RÉSUMÉ
This study was designed to synthesize quarternized chitosans (Q-CS) and explore their potential application in aqueous solubility enhancement of indomethacin (IND), a BCS class-II drug. Three different Q-CS; N,N,N-trimethyl chitosan chloride (TMC), N-(4-N'-methylpyridinylmethyl) chitosan chloride (mPyCS), and N-(4-N',N',N'-trimethylaminobenzyl) chitosan chloride (TmBzCS) were synthesized and characterized through various spectroscopic analysis. Q-CS-based solid-dispersion (SD) composites of IND (Q-CS-IND) were prepared using the spray-drying method and characterized through Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential-scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD). The solubility and dissolution profiles of SD-composites of IND were evaluated and compared with physical mixtures (PM). The IND contents were quantified and validated in the composites using UV-Vis spectrophotometer. FTIR and NMR analysis showed the successful preparation of Q-CS. TMC was found with the highest yield (55.13%) and mPyCS with the highest degree of quaternization (DQ) (63.37%). FT-IR analysis of IND-Q-CS composites demonstrated chemical interaction between carbonyl moieties of IND with functional groups of Q-CS. DSC and PXRD analyses demonstrated the transformation of IND in SD composites from crystalline to an amorphous form. All the IND-Q-CS composites were observed with a significant increase in the solubility and dissolution rate of the drug (1996.0 µg/min) compared to PM (1306.8 µg/min), which is higher than pure IND (791.6 µg/min). The contents of IND in TMC, mPyCS, and TmBzCS composites were 97.69-99.92%, 97.66-100.25%, and 97.18-100.11% respectively. Overall, the findings encourage the applications of Q-CS derivatives for increasing IND water solubility and warrant further in vivo biological profiling of IND composites.
Sujet(s)
Calorimétrie différentielle à balayage , Chitosane , Indométacine , Solubilité , Indométacine/composition chimique , Chitosane/composition chimique , Spectroscopie infrarouge à transformée de Fourier/méthodes , Calorimétrie différentielle à balayage/méthodes , Diffraction des rayons X/méthodes , Chimie pharmaceutique/méthodes , Microscopie électronique à balayage/méthodesRÉSUMÉ
In recent years, there has been a significant increase in the prevalence of thyroid diseases, particularly hypothyroidism. In this study, we investigated the impact and mechanisms of Chemical permeation enhancement(CPE) on transdermal permeation of levothyroxine sodium (L-T4) patches.We found that the combination of oleic acid (OA) and Azone (NZ) yielded the best transdermal permeation effect for L-T4.Subsequently, we also investigated the relevant propermeability mechanism.The results demonstrate that the combined application of OA and NZ significantly enhances the transdermal permeation of L-T4 compared to individual applications,it is attributed to two mechanisms: firstly, OA improves drug release by increasing the flowability of the pressure-sensitive adhesive (PSA) matrix; secondly, both OA and NZ act on the stratum corneum, especially facilitating L-T4 permeation through the hair follicle pathway. No skin irritation or cytotoxicity is observed with these final patches, which exhibit a remarkable therapeutic effect on hypothyroidism. this study contributes to the development of transdermal formulations of L-T4.
