Fig. 22.1
The hospital triad involved in dermatological medicine management and major outcome that should be considered by each protagonist
Firstly, active pharmaceutical ingredients (APIs), currently prescribed by dermatologist, exhibit low aqueous solubility (e.g., class II, diclofenac; class IV, sulfadiazine) and low permeability (e.g., class III, acyclovir, and class V, acetazolamide) which complicate the selection of excipients for compounding. Therefore, pre-formulation studies are usually necessary for screening appropriate excipients when compounded preparations prescribed are not detailed or indexed in the Pharmacopeia and the Formulary (i.e., national compendia for chemical and biological drug substances, dosage forms, and compounded preparations, excipients, medical devices, and dietary supplements). Both national compendia display substantial heterogeneity in their contents over the world.
Secondly, although medical and scientific literature detailed many original excipients, alone or in combination, enabling the formulation of APIs for topical treatment, few topical preparations are reported in the Pharmacopeia and the Formulary.
Thirdly, the suppliers of pharmaceutical grade excipients necessary for dosage forms and compounded preparations are (1) scarce, (2) sometimes located in foreign country limiting importation and/or exportation of pharmaceutical products, (3) not permanently approved by local health and safety regulatory authorities, and (4) not scaled for small production, packaging, and shipment of excipients and APIs to health-care hospital or clinical establishments.
Fourthly, the safety of excipients is recurrently questioned by authorities from the analysis of notable adverse effects imputable to excipients shifting their status from inactive to mystery ingredients, reducing again the width of the field of choice (Noiles and Vender 2010).
Fifthly, the conservation, the packaging, and storage of topical formulations is a major concern since the use and reuse of the preparation is an obvious source of human and exogenous contamination, a factor of physicochemical degradation (e.g., hydrolysis, oxidation) of APIs and excipients, and an issue for formulation instability (e.g., syneresis, creaming, sedimentation).
Again, the degree of purity of excipients, from different origins (i.e., from biological or mineral to chemical-based synthesis), is often weakened by concomitant components or processing aids, and the final use of excipients is not always known by the supplier. Therefore, the choice of appropriate excipients for topical compounding is also a compromise between pharmaceutical state of the art and the regulatory and availability status of excipients. Facing (i) the pharmaceutical compounding challenge, (ii) the inherent restrictions of available, authorized, and harmless excipients, (iii) the package features, surely, the simplest drug-excipient combination for ready-to-use and easy-handling product is highly needed for the formulation development of topicals.
However, the pharmacist experiences that, at some points, the development of topical preparation leads to consider top-ten recommendations:
1.
Avoiding the use of many excipients, to prefer straightforward process of preparation where APIs are quickly dissolved, miscible, or suspended in aqueous solvent supplemented by not more than three excipients
2.
To choose excipients insuring both physical and chemical stability of APIs, excipients, and formulation
3.
To reduce pH variation of formulation over time during skin exposure (skin surface – pH ~5.5)
4.
To check the probability to reuse and to avoid contamination of formulation
5.
To guarantee easy spreading and removal, sustainability, and aesthetical acceptability (i.e., feel, color, fragrance, absorbability) of formulation
6.
To permit optimal API penetration into skin structures (dermal delivery)
7.
To permit optimal API permeation through skin structures (transdermal delivery)
8.
To favor or to limit the buildup of APIs and excipients into the skin
9.
To improve the cutaneous tolerance to APIs and excipients
10.
To improve the efficacy of APIs into the skin or after percutaneous delivery
Therefore, few excipients might fulfill prerequisites detailed above. Among likely candidates, excipients forming thermosensitive (also called thermoresponsive or thermoreversible) hydrogels offer many advantages which have been extensively detailed in reviews published in the last decade (Jeong et al. 2012; Klouda and Mikos 2008; Ruel-Gariépy and Leroux 2004). The main intrinsic advantages of thermosensitive hydrogel are as follows: (1) high water content, (2) solubilizing properties for hydrophobic APIs, (3) control of swelling properties and gelling temperature, (4) adaptation for tailor-made formulations in specific dermatologic diseases, and (5) versatile skin drug delivery from either surface application, intradermal or subcutaneous injection.
In the followings sections, physicochemical properties of current and innovative thermosensitive polymers are presented, and then the actual and prospective dermatological applications of thermosensitive polymer-based formulations are emphasized.
22.2 Thermosensitive Polymers
22.2.1 General Considerations About Hydrogels
The gelation in the aqueous solvent is a complex phenomenon where a polymer initially soluble in water becomes more hydrophobic by (1) interaction with mineral ions (e.g., gellan gum, natural anionic heteropolysaccharide, sodium alginate, natural polysaccharide), (2) variation of pH (e.g., polymers carrying carboxylic acid, phosphoric acid, and amine groups) leading to a change of conformation and swelling behavior (Schmaljohann 2006), or (3) modification of temperature. As a result, a transparent or translucent semisolid polymeric matrix is obtained where the fluid flow is limited by entrapment and immobilization of the solvent molecules and possesses remarkable mechanical properties (deformation, viscoelastic properties) which facilitate further cutaneous spreading.
