CN1504191A - Cucurbitacin lipsome preparation method and formulation - Google Patents
Cucurbitacin lipsome preparation method and formulation Download PDFInfo
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- CN1504191A CN1504191A CNA021446334A CN02144633A CN1504191A CN 1504191 A CN1504191 A CN 1504191A CN A021446334 A CNA021446334 A CN A021446334A CN 02144633 A CN02144633 A CN 02144633A CN 1504191 A CN1504191 A CN 1504191A
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- cucurbitacin
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- liposome
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Abstract
The invention relates to a cucurbitacin liposome composition and its preparation, which has rather high encapsulation efficiency, and can be administered through vein, muscle, oral and nasal. The constituent percentage by weight of the composition are, cucurbitacin BE or cucurbitacin B 0.001-0.1%, phospholipids 0.1-10%, cholesterin 0-5%, the phospholipids can be lecithin, di-stearoyl phosphatidyl choline, di- palmityl phosphatidyl choline, di-oleoyl phosphatidyl choline, di- palmityl phosphatidyl ethanolamine, di-stearoyl phosphatidylglycerol. The preparation according to the invention can be prepared in the form of injection, oral liquid, syrup, drop and nasal spray
Description
Technical field:
The present invention relates to medical technical field, exactly it is to utilize phospholipid and cucurbitacin to form the cucurbitacin liposome prescription and the preparation thereof of fat.
Background technology:
Cucurbitacin be the Chinese medicine muskmelon pedicel (another name: Pedicellus Melo) extract, mainly contain Cucurbitacin B, E etc., be the effective ingredient of treatment hepatitis and hepatocarcinoma.The cucurbitacin sheet is used for the treatment of chronic hepatitis, and (cucurbitacin sheet pharmacy circular 1986,21 (6): 357), through Shanghai, ground 13 tame hospital clinicals such as Beijing, Chongqing, its effective percentage is 75.2%, and obvious effective rate is 44.6%.Observe the cucurbitacin sheet clinically and can improve chronic hepatitis common sympton and main physical signs more all sidedly, and have and significantly fall enzyme (S-GPT), the turbid descending (TTT, ZnTT) and fall the red matter effect of gallbladder, do not cause the S-GPT knock-on after the drug withdrawal, albumen inversion and hyperglobulinemia also there is tangible role of correcting, can also improve the non-specific cell immunocompetence of chronic hepatitis patient, no obvious toxic-side effects.With the exception of this, the cucurbitacin sheet can also be used for the treatment of primary hepatocarcinoma, through Shanghai, ground such as Beijing, Guangxi six tame hospital clinicals observe, and add up 169 examples, effective percentage 69%, obvious effective rate 39%.Clinical observation shows, this medicine and 5-fluorouracil are relatively, it improves symptom, eliminate liver pain, dwindle the tumor body, prolong life cycle, regain one's strength etc., all be better than matched group, and the toxic and side effects of chemotherapeutics (is treated hepatitis, hepatocarcinoma new drug cucurbitacin sheet Chinese herbal medicine 1987,18 (10): 21 as none, cucurbitacin treatment primary hepatocarcinoma 50 routine clinical observation new drugs and clinical 1984,3 (2): 21-22, the pharmacology of cucurbitacin and clinical practice Chinese herbal medicine 1992,23 (11): 605～608).The author is arranged recently with cucurbitacin sheet and chemotherapeutic associating, the treatment mid and late liver cancer, median survival interval was by 6.1 ± 7.12 months of single chemotherapeutic, (the cucurbitacin sheet adds the clinical observation on the therapeutic effect cancer 1989,8 (6) of chemotherapeutic treatment advanced primary liver cancer: 434～436) to bring up to 12.5 ± 7.54 months; Other has literary composition to find Cucurbitacin B, E (II) 20 μ g/ml are 82.6% to the kill rate of cancerous cell, when concentration is increased to 80 μ g/ml, its kill rate reaches 94.1%, influence to normal person's lymhocyte transformation rate then is respectively 90.6% and 89.5%, show that (II) has stronger lethal effect to nasopharyngeal carcinoma cell, it can promote normal lymphocytic transformation function simultaneously; Carrying out cucurbitacin sheet and existing medicine-discovery when MIEAOLING treatment chronic viral hepatitis B curative effect compares, the treatment group is taken the cucurbitacin sheet, oral meal, and 3 times on the 1st, each 2 was a course of treatment with 3～6 months.Matched group is taken the MIEAOLING sheet.The total effective rate of treatment group as a result is 67.4%, and the matched group total effective rate is 35.9%, P＜0.01 (cucurbitacin sheet treatment chronic hepatitis B 89 routine observation of curative effect Zhejiang College Of Traditional Chinese Medicine journals 1994,18 (4): 18～19); Have document to point out, the long medication course of treatment (6 week) can obviously suppress the liver proliferation of fibrous tissue, prevents fatty degeneration of liver and cirrhotic formation and development.Because indissoluble in the cucurbitacin water, in order to make injection, (Chinese Hospitals pharmaceutical journal 1985,5 (7): 27), and tween 80 easily produces haemolysis, and certain toxicity is arranged, and does not meet the requirement of modern medicines preparation to need to add tween 80 in prescription.(Chinese herbal medicine 1991,22 (2): 62), but envelop rate is lower, only is 41.8%, and is added with mixed surfactant in the prescription, is unsuitable for intravenous injection to have document to be made into liposome.
