CN107595777A - A kind of externally-applied medicinal composition containing minoxidil - Google Patents
A kind of externally-applied medicinal composition containing minoxidil Download PDFInfo
- Publication number
- CN107595777A CN107595777A CN201711066389.XA CN201711066389A CN107595777A CN 107595777 A CN107595777 A CN 107595777A CN 201711066389 A CN201711066389 A CN 201711066389A CN 107595777 A CN107595777 A CN 107595777A
- Authority
- CN
- China
- Prior art keywords
- minoxidil
- solution
- liposome
- propane diols
- take
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
For nitrogen oxides structure in minoxidil bulk drug molecule, easily degraded loses oxygen atom, and inventor intends solving this problem by introducing oxidizing acid in preparation system, in this application, is presented as the sulfuric acid formed in intraliposomal aqueous phase.It is simultaneously poor for minoxidil water solubility, the defects of largely causing skin irritatin using propane diols in usual external preparation, inventor passes through research, minoxidil liposome is prepared for using ammonium sulphate gradient, absorption of the skin to medicine can be promoted after a small amount of propane diols is mixed in liposome, simultaneously, the addition of liposome, stimulation of the propane diols to skin is alleviated, therefore does not remove the propane diols of finished product, is finally existed in the form of alcohol plastid.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of externally-applied medicinal composition and its system containing minoxidil
Preparation Method and purposes.
Background technology
Alopecia is the big problem that many people face, and has the reason for alopecia a lot, there is an alopecia seborrheica, blood-head alopecia,
Male pattern alopecia and hereditary factors alopecia.Though alopecia and alopecia areata not threat to life, can damage patient's to some extent
Appearance, physically and mentally healthy and quality of life is influenceed, often brings and has a strong impact on to patients ' psychological, work and social activities.
Minoxidil can extend the anagen phase, increase the hair follicle development of microminiaturization.According to experimental study, in the body of hair follicle
In outer culture, the growth time of culture hair follicle can be increased by adding minoxidil.Hair follicle HGF and blood vessel endothelium are thin
The intracellular growth factor is two essential growth factors of papilla, has important adjustment effect to the growth cycle of hair.
The report minoxidil such as Lachger can raise the expression of hair papilla cell Vascular endothelial growth factor mRNA.
It is taken as that minoxidil is stimulated by above-mentioned cell factor, maintains hair follicle growth and papilla vascularization and function, so as to
Played an important role in hair growth.
U.S. FDA in 1988 ratifies the treatment male androgen alopecia of 2% minoxidil external use liquid.2294 18 to 50 years old
The mild to moderate top alopecia of male patient, after treating 12 months, minoxidil group number of hairs increase, histology also demonstrates that minot
The hair that your group of ground grows also increases.Thereafter Trancik etc. applies 5% minot in 393 male androgen hair loss patients
Ground that, 2% minoxidil and placebo, were treated through 48 months, as a result counted ratio 2% using 5% minoxidil group hair
Minoxidil group is high by 45%, higher than placebo 5 times.
5% minoxidil solution of FDA approvals can be used as in male pattern alopecia and use within 1997.Price etc. carries out 2%, 5%
Minoxidil, placebo and not treatment group's double blind control research, are observed 96 weeks, either 2% or 5% minoxidil external application altogether
Hair growth and increase hair validity is being promoted to be above placebo and not treatment group, curative effect mostly occurs after the treatment 2~3
Individual month, but follow-up 4 weeks after drug withdrawal in 96 weeks, start alopecia occur again, this result also illustrates that minoxidil external curing promotes hair
Long effect occurs.
Minoxidil can promote hair growth by number of ways, and topical minoxidil system absorbs few.Fill
The clinical test divided confirms that minoxidil has the effect of preferable to androgenetic alopecia, alopecia areata, and large-scale clinical test has been demonstrate,proved
Real topical minoxidil hair growth is safe.
The mechanism of action of minoxidil external curing alopecia is as follows:
(1) propagation of hair follicle stimulating epithelial cell and differentiation：By the Hair follicle epithelial cells of normal person various concentrations minot
Cultivated in your liquid, in micro-molar concentration, minoxidil can hair follicle stimulating epithelial cell proliferation.Zoopery is shown：Minoxidil
Papilla, hair matrix, external root sheath and the quantity of hair surrounding annulus cell synthesis can be increased, so as to extend hair growth
Phase, fine hair on birds or animals hair is promoted to be converted to terminal hair.
