CN102258525A - Application of HQ-091212 to medicaments - Google Patents
Application of HQ-091212 to medicaments Download PDFInfo
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Abstract
The invention relates to application of a diterpene lactone compound (HQ-091212) shown as a formula (1) to the preparation of anti-tumor medicaments and immunosuppressive agents. The medicinal composition can be prepared into formulations which are easily absorbed and utilized by tissues and organs of mammals, and has a good application prospect in aspects of the treatment of hyperplastic diseases such as tumors and the like and immunological suppression.
Description
Technical field
The present invention relates to the application of HQ-091212 in preparation antitumor and immunosuppressive drug, the invention still further relates to employed pharmaceutical composition and the dosage form thereof that contains effective dose HQ-091212 and conventional pharmaceutical adjuvant in the application.
Background technology
The diterpenes diterpenoids lactones triptolide alcohol derivative extracts from Celastraceae Thunder God Calamus bejuco.Celastraceae Thunder God Calamus bejuco is distributed in various places and southwest on the south the Yangtze river basin.
Recent two decades comes studies show that the diterpenes diterpenoids lactones triptolide alcohol derivative has antitumor, antiinflammatory, immunosuppressant, antifertility, various active such as antibiotic, particularly aspect immunosuppressive action, two obedient class lactone Radix Tripterygii Wilfordii lactone alcohols have very strong pharmacologically active.
The diterpenes diterpenoids lactones triptolide alcohol derivative once entered clinical trial as PG490-88 except obtaining antitumor action research widely, be used for the treatment of leukemia.But the toxic and side effects that the diterpenes diterpenoids lactones triptolide alcohol derivative is bigger, too narrow treatment window has limited it and has used in clinical.The antitumor drug effect research of this analog derivative does not in the past have specificity mostly, so antitumor spectra is clear and definite inadequately.
Summary of the invention
The present invention is based on further investigation, carried out being different from the transformation and the modification of prior art, obtained a kind of at C to the Radix Tripterygii Wilfordii lactone alcohol structure activity relationship
14-position forms the derivant of the outer methylene structure of ring and sees formula (1).Further HQ-091212 is made various dosage forms by various preparation means, find that in pharmacological toxicology experimentation subsequently HQ-091212 makes enteric coated preparation artifact availability into and can obviously improve, the treatment window is wideer than other derivants, and especially obvious to the therapeutical effect of genital system tumor.HQ-091212 is efficient, the characteristics of low toxicity, high specificity, aspect the treatment proliferative disease bright development prospect is being arranged, thereby is finishing the present invention.
The purpose of this invention is to provide the application of the diterpenes diterpenoids lactones derivative (HQ-091212) shown in a kind of general formula (1) in preparation treatment tumor and immune disease medicine.
Medicine for treating tumor thing of the present invention is the medicine of treatment human reproductive system tumor.
Treatment immune disease medicine of the present invention is an immunosuppressant.
The medicine of treatment tumor of the present invention is the medicine of treatment carcinoma of prostate or the medicine of treatment ovarian cancer.
Treatment tumor of the present invention and immune disease medicine are the pharmaceutical composition that diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) and conventional pharmacy adjuvant are combined into.
In described pharmaceutical composition, the content of the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the described general formula (1) is 0.001～99.9wt%.
To be the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) be used with the amount of 0.001～50mg/kg the day dosage of described pharmaceutical composition.To be the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) be used with the amount of 0.01～5mg/kg for preferred day dosage.Such dosage can produce effective therapeutic effect usually.
The dosage form of described pharmaceutical composition is through the dosage form of gastrointestinal administration or non-through the gastrointestinal administration dosage form.
Described dosage form through gastrointestinal administration is solution, Emulsion, tablet, capsule etc.
Described dosage form through gastrointestinal administration is an enteric agents.
Described parenteral administration dosage form comprises injection type, through skin form of administration, transmucosal form of administration.
