Regulatory framework of pharmaceutical compounding and actual developments of legislation in Europe

Pharmaceutical preparations are medicines that the pharmacist makes for the special needs of the patients that the pharmaceutical industry cannot comply for economic and logistic reasons. Pharmacy compounding is still an important component of pharmacy practice and a valuable therapeutical service that is an integrant part of the modern health care system, but its legislation is not harmonized among European and US countries.In 2011 the Committee of Ministers of the Council of Europe has adopted a Resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients. Aim of this resolution is to harmonize quality assurance and standards for pharmacy-made medicinal products among European countries and to pass the gap in quality assurance and standards between preparation in pharmacies and medicines prepared by the pharmaceutical industry. This article will analyze the actual rules and technical norms that regulate compounding activity and the expectations resultants from the new European and US laws

Compounding of (Trans)Dermal Patches by Hot-Melt Ram Extrusion 3D Printing

(Trans)dermal patches (TP) are well-known pharmaceutical preparations designed to provide prolonged drug delivery through the skin to achieve a local, regional or systemic effect. TPs are often preferred to other topically-applied dosage forms since they make it possible to predetermine the drug absorption kinetic and to define the treated area. Thus, TPs can reduce the side effects on healthy skin and due to an undesired systemic drug absorption when localized cutaneous diseases or injuries have to be treated. TPs are produced by a solvent casting technique, but they cannot be easily compounded since, after solvent evaporation, significant modifications of the adhesive matrix, and therefore, of the drug release and adhesive properties, can occur over an unknown period of time, ranging from some days to weeks. These alterations cannot be monitored in a pharmacy setting. This work demonstrated the feasibility of the extemporaneous preparation of (trans)dermal patches by hot-melt ram extrusion 3D printing [1]. This technology makes it possible to easily define both the patch geometry and the dose according to patient needs. The TP preparation consists of three simple technological operations: (i) the drug, the film-forming material (Eudragit (Eu) RL, RS or blends thereof) and the plasticizer (triacetin, TRI, or try-butyl citrate, TBC), which confers the adhesive properties [2], are mixed in a mortar; (ii) the mixture is fed in to the chamber of the ramextruder and heated to 90 \ub0C; (iii) the melt mixture is printed with the desired geometry (thickness: 50 \u3bcm) on the backing layer and coupled with the release liner. The adhesive properties of printed patches were investigated by shear and 180\ub0-peel adhesion tests. The results showed that patches with suitable adhesive properties can be printed using 40% w/w of TRI or 50% w/w of TBC. The TRI containing patches showed higher shear adhesion values than TBC ones (p < 0.05). Since high values of shear adhesion are essential for the patch permanence onto the skin, TRI (40% w/w) was selected to print drug-loaded patches, using 2.34% w/w of ketoprofen (KP) and 3% of nicotine (NT) as model compounds. Neither drug affected the patch adhesive properties, even if a reduction of shear adhesion up to 8-folds was observed based on the drug type and the EuRL/EuRS ratio. Finally, the in vitro release studies showed that the EuRL/EuRS ratio impacted significantly on the release rate of both the tested drugs. According to the well-known characteristics of the two copolymers, the higher the concentration of EuRL in the matrix, the higher the release rate of both KP and NT. References: [1] Musazzi, U.M.; Selmin, F.; Ortenzi, M.A.; Mohammed, G.K.; Franz\ue9, S.; Minghetti, P.; Cilurzo, F. Personalized orodispersible films by hot melt ram extrusion 3d printing. Int. J. Pharm. 2018, 551, 52\u201359. [2] Quaroni, G.M.G.; Gennari, C.G.M.; Cilurzo, F.; Guylaine, D.; Creton, C.; Minghetti, P. Tuning the rheological properties of an ammonium methacrylate copolymer for the design of adhesives suitable for transdermal patches. Eur. J. Pharm. Sci. 2018, 111, 238\u2013246

Low-melting pressure-sensitive adhesives for (trans)dermal patches preparation by 3D printing

(Trans)dermal patches are designed to provide a prolonged drug delivery through the skin to achieve a local, regional or systemic effect. Usually, they are drug-in-adhesive systems, in which the drug is dispersed and/or dissolved in a pressure-sensitive adhesive (PSA) matrix, generally produced by a solvent casting method. This manufacturing approach requires expansive equipment that is not easily adaptable to the preparation of small or personalized batches. This work demonstrated the feasibility of the extemporaneous preparation of PSA-based (trans)dermal patches by hot-melt ram extrusion 3D printing. This technology allows defining easily both the patch geometry and the dose according to patient\u2019s needs avoiding the manipulation (i.e., the dosage form cutting) by the patient or the caregivers. According to the approach proposed for orodispersible film [1], the patch preparation consists of three simple technological operations: i) the drug and the PSA components (at least a polymer and a plasticizer) are mixed in a mortar; ii) the mixture is fed in the chamber of the ram-extruder and heated at a suitable temperature; iii) the melt mixture is printed with the desired geometry (thickness: 50 \u3bcm) on the backing layer and coupled with the release liner. Based on a previous experience, Eudragit (Eu) RL, RS or blends thereof plasticized with different amount of triacetin (40-60% w/w range) were tested as components of the PSA [2] while nicotine (NT) and ketoprofen (KP) were chosen as model compounds. The printed patches were characterized in terms of shear adhesion and 180\ub0-peel adhesion, other than drug content and drug release. The results showed that patches with suitable adhesive properties can be printed using 40% w/w of triacetin. Both drugs did not compromise the patch adhesive properties, even if the shear adhesion was significantly reduced. Finally, the in vitro release studies showed that the EuRL/EuRS ratio impacted significantly on the release rate of both the tested drugs. According to the well-known characteristics of the two copolymers, the higher the concentration of EuRL in the matrix, the higher the release rate of both KP and NT. Literature: [1] U.M. Musazzi, Int. J. Pharm. 2018, 551, 52-59. [2] G.M.G. Quaroni, Eur. J. Pharm. Sci. 2018, 111, 238-24

