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Design of Dosage Forms with Improved Biopharmaceutical Properties

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 25587

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Dr. Irina Terekhova

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Guest Editor

G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045 Ivanovo, Russia
Interests: drug delivery systems; supramolecular complexes; solid dispersions; cyclodextrins; polymers; metal organic frameworks

Dr. Nataliya Kochkina

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Guest Editor

G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045 Ivanovo, Russia
Interests: biocomposites; polymer films; biodegradable and biocompatible polymers; biotemplate synthesis; rheology

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Dear Colleagues,

The principal objective of any dosage form is to augment the high therapeutic activity, safety and low toxicity of the drug. Application of the effective dosage forms makes it possible to achieve the rapid onset of action following drug delivery; to improve pharmacologically important properties of the drugs such as aqueous solubility, dissolution rate, membrane permeability and bioavailability; to mask the undesirable taste or offensive odor of a drug substance; to provide drugs with predetermined rate and prolonged therapeutic effect; and to prepare drug products that are stable, effective and safe for consumption under specified suitable storage conditions. The desired dosage forms must have adequate metabolic stability so that the drug does not undergo excessive presystemic clearance and has a reasonable in vivo residence time. Thus, the design of dosage forms with appropriate and reliable in vivo performance is an important task of the pharmaceutical sciences. Structure–property relationships and testing in vitro and in vivo are essential to develop the proper dosage forms with improved properties.

Dr. Irina Terekhova
Dr. Nataliya Kochkina
Guest Editors

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Keywords

dosage form
drug
formulation
biopharmaceutical properties
solubility
permeability
bioavailability
effective medicines

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Published Papers (10 papers)

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Editorial

Jump to: Research

4 pages, 168 KiB

Open AccessEditorial

Design of Dosage Forms with Improved Biopharmaceutical Properties

by Nataliya Kochkina and Irina Terekhova

Pharmaceutics 2024, 16(1), 69; https://doi.org/10.3390/pharmaceutics16010069 - 2 Jan 2024

Viewed by 1367

Abstract

The development of a pharmaceutical product consists of giving a drug an optimal dosage form (a certain state of aggregation, consistency, structural, mechanical, physicochemical, and functional properties), which ensure stability, the possibility of accurate dosage, the required pharmacological effect, and ease of administration [...] Read more.

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

Research

Jump to: Editorial

15 pages, 16684 KiB

Open AccessArticle

β-Cyclodextrin Modified Hydrogels of Kappa-Carrageenan for Methotrexate Delivery

by Maria Nikitina, Nataliya Kochkina, Marianna Arinina, Valery Kulichikhin and Irina Terekhova

Pharmaceutics 2023, 15(9), 2244; https://doi.org/10.3390/pharmaceutics15092244 - 30 Aug 2023

Cited by 4 | Viewed by 1266

Abstract

This work is aimed at developing a kappa-carrageenan (kCR) gel with increased methotrexate (MTX) content. β-Cyclodextrin (βCD), which is able to inclusion complex formation with MTX, has been used to increase the drug concentration in the hydrogel. The rheological behavior of the designed gels was investigated and the influence of MTX and βCD on the viscoelastic properties of kCR gel was studied in detail. The effect of βCD and its concentration on the MTX-releasing rate from the kCR gels was examined. The properties of kappa- and iota-carrageenans loaded with MTX were compared and the differences observed were explained in terms of different binding affinities of MTX to these polymers. The obtained gels provided desirable viscoelastic properties useful for topical application. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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26 pages, 4664 KiB

Open AccessArticle

Optimization and In Vitro Characterization of Telmisartan Loaded Sodium Alginate Beads and Its In Vivo Efficacy Investigation in Hypertensive Induced Animal Model

by Ubaidulla Uthumansha, Kousalya Prabahar, Dilli Bhai Gajapathy, Mohamed El-Sherbiny, Nehal Elsherbiny and Mona Qushawy

Pharmaceutics 2023, 15(2), 709; https://doi.org/10.3390/pharmaceutics15020709 - 20 Feb 2023

