CN1682753A - Paeonal injection emulsion for anti-tumor and its preparing method - Google Patents
Paeonal injection emulsion for anti-tumor and its preparing method Download PDFInfo
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- CN1682753A CN1682753A CN 200510042537 CN200510042537A CN1682753A CN 1682753 A CN1682753 A CN 1682753A CN 200510042537 CN200510042537 CN 200510042537 CN 200510042537 A CN200510042537 A CN 200510042537A CN 1682753 A CN1682753 A CN 1682753A
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Abstract
The present invention relates to paeonal injection emulsion for treating tumor and is preparation process. The emulsion consists of liposoluble paeonal and water soluble glossy ganoderma polysaccharide as effective components. The paeonal injection emulsion has high and fast curative effect on tumor, high medicine content, and less toxic side effect.
Description
(1) technical field
The present invention relates to a kind of Paeonal injection emulsion for the treatment of tumor and preparation method thereof.
(2) background technology
Paeonol is one of main active of Cortex Moutan, has pharmacologically active widely, comprises analgesic, analgesia, anti-inflammation, atherosclerosis, anticoagulant and strengthen cellular immune function and antioxidation etc.Cause insider's concern in recent years gradually about the inside and outside antitumor action of paeonol.
Paeonol is a fat-soluble medicine, and tool is different to be smelt, and it is little peppery to distinguish the flavor of, and is dissolved in ethanol, methanol, insoluble in cold water, slightly soluble in the hot water, easily distillation, dosage forms such as existing ointment, coated tablet.The oral tablet dissolution rate is slow, and bioavailability is low; And injection poor stability and dosage big (approximately 17mg/Kg), the anticancer therapy drug administration by injection can be taked dosage forms such as enclose, solubilising and liposome entrapment, and these dosage form preparations are complicated, unstable, and medicament contg is low, is difficult to meet the demands.
Ganoderan also is used for the antineoplastic treatment, but it is a water soluble drug, can not carry out organic the combination with paeonol.
(3) summary of the invention
The present invention provides a kind of and has treated the Emulsion that tumor effect is good, rapid-action, medicament contg is high, be suitable for injecting in order to overcome the deficiency of above technology, and manufacturing method for above mentioned medicine.
The present invention realizes by following measure:
Paeonal injection emulsion for anti-tumor of the present invention, the injectable emulsion of making as effective ingredient by fat-soluble paeonol and water solublity ganoderan.
Paeonal injection emulsion of the present invention is to be made by the raw material of following components by weight percent:
Paeonol 10～70mg,
Ganoderan 20～100mg,
Oil phase 30～150mg.
Water 2～5ml,
Emulsifying agent is an amount of,
Co-emulsifier is an amount of.
Paeonal injection emulsion of the present invention, described oil phase are at least a of Ethyl linoleate, vegetable oil, oleic acid and ester thereof, nutmeg acid and ester thereof; Described emulsifying agent is at least a of polyoxyethylene castor oil, Poloxmer 188, phospholipid, poloxamer, polysorbas20,40,60,80, Polyethylene Glycol; Described co-emulsifier is at least a of 1,2 propylene glycol, glycerol, low-molecular-weight PEG; Described water contains at least a of phosphate buffer, glucose buffer.
The preparation method of Paeonal injection emulsion of the present invention may further comprise the steps:
(1) paeonol grinds to put in the appropriate vessel and becomes clear solution with the abundant mixed dissolution of oil phase; Emulsifying agent and co-emulsifier are transferred in the above-mentioned solution after with an amount of oil phase dissolving, and fully mix homogeneously makes the pastille oil phase;
(2) ganoderan is put in the appropriate vessel dissolving mixed with water and is made the pastille water;
(3) in the pastille oil phase, slowly add the pastille water under the stirring at low speed, then, carry out supersound process and make homogeneous latex emulsion; Emulsion is the canned injectable emulsion that makes after the degerming of microporous filter membrane granulate again.
Paeonol chemistry 2-hydroxyl by name-4-methoxyl group-1-Phenylethanone. among the present invention, molecular formula C
9H
10O
3, molecular weight 166.18.
The present invention adopts injectable emulsion, select emulsifying agent (as phospholipid, poloxamer, Tweens, sorbitol esters etc.), co-emulsifier (as propylene glycol, glycerol, low-molecular-weight PEG) and the oil phase (as oleic acid, linoleic acid and ester, lauryl alcohol etc.) of suitable species and ratio to make injectable emulsion, solved promptly that paeonol poor solubility, medicament contg are low, physical instability, abnormal flavour and irritating problem have been arranged, simultaneously, solved the immiscible difficult problem of paeonol and ganoderan again.
