3.2.2. Characteristics of Active Ingredients Most Frequently Prescribed in Preparation of Semi-Solid Dosage Forms, Their Most Common Combinations, and Comparison with German and USA Formulations
The ingredients described in this section and their prescription frequency are shown in
Table 6.
Depending on the concentration, salicylic acid produces a pronounced keratolytic effect, as well as anti-inflammatory, antifungal, and antibacterial action. Salicylic acid is mentioned in the DAC/NRF in the composition of several ointments, creams, and pastes. In these formulations, salicylic acid is used as the only active ingredient or in combination with dithranol or solution of coal tar in ethanol 96% (
v/
v) and polysorbate 80 [
10]. In Latvia, salicylic acid was prescribed as the only active ingredient in 72 prescriptions. USP Compounding Compendium describes the preparation of salicylic acid–zinc oxide paste [
11]. In Latvia, such a combination was found in 56 of the analyzed prescriptions. In the prescriptions issued by Latvian dermatologists and prepared in pharmacies, salicylic acid was most frequently combined with sulfur (424 prescriptions), isoconazole nitrate and diflucortolone valerate cream (72 prescriptions), prednisolone tablets (66 prescriptions), and birch tar (60 prescriptions). Such combinations can neither be found in the DAC/NRF nor in the USP Compounding Compendium [
10,
11].
Sulfur demonstrates antiparasitic, keratolytic, and antiseptic action [
17]. The DAC/NRF does not contain formulations with sulfur. In 1996, an ointment containing it was excluded from the DAC/NRF due to a negative sulfur use benefit-and-risk assessment [
10]. Prescription of sulfur in dermatological prescriptions is permitted with the evaluation of risks and benefits, and prescriptions with sulfur can be found in German dermatological literature [
17,
18]. The USP Compounding Compendium includes sulfur ointment, where sulfur is the only active ingredient [
11]. In Latvia, sulfur was prescribed as the only active ingredient in three prescriptions. In other analyzed prescriptions of Latvian dermatovenerologists, sulfur was most frequently combined with the same active ingredients with which salicylic acid was combined. Sulfur together with salicylic acid was prescribed in 424 prescriptions, with isoconazole nitrate and diflucortolone valerate cream in 73 prescriptions, with prednisolone tablets in 50 prescriptions, with birch tar in 47 prescriptions, and with zinc oxide in 43 prescriptions.
Prednisolone demonstrates anti-inflammatory and antipruritic action [
17]. The DAC/NRF contains creams with prednisolone prodrug prednicarbate and prednisolone acetate. In these formulations, prednisolone acetate is used as the only active ingredient, but prednicarbate is used alone and in combination with octenidine hydrochloride [
10]. Furthermore, prednisolone cream prescription can be found in German dermatological literature as a cheaper alternative for industrially manufactured prednisolone creams [
19]. The USP Compounding Compendium does not contain semi-solid dosage forms with prednisolone [
11]. Unlike in Germany, analyzed Latvian prescriptions used prednisolone tablets rather than bulk drug substance for the preparation of semi-solid dosage forms. In Latvia, prednisolone was prescribed as the only active ingredient in eight prescriptions. In the analyzed prescriptions of Latvian pharmacies, prednisolone was most often combined with the following active ingredients: salicylic acid (66 prescriptions); ampicillin trihydrate capsules (55 prescriptions); sulfur (50 prescriptions); zinc oxide (41 prescriptions); boric acid (39 prescriptions). Such combinations were not included in the DAC/NRF [
10].
Zinc oxide produces a desiccating action, as well as a mild anti-inflammatory and tightening action [
17]. Zinc oxide is mentioned in the DAC/NRF in the composition of several pastes, in addition to as a liniment. In these formulations, zinc oxide is used as the only active ingredient or in combination with the following active ingredients: dithranol, ichthammol, and bismuth subgallate [
10]. The USP Compounding Compendium includes ointment containing zinc oxide and pastes, where zinc oxide is the only active ingredient or in combination with salicylic acid [
11]. In Latvia, zinc oxide was prescribed as the only active ingredient in two prescriptions. In the analyzed prescriptions of Latvian pharmacies, zinc oxide was most often combined with the following active ingredients: salicylic acid (56 prescriptions); ichthammol (47 prescriptions); sulfur (43 prescriptions); prednisolone tablets (41 prescriptions); birch tar (32 prednisolone); resorcinol (32 prescriptions); bismuth subgallate (30 prescriptions). Out of these combinations in the DAC/NRF and USP Compounding Compendium, none can be found of zinc oxide with sulfur, prednisolone, and birch tar [
10,
11].
