ABSTRACT
Abstract Tadalafil (Tad) is a poorly water-soluble drug (BCS class II) that is used for the treatment of erectile dysfunction. An enhancement of aqueous solubility is vital to accelerate its onset of action and subsequently enhance its therapeutic effect. Binary and ternary mixtures of Tad with different amino acids (histidine, valine, alanine or arginine) and other excipients (mannitol and SLS) were prepared and then spray dried. The solubilizing efficiency and physicochemical characterization of all spray dried mixtures of Tad were studied. The optimum formulation was investigated in male rats to determine the onset of erection and the pharmacokinetic parameters of Tad. In general terms, the drug solubility of spray-dried formulae was enhanced compared to the crystalline form of the drug as a result of the formation of co-amorphous structures. The final result revealed that the Tad/alanine/mannitol spray-dried mixture (F10) showed the highest solubility and an improvement in its physicochemical characteristics. Moreover, F10 showed a significantly faster erection in rats with an improvement in Tad pharmacokinetic parameters when compared to the crystalline drug. Thus, F10 is selected as a promising formulation that successfully enhanced the bioavailability and the therapeutic efficacy of Tad.
Subject(s)
Solubility , Tadalafil/analysis , Pharmaceutical Preparations/analysis , Erectile Dysfunction/pathologyABSTRACT
The present study explored the effect of co-amorphous technology in improving the dissolution rate and stability of silybin based on the puerarin-silybin co-amorphous system prepared by the spray-drying method. Solid-state characterization was carried out by powder X-ray diffraction(PXRD), polarizing microscopy(PLM), Fourier transform infrared spectroscopy(FT-IR), differential scanning calorimetry(DSC), etc. Saturated powder dissolution, intrinsic dissolution rate, moisture absorption, and stability were further investigated. The results showed that puerarin and silybin formed a co-amorphous system at a single glass transition temperature which was higher than that of any crude drug. The intrinsic dissolution rate and supersaturated powder dissolution of silybin in the co-amorphous system were higher than those of the crude drug and amorphous system. The co-amorphous system kept stable for as long as three months under the condition of 40 ℃, 75% relative humidity, which was longer than that of the single amorphous silybin. Therefore, the co-amorphous technology could significantly improve the dissolution and stability of silybin.
Subject(s)
Calorimetry, Differential Scanning , Desiccation , Drug Compounding/methods , Drug Stability , Silymarin , Solubility , Spectroscopy, Fourier Transform Infrared , Technology , X-Ray DiffractionABSTRACT
@#Lenvatinib mesylate (LF), a multi-target tyrosinase inhibitor mainly used in the treatment of a variety of cancers, has low oral bioavailability mainly due to its gelation during the dissolution process. In the current study, in order to enhance dissolution and eliminate gelation of LF, a supramolecular coamorphous system of LF-baicalein (BAI) (molar ratio, 1∶1) was prepared by rotary evaporation and characterized by PLM, PXRD, DSC and FTIR. Results indicated the formation of coamorphous system with a single Tg of 118 °C. Different from original LF crystal, no gelation phenomenon was observed during the dissolution of coamorphous LF-BAI. In addition, the dissolution rate of LF was increased by 2.2-fold after coamorphization. Meanwhile, the dissolution rate of the co-former BAI was also enhanced by more than 25.4-fold. Stability test showed that the prepared coamorphous system had a good physical stability for at least 90 days under 25 °C/ 60%RH and 40 °C /75%RH conditions.
ABSTRACT
The solubility/dissolution, hygroscopicity and mechanical properties of drug candidates have a profound effect on oral bioavailability, processability and stability. The physicochemical properties of crystalline drug are closely related to inner crystal structure. Crystal engineering technologies, as strategies of altering the crystal structure and tailoring physicochemical properties at molecular level, possess the potential of enhancing the pharmaceutical performance of product. The current article reviewed the modification of drug solubility/dissolution, hygroscopicity and mechanical properties by crystal engineering technologies through polymorphic selection, amorphization/co-amorphization, as well as co-crystallization, which provided a reference for the applications of pharmaceutical crystallography in improving physicochemical properties and druggability.
