Pharmaceutical Uses of Cyclodextrins and Derivatives

Abstract

Due to their particular conformation, cyclodextrins have the remarkable characteristic of being able to include various kinds of molecule inside their hydrophobic cavity, conferring on them an environmental hydrophily. These inclusion compounds have completely new pharmacotechnical properties, but the most important ones concern increases in water solubility and bioavailability. When administered orally, the inclusion compounds decompose, allowing the free active ingredient to be absorbed by the gastro-intestinal mucosa. However, a certain proportion of inclusion compound is absorbed without any dissociation.

Some cyclodextrin derivatives are very interesting because of their very high water solubility, and also because of their low parenteral toxicity compared with the original β-cyclodextrin. However, in parenteral administration, it is absolutely necessary to study the pharmacokinetic and pharmacological characteristics of the inclusion compound, which must be considered as the true active ingredient.     

Cyclodextrins,Their Value in Pharmaceutical Technology

Cyclodextrins are cyclic oligosaccharides consisting of a variable number of glucose units (usually 6 to 81. The ring formed by cyclodextrins is externally very hydrophilic and relatively apolar internally. In liquid or solid medium, these molecules are capable of forming inclusion compounds with many other molecules. The inclusion compounds thus formed display interesting properties in comparison with the starting molecule.

In fact, inclusion may increase the stability of the guest molecules. Greater stability may be shown towards heat, resulting in lower volatility or higher thermal resistance. Greater stability may also be oxidation resistance. It may also concern the products in solution, whose hydrolysis may, in certain cases, be inhibited to varying degrees. For relatively insoluble active ingredients, inclusion may improve the solubility or dissolution rate. Depending on the stability constant of the inclusion compound formed, a better passage of the active ingredient through membranes may be observed. In vivo, this may be reflected by an increase in bioavailability, with a simultaneous increase in therapeutic effectiveness.     

Effect of hydroxypropyl beta-cyclodextrin on drug solubility in water-propylene glycol mixtures

Combined effects of cosolvency and inclusion complexation on drug solubility were studied using a model hydrophobic compound (carbamazepine) and a model hydrophilic compound (Compound S). Propylene glycol (PG) was used as the nonaqueous solvent, and deionized water was employed for the aqueous systems. Hydroxypropyl β-cyclodextrin (HPβCD) was chosen as the complexing agent and studied at concentrations up to 28% (w/v). Complex formation constants (K_c) and solubility enhancement ratios were determined for the respective compounds in various water/PG vehicles. The data suggested that the inclusion of the compounds was most favorable when water alone was used as the vehicle. However, the combined approach of cosolvency and complexation resulted in a significant increase in the total apparent solubility of carbamazepine (the hydrophobic compound). The same was not observed with Compound S (the hydrophilic model), since PG weakened the interactions between the molecule and HPβCD, and thus, no synergistic or additive effects were observed with the combined approach of complexation and cosolvency.     

Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics

Excipients form a major component of pharmaceutical formulations and are classified as any ingredient other than the active ingredient which is included within the product formulation to improve drug product performance. Functional uses of excipients include improving solubility and stability, safety and efficacy, as bulking agents in lyophilized formulations, tonicity agents, and aiding in controlled or prolonged drug delivery. Parenteral formulations are sterile, pyrogen-free; free of particulate matter and by-pass the body’s natural defense mechanisms. Excipients may demonstrate a synergistic effect when combined with an active ingredient but may also lead to unwanted reactions with the drugs and packaging components. Ideal excipients are required to be considered safe, inert and multifunctional. Contrary to the past, safety of excipients needs to be well established in order for their use in the pharmaceutical formulations. Therefore, careful consideration should be given while selecting an excipient. This review article provides an overview of the excipients used exclusively in small molecule and biological parenteral products including solutions, suspensions, and lyophilized formulations, information on the possible drug-excipient and drug-packaging interactions and the regulatory requirements for the use of pharmaceutical excipients. The readers will be able to have a comprehensive understanding of the excipients used in parenteral formulations.     