Cited by 5 | Viewed by 3203

Abstract

Background: Antihypertensive drug telmisartan (TEL) belongs to BCS class II, which is characterized by low water solubility and, consequently, low oral bioavailability. Gastroretentive systems may overcome the problems associated with low solubility of TEL and incomplete absorption by localizing the drug release in the stomach. The purpose of this study was to prepare TEL-loaded, oil-entrapped, floating alginate beads with the intent of enhancing the oral bioavailability of TEL for the treatment of hypertension. Methods: For the formulation and optimization of seventeen formulations of TEL-loaded oil-entrapped floating alginate beads, a central composite design was utilized. The concentration of sodium alginate (X1), the concentration of cross-linker (X2), and the concentration of sesame oil (X3) served as independent variables, whereas the entrapment efficiency (Y1), in vitro buoyancy (Y2), and drug release Q6h (Y3) served as dependent variables. Using the emulsion gelation method and calcium chloride as the cross-linking agent, different formulations of TEL alginate beads were produced. All formulations were evaluated for their entrapment efficiency percentage, in vitro buoyancy, and in vitro drug release. The optimal formulation of TEL alginate beads was prepared with and without oil and evaluated for entrapment efficiency percentage, in vitro buoyancy, swelling ratio, average size, and in vitro drug release. Using scanning electron microscopes, the surface morphology was determined. Using IR spectroscopy, the compatibility between the ingredients was determined. In vivo evaluation of the optimized formulation in comparison to the free TEL was done in hypertension-induced rats, and the systolic blood pressure and all pharmacokinetic parameters were measured. Results: The prepared beads exhibited a high entrapment efficiency percentage, in vitro buoyancy, and prolonged drug release. TEL was compatible with other ingredients, as approved by IR spectroscopy. The prepared TEL beads were spherical, as shown by the SEM. The relative bioavailability of TEL-loaded oil-entrapped beads was 222.52%, which was higher than that of the pure TEL suspension. The prepared TEL beads formulation exhibited a higher antihypertensive effect for a prolonged time compared to pure TEL suspension. Conclusions: It can be concluded that this innovative delivery method of TEL-loaded oil-entrapped beads is a promising tool for enhancing drug solubility and, thus, oral bioavailability and therapeutic efficacy, resulting in enhanced patient compliance. Furthermore, the in vivo study confirmed the formulation’s extended anti-hypertensive activity in animal models. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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28 pages, 6036 KiB

Open AccessArticle

Potential Oral Anticancer Therapeutic Agents of Hexahydrocurcumin-Encapsulated Chitosan Nanoparticles against MDA-MB-231 Breast Cancer Cells

by Feuangthit N. Sorasitthiyanukarn, Chawanphat Muangnoi, Clinton B. Gomez, Apichart Suksamrarn, Pranee Rojsitthisak and Pornchai Rojsitthisak

Pharmaceutics 2023, 15(2), 472; https://doi.org/10.3390/pharmaceutics15020472 - 31 Jan 2023

Cited by 5 | Viewed by 2558

Abstract

Hexahydrocurcumin-encapsulated chitosan nanoparticles (HHC-CS-NPs) were formulated by oil-in-water emulsification and ionotropic gelation and optimized using the Box–Behnken design. The particle size, zeta potential, and encapsulation efficiency of the optimized HHC-CS-NPs were 256 ± 14 nm, 27.3 ± 0.7 mV, and 90.6 ± 1.7%, respectively. The TEM analysis showed a spherical shape and a dense structure with a narrow size distribution. The FT-IR analysis indicated no chemical interaction between the excipients and the drugs in the nanoparticles, but the existence of the drugs was molecularly dispersed in the nanoparticle matrices. The drug release profile showed a preliminary burst release followed by a sustained release under simulated gastrointestinal (GI) and physiological conditions. A stability study suggested that the HHC-CS-NPs were stable under UV light, simulated GI, and body fluids. The in vitro bioaccessibility and bioavailability of the HHC-CS-NPs were 2.2 and 6.1 times higher than those of the HHC solution, respectively. The in vitro evaluation of the antioxidant, anti-inflammatory, and cytotoxic effects of the optimized HHC-CS-NPs demonstrated that the CS-NPs significantly improved the biological activities of HHC in radical scavenging, hemolysis protection activity, anti-protein denaturation, and cytotoxicity against MDA-MB-231 breast cancer cells. Western blot analysis showed that the apoptotic protein expression of Bax, cytochrome C, caspase-3, and caspase-9, were significantly up-regulated, whereas the anti-apoptotic protein Bcl-2 expression was down-regulated in the HHC-CS-NP-treated cells. Our findings suggest that the optimized HHC-CS-NPs can be further developed as an efficient oral treatment for breast cancer. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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27 pages, 4073 KiB

Open AccessArticle

Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation

by Aslıhan Arslan, Barbaros Yet, Emirhan Nemutlu, Yağmur Akdağ Çaylı, Hakan Eroğlu and Levent Öner

Pharmaceutics 2023, 15(2), 363; https://doi.org/10.3390/pharmaceutics15020363 - 20 Jan 2023