Prepare Emulsion of the present invention, it is characterized in that the comprehensive of injection and microemulsion technology, the oil phase of selection, emulsifying agent and co-emulsifier all are injection human body acceptable auxiliary.This Emulsion medicament contg height (content can reach 15mg/ml), good stability (under the room temperature injectable emulsion can preserve more than three months and phenomenons such as layering, flocculation do not take place), breast grain size is uniformly dispersed below 200nm, fast through the injection administration drug absorption, the bioavailability height.By setting up this disperse system, the dissolubility of paeonol improves under no alcoholic acid condition greatly, has overcome its dispersive difficulty in water, thereby can obtain higher drug effect under the condition of low dosage injection, reduce the zest of medication, improved patient's compliance.Prepare easyly, be easy to enlarge to produce.
The present invention utilizes emulsifying agent with paeonol and ganoderan, and the Paeonal injection emulsion of making is used for the treatment of tumor, finds to have beyond thought therapeutic effect, have rapid-action, the medicament contg height, tumor killing effect is good, toxic and side effects is little.Its preparation method have working condition and equipment simple, with low cost, be easy to realize industrialization.
(4) specific embodiment:
1. embodiment 1
Medicine 1 paeonol 70mg;
Medicine 2 ganoderan 30mg;
Water normal saline 5ml
Oil phase Ethyl linoleate 150mg
Emulsifying agent 1 polyoxyethylene castor oil is an amount of
2 Poloxmer 188 are an amount of for emulsifying agent
Co-emulsifier 1,2 propylene glycol is an amount of.
2. embodiment 2
Medicine 1 paeonol 30mg;
Medicine 2 ganoderan 60mg;
Water 5% glucose infusion liquid 3ml
Oil phase refined plant oil 50mg
Emulsifying agent 1 polyoxyethylene castor oil is an amount of
Emulsifying agent 2 Tween 80s are an amount of
Co-emulsifier 1,2 propylene glycol is an amount of.
3. embodiment 3
Medicine 1 paeonol 10mg;
Medicine 2 ganoderan 80mg;
Phosphatizing acid buffer 5ml such as water pH=7.4
Oil phase oil for injection 100mg
Emulsifying agent 1 lecithin is an amount of
2 Poloxmer 188 are an amount of for emulsifying agent
Co-emulsifier PEG400 is an amount of.
The preparation method of said medicine Emulsion is: paeonol is ground to put in the appropriate vessel become clear solution with the abundant mixed dissolution of oil phase; Emulsifying agent 1, emulsifying agent 2 and co-emulsifier are transferred in the above-mentioned solution after with the dissolving of an amount of oil phase, and fully mix homogeneously makes the pastille oil phase; Ganoderan is put in the appropriate vessel dissolving mixed with water make the pastille water; Under stirring at low speed, in the pastille oil phase, slowly add the pastille water, then, carry out supersound process and make homogeneous latex emulsion; Emulsion is the canned injectable emulsion that makes after the degerming of microporous filter membrane granulate again.
The usage of said medicine Emulsion and consumption: intravenous injection, once-a-day, each 3-5ml.
Get the injection medicament of embodiment 1, carry out following pharmacological toxicology experiment:
1. studies on acute toxicity: paeonol is given the LD of mice oral medication
50Be 3430mg/kg.It is paeonol 15mg/ml that the present invention is subjected to Cmax that dosage form is limit, intraperitoneal administration 1ml/20g of mice, i.e. paeonol 750mg/kgd, the general state of observing each experiment mice is good, outward appearance, hair color, stool, activity etc. are all normal, do not see obvious toxic-side effects.The maximum dosage-feeding that shows paeonol mouse peritoneal injection of the present invention is more than 750mg/kgd.Safety and low toxicity.
