Dear Colleagues, as is known, Atropine is used as eye drops in ophthalmology due to its mydriatic and cycloplegic effects. This week, we will examine together this formula (NRF 15.2.) included in the “German Standard Formulations”.
When 1-2 drops of atropine eye drops are instilled into the eye, it spreads over the cornea as a thin film layer. Since its osmotic pressure is equal to the aqueous humor of the anterior chamber, the active substance easily diffuses and induces long-lasting mydriasis and cycloplegia by paralyzing the pupillary sphincter.
Mydriasis begins in the 10th minute in a normal eye and reaches its maximal level in 30 minutes; this condition continues for approximately 2 days and gradually disappears. Since its pH is within normal limits, it is well tolerated by the eye. It is used prophylactically and therapeutically in cases where prolonged rest of the iris sphincter and ciliary muscle tissues is considered necessary, in inflammatory conditions of the eye such as iritis and keratitis, to prevent iritis and keep intraocular pressure under control after cataract surgeries, in corneal tears and burns, and to prepare the eye for ophthalmological examination. An hypersensitivity reaction to Atropine may occur in children as a result of prolonged use. In addition, it should be used with caution in children with pre-existing brain damage, Down syndrome, mongolism, and spastic paralysis. It is contraindicated in glaucoma. Since systemic absorption of ophthalmic Atropine may be possible, the use of the preparation in pregnant women should be carefully evaluated in terms of the risk-benefit ratio. Since Atropine may pass into breast milk in small amounts, adverse effects such as tachycardia, fever, and dry skin may be seen in breastfed infants whose mothers use Atrosol; therefore, its use in breastfeeding women should be carefully evaluated in terms of the risk-benefit ratio. Infants and young children are reported to be particularly sensitive to Atropine. Furthermore, the preparation must be used with great caution in children with spastic paralysis or brain damage. Facial flushing, skin rash, fever, dry mouth, fatigue, drowsiness, and accelerated heart rate may be observed. The dosage is adjusted according to the physician’s recommendation and the condition of the cases; usually, 1-2 drops are instilled daily in subacute and chronic cases. The drops should be instilled into the inner canthus of the eye, and the eye should be kept closed for 1-2 minutes after instillation.
If the following warnings are observed, the sterility and therapeutic activity of the eye drops will be preserved for a long time:
Wash your hands before using the preparation.
The dropper tip should not be touched, and the dropper should not touch the eye.
Once opened, the medicine must be consumed within a maximum of 15 days. If the medicine is not finished within this period, it should be discarded.
Formula:
Rp. 0.5 % 1 % 2 %
Atropinsulfat (Monohydrat) 0.050 g 0.100 g 0.200 g
Borsäure (Boric acid) 0.175 g 0.161 g 0.136 g
Thiomersal stock solution 1.0 g 1.0 g 1.0 g
Water for injections ad 10.0 g ad 10.0 g ad 10.0 g
Substances in the formula:
Atropine sulfate monohydrate – Atropinsulfat [ASK; Ph.Eur.] – Atropine sulfate [USP] – Sulfate d’atropine [FP]:
Atropine sulfate is colorless, odorless crystals or a white crystalline powder. It effloresces in dry air. Solubility according to the British Pharmacopoeia (BP): Very soluble in water; freely soluble in alcohol and glycerol; practically insoluble in chloroform and ether. Solubility according to the United States Pharmacopeia (USP): Soluble in water 1:0.5, boiling water 1:2.5, alcohol 1:5, and glycerol 1:2.5. The BP reports the pH of its 2% aqueous solution as 4.5–6.2. According to the BP, the pH of its injectable solution should be between 2.8 and 4.5. According to the USP, the pH of its injectable solution should be between 3.0 and 6.5, and the pH of its ophthalmic solution should be between 3.5 and 6.0.