Described injection type comprises intravenous form, intramuscular injection dosage form, subcutaneous injection dosage form, intradermal injection dosage form etc.
Describedly comprise external-use lotion, ointment, patch etc. through the skin form of administration.
Described transmucosal form of administration comprises sublingual administration dosage form, nasal cavity medicine, rectally dosage form, vagina administration dosage form, auditory meatus form of administration etc.
HQ-091212 among the present invention can obviously suppress the growth of human prostata cancer, ovarian cancer Nude Mice respectively with the oral dose administration of 3mg/kg and 10mg/kg.Its dosage will be according to treatment target, curee's age (monthly age or age in week), general health situation, route of administration, individual to the corresponding adjustment of works such as the sensitivity of medicine and the order of severity of the state of an illness, the curee is used the pharmaceutical preparation that contains The compounds of this invention treatment effective dose.
The general formulation of oral administration of the present invention and enteric dosage form, wherein in the test of nude mouse antitumor drug effect, oral crude drug 1,3,10mg/kg present significant dose-effect relationship, the inhibitory action to tumor growth of 10mg/kg slightly is better than the positive control docetaxel, and very little to the influence of nude mice body weight, obviously be better than docetaxel.
Enteric coated preparation of the present invention can improve its bioavailability, and the test of the preliminary pharmacokinetics of rat shows, enteric coated preparation can bring up to 15.2～19.8% from original 1.0～6.6% with the bioavailability of ordinary preparation.
In the intravenous administration Nude Mice test of pesticide effectiveness, quiet notes 1mg/kg HQ-091212 all has significant curative effect to carcinoma of prostate and ovarian cancer, inhibitory action to tumor growth is suitable with the positive control docetaxel, and very little to the influence of nude mice body weight, obviously is better than docetaxel.
Pharmaceutical composition of the present invention can be used for the treatment of the homoiothermic animal of suffering from proliferative diseases such as tumor, and described " tumor " comprises benign tumor and malignant tumor: benign tumor mainly contains fibroma, lipoma, hemangioma etc.; Malignant tumor mainly comprises the malignant tumor that taken place by epithelial tissue such as squamous cell carcinoma, breast carcinoma, ovarian cancer etc., by the histogenetic malignant tumor of mesoderm such as fibrosarcoma, osteosarcoma, lymphosarcoma, glioma etc., and the malignant tumor that takes place by the histogenetic malignant tumor of embryonic cell, neurocyte or immaturity with by hematopoietic cell etc.Be particularly useful for treatment conventional cell cytotoxic drug such as amycin, paclitaxel, docetaxel, vinorelbine etc. are had drug-fast tumor.Described " homoiothermic animal " comprises people and other animal, as rodent and mammal.The implication of described " proliferative disease " comprises tumor, atypical hyperplasia, but is not limited to tumor and atypical hyperplasia.
Pharmaceutical composition of the present invention can also be used for the disease relevant with tumor, comprises tumor diseases such as the tumor with multidrug resistance of carcinoma of prostate, human ovarian cancer, nonsmall-cell lung cancer, myelocytic leukemia, colon cancer, breast carcinoma, the mediation of P-170 glycoprotein such as the drug-fast breast carcinoma of amycin.
Preferably, pharmaceutical composition of the present invention is used for the treatment of carcinoma of prostate and ovarian cancer.
The effect experiment result of HQ-091212 shows among the present invention, be that gastrointestinal administration or parenteral administration all have stronger antitumor action, and do not have cross-resistance between cytotoxicity antitumor drug commonly used such as paclitaxel, amycin, the vinorelbine.It needs to be noted, with the line medicine docetaxel that is used for the treatment of ovarian cancer and carcinoma of prostate at present as positive control, HQ-091212 has shown the advantage of significant high-efficiency low-toxicity, it is surpassing the curative effect of docetaxel under 12mg/kg dosage to human prostata cancer PC-3 nude mice xenografts of human under dosage of 3mg/kg, and toxicity is lower than docetaxel.Under the high dose condition, also do not have any toxicity phenomenon and take place.Further the acute toxicity testing result shows, HQ-091212 among the present invention, half lethal dose (LD50) is up to 50mg/kg, compare with the half lethal dose (LD50=0.5mg/kg) of its lead compound Radix Tripterygii Wilfordii lactone alcohol and to have improved 100 times, thereby make the dosage range of safe handling greatly improve.Pharmaceutical composition of the present invention can be made the tissue that helps homoiothermic animal, the dosage form that organ absorbs, and it is having a good application prospect aspect proliferative diseases such as treatment tumor.
