Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice.

Cannabidiol (CBD), a major component of cannabis, has various effects, such as antiemetic and anxiolytic activities, and has recently been marketed as a supplement. The number of people using CBD during pregnancy is increasing, and there are concerns about its effects on the fetus. In addition, the scientific evidence supporting the fetal safety of CBD use during pregnancy is insufficient. To investigate CBD transfer from the mother to the fetus, a single intravenous dose of CBD was administered to pregnant mice in this study, and fetal pharmacokinetics (distribution and elimination) was analyzed. The transfer of CBD from the maternal blood to the fetus was rapid, and the compound accumulated in the fetal brain, liver, and gastrointestinal tract. Conversely, little CBD was transferred from the mother to the amniotic fluid. We analyzed the pharmacokinetics of CBD using a two-compartment model and found that the maternal and fetal half-lives of CBD were approximately 5 and 2 hours, respectively. Furthermore, we performed a moment analysis of the pharmacokinetics of CBD, observing a mean residence time of less than 2 hours in both the mother and fetus. These results suggest that once-daily CBD intake during pregnancy is unlikely to result in CBD accumulation in the mother or fetus. SIGNIFICANCE STATEMENT: CBD is currently marketed as a supplement, and despite its increasing use during pregnancy, little information concerning its fetal effects has been reported. In the present study, CBD was administered to pregnant mice, and the pharmacokinetics in the fetus was investigated using a two-compartment model and moment analysis. The results of these analyses provide important information for estimating the risk to the fetus if CBD is mistakenly consumed during pregnancy.

Novel Xyloglucan Sheet for the Treatment of Deep Wounds: Preparation, Physicochemical Characteristics, and in Vivo Healing Effects.

In the present study, a novel wound dressing made of xyloglucan (Xyl)-sucrose (Suc) hydrogel was developed for the treatment of deep wounds including pressure ulcers. The dressing was prepared by casing an aqueous solution of Xyl and sugar and then warming, and a hydrogel sheet was obtained. The in vitro characteristics of these sheets, such as their strength, extensibility, water content, adhesion potential, and water absorption, were examined. The strength, Young's modulus, and adhesion strength of the sheets were greater when they had a lower water content. Furthermore, adhesion and gradual water absorbability were similar to those of commercial dressings. These in vitro features suggest that Xyl sheets possess the physicochemical properties required for wound dressings. In the in vivo experiment, a Xyl sheet made from a mixture of 3.0% (w/v) Xyl solution and 33.3% (w/w) Suc, which displayed moderate strength and water content, was selected and compared with gauze, commercial polyurethane film, and Xyl/Suc (1 : 2) hydrogel using a rat deep wound model caused by serious frostbite. Wound healing rates based on reductions in wound areas were the best in the order of the sheet > hydrogel > commercial film > gauze. The sheet resulted in better wound surface states than the other preparations by improving the conditions. Thus, the potential applicability of Xyl sheets to the treatment of deep wounds was demonstrated.

Preparation and Evaluation of Stomatitis Film Using Xyloglucan Containing Loperamide.

Stomatitis induced by radiation therapy or cancer chemotherapy is a factor in sleep disorders and/or eating disorders, markedly decreasing patient quality of life. In recent years, disintegrating oral films that are easy to handle have been developed; therefore, we focused on the formulation of these films. We prepared an adhesive film for the oral cavity using xyloglucan (Xylo), which is a water-soluble macromolecule. We used loperamide, which has been reported to relieve pain caused by stomatitis effectively, as a model drug in this study. Films were prepared from Xylo solutions (3% (w/w)) and hypromellose (HPMC) solutions (1% (w/w)). Xylo and HPMC solutions were mixed at ratios of 1 : 1, 2 : 1, or 3 : 1 for each film, and films 2×2 cm weighing 3 g were prepared and dried at 37°C for 24 h. Physicochemical properties such as strength, adhesiveness, disintegration behavior, and dissolution of loperamide from films were evaluated. Films prepared from Xylo solution alone had sufficient strength and mucosal adhesion. On the other hand, films prepared from a mixture of Xylo and HPMC were inferior to those made from Xylo, but showed sufficient strength and mucosal adhesion and were flexible and easy to handle. The films prepared in this study are useful as adhesion films in the oral cavity.

