CN100377708C - Method for preparing tablet of hydroxy camptothecin and oral application - Google Patents
Method for preparing tablet of hydroxy camptothecin and oral application Download PDFInfo
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- CN100377708C CN100377708C CNB2004100131381A CN200410013138A CN100377708C CN 100377708 C CN100377708 C CN 100377708C CN B2004100131381 A CNB2004100131381 A CN B2004100131381A CN 200410013138 A CN200410013138 A CN 200410013138A CN 100377708 C CN100377708 C CN 100377708C
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Abstract
The present invention relates to a preparation method of a hydroxyl camptothecin tablet. The present invention aims to overcome the problem that the hydroxyl camptothecin tablet is directly pressed into a tablet and is scarcely absorbed when the hydroxyl camptothecin tablet is orally taken by a human body. In the present invention, a lactone ring in a hydroxyl camptothecin structure is opened through a medically acceptable alkaline solution, and a conventional method for preparing the tablet is used. Compared with the tablet prepared from the hydroxyl camptothecin of which the ring is not opened with a conventional method, the hydroxyl camptothecin tablet prepared with the method is that after the hydroxyl camptothecin tablet is orally taken by the human body, the bioavailability can be increased about by 4.8 times through the calculation of tested blood drug concentration and is equivalent to the bioavailability of foreign antineoplastic medicine for oral taking. The present invention conveniently treats the cancer of patients with tumour through the hydroxyl camptothecin.
Description
One, technical field
The invention belongs to the preparation method of antineoplastic agent hydroxycamptothecin tablet, be specifically related to the preparation method and the oral application of the absorbable hydroxycamptothecin tablet of human body.
Two, background technology
Hydroxy camptothecin is the natural plants alkali that extracts in the fruit of China endemic plant Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) (Camptotheca acuminate Decsne), it is the anticarcinogen that a unique up to now class acts on topoisomerase I (TOPO I), it can suppress topoisomerase I (TOPO I), cause the dna single chain interruption, suppress duplicating of DNA, act on the S phase of cell, can suppress the formation of tumor cell new vessels on every side simultaneously, inducing cancer cell is transferred and is died, and finally causes the death of cancerous cell.
It is wide that hydroxy camptothecin has anticancer spectrum, the characteristics of determined curative effect.At present domestic use clinically injection and lyophilized injectable powder arranged, be widely used in hepatocarcinoma, gastric cancer, colon cancer, bladder cancer, tumor of head and neck, pulmonary carcinoma, leukemic treatment.But when using, must under doctor or nurse's operation, just can finish injection.Therefore the listing of hydroxycamptothecin tablet must facilitate to tumor patient.
Because characteristics such as the water insoluble and ester dissolubility difference of hydroxy camptothecin, the direct compression of the hydroxy camptothecin of open loop (C-HCPT) not, the oral back of human body medicine is difficult to enter blood, therefore, the tablet that hydroxy camptothecin (C-HCPT) prepares according to a conventional method is extremely low at the oral back of human body blood drug level, and its bioavailability is on the low side when promptly carrying out the bioavailability test.Be difficult to reach the curative effect of clinical application.
Now Fa Ming " open-loop method " makes the hydroxy camptothecin lactonic ring open earlier, hydroxy camptothecin then is dissolved in water with carboxylate form (O-HCPT), the tablet of making again blood drug level after human body is oral obviously improves, bioavailability obviously improves, after medicine enters blood, influenced by blood pH, the carboxylate form of hydroxy camptothecin (O-HCPT) cyclization again becomes lactone form, thereby reaches the purpose that suppresses tumor.
Three, summary of the invention
(the C-HCPT direct compression, the oral almost non-absorbent problem of human body provides a kind of preparation method that can improve the hydroxycamptothecin tablet of bioavailability to the objective of the invention is to overcome hydroxy camptothecin.The hydroxy camptothecin sheet that this method makes is oral for human body.