Description of drawings
Fig. 1 is the influence sketch maps of oral, the quiet notes of HQ-091212 to human prostata cancer PC-3 Model in Nude Mice gross tumor volume.
Oral, the quiet notes of Fig. 2 .HQ-091212 are to the sketch map that influences of human prostata cancer PC-3 Model in Nude Mice body weight.
Fig. 3 is the influence sketch maps of oral, the quiet notes of HQ-091212 to human ovarian cancer SK-OV-3 Model in Nude Mice gross tumor volume.
Fig. 4 is the influence sketch maps of oral, the quiet notes of HQ-091212 to human ovarian cancer SK-OV-3 Model in Nude Mice body weight.
The specific embodiment
Below in conjunction with example the present invention is further set forth, but these embodiment never are any limitation of the invention that scope of the present invention is determined by claim.
Preparation embodiment 1
The following examples specify and contain HQ-091212, are applicable to the human several representative dosage form of using.
Pharmacology pharmacodynamic is estimated embodiment
EXPERIMENTAL EXAMPLE 1
HQ-091212 is to the in-vitro multiplication inhibitory action of human tumor cells
Method
Tumor cell is cultivated with RPMI 1640 or DMEM culture medium (Gibco), includes 10% hyclone, and condition of culture is 37 ℃, 5%CO
2Tumor cell inoculation after 24 hours, adds the HQ-091212 with the dimethyl sulfoxide preparation in the 96-orifice plate, and the final concentration that makes HQ-091212 in the culture medium is 0.0001-100 μ M; The final concentration of dimethyl sulfoxide is no more than 0.1% in the culture medium.HQ-091212 handled after 72 hours, discarded culture fluid, with cold trichloroacetic acid fixed cell.Use sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed then.Flush away with Tris dissolving and protein bound SRB, under 520nm wavelength is measured OD value with microplate reader not in conjunction with behind the SRB, calculates inhibitory rate of cell growth with following formula:
Suppression ratio=(OD value control wells-OD value dosing holes)/OD value control wells * 100%
According to each concentration suppression ratio, adopt Logit method calculation of half inhibitory concentration IC
50
The result
As seen from Table 1, HQ-091212 all has significant cytotoxicity to the growth of tumour cell of most of tumor type In vitro culture; The particularly important is, multidrug resistance tumor cells such as KBV200 to high expressed P-170 glycoprotein, MCF-7/ADR, K562/ADR still has significant cytotoxicity, and illustrating between HQ-091212 and the cytotoxicity antitumor drug of using always such as paclitaxel, amycin, the vinorelbine does not have cross-resistance.
Table 1.HQ-091212 is to the cytotoxic effect of cultured tumor cells in vitro
EXPERIMENTAL EXAMPLE 2
The HQ-091212 oral administration is to the curative effect of human prostata cancer PC-3 Nude Mice
Method
Human prostata cancer PC-3 is available from U.S. ATCC (American Type CultureCollection).
The BALB/c nude mouse, ♂, 6 ages in week are available from Chinese Academy of Sciences's Shanghai Experimental Animal Center.Feeding environment: SPF level.
