CN103156806B - A kind of thymalfasin in-situ gel preparation and preparation method thereof - Google Patents
A kind of thymalfasin in-situ gel preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to field of pharmaceutical preparations, particularly a kind of thymalfasin in-situ gel preparation and preparation method thereof.This thymalfasin in-situ gel preparation, is made up of thymalfasin, situ-gel material and organic solvent; In g/g/mL, the mass volume ratio of thymalfasin, situ-gel material and organic solvent is (2 ~ 4.5) ︰ (15 ~ 35) ︰ (100 ~ 150).Thymalfasin in-situ gel preparation provided by the invention has slow releasing function, and avoid the peak valley phenomenon of blood drug level, drug treating time is long, decrease times for spraying, dramatically reduce the misery of patient, improve the compliance of patient, and to skin and connective tissue nonirritant; The preparation method of this thymalfasin in-situ gel preparation is simple, and be beneficial to large-scale production, and Drug loading capacity is high, cost is low.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of thymalfasin in-situ gel preparation and preparation method thereof.
Background technology
Hepatitis B, is called for short hepatitis B, is a kind of by disease caused after hepatitis b virus infected body, is divided into acute hepatitis B and chronic hepatitis B two type.Wherein, chronic hepatitis B refer to Viral diagnosis be positive, the course of disease exceed half a year or date of the onset the indefinite and clinical a kind of type of hepatitis having chronic hepatitis to show; the symptoms such as clinical manifestation is weak, sitophobia, feel sick, abdominal distention, hepatalgia; hepatomegaly; quality is moderate hardness, has light tenderness, and the state of an illness comparatively severe one can with chronic hepatopathy face, spider angioma, liver palm, splenomegaly; liver function can time have exception or persistent anomaly, finally cause liver failure, liver cirrhosis or primary hepatocarcinoma etc.According to World Health Organization's statistics, whole world chronic hepatitis B virus infecton about has 300,000,000, and wherein major part is in Asia.In population of China, chronic hepatitis B virus carriers accounts for 10% ~ 15%, and in chronic hepatitis B patient, annual generation liver cirrhosis and hepatocarcinoma person account for 2% and 1% respectively, and therefore the medicine of Treatment chronic Hepatitis B has the market demand widely.
Thymalfasin (Thymosin) is a kind of medicine of Treatment chronic Hepatitis B, it is a kind of important T lymphocyte regulatory factor secreted by thymus, the lymphocytic maturation of T is promoted by stimulating peripheral blood lymphocyte mitogen, interferon-ALPHA, interferon gamma and the lymphokine such as interleukin-22, interleukin-13 level that after increasing antigen or mitogen activation, T cell is secreted, increase T cell surface lymphokine receptor level simultaneously; By the activation to cd4 cell, strengthen allosome and autologous mankind's mixed lymphocyte reaction.Clinical research shows that thymalfasin has good curative effect as a kind of immunomodulator in Treatment chronic Hepatitis B, and potential applicability in clinical practice is very bright.
At present, thymalfasin only has common injection type, occurs the peak valley phenomenon of blood drug level after per injection, very easily cause body to occur untoward reaction, and drug treating time is short; In addition, clinical practice is recommended inject weekly 2 times, successive administration 6 months, long term injections brings very large misery and inconvenience to patient, cause the compliance of patient very poor, based on this two problems that the agent of thymalfasin normal injection exists, be badly in need of a kind of long-acting and thymalfasin preparation with slow releasing function clinically to alleviate the misery of patient, improve the compliance of patient.Therefore, for clinical a kind of long-acting slow-release preparation of thymalfasin that provides has important practical significance.
