Pharmaceutical Uses of Cyclodextrins and Derivatives

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.     

Physico-chemical study of inclusion compound Phenothiazine-β-Cyclodextrin

Abstract

In this work, the authors have made many assays to prove the inclusion of phenothiazine in β-cyclodextrin.

The inclusion compound was prepared in two various ways and we have checked the inclusion using NMR and Differential Thermal Analysis tests.

This experimentation leads to other assays making inclusion compounds with molecules using the phenothiazine core and used in humans medicines.     

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.     

Fast dissolving electrospun polymeric films of anti-diabetic drug repaglinide: formulation and evaluation

Abstract

Objective: Repaglinide is a well-known FDA approved drug from category of meglitinide; used for the treatment of diabetes. However, its use is limited because of its poor water solubility which leads to erratic drug absorption. Present work focuses on formulation and evaluation of polyvinyl alcohol (PVA)-polyvinyl pyrrolidone (PVP) nanofibers to counter this problem of poor water solubility.

Significance: Prepared nanofibers with hydrophilic polymers were expected to tackle the problem of poor water solubility.

Methods: Nanofibers were prepared by electrospinning technique with the optimization of parameters affecting final product. Further prepared formulation was characterized using various techniques.

Results: Successful development of drug loaded nanofibers was commenced utilizing electrospinning technique. Further casted film of same polymeric blend was prepared and compared with nanofibers. Optimized nanofibers showed an average diameter of 600–800?nm with smooth surface morphology. Prepared nanofibers and casted film was analyzed in terms of surface morphology, mechanical strength, solid state of drug present, effects of hydrogen bond formation and drug release profile. Results from the glucose tolerance test suggested both the formulations to be having better control over glucose levels as compared to free drug.

Conclusion: Overall developed nanofibers presented themselves to be potential drug delivery candidates for drugs having poor water solubility.     

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.     

Tye Aqueous Solubility of Variously Substituted Barbituric Acids. I. Chemical Effects

Abstract

The aqueous solubility of fourteen variously substituted barbituric acid was determined at 25°C. There was an approximate relationship between aqueous solubility and the duration of activity. The magnitudes of solubility varied substantially for these compounds and these results are based upon the net chemical grouping effect from compound to compound. While several compounds possessed rather similar melting points, the solubilities also varied to a large extent. These results are discussed further in this communication.     

Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

Abstract

We report herein the synthesis, and the physicochemical and pharmacokinetic properties of N-acyloxymethyl prodrugs of allopurinol (Allop) (2a–f). Allop is a compound with activity against Trypanosoma cruzi, a causative agent of Chagas disease. Its pathology leads to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available. Relevant pharmaceutical properties (pK_a, stability, solubility, lipophilicity, in vitro permeability, binding protein, xanthine oxidase binding) were also determined. The results obtained showed that derivatives behave as prodrugs of Allop, since they exhibit improved physicochemical and pharmacokinetic properties relative to their precursor. This behavior turns these compounds into active reservoirs of Allop, and reduces its unfavorable characteristics, so 2a–f compounds are excellent candidates for the treatment of Chagas disease. This work is therefore an important contribution leading to the suppression of Chagas disease.     

Some Properties of an Ethoxylated Castor Oil and Ethoxylated Oleyl Alcohol

Abstract

Ethoxylated derivates have been used as surfactants for some years. In this work, ethoxylated castor oil and ethoxylated oleyl alcohol alone and/or their I:I mixtures were used as surfactants in oil/water type of emulsion systems.

The physicochemical properties of ethoxylated castor oil (Simulsol OL 50) and ethoxylated oleyl alcohol (Simulsol 98) have been investigated.

Both of these materials have properties associated with non-ionic surfactants, although considerably soluble in water, the compounds have slight solubility in nonpolar solvents.

Surface tensions of aqueous solutions were measured over a temperature range of 20°C to 40°C. CMC were determined by surface tension measurements. pH, refractive index, conductivity and density of the two surfactants were also determined.     

Dissociation constants,solubilities and dissolution rates of some selected nonsteroidal antiinflammatories

Abstract

Dissociation constants, solubilities and dissolution rates have been investigated for 16 nonsteroidal antiinflammatory active compounds which belong to several chemical groups within the small class of acidic drug substances. The antiinflammatories are mostly characterized by a very low aqueous solubility at lower pH-values. The solubilities increase rapidly with pH's higher than the pK_a. The pK_a-values of the investigated compounds range from 3.5 to 6.3 with a mean directed to 4.6. The dissolution rate determinations of equimolar amounts at pH 7.5 show a great variation from half a minute to 60 minutes for the 50% level.     