The strain of nude mouse subcutaneous vaccination PC-3 Human Prostate Cancer Cells, inoculum concentration is every Mus 5 * 10
6Individual cell is cut into 2mm with the nude mice tumor tissues then
3Square fritter, the nude mouse that was implanted in for 5～6 ages in week is subcutaneous, treats that tumor growth reaches 100mm at least
3After, with animal random packet HQ-091212: oral administration 1,3,10mg/kg, every day 1 time, continuous 3 weeks; Positive control docetaxel 15mg/kg, intravenous injection, 1 time weekly, totally 3 weeks.Measure gross tumor volume 2 times weekly, weigh, put to death animal on the 28th day, peel off tumor, claim tumor heavy.
Gross tumor volume (TV) computing formula is:
TV＝1/2×a×b2
Wherein a, b represent length and width respectively.
Estimate antitumor curative effect according to relative tumor propagation rate T/C (%).
RTV
T: treatment group relative tumour volume; RTV
C: solvent matched group relative tumour volume.
Tumour inhibiting rate (IR) computing formula is:
TW
T: treatment group tumor is heavy; TW
C: solvent matched group tumor is heavy.
The result
HQ-091212 obviously suppresses the growth of human prostata cancer PC-3 Nude Mice, and inhibitory action has tangible dose dependent.3, during the 10mg/kg administration, tumor propagation rate T/C% is respectively 15% and 7%, inhibitory rate to 85% and 93%, (T/C% is 20% to be better than the curative effect of positive control docetaxel, tumour inhibiting rate is 80% Fig. 1), and toxicity is starkly lower than docetaxel, because according to present dosage regimen, the HQ-091212 of 10mg/kg does not cause the mice weight loss, but docetaxel causes 20% decline (Fig. 2) of mice body weight.
EXPERIMENTAL EXAMPLE 3
The HQ-091212 intravenous administration is to the curative effect of human prostata cancer PC-3 Nude Mice
Method
Human prostata cancer PC-3 is available from U.S. ATCC (American Type CultureCollection).
The BALB/c nude mouse, ♂, age in 5-6 week is available from Shanghai Slac Experimental Animal Co., Ltd..Feeding environment: SPF level.
The strain of nude mouse subcutaneous vaccination PC-3 Human Prostate Cancer Cells, inoculum concentration is every Mus 5 * 10
6Individual cell is cut into 2mm with the nude mice tumor tissues then
3Square fritter, the nude mouse that was implanted in for 5～6 ages in week is subcutaneous, treats that tumor growth reaches 100mm at least
3After, with animal random packet HQ-091212: intravenous injection 1mg/kg, every day 1 time, continuous 3 weeks; Positive control docetaxel 15mg/kg, intravenous injection, 1 time weekly, totally 3 weeks.Measure gross tumor volume 2 times weekly, weigh, put to death animal on the 28th day, peel off tumor, claim tumor heavy.
Gross tumor volume (TV) computing formula is:
TV=1/2 * a * b2 wherein a, b represents length and width respectively.
Estimate antitumor curative effect according to relative tumor propagation rate T/C (%).
RTV
T: treatment group relative tumour volume; RTV
C: solvent matched group relative tumour volume.
Tumour inhibiting rate (IR) computing formula is:
TW
T: treatment group tumor is heavy; TW
C: solvent matched group tumor is heavy.
The result
HQ-091212 intravenous injection 1mg/kg also has obvious inhibitory action to the growth of human prostata cancer PC-3 Nude Mice, tumor propagation rate T/C% is 10%, inhibitory rate to 90%, (T/C% is 20% to be better than the curative effect of positive control docetaxel, tumour inhibiting rate is 80% Fig. 1), and toxicity is starkly lower than docetaxel, because according to present dosage regimen, the HQ-091212 of intravenous injection 1mg/kg does not cause the mice weight loss, but docetaxel causes 20% decline (Fig. 2) of mice body weight.
EXPERIMENTAL EXAMPLE 4
The HQ-091212 oral administration is to the curative effect of human ovarian cancer SK-OV-3 Nude Mice
Method
Human ovarian cancer SK-OV-3 is available from U.S. ATCC (American Type CultureCollection).