Summary of the invention
In view of this, the invention provides a kind of thymalfasin in-situ gel preparation and preparation method thereof.This thymalfasin in-situ gel preparation has slow releasing function, and avoid the peak valley phenomenon of blood drug level, drug treating time is long, decrease times for spraying, dramatically reduce the misery of patient, improve the compliance of patient, and to skin and connective tissue nonirritant; The preparation method of this thymalfasin in-situ gel preparation is simple, and be beneficial to large-scale production, and Drug loading capacity is high, cost is low.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides a kind of thymalfasin in-situ gel preparation, be made up of thymalfasin, situ-gel material and organic solvent;
In g/g/mL, the mass volume ratio of thymalfasin, situ-gel material and organic solvent is (2 ~ 4.5): (15 ~ 35): (100 ~ 150).
In-situ gel preparation is that macromolecular material is with after solution or semi-solid state administration, (as temperature, pH, ionic species and concentration, light and specific chemicals etc.) are stimulated to respond to external world at medicine-feeding part, there is the reversible transition of dispersion or conformation, thus the semisolid formed or solid preparation.In-situ gel preparation is before the injection in solution state, can flow into after injection and be filled in interstice, solution gel phase transformation can be there is in vivo after injection, form gelatin polymer, medicine is along with the continuous degraded of gelatin polymer, corrosion and slow releasing, thus reach the effect of slow release, extend the release cycle, reduce adverse effect.
As preferably, situ-gel material is a kind of or both the above mixture in thermosensitive in situ gel material, pH sensitive in situ gels research material, ionic strength sensitive type situ-gel material or biodegradable situ-gel material.
In embodiments more provided by the invention, situ-gel material is biodegradable situ-gel material.
In other embodiments provided by the invention, situ-gel material is the mixture of a kind of and biodegradable situ-gel material in thermosensitive in situ gel material, pH sensitive in situ gels research material or ionic strength sensitive type situ-gel material.
As preferably, biodegradable situ-gel material is selected from PEO-PPO, PLA, PLGA, PLA-PEG, PLGA-PEG, PNIPA or SAIB.
Preferably, biodegradable situ-gel material is selected from PLA or PLGA.
As preferably, the number-average molecular weight of PLGA is 10000 ~ 40000D.
As preferably, in PLGA, the mol ratio of lactic acid and hydroxyacetic acid is 75: 25 or 50: 50.
As preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87, methylcellulose, hypromellose, chitosan derivatives, PLA-PEG, PLGA-PEG, hydroxyethyl-cellulose, polycaprolactone-polyethylene glycol block copolymer or PNIPA.
Preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87, methylcellulose, PLA-PEG, PLGA-PEG, polycaprolactone-polyethylene glycol block copolymer or PNIPA.
More preferably, thermosensitive in situ gel material is selected from poloxamer188, PLURONICS F87 or methylcellulose.
As preferably, pH sensitive in situ gels research material is selected from CAP, HPMCP, carbomer or chitosan.
Preferably, pH sensitive in situ gels research material is selected from CAP or carbomer.
As preferably, ionic strength sensitive type situ-gel material is selected from alginate or gellan gum.
As preferably, organic solvent is selected from NMP, triacetin, ethyl lactate, glycerol formal, benzyl benzoate, dimethyl sulfoxine, acetone, ethanol, 2-arsenic pyrrolidone or Allyl carbonate.
Preferably, organic solvent is selected from NMP, ethyl lactate, glycerol formal, ethanol or 2-Pyrrolidone.
More preferably, organic solvent is NMP.
As preferably, the administering mode of thymalfasin in-situ gel preparation is intramuscular injection.
Present invention also offers a kind of preparation method of thymalfasin in-situ gel preparation, comprise the steps:
Situ-gel material is dissolved in organic solvent, obtains polymer solution;
Thymalfasin is mixed with polymer solution, temperature be 30 DEG C, rotating speed be the condition of 100 ~ 150rpm under stir 20 ~ 25min, through sterilizing, to obtain final product.