2. pharmacodynamic study
2.1 microemulsion of the present invention is to mice S
180Tumor-inhibiting action in the body of sarcoma
Under aseptic condition, extract the S of growth 7d
180The ascitogenous sarcoma mouse ascites, regulating cell concentration with normal saline is 1 * 10
6/ L, it is subcutaneous to be inoculated in the right axil of healthy Kunming mouse, and every 0.2ml is divided into model control group at random, positive drug KANGLAITE 2.5g/kg group and Emulsion 20mg/kg of the present invention, 45mg/kg, 94mg/kg three dosage groups.Every group of 12 mices, the administration of inoculation 24h pneumoretroperitoneum, every day 1 time, logotype 10d.Next day is put to death mice in drug withdrawal, and it is heavy with tumor to weigh.Calculate tumour inhibiting rate by following formula.Tumour inhibiting rate (%)={ the average tumor kind of the average tumor weight/matched group of 1-experimental group } * 100%.The test triplicate the results are shown in Table 1:
Table 1: to S
180The tumor-inhibiting action of sarcoma (three repetitions, n=36)
Heavy (g) tumour inhibiting rate of the average tumor of body weight (g) behind body weight (g) medicine before the group dosage medicine
(％)
Model contrast NS 21.4 ± 1.4 28.9 ± 2.14 1.42 ± 0.89
KANGLAITE 2.5g/kg 21.6 ± 0.69 25.6 ± 1.51 1.10 ± 0.77 22.4
The present invention's breast 94mg/kg 21.6 ± 2.27 22.4 ± 2.37 0.62 ± 0.43 56.3
Agent
The present invention's breast 45mg/kg 21.3 ± 1.49 25.4 ± 2.24 0.92 ± 0.57 35.1
Agent
The present invention's breast 20mg/kg 21.4 ± 1.58 27.1 ± 2.9 1.18 ± 0.64 16.7
Agent
Table 1 is found out Emulsion 20～100mg/kgd of the present invention, and the 10d lumbar injection is to the S of the right axil subcutaneous vaccination of mice continuously
180The growth of sarcoma promptly has obvious inhibitory action, between its tumour inhibiting rate 16～56%, along with the increase antitumor action enhancing of dosage.Show that Emulsion lumbar injection of the present invention has tangible tumor-inhibiting action, this effect has tangible dose-effect relationship.
2.2 microemulsion of the present invention is to tumor-inhibiting action in the body of mice ehrlich carcinoma (EAC solid type)
Extract the ehrlich carcinoma mouse ascites of growth 7d under aseptic condition, regulating cell concentration with normal saline is 1 * 10
6/ L, it is subcutaneous to be inoculated in the right axil of mice, and every 0.2ml is divided into model control group at random, positive drug KANGLAITE 2.5g/kg group and Emulsion 20mg/kg of the present invention, 45mg/kg, 94mg/kg three dosage groups.Every group of 12 mices, gastric infusion behind the inoculation 24h, every day 1 time, logotype 10d.Next day is put to death mice in drug withdrawal, and it is heavy with tumor to weigh.Calculate tumour inhibiting rate by following formula.
Tumour inhibiting rate (%)={ the average tumor kind of the average tumor weight/matched group of 1-experimental group } * 100%
Table 2: the tumor-inhibiting action of EAC solid type (is repeated for three times, n=36)
The heavy tumour inhibiting rate of weight average tumor behind the body weight medicine before the group dosage medicine
Model contrast NS 21.3 ± 0.97 26.3 ± 2.69 0.99 ± 0.25
KANGLAITE 2.5g/kg 22.1 ± 0.98 24.1 ± 1.93 0.75 ± 0.35 24.8
Emulsion 94mg/kg 21.4 of the present invention ± 0.97 25.7 ± 2.46 0.80 ± 0.29 46.0
Emulsion 45mg/kg 22.2 of the present invention ± 1.37 26.1 ± 1.12 0.73 ± 0.27 26.6
Emulsion 20mg/kg 21.9 of the present invention ± 0.84 22.7 ± 1.6 0.54 ± 0.20 19.1
Table 2 is found out Emulsion 20～94mg/kgd of the present invention, and the 10d lumbar injection promptly has obvious inhibitory action to the growth of the EAC solid type of the right axil subcutaneous vaccination of mice continuously, between its tumour inhibiting rate 19～46%, along with the increase antitumor action enhancing of dosage.Show that Emulsion lumbar injection of the present invention has tangible tumor-inhibiting action to the EAC solid type, and this effect there is tangible dose-effect relationship.
2.3 microemulsion of the present invention is to mice H
22Tumor-inhibiting action in the body of hepatocarcinoma
Under aseptic condition, extract the ascitic type H of growth 7d
22Liver cancer mouse ascites, with normal saline dilution in 1: 3, regulating cell concentration is 1 * 10
9/ L, it is subcutaneous to be inoculated in the right axil of mice, and every 0.2ml is divided into model control group at random, positive drug KANGLAITE 2.5g/kg group and Emulsion 20mg/kg of the present invention, 45mg/kg, 94mg/kg three dosage groups.Every group of 12 mices, gastric infusion behind the inoculation 24h, every day 1 time, logotype 10d.Next day is put to death mice in drug withdrawal, and it is heavy with tumor to weigh.It is the same to calculate the tumour inhibiting rate method.
