Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent

L-NDDP is a liposome-entrapped platinum compound currently in phase 2 clinical trials that has been shown to undergo intraliposomal activation. The degradation/activation kinetics of liposome entrapped cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [L-NDDP] at different conditions of pH, and temperature is presented. Liposomes were reconstituted in a solution of 0.9% sodium chloride (NaCl) in water (pH 5) at room temperature (formulation conditions currently used in the ongoing clinical trials). In the temperature experiments, L-NDDP 0.9% sodium chloride liposomes were incubated in a water-bath at 40, 60, and 80 degrees C. In the pH experiments, these solutions were compared to water, phosphate with and without chloride ion present, phosphate buffer without chloride ion at pH 3.1, 5.0, and 7.4, and glycine buffer with and without chloride ion. In 0.9% sodium chloride at room temperature, the chemical degradation/activation of liposome-bound NDDP was biphasic, with most of the degradation (approximately 45% conversion) occurring during the first hour after formation of the liposome suspension. NDDP degradation was pH dependent: when using pH 3 phosphate buffer as a reconstituting solution, liposome-bound NDDP degraded rapidly, whereas in pH 7.4 phosphate buffer it was stable for > 72 h. NDDP degradation was also temperature-dependent, the 50% point decreasing from 12 h at 25 degrees C to 9.5 h at 40 degrees C, 3.8 h at 60 degrees C, and 0.3 h at 80 degrees C when using 0.9% NaCl in water as a reconstituting solution. Using glycine buffer solution with and without NaCl at room temperature, no NDDP degradation over a 72 h period was observed at 25 degrees C; however, at 40 degrees C, only 68% NDDP remained intact at 72 h. Atomic absorption spectrophotometry (AAS) analysis of the eluting fractions after injection of L-NDDP samples reconstituted in chloride-containing and non chloride-containing solutions clearly indicated that the formation of DACH-Pt-Cl2 was only observed when chloride-containing solutions were used and was first detected at 3 h when using 0.9% NaCl in water as a reconstituting solution. These results indicate that pH and temperature, and not the presence of chloride ion, are the main factors leading to the activation of NDDP. Since 45% of NDDP is already degraded at 1 h in the same conditions, it is concluded that (1) the first active intermediates of L-NDDP formed within the liposomes are the DACH-Pt chloro-aquo and diaquo intermediates, and (2) the in vivo, antitumour activity of L-NDDP is most likely mediated by direct intracellular delivery of the active species.     

Stability of cefazolin sodium in various artificial tear solutions and aqueous vehicles

The stability of cefazolin sodium reconstituted in four artificial tear solutions, two acetate buffer solutions, phosphate buffer solution, and 0.9% sodium chloride injection was studied. Cefazolin was reconstituted in Tearisol, Isopto Tears, Liquifilm Forte, and Liquifilm Tears; acetate buffer solution at pH 4.5 and pH 5.7; phosphate buffer solution at pH 7.5; and 0.9% sodium chloride injection. The solutions were stored at 4 degrees C, 25 degrees C, and 35 degrees C for seven days. All of the solutions were inspected for particulates, turbidity, color, and odor. Five assay determinations on each of three samples of each formulation were performed using a stability-indicating high-performance liquid chromatographic assay. Cefazolin stability was influenced primarily by pH and storage temperature. Reconstitution of cefazolin sodium in the alkaline tear solutions Isopto Tears and Tearisol and in phosphate buffer solution resulted in particulate and color formation at 25 degrees C and 35 degrees C. Turbidity was noted after cefazolin sodium was reconstituted in Isopto Tears. No color or precipitate formation was evident after seven days at 25 degrees C and 35 degrees C in the formulations of acidic pH containing Liquifilm Tears, Liquifilm Forte, 0.9% sodium chloride injection or acetate buffer solution as the vehicles. The extent of degradation of cefazolin was substantially higher in the formulations of alkaline pH than in those of acidic pH at 35 degrees C and 25 degrees C. All of the formulations retained more than 90% of their initial concentration when stored at 4 degrees C. Cefazolin sodium, when reconstituted in artificial tear solutions with an acidic pH, is stable for up to three days at room temperature.     