The invention provides a kind of thymalfasin in-situ gel preparation and preparation method thereof.This thymalfasin in-situ gel preparation is made up of thymalfasin, situ-gel material and organic solvent; In g/g/mL, the mass volume ratio of thymalfasin, situ-gel material and organic solvent is (2 ~ 4.5): (15 ~ 35): (100 ~ 150).The present invention determines the release of thymalfasin in-situ gel preparation when 1d, 3d, 5d, 7d, 14d, 21d, 28d by experiment, result shows that this thymalfasin in-situ gel preparation has slow releasing function, avoid the peak valley phenomenon of blood drug level, drug treating time reaches more than 28d, only need monthly medication 1 time, decrease times for spraying, dramatically reduce the misery of patient, improve the compliance of patient; Entered in test mice body by the thymalfasin in-situ gel injection that the present invention is obtained and observe pathological section after 30 days, compared with blank group, skin and the connective tissue of test group mice are clear, thin film epithelium is column, cilium exists, have no chronic inflammatory cell infiltration, result shows that this thymalfasin in-situ gel preparation is to skin and connective tissue nonirritant; The preparation method of this thymalfasin in-situ gel preparation comprises: be dissolved in organic solvent by situ-gel material, obtains polymer solution; Thymalfasin is mixed with polymer solution, temperature be 30 DEG C, rotating speed stirs 20 ~ 25min under being the condition of 100 ~ 150rpm, through sterilizing, obtaining final product, preparation method is simple, and be beneficial to large-scale production, and Drug loading capacity is high, cost is lower.As can be seen here, this thymalfasin in-situ gel preparation has slow releasing function, and avoid the peak valley phenomenon of blood drug level, drug treating time is long, decreases times for spraying, dramatically reduces the misery of patient, improves the compliance of patient; The preparation method of this thymalfasin in-situ gel preparation is simple, and be beneficial to large-scale production, and Drug loading capacity is high, cost is low.
Accompanying drawing explanation
Fig. 1 shows the cumulative in vitro releasing curve diagram of the thymalfasin in-situ gel preparation provided by embodiment 1 in embodiment 17;
Fig. 2 shows the cumulative in vitro releasing curve diagram of the thymalfasin in-situ gel preparation provided by embodiment 2 in embodiment 17;
Fig. 3 shows the pathological section figure that embodiment 18 provides; Wherein, Fig. 3 (a) shows the pathological section figure of blank group, and Fig. 3 (b) shows that embodiment 1 provides thymalfasin in-situ gel preparation intramuscular injection to enter pathological section figure in experiment mice body after 30 days.
Detailed description of the invention
The invention discloses a kind of thymalfasin in-situ gel preparation and preparation method thereof, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
The abbreviation concrete meaning used in description and claims is as follows:
Abbreviation and English implication
PEO-PPO polyoxyethylene polyoxypropylene block copolymer
PLA polylactic acid
PLGA PLGA
PLA-PEG polylactic acid-polyethylene glycol block copolymer
PLGA-PEG polylactic-co-glycolic acid-polyethyleneglycol block copolymer
PNIPA poly-N-isopropyl acrylamide
SAIB acetic acid-isopropylformic acid. sucrose vinegar
HPMCP HP-55
NMPN-methyl adjoins pyrrolidone
In thymalfasin in-situ gel preparation provided by the invention and preparation method thereof, raw materials used medicine and reagent all can be buied by market.
