N-acetylcysteine is a white crystalline powder that is readily soluble in water and 96% ethanol. It is a thiol derivative, which is commonly used as a mucolytic, antioxidant, nephroprotectant, and antidote for acetaminophen poisoning8.

In addition to being a keratolytic agent, NAC modulates keratinocyte proliferation and differentiation. When NAC enters cells it is rapidly hydrolysed to cysteine, a precursor of glutathione, which is a well-studied antioxidant that maintains the cellular redox state. By decreasing free radicals and increasing cysteine levels, NAC increases glutathione levels, which inhibit inflammatory factors and promotes epidermal proliferation. Applied topically, NAC prevents irritation caused by radiotherapy and protects against solar erythema2,6,13,14.

N-acetylcysteine is an amino acid derivative with multiple therapeutic uses and rare adverse effects, which include pruritus, irritation, or burning sensations. Its dermal bioavailability is less than 3%, with hepatic metabolism and renal excretion, and so adverse effects such as nausea, vomiting, urticaria, or anaphylactic reactions are more common when NAC is administered orally or intravenously6.

The NAC molecule has a free SH group, which is responsible for the foul smell. This group undergoes deacetylation and its main metabolites are cystine and cysteamine. Thus, these two molecules were initially selected as possible alternatives. Carbocisteine is in the same therapeutic group (ATC classification: R05CB) and has a similar chemical structure to NAC9.

In addition, we searched PubChem8 for other different molecules with a similar structure to NAC that could be used as possible therapeutic alternatives. The molecules assessed were cystine, cysteamine, carbocisteine, cysteine, and methionine.

Cystine is a white crystalline powder that is almost insoluble in water and 96% ethanol. It dissolves in dilute solutions of alkaline hydroxides. Cystine is a sulphur-containing aliphatic amino acid biosynthesized from cysteine, and is present in many foods. It is involved in the metabolism of the skin and adnexa, and is a constituent of keratin. It is used as a dietary supplement and in the treatment of congenital homocystinuria. In addition, it is indicated in cases of diffuse alopecia, alopecia areata, acne, seborrheic eczema, nail diseases, psoriasis, and skin disorders with sulphur deficiency15.

Cysteamine is a white powder that is soluble in water and ethanol. It has an unpleasant smell due to the presence of free SH groups. Furthermore, it is not marketed as a raw material in Spain8.

Carbocisteine is a white crystalline powder that is soluble in dilute solutions of mineral acids and alkaline hydroxides, and is almost insoluble in water and 96% ethanol. It is a mucolytic agent that reduces the viscosity of bronchial secretions. Carbocisteine is used in respiratory tract disorders associated with excessive mucus such as bronchiectasis, asthmatic bronchitis, pulmonary emphysema, pneumonia, tuberculosis, cystic fibrosis, and in all conditions in which mucolytics and expectorants are required. It attains maximum stability at pH 5.5 to 7.5. It can sometimes cause nausea, headache, gastric discomfort, diarrhoea, and skin eruptions when administered orally16. Unlike NAC, the carbocisteine molecule lacks a free SH group that cannot be released during the oxidation process. This means that the carbocisteine molecule lacks a foul smell17.

Cysteine is a bright white crystalline powder. Because of its antibiotic properties, it is used in topical preparations for the treatment of various skin conditions. However, due to the presence of the free SH group, it has a certain acidic smell18.

Methionine is an almost white crystalline powder, fairly soluble in water and very slightly soluble in 96% ethanol. It dissolves in dilute acids and in dilute solutions of alkaline hydroxides. Methionine increases glutathione synthesis. It is used as an alternative to NAC in the treatment of paracetamol overdose to prevent liver damage. It also has lipotrophic action and is used as an adjuvant in the treatment of liver diseases, pancreatitis, schizophrenia, and urinary incontinence. It can be administered to treat alopecia and intervenes in keratinization processes. It can cause nausea, vomiting, drowsiness, and irritability when administered orally19.

Cysteine and cysteamine, despite being metabolites of NAC, have the free SH group in their molecule, which gives them the same unpleasant smell as NAC. Furthermore, cysteamine is not marketed as a raw material in Spain. For these reasons, they were rejected as therapeutic alternatives in the preparation of the MF (Table 1).