Sujet(s)
Administration par voie cutanée , Acide oléique , Absorption cutanée , Thyroxine , Acide oléique/composition chimique , Thyroxine/administration et posologie , Thyroxine/pharmacologie , Thyroxine/pharmacocinétique , Animaux , Absorption cutanée/effets des médicaments et des substances chimiques , Patch transdermique , Peau/métabolisme , Peau/effets des médicaments et des substances chimiques , Libération de médicament , Souris , Perméabilité , Hypothyroïdie/traitement médicamenteux , Hypothyroïdie/métabolisme , Humains , Chimie pharmaceutique/méthodes , MâleRÉSUMÉ
In this study, N, N '-bis {4- [(α-L- rhamnosyloxy) benzyl]} thiourea (PG-1), a phenolic glycoside compound was purified from Moringa seed. The PG-1 has attracted extensive attention due to its anti-cancer, antioxidant, anti-inflammatory and hypoglycemic properties. However, some of its physicochemical properties such as oral bioavailability has not been studied. Herein, a highly purified PG-1 was extracted and incorporated in multiple layered liposomes (PG-1-L) to avoid its burst release and enhance oral bioavailability. After appropriate characterization, it was discovered that the obtained PG-1-L was stable, homogeneous and well dispersed with the average particle size being 89.26 ± 0.23 nm. Importantly, the in vitro release and in vivo oral bioavailability of PG-1-L were significantly improved compared with PG-1. In addition, MTT results showed that compared with the free PG-1, PG-1-L displayed obvious inhibitory effect on the HepG2 cells, while the inhibitory effect on healthy non-malignant 3T6 and LO-2 cells was not significant, indicating that PG-1-L had high safety. In conclusion, PG-1-L can be used as a promising delivery system and an ideal novel approach to improve the oral bioavailability and anticancer activity of PG-1.
Sujet(s)
Biodisponibilité , Hétérosides , Liposomes , Moringa oleifera , Phénols , Graines , Moringa oleifera/composition chimique , Graines/composition chimique , Humains , Hétérosides/composition chimique , Hétérosides/administration et posologie , Hétérosides/pharmacologie , Hétérosides/isolement et purification , Animaux , Cellules HepG2 , Phénols/administration et posologie , Phénols/composition chimique , Phénols/isolement et purification , Phénols/pharmacocinétique , Taille de particule , Systèmes de délivrance de médicaments/méthodes , Souris , Mâle , Rats , Administration par voie orale , Chimie pharmaceutique/méthodes , Rat Sprague-DawleyRÉSUMÉ
Psoriasis is a chronic inflammatory disorder affecting over 100 million people, requires long-term therapy. Current treatments offer only symptomatic relief. However, phytoconstituents-based therapies like Silymarin (SLM) have shown promising effects. The study aims to develop, optimize, and evaluate a novel stable SLM NLC gel to improve anti-psoriatic activity by enhancing its permeability and retention into the dermal layer. SLM NLC formulation was prepared and optimized using 32 full factorial designs. The formulation was evaluated for the particle size, PDI, zeta potential, and % entrapment efficiency, evaluated by Transmission electron microscopy and thermal analysis. The freeze dried and prepared NLC-loaded gel was evaluated for physicochemical parameters, ex-vivo, and in-vivo studies. SLM-loaded NLC shows 624 nm particle size, 0.41 PDI, 92.95% entrapment efficiency, and -31.6 mV zeta potential. The sphere form of NLCs was confirmed using TEM. Controlled drug release was observed in ex vivo studies, low PASI score compared to disease control. Further, the levels of IL-6, TNF-α, and NF-κB were also reduced. The results are supported by histopathology showing minimal parakeratosis indicated in the SLM NLC-treated group. Prepared NLC-based shows enhance topical penetration and decrease the thickness of psoriatic plaques in the in vivo study.
Sujet(s)
Gels , Taille de particule , Psoriasis , Silymarine , Silymarine/pharmacologie , Silymarine/administration et posologie , Silymarine/composition chimique , Silymarine/pharmacocinétique , Psoriasis/traitement médicamenteux , Animaux , Absorption cutanée , Libération de médicament , Peau/métabolisme , Peau/effets des médicaments et des substances chimiques , Administration par voie cutanée , Chimie pharmaceutique/méthodes , Nanoparticules/composition chimique , Mâle , SourisRÉSUMÉ
The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0-8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.
