Mouthwash formula against fungal infections accompanied by inflammation and pain
Dear Colleagues, this week, we will examine together the mouthwash formula featured in the Belgian Pharmacopoeia to treat oral fungal infections characterized by inflammation and painful symptoms.
Formula:
Rp.
Nystatine 3,000,000 IU
Hydrocortisone 0.200 g
Lidocaine hydrochloride 0.400 g
Hydroxypropyl methylcellulose 4000 5.0 g
Glycerol 7.5 g
Peppermint oil 50 mg
Ethanol 96 percent 4.0 g
Water for preservation q.s. ad 500 g
Substances in the formula:
Nystatin- Fungicidin- Nistatina [Ph. Eur. 4]- Nystatinum [Ph. Eur. 4; Ph. Int. III]:
Nystatin is an antifungal antibiotic obtained from specific strains of Streptomyces noursei. It primarily contains tetraene-structured compounds, the main one being Nystatin A1. Nystatin A1 is a hygroscopic powder ranging in color from yellow to light brown, with a characteristic odor. Calculated on the dry basis, nystatin must contain not less than 4400 units of nystatin A1 per mg. Solubilities according to the British Pharmacopoeia (BP): Very slightly soluble in water; practically insoluble in alcohol, chloroform, and ether. According to the United States Pharmacopeia (USP): Slightly soluble in water; slightly or sparingly soluble in alcohol, methyl alcohol, n-propyl alcohol, and n-butyl alcohol; insoluble in chloroform and ether. The pH of its 3% aqueous suspension ranges between 6.5 and 8.0. In terms of chemical structure, it is very similar to amphotericin B; both are polyene antifungal agents. Due to lack of absorption from the gastrointestinal tract and its toxicity, nystatin is not used in the treatment of systemic fungal infections. Although suggested for the treatment of dermatophyte infections such as tinea capitis, it is only effective against Candida, and is most useful in cases of oropharyngeal, cutaneous, mucocutaneous, and vulvovaginal candidiasis. A liposomal formulation of nystatin intended for systemic use is under clinical investigation. This liposomal formulation is thought to possibly be effective against Aspergillus.
Like amphotericin B, nystatin binds to sterols present in both fungal and human cell membranes. Although nystatin mostly exhibits a fungistatic effect in vivo, it can exert a fungicidal effect at high concentrations or against highly susceptible microorganisms. It shows a higher affinity for ergosterol in the fungal cell membrane than for cholesterol; nevertheless, it is too toxic a drug to be used systemically. As a result of binding, the integrity of both fungal and human cell membranes is disrupted. This disruption leads to the leakage of potassium and other intracellular substances. Since bacterial cell membranes do not contain sterols, nystatin is ineffective against bacteria. Nystatin is also ineffective against protozoa, trichomonads, and viruses. Nystatin is administered orally, but is not absorbed from the gastrointestinal tract. When given orally, it is excreted in the feces almost entirely unchanged. It is used topically only. It is not absorbed through intact skin or mucous membranes.
Cortisol- 17-Hydroxycorticosterone- Hydrocortison [ASK; INN; Ph.Eur.]:
Hydrocortisone is a white or almost white, odorless, crystalline powder. It is practically insoluble or very slightly soluble in water; soluble 1:40 in alcohol and 1:80 in acetone; slightly soluble in chloroform; very slightly soluble in ether. According to the United States Pharmacopeia (USP), the pH of its enemas is 5.5-7.0, and the pH of its sterile suspensions is 5.0-7.0; the pH of the otic solution containing acetic acid reported in USP ranges between 2.0 and 4.0 when diluted with an equal volume of water. Hydrocortisone exhibits both mineralocorticoid and glucocorticoid activity. Like all topical corticosteroids, hydrocortisone exhibits anti-inflammatory, antipruritic, and vasoconstrictive effects when applied topically. In the treatment of allergic conditions, they reduce the allergic responses of certain cell types associated with the allergic response, such as mast cells and eosinophils. At the molecular level, free corticosteroids rapidly cross cell membranes and bind with high affinity to specific receptors located in the cytoplasm. Consequently, transcription and protein synthesis are affected. Their reduction of inflammation is based on numerous and diverse mechanisms: they reduce the release of leukocytic acid hydrolases, prevent the accumulation of macrophages at the site of inflammation, inhibit leukocyte adherence to the capillary wall, reduce capillary membrane permeability and resulting edema, decrease complement components, inhibit histamine and kinin release, and prevent scar tissue formation. They also reduce fibroblast proliferation and collagen deposition. Topical application of corticosteroids to the skin provides relief from inflammation and pruritus associated with acute or chronic dermatoses. Hydrocortisone is administered orally, parenterally, and topically. Hydrocortisone taken orally is absorbed rapidly. Systemic absorption from topical application sites varies depending on the condition of the skin in the treated area. Absorption of topical preparations is higher in damaged, inflamed, and occluded skin areas, or where the stratum corneum is thin, such as the eyelids, genital area, and face. Topical solutions, especially those applied to the oral mucosa, may undergo slight systemic absorption. Corticosteroids pass into breast milk and cross the placenta.
