CN101966150A - Houttuynin derivative lipid microsphere preparation and preparation method thereof - Google Patents
Houttuynin derivative lipid microsphere preparation and preparation method thereof Download PDFInfo
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- CN101966150A CN101966150A CN 201010291077 CN201010291077A CN101966150A CN 101966150 A CN101966150 A CN 101966150A CN 201010291077 CN201010291077 CN 201010291077 CN 201010291077 A CN201010291077 A CN 201010291077A CN 101966150 A CN101966150 A CN 101966150A
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Abstract
The invention belongs to the field of medicinal preparations and particularly relates to a preparation method of a lipid microsphere preparation of houttuynin and a houttuynin derivative. The lipid microsphere preparation contains the houttuynin or the houttuynin derivative. The preparation takes phospholipid and other surfactants as emulsifiers and takes high-purity plant oil as a solvent. Lipid microspheres are prepared by high-pressure homogenizing equipment. Compared with the conventional houttuynin injection, the lipid microsphere preparation avoids the application of latent solvents such as Tween and the like and remarkably improves the stability of a preparation.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of pharmaceutical composition and preparation method thereof, be specifically related to a kind of antibacterials houttuynine sodium bisulfite fat micro sphere preparation and preparation method thereof.
Background technology
Herba Houttuyniae has another name called Herba Houttuyniae, is the Saururaceae herbaceos perennial, is one of Chinese herbal medicine commonly used. and houttuynine sodium bisulfite (decanoylacetaldehyde) is the main effective ingredient in the Herba Houttuyniae.Houttuynine sodium bisulfite is a yellow oily liquid, is chilled to 6～8 ℃ of curing, is dissolved in methanol, ethanol, ether, petroleum ether and 5%NaOH solution, and is water insoluble, with FeCl
3Reaction takes on a red color, very easily polymerization.Pharmacological research and clinical practice show, it has obvious inhibitory action to Diplococcus pneumoniae, hemophilus influenza, Candida albicans, Bacillus typhi, staphylococcus aureus, escherichia coli and sporothrix, its biological activity is higher, has functions such as heat-clearing and toxic substances removing, detumescence and apocenosis, inducing diuresis for treating stranguria syndrome.Compare with Western medicine, it is antibiotic and the antiviral performance is more lasting, and safe in utilization.
Houttuynine sodium bisulfite itself is water insoluble, and character instability, polymerization takes place easily, the generation of polymer not only may cause untoward reaction, also can reduce its therapeutic effect, and is therefore at present domestic many with the constant houttuynin analog of chemical method synthesis of biologically active, as Sodium Houttuyfonate, neo-houttuyninums etc., with raising medicine dissolution and stability, but effect is still not satisfactory.
At present, market has Sodium Houttuyfonate sheet, dosage forms such as neo-houttuyninum injection now.But tablet exists the effective ingredient stripping slow, defectives such as onset in time.And injection is easily separated out crystallization because the dissolubility of houttuynine sodium bisulfite class medicine in water is little and unstable.Clear and definite regulation in the neo-houttuyninum of Chinese drug control department approval is received the operation instructions of injection, this product " when low temperature, may separate out milky point or crystallization, in hot water, soak molten after, still can use ".It is that the neo-houttuyninum of cosolvent is received injection and helped to improve medicine dissolution with the tween 80 that Chinese patent CN1404825A has described a kind of, but tween 80 has more side effect, causes hemolytic reaction as meeting, therefore has hidden danger in safety.Chinese patent CN1449834A has described application 2-hydroxypropyl neo-houttuyninum has been carried out enclose, hydrotropy, but price height, consumption ambassador its be restricted in actual applications.
For this reason, the inventor has developed a kind of houttuynine sodium bisulfite fat micro sphere preparation through continuous scientific experiments and research, can effectively address the above problem.
Summary of the invention
The objective of the invention is to solve problems of the prior art, a kind of good stability is provided, safe houttuynine sodium bisulfite fat micro sphere preparation.
Fat micro sphere preparation of the present invention is by active component houttuynine sodium bisulfite or derivatives thereof, oil for injection, and emulsifying agent, additives and water for injection process.