Sujet(s)
Biodisponibilité , Libération de médicament , Hypertension pulmonaire , Citrate de sildénafil , Solubilité , Goût , Citrate de sildénafil/pharmacocinétique , Citrate de sildénafil/administration et posologie , Animaux , Administration par voie orale , Rats , Mâle , Hypertension pulmonaire/traitement médicamenteux , Rat Wistar , Vasodilatateurs/pharmacocinétique , Vasodilatateurs/administration et posologie , Chimie pharmaceutique/méthodes , Systèmes de délivrance de médicaments/méthodesRÉSUMÉ
Physiologically based pharmacokinetic (PBPK) or physiologically based biopharmaceutics models (PBBM) demonstrated plethora of applications in both new drugs and generic product development. Justification of dissolution specifications and establishment of dissolution safe space is an important application of such modeling approaches. In case of molecules exhibiting saturable absorption behavior, justification of dissolution specifications requires development of a model that incorporates effects of transporters is critical to simulate in vivo scenario. In the present case, we have developed a semi-mechanistic PBBM to describe the non-linearity of BCS class III molecule metformin for justification of dissolution specifications of extended release formulation at strengths 500 mg and 1000 mg. Semi-mechanistic PBBM was built using physicochemical properties, dissolution and non-linearity was accounted through incorporation of multiple transporter kinetics at absorption level. The model was extensively validated using literature reported intravenous, oral (immediate & extended release) formulations and further validated using in-house bioequivalence data in fasting and fed conditions. Virtual dissolution profiles at lower and upper specifications were generated to justify the dissolution specifications. The model predicted literature as well as in-house clinical study data with acceptable prediction errors. Further, virtual bioequivalence trials predicted the bioequivalence outcome that matched with clinical study data. The model predicted bioequivalence when lower and upper specifications were compared against pivotal test formulations thereby justifying dissolution specifications. Overall, complex and saturable absorption pathway of metformin was successfully simulated and this work resulted in regulatory acceptance of dissolution specifications which has ability to reduce multiple dissolution testing.
Sujet(s)
Biopharmacie , Préparations à action retardée , Metformine , Modèles biologiques , Solubilité , Équivalence thérapeutique , Metformine/pharmacocinétique , Metformine/administration et posologie , Metformine/composition chimique , Préparations à action retardée/pharmacocinétique , Humains , Biopharmacie/méthodes , Libération de médicament , Chimie pharmaceutique/méthodes , Hypoglycémiants/pharmacocinétique , Hypoglycémiants/administration et posologie , Hypoglycémiants/composition chimique , Administration par voie orale , Absorption intestinaleRÉSUMÉ
The following article analyses the excipients used in the parenteral formulations registered by the U.S. Food and Drug Administration (FDA) in the years 2011 and 2021. It adds real-word data for parenteral excipients in approved products from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Irish Health Products Regulatory Authority (HPRA) in 2021. Maximum daily exposures (MDEs) for all parenteral excipients that had their amount listed either in the Medsafe or HPRA database are presented. Altogether, there were 355 excipients found in the parenteral dosage forms across all markets (US, New Zealand, and Ireland). Only 90 excipients (25.3%) were found in all three markets. In contrast, there were 187 (52.7%) excipients found in only one market. The MDE values of parenteral excipients from New Zealand and Ireland are frequently higher than the values found in the FDA inactive ingredients database (IID), adding important new information when the toxicity of these excipients is considered. There is a heterogenicity between the markets in use of parenteral excipients, with the US market leading in the number of total excipients as well as excipients present only in the US market. Nevertheless, there are several excipients not found in the US market that are registered in other markets. The comprehensive listing of parenteral excipients used worldwide presented in this article enables formulation scientists to quickly reference all potential parenteral excipients that are already proven safe and acceptable when designing a new parenteral formulation. Further, a list of new values for the MDE, often higher than those listed in the IID, provides important information for formulation scientists and toxicologists about the potential toxicity of these excipients.