Summary of the invention:
The objective of the invention is to be achieved by the following scheme, it is characterized in that: select natural or synthetic phospholipid, cucurbitacin is made liposome, realize intravenous injection target administration purpose; In order to improve the stability in the liposome storage process, also in liposome solutions, add suitable proppant, through lyophilization or spray drying, be made into pro-liposome, and available this precursor liposome preparation aseptic powder injection, tablet, granule, capsule etc.
Basic prescription involved in the present invention (liquid, volume is calculated by weight) is as follows:
Cucurbitacine (or Cucurbitacin B) 0.001～0.1%
Phosphatidase 10 .1～10%
Cholesterol 0～5%
Said phospholipid is lecithin (comprising soybean lecithin, Ovum Gallus domesticus Flavus lecithin), distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, dioleoyl phospholipid phatidylcholine, two palmityl PHOSPHATIDYL ETHANOLAMINE, distearyl phosphatidyl glycerol.
Being prepared as follows of liposome, pro-liposome:
(1) preparation of Cucurbitacine (or Cucurbitacin B) liposome
In proportion with Cucurbitacine (or Cucurbitacin B), phospholipid and/or be not dissolved in jointly in organic solvent such as ethanol, chloroform, dichloromethane etc. and the mixed solution thereof with cholesterol, reduction vaporization is removed organic solvent and is become thin film, add entry or buffer and (comprise phosphate buffer, citric acid salt buffer, tartrate buffer, pH=4.0～8.0), high-speed stirred or ultrasonic Treatment or pressurization are extruded, and promptly get Cucurbitacine (or Cucurbitacin B) liposome turbid liquor.
(2) preparation of pro-liposome
A. freeze-drying: in above-mentioned liposome, add proppant (as sucrose, lactose, glucose, trehalose, maltose, mannitol, sorbitol etc.), after the dissolving, carry out lyophilization, promptly.
B. spray drying method: add proppant (as sucrose, lactose, glucose, mannitol, sorbitol etc.) in above-mentioned liposome, after the dissolving, carry out spray drying, drying condition is as follows: inlet temperature is 80～160, and charging rate is 5～50mL/min.
When adopting Cucurbitacine (or Cucurbitacin B) the pro-liposome rehydration that above-mentioned freeze-drying and spray drying method method obtained, can disperse (or reconstruction) to become liposome in granularity and form and the stock solution not have the liposome of marked difference again.
(3) entrapment efficiency determination: get liposome liquid (if pro-liposome adds behind the water hydratable and surveys), carry out low temperature ultracentrifugation 2～4h. and accurately draw supernatant then, measure wherein medicament contg.According to formula computational envelope rate:
EN (%): (1-C
FreeThe * of)/Co) 100%
Wherein: EN represents envelop rate; C
Free, Co represents respectively and do not wrap in the liposome total Cucurbitacine (or Cucurbitacin B) concentration in (promptly free) Cucurbitacine (or Cucurbitacin B) concentration and the liposome liquid.
Advantage of the present invention is: the present invention has higher entrapment, and greater than 80%, " Cucurbitacine " or " Cucurbitacin B " is 1: 5～1: 500 with the weight ratio of described phospholipid in the said composition by Cucurbitacin B for made liposome, its envelop rate.Described liposome can be through administrations such as vein, muscle, oral cavity, nasal cavities.