Lidocaine- Lignocaine- Lignocaine- Lidocainum:
Lidocaine is a widely used antiarrhythmic and local anesthetic. Lidocaine is a crystalline powder, white to yellowish in color, with a characteristic odor. Its melting point ranges between 66-70°C. It is practically insoluble in water; very soluble in alcohol, chloroform, or methylene chloride; freely soluble in ether; soluble in oils. Lidocaine forms a mixture with prilocaine that has a lower melting point than either component alone. This eutectic mixture is used in topical dosage forms. The addition of 1:200,000 to 1:100,000 adrenaline to lidocaine solution slows the vascular absorption of the drug and prolongs its effect. When applied topically to mucous membranes, its action begins within 1-2 minutes and lasts for about 30-60 minutes.
Hydroxypropyl methylcellulose- Methylhydroxypropylcellulose- HPMC- Methylcellulose propylene glycol ether- Hipromelosa [INN]:
Hypromellose consists of white to yellowish-white or grayish-white, practically odorless, hygroscopic fibrous powder or granules. It dissolves in cold water forming a colloidal solution; it is practically insoluble in hot water, anhydrous alcohol, acetone, chloroform, ether, and toluene. The pH of a 1% w/w solution in carbon dioxide-free water ranges between 5.5 and 8.0. Hypromellose is a cellulose ether containing varying proportions of methoxy and 2-hydroxypropoxy groups. They are classified with a number indicating their viscosity (for example, hypromellose 4500). In the United States, they are also designated by a number: the first two digits of this number indicate the approximate percentage of methoxy groups, while the third and fourth digits represent the approximate percentage of hydroxypropoxy groups. Hypromellose 1828, hypromellose 2208, hypromellose 2906, and hypromellose 2910 are defined in the United States Pharmacopeia (USP).
Hydroxypropyl methylcellulose is an important excipient used for various purposes in pharmaceutical preparations. It is used as a binder and film-coating agent in tablets, and as a matrix material in tablets formulated as modified-release systems. It is included as a thickening agent in topical formulations, particularly ophthalmic preparations. It is also used as an adhesive in plastic bandages and as a wetting agent for rigid contact lenses.
Aqueous solutions of hydroxypropyl methylcellulose are stable between pH 3-11 and are resistant to enzymatic degradation. The viscosity of these solutions remains stable when stored for long periods. However, due to its susceptibility to microbial degradation, an antimicrobial preservative must be added. When hydroxypropyl methylcellulose is used as a viscosity enhancer in ophthalmic solutions, benzalkonium chloride may also be included in the formulation as a preservative.
Glycerin 98%- Glycerol [ASK; BP; DCF; FP; INN; P.Cx.79; Ph.Eur.]- Glycerolum anhydricum- Glycerol [ASK; BP; DCF; FP; INN; P.Cx.79; Ph.Eur.]- Wasserfreies Glycerol;
Glycerin is an excipient widely used for various purposes in pharmaceutical formulations and cosmetic products. It is used in oral, otic, ophthalmic, topical, and parenteral pharmaceutical formulations. While it is used for its moisturizing and emollient effects in topical pharmaceutical formulations, it is mostly useful as a solvent in parenteral formulations. In oral formulations, it is used as an antimicrobial preservative, sweetener, and viscosity-increasing agent. It serves as a plasticizer for gelatin in soft gelatin capsules and is also included in the composition of gelatin suppositories. Glycerin is a clear, colorless, sweet, hygroscopic, viscous liquid. It is miscible with water and alcohol; sparingly soluble in acetone; practically insoluble in chloroform, ether, fixed oils, and volatile oils. Its aqueous solutions are neutral to litmus. According to the United States Pharmacopeia (USP), the pH of Glycerin Oral Solution, USP is between 5.5 and 7.5. When combined with strong oxidizing agents such as potassium permanganate, glycerin becomes explosive. Such mixtures must be strictly avoided. In the presence of light, it turns black when in contact with zinc oxide or basic bismuth nitrate. When glycerin contaminated with iron is used, mixtures containing phenol, salicylate, and tannins darken in color. It complexes with boric acid to form glyceroboric acid, which has higher acidity than boric acid itself.
Peppermint essence- Peppermint essence- Essence de menthe poivrée- Menthae piperitae aetheroleum- Pfefferminzöl:
Peppermint essence is a volatile liquid obtained by steam distillation from the fresh aerial parts of the Mentha piperita (Labiatae) plant. It is colorless, pale yellow, or greenish-yellow. It has a characteristic peppermint aroma and an aromatic flavor that leaves a sensation of coolness in the mouth. It dissolves in alcohol (70%) in a 1:3 ratio, showing slight opalescence. Its composition includes menthol, menthone, and menthyl acetate. It should be stored in airtight containers at temperatures not exceeding 40°C and protected from light.