注射用卡络磺钠与注射用头孢他啶配伍稳定性考察

目的考察注射用头孢他啶与注射用卡络磺钠在0.9%氯化钠注射液中的配伍稳定性。方法室温[(25±1)℃]下,采用反相高效液相色谱法,以pH 7.0磷酸盐缓冲液∶乙腈(92∶8)为流动相,色谱柱:phe-nomenex Prodigy 5u ODS3 C18柱(150 mm×4.6 mm,5μm),利用二极管阵列检查器,测定不同厂家头孢他啶与卡络磺钠配伍后在0～6 h内的含量变化,同时,观察配伍液外观及pH值变化。结果本试验条件下,0～6 h内配伍液外观、pH值及卡络磺钠、头孢他啶含量变化不明显。结论室温下,注射用头孢他啶与注射用卡络磺钠在0.9%氯化钠注射液中6 h内稳定。     

Hydrolysis of nicotinyl 6-aminonicotinate

The degradation kinetics of nicotinyl 6-aminonicotinate in aqueous buffer solutions were studied over the pH range from 4.0 to 10.0. In all cases, pseudo-first-order kinetics were observed at constant hydronium ion concentration. The pH-rate profile indicated that the hydrolysis of nicotinyl 6-aminonicotinate may be described by at least two catalytic terms. In alkaline solution the hydrolysis is catalyzed primarily by hydroxyl ions. In acidic solution the hydrolysis may be attributed to either the water-catalyzed reaction of the protonated species or the hydronium ion catalyzed reaction of the free base. The resulting catalytic profile afforded a sharp pH minimum of approximately 5.90 at 65 degrees C. An activation energy of 16 Kcal/mol was obtained in a phosphate buffer solution at a pH of approximately 5.90 +/- 0.2. The first- and second-order reaction constants for water and hydroxyl ion catalysis were determined, and the temperature dependency of the reaction was studied. The buffer effect and solvent effect on the hydronium and hydroxyl ion catalysis was also investigated.     

Stability of the new antileukemic 4-pyranone derivative, BTMP, using HPLC and LC-MS analyses

The stability of the new antileukemic kojic acid derivative, 5-benzyloxy-2-thiocyanatomethyl-4-pyranone (BTMP) was investigated. The degradation of BTMP was studied using specific and reproducible HPLC and LC-MS methods. Accelerated stability studies of BTMP were conducted in 0.1 M hydrochloric acid solution, physiological phosphate buffer solution (pH 7.5) and basic phosphate buffer solution (pH 9.0) at 30, 40 and 60 degrees C, respectively. The degradation of BTMP was found to follow pseudo-first order kinetics. In basic solution (pH 9.0) BTMP underwent rapid hydrolysis at a degradation rate constant (0.183-0.638 h-1) and degradation half-life (3.67-1.06 h) depending on the temperature setting. On the other hand, BTMP was significantly stable in 0.1 M hydrochloric acid solution (kdeg: 0.0017-0.0052 h-1; degradation half-life t1/2: 408.6-135.7 h), whereas in physiological phosphate buffer solution (pH 7.5), BTMP was only moderately stable (kdeg: 0.006-0.231 h-1; degradation half-life: 117.7-3.0 h). Arrhenius plots were constructed to predict the degradation kinetic parameters of BTMP at 25 degrees C and 4 degrees C. LC-MS analyses confirmed the degradation of BTMP in basic solutions and indicated at least two degradation products; namely 5-benzyloxypyran-2-ol-4-one (m/z 217.8) and 2-thiocyanatomethylpyran-5-ol-4-one (m/z 181.6).     

Stability of irinotecan hydrochloride in aqueous solutions.

The stability of irinotecan after reconstitution in several vehicles for i.v. infusion was studied. Irinotecan hydrochloride injection was diluted in phosphate buffer solution (pH 4.0, 6.0, and 7.4), 5% dextrose injection, and 0.9% sodium chloride injection to a final concentration of 20 micrograms/mL. The solutions were stored at 25, 37, and 50 degrees C and assayed at intervals up to 24 hours by high-performance liquid chromatography for the concentration of the lactone form of irinotecan remaining. The effect of temperature and pH on the extent and rate of degradation of irinotecan was determined. The hydrolysis of irinotecan to its carboxylate form was reversible. The rate and extent of hydrolysis increased with increasing pH. The use of a weakly acidic vehicle, such as 5% dextrose injection, for reconstitution of irinotecan may maintain the drug's stability prior to administration.     