1, hydroxycamptothecin tablet is characterized in that forming (all being weight percentage) by following supplementary material
Hydroxy camptothecin 2-10%
Starch 10-40%
Microcrystalline Cellulose 10-40%
Glycine 4-20%
Carboxymethylstach sodium 2-8%
Magnesium stearate 0.2-0.5%
2, raw material-the hydroxy camptothecin of preparation hydroxycamptothecin tablet must be handled in advance: it is characterized in that earlier (lactonic ring of ester type structure C-HCPT) is opened with hydroxy camptothecin, make it become carboxylate form (O-HCPT), concrete grammar is: hydroxy camptothecin is adopted medically acceptable alkali liquor (sodium hydroxide solution or sodium carbonate liquor), make its dissolving, add the pH value regulator then, regulate pH value 9.0-9.5, sabot is put in the freezer dryer,-55 ℃ of vacuums is under the condition of 0.01mbar, lyophilization 36 hours, collect dry thing, get the hydroxy camptothecin carboxylate (O-HCPT) of open loop.
3, described alkali liquor is sodium hydroxide solution or sodium carbonate liquor.Its concentration of lye sodium hydroxide is 0.1-1% (W/L), and sodium carbonate is 0.5-2.0% (W/L).
4, described pH regulator agent is a glycine.
5, the preparation method of hydroxycamptothecin tablet, step is as follows:
(1) adjuvant in will writing out a prescription is respectively crossed 80 mesh sieves, and it is standby that other prepares 4% starch slurry.
(2) adjuvant in will writing out a prescription respectively (removing magnesium stearate) mix homogeneously is standby.
(3) with the hydroxy camptothecin carboxylic acid sodium of preparation method 2 and the adjuvant in above-mentioned (2) by etc. the abundant mix homogeneously of incremental method.
(4) make soft material with the starch slurry of binding agent 4%, granulate with 40 mesh sieves, granule is in 70 ℃ of dryings, and with 40 mesh sieve granulate.
(5) granule adds the magnesium stearate of recipe quantity, mix homogeneously, tabletting.
(6) use the film coating agent coating.
This hydroxycamptothecin tablet reasonable recipe, good stability, coatedly prevent the product oxidation, prolong the effect duration of medicine, also being convenient to storage, transportation and patient uses, the tablet content of gained, dissolution all meet state quality standard, apply to the treatment of malignant tumor such as primary hepatocarcinoma, human primary gastrointestinal cancers, bladder cancer, tumor of head and neck, pulmonary carcinoma, leukemia clinically.
Zhi Bei hydroxycamptothecin tablet confirms through the test of human body oral administration biaavailability as stated above, its bioavailability reaches 31.95% (26.4～35.8), eliminates half-life: 6.17h in the short time lag (0.14h), body, oral back 2～3h reaches maximum concentration, and 6h still can keep higher concentration.And the test of the oral administration biaavailability of the hydroxycamptothecin tablet (not opening lactonic ring) of preparation confirms that its thing availability has only 7% according to a conventional method.The preparation method of hydroxycamptothecin tablet of the present invention, its human body oral administration biaavailability are 4.8 times of hydroxy camptothecin sheet of conventional method preparation.
Four, description of drawings
Hydroxy camptothecin sheet preparation technology flow chart
Five, specific embodiments
Embodiment 1:
Hydroxy camptothecin 2%
2% sodium carbonate is an amount of
Starch 35%
Microcrystalline Cellulose 35%
Glycine 22%
Carboxymethyl starch sodium 5.7%
Magnesium stearate 0.3%
The preparation method of hydroxycamptothecin tablet, step is as follows:
(1) 350 grams of the starch in will writing out a prescription respectively, microcrystalline Cellulose 350 grams, carboxymethyl starch sodium 57 grams are crossed 80 mesh sieves respectively, and it is standby that other prepares 4% starch slurry.
(2) adjuvant in will writing out a prescription respectively (removing magnesium stearate) mix homogeneously is standby.
(3) hydroxy camptothecin is added 2% sodium carbonate liquor and make its dissolving in right amount, add glycine and regulate pH value 9-9.5, sabot is put in the freezer dryer,-55 ℃ of vacuums is under the condition of 0.01mbar, lyophilization 36 hours, collect dry thing, get the hydroxy camptothecin carboxylate (O-HCPT) of open loop.Dry thing and the adjuvant in (2) are pressed abundant mix homogeneously such as incremental method such as grade.
(4) binding agent is made soft material with 4% starch slurry, granulate with 40 mesh sieves, granule is in 70 ℃ of dryings and with 40 mesh sieve granulate.
(5) granule adds the magnesium stearate of recipe quantity, mix homogeneously, tabletting.About 10000.
(6) use the film coating agent coating.