Evaluation of matrix type mucoadhesive tablets containing indomethacin for buccal application.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to systemic side effects. To avoid these side effects and treat local lesions effectively, a matrix type mucoadhesive tablet was developed. A mixture of hard fat, ethylcellulose (EC) and polyethylene glycol (PEG) was used as a matrix base, and indomethacin (IMC) was used as the principal agent. In tablets consisting of hard fat, EC and IMC, the drug release was sustained. In tablets consisting of hard fat, EC, considerable amounts of PEG and IMC, the drug release was relatively increased and IMC existed as the molecular phase or in an amorphous state. The in vitro adhesive force of the tablets consisting of hard fat, EC, considerable amounts of PEG and IMC was significantly increased as compared with the tablets consisting of hard fat and IMC. A significantly high tissue concentration and significantly low plasma concentration were observed after buccal administration of this matrix type mucoadhesive tablet as compared with that after oral administration of IMC. Thus, the matrix type mucoadhesive tablet has good potential as a preparation for the treatment of pain due to oral aphtha.

Formulation and evaluation of matrix type mucoadhesive tablets aimed at treating oral aphtha.

CONTEXT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to the side effects of thrombocytopenia. OBJECTIVE: To avoid systemic side effects, a matrix type mucoadhesive tablet as a topical application preparation to treat oral aphtha was developed. METHODS: A mixture of hard fat with a low irritant property and mucoadhesive polymers was used as the matrix base, and indomethacin was used as a model drug. RESULTS: Among the water-soluble polymers, carbopol and xanthan gum increased the adhesive force of tablets prepared by the suspending method, but the tensile strength was not increased. Tablets containing ethylcellulose 10 or 45 (EC10, EC45) from a water-insoluble polymer increased the adhesive force and tensile strength. Tablets prepared by the dissolve-drying method containing EC45 showed a 1.8-fold increase of adhesiveness to the eggshell membrane compared with hard fat tablets, and showed a sustained release of the drug (17%) over an 8 h period. The drug release was increased to 28% by a modification to the dissolve-drying method using EC10. CONCLUSIONS: Since this matrix type tablet has long-acting properties, adhesiveness and low irritating properties, its potential as a newly designed preparation to treat oral aphtha is suggested.

Kinetic analysis of in vitro and in vivo release of prednisolone from the conjugate of glycol-chitosan and succinyl-prednisolone.

Recently, many people have developed rheumatoid arthritis (RA), and prednisolone (PD) is often used for treatment; however, long use and a large dose of PD can cause toxic side effects. In this study, in order to enhance the therapeutic effects and to suppress the toxic side effects, the conjugate (GC-SP) was prepared by coupling between glycol-chitosan (GC) and succinyl-prednisolone (SP). The drug-release properties of GC-SP were examined and analyzed kinetically. The plasma concentration-time profiles of GC-SP and released PD were investigated after i.v. injection to normal rats, and their pharmacokinetic profiles were analyzed. PD was stable and released gradually (ca. 1%/h) from GC-SP at physiological pH, while PD was unstable at basic pH and the release from GC-SP was accelerated at basic pH. GC-SP showed good systemic retention (more than 16-fold area under the plasma concentration-time curve (AUC) as compared to PD alone), and released PD gradually in vivo. The in vivo release rate was calculated to be much faster than the in vitro rate. From these results, it is expected that GC-SP will be accumulated at inflammatory sites based on enhanced permeability and retention (EPR) effects, and release PD there effectively.

[Preparation and evaluation of taste masked orally disintegrating tablets with granules made by the wet granulation method].

Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets were prepared using the direct compression method. Microcrystalline cellulose (Avicel® PH-302) and mannitol were added as excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a sufficient masking effect was obtained at the YO/FU ratio of 1 or more. Furthermore, it was found that the masking effect achieved by YO granules made with the wet granulation method was similar to or better than that produced by the granules made with dry granulation method. All types of tablets displayed sufficient hardness (over 3.5×10(-2) kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU increased. In the mixing ratio of FU/YO=1/1, the hardness of tablets with granules made by the wet granulation method exceeded that of tablets with granules made by the dry granulation method, with minimal differences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YO-containing granules made by the wet granulation method using MA as a binding agent.

Preparation and evaluation of medicinal carbon oral films.

Medicinal carbon (MC) films, which can be taken more easily than other dosage forms, were prepared using sodium carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) and alginic acid sodium (ALG) as film base materials. Brilliant blue FCF (BB) was used as a model drug. The films containing MC had sufficient strength and disintegration time, but their ability to adsorb BB was clearly inhibited compared to that of MC in powder form. When ALG was used as the film base, the BB adsorption capacity of MC film was approximately 50% of that of MC powder. In an attempt to improve this adsorption ability, two saccharides, sorbitol (SOR) and maltitol (MT), were separately added to MC at a mixing ratio of 1 : 1 by weight. When ALG was the film base, MC films containing SOR or MT showed rapid adsorption profiles and had greatly increased capacities for BB adsorption compared with films containing MC alone. SOR was superior to MT as an additive, though both gave MC-containing films a BB adsorption capacity almost equal to that of MC powder after 24 h, and physical mixtures tended to have better BB adsorption capacities than pre-treatment mixture. In addition, both SOR and MT tended to increase vertical strength of films, but neither additive in either type of mixture had a clear effect on disintegration time. When CMC or HPMC was used as the film base, on the other hand, the addition of SOR or MT caused hardly any improvement in adsorption ability. The above results demonstrate that ALG is useful as a film base material for the preparation of MC films, and that MC films with sufficient strength and adsorption capacities equal to those of MC powders can be produced using a physical mixture of MC and SOR on an ALG base.

[Preparation of orally disintegrating tablets for masking of unpleasant taste: comparison with corrective-adding methods].

Many orally disintegrating tablets have recently been developed to improve oral ingestion and usability and are widely administered clinically, resulting in improved quality of life for patients. Since orally disintegrating tablets rapidly disintegrate in the mouth, the masking of unpleasant taste is important. We investigated the masking of the taste of furosemide (FU) as a model drug with correctives and prepared orally disintegrating tablets. Using maltitol (MA) as a corrective, granules were prepared employing mixing, coating, and mixing/coating methods using a desktop granulator. Each preparation was subjected to tasting. The taste was masked well when granules were prepared by the mixing and mixing/coating methods. Tablets were prepared from these granules with mannitol and crystalline cellulose added as fillers. Tablets made from granules prepared by the mixing and mixing/coating methods showed appropriate strength and disintegrated rapidly. When the amount of MA was increased in the mixing method, the disintegration time was prolonged, and thus the amount should be determined considering both taste masking and disintegration property. The results showed that orally disintegrating tablets of insoluble drugs with an unpleasant taste such as FU should be prepared with the taste masked employing the methods used in this study.

Preparation of orally disintegrating tablets with taste-masking function: masking effect in granules prepared with correctives using the dry granulation method and evaluation of tablets prepared using the taste-masked granules.