Drug solubility in fatty acids as a formulation design approach for lipid-based formulations: a technical note

Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02?μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120?mg/mL to over 1?g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.     

Solubilization of biphenyl dimethyl dicarboxylate by cosolvency

Biphenyl dimethyl dicarboxylate (BDD) is a synthetic analogue of schizandrin C, one of the components isolated from Fructus schizandrae, and has been widely prescribed for improvement of liver functions and symptoms of patients with liver disease. However, its oral preparations have been known to have limited bioavailability due to its extremely low solubility in water, and its solubility problem also limits preparation of its parenteral dosage forms. In this research, we searched for solvent systems to solubilize BDD to overcome these problems. The ternary solvent systems of N,N'- dimethylacetamide (DMA)/alcohol/water and Cremophor EL/DMA/alcohol were studied intensively for this purpose. BDD was solubilized effectively in these cosolvents, and the results showed that the cosolvent systems were effective for solubilizing BDD up to the concentration that might be employed for preparation of parenteral dosage forms. Formulation of a BDD concentrate for intravenous infusion was proposed employing the cosolvent system of Cremophor EL/DMA/alcohol.     

Solubilization of Biphenyl Dimethyl Dicarboxylate by Cosolvency

Biphenyl dimethyl dicarboxylate (BDD) is a synthetic analogue of schizandrin C, one of the components isolated from Fructus schizandrae, and has been widely prescribed for improvement of liver functions and symptoms of patients with liver disease. However, its oral preparations have been known to have limited bioavailability due to its extremely low solubility in water, and its solubility problem also limits preparation of its parenteral dosage forms. In this research, we searched for solvent systems to solubilize BDD to overcome these problems. The ternary solvent systems of N,N′- dimethylacetamide (DMA)/alcohol/water and Cremophor EL/DMA/alcohol were studied intensively for this purpose. BDD was solubilized effectively in these cosolvents, and the results showed that the cosolvent systems were effective for solubilizing BDD up to the concentration that might be employed for preparation of parenteral dosage forms. Formulation of a BDD concentrate for intravenous infusion was proposed employing the cosolvent system of Cremophor EL/DMA/alcohol.     

Preformulation studies of novel 5′-O-carbonates of lamivudine with biological activity: solubility and stability assays

As a part of preformulation studies, the aim of this work was to examine the solubility and stability of a series of 5′-O-carbonates of lamivudine with proven antihuman immunodeficiency virus activity. Solubility studies were carried out using pure solvents (water, ethanol and polyethylene glycol 400 [PEG 400]), as well as cosolvents in binary mixture systems (water–ethanol and water–PEG 400). These ionizable compounds showed that their aqueous solubility is decreasing as the carbon length of the substituent moiety increases, but being enhanced as the pH was reduced from 7.4 to 1.2. Thus, 3TC-Metha an active compound of the series, with an intrinsic solubility at 25?°C of 17?mg/mL, was about 70 times more soluble than 3TC-Octa (0.24?mg/mL), and at pHs of 1.2, 5.8 and 7.4 had intrinsic solubilities of 36.48, 19.20 and 15.40?mg/mL, respectively. In addition, the solubility was enhanced significantly by using ethanol and PEG 400 as cosolvents. A stability study was conducted in buffer solutions at pH 1.2, 5.8, 7.4 and 13.0 and in human plasma at 37?°C. Stability-indicating high-performance liquid chromatography procedure was found to be selective, sensitive and accurate for these compounds and good recovery, linearity and precision were also observed.     