Embodiment 2:
Hydroxy camptothecin 5%
0.8% sodium hydroxide is an amount of
Starch 34.5%
Microcrystalline Cellulose 34.5%
Glycine 20%
Carboxymethyl starch sodium 5.7%
Magnesium stearate 0.3%
The preparation method of hydroxycamptothecin tablet, step is as follows:
(1) 414 grams of the supplementary product starch in will writing out a prescription respectively, microcrystalline Cellulose 414 grams, carboxymethyl starch sodium 68.4 grams are crossed 80 mesh sieves respectively, and it is standby that other prepares 4% starch slurry.
(2) respectively that above-mentioned adjuvant (removing magnesium stearate) mix homogeneously is standby.
(3) hydroxy camptothecin 60 gram is added 0.8% sodium hydroxide solution and make its dissolving in right amount, add glycine and regulate pH value 9-9.5, sabot is put in the freezer dryer,-55 ℃ of vacuums is under the condition of 0.01mbar, lyophilization 36 hours, collect dry thing, get the hydroxy camptothecin carboxylate (O-HCPT) of open loop.Dry thing and the adjuvant in (2) are pressed abundant mix homogeneously such as incremental method such as grade.
(4) binding agent is made soft material with 4% starch slurry, granulate with 40 mesh sieves, granule is in 70 ℃ of dryings and with 40 mesh sieve granulate.
(5) granule adds the magnesium stearate of 3.6 grams, mix homogeneously, tabletting.About 12000.
(6) use the film coating agent coating.
The test of hydroxy camptothecin (HCPT) tablet human bioavailability
The test chamber Li Su of Guangzhou Tumour Prevention ﹠ Cure Centre, Zhongshan Medical Univ.
The bioavailability of purpose: Preliminary Determination HCPT
Method:
1, case inclusion criteria:
1) confirms the first late malignant tumour of controlling through pathology and cytology; 2) 18～40 years old age; 3) sex: the male 4) physical situation: 0-1 level (ECOG sees adnexa 1 for details); 5) body weight can not be excessive with a collection of experimenter's great disparity in standard body weight ± 10% scope; Standard body weight=[height (cm)-80] * 0.7 or standard body weight=[height (cm)-170] * 0.6+62; 6) granulocyte (ANC)＞2.0 * 10
9/ L or WBC＞4.0 * 10
9/ L, platelet (pt)＞100 * 10
9/ L; Hemoglobin＞9g/dl; ALT＜upper limits of normal is 2 times when 7) neoplasm metastasis being arranged, or hepatic metastases is arranged but 5 times of ALT＜upper limits of normal; 8) blood Cr＜upper limits of normal is 1.5 times; 9) in the past the treatment stop＞30 days; 10) estimate life cycle＞3 month; 11) patient agrees to participate in this research;
2, instrument and reagent
Instrument: Agilent 1100 highly effective liquid phase chromatographic systems comprise quaternary pump, fluorescence detector, sample device automatically;
Reagent: the chromatographically pure of methanol, acetonitrile Fisher company, water is distilled water, other reagent is the analytical reagent medicament sources: hydroxycamptothecin tablet, injection, reference substance are provided free by Hubei Li Shizhen (1518-1593 A.D.) pharmaceutcal corporation, Ltd.
3, dosage and usage:
The bioavailability test:
First day intravenously administrable, hydroxy camptothecin (HCPT) injection, dosage 12mg/m
2, add NaCL 250ml iv drip, drip off in 1 hour.
Oral administration after the 8th day: overnight fasting is 10 hours before the test, in (medicine) being taken before meal hydroxycamptothecin tablet in morning next day, with 150～200ml warm water delivery service, can drink water after taking medicine 2 hours again, has meal after 4 hours.(experimenter should avoid strenuous exercise after taking medicine, and also must not lie in bed for a long time, and medication and viewing duration must not use radiotherapy, chemotherapy and other biological response modifier.