Concrete, fat micro sphere preparation of the present invention, be processed into by the composition that following unit is weight percentage:
Houttuynine sodium bisulfite or derivatives thereof 0.1～4%,
Oil for injection 5～30%,
Emulsifying agent 0.5～5%,
Additives 0～5%,
All the other are water for injection.
Wherein, described oil for injection is one or more in midchain oil, safflower oil, soybean oil, Oleum Hippophae, the Oleum Camelliae;
Wherein, described emulsifying agent is Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrolecithin, synthetic phospholipid, phospholipid-polyethyleneglycol derivative, polyethylene glycol-propylene glycol block copolymer, one or more in other amphoteric macromolecule polymers;
Wherein, described additives are one or more in pH regulator agent, isoosmotic adjusting agent, antioxidant or the chelating agent; Described pH regulator agent is hydrochloric acid or sodium hydroxide, described isoosmotic adjusting agent is a glycerol, and described antioxidant is vitamin E, and described chelating agent is EDTA, press injection and form weight percent meter, content is respectively 0.01～1%, 0.1～2.5%, 0.1～1% and 0.01～1%.
Wherein, the chemical structural formula of described houttuynine sodium bisulfite or derivatives thereof is (I), (II), (III), (IV), (V) etc.
R：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (I)
R
1：CH
3，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (II)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (III)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (IV)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical constitution formula V of derivant
Preferably, the prescription of described fat micro sphere preparation of the present invention is formed in an embodiment.
Another object of the present invention is to provide the preparation method of houttuynine sodium bisulfite fat micro sphere preparation.
Preparation method of the present invention may further comprise the steps:
(1) under 70 ℃ of water-baths and nitrogen protection, with oil for injection emulsifying agent is dissolved fully, add houttuynine sodium bisulfite and derivant and antioxidant, feed nitrogen protection, heated and stirred makes its dissolving, gets oil phase;
(2) isoosmotic adjusting agent, chelating agent are dissolved in the water for injection, get water;
(3) oil phase is added aqueous phase lentamente, shear 20min under the nitrogen protection simultaneously, obtain colostrum;
(4) with the colostrum for preparing, carry out homogenizing with high pressure homogenizer, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings get final product.
Other preferred manufacturing procedure of the present invention in an embodiment.
Preparation of the present invention is an injection preparation.
In the preparation of the present invention, houttuynine sodium bisulfite and derivant thereof are wrapped in the lipoid microsphere, and this makes houttuynine sodium bisulfite and derivant thereof the dissolubility in water improve greatly, has improved drug loading, have also improved stability of formulation simultaneously.Lipoid microsphere is as the medicine carrying body in addition, and avirulence and immunogenicity reduce medicine irritation, have reduced the toxic and side effects of medicine well.
The present invention has improved the stability of injection compared with prior art, has prolonged the shelf-life of medicine, improve the dissolubility of medicine, guaranteed the safety of medicine, and, preparation technology of the present invention is simpler, has saved time and cost, is fit to large-scale production.In addition, preparation of the present invention, its prescription composition and preparation method also all are that the screening of process science gets, and have produced useful effect.
The specific embodiment
The invention will be further described by following specific embodiment, but not as limitation of the present invention.
Embodiment 1, houttuynine sodium bisulfite derivant fat micro sphere preparation (0.1%):
Preparation technology:
(1) under 70 ℃ of water-baths and nitrogen protection, with 100g injection soybean oil the 12g Ovum Gallus domesticus Flavus lecithin is dissolved fully, add 1g houttuynine sodium bisulfite (I) type derivant and 10g vitamin E, heated and stirred makes its dissolving, gets oil phase;
(2) 22.5g glycerol and 5g EDTA are dissolved in the 500ml water, get water;
(3) oil phase is added dropwise to aqueous phase lentamente, shears (shear rate is 10000r/min) 20min under the nitrogen protection simultaneously, water for injection is supplemented to 1000ml, obtains colostrum, regulates about pH value to 7.0 with sodium hydroxide or hydrochloric acid in case of necessity;
Under the pressure of (4) 800～900bar, high pressure homogenizer homogenizing colostrum 5～8 times, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings obtain final products.