The BALB/c nude mouse, ♀, 6 ages in week are available from Chinese Academy of Sciences's Shanghai Experimental Animal Center.Feeding environment: SPF level.
Nude mouse subcutaneous vaccination SK-OV-3 human oophoroma cell line, inoculum concentration is every Mus 5 * 10
6Individual cell is cut into 2mm with the nude mice tumor tissues then
3Square fritter, the nude mouse that was implanted in for 5～6 ages in week is subcutaneous, treats that tumor growth reaches 100mm at least
3After, with animal random packet HQ-091212: oral administration 1,3,10mg/kg, every day 1 time, continuous 3 weeks; Positive control docetaxel 15mg/kg, intravenous injection, 1 time weekly, totally 3 weeks.Measure gross tumor volume 2 times weekly, weigh, put to death animal on the 28th day, peel off tumor, claim tumor heavy.
Gross tumor volume (TV) computing formula is:
TV=1/2 * a * b2 wherein a, b represents length and width respectively.
Estimate antitumor curative effect according to relative tumor propagation rate T/C (%).
RTV
T: treatment group relative tumour volume; RTV
C: solvent matched group relative tumour volume.
Tumour inhibiting rate (IR) computing formula is:
TW
T: treatment group tumor is heavy; TW
C: solvent matched group tumor is heavy.
The result
HQ-091212 obviously suppresses the growth of human ovarian cancer SK-OV-3 Nude Mice, and inhibitory action has tangible dose dependent.During the 10mg/kg administration, tumor propagation rate T/C% is respectively 20%, inhibitory rate to 80%, (T/C% is 18% with the therapeutic equivalence of positive control docetaxel, tumour inhibiting rate is 82% Fig. 3), and toxicity is starkly lower than docetaxel, because according to present dosage regimen, the HQ-091212 of 10mg/kg does not cause the mice weight loss, but docetaxel causes 16% decline (Fig. 4) of mice body weight.
EXPERIMENTAL EXAMPLE 5
The HQ-091212 intravenous administration is to the curative effect of human ovarian cancer SK-OV-3 Nude Mice
Method
People's human ovarian cancer SK-OV-3 is available from U.S. ATCC (American Type CultureCollection).
The BALB/c nude mouse, ♂, age in 5-6 week is available from Shanghai Slac Experimental Animal Co., Ltd..Feeding environment: SPF level.
Nude mouse subcutaneous vaccination SK-OV-3 human oophoroma cell line, inoculum concentration is every Mus 5 * 10
6Individual cell is cut into 2mm with the nude mice tumor tissues then
3Square fritter, the nude mouse that was implanted in for 5～6 ages in week is subcutaneous, treats that tumor growth reaches 100mm at least
3After, with animal random packet HQ-091212: intravenous injection 1mg/kg, every day 1 time, continuous 3 weeks; Positive control docetaxel 15mg/kg, intravenous injection, 1 time weekly, totally 3 weeks.Measure gross tumor volume 2 times weekly, weigh, put to death animal on the 28th day, peel off tumor, claim tumor heavy.
Gross tumor volume (TV) computing formula is:
TV=1/2 * a * b2 wherein a, b represents length and width respectively.
Estimate antitumor curative effect according to relative tumor propagation rate T/C (%).
RTV
T: treatment group relative tumour volume; RTV
C: solvent matched group relative tumour volume.
Tumour inhibiting rate (IR) computing formula is:
TW
T: treatment group tumor is heavy; TW
C: solvent matched group tumor is heavy.
The result
HQ-091212 intravenous injection 1mg/kg also has obvious inhibitory action to the growth of human prostata cancer PC-3 Nude Mice, tumor propagation rate T/C% is 19%, inhibitory rate to 81%, (T/C% is 18% with the therapeutic equivalence of positive control docetaxel, tumour inhibiting rate is 82% Fig. 3), and toxicity is starkly lower than docetaxel, because according to present dosage regimen, the HQ-091212 of intravenous injection 1mg/kg does not cause the mice weight loss, but docetaxel causes 20% decline (Fig. 4) of mice body weight.