Sujet(s)
Excipients , Food and Drug Administration (USA) , Excipients/analyse , Excipients/composition chimique , États-Unis , Nouvelle-Zélande , Humains , Irlande , Agrément de médicaments , Perfusions parentérales , Chimie pharmaceutique/méthodesRÉSUMÉ
INTRODUCTION: The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of the raw materials. Existing knowledge on the role of raw material properties in batch processing is however not directly transferable to continuous processes, due to the inherent differences between batch and continuous processes. AREAS COVERED: A review is performed to evaluate the role of excipient properties for different unit operations used in continuous manufacturing processes. Unit operations that will be discussed include feeding, blending, granulation, final blending, and compression. EXPERT OPINION: Although the potency of continuous manufacturing is widely recognized, full utilization still requires a number of challenges to be addressed effectively. An expert opinion will be provided that discusses those challenges and potential solutions to overcome those challenges. The provided overview can serve as a framework for the pharmaceutical industry to push ahead process optimization and formulation development for continuous manufacturing processes.
Sujet(s)
Chimie pharmaceutique , Préparation de médicament , Industrie pharmaceutique , Excipients , Poudres , Comprimés , Excipients/composition chimique , Chimie pharmaceutique/méthodes , Préparation de médicament/méthodes , Humains , Technologie pharmaceutique/méthodes , Préparations pharmaceutiques/composition chimiqueRÉSUMÉ
The principal aim of this study was to optimize analytical methodology based on mass spectrometry for the evaluation of the quality of recombinant human insulin and its analogs. In this study ESI-MS was used to assess the quality of human insulin, short acting insulin analogs, insulin lispro, insulin aspart and insulin glulisine and long acting analogs including insulin glargine, insulin degludec, and insulin detemir, in respective pharmaceutical formulations. In this study, with the aimed to optimize analytical conditions, different factors influencing the analytical performance such as pH, ionic strength, sample dilution, organic solvent addition were addressed. The study results demonstrated that MS is a suitable technique for the analysis of biotechnological compounds like insulin and its analogs. Although the obtained results provide an important information regarding this methodology, further studies are needed to validate this analytical approach and check for its suitability to be used in the regulatory environment.
Sujet(s)
Insuline , Spectrométrie de masse ESI , Spectrométrie de masse ESI/méthodes , Insuline/composition chimique , Insuline/analyse , Insuline/analogues et dérivés , Contrôle de qualité , Concentration en ions d'hydrogène , Humains , Concentration osmolaire , Hypoglycémiants/composition chimique , Hypoglycémiants/analyse , Insuline à longue durée d'action/composition chimique , Chimie pharmaceutique/méthodes , Solvants/composition chimiqueRÉSUMÉ
Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.
Sujet(s)
Chimie pharmaceutique , Taille de particule , Suspensions , Chimie pharmaceutique/méthodes , Préparation de médicament/méthodes , Indométacine/composition chimique , Eau/composition chimique , Sonication/méthodes , Cinnarizine/composition chimique , Science des ultrasons/méthodes , Technologie pharmaceutique/méthodes , Halopéridol/composition chimique , Excipients/composition chimiqueRÉSUMÉ
The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.
Sujet(s)
Biodisponibilité , Indoles , Solubilité , Indoles/pharmacocinétique , Indoles/composition chimique , Indoles/administration et posologie , Administration par voie orale , Animaux , Chimie pharmaceutique/méthodes , Calorimétrie différentielle à balayage/méthodes , Diffraction des rayons X/méthodes , Mâle , Spectroscopie infrarouge à transformée de Fourier/méthodes , Préparation de médicament/méthodes , Lapins , Polymères/composition chimique , Technologie d'extrusion par fusion à chaud/méthodes , Libération de médicamentRÉSUMÉ
In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.