Among the three remaining molecules, carbocisteine was selected as a possible therapeutic alternative because it met all the selection criteria: structural similarity to NAC, belonging to the same therapeutic group, having the same mechanism of action and same authorized indication as a mucolytic, lacking a free SH group, and being available as a raw material in Spain.

Both cystine and methionine were considered as a second choice in case the MF of carbocisteine could not be developed or was not effective for the indication sought (i.e. a keratolytic in the topical treatment of ichthyosis). However, although raw material is available, there is no marketed drug containing either of these molecules as a monocomponent, which implies a lack of information on their safety (Table 1).

The raw carbocisteine material was acquired from the Acofarma laboratory, which is authorized by the AEMPS for the distribution of raw materials20.

To determine the concentration of carbocisteine to be used in the MF, we took as a reference the concentration of NAC (10%) plus urea (5%). This mixture is synergetic, because urea, which is also a keratolytic agent, offers an optimal pharmacological effect and also seems to provide the most effective transcutaneous penetration of the active ingredients6,21.

We selected the same excipients as those used in the standard NAC MF, due to the good tolerance demonstrated with their use in our hospital22. In addition, by using the same excipients, effectiveness could also be compared by making minimal variations in the MF.

Given the characteristics of the patients and the disease, in which these MFs should be applied over large areas of the body, we kept the nonionic self-emulsifying O/W absorption base. This base makes application easier, achieves better homogenization without residue or an oily sensation, and is easily absorbable and dermatologically innocuous1,5,22.

Glycerine is an osmotic dehydrating agent with hygroscopic and lubricating properties. It also has local and topical anti-inflammatory activity, and is an emollient which protects and softens the skin1,5.

Rosemary essence had already been incorporated into the initial NAC and urea MF to reduce its smell to acceptable levels5. By substituting the NAC for carbocisteine, the sulphurous smell was eliminated and it was no longer necessary to add the rosemary essence.

The first step in the development and preparation of the MF was to try to solubilize the carbocisteine with sodium hydroxide (NaOH) in the water phase. However, this was only achieved when the formula had a pH of at least 8. This pH level was not appropriate because it was outside the range of maximum stability of the active principle (AP), neither was it appropriate for chronic use over the entire body surface.

The next step was to pulverize the powder in a mortar and moisten it with glycerine. A paste was obtained which was added into the cooling phase once the emulsion was created. However, the particle size was inadequate because it was noticeable to the touch after application. To eliminate this effect, the particle size was reduced by pulverizing it using an electric grinder. The resulting powder was then moistened with glycerine and incorporated into the water phase under constant stirring.

We used NaOH to adjust the pH level to between 5 and 6, which is appropriate for application over the entire body surface and is within the maximum stability range of the AP.

Table 2 shows the composition of the original NAC MF and the new carbocisteine and urea MF.

We established a validity period of 30 days, which is line with the criteria described in the GBBP's risk matrix for nonsterile and nonoral watercontaining preparations12.

In accordance with the emulsion preparation procedure described in the National Formulary (PN/L/FF/002/00), we conducted the following controls11:

• •

  Organoleptic characteristics: white, uniform, homogeneous, and odourless O/W cream over its established shelf life.

• •

  Type of the emulsion according to the PN/L/CP/002/00 procedure: stable over its established shelf life.

• •

  pH control according to PN/L/CP/001/00 procedure as a O/W emulsion: within the pH of maximum stability of the AP over its shelf life. Table 3 shows the pH values.

  Table 3.

  pH determination values

  ph determination time	pH values (mean ± SD)
  Day 0	5.5 ± 0.4
  Day +30	5.5 ± 0.5

  SD: standard deviation.

Figure 1 shows the standard operating procedure for the new carbocisteine plus urea MF.

Figure 1.

Standard Operating Procedure for the new carbocisteine magistral formula.

(0,51MB).

Initial authorization was obtained for the carbocisteine-urea MF developed for patients with lamellar ichthyosis who were previously receiving the NAC MF. After obtaining the relevant authorizations, the new MF was applied to small specific areas of the body to assess tolerance, the absence of adverse effects, and effectiveness17.

The carbocisteine and urea MF was incorporated into the arsenal of topical treatments available to treat patients with ichthyosis in our hospital, given that there were no side effects, tolerance was good, effectiveness was at least similar to that of the NAC MF, and there was the added benefit of greater acceptance due to the absence of a bad smell17.