The effect of buffering on the stability of reconstituted benzylpenicillin injection

The stability of benzylpenicillin sodium injection after reconstitution was investigated using a stability-indicating high pressure liquid chromatography (HPLC) method. Benzylpenicillin reconstituted in water for injections, diluted in 0.9 per cent sodium chloride infusion in Minibags and stored at 5C was stable for two days (based on t/90 per cent calculations). The effect of reconstituting benzylpenicillin in citrate buffer at pHs between 6 and 8 was investigated. Maximum stability was found to occur in the pH range 6.5-7.5. The stability of buffer-reconstituted benzylpenicillin diluted in 0.9 per cent sodium chloride infusion was then investigated. Results indicated that benzylpenicillin injection 600mg reconstituted in 3.6ml citrate buffer within the pH range 6.5 to 7.5, diluted in 50ml 0.9 per cent sodium chloride in Minibags and stored at 5C, may be assigned a shelf life of at least 28 days.     

Hydrolysis of l-phenylalanine mustard (melphalan). II. Further observations on the effects of pH,chloride ions and buffers on the rate of reaction

The effects of pH (3.7—13), ionic strength, buffer composition (acetate, phosphate and borate) and buffer concentration (15–200 mM) on the rate of degradation of melphalan in the presence 0.3 M chloride at 50 ± 0.1 °C were investigated using high-performance liquid chromatography. In addition, the data published in the literature for the degradation of phosphoramide mustard have been compared with those of melphalan, placing emphasis on mechanisms of hydrolysis and the effects of pH and chloride. In the presence of chloride, the degradation rate of melphalan was influenced by pH and buffer composition but not by ionic strength. These effects were not seen in the absence of added chloride and have been explained in terms of competition between chloride and other nucleophiles such as the hydroxide ion, water and buffer components for the active intermediate of the alkylating agent. These results help to explain differences in reported values for the rates of hydrolysis of various alkylating agents in the presence of chloride.     

Degradation kinetics of phentolamine hydrochloride in solution

The degradation kinetics of phentolamine hydrochloride in aqueous solution over a pH range of 1.2 to 7.2 and its stability in propylene glycol- or polyethylene glycol 400-based solutions were investigated. The observed rate constants were shown to follow apparent first-order kinetics in all cases. The pKa determination for phentolamine hydrochloride was found to be 9.55 +/- 0.10 (n = 5) at 25 +/- 0.2 degrees C. This indicated the protonated form of phentolamine occurs in the pH range of this study. The pH-rate profile indicated a pH-independent region (pH 3.1-4.9) exists with a minimum rate around pH 2.1. The catalytic effect of acetate and phosphate buffer species is ordinary. The catalytic rate constants imposed by acetic acid, acetate ion, dihydrogen phosphate ion, and monohydrogen phosphate ion were determined to be 0.018, 0.362, 0.036, and 1.470 L mol-1 h-1, respectively. The salt effect in acetate and phosphate buffers followed the modified Debye-Huckel equation quite well. The ZAZB value obtained from the experiment closely predicts the charges of the reacting species. The apparent energy of activation was determined to be 19.72 kcal/mol for degradation of phentolamine hydrochloride in pH 3.1, 0.1 M acetate buffer solution at constant ionic strength (mu = 0.5). Irradiation with 254 nm UV light at 25 +/- 0.2 degrees C showed a ninefold increase in the degradation rate compared with the light-protected control. Propylene glycol had little or no effect on the degradation of phentolamine hydrochloride at 90 +/- 0.2 degrees C; however, polyethylene glycol 400 had a definite effect.     