A new mucoadhesive dosage form for the management of oral lichen planus : formulation study and clinical study

The work aimed at studying a new mucoadhesive prolonged release tablet containing 24\u3bcg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n=16) who received three applications-a-day over 4weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123\u3bcg/application) extemporary mixed with Orabase\u2122 (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n=2) and taste alteration (n=4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24\u3bcg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment

Poly(methyl methacrylate) salt as film forming material to design orodispersible films

This work aims to evaluate the possible use of a poly(sodium methacrylate, methyl methacrylate) (NaPMM2) plasticized by PEG400 in design orodispersible films (ODF). Placebo ODF prepared by solvent casting were intended to study the impact of the polymer/plasticizer ratio and residual moisture on disintegration time, stickiness and mechanical properties. The drug loading capacity was assessed using ketoprofen and paracetamol. Placebo ODF containing PEG400 in the 10\u201330% w/w range and 10\u201315% of residual moisture content were easy-to-handle, packed without failures and completely dissolved within 30\u202fs. NaPMM2/PEG in 80/20 ratio allowed up to 70% of paracetamol loading, which appeared as the largest value described in literature. This ODF showed good mechanical properties and disintegration time. The same formulation loaded with 25% or 50% ketoprofen (pKa\u202f=\u202f4.45) swelled without disintegrating, because of a partial protonation of NaPPM2, as verified by ATR-FTIR spectroscopy. However, the addition of 5% surfactants allowed the formulation of ODF containing 25% ketoprofen that disintegrated within one minute and guaranteed the complete drug dissolution within 5\u202fmin. All the presented data, discussed in the framework of information available on such copolymer, highlighted its versatility in the design of orodispersible dosage forms

A glimpse in critical attributes to design cutaneous film forming systems based on ammonium methacrylate

A film forming system based on Eudragit\uae RL (EuRL) was designed aiming to evidence the relevance of formulative variables on the following critical attributes: film forming rate, outward stickiness, Young modulus (Y) and in vitro drug skin permeation. Different solvent mixtures (acetone and isopropanol in the range from 10:90 to 40:60 v/v), polymer concentrations (10-30 % w/w), and plasticizer types and concentrations (triacetin or tributyl citrate, up to 50% of EuRL) were evaluated. EuRL dissolved in 80/20 or 70/30 v/v isopropanol/acetone mixtures at the concentration of 20% and plasticized with tributyl citrate (20 or 30% with respect to polymer) gave films with negligible stickiness and Y lower than 3 MPa. This value should assure an intimate and prolonged contact with the skin since it was significantly lower than Y of human stratum corneum (55 MPa). The optimized formulations were able to sustain the skin permeation of ibubrofen, ketoprofen and flurbiprofen and evidenced the importance of each formulative variable. In particular, relatively slow solvent evaporation rate can determine an initial \u201cburst\u201d effect and can influence the drug permeation in the initial hours. Conversely, when the solvent evaporation rate is not discriminant, the thermodynamic activity remains the main parameter driving the skin permeation

Mucoadhesive Interpolyelectrolyte Complexes for the Buccal Delivery of Clobetasol

This work aimed to investigate the feasibility to design: (a) a mucoadhesive interpolyelectrolyte complex (IPEC) loaded with clobetasol propionate (CP) intended to treat oral lichen planus and (b) individuate an orodispersible dosage form suitable for its administration. IPECs were synthesized by mixing Eudragit\uae E PO (EPO) and different grades of cross-linked polyacrylate derivatives, in different molar ratios, namely 1:1, 1:2, and 2:1. All IPECs resulted at nanoscale independently of their composition (120\u2013200 nm). Both zeta-potentials (\u3b6) and mucoadhesive performances were influenced by the ratio between polymers. On the bases of the preliminary data, IPECs made of Polycarbophil and EPO in the 1:2 ratio were loaded with CP. The encapsulation efficiency was up 88% independently of the CP-IPEC ratio. The drug encapsulation caused IPEC destabilization in water, as it was noticed by the increase of \u3b6 values and the formation of aggregates. Oral lyophilisates were prepared by freeze-drying slurries made of placebo or CP loaded IPECs, maltodextrin with a dextrose equivalent 38 and Span\uae80. The optimized formulation permitted to obtain a fast disintegration upon contact with water reducing the tendency of IPECs to aggregate. Moreover, oral lyophilisates allowed improving the apparent solubility of CP throughout the in vitro release experiment

In situ film forming fibroin gel intended for cutaneous administration

The possible use of regenerated silk fibroin gels as in situ film forming formulations for cutaneous administration of drugs was studied. Ethanol was selected as volatile and skin tolerant solvent to favor the sol-gel transition of silk fibroin solutions. Glycerin was chosen to ameliorate the gel texture profile. Eighteen placebo formulations were prepared to individuate the optimal component ratios as a function of the texture analysis, spreadability and drying time. The in vitro biopharmaceutical performance was investigated by in vitro permeation test through human epidermis on formulations loading caffeine as a model drug. The data evidenced that the optimal technological performances were achieved using gels containing 70% ethanol and silk fibroin/glycerin ratio from 0.18 to 0.36. The caffeine flux (J) through the skin was significantly improved due to an increase of the drug thermodynamic activity (hydro-alcoholic solution: J 3c0.8\u3bcg/cm(2)/h; in situ formed film: J 3c1.4-1.7\u3bcg/cm(2)/h). In conclusion, silk fibroin can be advantageously proposed as a novel film forming material to develop dosage forms to be topically applied