The improvement of bioavailability of poorly water-soluble drugs is important for oral administration. Amorphization is one of the techniques that has been commonly used for solubility enhancement.1,2) Amorphous material of drug can be obtained by several methods, e.g., spray-drying, 3) solid dispersion, 4) co-grinding with cyclodextrins 5) or crystalline cellulose, 6) and mixing with porous materials. 7,8) Porous materials have a unique capacity to adsorb organic compounds due to their large specific surface area and porous structure. Activated carbon, porous crystalline cellulose, and zeolites are examples of porous materials that have been used widely for pharmaceuticals. [9][10][11] Folded sheets mesoporous material (FSM-16) has been synthesized by an intercalation of quaternary ammonium surfactant as a template in a layered polysilicate kanemite, followed by calcination.12-16) FSM-16 is composed of hexagonal channels and has extremely large specific surface area and large pore volume. Due to its highly uniform porous structure with hexagonal arrays, FSM-16 is widely used as a reactor for catalytic reaction, as an adsorbent and as a host for the inclusion of large molecules. 17,18) Itoh et al. 19) studied the photostability of chlorophyll a after adsorption into FSM-16. The enhancement of the photostability was attributable to the interactions between chlorophyll and FSM-16 to form chlorophyll-FSM conjugate, and also between two chlorophyll molecules to form a chlorophyll dimer within the pores of FSM-16.In the previous paper, we investigated the use of FSM-16 for pharmaceutical applications. We reported the change in molecular state of salicylamide from crystal to amorphous by adsorption into the FSM-16 channels during sealed-heating process. The amorphization of the drug accordingly resulted in enhanced dissolution of sealed-heated sample. 20) In the present study, three kinds of FSM-16 with different pore diameters [FSM-16(Oc), FSM-16(Do) and FSM-16(Doc)] were employed to investigate the molecular state of the drug and its interaction with FSM-16. Flurbiprofen (FBP), a poorly water-soluble non-steroidal anti-inflammatory drug, was used as a model compound. Changes in the molecular state of FBP were investigated using powder X-ray diffractometry, thermal analysis and FT-IR spectroscopy. The changes in pore diameter and specific surface area of samples prepared by various methods were investigated using small angle X-ray scattering and nitrogen gas adsorption BET method for understanding the effect of adsorption of FBP molecules on pore structure of FSM-16. ExperimentalMaterials Flurbiporfen (FBP) of reagent grade was kindly supplied by Kaken Pharmaceutical, Co. Ltd., Japan, and was used without further purification. Three kinds of mesoporous silica FSM-16, i.e., FSM-16(Oc), FSM-16(Do) and FSM-16(Doc), were kindly supplied by Toyota Central R&D Labs., Inc., Japan. Mean pore width and specific surface area of FSM-16(Oc), FSM-16(Do), FSM-16(Doc) were 16.0, 21.6, 45.0 Å and 700, 1250, 1040 m 2 /g, respectively...
Several techniques have been widely applied to enhance the bioavailability of poorly water-soluble drug, for examples, inclusion complex formation, 1,2) polymeric nanoparticle, 3) solid dispersion, 4) and particle size reduction by grinding. 5,6) Micron-sized particles can be produced by grinding but particles at the nanometer level are difficult to obtain by the dry milling method. In the past few years, there are many publications focusing on the preparation of drug particles at the nanometer level by co-grinding with additives. [7][8][9][10][11][12][13][14] In previous studies, we have reported the formation of pranlukast nanoparticle with mean particle size around 200 nm by co-grinding with CDs.10) Co-grinding with CDs could be applied as a nanoparticle preparation method for various kinds of poorly water-soluble drugs. [10][11][12] We also found that moisture content in the co-grinding process was an important factor and a suitable moisture condition during co-grinding was indispensable for nanoparticle formation. 13)Pranlukast is a cysteinyl leukotriene receptor antagonist which is chemically described as (4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran). Pranlukast is practically insoluble (1.2 mg/ml H 2 O at 25°C), resulting in poor absorption after oral administration.Environmental scanning electron microscopy (ESEM) can be used to observe samples in a moist condition by controlling water vapor pressure in the microscope specimen chamber. The observation of wet organic samples by ESEM has been reported recently. 