EXPERIMENTAL EXAMPLE 6
The preliminary pharmacokinetics research of HQ-091212
Method
Adopt male Sprague-Dawley rat (the about 250g of body weight) to carry out the pharmacokinetics experiment, rat is divided into four groups at random, each two groups of male and female, every group of 3 rats.Wherein, first group (♂) and second group of (♀) intravenous administration HQ-091212 (i.v.; Dosage: 2mg/kg); The 3rd group (♂) and the 4th group of (♀) oral administration HQ-091212 (p.o.; Dosage: 10mg/kg).After the rat administration,, use the concentration of the HQ-091212 in the LC/MS technical measurement blood plasma, and adopt non-compartment model method to calculate relevant pharmacokinetic parameters by different time points (0,5,15,30min, 1,2,5,8h) blood sampling.
The result
The HQ-091212 pharmacokinetic studies of carrying out the male and female rat shows that after the p.o. administration, male rat absorbs peak time (T
Max) be about 0.58h, female rats T
MaxBe about 0.83h; Blood drug level (C when reaching the peak
Max) on rat 71.4 ± 25.8 (female) and 31.6 ± 19.6ng/mL (hero); Rat serum concentration area under curve (AUC) is respectively 141 ± 73 (female) and 52.4 ± 25.3ng/h/kg (hero); Oral administration biaavailability after the rat p.o. administration is respectively 2.1～6.6 (female) and 1.0～2.9% (heros).I.v. behind the administration HQ-091212, this chemical compound is at the intravital elimination of rat half-life (T
1/2) be 0.73 ± 0.33 (female) and 0.40 ± 0.03h (hero), mean residence time (MRT) is 0.78 ± 0.11 (female) and 0.57 ± 0.03h (hero) in the body, HQ-091212 clearance rate (CL) in the rat body is respectively 3.04 ± 1.05 (female) and 3.71 ± 0.21L/h/kg (hero), its volume of distribution (V
Ss) be respectively 2.27 ± 0.38 (female) and 2.10 ± 0.04L/kg (hero).
EXPERIMENTAL EXAMPLE 7
HQ-091212 single oral administration acute toxicity
The ICR mice, body weight 20-22 gram, female, hero half and half is available from Shanghai Si Laike experimental animal Co., Ltd.The HQ-091212 of mice single oral (filling stomach) various dose.Observe mortality rate and toxicity situation after the administration, observed altogether 14 days, use the Bliss method according to mortality rate and calculate LD
50LLDT-144 is to the LD of ICR mice single oral
50Be 50mg/kg.Female, male mice does not have notable difference to its sensitivity.
The probability of utilizing on the industry
Tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention, particularly 14-dehydroxylation-14-methylene Radix Tripterygii Wilfordii lactone alcohol (HQ-091212) obviously suppresses the growth of the tumor cell of multiple In vitro culture, and inhibitory action has tangible dose dependent, its IC
50Between 40-800nM, show that HQ-091212 has very strong anti tumor activity in vitro.
Further drug effect experimental results show that HQ-091212 has the obvious suppression effect for the growth of human prostata cancer PC-3 nude mouse subcutaneous transplantation tumor and human ovarian cancer SK-OV-3 nude mouse subcutaneous transplantation tumor in the body, animal subject does not have body weight reduction phenomenon in the effect experiment in vivo, do not show tangible toxicity, its curative effect and safety all are better than the positive control docetaxel.The growth inhibited that shows the HQ-091212 genital system tumor has remarkable effect.Preliminary acute toxicity testing shows HQ-091212 (LD
50Be 50mg/kg), as antitumor drug, this treatment window is bigger.
All experimental results show that all HQ-091212 has characteristics efficient, low toxicity aspect the tumor disease in treatment, have good being used for the treatment of comprise carcinoma of prostate, human ovarian cancer etc. the application prospect of genital system tumor disease.