(2) angiogenesis is promoted：Increase local blood supply：Hair growth is sought by the blood vessel network supply of papilla
Support, in the different growth periods of hair, the mRNA expression of vascular endothelial growth factor is different, growth period vascular endothelial cell
Growth factor mRNA strong expressions in dermal papilla cell, but then express in catagen and stand-down less.Experiment shows, rice
Promise you in dose dependent increase Vascular endothelial growth factor mRNA and its albumen expression, so as to promote papilla
Vascularization, increase local blood supply.
(3) open potassium channel：Potassium channels opening is the important step of regulating hair growth, outer real inside animal model
Test and show that minoxidil is potassium channel activator, the permeability of potassium ion can be increased, prevent calcium ion from flowing into intracellular, as a result
When causing free calcium ion concentration in cell to decline, and having calcium ion, EGF hair growth inhibition.
At present, the formulation of the minoxidil local topical formulation of Clinical practice mainly has solution, tincture, gel, spray
Mist agent, liniment, specification have 2% and 5% two kind, and 2% specification man and Ms can be used, and 5% specification is only applicable to man.
Minoxidil (minoxidil) stimulates the growth of hair, for treating male sex hormone type alopecia.But majority uses
Person feeds back solution dosage on the market, and local skin can be caused to stimulate with allergy (because the content height of propane diols, solution
50%) content of middle propane diols is；Also in-convenience in use waiting.But if only using purified water as solvent, minoxidil exists
In external preparation with form of suspension in the case of, active ingredient minoxidil is not dissolved in medium, and only exists in suspended state,
Active ingredient can not thoroughly be absorbed into body, therefore cannot fully show its therapeutic effect.Moreover, it is liquid in external preparation
In the case of body form, because it is difficult to keep time enough on the region applied, active ingredient minoxidil
Can not be by enough absorptions, therefore bioavailable efficiency is just reduced, and therefore can not fully show the therapeutic effect of minoxidil.
But in the case where external preparation is gel form, it can keep on the region (such as scalp) applied
Time enough, therefore absorption and the bioavailable efficiency of minoxidil are increased, and show preferable therapeutic effect.Cause
This, researcher provides the external preparation for including minoxidil of gel form using a variety of trials.
For example, United States Patent (USP) 5225189 discloses a kind of gel combination, it includes active ingredient minoxidil, water, card
Ripple nurse (Carbomer) thickener, pharmaceutically useful glycol (such as propane diols), ethanol or isopropanol and water-soluble or alcohol
In amine.In the gel combination, minoxidil is dissolved together with glycol (such as propane diols), and tool is provided in the form of gel
There is the preparation of carbomer thickener.
WO 02/11698 discloses a kind of gel combination, and it includes active ingredient minoxidil, non-carbomer (Non-
Carbomer) thickener and pharmaceutically useful solvent (for example, glycol such as propane diols and alcohol such as ethanol etc.).In said composition
In, minoxidil dissolves together with the solvent of such as glycol (for example, propane diols), and offer has Fei Kabo in the form of gel
The composition of nurse thickener.
But in the external preparation of gel form in the prior art, although minoxidil to a certain extent with it is all
Solvent such as propane diols is dissolved together, but the dissolution of minoxidil and propane diols is but restricted.For example, prior art
In gel external preparation be difficult to minoxidil dissolving reach 3wt% or more high concentration under keep stable gel phase, and
Therefore effective therapeutic action can not be played to alopecia etc..
Minoxidil, English name：MINOXIDIL, chemical name：6-1- piperidyls (2,4- pyrimidinediamines, 3- oxides.Press
Dry product calculates, molecular formula C9H15N5O.For white or off-white color crystalline powder.Dissolve in glacial acetic acid, in ethanol
It is slightly molten, the slightly soluble in chloroform or water, soluble,very slightly in acetone.Specifically data are：
Minoxidil structural formula is as follows：
As above formula is visible, nitrogen oxides structure is contained in molecular structure, is easily reduced into reducing substances, sloughs oxygen
Atom, form the impurity of following structure：
Above-mentioned impurity is the minoxidil impurity E described in European Pharmacopoeia.