14,15) In this study, the effects of grinding time, moisture content and CD content on the nanoparticle formation were evaluated by means of UV quantitative determination and particle size analysis. High-resolution scanning electron microscope was employed to observe the surfaces of the ground mixtures prepared under various conditions. Moreover, ESEM was used to observe the drug particles after dispersal into water.The mechanism for nanoparticle formation was discussed. ExperimentalMaterials Pranlukast hemihydrate was received from Ono Pharmaceutical Co., Ltd., Japan as jet-milled material. b-Cyclodextrin (b-CD) was kindly supplied by Nihon Shokuhin Kako Co., Ltd., Japan as a hydrate form (b-CD · 10.5H 2 O). The water content of b-CD was measured by the Karl-Fischer method and was found to be 14.2 w/w%. The anhydrous form of b-CD was obtained by drying b-CD · 10.5H 2 O in vacuum at 110°C for 3 h and the water content was limited to less than 1%. All chemicals used were of reagent grade. Preparation of Ground MixturesThe physical mixture of anhydrous b-CD and pranlukast was prepared at molar ratios of 1 : 2, 1 : 1, and 2 : 1 (b-CD : pranlukast) in a glass vial using a vortex mixer. To control the moisture content during the co-grinding process, the required amount of distilled water was added to the physical mixture and mixed homogeneously. The ground mixture was obtained by grinding the physical mixture in a vibrational rod mill (TI-200, Heiko Seisakusho, Japan) with ...
Amylose is a polysaccharide consisting of a-1,4-linked D-(ϩ)-glucopyranoses which take three helical forms, namely; A-, B-, and V-amyloses.1,2) A-and B-structures are found in native amyloses with a double helix, while the V-structure is formed at inclusion compound formation with a complexing ligand. Several kinds of guest compounds can be included in the hydrophobic core of V-amylose and normally V-amylose takes a single helical structure with 6 glucose units per turn (6 1 -helix). [3][4][5][6] However, when amylose adopts larger guests, the structure of V-are found to be a 7 1 -helix 7-9) or 8 1 -helix [10][11][12] depending on the size of guest molecules. The inclusion compounds are usually prepared from aqueous solution of amylose by adding an alcoholic solution of guest compound.The sealed-heating method can be used to prepare inclusion compounds of cyclodextrin. [13][14][15] Previously we have applied the sealed-heating method for the preparation of amylose inclusion compounds with several guest molecules. [16][17][18][19] Salicylic acid analogues, 16,17) benzoic acid analogues 18) and 2-naphthol 19) are examples of guest molecules that could form inclusion compound with amylose by the seal-heating method. We also reported that the vapor pressure of the guest and the water content in the sealed-heating process were significant factors for the formation of inclusion compound. 16,17) Powder X-ray diffraction and infrared spectroscopy were used to investigate the interaction between amylose and guest molecules.In the present study, we prepared the inclusion compound between amylose and PA by sealed-heating method. Since the powder X-ray diffraction patterns provide only the structure change of amylose, solid state NMR spectroscopy was used in order to estimate the molecular state and molecular mobility of PA in the inclusion compound. The effect of heating temperature and the size of guest molecules on the inclusion compound formation were also investigated. ExperimentalMaterials Linear amylose of molecular weight 102500 (AS100) was kindly supplied by Ezaki Glico Co., Ltd. The particle size of AS100 was controlled between 42.5 and 150 mm by sieving. p-Aminobenzoic acid (PA), methyl p-aminobenzoate (MPA), ethyl p-aminobenzoate (EPA), butyl paminobenzoate (BPA) were purchased from Nakalai Tesque, Japan. Propyl p-aminobenzoate (PPA) was obtained from Tokyo Kasei Kogyo Co., Ltd. All chemicals were of reagent grade.Sample Preparation and Sealed-Heating Procedure A physical mixture was prepared at a mixing ratio of 1 : 1 and 1 : 2 (6 glucose units: PA) in a glass vial for 5 min using a vortex mixer. As a pretreatment, AS100 was dried at 100°C for 3 h and then humidified at 33% relative humidity at 25°C for 1 d before use. The water content of AS100 after humidification was determined by the Karl-Fischer method and was estimated to be 8.0%. A physical mixture (200 mg) was sealed in a 2 ml glass ampoule and then heated at various temperatures for a definite time.Powder X-Ray Diffractometry Powder X-ray diffraction (...
Cogrinding with a beta-CD of higher water content can be an effective method to prepare fine drug particles at the submicron level.
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