Below in conjunction with embodiment, set forth the present invention further:
The preparation of embodiment 1 thymalfasin in-situ gel preparation
Take 25gPLGA(Mn=10000, LA:GA=75:25), add in 100mLNMP solvent, mixing, is mixed with polymer solution, then thymalfasin crude drug 3.5g is added, heated at constant temperature stirs (temperature 30 DEG C, 100rpm) 20min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 2 thymalfasin in-situ gel preparation
Take 30gPLGA(Mn=15000, LA:GA=50:50), add in 100mLNMP solvent, mixing, is mixed with polymer solution, then thymalfasin crude drug 3.5g is added, heated at constant temperature stirs (temperature 30 DEG C, 120rpm) 20min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 3 thymalfasin in-situ gel preparation
Take 25gPLGA(Mn=20000, and 4g poloxamer188 LA:GA=50:50), be dissolved in 110mLNMP, mixing, is mixed with polymer solution, then 3g thymalfasin is added, heated at constant temperature stirs (temperature 30 DEG C, 100rpm) 25min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 4 thymalfasin in-situ gel preparation
Take 20gPLGA(Mn=25000, and 5g poloxamer188 LA:GA=50:50), be dissolved in 130mLNMP, mixing, is mixed with polymer solution, then 3g thymalfasin is added, heated at constant temperature stirs (temperature 30 DEG C, 100rpm) 20min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 5 thymalfasin in-situ gel preparation
Take 15gPLGA(Mn=40000, LA:GA=50:50), after adding 120mLNMP dissolution with solvents, add thymalfasin crude drug 4g, heated at constant temperature stirs (temperature 30 DEG C, 150rpm) 25min, form translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 6 thymalfasin in-situ gel preparation
Take 16gPEO-PPO, after adding 140mL triacetin dissolution with solvents, add thymalfasin crude drug 2g, heated at constant temperature stirs (temperature 30 DEG C, 110rpm) 21min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 7 thymalfasin in-situ gel preparation
Take 18gPLA, after adding 150mL ethyl lactate dissolution with solvents, add thymalfasin crude drug 2.5g, heated at constant temperature stirs (temperature 30 DEG C, 120rpm) 22min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 8 thymalfasin in-situ gel preparation
Take 20gPNIPA, after adding 105mL glycerol formal dissolution with solvents, add thymalfasin crude drug 3g, heated at constant temperature stirs (temperature 30 DEG C, 130rpm) 23min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 9 thymalfasin in-situ gel preparation
Take 22g PLURONICS F87, after adding the dissolving of 115mL benzyl benzoate, add thymalfasin crude drug 3.5g, heated at constant temperature stirs (temperature 30 DEG C, 140rpm) 24min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 10 thymalfasin in-situ gel preparation
Take 24g methylcellulose, after adding the dissolving of 125mL dimethyl sulfoxine, add thymalfasin crude drug 4g, heated at constant temperature stirs (temperature 30 DEG C, 150rpm) 20min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 11 thymalfasin in-situ gel preparation
Take 20g chitosan derivatives and 8gPLA, after adding 135mL acetone solution, add thymalfasin crude drug 4.5g, heated at constant temperature stirs (temperature 30 DEG C, 105rpm) 21min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 12 thymalfasin in-situ gel preparation
Take 30g CAP, after adding 145mL dissolve with ethanol, add thymalfasin crude drug 2.4g, heated at constant temperature stirs (temperature 30 DEG C, 115rpm) 22min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 13 thymalfasin in-situ gel preparation
Take 30g carbomer and 3gPLGA, after adding the dissolving of 100mL2-arsenic pyrrolidone, add thymalfasin crude drug 2.8g, heated at constant temperature stirs (temperature 30 DEG C, 125rpm) 23min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 14 thymalfasin in-situ gel preparation
Take 35g alginate, after adding the dissolving of 120mL Allyl carbonate, add thymalfasin crude drug 3.2g, heated at constant temperature stirs (temperature 30 DEG C, 135rpm) 24min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The preparation of embodiment 15 thymalfasin in-situ gel preparation
Take 30g gellan gum and 4gPLA, after adding the dissolving of 150mL ethyl lactate, add thymalfasin crude drug 3.6g, heated at constant temperature stirs (temperature 30 DEG C, 145rpm) 25min, forms translucent medicine carrying sol system, through gamma Rays sterilizing, to obtain final product.