3, measure the hydroxy camptothecin method
1) chromatographic condition: chromatographic column: Varian SP-C18 short column (4mm * 150mm); Mobile phase: 0.075mol/L Ammoniom-Acetate buffer (PH6.4)-acetonitrile (78: 22) contains the phosphoric acid triethylamine of 5mmol/L; Detect wavelength; Emission wavelength 550nm, excitation wavelength 362nm; Flow velocity: 1.000ml/min; Column temperature: the formulation of room temperature standard curve: precision takes by weighing hydroxy camptothecin lactone reference substance 1.0mg, dissolve with acetonitrile-citric acid (1: 1), dilute with blank plasma, make that ultimate density is 2,5,10,25,50,75,100,250,500,750,1000,1500,2000ng/ml, get cold methanol-acetonitrile (1: 1) that 200ul adds 200ul and jolt mixing, with 10000rpm/min high speed centrifugation 5min, get supernatant 20ul direct injected.
2) collection of sample:
Intravenously administrable: before administration, in the administration 30 ', after the administration at once, 5 ', 30 ', 1h, 2h, 4h, 8h, 10h, 16h blood drawing 2ml put in the heparin test tube.
Oral administration: before oral, oral back 30 ', 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 12h, 16h blood drawing 2ml put in the heparin test tube.
3) mensuration of sample: the same
The result
1, standard curve: 7 points getting concentration and be 2ng/ml～100ng/ml are made standard curve, obtain Y=0.016+5.2 * 10
-4X (r=0.987) gets concentration and is 7 points of 250ng/ml～2000ng/ml and makes standard curve, obtains Y=-3.30+9.27 * 10
-3X (r=0.993)
2, stability test: an amount of hydroxy camptothecin lactone reference substance concentrated solution of accurate absorption, add in the blank plasma, make it to become the blood sample (it is the same to extract preparation method) of hydroxycamptothecin containing 10ng/ml, measure the content of hydroxy camptothecin lactone in 48 hours.The result is as follows:
| Time | 0h | 6h | 24h | 48h | RSD(％) |
| Reference substance (H) | 0.25 | 0.25 | 0.26 | 0.26 | 0.25 |
| Plasma sample (H) | 0.24 | 0.23 | 0.19 | 0.13 | 2.16 |
As can be seen, hydroxy camptothecin lactone contrast liquid can keep stable in 48h, but in blood plasma, can only keep stable, stable in the daytime very poor in 6h, preferably does the conformal standard curve every day so this is tested.
3, yield test
Get the contrast liquid and the blood sample (5ng/ml, 100ng/ml, 2000ng/ml) of basic, normal, high three concentration and make recovery test
| Concentration C (ng/ml) | Absolute recovery (%) | Relative recovery (%) |
| 5 | 73.5 | 130.0 |
| 100 | 96.2 | 108.5 |
| 2000 | 92.9 | 98.6 |
This method is fit to the mensuration of HCPT pharmacokinetics.
3, the bioavailability trial test of hydroxycamptothecin tablet
Case load: 5 examples, age: 35-56y, male 4 examples, women 1 example; Nasopharyngeal carcinoma 2 examples, pulmonary carcinoma 2 examples, the esophageal carcinoma 1 example
Hydroxyl is liked the haemoconcentration of plain alkali tablet after oral:
| Lot number 1 haemoconcentration (ng/ml) | Lot number haemoconcentration 2 (ng/ml) | ||||
| Patient | 1 | 2 | 3 | 4 | 5 |
| 30min | / | / | / | / | / |
| 1h | 2 | 2.1 | 2.1 | 2.3 | 2.1 |
| 1.5h | 6.1 | 5.8 | 6.3 | 22.5 | 19.3 |
| 2h | 6.0 | 5.7 | 6.4 | 22.4 | 19.7 |
| 3h | 6.0 | 6.0 | 6.2 | 22.1 | 19.2 |
| 4h | 2.1 | 2.2 | 2.1 | 8.2 | 8.8 |
| 5h | / | / | / | 2.3 | 2.0 |
| 6h | / | / | / | / | / |
| 7h | / | / | / | / | / |
| 8h | / | / | / | / | / |
| 12h | / | / | / | / | / |
| 16h | / | / | / | / | / |
| AUCng.h/ml | 16.2 | 16.0 | 16.0 | 61.05 | 55.5 |
The metabolism situation of hydroxy camptothecin injection (controlled trial) in patient's blood plasma, the same (12mg/m of dosage and assay method
2, be total to 15mg), record blood drug level such as following table:
| Time | 0min | 5min | 10min | 30min | 1h | 2h | 4h | 8h | 12h |
| Concentration (ng/ml) | 1081.6 | 754.6 | 431.4 | 210.7 | 87.5 | 43.1 | 25.7 | 10.8 | 2.3 |
| AUC | 874.8ng·h/ml | ||||||||
The bioavailability that can tentatively judge hydroxycamptothecin tablet thus is:
AUC tablet/AUC injection * 100%=(61.05/874.8) * 100%=7.0%
The clinical trial of hydroxy camptothecin (carboxylic acid sodium type) tablet absolute bioavailability
The test chamber Li Su of Guangzhou Tumour Prevention ﹠ Cure Centre, Zhongshan Medical Univ.