Cited by 9 | Viewed by 4067

Abstract

Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex^®, and faster t_max 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate). Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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15 pages, 4027 KiB

Open AccessArticle

Diammonium Glycyrrhizinate-Based Micelles for Improving the Hepatoprotective Effect of Baicalin: Characterization and Biopharmaceutical Study

by Xingxing Dai, Yuyao Liao, Cuiting Yang, Yingying Zhang, Minfang Feng, Yuting Tian, Qingsong Qu, Mengke Sheng, Zhixun Li, Xinhui Peng, Shuai Cen and Xinyuan Shi

Pharmaceutics 2023, 15(1), 125; https://doi.org/10.3390/pharmaceutics15010125 - 30 Dec 2022

Cited by 6 | Viewed by 2132

Abstract

Saponins are an important class of surface-active substances. When formulated as an active ingredient or co-used with other drugs, the effect of their surface activity on efficacy or safety must be considered. In this paper, diammonium glycyrrhizinate (DG), a clinical hepatoprotective drug that has long been used as a biosurfactant, was taken as the research object to study its combined hepatoprotective effect with baicalin (BAI). Animal experiments proved that the preparation of DG and BAI integrated into micelles (BAI-DG Ms) had a better protective effect on acute liver injury caused by carbon tetrachloride than the direct combined use of the two. From the perspective of biopharmaceutics, the synergistic mechanism of BAI-DG Ms was further explored. The results showed that after forming BAI-DG Ms with DG, the solubility of BAI increased by 4.75 to 6.25 times, and the cumulative percentage release in the gastrointestinal tract also increased by 2.42 times. In addition, the negatively charged BAI-DG Ms were more likely to penetrate the mucus layer and be absorbed by endocytosis. These findings provide support for the rational application of glycyrrhizin, and other saponins. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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13 pages, 2271 KiB

Open AccessArticle

Regularities of Encapsulation of Tolfenamic Acid and Some Other Non-Steroidal Anti-Inflammatory Drugs in Metal-Organic Framework Based on γ-Cyclodextrin

by Ekaterina Delyagina, Anna Garibyan, Mikhail Agafonov and Irina Terekhova

Pharmaceutics 2023, 15(1), 71; https://doi.org/10.3390/pharmaceutics15010071 - 26 Dec 2022

Cited by 3 | Viewed by 2148

Abstract

Metal-organic frameworks based on cyclodextrins (CDs) have been proposed as promising drug delivery systems due to their large surface area, variable pore size, and biocompatibility. In the current work, we investigated an incorporation of tolfenamic acid (TA), a representative of non-steroidal anti-inflammatory drugs (NSAIDs), in a metal-organic framework based on γ-cyclodextrin and potassium cations (γCD-MOF). Composites γCD-MOF/TA obtained by absorption and co-crystallization methods were characterized using powder X-ray diffraction, low temperature nitrogen adsorption/desorption, scanning electron microscopy, and FTIR spectroscopy. It was demonstrated that TA loaded in γCD-MOF has an improved dissolution profile. However, the inclusion of TA in γ-CD reduces the membrane permeability of the drug. A comparative analysis of the encapsulation of different NSAIDs in γCD-MOF was performed. The impact of NSAID structure on the loading capacity was considered for the first time. It was revealed that the presence of heterocycles in the structure and drug lipophilicity influence the loading efficiency of NSAIDs in γCD-MOF. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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21 pages, 5885 KiB

Open AccessArticle

Preparation and Evaluation of Modified Chitosan Nanoparticles Using Anionic Sodium Alginate Polymer for Treatment of Ocular Disease

by Vaishnavi A. Bhosale, Vaibhavi Srivastava, Bhavana Valamla, Rati Yadav, Shashi Bala Singh and Neelesh Kumar Mehra

Pharmaceutics 2022, 14(12), 2802; https://doi.org/10.3390/pharmaceutics14122802 - 14 Dec 2022

