CN105997873A - Oil-in-water type terazosin nanoemulsion antihypertensive drug - Google Patents
Oil-in-water type terazosin nanoemulsion antihypertensive drug Download PDFInfo
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- CN105997873A CN105997873A CN201610545503.6A CN201610545503A CN105997873A CN 105997873 A CN105997873 A CN 105997873A CN 201610545503 A CN201610545503 A CN 201610545503A CN 105997873 A CN105997873 A CN 105997873A
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- Prior art keywords
- terazosin
- nanoemulsion
- drug
- antihypertensive drug
- oil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
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Abstract
The invention discloses an oil-in-water type terazosin nanoemulsion antihypertensive drug. The grain size of the nanoemulsion antihypertensive drug ranges from 45.3 nm to 92.4 nm, the nanoemulsion antihypertensive drug is prepared from, by mass, 1%-15% of terazosin, 15%-40% of surface active agent, 0-20% of cosurfactant and the balance distilled water, and the sum of the mass percent of the raw materials is 100%. The nanoemulsion is small in emulsion droplet grain, even in distribution, low in viscosity and good in fluidity. After the water-soluble drug terazosin is prepared into the nanoemulsion dosage form, the stability and drug effect of terazosin are improved, the antihypertensive effect is obviously improved, the half-life period of the drug is prolonged, and the dosing frequency is decreased.
Description
Technical field
The invention belongs to field of medicaments, relate to the novel form of a kind of antihypertensive drug terazosin, particularly to one
Oil-in-water type terazosin nanoemulsion antihypertensive drug.
Technical background
Terazosin (Terazosin) molecular formula: C19H25N5O4.Molecular weight: 387.44.No. CAS: 63590-64-7.This
Product are Selective α1 receptor blocker, can reduce peripheral vascular resistance, and contraction pressure and diastolic pressure are had reduction effect.Hypertension
In animal, terazosin by reduce Total peripheral vascular resistance so that blood pressure reduce.The vasodilation of terazosin, blood pressure
Reduction effect seems mainly caused by α 1～adrenoreceptor block.Upon administration in 15 minutes, terazosin
Blood pressure is made to be gradually lowered.Suffer from slight (about 77%, diastolic pressure 95～105mmHg) or moderate (about 23%, diastolic pressure 105
～115mmHg) patient of hypertension, according to 5～the accumulated dose of 20mg/ days, give terazosin once-or twice-a-day and carry out
Clinical trial.The same with all antagonisies, because terazosin first or can make blood pressure dramatic decrease after front administration several times, because of
This initial dose is 1mg, is then adjusted to a certain fixed dosage or is adjusted to a certain specific blood pressure terminal (relaxing of usual dorsal position
Open pressure for 90mmHg).Between being administered, the end of term (usual 24 hours) measures blood pressure, and result shows, hypotensive effect continues whole phase,
Generally, the contraction pressure drop of dorsal position is low than blank big 5～10mmHg, the reduction big 3.5～8mmHg of diastolic pressure.After administration, 24 is little
Time measure, heart rate does not changes.The amount causing blood pressure response is similar with prazosin, but less than hydrochlorothiazide.Terazosin is low dose of
Group reduces the T-CHOL of patient, low-density and very low density lipoprotein (VLDL) the most significantly.
Existing such as the antihypertensive drugs of terazosin tablet currently on the market, although from gastrointestinal absorption, but to inhale after Kou Fu
Receiving not exclusively, additionally the dissolution rate of medicine is slow, and poor bioavailability adds terazosin effect slow so that spy draws azoles
The drug effect of piperazine cannot be fully used.
Summary of the invention
For shortcomings and deficiencies present in prior art, it is an object of the invention to provide a kind of can be by efficient blood pressure lowering
Water soluble drug terazosin is prepared as nano-emulsion dosage form, and drug distribution is uniform, good stability, permeability are high, dissolubility
The terazosin nanoemulsion antihypertensive drug good, bioavailability is high.
The technical scheme realizing foregoing invention purpose is: a kind of oil-in-water type terazosin nanoemulsion antihypertensive drug,
It is characterized in that the particle diameter of this medicine between 45.3～92.4nm, mean diameter is 67.1nm, its raw material and each raw materials quality
Percentage ratio is:
Terazosin 1%～15%
Surfactant 15%～40%
Cosurfactant 0～20%
Remaining composition is distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
Described surfactant is polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or pool
In Luo Shamu 188 any one or with the mixture of span80, these surfactants are to human body low toxicity, safe, non-stimulated.