Sujet(s)
Antifongiques , Candidose buccale , Libération de médicament , Miconazole , Impression tridimensionnelle , Miconazole/administration et posologie , Miconazole/composition chimique , Miconazole/pharmacocinétique , Antifongiques/administration et posologie , Antifongiques/composition chimique , Antifongiques/pharmacocinétique , Administration par voie buccale , Candidose buccale/traitement médicamenteux , Humains , Zéine/composition chimique , Muqueuse de la bouche/métabolisme , Muqueuse de la bouche/microbiologie , Povidone/composition chimique , Perméabilité , Systèmes de délivrance de médicaments/méthodes , Animaux , Chimie pharmaceutique/méthodes , EnfantRÉSUMÉ
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
Sujet(s)
Adénine , Benzamides , Chimie pharmaceutique , Lipides , Nitriles , 3-Phényl-2-thiohydantoïne , Pipéridines , Solubilité , Température , Nitriles/composition chimique , Nitriles/administration et posologie , Pipéridines/composition chimique , Pipéridines/administration et posologie , Pipéridines/pharmacocinétique , Benzamides/composition chimique , Benzamides/pharmacocinétique , Adénine/analogues et dérivés , Adénine/composition chimique , Adénine/administration et posologie , 3-Phényl-2-thiohydantoïne/pharmacocinétique , 3-Phényl-2-thiohydantoïne/administration et posologie , Lipides/composition chimique , Animaux , Chimie pharmaceutique/méthodes , Préparation de médicament/méthodes , Mâle , Pyrimidines/pharmacocinétique , Pyrimidines/composition chimique , Pyrimidines/administration et posologie , Stabilité de médicament , Cristallisation/méthodes , Pyrazoles/composition chimique , Pyrazoles/pharmacocinétique , Pyrazoles/administration et posologie , Lipolyse/effets des médicaments et des substances chimiques , RatsRÉSUMÉ
The compound Salvia Recipe has been shown to have a relatively significant curative effect in management of cardiovascular and cerebrovascular diseases. This work aimed to prepare a thermosensitive in situ gel (ISG) delivery system that utilizes Poloxamer 407, Poloxamer 188, and hydroxypropyl methylcellulose for ocular administration of the compound Salvia recipe to treat cardiovascular and cerebrovascular diseases. The central composite design-response surface method was utilized to improve the prescription of the gel. The formulated gel was characterized and assessed in terms of stability, retention time, in vitro release, rheology, ocular irritation, pharmacokinetics studies, and tissue distribution. The gel was a liquid solution at room temperature and became semisolid at physiological temperature, prolonging its stay time in the eye. Pharmacokinetics and tissue distribution experiments indicated that thermosensitive ISG had enhanced targeting of heart and brain tissues. Additionally, it could lower drug toxicity and side effects in the lungs and kidneys. The compound Salvia ophthalmic thermosensitive ISG is a promising drug delivery system for the management of cardiovascular and cerebrovascular illnesses.
Sujet(s)
Administration par voie ophtalmique , Systèmes de délivrance de médicaments , Gels , Salvia , Animaux , Salvia/composition chimique , Systèmes de délivrance de médicaments/méthodes , Distribution tissulaire , Température , Poloxamère/composition chimique , Lapins , Oeil/effets des médicaments et des substances chimiques , Oeil/métabolisme , Chimie pharmaceutique/méthodes , Dérivés de l'hypromellose/composition chimique , Mâle , Rhéologie , Médicaments issus de plantes chinoises/administration et posologie , Médicaments issus de plantes chinoises/composition chimique , Médicaments issus de plantes chinoises/pharmacocinétiqueRÉSUMÉ
Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11-19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.