The mensuration of thymalfasin content in embodiment 16 thymalfasin in-situ gel preparation
The thymalfasin in-situ gel preparation that Example 1 ~ 3 is obtained, measures medicament contg according to medicine assay method.Concrete grammar is: precision takes the content of mix homogeneously under loading amount item and is about 25mg, puts in 100mL measuring bottle, adds dissolve with methanol and be diluted to scale, shaking up, as need testing solution.Another precision takes thymalfasin reference substance 50mg, puts in 50mL measuring bottle, adds mobile phase and dissolves and be quantitatively diluted to scale, shake up.Precision measures 5mL, puts in 50mL measuring bottle, is quantitatively diluted to scale with mobile phase, shake up, in contrast product solution.Precision measures reference substance solution and each 20 μ L of need testing solution, respectively injection liquid chromatography, record chromatogram, and by external standard method with calculated by peak area, obtain the sign content of medicine, measurement result is in table 1.
The assay result of table 1 thymalfasin
As shown in Table 1, the sign content of the thymalfasin in-situ gel preparation that embodiment 1 ~ 3 is obtained, between 96.0% ~ 97.7%, all meets national drug content standard.The meansigma methods of thymalfasin in-situ gel preparation sign content prepared by embodiment 1 is the RSD(relative standard deviation of 97.3%, 3 batches) be 0.21%; It is the RSD of 96.3%, 3 batches is 0.37% that thymalfasin in-situ gel preparation prepared by embodiment 2 indicates the meansigma methods of content; It is the RSD of 97.3%, 3 batches is 0.42% that thymalfasin in-situ gel preparation prepared by embodiment 3 indicates the meansigma methods of content, and result shows that the stability of the thymalfasin in-situ gel preparation of same batch is high.
The thymalfasin in-situ gel preparation that Example 4 ~ 15 obtains carries out the mensuration of medicament contg, the result that result and embodiment 1 ~ 3 record is close, show that the obtained thymalfasin in-situ gel preparation of embodiment 4 ~ 15 all meets national drug content standard, the stability of the thymalfasin in-situ gel preparation of same batch is high.
The mensuration of embodiment 17 thymalfasin in-situ gel preparation release
The thymalfasin in-situ gel preparation that Example 1 and embodiment 2 obtain, measures release according to drug release determination method.Concrete grammar is: precision takes thymalfasin in-situ gel preparation (being equivalent to thymalfasin 5mg), be injected in release medium (PBS=7.4), solvent diffuse, after solid block to be formed, be placed in 37 ± 0.1 DEG C of constant temperature oscillation instrument vibration releases, rotating speed 100rpm, respectively at 1 day, 3 days, 5 days, 7 days, 14 days, 21 days, sampling in 28 days, and the release medium more renewed after sampling, cumulative release percentage ratio is calculated by high performance liquid chromatography, with release time (day) and cumulative release amount (%), draw curved figure release profiles, the results are shown in Table 2, release curve chart is as Fig. 1, shown in Fig. 2.
The measurement result of table 2 thymalfasin in-situ gel preparation release
From table 2, Fig. 1 and Fig. 2, the thymalfasin in-situ gel preparation that embodiment 1 and embodiment 2 provide has obvious slow releasing function, and avoid the peak valley phenomenon of drug level, drug treating time is long, decreases administration number of times, and has good homogeneity.
The thymalfasin in-situ gel preparation that Example 3 ~ 15 obtains carries out drug release determination, the result that result and embodiment 1 and embodiment 2 record is close, show that the thymalfasin in-situ gel preparation that embodiment 3 ~ 15 provides has obvious slow releasing function equally, avoid the peak valley phenomenon of drug level, drug treating time is long, decrease administration number of times, and there is good homogeneity.
Embodiment 18 thymalfasin in-situ gel preparation is to skin and the irritating detection of connective tissue
Experimental animal: Adult New Zealand White Rabbit, body weight is at 2.0 ~ 2.5kg.