ABSTRACT
Bexarotene is a synthetic analogue of retinoic acid and exerts protective effects on the nervous system. However, low bioavailability and poor solubility of the crystal type I form severely limits the application of bexarotene in the clinic. A co-amorphous sample of bexarotene-PVP-K30 was prepared and the structure was characterized by X-ray diffraction and infrared spectroscopy. To determine the pharmacokinetics and tissue distribution of bexarotene, an LC-MS method was established to profile and quantify bexarotene in plasma and tissues of SD rats. In vitro dissolution indicated that the co-amorphous form improved the dissolution of bexarotene in pure water 4.17-fold. After rats were orally administered bexarotene or bexarotene-PVP-K30 co-amorphous (equivalent to 30 mg·kg-1 bexarotene) the AUC of bexarotene was 7 034.89 and 10 174.03 μg·L-1·h respectively, the peak time was advanced from 7.33 h to 0.9 h with the amorphous form, and Cmax was enhanced from 627.76 to 3 011.88 μg·L-1. The co-amorphous form yielded higher concentrations of bexarotene in various tissues, especially brain, liver and kidney. Animal welfare and experimental procedures complied with the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. The results indicate that bexarotene-PVP-K30 co-amorphous improves the pharmacokinetic characteristics of bexarotene and provides preclinical data in support of bexarotene-PVP-K30 for the treatment of brain diseases.
ABSTRACT
@#Dabigatran etexilate mesylate(DE)and tadalafil(TD)are BCS class II drugs with poor water solubility. 〓 In this study coamorphization technique was used to improve their solubilities/dissolutions and hence to enhance their oral absorptions. The coamorphous DE-TD were prepared by solvent-evaporation method and characterized by PXRD, DSC, FTIR and TGA. In addition, dissolution behavior and physical stability were also investigated. Only halo pattern and a single Tg of 119 °C was observed on the PXRD and DSC of the co-evaporated product, respectively, indicating the formation of coamorphous DE-TD. FTIR result suggested that a hydrogen bond was probably formed between N-H group of DE and C==O group of TD. In comparison to crystalline counterparts, coamorphous DE-TD showed a significantly improved intrinsic dissolution rate and prolonged supersaturation time in intrinsic dissolution and supersaturation dissolution studies, respectively. No crystallization was observed under affecting factors testing(30 days)as well as long-term and accelerated stability testing(90 days)for the prepared coamorphous DE-TD under 25°C/60%RH or 40°C/75%RH, while amorphous DE crystalized at 10 days under 25 ℃/75% RH.
ABSTRACT
OBJECTIVE：To prepare Co-amorphous curcumin （CUR）-tryptophan （TRY） （Co-amorphous CUR-TRY）， and to study its pharmacokinetic characteristics in rats. METHODS： Co-amorphous CUR-TRY was prepared by ball milling method. differential scanning calorimetry （DSC） and powder X-ray diffraction （XRD） were used to characterize Co-amorphous CUR-TRY. The in vitro dissolution rate （dissolution） of Co-amorphous CUR-TRY， CUR and CUR-TRY physical mixture were compared under sink condition and non-sink condition. 18 SD rats were selected and randomly divided into Co-amorphous CUR-TRY group （155.43 mg/kg）， CUR raw material group （100 mg/kg）， CUR-TRY physical mixture group （155.43 mg/kg）， with 6 rats in each group. They were given relevant medicine intragastrically once. Each blood samples 0.3 mL were collected from orbital venous plexus 0.167， 0.33， 0.5， 0.75， 1， 1.5， 2， 4， 6， 8， 10， 12， 24 h after medication. UPLC-MS/MS was used to determine plasma concentration of CUR in rats. The pharmacokinetic study was performed by using DAS 3.0 software. RESULTS： DSC and XRD showed that Co-amorphous CUR-TRY was successfully prepared. Under sink condition （120 min）， compared with CUR raw material [cumulative dissolution rate of CUR is （36.79±3.79）％] and CUR-TRY physical mixture [cumulative dissolution rate of CUR is （33.12±0.68）％]， cumulative dissolution rate of CUR in Co-amorphous CUR-TRY （90.37±2.52）％ was improved significantly （P＜0.01）. Under non-sink condition， compared with CUR raw material and CUR-TRY physical mixture， CUR of Co-amorphous CUR-TRY exhibited dissolution and maintained supersaturation for a long time. Pharmacokinetic study showed that compared with CUR raw material group and CUR-TRY physical mixture group， cmax， AUC0-24 h and AUC0-∞ were increased significantly in Co-amorphous CUR-TRY group （P＜0.01）； Relative bioavailability of CUR was improved by 2.14 and 1.86 fold （P＜0.01）. CONCLUSIONS：Prepared Co-amorphous CUR-TRY can effectively improve in vitro dissolution and in vivo bioavailability in rats of CUR.
