Benefits of Inclusion Complexes (Cyclodextrin–Antibiotic) in Anti-Bacterial Therapy: History
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Contributor:
Mariana Grecu
,
Bogdan Minea
,
Liliana-Georgeta Foia
,
Andra-Cristina Bostanaru-Iliescu
,
Liviu Miron
,
Valentin Nastasa
,
Mihai Mares

Cyclodextrins (CDs) are a family of carrier molecules used to improve the pharmacokinetic parameters of therapeutic molecules. These cyclic oligosaccharides have medical and pharmaceutical applications by being able to form inclusion complexes with molecules that are poorly soluble in water. The benefits of these complexes are directed towards improving the chemical and biological properties—i.e., solubility, bioavailability, stability, non-toxicity and shelf life of drug molecules.

  • cyclodextrin
  • inclusion complex
  • antibiotic
  • antibacterial
  • veterinary medicine

1. Introduction

Starting from the fact that many of the drugs used in therapeutics have their limitations (unsatisfactory bioavailability and distribution, high toxicity, limited efficacy, active residues, etc.), controlled release systems or carrier molecules have been used to improve their pharmacokinetic profile [1][2]. A group of carrier molecules used in the pharmaceutical industry is represented by cyclodextrins (CDs), obtained by the enzymatic conversion of starch into glucopyranose units organized in a cyclic structure. Structurally, CDs have an inner cavity where various poorly soluble medicinal substances can be included to form soluble inclusion complexes, with great stability both in the solid phase and in the aqueous phase due to the ring structure they possess [3][4].
These characteristics make CDs, and their derivatives have a variety of practical applications in many fields, such as the pharmaceutical industry, medicine, cosmetics, biotechnology, nanotechnology, agriculture, the food industry, the textile industry, the paint industry, etc. However, the most important field of use of inclusion complexes with CDs is the pharmaceutical one in the context of the constant launch of new drugs [5].
In the pharmaceutical industry, CDs are frequently used, mainly due to their ability to significantly increase the solubility of a poorly soluble medicinal substance [6][7], without changing its physical, chemical and biological properties. In medicine, they are used in particular to improve the chemical stability and to increase the bioavailability of drugs [8]. CDs are also used to reduce the irritation caused by the drug at the injection site, to minimize or reduce the unwanted side effects of some drugs at the gastrointestinal or ocular level and for complete renal elimination from the body [9]. At the same time, they are also used to reduce or completely eliminate the unpleasant smell or taste of some active principles, to reduce the incompatibilities and drug interactions that can occur between the active principles and excipients [10][11]. It is also specified that they can be used as potential antidotes in organophosphorus poisoning in animals [12]. CDs prevent drug degradation such as oxidation, hydrolysis, and photodegradation and extend drug shelf life [13][14].