Described cosurfactant is any one in dehydrated alcohol, 1,2-PD, PEG400 or glycerol
Kind or several mixture.
The present invention adds bland cosurfactant such as ethanol, 1,2-PD, glycerol or poly-in medicine
Ethylene glycol 400, in addition to hydrotropy effect, cosurfactant is primarily to adjust the hydrophile-lipophile balance value of surfactant
(HLB) profit and the rigidity of limitans so that oil water interfacial tension reduces further, are increased.Cosurfactant is incorporated into boundary
In facial film, promote the formation of radius of curvature very membranelle, expand the newborn district area of nano-emulsion.
A kind of terazosin nano-emulsion of the present invention is administered orally, and reduces medicine first pass effect in vivo, and creates
New property water soluble drug is prepared as nano-emulsion dosage form, improve the treatment ability of medicine.Improve the blood pressure lowering of terazosin
Ability, makes that blood pressure lowering is more stable, effect is more preferable.
The terazosin nano-emulsion of the present invention compared with prior art, has the advantage that
1. the diameter of aspirin particle of the terazosin resisting hypertension nano-emulsion of the present invention is between 45.3～92.4nm, mean diameter
For 67.1nm, it is to add surfactant and cosurfactant, is titrated to the distilled water being dissolved with terazosin uniform, saturating
Bright nano-emulsion system.The nano-emulsion formed reaches more than 5.1% containing terazosin.
2. the terazosin resisting hypertension nano-emulsion of the present invention is evenly distributed, and system is transparent, good stability, has relatively low table
Surface tension, has good mobility, taking convenience.
3. the terazosin resisting hypertension nano-emulsion of the present invention is swallowed by reticuloendothelial cell rapidly after being administered, and makes medicine fast
Speed onset, and maintain constant blood drug level and pharmacodynamics effect, improve the bioavailability of medicine, strengthen drug effect, reduce medicine
Consumption and access times.
4. the terazosin resisting hypertension nano-emulsion efficacy stability of the present invention, consumes energy low.
5. can be made into oral liquid after the present invention makes nano-emulsion directly to take, also can encapsulate or lyophilised powder technology through capsule
Deng process.
Detailed description of the invention
Inventor provides concrete preparation method embodiment and uses the test of pesticide effectiveness to further illustrate the effect of medicine of the present invention
Really.
Test example 1 terazosin of the present invention nanoemulsion antihypertensive drug size is analyzed
The present invention detects through transmission electron microscope, and drop is that class is spherical, and good dispersion, without adhesion.Through Malvern granularity
Analyser detects its diameter Distribution between 45.3～92.4nm, and mean diameter is 67.1nm.
Test example 2 terazosin of the present invention nanoemulsion antihypertensive drug stability analysis
Terazosin nanometer of the present invention is observed by following centrifugal test, photo-stability testing, temperature stability test etc.
The stability of breast antihypertensive drug, observes whether the present invention has the wild effects such as layering, muddiness or crystal precipitation.
1. high speed centrifugation test
Take the terazosin nanoemulsion antihypertensive drug of the present invention prepared in right amount in centrifuge tube, with 15000r/min
Rotating speed be centrifuged 10min, after centrifugal test, terazosin nanoemulsion antihypertensive drug of the present invention still keep centrifugal before clear
Clear bright, have no the wild effects such as layering, muddiness or crystal precipitation.
2. photo-stability testing
The terazosin nanoemulsion antihypertensive drug prepared in right amount is loaded transparent good vial colourless, transparent
In, seal, be positioned over 10d under normal lighting conditions, observe respectively at 1d, 2d, 4d, 6d, 8d, 10d sampling.Result shows Te La
Azoles every part of sample of piperazine nanoemulsion antihypertensive drug all keeps clear, has no the instability such as layering, muddiness or crystal precipitation
Phenomenon.
