Lucky bags in pharmacy and everyday lifeBy Sandra Klein and Thomas ZoellerCyclodextrins are molecular sugar bags that can enclose lipophilic substances inside.This changes their properties.This makes the glucose rings coveted "piñatas" in everyday products, but also in pharmacy.For a long time, cyclodextrins (CD) were used almost exclusively in the food, cosmetics and household goods industries.The carbohydrate excipients served mainly as flavor stabilizers, to eliminate unpleasant tastes and odors and thus to improve the quality of food and beverages (1, 2) (Table 1).Many other areas of application have followed in the last two decades.Until the early 1990s, the proportion used for the manufacture of pharmaceuticals accounted for less than 5 percent of total sales.Since the 1980s, CDs have been used as additives in foods, in the early years mainly to stabilize flavorings.With their help, the mostly oily aromas can be complexed into powder-like products, which increases their stability and makes processing easier.As a side effect, packaging costs are reduced because stabilized flavors require less complex packaging (3).Since aromas such as vanillin, menthol, cinnamon or orange oil in the form of CD complexes are less sensitive to light, heat, oxygen and humidity, their shelf life is also increased (4).Similar to flavors, omega-3, -6 and -9 fatty acids can also be stabilized by CD complexation.The odor and taste masking potential of the cyclodextrins is also positive here.The additives are very often used today to conceal, for example, bitter substances from grapefruit juice, coffee, tea or ginseng, or to mask bad odors in fish oil or garlic oil.For an odor or taste to be perceived as unpleasant, the substance responsible for it must come into direct contact with the receptor proteins on the ciliary membrane in the nose or the taste buds on the tongue.However, this is only possible if the substance is present on the receptors in a free and dissolved form.Completely insoluble or non-evaporable substances cannot develop any smell or taste.In order to mask odors or tastes, the odorous, flavoring or bitter substances must form a stable complex with the CD molecule.The efficiency of this process depends on the complex formation constant, the pH value (ionized molecules form less stable complexes) and the host-guest ratio (optimal = 1:1).The hydrated CD case shields the molecule so well that it can no longer interact with olfactory and taste receptors: the sensors are switched off.In addition to the classic use as a stabilizer, odor and taste corrector, new areas of application are constantly opening up for cyclodextrins in the food industry.For example, the current focus is on reducing the cholesterol content of butter, cheese or eggs.The natural cyclodextrins in particular are very well suited for use in cosmetics.The main purpose is also the stabilizing effect.It is found in anti-aging products as a stabilizer of linoleic acid, retinol and α-tocopherol (3).These are substances that protect lipid molecules in cell membranes from oxidative destruction, prevent premature skin aging and mitigate UV-induced skin and tissue damage.However, these substances are highly sensitive to UV radiation, higher temperatures and atmospheric oxygen.However, the use of the CD complexes increases the stability of preparations containing linoleic acid, retinol and α-tocopherol.At the same time, the additives have another positive effect: by releasing linoleic acid, retinol and α-tocopherol from their cavity in a controlled manner, they indirectly prolong and intensify the effect.The acid-labile and difficult-to-handle anti-wrinkle ingredient linolenic acid has recently become available as a stable CD complex for cosmetics.In addition to the stabilizing effect, cyclodextrins also have other positive properties in cosmetics.Here, too, they can encapsulate or cover up odors in a targeted manner.Important examples are bad odors that arise during the process of self-tanning the skin with dihydroxyacetone or bleaching the skin with glutathione.Cyclodextrins make the use of such products much more pleasant.The release control effect is also used in many ways by packing components that determine the effectiveness in CD microcapsules.For example, the researchers can achieve a continuous release of menthol from the preparation of after-sun products, which the consumer notices as a lasting, pleasantly cooling effect.The same procedure is used to prevent the highly volatile tea tree oil from the Melaleuca alternifolia shrub from prematurely evaporating after application to the skin.A continuous release and persistent antibacterial effect is used today in various acne preparations.The excipient also masks the odor of the oil, which is said to improve user compliance (5).Of course, the textile industry is also interested in the odor-binding effect.By first functionalizing CD molecules and then covalently attaching them to textile and cellulosic fibers, they can be processed into textiles in such a way that they do not become detached during the washing process (6).The bound cyclodextrins retain their ability to form