Alcohol plastid is used exclusively for a kind of special liposome vectors of Drug Percutaneous Absorption, is carried first by touitou etc.
Go out, the cholesterol in liposome is replaced with the alcohol of higher concentration.Compared with conventional liposome, have particle diameter smaller, envelop rate is high,
The advantages of drugloading rate is big, there is a more preferable flexibility, transdermal efficiency high, and skin hold-up is big, therefore alcohol plastid is administered in New Percutaneous
Got most of the attention in system research.
The cuticula of dense regular is the barrier of Drug Percutaneous Absorption, and alcohol plastid promotes drug transdermal to inhale as pharmaceutical carrier
The mechanism of receipts mainly has two kinds：1. penetrate mechanism：The imitated vesicle structure that alcohol plastid is formed carries medicine and is directed through cuticula, due to
There is (ethanol, isopropanol, propane diols) in the alcohol of phospholipid layer middle and high concentration (20%~45%), alcohol plastid has preferably than liposome
Flexible and film mobility, therefore penetration depth is deeply more many than liposome, drug transdermal efficiency significantly improves；2. merge machine
System：The phosphatide of alcohol plastid is merged with Stratum corneum lipids, and the structure of cuticula dense regular is disturbed, while medicine is released from vesica
Release, penetrate skin alone.
The addition of alcohol, it is the main reason for transdermal efficiency of alcohol plastid strengthens.On the one hand, alcohol, which inherently has, promotees infiltration work
With can reduce the critical-temperature of Stratum corneum lipids, increase its mobility；On the other hand, the addition of alcohol makes the particle diameter of alcohol plastid
Smaller, the mobility of imitated vesicle structure is stronger, and also there occurs the change beneficial to infiltration for zeta current potentials.
In current research, ethanol can be substituted with propane diols or other nontoxic aliphatic alcohols and prepare alcohol plastid.
The mechanism of gradient method Active loading.
Adriamycin long circulating liposome, it is first liposomal pharmaceutical preparation ratified by FDA of nineteen ninety-five, while is also one
The individual successful case that amphipathic weak base is encapsulated using ammonium sulphate gradient.At which in side, using sulfate radical as ammonium ion
Anion.The success for the adriamycin facilitated below the reason for three aspects：
First, lipid bilayer is to amino molecule (Pd=0.12cm/s) and ammonium sulfate ion (Pd<10-12Cm/s) permeability coefficient
Huge spread, can effectively facilitate the proton gradient of cross-film.
Second, Doxorubicin molecules can form colloidal precipitate with the sulfate ion in intraliposomal aqueous phase, can be effective
The drugloading rate of liposome is improved, and medicine can be controlled from the rate of release in liposome.
3rd, adriamycin Octanol/water Partition Coefficients relatively low in interior aqueous phase, and in outer aqueous phase, octanol/water distribution system
It is several then higher so that liposome can be effectively ensured that medicine is not permeable to be leaked.
The effect of ammonium ion is exactly the ammonium ion gradient to form cross-film, so as to drive amphipathic weak base to be loaded into acid lipid
In internal aqueous phase.Medicine drive force source is carried in the peculiar property of ammonium ion, that is, ammonium ion can be changed into water with reversible
Amino molecule and proton, i.e.,：
And lipid bilayer has very high permeability for amino molecule.But this dissociation is that pH is relied on, as above
Shown in formula, pH is higher, and dissociation is more thorough, so as to obtain more amino molecules and proton, when the ph is lower, then balances and moves to the left
It is dynamic, it is exactly that ammonium ion does not dissociate from apparent.Encapsulating of the liposome for amphipathic weak base is just needed in liposome
Ammonium ion in aqueous phase be present, it is changed into amino molecule and proton after dissociating, due to amino molecule for lipid bilayer with very strong
Penetration power, so as to be diffused into outside liposome in aqueous phase, and proton has been stayed in the interior aqueous phase of liposome, this just ammonium ion ladder
The transmembrane pH gradient of lipid bilayer is formd on the basis of degree again, i.e.,：
[H+]lipoccme＞ ＞ [H+]medium。
It is, the acidity that the interior aqueous phase of liposome becomes.And this sour environment prevents the further solution of ammonium ion
From the diffusion with amino molecule, therefore stabilize whole liposome system.After amphipathic weak base drug is added, medicine can hydrogen from
Under the driving of son, cross-film is diffused into its interior aqueous phase.In interior aqueous phase, medicine is protonated, and is consumed a part of proton, is carried
The high pH gradient of environment so that the dissociation of ammonium ion is continued, so as to which drug absorption continuously is entered into lipid
In the interior aqueous phase of body.This process can continue to ammonium ion completely by amphipathic weak base it is completely depleted untill.