ABSTRACT
Objective To prepare a co-amorphous complex of piperine (PIP) and triterpenoids from Ligustri Lucidi Fructus (TLLF) to improve the dissolution of TLLF. Methods TLLF-PIP co-amorphous complex was prepared using solvent evaporation method. The microscopic structure of co-amorphous complex (CAC) was analyzed using differential scanning calorimetry (DSC), scanning electronmicroscopy (SEM), and powder X-ray diffraction (PXRD), the optimal ratio of the two components was investigated through the thermal stability experiment. Ultraviolet-visible spectrophotometry (UV-Vis) and high performance liquid chromatography (HPLC) were applied to determine the amount of TLLF, PIP and the individual components, ursolic acid (UA) and oleanolic acid (OA), respectively. The interaction of the optimal CAC was analyzed by Fourier transform infrared spectroscopy (FTIR), and its solubility and dissolution behavior in vitro were also studied to evaluate the formation of the preparation. Results PXRD analysis indicated that the TLLF-PIP-CAC with a mass ratio of 1:1 exhibited a stable amorphous state, which particles presented in near-spherical shape. FTIR results indicated that there are some hydrogen interactions between the moleculars of TLLF and PIP. The solubility and dissolution determination exhibited a pairwise released behavior with improved triterpenoids and decreased piperine dissolution. Conclusion The prepared TLLF-PIP-CAC can significantly improve the dissolution and amorphous stability of TLLF, which may provide a reference for the compatibility of insoluble compound in traditional Chinese medicine.
ABSTRACT
Tadalafil (TD), a phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, has a low oral bioavailability due to its extremely poorly aqueous solubility. The aim of this study was to enhance its solubility and dissolution by coamorphization with dapoxetine (DP), a selective serotonin reuptake inhibitor to manage premature ejaculation. Coamorphous TD-DP (molar ratio, 1:1) was prepared by solvent-evaporation method and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The supersaturated dissolution of TD from coamorphous TD-DP was investigated in various aqueous media and compared to that of crystalline TD. In addition, physical stability of coamorphous system was also evaluated under the conditions of 40℃/75% relative humidity (RH) and 25℃/60% RH for 90 days. DSC thermogram and PXRD pattern indicated the formation of the coamorphous TD-DP. In comparison to original TD crystal, the dissolution of TD from coamorphous system were significantly enhanced in various media (water, 0.01 mol·L-1 HCl and pH 4.5 phosphate buffer). In addition, no crystallization phenomenon of the prepared coamorphous system was observed until 90 days' storage under 25℃/60% RH. However, when temperature and humidity were increased to 40℃/75% RH, the coamorphous TD-DP was recrystallized easily.
ABSTRACT
Objective: To prepare scutellarin-piperine co-amorphous complex, in order to improve their dissolution and solubility. Methods: Scutellarin-piperine co-amorphous complex was prepared using solvent evaporation method. The microscopic structure and physicochemical properties of co-amorphous complex were analyzed using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and infrared vibrational spectra (IR). And its in vitro release also was investigated. The formation of the co-amorphous complex in scutellarin and piperine was studied. Results: DSC and XRD analysis suggested that scutellarin and piperine may be present as amorphous substance. IR results indicated molecular interactions between scutellarin and piperine. The in vitro release determination results of scutellarin-piperine co-amorphous complex showed accumulated dissolution rate of scutellarin and piperine could both be improved. Conclusion: The drug-drug co-amorphous system can provide certain reference for insoluble drugs to improve their dissolution and solubility.
ABSTRACT
@#In this study, coamorphous simvastatin-gliclazide was prepared and characterized. Its single-phase amorphous nature was demonstrated. The hydrogen bond between the O-H group of simvastatin and sulfonylurea C=O group of gliclazide was revealed to be the trigger for the amorphization of gliclazide, which is difficult to form an amorphous state in other methods. Coamorphous simvastatin-gliclazide can significantly enhance the solubility and dissolution of gliclazide, without obvious effect on simvastatin. Compared with amorphous simvastatin, coamorphous simvastatin-gliclazide showed improved physical stability in the cunrent study.