complexes and can pick up unpleasant odors such as cigarette smoke or animal odors through host-guest complexes.Human scents are also concealed.By complexing essential components of the sweat, microbiological processes are stopped: there is no smell of sweat.During washing, the entrapped compounds are removed from the CD molecules and the anchored sugar sachets are once again available for odor absorption.Such effects are very popular today in the development and manufacture of functional and sportswear.However, the cyclodextrins anchored on the textile fiber can also be used in the opposite way to release fragrances or skin care substances in a targeted manner.For this purpose, the molecules are loaded with perfumes, almond or avocado oil, sunscreen, vitamin E or aloe vera extract, for example.When they come into contact with the skin, they release them again in a controlled manner due to heat, moisture or friction.In addition, research is being carried out into the enrichment of tissues with pharmaceutical agents.Such a technology could help to dose the active and care ingredients for allergies, neurodermatitis, psoriasis or athlete's foot directly where they are needed.In 1999, Febreze® (Procter & Gamble) became the world's first CD-based odor neutralizer on the German market.The product uses the complexing properties of cyclodextrins to bind unpleasant odors from the air, from upholstery, shoes and other textiles quickly and easily.Such odor neutralizers and textile fresheners are now being marketed by many companies and are pushing the previously common fragrance sprays into the background, particularly because of their harmlessness.The examples show how widespread cyclodextrins and their derivatives are in everyday life.The pharmacist is particularly interested in their use in pharmaceutical dosage forms, which is explained in more detail below.There are also various reasons for using cyclodextrins and their derivatives in pharmacy.They are often used to reduce or avoid irritation of physiological barriers, for example the gastrointestinal mucosa or the retina of the eye, to mask the bad smell or taste of a drug or excipient, or to prevent interactions between drugs and/or excipients stop.Not to be forgotten: CDs improve the solubility of poorly soluble drugs, which is often associated with improved bioavailability of the substance.Table 2 summarizes approved CD-containing medicinal products.The use of CD in aqueous eye drops has a number of advantages.Complexed lipophilic drugs are less irritating to the eye and have higher bioavailability.At the same time, the stability of the drug molecules, which is often low in aqueous media, increases;CDs thus make a significant contribution to improving the shelf life of the preparations (11-13).Furthermore, cyclodextrins can also cause retardation effects, especially when readily soluble drug molecules are complexed and at the same time there is an excess of excipient, which strongly shifts the equilibrium between free/dissolved and complexed drug to the side of the complex and thus slows down absorption via the cornea .Usually, not the natural CDs are used for eye drops, but their readily soluble derivatives, more precisely the hydroxypropyl derivatives of β- and γ-CD, partially methylated β-CD and sulfobutyl ether-β-CD (11-13).Due to their high molar mass and hydrophilicity, neither the excipients alone nor the drug-CD complexes are absorbed through lipophilic membranes.This means that the cyclodextrins remain in the tear fluid after application and keep the drug, which is poorly soluble per se, in solution until they can release it from their cavity at the cornea.Then the drug can penetrate into the lipophilic corneal epithelium.Various in-vivo studies with lipophilic medicinal substances such as steroids and corticosteroids have shown that with the addition of CD, compared to pure medicinal substance solution, far greater concentrations of active substance are kept in solution and take effect after permeation through the cornea.Increased bioavailability was demonstrated for all drugs tested.Despite these positive findings, only a few ophthalmic medicines containing CD are commercially available worldwide.In Germany, only one finished medicinal product containing diclofenac sodium is currently approved.This contains 2-hydroxypropyl-γ-CD, which increases the solubility of the drug, prevents interactions between the active ingredient and the preservative and thus improves the shelf life of the preparation.By replacing the originally used polyoxyethylene 35 castor oil, a nonionic surfactant, it was possible to achieve a shelf life of 36 months at room temperature with the same bioavailability, while the old galenic form was only stable for 24 months when stored in the refrigerator (14).However, cyclodextrins also have negative effects on the eye.It cannot be completely ruled out that they are stored in the cornea or damage it by releasing cholesterol and phospholipids.A strong interaction with various preservatives such as benzalkonium chloride or parabens has also been demonstrated (15), which makes use in multi-dose containers