Test method: thymalfasin in-situ gel preparation intramuscular injection obtained for embodiment 1 is entered in experimental animal body, after 30 days, the method that new zealand white rabbit takes auricular vein to inject air is put to death, cut skin of neck, perusal cervical region, then getting skin of neck length and width is that the tissue of about lcm × 2cm carries out HE dyeing.Dyeing course: be placed in 10% formalin fixing (24 hours), carry out routine paraffin wax embedding and section, rear hematoxylin, Yihong (HE) dyeing, be placed in paraffin section on microscope slide and dewax, obtain tissue slice.Under light microscopic, (X20) observes tissue slice, and observed result as shown in Figure 3.
As shown in Figure 3, compared with blank, the skin of injection thymalfasin in-situ gel preparation after 30 days and connective tissue are without significant change, organizational structure is clear, thin film epithelium is column, cilium exists, and has no chronic inflammatory cell infiltration, shows that the obtained thymalfasin in-situ gel preparation of embodiment 1 is to skin and connective tissue nonirritant.
The thymalfasin in-situ gel preparation that Example 2 ~ 15 obtains adopts the pathological change of above-mentioned test method detection of skin and connective tissue, the result of the thymalfasin in-situ gel preparation that result is as obtained in embodiment 1 is similar, shows that the obtained thymalfasin in-situ gel preparation of embodiment 2 ~ 15 is to skin and the same nonirritant of connective tissue.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (3)
1. a thymalfasin in-situ gel preparation, is characterized in that, is made up of thymalfasin, situ-gel material and organic solvent;
In g/g/mL, the mass volume ratio of described thymalfasin, described situ-gel material and described organic solvent is (2 ~ 4.5): (15 ~ 35): (100 ~ 150);
Described situ-gel material is biodegradable situ-gel material, and described biodegradable situ-gel material is PLGA; The number-average molecular weight of described PLGA is 10000 ~ 40000D; In described PLGA, the mol ratio of lactic acid and hydroxyacetic acid is 75:25 or 50:50;
Described organic solvent is NMP.
2. thymalfasin in-situ gel preparation according to claim 1, is characterized in that, the administering mode of described thymalfasin in-situ gel preparation is intramuscular injection.
3. a preparation method for thymalfasin in-situ gel preparation as claimed in claim 1 or 2, is characterized in that, comprises the steps:
Described situ-gel material is dissolved in described organic solvent, obtains polymer solution;
Thymalfasin is mixed with described polymer solution, temperature be 30 DEG C, rotating speed be the condition of 100 ~ 150rpm under stir 20 ~ 25min, through sterilizing, to obtain final product.
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| CN103432570B (en) * | 2013-09-09 | 2015-10-07 | 深圳翰宇药业股份有限公司 | A kind of thymalfasin sustained-release micro-spheres and preparation method thereof |
| CN103494769B (en) * | 2013-10-08 | 2015-12-23 | 深圳翰宇药业股份有限公司 | A kind of compound long-acting in-situ gel injection agent for the treatment of chronic viral hepatitis B and preparation method thereof |
| CN111297844A (en) * | 2020-04-13 | 2020-06-19 | 中国农业科学院兰州畜牧与兽药研究所 | Injection type leonurine hydrochloride acupoint implantation gel, preparation method and content determination method thereof |
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| CN1903172A (en) * | 2006-07-10 | 2007-01-31 | 张文芳 | Poloxamer thymic peptide alpha 1 long-acting temp.-sensing gel |
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| CN1903172A (en) * | 2006-07-10 | 2007-01-31 | 张文芳 | Poloxamer thymic peptide alpha 1 long-acting temp.-sensing gel |
Non-Patent Citations (1)
| Title |
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| In vitro and in vivo study of thymosin alpha1 biodegradable in situ forming poly (lactide-co - glycolide) implants;Qingfeng Liu，etal;《International Journal of Pharmaceutics》;20100725;第122-129页 * |
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