3. temperature stability test
The terazosin nanoemulsion antihypertensive drug prepared in right amount is loaded in the flint glass bottle that transparency is good, close
Envelope, is positioned in 4 DEG C, room temperature (25 DEG C) and 40 DEG C three each 30d of investigation that keeps sample under temperature conditions, observes every 5d sampling.Result
Showing, terazosin nanoemulsion antihypertensive drug all keeps clear under these three kinds of temperature conditionss, has no layering, muddiness
Or the wild effect such as crystal precipitation.
4. long-term stable experiment
3 batches of nano-emulsions are sealed in Brown Glass Brown glass bottles and jars only, are placed under the conditions of (25 ± 2) DEG C, relative humidity (60 ± 5) % 12
Individual month, sample when 0,3,6,9 and 12 months, investigate character and the changes of contents of nano-emulsion, and list of references statistical
Analysis method, calculates the effect duration of terazosin nanoemulsion antihypertensive drug.Result of the test shows under the conditions of long term test, special
The outward appearance drawing azoles piperazine nanoemulsion antihypertensive drug is always maintained at clear and bright, homogeneous, has no that layering, complexion changed, flocculation and breakdown of emulsion etc. are existing
As；Terazosin content in system extends in time and is gradually lowered, the linear regression that its content-time changing curve provides
Equation, the effect duration calculating terazosin nanoemulsion antihypertensive drug is 37.25 months (with time short person as standard).
The special present invention of test example 3 rat tails manometry mensuration draws azoles piperazine nanoemulsion antihypertensive drug (embodiment 1)
Drug effect (with commercially available terazosin sheet contrast)
SHR rat 40 is only randomly divided into 4 groups, and often group 10, is set to terazosin sheet group, terazosin nano-emulsion group
With positive blank group, first two groups give terazosin sheet suspension, terazosin nano-emulsion each 15mg/kg d respectively, are dissolved in drink
Water is administered, 1 time/d, continuous 12 weeks.WKY rat 10 is Normal group, and 10 positive controls of SHR rat are not administered
Thing, normal water.
Measure each group of rat tail artery blood pressure.(before medication) pressure measurement 1 time when Mus age is 6 weeks, 7 weeks ages of Mus are (after medication 1
Week) pressure measurement 1 time, survey 1 blood pressure the most week about, until experiment terminates.The results are shown in Table 1.
The comparison (x ± s, n=10) of rat SBP respectively organized by table 1
Result shows, terazosin nano-emulsion compares with positive controls, terazosin sheet group, and difference is the most notable, table
Bright terazosin not only can significantly reduce the blood pressure of positive rats, and antihypertensive effect effect is more compared with commercially available terazosin sheet
For significantly.
Test example 4 toxicity test
1. toxicological study project and conclusion:
The thing medicine of the present invention in strict accordance with new drug nonphosphorylated neurofilament H method and commercially available terazosin tablet contrast into
Gone acute toxicity test, repeated dose toxicity test, genetic toxicity test (include the test of Salmonella reversion test, Micronuclei In The Mouse Bone Marrow,
In vitro culture mammalian cell chromosome mutation test), reproductive toxicity test (General Reproductiv e Toxicity Assessment, sensitive period to teratogenic agent
Toxicity test, perinatal toxicity test), carcinogenic test, immunotoxicity test and Local irritation study, result of the test is as follows.
The thing medicine of the present invention is to Mouse Acute Toxicity experiment conclusion: contrasting with commercially available terazosin tablet, terazosin is received
Rice breast does not occurs measuring interior untoward reaction and death.
The genetoxics such as the Salmonella reversion test of thing medicine, mouse inbred strain and the testis chromosomal aberration test of the present invention
The result of test is feminine gender.
Rat 30d feeds the result of product of the present invention and shows: contrast with commercially available terazosin tablet, within experimental period, special
In drawing the metering of azoles piperazine nano-emulsion, each test group of animals growth promoter is good, body weight, food ration, routine blood test, blood biochemistry, organ coefficient
Etc. index all within normal range, histopathologic examination's also no abnormality seen.
The medicine long term toxicity test conclusion of the present invention: contrasting with commercially available terazosin tablet, within experimental period, spy draws azoles
In the metering of piperazine nano-emulsion, this medicine has no rat untoward reaction for three months at continuous gastric infusion, and every Index for examination is all just
In the range of Chang, its main organs of pathologic finding and target organ are showed no the toxic pathological change that this guiding drug rises.