(10-Hydroxycamptothecin HCPT) is a kind of antitumor drug that extracts to hydroxy camptothecin from China distinctive a kind of jade field section plant camptotheca acuminata.The inhibition topoisomerase I that it is special and be subjected to extensive studies, clinical before experiment show that this product comprises that to kinds of tumors gastroenteric tumor (comprising cancer of pancreas), ovarian cancer, primary hepatocarcinoma, bladder cancer, nonsmall-cell lung cancer etc. are effective.The lot of documents report, camptothecine not only drug administration by injection has clear and definite curative effect, and its oral medication also has significant curative effect, as topotecan, CPT-11 etc.By national Clinical Researches of New Drugs official written reply (2001XL0588), the hydroxycamptothecin tablet that Li Shizhen (1518-1593 A.D.) pharmaceutcal corporation, Ltd in Wuhan produces is carried out clinical trial by Zhongshan Univ. Cancer Cure Center.For ease of determining the suitable dose of oral tablet, carry out the test of tablet bioavailability.Now finished the test of the bioavailability of tablet, be summarized as follows:
One, test objective
Determine the absolute bioavailability of hydroxycamptothecin tablet, the clinical suitable dose of pharmacokinetics behavior and hydroxycamptothecin tablet.
Two, test material
Instrument
Agilent 1100 highly effective liquid phase chromatographic systems, Agilent 1100 quaternary pump, Agilent 1100 fluorescence detectors, presica 125A electronic analytical balance, PHSJ-3F expenditure (F).
Five, result
1, case data
Altogether the MethodsThe cases enrolled number is 8 examples, is the male, age 27～52y, body weight all within the scope of standard body weight, nasopharyngeal carcinoma 3 examples, pulmonary carcinoma 2 examples, tumor of head and neck 1 example, hepatocarcinoma 2 examples (postoperative).See Table 3
Table 3 eight routine patients' the data of falling ill
| Name | Sex | Age | Height (cm) | Body weight (kg) | The blood drawing time point |
| Pan * * | The man | 43 | 168 | 59 | 0.5h，1h，2h，3h，4h，5h，6h，10h，12h，24h |
| Old * * | The man | 45 | 165 | 61 | 0.5h，1h，2h，3h，3.5h，4h，5h，6h，10h，12h，24h |
| Liu * * | The man | 52 | 172 | 68 | 0.5h，1h，2h，3h，3.5h，4h，5h，6h，8h，10h，12h，24h |
| Lu * * | The man | 48 | 164 | 58 | 0.5h，1h，2h，3h，4h，5h，6h，8h，12h，24h |
| The king * * | The man | 27 | 170 | 68 | 0.5h，1h，2h，3h，4h，5h，6h，8h，12h，24h |
| Lee * * | The man | 56 | 157 | 60 | 0.5h，1h，2h，3h，3.5h，4h，5h，6h，8h，10h，12h，24h |
| Leaf * * | The man | 32 | 163 | 54 | 0.5h，1h，2h，3h，4h，5h，6h，7h，9h，13h，24h |
2, blood drug level and pharmacokinetic parameter in the body of hydroxy camptothecin injection
Give behind the HCPT blood drug level half interval contour for the moment with patient's vein, as table 4 and Fig. 1,2, substitution 3P8 software carries out the compartment model match, show that curve is tangible two-phase and disposes feature, meet two chamber models through further proof hydroxy camptothecin at the intravital pharmacokinetics of people, and meet the first order kinetics elimination.Its main pharmacokinetic parameters is shown in Table 5.