注射用丹参多酚酸盐成品输液的稳定性

目的 考察注射用丹参多酚酸盐成品输液稳定性.方法 分别考察室温(25℃)和冷藏(4℃)条件下,注射用丹参多酚酸盐的3种临床常用成品输液在0~8 h间的有效成分的含量、输液外观、pH值及不溶性微粒的数量的变化.结果 注射用丹参多酚酸盐与胰岛素在5%葡萄糖注射液中混合调配后,无论在室温或冷藏条件下,2 h内成品输液丹酚酸B含量下降均超过10%,溶液pH值超过6,≥10μm不溶性微粒的数量超过25个/毫升,≥25μm不溶性微粒的数量超过3个/毫升.使用5%葡萄糖注射液和0.9%氯化钠注射液稀释的成品输液,室温保存8 h稳定.然而,在冷藏条件下,0.9%氯化钠注射液稀释后的成品输液6 h内不溶性微粒数超出规定范围,而5%葡萄糖注射液稀释后的成品输液2 h内不溶性微粒的数量超出规定范围.结论 注射用丹参多酚酸盐不宜与胰岛素配伍使用.在冷藏条件下,建议采用0.9%氯化钠注射液稀释后的成品输液保存不得超过6 h,采用5%葡萄糖注射液稀释后的成品输液保存不得超过2 h.     

Solution stability of ciclosidomine

The stability of N-cyclohexanecarbonyl-3-(4-morpholino)-sydnone imine hydrochloride (ciclosidomine) in solution was studied as a function of pH, temperature, ionic strength, and buffer species. The rate of hydrolysis in the absence of light was found to be apparent first order in drug and general acid- and base-catalyzed reactions. The pH rate profile at an ionic strength of 0.1 M at 60 degrees C had a minimum value near pH 6. Change in ionic strength in the range of 0.05 to 0.2 M did not affect the rate of degradation at pH 7 (carbonate buffer) or pH 2 (phosphate buffer) at 60 degrees C. Similar degradation rates were noticed in air or nitrogen in the dark at pH 3, 5, and 6. However, degradation in light was very rapid in either case at pH 3, 5, and 6, and, therefore, the protection of solutions from light was required during all studies. The time for 10% loss of drug in solution at pH 6 in dilute phosphate or citrate buffer at an ionic strength of 0.154 M was projected to be 9 months at 20 degrees C and 2.6 months at 30 degrees C.     

Stability and compatibility studies of zorubicin in intravenous fluids and PVC infusion bags

The stability of zorubicin (ZOR) in admixtures for continuous intravenous infusion was studied. ZOR was reconstituted and diluted to 600 μg ml⁻¹ for simulated infusion and to 250 and 1000 μg ml⁻¹ for storage in poly(vinyl chloride) (PVC) bags containing 5% dextrose injection or 0.9% sodium chloride injection (0.9% NaCl). Bags were then stored at refrigerated temperature (4°C) and in the dark for 24 h. ZOR concentrations in each admixture were tested by stability-indicating high-performance liquid chromatographic (HPLC) assay with ultraviolet detection. No substantial loss of ZOR was observed during simulated infusions (n = 4) using PVC infusion bags and administration sets over a 1 h infusion. The drug stored at 4°C in the dark in PVC bags showed that it is highly unstable at 250 μg ml⁻¹ in 0.9% NaCl injection and in 5% dextrose injection. On the other hand, under the same storage conditions, at 1000 μg ml⁻¹, ZOR is more stable in 0.9% NaCl injection (6 h) than in 5% dextrose (4 h). The reported superior stability of the 1000 μg ml⁻¹ in 0.9% NaCl can be explained, at least in part, by the difference in pH. Changes in pH, particularly a decrease, seem to affect adversely the stability of ZOR. In fact, ZOR is rapidly converted into daunorubicin, the dominant degradation product, which is more cardiotoxic than the parent drug. Therefore, several precautions must be observed when the commercial product (Rubidazone) is prepared and reconstituted in i.v. fluids and containers.     

Stability study of the anticonvulsant enaminone (E118) using HPLC and LC-MS.