Novel hydrophobicity ruler approach for determining the octanol/water partition coefficients of very hydrophobic compounds via their polymer/solvent solution distribution coefficients

A novel hydrophobicity ruler approach for determining the octanol/water partition coefficients of very hydrophobic compounds is proposed, which is an indirect method that measures the polymer/solvent solution distribution coefficients (log Kp/s) of reference and unknown compounds. The log Kp/s values of the unknown compounds can be calibrated to their log Ko/w values via the correlation of the log Kp/s values of the reference compounds with their log Ko/w values. An organic solvent was used to increase the solubility of the very hydrophobic compounds in the aqueous solution, so that their concentrations and absorption amounts were high enough to be measured precisely. The solvent also reduced the hydrophobicity scale of the very hydrophobic compounds and controlled the amounts absorbed into the polymer phase, so that compounds spanning a very wide range of log Ko/w values could be measured in a single measurement and the coexisting compounds would not interfere each other. Poly(dimethylsiloxane) (PDMS), aqueous methanol solutions, and a series of 21 PCB (polychlorinated biphenyl) compounds were used to demonstrate the principle of the hydrophobicity ruler approach. The PCB compounds with known experimental log Ko/w values served as reference compounds, whereas the PCB compounds without known log Ko/w values were determined. The log Ko/w values determined for PCB126, PCB187, PCB197, PCB180, PCB170, and PCB195 were 6.94, 7.84, 8.33, 8.17, 7.92, and 8.49, respectively. The correlation of the log Kp/s values of the reference PCB compounds with their log Ko/w values was linear (log Ko/w=2.56 log Kp/s+1.08, R2=0.95). The hydrophobicity ruler approach is also a valuable tool for validating the experimental and theoretical log Ko/w values and identifying outliers in log Ko/w databases.     

Selection of Kavalactones by Complexation of Kava Extract with Cyclodextrins

Kavalactones, active ingredients extracted from Piper methysticum Forst. Piperaceae, have many therapeutic properties including relaxing, anaesthetic, analgesic, and antifungic properties. Kavalactones are insoluble in aqueous vehicles. These active ingredients are inclused in cyclodextrins to improve their water solubility and to realize a galenic form.

Gamma cyclodextrin (γ-CD) and beta cyclodextrin (β-CD) were used. The amounts of kavalactones inclused in cyclodextrins have been measured by HPLC with UV spectrophotometric detection.

The results showed that besides increasing the water solubility of kavalactones, the complexation leads to a selection of the most active compounds that are preferentially included.     

Solubility and dissolution enhancement strategies: current understanding and recent trends

Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.     

Fast-dissolving carvacrol/cyclodextrin inclusion complex electrospun fibers with enhanced thermal stability,water solubility,and antioxidant activity

Carvacrol is a known antioxidant molecule and commonly used in food and cosmetics as a flavor and fragrance agent; however, carvacrol has major issues such as high volatility, low water solubility, and stability. In this study, carvacrol/cyclodextrin inclusion complex fibers (carvacrol/CD-IC fibers) were produced via electrospinning in order to enhance thermal stability, water solubility and shelf-life of carvacrol having antioxidant activity. The phase solubility and computational modeling studies showed that carvacrol can form inclusion complexes with two types of modified CDs, hydroxypropyl-β-cyclodextrin (HPβCD) and hydroxypropyl-γ-cyclodextrin (HPγCD). The carvacrol/cyclodextrin inclusion complex electrospun fibers (carvacrol/HPβCD-IC fibers and carvacrol/HPγCD-IC fibers) were obtained as free-standing fibrous webs. Although pure carvacrol is highly volatile, the electrospun carvacrol/CD-IC fibers were quite effective to preserve high amount of carvacrol due to the inclusion complexation. In addition, carvacrol/CD-IC fibers have shown higher temperature stability for carvacrol. Moreover, carvacrol/CD-IC fibers showed more effective antioxidant activity as compared to pure carvacrol. The carvacrol/CD-IC fibrous webs have shown fast-dissolving character in water due to the enhanced water solubility of carvacrol/CD-IC and their ultrafine fiber structure. In short, encapsulation of carvacrol in electrospun CD-IC fibrous webs has shown potentials for food and oral care applications due to free-standing and fast-dissolving character along with high water solubility, high temperature stability and enhanced antioxidant by carvacrol/cyclodextrin inclusion complexation.     