The specific embodiment:
Embodiment 1: the preparation of Cucurbitacine (Cucurbitacin B content is greater than 60%) liposome
Prescription:
Cucurbitacine 0.01g
Soybean lecithin 1g
Ethanol is an amount of
The phosphate buffer of pH6.8 is an amount of
Make 100ml
Preparation technology:
Take by weighing the soybean lecithin and the Cucurbitacine of recipe quantity, place beaker, add an amount of dissolve with ethanol after, add phosphate buffer, aquation 1～2 hour, the cucurbitacin liposome solutions.The gained liposome carries out entrapment efficiency determination, and its envelop rate is 95.3%.
Embodiment 2: the preparation of Cucurbitacine (Cucurbitacin B content is greater than 80%) liposome
Prescription:
Cucurbitacine 0.1g (10mmol)
Hydrogenated soy phosphatidyl choline 1g
Ethanol is an amount of
The phosphate buffer of pH7.4 is an amount of
Make 100ml
Preparation technology: the same, envelop rate is 86.5%.
Embodiment 3: the preparation of Cucurbitacine (Cucurbitacin B content is greater than 80%) liposome
Prescription:
Cucurbitacine 0.02g
Ovum Gallus domesticus Flavus lecithin 4g
Cholesterol 1g
Ethanol is an amount of
The citrate buffer of pH4 is an amount of
Make 100ml
Preparation technology: the same, envelop rate is 83.7%.
Embodiment 4: the preparation of Cucurbitacin B (content is greater than 90%) liposome
Prescription:
Cucurbitacin B 0.05g
Distearoyl phosphatidylcholine 2g
Dichloromethane is an amount of
The phosphate buffer of pH7.4 is an amount of
Make 100ml
Preparation technology: the distearoyl phosphatidylcholine and the Cucurbitacin B that take by weighing recipe quantity, place beaker, after adding an amount of dichloromethane dissolving, reduction vaporization is removed organic solvent and is become thin film, add phosphate buffer, aquation 1～2 hour, high pressure homogenizer was handled 10 minutes, cross the 0.22um filter membrane, get the cucurbitacin liposome solutions.The gained liposome carries out entrapment efficiency determination, and its envelop rate is 91.0%.
Embodiment 5: the preparation of Cucurbitacin B (content is greater than 90%) liposome
Prescription:
Cucurbitacin B 0.2g (10mmol)
Hydrogenated soy phosphatidyl choline 20g
Ethanol is an amount of
The phosphate buffer of pH7.4 is an amount of
Make 1000ml
Preparation technology: with " embodiment four ", the envelop rate of gained liposome is 90.8%.Add lactose by 7% concentration in this liposome, carry out spray drying after the dissolving, get pro-liposome, the envelop rate after this pro-liposome aquation is 89.6%.The gained pro-liposome can further be made tablet, capsule, granule etc.
Embodiment 6: the preparation of Cucurbitacine (Cucurbitacin B content is greater than 80%) pro-liposome
Prescription:
Cucurbitacine 0.05g
Ovum Gallus domesticus Flavus lecithin 2g
Cholesterol 0.1g
Ethanol is an amount of
The phosphate buffer of pH7.4 is an amount of
Make 100ml
Preparation technology: with " embodiment one ", the envelop rate of gained liposome is 88.8%.Add sucrose by 5% concentration in this liposome, carry out lyophilization after the dissolving, get pro-liposome, the envelop rate after this pro-liposome aquation is 91.6%.
Embodiment 7: the syrupy preparation of Cucurbitacine (Cucurbitacin B content is greater than 80%) liposome
Prescription:
Cucurbitacine 0.03g
Soybean lecithin 10g
Ethanol is an amount of
The citrate buffer of pH5 is an amount of
Simple syrup is an amount of
Make 100ml
Preparation technology:
Take by weighing the soybean lecithin and the Cucurbitacine of recipe quantity, place beaker, add an amount of dissolve with ethanol after, add citrate buffer, aquation adds simple syrup, homogenizer was handled 20 minutes, cucurbitacin liposome syrup solution.The gained liposome carries out entrapment efficiency determination, and its envelop rate is 90.1%.