Peppermint oil is an oil with a characteristic peppermint odor, colorless, light yellow, or greenish-yellow in color, and has a cooling, pungent aromatic taste. It contains menthol, menthone, and menthyl acetate. The British Pharmacopoeia (BP) states that it should contain 4.4-10% w/w esters calculated as menthyl acetate; not less than 44% w/w free alcohols calculated as menthol; and 15-32% ketones calculated as menthone. The United States National Formulary (USNF) states that it must contain not less than 5% esters calculated as menthyl acetate, and not less than 50% total menthol, free or combined as esters. Peppermint essence is used as a flavoring agent in pharmaceutical preparations. It may cause irritation and rarely hypersensitivity reactions. Enteric-coated capsules containing peppermint essence should not be taken immediately after meals or concurrently with antacids.
Alcohol- Ethanol- Ethyl alcohol- Spiritus vini- Weingeist- Ethanolum- Alcoholum:
Alcohol is a mixture of ethyl alcohol and water. In the British Pharmacopoeia (BP), alcohol is referred to as “Ethanol (96 per cent)” and is defined as containing not less than 96.0% and not more than 96.6% v/v. It is a clear, colorless, mobile liquid with a characteristic odor and a burning taste; it is volatile and ignites readily, burning with a smokeless blue flame. It is miscible with water; upon mixing, the temperature of the mixture rises and the volume contracts. It is miscible with chloroform, ether, glycerol, and most other organic solvents. According to the BP, dehydrated ethanol (Ethanol, BP 1993; absolute alcohol; dehydrated alcohol) must contain not less than 99.4% v/v or 99.0% w/w C2H5OH (density 788.16 to 791.2 kg/m3). According to the United States Pharmacopeia (USP), dehydrated alcohol (Dehydrated Alcohol, USP 23) contains not less than 99.5% v/v or 99.2% w/w C2H5OH (specific gravity not more than 0.7964 at 15.56°C). According to the BP, dilute alcohol (Dilute Ethanols, BP 1993) is available in several different concentrations, one of which is 90% ethanol, also known as “Rectified Spirit”. Dilute ethanol is a mixture of ethyl alcohol and water; it should contain not less than 69.1% v/v and not more than 71.0% v/v, and not less than 61.5% w/w and not more than 63.5% w/w C2H6O. Alcohol strength is expressed as a percentage by weight at a specific temperature.
Although ethyl alcohol is effective at concentrations of 60-90%, a 70% concentration (vol/vol) exhibits optimal efficacy for skin antisepsis. Conversely, when the concentration drops below 50%, it largely loses its activity. The English explanation seen on the hand sanitizer page regarding the effect of 70-degree alcohol is quite clear: “70 percent alcohol is the most antiseptic ratio, killing 99.9% of bacteria in one minute.”
Water for preservation- Gereinigtes Wasser [ASK]- Aqua purificata [IP3]- Wasser, gereinigtes [Ph.Eur.]:
Distilled water is high-purity water prepared by the distillation of drinking water and used as a solvent or vehicle in many pharmaceutical formulations. It is a clear and colorless liquid, free from characteristic odor and taste. When “water” is mentioned in pharmacy, distilled water should be understood. The shelf-life/usage period of distilled water is limited. In every case, it should be boiled before use. Because additional properties are required for water used in parenteral preparations, water for injection must be used for that purpose. In addition, deionized water may be used instead of distilled water in pharmaceutical preparations where its use is permitted because it is cheaper and easier to obtain.
Preparation of the formula:
The active substances are weighed separately. In a beaker on a magnetic stirrer, 300 g of distilled water is heated to 80 0C, 5 g of hydroxypropyl methylcellulose 4000 is added, and stirring is continued while allowing it to cool down to room temperature. In another beaker, also on a magnetic stirrer, 4 g of ethanol (96%), 50 mg of peppermint oil, and 7.5 g of glycerol are mixed until homogeneous and then added to the mixture in the other beaker that has cooled to room temperature. Meanwhile, the second beaker is rinsed with approximately 5 g of distilled water, which is then added to the mixture in the first beaker. In a third beaker, 0.4 g of lidocaine is dissolved in approximately 100 g of distilled water. To this solution, the nystatin equivalent to 3,000,000 IU and 0.200 g of hydrocortisone are added under magnetic stirring. The solution in this beaker is added to the main beaker. The third beaker is rinsed with approximately 50 g of distilled water and added to the main beaker. The solution, thoroughly mixed on the magnetic stirrer, is made up to 500 g with distilled water. It is stored in an amber glass bottle.
Some physicians add 1 g of neomycin sulfate to this formula. Its shelf life is 2 months, and its period of use is limited to 2 months. The bottle must be shaken before use. Gargle four times daily by adding 1 tablespoon into a glass of water.
The amount of nystatin to be weighed in the formula to prepare 500 g of suspension:
According to the latest edition of the European Pharmacopoeia, nystatin must contain at least 4,400 IU/mg of active substance calculated on the dried substance.
y (nystatin in grams) = 3,000,000 / (Activity (IU/mg) x 1000)
In this case, 0.681 g of nystatin should be weighed.
Wishing you a good week…
Pharm. Ahmet Nezihi Pekcan, Specialist Pharmacist
Pekcan Pharmacy – Konya
[email protected]
Tel: (332) 3520657
http://www.majistralformul.com/
References:
1-Belgian Pharmacopoeia (2010).
2-RxMediaPharma®2016 Interactive Drug Information Source.