Albendazole solution formulation via vesicle-to-micelle transition of phospholipid-surfactant aggregates

Objective: To reveal the physicochemical mechanisms governing the solubilization of albendazole in surfactant and phospholipid-surfactant solutions and, on this basis, to formulate clinically relevant dose of albendazole in solution suitable for parenteral delivery.

Significance: (1) A new drug delivery system for parenteral delivery of albendazole is proposed, offering high drug solubility and low toxicity of the materials used; (2) New insights on the role of surface curvature on albendazole solubilization in surfactant and surfactant-phospholipid aggregates are provided.

Methods: The effect of 17 surfactants and 6 surfactant-phospholipid mixtures on albendazole solubility was studied. The size of the colloidal aggregates was determined by light-scattering. The dilution stability of the proposed formulation was assessed by experiments with model human serum.

Results: Anionic surfactants increased very strongly drug solubility at pH?=?3 (up to 4?mg/mL) due to strong electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. This effect was observed with all anionic surfactants studied, including sodium dodecyl sulfate, double chain sodium dioctylsulfosuccinate (AOT), and the bile salt sodium taurodeoxycholate. The phospholipid-surfactant mixture of 40% sodium dipalmitoyl-phosphatidylglycerol +60% AOT provided highest albendazole solubilization (4.4?mg/mL), smallest colloidal aggregate size (11?nm) and was stable to dilution with model human serum at (and above) 1:12 ratio.

Conclusions: A new albendazole delivery system with high drug load and low toxicity of the materials used was developed. The high solubility of albendazole was explained with vesicle-to-micelle transition due to the larger interfacial curvature preferred for albendazole solubilization locus.     

Formulation of Long-Acting Quinacrine Hydrochloride Pellets in Different Matrices I

Abstract

In this study, quinacrine hydrochloride, which is a very soluble drug in water was selected as the active ingredient to formulate a long-acting dosage form. The prolonged release form is obtained by incorporating the drug in an inert solid matrix. Since it is believed that if the correct matrix and hardness is chosen the drug release can be controlled. The effect of different fatty acids, fatty alcohols, polymers and waxes individually or in combinations were investigated.     

Factors Affecting Rate of Dissolution of Prednisone from Tablets

Abstract

A study was carried out to evaluate some parameters which may have an effect on the dissolution rate of prednisone from tablets. The parameters examined involving formulation were: diluent proportion (Lactose-starch), dissintegrant type (starch, explotab (sodium starch glycolate) type of binder (starch paste, gelatine water solution and PVP alcoholic solution), lubricant, and dye concentration. The Manufacturing variables studied were: method of manufacture (wet granulation, direct compression and double compression), granule size in wet granulation and tablet hardness. dissolution profiles of tablets storaged 2 months at 45°C were compared with those of fresh samples. Tablets prepared with prednisone five years old, tablets with fresh active ingredient and tablets with two different prednisone concentrations (5 and 50 mg per tablet) were used for other evaluations.

In all cases micronized prednisone was used and all batches were physically and chemically evaluated before studying their dissolution following the USP basket method.

The parameters studied that affected significatively dissolution rate of prednisone were: type of binder, lubricant concentration, method of manufacture, active ingredient, age and prednisone concentration.     

The Strength of Microcrystalline Cellulose Pellets: The Effect of Granulating with Water/Ethanol Mixtures

Abstract

Pellets were prepared by wet granulating with various ethanol/water mixtures utilizing the extrusion/marumerization process. Binary mixtures of 10% active ingredient and 90% Microcrystalline Cellulose (Avicel PH-101) were found to form pellets when granulated with 95% ethanol but not with absolute alcohol. Differences in friability and dissolution were observed between water granulated and 95% ethanol granulated pellets. When mixtures were granulated with varying ethanol/water mixtures, pellets became stronger and harder as the mole fraction of water increased in the ethanol/water mixture used to granulate. experiments showed water granulated pellets were not very compressible whereas 95% ethanol granulated pellets exhibited excellent compressibility.     

Improved stability of solid dispersions of manidipine with polyethylene glycol 4000/copovidone blends: application of ternary phase diagram

Context: Manidipine (MDP) is generally used clinically as an antihypertensive agent; however, the bioavailability of orally administered MDP is limited due to their very low water solubility.