Embodiment 2, houttuynine sodium bisulfite derivant fat micro sphere preparation (4%):
Preparation technology:
(1) under 70 ℃ of water-baths and nitrogen protection, with 300g injection soybean oil the 24g Ovum Gallus domesticus Flavus lecithin is dissolved fully, add 40g houttuynine sodium bisulfite (II) type derivant and 10g vitamin E, heated and stirred makes its dissolving, gets oil phase;
(2) 22.5g glycerol and 5g EDTA are dissolved in the 500ml water, get water;
(3) oil phase is added dropwise to aqueous phase lentamente, shears (shear rate is 10000r/min) 20min under the nitrogen protection simultaneously, water for injection is supplemented to 1000ml, obtains colostrum, regulates about pH value to 7.0 with sodium hydroxide or hydrochloric acid in case of necessity;
Under the pressure of (4) 800～900bar, high pressure homogenizer homogenizing colostrum 5～8 times, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings obtain final products.
Embodiment 3, middle long-chain houttuynine sodium bisulfite derivant fat micro sphere preparation (1%):
Preparation technology:
(1) under 70 ℃ of water-baths and nitrogen protection, with 100g injection soybean oil and 100g injection midchain oil mixing,, add 40g houttuynine sodium bisulfite (III) type derivant and 10g vitamin E more earlier with its dissolving 24g Ovum Gallus domesticus Flavus lecithin, heated and stirred makes its dissolving, gets oil phase;
(2) 22.5g glycerol and 5g EDTA are dissolved in the 500ml water, get water;
(3) oil phase is added dropwise to aqueous phase lentamente, shears (shear rate is 10000r/min) 20min under the nitrogen protection simultaneously, water for injection is supplemented to 1000ml, obtains colostrum, regulates about pH value to 7.0 with sodium hydroxide or hydrochloric acid in case of necessity;
Under the pressure of (4) 800～900bar, high pressure homogenizer homogenizing colostrum 5～8 times, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings obtain final products.
Embodiment 4, houttuynine sodium bisulfite derivant fat micro sphere preparation (4%):
Preparation technology:
(1) under 70 ℃ of water-baths and nitrogen protection, with 300g injection Oleum Camelliae the 24g soybean lecithin is dissolved fully, add 40g houttuynine sodium bisulfite (IV) type derivant and 10g vitamin E, heated and stirred makes its dissolving, gets oil phase;
(2) 25g glycerol and 5g EDTA are dissolved in the 500ml water, get water;
(3) oil phase is added dropwise to aqueous phase lentamente, shears (shear rate is 10000r/min) 20min under the nitrogen protection simultaneously, water for injection is supplemented to 1000ml, obtains colostrum, regulates about pH value to 7.0 with sodium hydroxide or hydrochloric acid in case of necessity;
Under the pressure of (4) 800～900bar, high pressure homogenizer homogenizing colostrum 5～8 times, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings obtain final products.
Embodiment 5, houttuynine sodium bisulfite derivant fat micro sphere preparation (2%)
Preparation technology:
(1) under 70 ℃ of water-baths and nitrogen protection, with 200g injection Oleum Hippophae the 20g hydrolecithin is dissolved fully, add 20g houttuynine sodium bisulfite (V) type derivant and 10g vitamin E, heated and stirred makes its dissolving, gets oil phase;
(2) 25g glycerol and 5g EDTA are dissolved in the 500ml water, get water;
(3) oil phase is added dropwise to aqueous phase lentamente, shears (shear rate is 10000r/min) 20min under the nitrogen protection simultaneously, water for injection is supplemented to 1000ml, obtains colostrum, withers about joint pH value to 7.0 with sodium hydroxide or hydrochloric acid in case of necessity;
Under the pressure of (4) 800～900bar, high pressure homogenizer homogenizing colostrum 5～8 times, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings obtain final products.