The regional ionic strength upon the outermost layer of the skin, the stratum corneum, is likely insufficient to elicit gelation with ionic-responsive polymers (i.e., making necessary pre-gelation of formulation containing appropriate ionic strength) (Aust et al. 2012), while acidic pH (~5.5) at the skin surface do not allow a gelation of common acidic polymer (e.g., carbomer). Besides, the regulation of body temperature, one of the major skin functions in homeostasis, might be exploited for the successful development of thermosensitive hydrogels.
Moreover, interactions between skin and thermosensitive polymers have been of growing interest in the past decades as (1) intimate properties and mechanics of such polymers were gradually documented and (2) skin is regarded as a promising alternative to traditional oral or parenteral routes for the administration of active pharmaceutical ingredients. Furthermore, interesting parallels between skin or subcutaneous tissues and hydrogels in terms of chemical and physical characteristics draw exciting perspectives for future developments in experimental and clinical fields (Lee et al. 2009).
22.2.2 General Considerations About Thermosensitive Hydrogels
The ability for a solution of polymer to modify its bulk viscosity in response to temperature variation is called thermosensitivity. Generally natural polymer solutions form gels at low temperature and liquefy when temperature rises, but chemically modified polymers or synthetic polymers may exhibit opposite behavior defined as reverse thermosensitivity. As the physical state (i.e., free flowing or non-flowing during usage time) can be controlled by thermal modulation, formulas containing those polymers may have innovating pharmaceutical applications due to control of solute transport abilities and biocompatibility. Various polymeric molecules exhibit thermosensitive properties such as natural polymers (e.g., gelatin, agarose, carrageenans), modified natural polymers (e.g., cellulose derivatives, chitosan, dextran, xyloglucan), synthetic polymers (e.g., N-isopropylacrylamide and its copolymers), or poloxamers (i.e., poly(ethylene oxide)/poly(propylene oxide), polyethylene glycol/polyester copolymers) (Table 22.1) (Jeong et al. 2012; Klouda and Mikos 2008; Ruel-Gariépy and Leroux 2004).
Table 22.1
Structures and formulas of polymers currently used for thermosensitive hydrogel formulations in commercial products or pharmaceutical compounding
Polymers | Formula | Molecular weight (g.mol−1) | USP/Eur. Ph | CAS number |
|---|---|---|---|---|
Gelatin② | e.g., -Ala-Gly-Pro-Arg-Gly-Glu-4Hyp-Gly-Pro- | 15,000–250,000 | Referenced/referenced | 9000-70-8 |
Agarose② (Agar) |  | 306 • n | Referenced/referenced | 9063-31-4 |
Carrageenans② |  | 451 • n | Referenced/not referenced | 9000-07-1 |
Cellulose derivatives |  R = -H, -CH3, -CH2CH2OH,-CH2CH(OH)CH3 -CH2OCH2COONa | |||
Methylcellulose④ | 10,000–220,000 | Referenced/referenced | 9004-67-5 | |
Hydroxyethylcellulose② | – | Referenced/referenced | 9004-62-0 | |
Hydroxypropyl-cellulose① | 50,000–1,250,000 | Referenced/referenced | 9004-64-2 | |
Hydroxyethyl methylcellulose① | – | Not referenced/not referenced | 9032-42-2 | |
Hydroxypropyl-methylcellulose① | 10,000–1.500,000 | Not referenced/referenced | 9004-65-3 | |
Carboxymethyl cellulose sodium② | 90,000–700,000 | Referenced/referenced | 9004-32-4 | |
Chitosan② |  | 320 • n | Not referenced/referenced | 9012-76-4 |
Poloxamers |  | |||
124③ | a: 10–15; b: 18–23 | 2,090–2,360 | Referenced/referenced | 9003-11-6 |
188③ | a: 75–85; b: 25–30 | 7,680–9.510 | Referenced/referenced | 9003-11-6 |
237③ | a: 60–68; b: 35–40 | 6,840–8,830 | Referenced/referenced | 9003-11-6 |
338③ | a: 137–146; b: 42–47 | 12,700–17,400 | Referenced/referenced | 9003-11-6 |
407③ | a: 95–105; b: 54–60 | 9,840–14,600 | Referenced/referenced | 9003-11-6 |
Polyesters copolymersa | 2,000–100,000 or higher | Not referenced/not referenced | ||
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