The stability of the new chemical synthetic enaminone derivative (E118) was investigated using a stability-indicating high-performance liquid chromatography (HPLC) procedure. The examined samples were analyzed using a chiral HSA column and a mobile phase (pH 7.5) containing n-octanoic acid (5 mM), isopropyl alcohol and 100 mM disodium hydrogen phosphate solution (1:9 v/v) at a flow rate of 1 ml min(-1). The developed method was specific, accurate and reproducible. The HPLC chromatograms exhibited well-resolved peaks of E118 and the degradation products at retention times <5 min. The stability of E118 was performed in 0.1 M hydrochloric acid, 0.1 M sodium hydroxide, water/ethanol (1:1) and phosphate buffer (pH approximately 7.5) solutions. E118 was found to undergo fast hydrolysis in 0.1 M hydrochloric acid solution. The decomposition of E118 followed first order kinetics under the experimental conditions. The results confirmed that protonation of the enaminone system in the molecule enhanced the hydrolysis of E118 at degradation rate constant of 0.049 min(-1) and degradation half-life of 14.1 min at 25 degrees C. However, E118 was significantly stable in 0.1 M sodium hydroxide, physiological phosphate buffer (pH 7.5) and ethanol/water (1:1) solutions. The degradation rate constants and degradation half-lives were in the ranges 0.0023-0.0086 h(-1) and 80.6-150.6 h, respectively. Analysis of the acid-induced degraded solution of E118 by liquid chromatography-mass spectrometry (LC-MS) revealed at least two degradation products of E118 at m/z 213.1 and 113.1, respectively.     

Stability and compatibility of four anthracyclines: doxorubicin, epirubicin, daunorubicin and pirarubicin with PVC infusion bags

A rapid isocratic technique was developed for the analysis of four anthracyclines (doxorubicin, epirubicin, daunorubicin and pirarubicin) in parenteral solutions using high pressure liquid chromatography (HPLC) with fluorescence detection and a C18 Hypersil ODS column. The availability and compatibility of these drugs from solutions infused via PVC infusion bags through PVC administration sets have been examined. No significant drug loss was observed during simulated infusions (n=4) for 24 h using PVC infusion bags and administration sets. No significant difference was found between infusion solutions (5% glucose or 0.9% NaCl), except for pirarubicin. The reconstitution of pirarubicin in 0.9% NaCl was impossible, because we observed a precipitation of the compound in solution. The stability of the drugs was also studied in solution, in PVC bags after storage at 4°C with protection from light. The results show the stability of doxorubicin, epirubicin and daunorubicin during 7 days of storage to be satisfactory, irrespective of the infusion solution (5% glucose or 0.9% NaCl). In the case of pirarubicin, the stability of the drug was satisfactory during 5 days of storage in 5% glucose, but beyond, we observed a degradation of the compound with formation of doxorubicin in the infusion solution.     

Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes

cis-Bis(neodecanoato)(trans-(R,R)-1,2-diaminocyclohexane)platinum( II) [L-NDDP] is a liposome incorporated lipophilic cisplatin analogue that has shown promising antitumor activity against tumors resistant to cisplatin and liver metastases in mice. L-NDDP is currently under clinical evaluation. However, NDDP is an isomeric mixture of different species having various isomeric neodecanoic moities as liganded leaving groups. A series of new highly lipid-soluble cis-bis(neodecanoato)(trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) [Pt] complexes, using single isomers of neodecanoic acid, were synthesized and characterized by analytical and spectroscopic techniques (infrared and 195Pt NMR). Multilamellar vesicles (MLVs) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a molar ratio of 7:3 were used as carriers of the Pt complexes. The efficiency of incorporation of the liposomal-platinum (L-Pt) preparations was greater than 95% and stability in normal saline at 4 degrees C was greater than 95% at day 14 in each case. The iv LD50 values of all L-Pt preparations tested were in the range of 62.3 to 104 mg/kg. The % T/C obtained after a single ip injection of the optimal dose of L-Pt preparations against L1210 leukemia was in the range of 150 to 253 (160 for cisplatin). When a multiple ip injection schedule was used (on days 1, 5, and 9) the L-Pt preparations of R,R complexes (1, 7, and 9) were more active than cisplatin at the optimal dose (% T/C = 257 for each vs 220 for cisplatin). The L-Pt preparations of R,R complexes were also markedly active against L1210 leukemia resistant to cisplatin (% T/C 355, 231, and 185 respectively vs 112 for cisplatin). These studies show that the single isomers of NDDP are comparable to the original isomeric mixture in terms of toxicity and biological activity.     

Kinetics of degradation of cefazolin and cephalexin in aqueous solution.