Metronidazole has antibacterial, antiparasitic, and anti-inflammatory properties [
17]. The DAC/NRF contains creams and a gel containing metronidazole as the only active ingredient and in combination with erythromycin [
10]. Such a combination can also be found in the analyzed Latvian prescriptions. Metronidazole was prescribed as the only active ingredient in 65 analyzed Latvian prescriptions. The USP Compounding Compendium does not include semi-solid dosage forms with metronidazole [
11]. Metronidazole tablets rather than bulk drug substance were mainly used for the preparation of semi-solid dosage forms in the analyzed Latvian prescriptions. Latvian dermatovenerologists most frequently combined metronidazole with the following active ingredients: sulfur (31 prescriptions); salicylic acid (27 prescriptions); clotrimazole cream (20 prescriptions); isoconazole nitrate and diflucortolone valerate cream (13 prescriptions); erythromycin tablets (13 prescriptions). As already mentioned, out of these combinations, only a metronidazole combination with erythromycin can be found in the DAC/NRF.
Dexamethasone from the first class of steroids demonstrates anti-inflammatory and antipruritic action [
17]. The DAC/NRF describes only the preparation of dexamethasone 1% and 10% trituration, but the formulations containing dexamethasone are not included in this formulary [
10]. Ointments, creams, and hydrogels containing dexamethasone can be found in German dermatological literature [
17,
18]. The USP Compounding Compendium does not include semi-solid dosage forms with dexamethasone [
11]. Dexamethasone tablets rather than bulk drug substance were used for the preparation of semi-solid dosage forms in the analyzed prescriptions of Latvian pharmacies. Dexamethasone was prescribed as the only active ingredient in six prescriptions. In the analyzed prescriptions of Latvian pharmacies, dexamethasone was most frequently combined with the following active ingredients: salicylic acid (43 prescriptions); fluocinolone acetonide ointment (22 prescriptions); benzocaine (21 prescriptions); birch tar (21 prescriptions); sulfur (17 prescriptions).
Birch tar is not included in the DAC/NRF, German dermatological literature, or the USP Compounding Compendium [
10,
11,
17,
18,
19]. The DAC/NRF includes coal tar, which is used in the preparation of ointments and creams. In the DAC/NRF, coal tar is not combined with other active ingredients, but is used as the only active ingredient [
10]. The USP Compounding Compendium also uses coal tar, but in combination with zinc oxide in the respective ointments [
11]. In the analyzed prescriptions of Latvian pharmacies, birch tar was prescribed, which demonstrates a disinfecting and local irritant action [
20]. In these prescriptions, birch tar was most frequently combined with the following active ingredients: salicylic acid (60 prescriptions); sulfur (47 prescriptions); zinc oxide (32 prescriptions); turpentine oil (30 prescriptions); dexamethasone tablets (21 prescriptions). Birch tar was prescribed as the only active ingredient in three prescriptions.
In Germany, the use of boric acid and its salts for the preparation of semi-solid dosage forms is prohibited due to low efficacy and risk of resorptive poisoning. Boric acid can be used only in the preparation of homeopathic preparations, as well as in the preparation of eye drops, where it is used as a buffer [
10]. The USP Compounding Compendium also does not include semi-solid dosage forms with boric acid [
11]. Latvian dermatologists still prescribe boric acid, most probably as an antiseptic; in the analyzed prescriptions, the most common combinations were with prednisolone tablets (39 prescriptions), ampicillin trihydrate capsules (36 prescriptions), and zinc oxide (13 prescriptions).