Sujet(s)
Flurbiprofène , Hydroxyde de sodium , Solubilité , Flurbiprofène/composition chimique , Hydroxyde de sodium/composition chimique , Méglumine/composition chimique , Lysine/composition chimique , Trométhamine/composition chimique , Anti-inflammatoires non stéroïdiens/composition chimique , Cristallisation , Chimie pharmaceutique/méthodes , Concentration en ions d'hydrogèneRÉSUMÉ
The paper provides a demonstration of how UV/VIS imaging can be employed to evaluate the crushing strength, friability, disintegration time and dissolution profile of tablets comprised of solely white components. The samples were produced using different levels of compression force and API content of anhydrous caffeine. Images were acquired from both sides of the samples using UV illumination for the API content prediction, while the other parameters were assessed using VIS illumination. Based on the color histograms of the UV images, API content was predicted with 5.6â¯% relative error. Textural analysis of the VIS images yielded crushing strength predictions under 10â¯% relative error. Regarding friability, three groups were established according to the weight loss of the samples. Likewise, the evaluation of disintegration time led to the identification of three groups: <10â¯s, 11-35â¯s, and over 36â¯s. Successful classification of the samples was achieved with machine learning algorithms. Finally, immediate release dissolution profiles were accurately predicted under 5â¯% of RMSE with an artificial neural network. The 50â¯ms exposition time during image acquisition and the resulting outcomes underscore the practicality of machine vision for real-time quality control in solid dosage forms, regardless of the color of the API.
Sujet(s)
Caféine , Libération de médicament , Solubilité , Comprimés , Caféine/composition chimique , , Rayons ultraviolets , Chimie pharmaceutique/méthodes , Apprentissage machine , Préparation de médicament/méthodesRÉSUMÉ
A new theory for the dispersibility enhancing effect of excipient fines for adhesive mixtures for inhalation is presented in this paper, while at the same time the shortcomings of current hypotheses are discussed. The proposed mechanism, denoted the 'viscoelastic damping effect', states that the presence of fines particles acts to dampen the collisions between carrier particles during mixing. As a consequence, fewer fine particles are 'irreversibly' pressed into the carriers, which in turn entails a higher fine particle fraction. The mechanism was demonstrated experimentally at different levels of added lactose fines by studying the influence of processing on fine particle fraction. This approach furthermore enabled quantification of the effect. All fine particles present in the blend (APIs and excipient fines) act together to exert the damping effect. The proposed mechanism is able to explain the main body of published data, including the effect of added excipient fines, the effect of an increased drug load, and the effect of removal of carrier fines. The viscoelastic damping mechanism is general in nature and conveys a broader and more general understanding of the behavior of adhesive mixtures for inhalation.
Sujet(s)
Adhésifs , Excipients , Lactose , Taille de particule , Lactose/composition chimique , Excipients/composition chimique , Administration par inhalation , Adhésifs/composition chimique , Chimie pharmaceutique/méthodes , Vecteurs de médicaments/composition chimiqueRÉSUMÉ
Polymorphism can be a valuable tool as well as an impediment in the development and approval of pharmaceuticals, providing an opportunity to tune active pharmaceutical ingredient (API) physicochemical properties. The control of polymorphism in cocrystalline systems and other multicomponent forms remains underexplored. The study herein aims to investigate the potential of several techniques, liquid-assisted grinding (LAG), solvent evaporation (SE), supercritical enhanced atomization (SEA) and electrospraying, to control the cocrystal polymorphic outcome of three cocrystals: isonicotinamide-citric acid (IsoCa), ethenzamide-saccharin (EthSac) and ethenzamide-gentisic acid (EthGa). Solvent selection employing LAG and SE showed little effect on polymorphic outcome. Electrospraying and SEA primarily produced the α form of IsoCa, with process parameter variations leading to the ß form during SEA, and a mixture of α and γ from electrospraying. Electrospraying led to the stable form I of EthSac, while SEA could produce pure form II, and a mixture. Electrospraying produced the form I of EthGa while SEA could produce form II, with an unknown polymorphic impurity. Density functional theory (DFT) computed electron density (ED) maps of cocrystal polymorph binary systems further rationalised the polymorphic predominance observed through the electrospraying. Ultimately this study provides a general road map for polymorph selection via atomization-based methodologies.