Table 3: to H
22The tumor-inhibiting action of hepatocarcinoma (three repetitions, n=36)
The heavy tumour inhibiting rate of weight average tumor behind the body weight medicine before the group dosage medicine
Model contrast NS 21.3 ± 0.92 26.3 ± 2.65 1.31 ± 0.35
KANGLAITE 2.5g/kg 22.2 ± 0.97 24.1 ± 1.9 0.87 ± 0.38 33.15
Emulsion 94mg/kg 21.9 of the present invention ± 0.83 22.9 ± 1.77 0.60 ± 0.19 54.14
Emulsion 45mg/kg 22.2 of the present invention ± 1.40 26.1 ± 1.1 0.85 ± 0.33 34.14
Emulsion 20mg/kg 21.5 of the present invention ± 0.97 25.2 ± 2.45 0.97 ± 0.38 25.64
Table 3 is found out Emulsion 20～94mg/kgd of the present invention, and the 10d lumbar injection has the H of leaf subcutaneous vaccination to mice continuously
22The growth of hepatocarcinoma promptly has obvious inhibitory action, between its tumour inhibiting rate 25～54%, along with the increase antitumor action enhancing of dosage.Show that Emulsion lumbar injection of the present invention is to H
22Hepatocarcinoma has tangible tumor-inhibiting action, and this effect has tangible dose-effect relationship.
Claims (4)
1. Paeonal injection emulsion for anti-tumor is characterized in that: the injectable emulsion of being made as effective ingredient by fat-soluble paeonol and water solublity ganoderan.
2. according to the Paeonal injection emulsion of claim 1, it is characterized in that: be to make by the raw material of following components by weight percent:
Paeonol 10～70mg,
Ganoderan 20～100mg,
Oil phase 30～150mg,
Water 2～5ml,
Emulsifying agent is an amount of,
Co-emulsifier is an amount of.
3. Paeonal injection emulsion according to claim 2 is characterized in that: described oil phase is at least a of Ethyl linoleate, vegetable oil, oleic acid and ester thereof, nutmeg acid and ester thereof; Described emulsifying agent is at least a of polyoxyethylene castor oil, Poloxmer 188, phospholipid, poloxamer, polysorbas20,40,60,80, Polyethylene Glycol; Described co-emulsifier is at least a of 1,2 propylene glycol, glycerol, low-molecular-weight PEG; Described water contains at least a of phosphate buffer, glucose buffer.
4. the preparation method of Paeonal injection emulsion according to claim 1 is characterized in that: may further comprise the steps:
(1) paeonol grinds to put in the appropriate vessel and becomes clear solution with the abundant mixed dissolution of oil phase; Emulsifying agent and co-emulsifier are transferred in the above-mentioned solution after with an amount of oil phase dissolving, and fully mix homogeneously makes the pastille oil phase;
(2) ganoderan is put in the appropriate vessel dissolving mixed with water and is made the pastille water;
(3) in the pastille oil phase, slowly add the pastille water under the stirring at low speed, then, carry out supersound process and make homogeneous latex emulsion; Emulsion is the canned injectable emulsion that makes after the degerming of microporous filter membrane granulate again.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510042537 CN1279922C (en) | 2005-03-04 | 2005-03-04 | Paeonal injection emulsion for anti-tumor and its preparing method |
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|---|---|---|---|
| CN 200510042537 CN1279922C (en) | 2005-03-04 | 2005-03-04 | Paeonal injection emulsion for anti-tumor and its preparing method |
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| Publication Number | Publication Date |
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| CN1682753A true CN1682753A (en) | 2005-10-19 |
| CN1279922C CN1279922C (en) | 2006-10-18 |
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|---|---|---|---|
| CN 200510042537 Expired - Fee Related CN1279922C (en) | 2005-03-04 | 2005-03-04 | Paeonal injection emulsion for anti-tumor and its preparing method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058530A (en) * | 2010-12-14 | 2011-05-18 | 于荣敏 | Ganoderma lucidum polysaccharide oral nanoemulsion and preparation method thereof |
| CN116509841A (en) * | 2023-04-28 | 2023-08-01 | 湖南中医药大学 | Antitumor composition, liposome, preparation method and application |
-
2005
- 2005-03-04 CN CN 200510042537 patent/CN1279922C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058530A (en) * | 2010-12-14 | 2011-05-18 | 于荣敏 | Ganoderma lucidum polysaccharide oral nanoemulsion and preparation method thereof |
| CN116509841A (en) * | 2023-04-28 | 2023-08-01 | 湖南中医药大学 | Antitumor composition, liposome, preparation method and application |
| CN116509841B (en) * | 2023-04-28 | 2024-08-13 | 湖南中医药大学 | Antitumor composition, liposome, preparation method and application |
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| Publication number | Publication date |
|---|---|
| CN1279922C (en) | 2006-10-18 |
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Granted publication date: 20061018 Termination date: 20110304 |