Blood drug level behind the table 48 routine patient infusion HCPT
| Patient number | Concentration-time (ug/L) (instil and finish the back) | |||||||||
| 0’ | 5’ | 15’ | 30’ | 1h | 2h | 4h | 8h | 12h | 24h | |
| 1 | 2627.8 | 1998.6 | 1281 | 893.1 | 496.9 | 323.8 | 173.8 | 62.3 | 12.7 | 7.5 |
| 2 | 4896.3 | 4167.5 | 2532.9 | 1763.6 | 917.5 | 475.2 | 180.9 | 38.6 | 11.53 | 2.1 |
| 3 | 2054.6 | 1208.5 | 920.0 | 650.8 | 381.5 | 150.8 | 52.7 | 6.9 | / | / |
| 4 | / | 1862.3 | 343.16 | 227.6 | 123.8 | 60.4 | 18.1 | 9.6 | / | 5.5 |
| 5 | 3477.7 | / | 1496.9 | 1093.1 | 746.9 | 246.9 | 106.5 | 43.6 | 20 | 2.5 |
| 6 | 1516.2 | / | 477.6 | 266.2 | 158.5 | 87.3 | 81.5 | 10.8 | 3.46 | / |
| 7 | 2477.6 | / | 708.5 | 381.5 | 150.8 | 50.8 | 15.2 | 6.3 | / | |
| 8 | 2321.5 | 1201.5 | 872.9 | 545.2 | 165.8 | 90.5 | 65.9 | 42.4 | 26.1 | 5.2 |
The main pharmacokinetic parameter of quiet notes HCPT in 8 patient's bodies of table 5 '
| Parameters | C max (μg/L) | T 1/2α (h) | T 1/2β (h) | V c (L) | AUC (μg/L.h) | CL | K 10 (h -1) | K 12 (h -1) | K 21 (h -1) | MRT |
| X±s | 3083± 408 | 0.39 ± 0.17 | 4.27 ± 2.25 | 5.76 ± 4.8 | 2171.6± 515 | 7.86 ± 5.14 | 1.52 ± 0.69 | 0.39 ± 0.19 | 0.36 ±0.29 | 2.11 ± 0.72 |
| 1 | 3808.64 | 0.42 | 8.72 | 3.73 | 2459.76 | 4.88 | 1.31 | 0.34 | 0.10 | 1.94 |
| 2 | 7739.52 | 0.68 | 3.97 | 2.94 | 4589.51 | 2.61 | 0.89 | 0.11 | 0.20 | 1.44 |
| 3 | 1600.29 | 0.26 | 1.31 | 4.52 | 1747.13 | 6.87 | 1.52 | 0.76 | 0.93 | 1.97 |
| 4 | 903.82 | 0.47 | 4.67 | 17.22 | 675.85 | 17.75 | 1.03 | 0.37 | 0.21 | 2.38 |
| 5 | 4241.06 | 0.46 | 3.79 | 3.56 | 3224.14 | 3.72 | 1.05 | 0.37 | 0.26 | 1.97 |
| 6 | 1360.25 | 0.12 | 1.98 | 3.02 | 1311.15 | 9.15 | 3.03 | 0.20 | 0.64 | 1.51 |
| 7 | 1929.99 | 0.30 | 5.37 | 5.38 | 1193.71 | 10.05 | 1.87 | 0.38 | 0.15 | 5.62 |
| 8 | 2162.45 | 0.37 | 4.52 | 4.63 | 3346.28 | 5.99 | 3.35 | 0.23 | 0.69 | 3.94 |
3, blood drug level and pharmacokinetic parameter in the body of hydroxycamptothecin tablet
The patient presses 12mg/m
2Blood drug level one time graph such as table 6 and Fig. 3 behind the oral dose HCPT.Its main pharmacokinetic parameters is shown in Table 7.The first order kinetics that is absorbed as of oral HCPT absorbs, the speed limit process of oral absorption for eliminating.