In 1999, mercuric oxide was removed from the DAC/NRF [
10]. It is also not included in the USP Compounding Compendium [
11]. In Latvia, mercuric oxide is still prescribed as an antiseptic and as the only active ingredient (38 prescriptions), but it is also found in combinations. The most common combinations were with the following active ingredients: salicylic acid (16 prescriptions); prednisolone tablets (nine prescriptions).
Ampicillin is an antibiotic from the group of broad-spectrum penicillins [
21]. Formulations with ampicillin are not included in the DAC/NRF and USP Compounding Compendium [
10,
11]. Latvian prescriptions include ampicillin trihydrate oral capsules rather than bulk drug substance; the most common combinations were with prednisolone tablets (55 prescriptions), boric acid (36 prescriptions), ichthammol (17 prescriptions), and zinc oxide (16 prescriptions). Ampicillin was not used as the only active ingredient in semi-solid dosage forms.
Diphenhydramine hydrochloride is a histamine H1 antagonist [
22]. The DAC/NRF and USP Compounding Compendium do not contain formulations with this active ingredient [
10,
11]. In Germany, the antipruritic and antihistamine effect of locally used diphenhydramine hydrochloride is subject to discussion, and its use is also limited due to the risk of potential sensibilization [
23]. At the same time, there are industrially manufactured medicines—gels with diphenhydramine hydrochloride [
24,
25]. USA literature mentions extemporaneously compounded gels containing diphenhydramine hydrochloride [
6]. In Latvia, diphenhydramine hydrochloride was not used as the only active ingredient in the preparation of semi-solid dosage forms; it was most frequently combined with the following active ingredients: sulfur (34 prescriptions); salicylic acid (32 prescriptions); procaine hydrochloride (15 prescriptions); dexamethasone tablets (14 prescriptions).
Ichthammol demonstrates anti-inflammatory and antiseptic action [
17]. The DAC/NRF contains a cream and a paste containing ichthammol, where ichthammol is in combination with zinc oxide [
10]. Such a combination can also be found in the analyzed Latvian prescriptions. The USP Compounding Compendium contains ichthammol ointment, where ichthammol is the only active ingredient [
11]. In Latvia, ichthammol was prescribed as the only active ingredient in one prescription. In the analyzed prescriptions of Latvian pharmacies, ichthammol was most often combined with the following active ingredients: zinc oxide (47 prescriptions); prednisolone tablets (37 prescriptions); resorcinol (32 prescriptions); ampicillin trihydrate capsules (17 prescriptions); salicylic acid (12 prescriptions).
Benzocaine demonstrates anesthetic and analgesic action [
17]. The DAC/NRF and USP Compounding Compendium do not contain formulations with benzocaine [
10,
11]. German dermatological literature describes benzocaine ointments, creams, and gels [
17,
18]. In Latvia, benzocaine was prescribed as the only active ingredient in one prescription. In the analyzed prescriptions of Latvian pharmacies, benzocaine was most frequently combined with the following active ingredients: dexamethasone tablets (21 prescriptions); salicylic acid (16 prescriptions); fluocinolone acetonide ointment (12 prescriptions); prednisolone tablets (10 prescriptions).
Bismuth subgallate demonstrates tightening and antiseptic properties [
17]. As described previously, the DAC/NRF includes a paste which contains a combination of bismuth subgallate and zinc oxide [
10]. Also, in the analyzed Latvian prescriptions, bismuth subgallate was most frequently combined with zinc oxide (30 prescriptions). The USP Compounding Compendium does not contain semi-solid dosage forms with bismuth subgallate [
11].
Resorcinol demonstrates keratolytic and antiseptic action [
26]. All formulations with resorcinol were removed from the DAC/NRF in 1996 [
10]. In Germany, the use of resorcinol in dermatology is subject to discussion. Alternatives with a better risk–benefit ratio are offered. For example, chlorhexidine gluconate may be used as an antiseptic, but salicylic acid is offered for a keratolytic effect [
26]. The USP Compounding Compendium does not contain semi-solid dosage forms with resorcinol for use in dermatology [
11]. In the analyzed prescriptions of Latvian pharmacies, resorcinol was most frequently prescribed in the following combination: resorcinol–prednisolone tablets–zinc oxide–ichthammol (32 prescriptions); 12 of these prescriptions also contained ampicillin trihydrate capsules.