more difficult.Furthermore, crusting of the eyelids was observed in some in-vivo studies, particularly in patients with "dry eyes" after application of preparations with a high CD content, which many subjects found unpleasant (12).These negative effects of cyclodextrins can now be eliminated by adjusting the concentration ratios of drug, CD and other excipients.In any case, they only apply to a few representatives within the large family of cyclodextrins and their derivatives.Nevertheless, they will probably continue to limit their use in eye drops.The use of cyclodextrins in parenteral dosage forms primarily serves to convert poorly soluble drugs into an injectable (intravenous, intramuscular, subcutaneous) form and at the same time to avoid irritation at the puncture site.The stabilizing effect of the CD makes it possible to keep even medicinal substances that are sensitive to hydrolysis in solution in an aqueous medium for a longer period of time without decomposition occurring.This effect is particularly important for substances that are administered as a continuous drip infusion.When developing parenterals, particular attention must be paid to the safety and harmlessness of the cyclodextrin.The natural compounds, especially α- and β-CD, are generally not suitable for parenteral use.However, toxicological studies have confirmed the safety of 2-HP-β-CD and SBE-β-CD (16-18).Due to this fact and the much better water solubility, these derivatives are suitable for the production of parenteral dosage forms.According to current literature, seven parenterals containing 2-HP-β-CD or SBE-β-CD are approved worldwide (Table 2).There are three on the market in Germany (10).It is an itraconazole concentrate (2-HP-β-CD) for solution for infusion for the treatment of histoplasmosis and severe systemic mycoses, a voriconazole-containing powder (SBE-β-CD) for solution for infusion also for the treatment of severe Systemic mycoses and a powder containing ziprasidone mesylate (SBE-β-CD) for solution for injection for the rapid and short-term control of agitation in patients with schizophrenia.As can be seen from the indications, all commercial preparations are medications that have to act quickly and extremely reliably, to which the β-CD derivatives make a significant contribution.In addition, there are also various α-CD-containing powders for the production of parenteral alprostadil (PGE1) dosage forms on the German market.These are used to treat erectile dysfunction and stage III and IV chronic arterial disease.The preparations each contain very small amounts of α-CD, which should not cause any problems if used correctly after the injection or infusion.Nevertheless, it is not to be expected that further α-CD-containing preparations for parenteral use will appear on the market in the future, but that the CD derivatives will prevail here.The trend is towards derivatives, not only for parenterals, but also for peroral dosage forms.At present, however, β-cyclodextrin still dominates.The main function of the excipient in enteric-coated omeprazole preparations (Table 2) is to stabilize and improve the solubility of the acid-sensitive drug.This not only increases the storage stability of the preparations.Due to the complexation, the active ingredient remains stable during the passage through the stomach, even if a small amount of gastric juice penetrates the interior of the dosage form despite the gastric juice-resistant coating.After dissolution of the enteric coating, omeprazole is released in the small intestine.Natural β-CD is also found in lozenges containing dextromethorphan-HBr for cough suppression.Here it also serves as a stabilizer and solubility enhancer.It also masks the bad taste of dextromethorphan-HBr (19).In thyme pastilles, the glucose ring prevents the thyme oil from evaporating and thus increases the storage stability of the preparations.In addition, when the lozenges are sucked, it ensures a controlled release of the antimicrobial thyme extract and thus increases its effectiveness.Systemic fungal infections can sometimes be life-threatening in immunocompromised patients.A number of new, potent antimycotics have been developed in recent years, but their bioavailability is often severely limited due to the poor solubility of the substances.One of the most difficult candidates in this class of active substances is itraconazole. This was the first approved orally bioavailable active substance with a clinically significant effect against Candida and Aspergillus species, the two most common human pathogenic fungi (8).Itraconazole is a broad-spectrum triazole antifungal, but with a pKa of 4, a logP > 5 and an aqueous solubility of only 1 ng/mL (8), it exhibits physicochemical properties that make formulation development extremely difficult.Nevertheless, some itraconazole preparations are already on the market.In the classic oral formulation, pellets are used in which the poorly soluble active ingredient is finely distributed on the surface.The increase in surface area achieved in this way can significantly improve the rate of dissolution in an empty stomach, i.e. in the acidic