Sujet(s)
Cristallisation , Nicotinamide , Saccharine , Nicotinamide/composition chimique , Saccharine/composition chimique , Solvants/composition chimique , Chimie pharmaceutique/méthodes , Théorie de la fonctionnelle de la densité , Salicylamides/composition chimique , Préparation de médicament/méthodes , Préparations pharmaceutiques/composition chimiqueRÉSUMÉ
To ensure product stability, it is critical to maintain the monohydrate state of cyclophosphamide following lyophilization, as this is the most stable solid form of the Cyclophosphamide. On the other hand, because of their limited aqueous solubility and stability, non-aqueous solvents are preferred for determining the composition and stability of bulk solutions. Hence, the purpose of this study was to use non-aqueous solvents for determining the composition and stability of bulk solutions, and to shorten the lyophilization process by retaining the cyclophosphamide monohydrate. Furthermore, prior to selecting the solvent for the bulk solution consisting of 90:10 tertiary butyl alcohol (TBA) and acetonitrile (ACN), various factors were taken into account, including the freezing point, vapor pressure of solvents, solubility, and stability of cyclophosphamide monohydrate. The concentration of the bulk solution was adjusted to 200 mg/mL in order to optimize the fill volume, enhance sublimation rates at lower temperatures during primary drying, and eliminate the need for secondary drying. The differential scanning calorimetry (DSC) measurements of bulk solution were used to improve the lyophilization cycle. The lyophilization cycle opted was freezing at a temperature of -55 °C with annealing step at -22 °C by which the reconstitution time was significantly reduced. The drying was performed at below - 25 °C while maintaining a chamber pressure of 300 mTorr. The complete removal of non-aqueous solvents was achieved by retaining water within the system. The presence of cyclophosphamide monohydrate was confirmed using X-ray diffraction (XRD). The reduction of lyophilization process time was established by conducting mass transfer tests and evaluating the physicochemical properties of the pharmaceutical product. Using non-aqueous solvents for freeze-drying cyclophosphamide is a viable option, and this study provides significant knowledge for the advancement of future generic pharmaceuticals.
Sujet(s)
Acétonitriles , Cyclophosphamide , Stabilité de médicament , Lyophilisation , Solubilité , Solvants , Lyophilisation/méthodes , Cyclophosphamide/composition chimique , Solvants/composition chimique , Acétonitriles/composition chimique , Chimie pharmaceutique/méthodes , Calorimétrie différentielle à balayage/méthodes , Préparation de médicament/méthodes , Alcool tert-butylique/composition chimique , Congélation , TempératureRÉSUMÉ
Fenbendazole is an antiparasitic drug widely used in veterinary medicine to treat parasitic infections caused in animals like cattle, horses, sheep, and dogs. Recently, it has been repositioned as a potential alternative for cancer treatment. However, it is a highly hydrophobic molecule (0.9 ug/mL), which can compromise its dissolution rate and absorption. Thus, this work aimed to apply a nanotechnological approach to improve drug solubility and dissolution performance. Fenbendazole nanoparticles stabilized by different poloxamers were obtained by lyophilization without cryoprotectants. The behavior of the drug in the solid state was analyzed by X-ray diffractometry, differential scanning calorimetry, and infrared spectroscopy. The nanosystems were also evaluated for solubility and dissolution rate. A long-term stability evaluation was performed for three years at room temperature. The yields of the lyophilization ranged between 75 and 81% for each lot. The nanoparticles showed a submicron size (< 340 nm) and a low polydispersity depending on the stabilizer. The physicochemical properties of the prepared systems indicated a remarkable amorphization of the drug, which influenced its solubility and dissolution performance. The drug dissolution from both the fresh and aged nanosystems was significantly higher than that of the raw drug. In particular, nanoparticles prepared with poloxamer 407 showed no significant modifications in their particle size in three years of storage. Physical stability studies indicated that the obtained systems prepared with P188, P237, and P407 suffered certain recrystallization during long storage at 25 °C. These findings confirm that selected poloxamers exhibited an important effect in formulating fenbendazole nanosystems with improved dissolution.