Lactic acid has antiseptic, keratolytic, and escharotic action [
17]. In the DAC/NRF, lactic acid is mentioned as an excipient for stabilization of pH for a cream with urea [
10]. German dermatological literature describes ointments and creams where lactic acid is an active ingredient [
17,
18]. The USP Compounding Compendium does not contain semi-solid dosage forms with lactic acid [
11], but USA literature contains an ointment where the function of lactic acid is to increase hydration of the skin. In this ointment, lactic acid was combined with urea and triamcinolone acetonide [
6]. In the analyzed prescriptions of Latvian pharmacies, lactic acid was most frequently combined with salicylic acid (32 prescriptions). In total, 26 prescriptions included only these two active ingredients, but five prescriptions also contained sulfur, and one prescription contained ichthammol along with this combination. Lactic acid was prescribed as the only active ingredient in one prescription.
Turpentine oil demonstrates local irritant, analgesic, and antiseptic action [
20]. The DAC/NRF does not contain semi-solid dosage forms with turpentine oil used in dermatology [
10]. The USP Compounding Compendium does not include semi-solid dosage forms with turpentine oil [
11]. In the analyzed prescriptions of Latvian pharmacies, turpentine oil was most often prescribed in two main combinations: turpentine oil–salicylic acid–birch tar–sulfur–zinc oxide (17 prescriptions) and turpentine oil–salicylic acid–birch tar–sulfur–zinc oxide–benzocaine (12 prescriptions). In Latvia, an ointment containing turpentine oil is also produced industrially.
Procaine hydrochloride is an anesthetic and analgesic agent [
17]. The DAC/NRF does not contain formulations with this active ingredient, but German dermatological literature describes ointments, creams, and hydrogels with it [
10,
17]. The USP Compounding Compendium does not contain semi-solid dosage forms with procaine hydrochloride [
11]. In the analyzed prescriptions of Latvian pharmacies, procaine hydrochloride was most frequently combined with salicylic acid (27 prescriptions) and sulfur (26 prescriptions).
Erythromycin has bacteriostatic and, in large doses, bactericide action [
17]. The DAC/NRF contains creams and gels with erythromycin as the only active ingredient or, as described above, in combination with metronidazole. It is emphasized in the DAC/NRF that the dosage forms with erythromycin should only be prepared based on standardized prescriptions, because erythromycin has low stability depending on the pH environment [
10]. The USP Compounding Compendium does not contain semi-solid dosage forms with erythromycin [
11]. Oral erythromycin tablets rather than bulk drug substance were used for the preparation of semi-solid dosage forms in the analyzed prescriptions of Latvian pharmacies. In these prescriptions, erythromycin was most frequently combined with metronidazole (13 prescriptions). In one prescription, erythromycin was combined with a boric acid, lactic acid, zinc oxide, and fluocinolone acetonide ointment. Erythromycin was prescribed as the only active ingredient in four prescriptions.
Menthol demonstrates hyperemic, antirheumatic, analgesic, and antipruritic action [
17]. The DAC/NRF contains ointments and cream with menthol. In these formulations, menthol is used as the only active ingredient or in combinations, which are not used in dermatology, such as menthol–camphor–methyl salicylate and menthol–camphor–turpentine oil–eucalypt oil–mountain pine oil [
10]. The USP Compounding Compendium does not contain semi-solid dosage forms with menthol, but USA literature describes the preparation of a testosterone–menthol eutectic ointment, as well as the preparation of a lip balm containing menthol [
5,
11]. In the analyzed prescriptions of Latvian pharmacies, the most frequent combination of active ingredients was menthol–diphenhydramine hydrochloride–boric acid (six prescriptions). Industrially manufactured creams or ointments with corticosteroids, and corticosteroids together with antibiotics or antifungal agents were added to this combination.