Test example 5 pharmacokinetics
Result of the test shows, the oral rear male of terazosin resisting hypertension Nano medication (embodiment 1) breast of the present invention suffers from
Person substantially completely absorbs after taking medicine.The immediately after meals impact on degree of absorption of taking medicine is minimum, but makes plasma concentration peak time
Postpone about 30 minutes.Liver first pass metabolism is the least.Within after taking medicine about 1 hour, reaching peak value, the half-life is about 15 hours.Plasma protein
Combination rate is 90-94%.About 40% through homaluria, and about 60% discharges with feces.
Embodiment 1
Accurately weigh EL40 28g and ethanol 4g to stir under the conditions of room temperature (25 DEG C), be slowly dropped into the most wherein
It is dissolved with the distilled water of terazosin.Along with the increase of the distillation water yield, system stickiness increases, when the amount adding distilled water makes body
Be from Water-In-Oil become oil-in-water type nano-emulsion time, system viscosity is thinning from the state of thickness, and now produce is i.e. nothing
The terazosin nano-emulsion that color is transparent, the amount now adding water is 62.9g, terazosin is 5.1g.This ratio is spy and draws azoles
The optimal proportion of piperazine resisting hypertension nano-emulsion.
Following example step is with embodiment 1:
Embodiment 2
EL40 32g, 1,2-PD 4g, the amount of water is 60g, and terazosin is 4g.
Embodiment 3
RH40 24g, glycerol 4g, the amount of water is 65.3g, and terazosin is 6.7g.
Embodiment 4
RH40 24g, ethanol 8g, the amount of water is 61.6g, and terazosin is 6.4g.
Embodiment 5
Tween 80 24g, glycerol 3g, the amount of water is 66g, and terazosin is 7g.
Embodiment 6
Tween 80 20g, PEG400 15g, the amount of water is 60g, and terazosin is 5g.
Embodiment 7
EL40 20g, span80 10g, the amount of water is 69g, terazosin 1g.
Embodiment 8
RH40 25g, span80 5g, the amount of water is 60g, 1,2-PD 5g, terazosin 5g.
Embodiment 9
Tween 80 20g, span80 10g, the amount of water is 55g, PEG400 5g, terazosin 10g.
Embodiment 10
PLURONICS F87 20g, span80 5g, glycerol 5g, the amount of water is 55g, terazosin 15g.
Embodiment 11
EL40 25g, the amount of water is 64g, PEG400 5g, glycerol 5g, terazosin 1g.
Claims (2)
1. an oil-in-water type terazosin nanoemulsion antihypertensive drug, it is characterised in that its raw material and mass percent thereof
For:
Terazosin 1%～15%
Surfactant 15%～40%
Cosurfactant 0～20%
Remaining composition is distilled water, and the mass percent sum of above-mentioned raw materials is 100%；
Described surfactant is: polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or pool Lip river are husky
In nurse 188 any one or with the mixture of span80；
Described cosurfactant be in dehydrated alcohol, 1,2-PD, PEG400 or glycerol any one or
Several mixture.
Oil-in-water type terazosin nanoemulsion antihypertensive drug the most according to claim 1, it is characterised in that this medicine
Particle diameter is between 45.3～92.4nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610545503.6A CN105997873A (en) | 2016-06-23 | 2016-06-23 | Oil-in-water type terazosin nanoemulsion antihypertensive drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610545503.6A CN105997873A (en) | 2016-06-23 | 2016-06-23 | Oil-in-water type terazosin nanoemulsion antihypertensive drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105997873A true CN105997873A (en) | 2016-10-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610545503.6A Pending CN105997873A (en) | 2016-06-23 | 2016-06-23 | Oil-in-water type terazosin nanoemulsion antihypertensive drug |
Country Status (1)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727311A (en) * | 2016-12-30 | 2017-05-31 | 河南牧翔动物药业有限公司 | A kind of oil-in-water type orixine nano-emulsion and preparation method thereof |
| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
-
2016
- 2016-06-23 CN CN201610545503.6A patent/CN105997873A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727311A (en) * | 2016-12-30 | 2017-05-31 | 河南牧翔动物药业有限公司 | A kind of oil-in-water type orixine nano-emulsion and preparation method thereof |
| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
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Application publication date: 20161012 |