The blood drug level of the oral HCPT of table 6
| Patient number | Concentration-time (ug/L) (back of taking medicine) | AUC (ug/L.h) | |||||||||
| 30’ | 1h | 2h | 3h | 4h | 5h | 6h | 8h | 12h | 24h | ||
| 1 | 76.6 | 63.0 | 169.7 | 148.4 | 144.5 | 191.02 | 76.6 | 45.8 | 21.6 | 20.6 | 1285.0 |
| 2 | 444.5 | 619.1 | 444.5 | 580.3 | 231.2 | 178.8 | 142.0 | 70.2 | 45.0 | 31.2 | 3103.7 |
| 3 | 64.9 | 73.4 | 123.4 | 137.1 | 115.0 | 109.8 | 71.6 | 32.4 | 14.8 | 7.9 | 942.7 |
| 4 | 45.6 | 530.8 | 151.8 | 162.5 | 158.6 | 142.1 | 80.7 | 43.2 | 24.3 | 14.5 | 1210.2 |
| 5 | 72.4 | 123.1 | 133.6 | 125.1 | 105.4 | 92.3 | 68.4 | 54.7 | 30.3 | 10.2 | 1180.6 |
| 6 | 52.6 | 80.1 | 88.6 | 91.4 | 77.7 | 69.4 | 36.1 | 13.5 | 8.5 | 5.2 | 607.6 |
| 7 | 72.1 | 83.4 | 113.3 | 118.6 | 114.7 | 82.8 | 46.9 | 22.1 | 10.3 | 8.4 | 765.5 |
| 8 | 51.3 | 90.2 | 84.6 | 74.2 | 45.5 | 35.6 | 34.3 | 25.9 | 12.5 | 8.2 | 612.0 |
The main pharmacokinetic parameter of the oral HCPT of table 7
| Parameters | C max (μg/L) | T 1/2α (h) | T 1/2β (h) | T max (μg/L) | T lag (μg/L) | AUC (μg/L·h) | K (h -1) | F (％) |
| X±s | 169.7 ± 56.8 | 1.73 ± 0.18 | 6.17 ± 0.32 | 2.37 ± 0.70 | 0.14 ± 0.04 | 693.8 ± 23.5 | 0.16 ± 0.08 | 31.95 ± 3.4 |
4, the bioavailability of hydroxycamptothecin tablet test
8 routine tumor patients are oral hydroxycamptothecin tablet 12mg/m on an empty stomach
2, its absolute bioavailability is 26.4～35.8%, and the average absolute bioavailability is 31.95% ± 3.4%, and CV is 9.98% less than 15%.Oral back reached maximum concentration, C in 2-3 hour
MaxBe 169.7 ± 56.8ug/L, still kept higher concentration, C to 6 hours
6Be 69.58ug/L, 12 hours concentration is greater than 10ug/L.Each patient's bioavailability (F) result such as table 6
Table 6 hydroxycamptothecin tablet absolute bioavailability in the patient body
| Patient number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | Meansigma methods |
| Absolute bioavailability (%) | 28.7 | 34.9 | 34.4 | 30.9 | 26.4 | 34.4 | 35.8 | 30.1 | 31.95 |
Six, discuss
Hydroxy camptothecin is the homologue of camptothecine (CPT), and compare its active anticancer and antitumor spectra increases with the latter, but the toxicity minimizing, a large amount of clinical trials shows has clear and definite curative effect to some tumor.Camptothecine can be special the inhibition topoisomerase I, do not have cross tolerance with other series antineoplastic medicament, and have synergism with some medicines such as cisplatin; Research and development to camptothecin homologue constantly occurs, as CPT-11 and Topotecan.
In the test, HCPT tablet oral absorption meets one-level absorption dynamics process, and short time lag (0.14h) reaches effective treatment concentration rapidly, average C
MaxBe 169.7ug/L, T
MaxBe 2.37h, still keep higher concentration behind the 6h, 12h concentration is greater than 10ug/L, and absolute bioavailability 26.4～35.8% is close with Topotecan tablet bioavailability (32～44%).T when oral
1/2 αBe 1.73h, t
1/2 β6.19h; T during quiet notes
1/2 α, t
1/2 βBe respectively 0.39h and 4.27h, contrast two route of administration, visible oral giving wanted t
1/2Move phenomenon after slightly being, this may heavily absorb with the circulation of intestinal, liver and exist, and digests and assimilates and relevant with the factors such as individual variation of gastric emptying rate, awaits further research.
Hydroxy camptothecin I clinical trial phase studies show that: its injection recommended dose is 12mg/m
2, logotype 5 days, 21 days is 1 course of treatment, main dose-limiting toxicity is bone marrow depression and diarrhoea.After the research is delivered, some hospital's reflection, recommended dose is higher.Estimate and hydroxy camptothecin aqueous injection less stable that easily degraded is relevant to store the back.Thereafter we once to stability preferably freeze-dried powder carry out applied research, the result is with 6mg/m
2/ day continuous drip was advisable in five days.The hydroxycamptothecin tablet bioavailability that the Wuhan Li Shizhen (1518-1593 A.D.) Pharmaceutical that we study is produced is 26.4～35.8%, and similar with the bioavailability (32-44%) of ToPotecan tablet, peak time 2～3h can keep higher concentration to 6h, oral 12mg/m
2After, the 12h bioavailability still＞10ug/L.Therefore, recommending hydroxycamptothecin tablet clinical experiment dosage is 6-10mg/m
2/ 12h, oral continuous 5 days is a course of treatment, is equivalent to per 12 hours oral 2-3 sheets and is advisable.