gastric juice.However, in patients with a chronically elevated gastric pH value, for example in elderly people, AIDS patients or after taking antacids, H2 blockers or acid secretion inhibitors, the pH-dependent dissolution rate drops considerably.Therefore, the advice on taking “taken whole with an acidic drink (e.g. cola) or directly after a meal” applies, whereby in the latter case the pH value is not used, but rather the more lipophilic intragastric environment is used to solubilize the active substance (20). .Both intake conditions can prove to be difficult, especially for the patient collective mentioned.For this reason, an itraconazole solution for the treatment of oral and/or esophageal candidiasis in HIV-positive and other immunosuppressed patients and for the prevention of systemic mycoses was offered in Europe and the USA in 1997.In the oral solution, 2-HP-β-CD is used to solubilize the drug.This gives a product that has a high absorption rate and improved bioavailability when taken on an empty stomach.Even multimorbid patients or children can easily take the solution.In addition, the dose can be individually adjusted very easily (21).A parenteral dosage form followed in 1999, also with 2-HP-β-CD as a solubilizer.It is remarkable that this derivative has been used to increase the aqueous solubility of itraconazole (1 ng/ml) to over 10 mg/ml with such reliability that physicians can even administer the solution intravenously with ease.Both 2-HP-β-CD-containing products have been shown to be safe in clinical studies and are well established in both the European and US markets.Of all CD-containing pharmaceuticals, they are used most frequently.The reasons certainly lie in the clinical importance of itraconazole, but also in the good tolerability of the preparations.The 2-HP-β-CD-containing dosage forms are therefore a very good example of how technologists were able to develop an effective drug from a highly potent active ingredient with no significant bioavailability using sophisticated galenics.In the future, both the established CD derivatives and new compounds will become more important as excipients for drugs.This is being researched in many laboratories, including at the Institute for Pharmaceutical Technology at the Goethe University in Frankfurt am Main.Here, pharmacists are working with a new β-CD derivative, namely hydroxybutenyl-β-cyclodextrin (HBen-β-CD).Good water solubility (> 500 g/L) and physiological harmlessness have been demonstrated for HBen-β-CD (22).The goal of a first series of tests was to develop a solid peroral dosage form for itraconazole that has a significantly higher bioavailability compared to the pure drug.For this purpose, an itraconazole-HBen-β-CD complex was first prepared and its solubility and drug release in various physiologically relevant media were determined (Table 3).*detailed composition from the authorsThe solubility of itraconazole in aqueous media is so low that the dissolved or released active substance concentration of the pure drug was below the detection limit in all media.In contrast, solubilities of up to 8 mg/ml were measured for the itraconazole (HBen-β-CD) complex, especially under test conditions of the fasting stomach.These results were reflected in the subsequent release studies.A standard dose of 100 mg itraconazole was completely released in a very short time in the paddle experiment in 500 ml test medium under conditions of an empty stomach (pH 1.2).In all other test media, too, the release of the active ingredient from the HBen-β-CD complex was significantly better than that of the pure drug.The test formulation was then tested in a pharmacokinetic study in Sprague-Dawley rats;the resulting plasma levels were compared with those after application of a commercially available solid dosage form to the same animals.Irrespective of the prandial status of the application, the bioavailability after administration of the itraconazole-HBen-β-CD complex was significantly higher than after the commercial dosage form (19% to 20% versus 10.8% absorbed) (23).Overall, the in-vivo study confirmed the good results of the in-vitro studies.She also showed that the formulation as an itraconazole-HBen-β-CD complex can significantly improve the bioavailability of the drug and at the same time eliminate the "food effects" typical of itraconazole.This allows the dosage form to be taken with or without meals, which could increase patient compliance.It is now necessary to show whether the results can be transferred to human applications.The examples mentioned show very clearly that the CD derivatives not only make a significant contribution to the stabilization and improvement in the solubility of classic active substances, but can also have a positive effect on the bioavailability of medicinal substances.They are also suitable for the formulation of proteins, peptides and oligonucleotides, in which case the stabilizing and protective function will be more important (8).One thing is certain: Although cyclodextrins were discovered more than 100 years ago, they will continue to be of great importance for drug formulation in the future.