium
  • Inhibits as well as vitamin B6
  • Adverse effect: Peripheral neuritis (caused by the depletion or inhibition of vitamin B6)
  • Prevention: Pyridoxine (vitamin B6), given especially to people having risk factors such as pregnancy, lactation, HIV infection, alcoholism, diabetes, and many others
• Pyrazinamide


  • First line drug for short-term treatment of tuberculosis (given for only 2 months)
  • Adverse effect: Hepatotoxicity
  • Has an amide functional group and a pyrazine ring (benzene ring with two N in the para position)
  • Must be enzymatically hydrolyzed to pyrazinoic acid (active form) by pyrazinamidase (amidase enzyme present in the bacteria itself)
• Ethambutol


  • Only active against dividing mycobacteria
  • Bacteriostatic agent which acts by obstructing the formation of cell wall, thereby, the disruption of the whole bacteria
  • Rapidly absorbed after oral administration
  • Adverse effects: Optic neuritis (sudden loss of vision either partial or complete, sudden blurred or foggy vision, and some pain in the movement of the affected eye)
  • Loss of ability to discriminate color between red and green (color blind)
• Rifampin (Rifampicin)


  • Semi-synthetic rifamycin from rifamycin B
  • Isolated from Streptomyces mediterranea
  • Inhibits G(+) bacteria by inhibiting the start of RNA synthesis
  • Bactericidal
  • A/E: Reddish secretions (red-orange urine)
• Streptomycin


  • Only aminoglycoside used for tuberculosis
  • MOA: Inhibition of protein synthesis, specifically, of the 30s subunit
  • The first antibiotic effective in the treatment of TB (discovered by Selman Waksman in 1994)
  • Adverse effects: Ototoxicity and nephrotoxicity
• Clofazimine


  • Not used to treat TB; grouped accordingly because of the causative agent of leprosy which is also a Mycobacterium specie called Mycobacterium leprae
  • Basic red dye used in the treatment of leprosy, including dapsone-resistant form
  • Brand name: Lamprene (used together with rifampicin and dapsone to treat leprosy)
  • Adverse effect: Hyperpigmentation
• National TB Control Program

  • Organized in 1978
  • Envisions the country to be TB-free
  • TB DOTS Centers (WHO recommendation)
  • DOTS - directly observed treatment short-course
  • Currently, the standard therapy used for tuberculosis patients is a combination of 4 or 5 drugs with an acronym of RIPE or RIPES
• Drugs in RIPE/RIPES regimen

  • Rifampicin
  • Isoniazid
  • Pyrazinamide
  • Ethambutol
  • Streptomycin (greater toxicity)
• Fungi


  • Eukaryotic organism (have true nucleus)
  • Resistant to antibiotic
  • Most are not pathogenic to humans
  • Immunocompromised patients are most susceptible
• Types of fungal infections

  • Superficial Mycoses (most common, caused by dermatophytes, Tinea or ringworm)
  • Systemic Mycoses (soil-inhabiting saprophytes with the ability to adapt to the internal environment of the host, deep-seated and very difficult to get rid of as they have a sporadic distribution)
  • Opportunistic Fungal Infection (overuse of antibacterial antibiotics, immunosuppressive agents, cytotoxins, and steroids, Candidiasis, Aspergillosis, Mucormycosis)
  • Subcutaneous Fungal Infection (both skin and subcutaneous tissue are involved, but typically no dissemination to the internal organs occurs, Chromomycosis, Sporotrichosis, Mycetoma, Lobomycosis, and Entomophthoromycosis)
• Dermatophytoses


  • Collectively called tinea or ringworm
  • Since these infections tend to be topical, their treatment must also be topical or directed to the surface area of the skin. However, the skin is a barrier to drug penetration and many of these topical agents can work best if an adjuvant is added to open the barrier function of the skin
  • An example of an adjuvant or an agent that can open the barrier function of the skin are keratolytic agents such as salicylic acid
• Fatty acids


  • Adults have an acidic, fatty substances in and on the skin called sebum
  • Natural antifungal agent; part of innate immune system
  • Used for years with the idea that if a substance similar to sebum could be applied to the infected area and this effect of sebum would be augmented and the fungi could be eradicated
  • High molecular weight fatty acids (MW FA) = low volatility
  • Salts of fatty acids are also fungicidal which provides provide non-volatile forms for topical application
• Propionic acid


  • Antifungal agent that is nonirritating and nontoxic
  • After application, it is present in perspiration in low concentrations (~0.01%)
  • Clear corrosive liquid with a characteristic odor soluble in water and in alcohol
  • Salts are nonvolatile and odorless (e.g. sodium propionate, potassium propionate, calcium propionate, and ammonium propionate)
• Undecylenic acid


  • IUPAC name: 10-undecenoic acid
  • Brand names: Desenex, Cruex
  • Obtained from destruction of castor oil
• Sebum


  Acidic, fatty substances in and on the skin of adults
• Sebum


  • Natural antifungal agent
  • Part of innate immune system
• Sebum was used with the idea that if a substance similar to it could be applied to the infected area, the effect would be augmented and the fungi could be eradicated
• High molecular weight fatty acids (MW FA)

  Low volatility
• Salts of fatty acids

  • Fungicidal
  • Provide non-volatile forms for topical application