Seven, conclusion:
1) the oral two-compartment model that is in vivo of HCPT, absorbing, eliminating is the first order kinetics process, is absorbed as the speed limit process of elimination.
2) the average absolute bioavailability of HCPT tablet is 31.95%.
Claims (5)
1. the preparation method of the absorbable hydroxycamptothecin tablet of human body is characterized in that forming (all being weight percentage) by following supplementary material.
Hydroxy camptothecin 2-10%
Starch 10-40%
Microcrystalline Cellulose 10-40%
Glycine 4-20%
Carboxymethylstach sodium 2-8%
Magnesium stearate 0.2-0.5%
Above supplementary material is formed when making tablet, need the principal agent hydroxy camptothecin is dissolved with alkali liquor (0.1～1% sodium hydroxide or 0.5～2% sodium carbonate liquor), obtain the hydroxy camptothecin carboxylic acid sodium salt, the tablet that this method makes is absorbed by the body easily through human body is oral, and bioavailability can reach 31.95% (seeing description 7-11 page or leaf).
As lack this step, and will cause human bioavailability (7%) on the low side, (seeing description 4-6 page or leaf) is difficult for being absorbed by the body.
2. according to claim 1: the preparation method of the absorbable hydroxycamptothecin tablet of a kind of human body, raw material-the hydroxy camptothecin of preparation hydroxycamptothecin tablet must be handled in advance: it is characterized in that earlier the lactonic ring of hydroxy camptothecin (ester type structure is called for short C-HCPT) being opened, make it become carboxylate form (being called for short O-HCPT), concrete grammar is: get hydroxy camptothecin and adopt medically acceptable alkali liquor (0.1～1% sodium hydroxide or 0.5～2% sodium carbonate liquor) with the hydroxy-camptothecin alkali dissolution, add the pH value regulator then, regulate pH value 9.0-9.5, sabot is put in the freezer dryer,-55 ℃ of vacuums is under the condition of 0.015mBar degree, lyophilization 36 hours, collect dry thing, get the hydroxy camptothecin carboxylate (O-HCPT) of open loop.
3. method as claimed in claim 2 is characterized in that described alkali liquor is sodium hydroxide solution or sodium carbonate liquor.Its concentration of lye sodium hydroxide is 0.1-1% (W/L), and sodium carbonate is 0.5-2.0% (W/L).
4. according to claim 1: the preparation method of the absorbable hydroxycamptothecin tablet of a kind of human body, step is as follows:
(1) adjuvant in will writing out a prescription is respectively crossed 80 mesh sieves, and it is standby that other prepares 4% starch slurry.
(2) adjuvant in will writing out a prescription respectively (removing magnesium stearate) mix homogeneously is standby.
(3) with the adjuvant in (2) in the hydroxy camptothecin carboxylic acid sodium of gained in claims 2 and the claim 4 by the abundant mix homogeneously of equivalent incremental method.
(4) binding agent is made soft material with 4% starch slurry, granulate with 40 mesh sieves, granule is in 70 ℃ of dryings, and with 40 mesh sieve granulate.
(5) granule adds the magnesium stearate of recipe quantity, mix homogeneously, tabletting.
(6) use the film coating agent coating.
5. this tablet adopts film-coated technique, can prevent the product oxidation and the moisture absorption.
(1) get hydroxypropyl emthylcellulose HPMC45g, Polyethylene Glycol 10g, Pulvis Talci 22g, coloring agent 23g, mix homogeneously is crossed 100 mesh sieves, is the film coating powder.
(2) slowly add purified water 880ml, after the employing milling treatment of colloid, stirred 40 minutes, as coating solution, the viscosity scope is controlled at 80～250cps.
(3) be sprayed on the hydroxy camptothecin sheet 42 ℃ of sheet temperature, coating weightening finish 3%.
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