Embodiment 6, formulation screening test
1, the selection of oil for injection
This experiment has adopted soybean oil, midchain oil, safflower oil, Oleum Hippophae and Oleum Camelliae to prepare the fat micro sphere preparation of houttuynine sodium bisulfite and derivant thereof respectively respectively, newborn outward appearance is evenly good eventually, layering and floating oil phenomenon all do not appear, get the lipid microsphere injection 1ml that makes respectively, dilute 1000 times, with the dynamic laser light scattering experimental instrument detection particle diameter of U.S. marvlen company.The result shows that it is even that above oil for injection makes microspherulite diameter, and 70% particle diameter is less than 500nm, and 100% particle diameter meets the related request of used for intravenous injection fat micro sphere preparation less than 1 μ m.Wherein, with soybean oil and midchain oil optimum, 90% particle diameter is less than 500nm, and 100% particle diameter is less than 1 μ m.
2, the selection of emulsifying agent
This experiment adopts Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrolecithin as the fat micro sphere preparation for preparing houttuynine sodium bisulfite and derivant thereof respectively, newborn outward appearance is evenly good eventually, layering and floating oil phenomenon all do not appear, get the lipid microsphere injection 1ml that makes respectively, dilute 1000 times, with the dynamic laser light scattering experimental instrument detection particle diameter of U.S. marvlen company.The result shows that it is even that above oil for injection makes microspherulite diameter, and 70% particle diameter is less than 500nm, and 100% particle diameter meets the related request of used for intravenous injection fat micro sphere preparation less than 1 μ m.Wherein, with the Ovum Gallus domesticus Flavus lecithin optimum, 85% particle diameter is less than 500nm, and 100% particle diameter is less than 1 μ m.
3, the selection of isoosmotic adjusting agent
This experiment selects for use glycerol as isoosmotic adjusting agent, oozes to guarantee that fat micro sphere preparation waits in human body, and it is 300～400mOsm/L that permeability manometer (cryoscopic method) is measured each whole newborn osmotic pressure, meets the related request of used for intravenous injection fat micro sphere preparation.
4, the selection of chelating agent
Ionic complexing agent EDTA is selected in this experiment for use, to reduce the concentration of free cations in the microsphere, helps to improve the stability of fat micro sphere preparation.Newborn outward appearance is evenly good eventually for gained, layering and floating oil phenomenon all do not occur, gets the fat micro sphere preparation 1ml that makes respectively, dilutes 1000 times, with the dynamic laser light scattering experimental instrument detection particle diameter of U.S. marvlen company.The result shows that it is even that above oil for injection makes microspherulite diameter, and 70% particle diameter is less than 500nm, and 100% particle diameter meets the related request of used for intravenous injection fat micro sphere preparation less than 1 μ m.
5, antioxidant
The antioxidant vitamin E is selected in this experiment for use, in case oxidation and cause the character instability.Newborn outward appearance is evenly good eventually for gained, layering and floating oil phenomenon all do not occur, gets the lipid microsphere injection 1ml that makes respectively, dilutes 1000 times, with the dynamic laser light scattering experimental instrument detection particle diameter of U.S. marvlen company.The result shows that it is even that above oil for injection makes microspherulite diameter, and 70% particle diameter is less than 500nm, and 100% particle diameter meets the related request of used for intravenous injection fat micro sphere preparation less than 1 μ m.
After above-mentioned screening layer by layer, just determined prescription composition of the present invention.
Claims (9)
1. houttuynine sodium bisulfite derivant fat micro sphere preparation, be processed into by the composition that following unit is weight percentage:
Houttuynine sodium bisulfite or derivatives thereof 0.1～4%,
Oil for injection 5～30%,
Emulsifying agent 0.5～5%,
Additives 0～5%,
All the other are water for injection
Wherein, described oil for injection is one or more in midchain oil, safflower oil, soybean oil, Oleum Hippophae, the Oleum Camelliae;
Wherein, described emulsifying agent is Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrolecithin, synthetic phospholipid, phospholipid-polyethyleneglycol derivative, polyethylene glycol-propylene glycol block copolymer, one or more in other amphoteric macromolecule polymers;
Wherein, described additives are one or more in pH regulator agent, isoosmotic adjusting agent, antioxidant or the chelating agent.