Atropine is a natural tertiary amine with antimuscarinic action extracted from deadly nightshade (Atropa belladonna). It is also used to induce mydriasis in eye examinations. The primary clinical effects of atropine are: Reduction in salivary, bronchial, and sweat secretions; mydriasis and cycloplegia (paralysis of accommodation) in the eye; changes in heart rate (bradycardia at small doses; tachycardia due to increased inhibitory vagal tone as a result of blockade of M2-type muscarinic receptors at doses of 0.5 mg and above); relaxation of the detrusor smooth muscle of the bladder and increase in smooth muscle tone in the trigone region; partial inhibition of the stimulatory effect of parasympathetic nerve stimulation on the motor activity of gastrointestinal smooth muscle, and reduction in the tone of wall muscles along with the frequency and amplitude of spontaneous peristaltic movements (antispasmodic effect and constipation due to prolonged transit time of intestinal contents). At high doses, atropine affects nicotinic receptors in autonomic ganglia, causing restlessness, hallucinations, disorientation, and/or delirium. Unlike scopolamine, atropine does not cause CNS depression (drowsiness, euphoria, amnesia, fatigue, reduction in REM sleep) at usual therapeutic doses. The antimuscarinic efficacy of Atropine is higher on the heart, bronchi, and gastrointestinal smooth muscles, whereas it is weaker on the iris, ciliary muscle, salivary, sweat, and bronchial glands.
Boric acid – Acide borique [DCF; FP] – Acido borico [FU] – Boric acid [BP; INCI; NF; P.Cx.79]:
Boric acid exists as odorless white crystals or shiny scales, or as a white crystalline powder that feels greasy to the touch. When heated to 100°C, it loses water and slowly transforms into metaboric acid (HBO2). When heated to 140°C, it transforms into tetraboric acid (H2B4O7), and when heated to higher temperatures, into boron trioxide (B2O3). It is soluble 1:20 in water, 1:3.6 in boiling water, 1:16 in alcohol, 1:6 in boiling alcohol, and 1:4 (85%) in glycerin. Boric acid forms a more acidic complex with glycerin than by itself. The pH of its 3.3% solution in carbon dioxide-free water is between 3.8 and 4.8. Its aqueous solutions should be stored in tightly closed containers.
When applied topically, these solutions are known to have greater bacteriostatic activity compared to forms containing an oily base (cream/ointment).
Boric acid is a drug with weak bacteriostatic and fungistatic effects. It is used topically. Its ophthalmic preparations are used in the treatment of eye irritation and inflammation. Its topical preparations are useful for soothing irritated skin, in skin lesions, burns, and other skin irritation cases. Vaginal candidiasis caused by Candida glabrata and other non-albicans species often responds favorably to topical boric acid therapy. Topical boric acid preparations may cause systemic toxicity, especially when applied to broken skin. Its current use has lost its former significance due to the availability of more effective and less toxic medications. In eye drops, it is often used with borax for buffering and antimicrobial effects. ATTENTION! Neither boric acid nor borax is used for systemic effect (internally).
ATTENTION! Pharmacists are advised not to dispense powdered boric acid to patients. Preparations containing more than 5% boric acid in powder form should not be applied to abraded or oozing skin surfaces due to the risk of toxicity. Boric acid preparations should not be used in infants and young children.
Boric acid is a weak topical anti-infective agent with fungistatic and bacteriostatic properties. The exact mechanism of the antibacterial and antifungal effects of boric acid is unknown. Boric acid shows a slow bacteriostatic effect against staphylococci and streptococci. Its effect in the vagina is thought to be related to increasing vaginal pH. Increasing vaginal pH enhances penetration through the fungal cell wall and causes disruption of the cell wall structure.
Applied as a mild antiseptic in the inflamed eye (e.g., in the form of a solution or ointment), boric acid exhibits slightly acidic properties and is frequently used for its antiseptic effect. It disrupts cell membrane permeability by causing coagulation of bacterial cell wall proteins. While its 5% aqueous solutions exhibit a phagocytic effect, its 2–4% solutions prevent the proliferation and growth of bacteria.