Cited by 15 | Viewed by 3000

Abstract

Mucoadhesive nanoparticles offer prolonged drug residence time at the corneal epithelium by adhering to the mucous layer of the eye. Here, in this research investigation, voriconazole-loaded chitosan mucoadhesive nanoparticles (VCZ-MA-NPs) were modified to mucous-penetrating nanoparticles (VCZ-MP-NPs) by coating them with anionic polymer sodium alginate. The ionic gelation method was utilized to prepare mucoadhesive chitosan nanoparticles, which were further coated with sodium alginate to obtain the surface properties essential for mucous penetration. The developed VCZ-MA-NPs and VCZ-MP-NPs were evaluated extensively for physicochemical delineation, as well as in vitro and ex vivo studies. The particle size, polydispersity index, and ζ potential of the VCZ-MA-NPs were discovered to be 116 ± 2 nm, 0.23 ± 0.004, and +16.3 ± 0.9 mV, while the equivalent values for VCZ-MP-NPs were 185 ± 1 nm, 0.20 ± 0.01, and −24 ± 0.9 mV, respectively. The entrapment efficiency and drug loading were obtained as 88.06%±1.29% and 7.27% ± 0.95% for VCZ-MA-NPs and 91.31% ± 1.05% and 10.38% ± 0.87% for VCZ-MP-NPs, respectively. The formulations were found to be stable under different conditions (4 °C, 25 °C, and 40 °C). Chitosan nanoparticles and modified nanoparticles showed a spherical and smooth morphology under electron microscopic imaging. An excised caprine cornea was used for the ex vivo permeation study, exhibiting 58.98% ± 0.54% and 70.02% ± 0.61% drug permeation for VCZ-MA-NPs and VCZ-MP-NPs, respectively. The findings revealed that the mucous-penetrating nanoparticles could effectively pass through the corneal epithelium, thus overcoming the mucous barrier and fungal layer of the eye, which highlights their potential in the treatment of fungal keratitis. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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15 pages, 5826 KiB

Open AccessArticle

Alginate-Derivative Encapsulated Carbon Coated Manganese-Ferrite Nanodots for Multimodal Medical Imaging

by Pemula Gowtham, Koyeli Girigoswami, Pragya Pallavi, Karthick Harini, Ilangovan Gurubharath and Agnishwar Girigoswami

Pharmaceutics 2022, 14(12), 2550; https://doi.org/10.3390/pharmaceutics14122550 - 22 Nov 2022

Cited by 26 | Viewed by 2429

Abstract

Carbon-decorated ferrite nanodots (MNF@Cs) have been enhanced with superparamagnetism and higher fluorescence quantum yield by encapsulation with an alginate derivative to create a cost-effective and less toxic multimodal contrast agent for replacing the conventional heavy metal Gd-containing contrast agent used in MR imaging. The novel surface-engineered particles (MNF@C-OSAs), devoid of labels, can simultaneously provide both longitudinal and transverse relaxation-based magnetic resonance imaging (MRI) and fluorescence emission. According to the findings of in vitro studies, the calculated molar relaxivities and the molar radiant efficiencies are indicative of the multimodal efficacy of MNF@C-OSA as compared with MNF@C particles and conventional contrast agents used in medical imaging. MNF@C-OSAs were shown to be significantly biocompatible and negligibly toxic when assessed against A549 cells and zebrafish embryos, indicating their potential for use as theranostic agents. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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12 pages, 2940 KiB

Open AccessArticle

Fluorescein-Labeled Thiacalix[4]arenes as Potential Theranostic Molecules: Synthesis, Self-Association, and Antitumor Activity

by Alan Akhmedov, Olga Terenteva, Evgenia Subakaeva, Pavel Zelenikhin, Ramilia Shurpik, Dmitriy Shurpik, Pavel Padnya and Ivan Stoikov

Pharmaceutics 2022, 14(11), 2340; https://doi.org/10.3390/pharmaceutics14112340 - 30 Oct 2022

Cited by 2 | Viewed by 1918

Abstract

In this paper, a series of thiacalix[4]arenes were synthesized as potential theranostic molecules for antitumor therapy. We propose an original strategy for the regioselective functionalization of thiacalix[4]arene with a fluorescent label to obtain antiangiogenic agent mimetics. The aggregation properties of the synthesized compounds were determined using the dynamic light scattering. The average hydrodynamic diameter of self-associates formed by the macrocycles in 1,3-alternate conformation is larger (277–323 nm) than that of the similar macrocycle in cone conformation (185–262 nm). The cytotoxic action mechanism of the obtained compounds and their ability to penetrate into of human lung adenocarcinoma and human duodenal adenocarcinoma cells were established using the MTT-test and flow cytometry. thiacalix[4]arenes in 1,3-alternate conformation did not have a strong toxic effect. The toxicity of macrocycles in cone conformations on HuTu-80 and A549 cells (IC₅₀ = 21.83–49.11 µg/mL) is shown. The resulting macrocycles are potential theranostic molecules that combine both the pharmacophore fragment for neoplasmas treatment and the fluorescent fragment for monitoring the delivery and biodistribution of nanomedicines. Full article

(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)

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