Because minoxidil water solubility is poor, it is more difficult to the water soluble preparation of mass fraction more than 2%, such as spray is made,
Solution etc..
Therefore a kind of higher preparation of the stable minoxidil content of anxious property to be developed, especially external preparation, are used for
The more typical indication such as hair growth, alopecia areata.
The content of the invention
As described above, minoxidil bulk drug can degrade under oxidative conditions, generate impurity E, at the same it is water-soluble compared with
Difference.
To reduce the content of impurity E in preparation, and solve that minoxidil water soluble preparation minoxidil content is low to ask
Topic.Inventor draws a kind of externally-applied medicinal composition containing minoxidil by research, by main ingredient minoxidil, lecithin,
Cholesterol, propane diols, ammonium sulfate, glacial acetic acid, sodium hydroxide, purified water composition.Said composition is further made as follows
It is standby into externally applied spray：
Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in propane diols, it is molten to obtain minoxidil propane diols
Liquid, it is standby；
Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；
Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, be acetic acid-vinegar with NaOH solution adjustment solution ph
Sour sodium cushioning liquid, resulting solution need to be isotonic with ammonium sulfate obtained by step 2；
Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in ethanol in proper amount, obtains the ethanol solution of lipid；
Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe
In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；
Step 6：Blank liposomes liquid solution obtained by taking step 5, is placed in bag filter, is placed in Acetic acid-sodium acetate obtained by step 3
In cushioning liquid, stirring, 30min changes solution once, continuously changes 3 times, liposome solutions are taken out from bag filter, standby；
Now, due to the effect of dialysis, concentration of alcohol is significantly diluted in system, can be ignored.
Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, take minoxidil propane diols obtained by step 1
Solution, it is added in liposome solutions obtained by step 6, insulated and stirred 30min, is obtained along chamber wall in a manner of syringe injects
Carry medicine minoxidil alcohol plastid solution；
Propane diols is now introduced due to the addition of minoxidil propylene glycol solution in system.
Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, it is rice
Your alcohol plastid external spraying agent of promise ground.
Characterized in that, step 3 resulting solution pH value is 6.5-7.0, and with step 2 obtained by ammonium sulfate etc.
Ooze.
The preparation method of above-mentioned liposome is ammonium sulphate gradient, due to not removing the propane diols in finished product, therefore institute
It is alcohol plastid solution, the i.e. liposome solutions containing propane diols to obtain solution, and this solution can promote absorption of the skin to medicine.
The minoxidil alcohol plastid external spraying agent, PG concentration 15%-45%.
Unit dose minoxidil content is 1.0%-3.0%.
The externally-applied medicinal composition containing minoxidil, unit formulation composition are as follows：
The externally-applied medicinal composition containing minoxidil, is further prepared into external spraying agent as follows：
Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in recipe quantity propane diols, obtain minoxidil the third two
Alcoholic solution, it is standby；
Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；
Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, solution ph is adjusted to 6.5-7.0 with NaOH solution,
For NaAc_HAc buffer solution, resulting solution and ammonium sulfate obtained by step 2 are isotonic；
Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in the ethanol of part, obtains the ethanol solution of lipid；
Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe
In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；
Step 6：Take blank liposomes liquid solution obtained by step 5, be placed in bag filter, the step of being placed in 100 times of volumes three gained
In NaAc_HAc buffer solution, stirring, 30min changes solution once, continuously changed 3 times, and it is molten that liposome is taken out from bag filter
Liquid, this step are used to build the pH gradient between intraliposomal aqueous phase and outer aqueous phase, and outer aqueous phase pH is 6.5-7.0, interior aqueous phase pH
About 1.0-2.0, it is standby to obtain liposome solutions；
Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken,
It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried
Your alcohol plastid solution of promise ground, the minoxidil in this step in propylene glycol solution exists with molecular state, due to amino in molecule
Nitrogen-atoms exists for meta-alkalescence, in the presence of aqueous phase pH gradient inside and outside liposome, is passively enriched in the relatively low liposomes of pH
In the sulfuric acid solution of interior aqueous phase；
Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot
That alcohol plastid external spraying agent.