Boric acid causes acute poisoning when ingested orally by accident. Nausea, diarrhea, abdominal pain, erythematous rash, and desquamation on the skin and mucous membranes may occur. CNS stimulation or depression develops. Convulsions and hyperpyrexia may be seen. It can cause tubular necrosis in the kidneys. Death occurs within 3–5 days due to circulatory collapse and shock. With repeated use, it can accumulate and cause chronic toxicity due to its slow elimination from the body. Symptoms of chronic poisoning include anorexia, gastrointestinal disturbances, debility, confusion, dermatitis, menstrual disorders, anemia, convulsions, and alopecia. Fatalities have been reported, particularly in young children, due to accidental ingestion of boric acid solutions or application to large areas of broken skin. Therefore, boric acid preparations should not be used in infants and young children. It is recommended that boric acid should not exceed 5% in talc and 0.5% in preparations used for oral hygiene. Talcum powders containing boric acid should not be used in children under 3 years of age. Preparations containing boric acid should not be applied to large areas of damaged or abraded skin. Irrigation of body cavities with preparations containing boric acid is no longer recommended due to the risk of toxicity. Boric acid and borax are substances that cause pulmonary irritation when inhaled. Poisoning treatment is symptomatic.
Boric acid is absorbed from the gastrointestinal tract (upon accidental ingestion), damaged skin, wounds, and mucous membranes. It is not readily absorbed when applied topically to intact skin. Approximately 50% of the absorbed amount is excreted in the urine within 12 hours, while the remainder is excreted within 5–7 days.
Thimerosal – Thiomersal – Mercurothiolate sodique [DCF; FP] – Tiomersal [INN; DCIT] – Mercurothiolate:
Thimerosal is a light cream-colored crystalline powder with a characteristic odor. It is soluble 1:1 in water and 1:12 in alcohol; practically insoluble in ether. The pH of its 1% solution is 6–8. According to the United States Pharmacopeia (USP), Thimerosal Tincture (USP 23), Thimerosal Topical Aerosol (USP 23), and Thimerosal Topical Solution (USP 23) must be stored at a temperature not exceeding 40°C. The pH of Thimerosal Topical Solution (USP 23) is between 9.6 and 10.2. It is incompatible with heavy metals, sulfides, potassium permanganate, and iodine. The presence of trace amounts of iron ions in thimerosal solutions greatly increases drug oxidation. Thimerosal may form a precipitate in slightly acidic solutions.
Thimerosal is an organic mercury compound used as a topical antiseptic. It exhibits bacteriostatic and fungistatic effects. It is used for skin antisepsis before surgery or in first aid. It is used topically at a 0.1% concentration. It is used as a preservative in pharmaceutical and biological preparations at concentrations of 0.01% to 0.02%. It is also included in the composition of preparations used for the care of soft contact lenses. Frequent and prolonged application to large skin surfaces may cause severe mercury poisoning due to the mercury it contains.
Note: The stock solution below was used in the formula.
Thiomersal stock solution 0.02% (NRF S.4.)
Thiomersal 0.020 g
Water for injections ad 100.0 g
Apyrogenic distilled water – Bidistilled water – Wasser für Injektionszwecke [ASK; Ph.Eur.] – Water for injections [BP; USAN; USP]:
Water for injections is a pyrogen-free, clear, and colorless liquid with no specific taste. In the United States Pharmacopeia (USP XXII), it is defined as purified water obtained by distillation or reverse osmosis. It contains no added substances. It appears under the title “Water for Injections” in the British Pharmacopoeia (BP 1993) and the European Pharmacopoeia (PhEur 1990) and consists of two parts: “Water for Injections in Bulk,” used in the preparation of parenteral formulations, and “Sterilised Water for Injections,” used for dissolving or diluting preparations or substances prior to parenteral administration.
Preparation of the formula:
It must be prepared to be sterile, isotonic, and isohydric. The separately weighed substances are dissolved in a calculated amount of Water for injections, and finally, the Thiomersal stock solution is added. Sterilization conditions must be observed while preparing the preparation. In formulas prepared in pharmacy and hospital laboratories, water for injections must strictly be used and filtered sterilely through a membrane filter or a syringe with a membrane filter into a previously sterilized bottle.
Wishing you a good week…
References:
1- Standardisierte Rezepturen, 2017
2- RxMediaPharma® 2017 Interactive Drug Information Source.
Specialist Pharmacist Ahmet Nezihi Pekcan
Pekcan Pharmacy – Konya
[email protected]
Tel: (332) 3520657
http://www.majistralformul.com/