2. preparation according to claim 1, it is characterized in that, described pH regulator agent is hydrochloric acid or sodium hydroxide, described isoosmotic adjusting agent is a glycerol, described antioxidant is vitamin E, described chelating agent is EDTA, presses injection and forms weight percent meter, and content is respectively 0.01～1%, 0.1～2.5%, 0.1～1% and 0.01～1%.
3. preparation according to claim 1 is characterized in that, the chemical structural formula of described houttuynine sodium bisulfite or derivatives thereof is (I), (II), (III), (IV), (V)
R：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (I)
R
1：CH
3，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (II)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (III)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical structural formula of derivant (IV)
R
2：H，Na，K，Ca
+，Mg
+etc
CH
3，CH
3CH
2，CH
3(CH
2)m，CH
3CH(CH
3)(CH
2)m，
n：1_20；m：1_10
The chemical constitution formula V of derivant.
4. preparation according to claim 1 is characterized in that, is processed into by the composition that following unit is weight percentage:
5. preparation according to claim 1 is characterized in that, is processed into by the composition that following unit is weight percentage:
6. preparation according to claim 1 is characterized in that, is processed into by the composition that following unit is weight percentage:
7. preparation according to claim 1 is characterized in that, is processed into by the composition that following unit is weight percentage:
8. preparation according to claim 1 is characterized in that, is processed into by the composition that following unit is weight percentage:
9. the preparation method of the described preparation of claim 1 may further comprise the steps:
(1) under 70 ℃ of water-baths and nitrogen protection, with oil for injection emulsifying agent is dissolved fully, add houttuynine sodium bisulfite and derivant and antioxidant, feed nitrogen protection, heated and stirred makes its dissolving, gets oil phase;
(2) isoosmotic adjusting agent, chelating agent are dissolved in the water for injection, get water;
(3) oil phase is added aqueous phase lentamente, shear 20min under the nitrogen protection simultaneously, obtain colostrum;
(4) with the colostrum for preparing, carry out homogenizing with high pressure homogenizer, filtering with microporous membrane fills nitrogen, embedding, 115 ℃ of autoclavings get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010291077 CN101966150A (en) | 2010-09-25 | 2010-09-25 | Houttuynin derivative lipid microsphere preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010291077 CN101966150A (en) | 2010-09-25 | 2010-09-25 | Houttuynin derivative lipid microsphere preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101966150A true CN101966150A (en) | 2011-02-09 |
Family
ID=43545419
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010291077 Pending CN101966150A (en) | 2010-09-25 | 2010-09-25 | Houttuynin derivative lipid microsphere preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101966150A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336868A (en) * | 2020-10-28 | 2021-02-09 | 西安力邦医美科技有限公司 | Polyethylenimine matrine lipid microsphere antifungal preparation and application thereof |
| CN114652682A (en) * | 2022-03-07 | 2022-06-24 | 河南省医药科学研究院 | New houttuynin sodium and cisplatin co-loading acidic sensitive liposome preparation and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686411A (en) * | 2005-04-20 | 2005-10-26 | 张文芳 | Houttuynia emulsion for injection and its preparation method |
| CN1853620A (en) * | 2005-04-29 | 2006-11-01 | 诺氏制药（吉林）有限公司 | Fat emulsion of houttuynin analog |
-
2010
- 2010-09-25 CN CN 201010291077 patent/CN101966150A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686411A (en) * | 2005-04-20 | 2005-10-26 | 张文芳 | Houttuynia emulsion for injection and its preparation method |
| CN1853620A (en) * | 2005-04-29 | 2006-11-01 | 诺氏制药（吉林）有限公司 | Fat emulsion of houttuynin analog |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336868A (en) * | 2020-10-28 | 2021-02-09 | 西安力邦医美科技有限公司 | Polyethylenimine matrine lipid microsphere antifungal preparation and application thereof |
| CN114652682A (en) * | 2022-03-07 | 2022-06-24 | 河南省医药科学研究院 | New houttuynin sodium and cisplatin co-loading acidic sensitive liposome preparation and preparation method thereof |
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Application publication date: 20110209 |