2. Applications of CD–Antibiotic in Anti-Bacterial Therapy

The discovery of antibiotics was a major milestone in the history of medicine as they saved many human and animal lives. However, the use of these initially miraculous drugs was quickly accompanied by the emergence of antibiotic-resistant bacterial strains, which represent a global public health problem and a serious concern in finding alternative solutions to reduce antibiotic use [15]. Today, the rate at which antibiotic resistance is developing and the rapidity of its spread among different bacterial species is extremely alarming. New forms of resistance to antibiotics spread very easily on all continents, which implies prolonged and more expensive treatments, with sometimes the appearance of severe side reactions and even death.
The treatment of infections in animals can be done either with time-dependent antibiotics (beta-lactams, macrolides, glycopeptides), which require long periods of administration, or with concentration-dependent antibiotics (aminoglycosides, fluoroquinolones), which require high concentrations for antibacterial activity [16]. In both cases, the amounts of residue can be very high and even have a long half-life. Additionally, these antibiotic residues are difficult to remove from food products, they can last a long time (days, months) in the environment and can present a real danger to human and animal health. At the same time, due to the appearance of superbug bacteria, resistant to several classes of antibiotics, these antibiotics lose their therapeutic effectiveness [17].
The development of new antibiotics could not fundamentally solve the problem. The new conventional antibiotics only temporarily improved the situation, because bacteria developed resistance after their long-term use [18]. One of the effective ways that alleviated the resistance of bacteria to antibiotics was their complexation with CDs or their derivatives. Through this technology, an improvement in the therapeutic index (through the controlled release of antibiotics), a reduction in the dosage and the administration interval was achieved [19][20].
Enrofloxacin, a third-generation fluoroquinolone, is a broad-spectrum antimicrobial against many bacterial diseases in animals. The bactericidal activity of enrofloxacin, however, is dependent on the concentration, it has a poor solubility in water, which greatly limits its applicability and therapeutic effect. Wei et al. evaluated through their studies the effectiveness of enrofloxacin and florfenicol complexed with γ-CD. They observed that the new compounds developed much better antimicrobial activity, demonstrated by the fact that the zones of inhibition for E. coli and S. aureus were much clearer [21]. Complexing it with 2-hydroxypropyl-β-CD (HP-β-CD), a CD derivative, resulted in a stable inclusion complex with significantly improved solubility (increased by 32.5%) for enrofloxacin [21][22]. Ding Y. et al. observed a 916-fold improvement in the solubility of complexed enrofloxacin compared to previous studies (169-fold), thus demonstrating that the pharmaceutical, absorption and bioavailability properties of enrofloxacin were significantly modified after complexation with HP-β-CD. The modification of the physical and chemical properties led to the increase of the therapeutic efficacy, to the reduction of the treatment interval, of the amount of antibiotic used and implicitly of the residue, compared to the treatment period of commercial enrofloxacin [22].
The formation of the inclusion complex β-CD–norfloxacin, another fluoroquinolone of the second generation, with antimicrobial effect and broad spectrum of activity—used both in human medicine and in veterinary medicine—was described by Chierentin L. et al., by exploring the structure affinity relationship for norfloxacin in solid and aqueous phases. It was observed that the solubility of norfloxacin was significantly increased by complexation with β-CD. Thermal analysis also showed that the stability of norfloxacin was improved in the presence of β-CD. Microbiological studies have shown that the product complexed with β-CD has a better potency compared to the pure drug due to the improvement of pharmaceutical (stability, dissolution, solubilization), pharmacokinetic (absorption, transport, release and bioavailability) and toxicological (dose and, implicitly, toxic level reduction) properties [23].
Another inclusion complex developed was the one between HP-β-CD and florfenicol, a broad-spectrum antibiotic used in many countries for the treatment of infectious diseases in animals and birds caused by susceptible strains. Since florfenicol has poor solubility in water, it is necessary to use it in large doses, which significantly limits its use. Fan G. et al. analyzing the physical properties of the inclusion complex (Florfenicol–HP-β-CD) compared to simple Florfenicol, observed after intramuscular injection in Beagle dogs, an improvement in pharmacokinetic parameters (elimination half-life [t1/2β], the transport rate constant [K10, K12, K21] and the maximum concentration [Cmax]. In contrast, the half-life of the distribution process [t1/2α], the absorption rate constant (Ka) and the apparent volume of distribution (V1/F) decreased [24]. These results suggest that parenteral administration of Florfenicol–HP-β-CD is promising in antimicrobial therapy, having much higher bioavailability at low doses.
Various other antibiotics used in both human and veterinary medicine have been complexed mostly with β-CD or its derivatives (Table 1), such that by the end of 2021, more than 200 publications discussing the complexation of CDs with antibiotics and other anti-infective agents, including beta-lactams (amoxicillin), tetracyclines (tetracycline, doxycycline), quinolones, macrolides (erythromycin, clarithromycin), aminoglycosides (gentamycin, amikacin), polypeptides (colistin), nitroimidazoles (metronidazole), and oxazolidinones (furazolidone), were registered [19]. These studies focused on improving solubility, altering the drug release profile, slowing drug degradation, improving biological membrane permeability and increasing antimicrobial activity. Although these inclusion complexes are used in human medicine, some of them do have the potential for veterinary use, because the plain non-complexed active drug molecules are already being used in veterinary medicine.
Table 1. Brief overview of the inclusion complexes of antibacterial drugs used in veterinary medicine.
Active
Compound		 Activity Spectrum Treated
Species		 CD Type Characterization Stoichiometry
Guest: Host		 References
Enrofloxacin Staphylococcus, Escherichia coli, Proteus, Klebsiella, Pasteurella multocida, Pseudomonas, Rickettsia, Chlamydophila felis, Actinobacillus pleuropneumoniae, Haemophilus parasuis, and Streptococcus suis, Mannheimia haemolytica and Haemophilus somni all animal species γ-CD FT-IR, 1H-NMR, SEM, UV spectroscopy, HPLC, Dissolution Studies 1:1 [22][25]
Norfloxacin Mycoplasma, Gram-positive (staphylococci, streptococci, etc.) and Gram-negative (colibacilli, Pasteurella spp., Salmonella spp.) cattle, sheep, goats, pigs and birds β-CD DSC, TGA, FT-IR, XRD, SEM, NMR spectrometry, HPLC, Dissolution Studies 1:1 [23][25]
Florfenicol Gram-positive bacilli and Gram-negative cocci and Mycoplasma cattle, sheep and pigs HP-β-CD SEM, XRD, DSC, FT-IR, 1H-NMR 1:1 [24][25]
Amoxicillin Gram-positive bacteria, in particular streptococcal bacteria causing upper respiratory tract infections all animal species HP-β-CD MDS, IMC, MM, HPLC 1:1 [19][25]
Gentamicin sulphate Aerobic Gram-negative bacteria (e.g., Escherichia coli, Klebsiella pneumoniae, Serratia spp. and Enterobacter spp.), Pseudomonas aeruginosa, and some strains of Neisseria, Moraxella, and Haemophilus horse, foal, cattle, calf, pig, dog, cat β-CD SEM, FT-IR, TGA n/a [19][25]
Metronidazole Protozoans (Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis) and most Gram-negative (Bacteroides and Fusobacterium) and Gram-positive (pepto-streptococci and Clostridia spp.) anaerobic bacteria dogs and cats HP-β-CD Rheology, SEM, NMR, FT-IR, DSC, TGA, XRD, Dissolution Studies n/a [19][25]

This entry is adapted from the peer-reviewed paper 10.3390/molecules28145565

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