Embodiment 8: the preparation of Cucurbitacine (Cucurbitacin B content is greater than 60%) liposome spraying agent
Prescription:
Cucurbitacine 0.1g
Two palmityl PHOSPHATIDYL ETHANOLAMINE 3g
Ethanol is an amount of
The phosphate buffer of pH7.4 is an amount of
Make 100ml
Preparation technology: operation is with " embodiment four ", and its envelop rate is 90.1%.
Claims (6)
1, cucurbitacin liposome prescription and preparation thereof is characterized in that: component is formed as follows by weight percentage:
Cucurbitacine or Cucurbitacin B 0.001～0.1%
Phosphatidase 10 .1～10%
Cholesterol 0～5%
2, cucurbitacin liposome prescription according to claim 1 and preparation thereof is characterized in that: said phospholipid is lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, dioleoyl phospholipid phatidylcholine, two palmityl PHOSPHATIDYL ETHANOLAMINE, distearyl phosphatidyl glycerol.
3, cucurbitacin liposome prescription according to claim 1 and preparation thereof, it is characterized in that: liposome can be made preparations such as injection, oral liquid, syrup, drop, nasal spray.
4, cucurbitacin liposome prescription according to claim 3 and preparation thereof, it is characterized in that: injection comprises injection and aseptic powder injection.
5, cucurbitacin liposome prescription according to claim 4 and preparation thereof is characterized in that: aseptic powder injection is to add suitable proppant or excipient in the injection, obtains by spray drying and lyophilization.
6, cucurbitacin liposome prescription according to claim 5 and preparation thereof, it is characterized in that: said proppant is a kind of or any two or more blended polyhydric alcohol, comprises sucrose, lactose, glucose, trehalose, maltose, mannitol, sorbitol etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021446334A CN100377712C (en) | 2002-11-28 | 2002-11-28 | Cucurbitacin lipsome preparation method and formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021446334A CN100377712C (en) | 2002-11-28 | 2002-11-28 | Cucurbitacin lipsome preparation method and formulation |
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| Publication Number | Publication Date |
|---|---|
| CN1504191A true CN1504191A (en) | 2004-06-16 |
| CN100377712C CN100377712C (en) | 2008-04-02 |
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| CNB021446334A Expired - Fee Related CN100377712C (en) | 2002-11-28 | 2002-11-28 | Cucurbitacin lipsome preparation method and formulation |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333736C (en) * | 2004-07-26 | 2007-08-29 | 杨东平 | Medication for treating ascites of liver, cirrhosis of liver and liver cancer in early stage |
| WO2007140681A1 (en) * | 2006-05-30 | 2007-12-13 | Shenyang Pharmaceutical University | The use of cucurbitacins or cucurbitacin compositions in preparation of medicaments for raising leukocytes |
| CN1706371B (en) * | 2005-05-27 | 2010-11-10 | 沈阳药科大学 | Efficient sword-like iris seed preparation and its preparation process |
| CN101062040B (en) * | 2007-05-31 | 2011-11-16 | 沈阳药科大学 | Stable type cucurbitacin liquid formula and the agent thereof |
| CN106137966A (en) * | 2015-03-26 | 2016-11-23 | 天津药物研究院有限公司 | Cucurbitacin B nanometer liposome and preparation thereof |
-
2002
- 2002-11-28 CN CNB021446334A patent/CN100377712C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333736C (en) * | 2004-07-26 | 2007-08-29 | 杨东平 | Medication for treating ascites of liver, cirrhosis of liver and liver cancer in early stage |
| CN1706371B (en) * | 2005-05-27 | 2010-11-10 | 沈阳药科大学 | Efficient sword-like iris seed preparation and its preparation process |
| WO2007140681A1 (en) * | 2006-05-30 | 2007-12-13 | Shenyang Pharmaceutical University | The use of cucurbitacins or cucurbitacin compositions in preparation of medicaments for raising leukocytes |
| CN101062040B (en) * | 2007-05-31 | 2011-11-16 | 沈阳药科大学 | Stable type cucurbitacin liquid formula and the agent thereof |
| CN106137966A (en) * | 2015-03-26 | 2016-11-23 | 天津药物研究院有限公司 | Cucurbitacin B nanometer liposome and preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100377712C (en) | 2008-04-02 |
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Granted publication date: 20080402 Termination date: 20121128 |