By testing further explanation present patent application as follows.
For nitrogen oxides structure in minoxidil bulk drug molecule, easily degraded loses oxygen atom, inventor intend by
Oxidizing acid is introduced in preparation system to solve this problem, in the present patent application, is presented as in intraliposomal aqueous phase and is formed
Sulfuric acid.It is simultaneously poor for minoxidil water solubility, largely cause skin irritatin using propane diols in usual external preparation
The defects of, inventor is prepared for minoxidil liposome using ammonium sulphate gradient, mixed in liposome a small amount of by research
Absorption of the skin to medicine can be promoted after propane diols, meanwhile, the addition of liposome, alleviate stimulation of the propane diols to skin and make
With, therefore the propane diols of finished product is not removed, finally exist in the form of alcohol plastid.
The every detection of experiment proof gained externally applied spray meets standard, and skin absorbs well, while degradation impurity E life
Into being suppressed significantly, greatly increase and the stability of product, reached initial purpose of the invention.
Experiment one：The generation experiment of bulk drug impurity E
This experiment mainly investigates minoxidil under solution state, and acid used is to its caused degradation in preparation.Adopt respectively
With various concentrations hydrochloric acid, sulfuric acid and nitric acid under room temperature and 40 DEG C of heating conditions under the conditions of carry out investigating its catabolite impurity E.
Result of the test is as follows：
It can be seen that from above-mentioned test data with the extension of time, impurity E substantially increases in hydrochloric acid solution, sulfuric acid
It is oxidizing acid with nitric acid, can effectively suppresses the production of impurity E, it is especially the most obvious with high-concentration sulfuric acid, therefore select sulphur
Acid is the stabilizer in minoxidil external preparation, the sulphur built in the present invention for intraliposomal aqueous phase by ammonium sulphate gradient
Acid.
Experiment two：Prescription screening is tested
Rule of thumb design, the mass ratio of lecithin and cholesterol is 4 in Liposome film-forming material:1, as phosphatide mass fraction is
8%, then cholesterol mass fraction is 2%, following composition：
Preparation technology：
Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in propane diols, it is molten to obtain minoxidil propane diols
Liquid, it is standby；
Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；
Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, solution ph is adjusted to 6.5-7.0 with NaOH solution,
For NaAc_HAc buffer solution, resulting solution need to be isotonic with ammonium sulfate obtained by step 2；
Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in the ethanol of part, obtains the ethanol solution of lipid；
Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe
In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；
Step 6：Take blank liposomes liquid solution obtained by step 5, be placed in bag filter, the step of being placed in 100 times of volumes three gained
In NaAc_HAc buffer solution, stirring, 30min changes solution once, continuously changed 3 times, and it is molten that liposome is taken out from bag filter
Liquid, this step are used to build the pH gradient between intraliposomal aqueous phase and outer aqueous phase, and outer aqueous phase pH is 6.5-7.0, interior aqueous phase pH
About 1.0-2.0, it is standby to obtain liposome solutions；
Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken,
It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried
Your alcohol plastid solution of promise ground, the minoxidil in this step in propylene glycol solution exists with molecular state, due to amino in molecule
Nitrogen-atoms exists for meta-alkalescence, in the presence of aqueous phase pH gradient inside and outside liposome, is passively enriched in the relatively low liposomes of pH
In interior aqueous phase；
Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot
That alcohol plastid external spraying agent.
Test result analysis：Above-mentioned prescription one, prescription five, the preparations shaping of prescription nine is preferable, epigranular, and envelop rate is good
It is good.
Experiment three：Product property detection experiment
By above-mentioned screening, it is determined that the prescription and preparation technology of three specification minoxidil external spraying agents.