Inclusion Complexation of Lorazepam with Different Cyclodextrins Suitable for Parenteral Use

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-7-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-β-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-β-CD or malt-β-CD only half of that concentration can be dissolved. HP-γ-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-β-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-β-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-β-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-β-CD and around 65–70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.     

钙基纳米蒙脱土/聚磷酸铵复合物的结构与性质

通过在聚磷酸铵(APP)缩聚反应过程中加入钙基纳米蒙脱土(CaMMT), 制备CaMMT/APP复合物, 以提高CaMMT在APP中的分散性, 并提高其热性能。采用FTIR、 XRD、 TGA、 ³¹P核磁共振(³¹P NMR)以及水溶解性和pH值测试等, 表征了添加不同质量分数的CaMMT和在不同温度下制备得到的CaMMT/APP复合物的结构和性质。测试分析表明: CaMMT/APP中CaMMT是完全剥离的, 表明CaMMT在APP中分散性好。随着复合物中CaMMT含量增加, 复合物中Ⅰ型结晶APP比例提高, APP聚合度下降, 复合物水溶性增大, 起始分解温度降低, 但800 ℃时复合物的残余质量分数更高。当CaMMT的添加量相同时, 添加CaMMT时反应体系的温度越高, 越有利于生成高聚合度的结晶Ⅱ型APP, 复合物的水溶性也降低, 热性能提高, 温度为210 ℃, 复合物在800 ℃的残余质量分数为29.69%, 当温度为300 ℃时, 复合物残余质量分数上升至53.75%。     

Cyclodextrins in the Pharmaceutical Field

Abstract

Cyclodextrins (CyDs) are cyclic oligosaccharides, containing a minimum of six D-(+)-glycopyranose units attached by α-1, 4-linkages produced by the action of the cyclodextrin-trans-glycosidase enzyme on a medium containing starch. CyDs are somewhat cone-shaped. The outside of CyDs is hydrophilic and the inside of the cavity is hydrophobic in character. If a molecule fits entirely or at least partially into the cavity, an inclusion complex may be formed. In general, hydrophobic molecules, rather than hydrophilic ones, have a higher affinity to the CyD cavity in aqueous solutions. The CyD complexes thus formed are stabilized by various intermolecular forces, such as hydrophobic interaction, van der Waals forces, hydrogen bonding, release of high energy water molecules in complex formation and release of strain energy in the macromolecular CyD ring. Orally administered CyDs have shown to be harmless, because insignificant amounts are absorbed.

Parenterally administered natural CyDs may cause severe nephrotoxicity, particularly β-CyD, due to the formation of low solubility of β-CyD-cholesterol complexes which precipitate in the kidney. Parenterally administered natural CyDs may also cause shape changes and hemolysis of human erythrocytes. Hydroxyalkylated-β-CyDs appear to lack these toxic potentials.

Molecular encapsulation may occur both in the solid state and in solution. Physicochemical properties of the guest molecule may be changed by CyD inclusion complexation. These alterations provide methods to characterize and detect inclusion. There are methods to detect inclusion in solid state and in solution. Some of the methods used to detect inclusion in solution may also be used to determine the complex stability constant. The alteration of physicochemical properties of the guest molecule may be useful to enhance drug properties such as solubility, dissolution rate, bioavailability, stability or to reduce side effects.     

Preformulation characterization of topical Ibuprofen Piconol

Development of a topical pharmaceutical is facilitated by generation of a different type of preformulation profile than needed prior to tablet or parenteral product development. Ibuprofen piconol is a non-steroidal, anti-inflammatory (NSAID) drug marketed in Japan for the topical relief of primary thermal burns and sunburns. A complete preformation characterization was completed for this compound and is reported here to serve as a template for development of future topical drug products. The physical properties compiled include melting properties, specific gravity, viscosity, hygroscopicity, moisture content, acid-base properties, surface tension, solubility and partitioning. Chemical stability results are given for the bulk drug, the drug in solution, and the drug after formulation in both a cream and an ointment. These studies indicate that ibuprofen piconol is a chemically stable, slightly hygroscopic liquid that strongly partitions into the oil phase and shows no indication of surface activity. This drug has very limited solubility in water (16.5 ppm), modest solubility in glycerol (16.4 mg/ml), and is miscible with less polar organics except for silicone fluids.     

Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-7-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-β-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-β-CD or malt-β-CD only half of that concentration can be dissolved. HP-γ-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-β-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-β-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-β-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-β-CD and around 65-70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.     

Improvement of dissolution properties of furosemide by complexation with beta-cyclodextrin

The purpose of this study was to increase the solubility of furosemide (FR) with inclusion compound of beta-cyclodextrin (beta-CD). The interaction between FR and beta-CD in solution was studied by the solubility method. The phase solubility studies reveal a Bs-type diagram with an inclusion complex of 1:1 molar ratio and a stability constant of 823.5 M(-1). The solid complexes of FR with beta-CD were prepared by using freeze-drying, kneading, and co-precipitation methods. In addition, the physical mixture was prepared for comparison. Inclusion complexation was confirmed by the results from the studies of x-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. The rates of release of the active material from the resulting complexes were determined from dissolution studies using the flow-through cell method. The dissolution rate of FR was significantly enhanced by inclusion of the beta-CD in the formulations. The rate of release of the active material was found to be dependent on the preparation method of the complexes, and the drug prepared by the kneading method was shown to have the fastest dissolution profile compared to the other methods used in this study.     

Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology

Carfentanil (CFTN), a derivative of fentanyl, is highly effective as an analgesic, but its relatively poor solubility in water has limited its nasal application. The objective of this study was to develop the new CFTN-CD inclusion technology to increase the solubility of CFTN. The inclusion compound CFTN–DM-β-CD was prepared by the ultrasonic method and characterized using X-ray powder diffraction and morphological shapes analysis (the scanning electron microscopy). The in vitro dissolution profiles of CFTN–DM-β-CD were assessed in hydrochloric acid and phosphate buffer. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with CFTN–DM-β-CD (250?µg/kg) by intravenous, intramuscular injection, oral, or nasal drops. The results showed that CFTN was successfully enveloped by DM-β-CD. The in vitro cumulative dissolution of CFTN–DM-β-CD was obviously enhanced compared to free CFTN in two buffers. Nasal ciliotoxicity studies have shown that the CFTN–DM-β-CD does not exhibit higher nasal ciliotoxicity than that of free CFTN. Pharmacokinetic studies demonstrated that CFTN–DM-β-CD by nasal administration was absorbed more rapidly and has higher C_max and bioavailability than that of either intramuscular injection or oral administration. In conclusion, the CFTN–DM-β-CD nasal spray was shown to be a relatively safe dosage form for the rapid and effective intranasal delivery of CFTN.     

Preformulation characterization of topical Ibuprofen Piconol

Abstract

Development of a topical pharmaceutical is facilitated by generation of a different type of preformulation profile than needed prior to tablet or parenteral product development. Ibuprofen piconol is a non-steroidal, anti-inflammatory (NSAID) drug marketed in Japan for the topical relief of primary thermal burns and sunburns. A complete preformation characterization was completed for this compound and is reported here to serve as a template for development of future topical drug products. The physical properties compiled include melting properties, specific gravity, viscosity, hygroscopicity, moisture content, acid-base properties, surface tension, solubility and partitioning. Chemical stability results are given for the bulk drug, the drug in solution, and the drug after formulation in both a cream and an ointment. These studies indicate that ibuprofen piconol is a chemically stable, slightly hygroscopic liquid that strongly partitions into the oil phase and shows no indication of surface activity. This drug has very limited solubility in water (16.5 ppm), modest solubility in glycerol (16.4 mg/ml), and is miscible with less polar organics except for silicone fluids.