We investigated several methods of taste masking in the preparation of orally disintegrating tablets (ODTs), using furosemide (FU) as a model drug. Four types of FU preparations were prepared: granules with maltitol (MA), granules with yogurt powder (YO), a physical mixture of FU and MA, and a physical mixture of FU and YO. All taste-masking granules were prepared using the dry granulation method. The taste of each type of preparation was evaluated. All four preparations markedly improved the taste of the FU tablets, but the mixing ratios of the correctives did not affect the masking effect. No difference in masking effect was found between MA and YO in the physical mixtures, but the masking effect in the granules with YO was superior to that of the granules with MA. Taste-masked FU tablets were prepared using the direct compression method; crystalline cellulose (Avicel PH-302) and mannitol were added as excipients at the mixing ratio of 1/1. All four types of tablets displayed sufficient hardness, but MA-containing tablets were harder than YO-containing tablets. The hardness of the tablets prepared from YO granules increased as the YO content increased. The most rapidly disintegrating tablets were those of YO granules prepared at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s, followed by the tablets of MA granules prepared at a mixing ratio of FU/MA=1/1. The disintegration times of the tablets made from physical mixtures, in contrast, were longer than 200 s. Disintegration time lengthened as the mixing ratio of YO or MA increased. The hardness and disintegration time of these tablets could be controlled by varying the compression pressure. We found that YO is more useful than MA in masking unpleasant tastes and confirmed that orally disintegrating tablets with taste-masking function can be prepared using granules of YO prepared using the dry granulation method as a new corrective.

Preparation and biodisposition of methoxypolyethylene glycol amine-poly(DL-lactic acid) copolymer nanoparticles loaded with pyrene-ended poly(DL-lactic acid).

A formyl group-ended poly(DL-lactic acid) (PLA-aldehyde), synthesized in the same manner as reported previously, was utilized to produce the polymeric marker for PLA-related nanoparticles. Namely, pyrene-ended poly(DL-lactic acid) (PLA-pyrene) was prepared as a polymeric marker by the reductive amination of PLA-aldehyde and aminopyrene. Methoxypolyethylene glycol amine-poly(DL-lactic acid) block copolymer (PLA-(MeO-PEG) nanoparticles loaded with PLA-pyrene were prepared, and examined on retention of PLA-pyrene in the nanoparticles, and biodisposition in normal and sarcoma-180 solid tumor-bearing mice. PLA-pyrene was retained stably in PLA-(MeO-PEG) nanoparticles in a PBS-ethanol (7:3, v/v) mixture and a plasma-PBS (1:1, v/v) mixture, indicating that PLA-pyrene might be a useful marker of PLA-(MeO-PEG) nanoparticles themselves. After i.v. injection in normal rats, the plasma level of PLA-pyrene was very high for initial 8h, and accumulated gradually into organs, especially spleen and liver. After i.v. injection in tumor-bearing mice, similar biodistribution profiles of PLA-pyrene were observed, and PLA-pyrene was accumulated well in tumor, suggesting that PLA-(MeO-PEG) nanoparticles should be delivered efficiently to solid tumors. It is suggested that PLA-pyrene might be a useful probe of the nanoparticles themselves. In addition, it was demonstrated that PLA-(MeO-PEG) nanoparticles should be a useful drug carrier for passive tumor targeting.

In vivo evaluation of Kumazasa extract and chitosan films containing the extract against deep skin ulcer model in rats.

Kumazasa extract (KE) and its whole solid component (EXT)-containing chitosan films produced by drying in air and lyophilization, abbreviated to ND and FD films, respectively, were examined for efficacy and healing features using a deep skin ulcer model in rats. Their effects were compared with those of clinically available dosage forms, Beschitin W, Geben cream and U-PASTA. KE alone exhibited a better effect as compared with other preparations, and FD films also more effective than control in the early stage. Histological analysis showed that KE alone reduced necrosis rapidly and accelerated granulation. ND films delayed healing rate as compared with control. FD films showed histological features between control and KE alone, but tended to delay healing rate in the later period. Thus, reduction rate of wound area and histological features suggested that KE alone should be excellent for the promotion of wound healing. Although FD films were less effective than KE alone, they were superior as to usability such as changing the preparation.

In vitro and in vivo characterization of nanoparticles made of MeO-PEG amine/PLA block copolymer and PLA.