The kinetics of degradation of cefazolin and cephalexin in aqueous solution were investigated at 60 degrees C and constant ionic strength over the entire pH range. The observed degradation rates were obtained by measuring the residual cephalosporin and were shown to follow pseudo-first-order-kinetics. They were influenced significantly by solvolytic and hydroxide ion catalysis. No primary salt effect was observed in the acid or basic pH region. Of the buffer systems employed in the kinetics studies only the phosphate buffer system showed a catalytic effect. The pH-rate profile for cefazolin showed a degradation minimum between pH 5.5 and 6.5. Cephalexin did not show a pH minimum in that region. The apparent energies of activation were determined for cefazolin and cephalexin at pH 5.5 and were calculated to be 24.3 Kcal/mole and 26.2 Kcal/mole, respectively. The agreement between the calculated theoretical pH-rate profiles and the experimental points for both compounds support the hypothesis presented concerning the reactions involved in their respective degradation pathways.     

注射用氯诺昔康与盐酸吗啡注射液在0.9%氯化钠注射液中的稳定性

目的 考察注射用氯诺昔康与盐酸吗啡注射液在0.9%氯化钠注射液中的稳定性. 方法 在室温(20±1) ℃避光条件下,观察和检测注射用氯诺昔康与盐酸吗啡注射液在0.9%氯化钠注射液中配伍液在72 h内的外观及pH变化,并用反相高效液相色谱法测定氯诺昔康与盐酸吗啡的含量. 结果配伍液72 h内外观、pH及含量均无明显变化. 结论 室温条件下,注射用氯诺昔康与盐酸吗啡注射液在0.9%氯化钠注射液中72 h内稳定.     

Intropin (dopamine hydrochloride) intravenous admixture compatibility. Part 1: stability with common intravenous fluids.

The stability of dopamine hydrochloride (Intropin) in several large-volume parenteral solutions was studied. Admixtures of dopamine were assayed by colorimetric and chromatographic procedures. Admixtures (800 mug dopamine per ml) in the following intravenous fluids in glass bottles at pH 6.85 or below were found to be chemically and physically stable for at least 48 hours at room temperature: dextrose 5%, dextrose 5% and sodium chloride 0.9%, 5% dextrose in 0.45% sodium chloride, dextrose 5% in lactated Ringer's solution, lactated Ringer's injection, 0.9% sodium chloride, 1/6 molar sodium lactate, and 20% mannitol. The admixture of dopamine in 5% dextrose was stable for a minimum of seven days at 5 C. A 5% dextrose-dopamine admixture in a polyvinylchloride bag was stable for at least 24 hours at room temperature. The admixture of dopamine in 5% sodium bicarbonate solution produced an unstable solution of pH 8.20. A chemical and physical change (development of a pink color) was observed in this admixture. It is recommended that dopamine not be added to 5% sodium bicarbonate solution or any alkaline intravenous solution.     

注射用氯诺昔康在不同pH值氯化钠注射液中的稳定性考察

目的考察注射用氯诺昔康在不同pH值(4.5～7.0)0.9%氯化钠注射液中的稳定性。方法采用高效液相色谱法测定配伍液中氯诺昔康的含量,考察室温条件下氯诺昔康在不同pH值0.9%氯化钠注射液中8 h含量变化,并观察和检测配伍液的外观及pH值变化。结果注射用氯诺昔康在不同pH值0.9%氯化钠注射液中的含量、外观与pH值均无明显变化。结论注射用氯诺昔康在不同pH值0.9%氯化钠注射液中8 h均保持稳定。     

痰热清注射液与注射用头孢哌酮钠的配伍稳定性考察

目的 考察痰热清注射液与注射用头孢哌酮钠在0.9％氯化钠注射液中的配伍稳定性.方法 在室温(25℃)下采用紫外分光光度法测定痰热清注射液和注射用头孢哌酮钠在0.9％氯化钠注射液中配伍6h内不同时间点的含量,并观察配伍液的外观、微粒及pH变化.结果 两药配伍后6h内的含量、pH、外观及不溶性微粒均无明显变化.结论 痰热清注射液与注射用头孢哌酮钠在0.9％氯化钠注射液中配伍后于室温下6h内可使用.