Objective: The objectives of this research were, therefore, to increase the solubility of MDP by the formation of ternary solid dispersions (tSD) with polyethylene glycol 4000 (PEG4000) and copovidone and to improve their stability.

Methods: Solid ternary phase diagram was constructed to find homogeneous solid dispersion region after melting and solidifying at low temperature with different quenching substances. The pulverized powder of solid dispersions was then determined, for their physicochemical properties, by differential scanning calorimetry, powder X-ray diffractometry, Fourier transform infrared (FTIR) spectroscopy and hot stage microscopy. The solubility and dissolution of MDP from the tSD were investigated. The physical stability of tSD was also determined under accelerated condition at 40?°C/75% relative humidity (RH) for 6 months.

Results and discussion: The results showed that MDP was molecularly dispersed in PEG4000 and copovidone when the tSD was created from homogeneous region of solid ternary phase diagram. FTIR results confirmed that strong hydrogen bonding was presented between MDP and copovidone, leading to a significant increase in the solubility and dissolution of MDP. After storage at accelerated condition (40?°C/75%RH) for 6 months, the tSD still showed a good appearance and high solubility.

Conclusion: The results of this study suggest that tSD prepared by melting has promising potential for oral administration and may be an efficacious approach for improving the therapeutic potential of MDP.     

Inclusion Complexation of 4-Biphenylacetic Acid with β-Cyclodextrin

Abstract

The preparation of an inclusion complex of 4-biphenylacetic acid (BPAA), a non-steroidal antiinflammatory drug, with β-cyclo-dextrin is described. The presumible structure of the inclusion system, the molar ratio, which was found 1:1, and the formation constant were calculated by the analysis of IR, UV, DSC, X-ray diffraction, and ¹H-NMR. Dissolution rate and solubility were also studied. BPAA solubility in water resulted significantly (4,2-fold) increased by complexation, such as its dissolution rate which appears, in the first 12 min, 18 times greater for the complex than the drug alone.     

The influence of bile salts on the distribution of simvastatin in the octanol/buffer system

Abstract

Introduction: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability.

Methods: LogD values of SVA and SVL with or without bile salts were measured by liquid–liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes.

Results: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results.

Conclusions: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.     

III. Segregation of Active Constituents from Tablet Formulations During Grinding: Effects on Coated Tablet Formulations

Abstract

Grinding or milling coated tablets in preparation for their assay can cause the physical separation of an active ingredient from the coating and other tablet components. This phenomenon has been shown to partially account for the poor reproducibility between duplicate assays, and for discrepancies among assays for the same group of tablets but which were composited by different methods.

The effect of compositing methods on the assay results is shown with commercial enteric coated aspirin tablets from various manufacturers. Samples for assay were prepared by manual grinding with a glass mortar and pestle, mechanical grinding with an electric tablet grinder, direct dissolution of the tablets in a suitable solvent, and uncoating of the tablets with an organic solvent prior to their manual grinding.

Suggestions are offered to minimize the effects of segregation of an active tablet ingredient during grinding or milling on the assay results.     

Microemulsion systems containing bioactive natural oils: an overview on the state of the art

Abstract

Natural oils are extremely complex mixtures containing compounds of different chemical nature. Some of them have physiological or therapeutic activities that may act either alone or in synergy. Therefore, they are used in the pharmaceutical, agronomic, food, sanitary and cosmetic industries. Today, the interest in bioactive natural oils is growing due to their immense potential to prevent and treat numerous human diseases. Formulation in microemulsions (MEs) containing natural oils appeared suitable to improve pharmaceutical and biopharmaceutical properties of bioactive compound derivatives from these oils. Microemulsion systems are thermodynamically stable, transparent, and are isotropic dispersions consisting of oil and water stabilized by an interfacial film of surfactants, typically in combination with a cosurfactant. They can protect labile compounds from premature degradation, control release, increase solubility and hence enhance the bioavailability of poorly bioavailable compounds. The aim of this work was to review the various advantages of bioactive compounds presented in natural oil loaded ME systems to be used as delivery systems. First, the state of the art of the parameters involved in the ME formation, including the basic concepts of the physicochemical formulation of the ME systems, and the main aspects of production and the energy responsible for their formation were reported. The second section describes the use of ME systems and reviews the recent applications of natural oil-loaded in the ME systems as the bioactive compound in the formulation.     

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.