Claims (14)
1. the application of the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) in preparation treatment tumor and immune disease medicine
2. application as claimed in claim 1 is characterized in that, the medicine of described treatment tumor is the medicine of treatment carcinoma of prostate or the medicine of treatment ovarian cancer.
3. application as claimed in claim 1 is characterized in that, described treatment immune disease medicine is an immunosuppressant.
4. application as claimed in claim 1 is characterized in that, described treatment tumor and immune disease medicine are the pharmaceutical composition that diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) and conventional pharmacy adjuvant are combined into.
5. application as claimed in claim 4 is characterized in that, in described pharmaceutical composition, the content of the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the described general formula (1) is 0.001～99.9wt%.
6. application as claimed in claim 3 is characterized in that, to be the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) be used with the amount of 0.001～50mg/kg the day dosage of described pharmaceutical composition.
7. application as claimed in claim 6 is characterized in that, to be the diterpenes diterpenoids lactones derivative (HQ-091212) shown in the general formula (1) be used with the amount of 0.01～5mg/kg the day dosage of described pharmaceutical composition.
8. application as claimed in claim 4 is characterized in that, the dosage form of the described pharmaceutical composition of described pharmaceutical composition is through the dosage form of gastrointestinal administration or non-through the gastrointestinal administration dosage form.
9. application as claimed in claim 8 is characterized in that, described dosage form through gastrointestinal administration is solution, Emulsion, tablet, capsule.
10. application as claimed in claim 8 is characterized in that, described dosage form through gastrointestinal administration is the enteric dosage form.
11. application as claimed in claim 8 is characterized in that, described parenteral administration dosage form comprises injection type, through skin form of administration, transmucosal form of administration.
12. application as claimed in claim 11 is characterized in that, the described injection type of described pharmaceutical composition comprises intravenous form, intramuscular injection dosage form, subcutaneous injection dosage form, intradermal injection dosage form.
13. application as claimed in claim 11 is characterized in that, the described of described pharmaceutical composition comprises external-use lotion, ointment, patch through the skin form of administration.
14. application as claimed in claim 11 is characterized in that, the described transmucosal form of administration of described pharmaceutical composition comprises sublingual administration dosage form, nasal cavity medicine, rectally dosage form, vagina administration dosage form, auditory meatus form of administration.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014056401A1 (en) * | 2012-10-09 | 2014-04-17 | 上海汇伦生命科技有限公司 | Double-bond substituted tripterygium wilfordii lactone derivative and preparation method and use thereof |
| CN104478832A (en) * | 2015-01-05 | 2015-04-01 | 富阳鸿祥技术服务有限公司 | Diterpene compound, pharmaceutical composition containing same and preparation method and usage thereof |
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| CN1726025A (en) * | 2002-12-17 | 2006-01-25 | 泛华医药公司 | Triptolide derivatives as immunomodulator and anticancer agents |
| CN101049300A (en) * | 2006-04-04 | 2007-10-10 | 中国科学院上海药物研究所 | Composition of medication containing lactone derivative of triperygium wilfordii, medicament form, and application |
| CN101255186A (en) * | 2008-04-10 | 2008-09-03 | 中国科学院上海药物研究所 | Tripterygium wilfordii diterpenes diterpenoids lactones derivative and uses thereof |
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| WO2014056401A1 (en) * | 2012-10-09 | 2014-04-17 | 上海汇伦生命科技有限公司 | Double-bond substituted tripterygium wilfordii lactone derivative and preparation method and use thereof |
| CN104478832A (en) * | 2015-01-05 | 2015-04-01 | 富阳鸿祥技术服务有限公司 | Diterpene compound, pharmaceutical composition containing same and preparation method and usage thereof |
| CN104478832B (en) * | 2015-01-05 | 2016-04-20 | 项敬来 | Diterpene compound, containing its pharmaceutical composition and its preparation method and application |
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