The preparative method of a block copolymer of poly(dl-lactic acid) (PLA) and methoxypolyethylene glycol amine (MeO-PEG(N)), named PLA-(MeO-PEG), was refined. The degree of introduction of MeO-PEG(N) into PLA increased up to 55% (mol/mol) using a dichloromethane/methanol mixture (1:1, v/v) as a solvent at the reductive amination and taking all the fractions of the first peak in gel-chromatography. Plain and 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine (DiD)-loaded nanoparticles prepared using the PLA/PLA-(MeO-PEG) mixture of 45:55 (mol/mol) showed a mean size of 113 and 154 nm, respectively, and a positive zeta potential in water. DiD solution, i.v. administered, showed a lower plasma level and high distribution in liver, though DiD was distributed into the blood cells to a fair extent. Nanoparticles exhibited a higher plasma concentration of DiD than the DiD solution at 1 and 8h, though DiD was distributed into the liver and spleen to a fair extent. Nanoparticles made of the PLA/PLA-(MeO-PEG) mixture of 44:55 (mol/mol) showed better plasma retention than those made of the PLA/PLA-(MeO-PEG) mixture of 64:36 (mol/mol). It is suggested that the PLA/PLA-(MeO-PEG) mixture nanoparticles with a higher PEG/PLA ratio should be useful as a carrier for the elevation of the plasma concentration of lipophilic drugs.

Preparation of a PLA-PEG block copolymer using a PLA derivative with a formyl terminal group and its application to nanoparticulate formulation.

A novel poly(DL-lactic acid) (PLA) derivative with a diethoxy propanol ester at the end, named PLA-acetal, was synthesized by ring opening polymerization using DL-lactide and 3,3-diethoxy propanol. PLA-acetal was hydrolyzed to a PLA derivative with a formyl group, named PLA-aldehyde, by acid treatment. Reductive amination between PLA-aldehyde and methoxypolyethylene glycol amine (MeO-PEG(N)) gave the block copolymer (PLA-(MeO-PEG(N))). Nanoparticles were prepared by emulsification-solvent evaporation or solvent diffusion using PLA-(MeO-PEG(N)) or a conventional methoxypolyethylene glycol-PLA block copolymer, PLA-(MeO-PEG(O)). PLA-(MeO-PEG(N)) nanoparticles had a particle size of 60-340 nm, dependent on the preparative procedure, while PLA-(MeO-PEG(O)) nanoparticles prepared by solvent diffusion showed a particle size of 60 nm. The PLA-(MeO-PEG) nanoparticles with a smaller PEG introduction degree exhibited a more negative zeta potential. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) could be incorporated efficiently in PLA-(MeO-PEG(N)) nanoparticles. It is suggested that PLA-aldehyde should be useful as a functional intermediate for derivatization of PLA, and PLA-(MeO-PEG(N)) can be used for the preparation of PEG-coated PLA nanoparticles.

Antitumor characteristics of methoxypolyethylene glycol-poly(DL-lactic acid) nanoparticles containing camptothecin.

The novel nanoparticles (CPT-NP) were prepared by the solvent evaporation method using methoxypolyethylene glycol-poly(DL-lactic acid) block copolymer as a matrix and camptothecin (CPT) as an antitumor agent, and the antitumor characteristics were examined in vitro and in vivo. The mean diameter of CPT-NP was approximately 250 nm. The drug release from CPT-NP in phosphate-buffered saline, pH 7.4, depended on the particle concentration; in the diluted condition, the initial rapid release was greater and subsequent gradual release was faster. After i.v. administration (0.5 mg CPT eq./kg) in rats, CPT-NP showed a longer plasma retention than CPT solution. In both single (2.5 mg CPT eq./kg) and double (2.5 mg CPT eq./kg x 2) administration to mice bearing sarcoma 180 solid tumor, CPT-NP were much more effective than CPT solution; especially, the tumor disappeared completely in three of the four mice in twice administration of CPT-NP, when the body weight did not decrease markedly. After i.v. administration to the tumor-bearing mice, CPT-NP showed better plasma retention, and high and long tumor localization. CPT-NP are suggested to greatly improve the efficacy of CPT due to their pharmacokinetic features.