Preparation technology：
Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in propane diols, it is molten to obtain minoxidil propane diols
Liquid, it is standby；
Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；
Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, solution ph is adjusted to 6.5-7.0 with NaOH solution,
For NaAc_HAc buffer solution, resulting solution need to be isotonic with ammonium sulfate obtained by step 2；
Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in the ethanol of part, obtains the ethanol solution of lipid；
Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe
In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；
Step 6：Take blank liposomes liquid solution obtained by step 5, be placed in bag filter, the step of being placed in 100 times of volumes three gained
In NaAc_HAc buffer solution, stirring, 30min changes solution once, continuously changed 3 times, and it is molten that liposome is taken out from bag filter
Liquid, this step are used to build the pH gradient between intraliposomal aqueous phase and outer aqueous phase, and outer aqueous phase pH is 6.5-7.0, interior aqueous phase pH
About 1.0-2.0, it is standby to obtain liposome solutions；
Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken,
It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried
Your alcohol plastid solution of promise ground, the minoxidil in this step in propylene glycol solution exists with molecular state, due to amino in molecule
Nitrogen-atoms exists for meta-alkalescence, in the presence of aqueous phase pH gradient inside and outside liposome, is passively enriched in the relatively low liposomes of pH
In interior aqueous phase；
Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot
That alcohol plastid external spraying agent.
Centrifugal sedimentation is tested：
Prescription one is taken respectively, prescription five, the minoxidil alcohol plastid sample of prescription nine, is put and is centrifuged 30min under 100,000 g, see whether
Layering, is not as a result layered.
Surface potential：
Under the conditions of room temperature (25 DEG C), prescription one, prescription five, water beyond the minoxidil alcohol plastid sample suspension of prescription nine is appropriate are taken
Phase buffer solution is diluted to finite concentration, is added in the sample cell of the Zeta potential analyzer after being corrected with correcting fluid, measure
Zeta potential.As a result it is as shown in the table：
The peak moment analysis of the zeta current potentials of table 1
Due to the reason containing part phosphatidylserine in lecithin used, therefore alcohol plastid surface Zeta potential is negative
Value, simultaneously because alcohol plastid surface charge, therefore increase its suspension stability, it is not layered and is precipitated.
Alcohol plastid envelop rate：
Prescription one, prescription five are taken, the minoxidil alcohol plastid sample of prescription nine is surveyed using ultrafiltration-efficient liquid phase ultraviolet detection method
Determine envelop rate.Concrete operations are as follows：
(1) prescription one is taken, prescription five, the minoxidil alcohol plastid sample of prescription nine is appropriate, can pass through appropriate dilution, be added to ultrafiltration
In device, ultrafiltration appropriate time, take filter liquor appropriate, suitably diluted with mobile phase into HPLC and detect drug concentration, be free drug
Content (ρ1)；
(2) take the liposome of same concentration appropriate, be demulsified with 10% triton x-100, to flow the identical multiple of phase dilution, obtain medicine
Thing total content (ρ2) HPLC measure, determine 3 times, by E (%)=(1- ρ1/ρ2The computational envelope rate of) × 100%.As a result see the table below.
The entrapment efficiency of the minoxidil alcohol plastid of table 2
As shown in upper table data, gained minoxidil alcohol plastid envelop rate is all higher than 95%, very well, outer without removing
Minoxidil in aqueous phase can reach therapeutic effect.
Experiment five：Accelerated stability experiment in 6 months
Above-mentioned 3 specification minoxidils spray (3 prescriptions in embodiment 1) and commercially available product are taken up to glad 2% (containing packaging) four of falling thick and fast
Numbering A-D puts 40 DEG C ± 2 DEG C to group sample respectively respectively, is stored 12 months under the conditions of 75% ± 5%RH, respectively at 0 month, January, and 3
Month, in June, in December, relevant nature is measured by sampling, obtains corresponding data, it is as shown in the table：
The embodiment 1 of table 3 is compared with marketed tablet sample stability
It can be seen from upper table data according to prescription described in embodiment 1-3 of the present invention and the minot prepared by technique
That external spraying agent, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 12 months, alcohol plastid is due in membrane material
In add the reason of cholesterol, basic No leakage, because the presence of phosphatidylserine makes alcohol plastid surface bear electricity, disperse
Repulsion is produced between vesica, therefore without phenomenon is divided into, its content, relevant material is varied from, but content exceedes
98.5%, maximum single impurity is less than 0.1%, and total impurities is below 0.4%, and impurity E is less than 0.1%；Correspond, commercially available rice
Promise your spray after accelerating storage in 12 months, its content falls to approximately 95%, and maximum single impurity rises to about 1.2%,
Impurity E increases to about 1.3%, and total impurities is then more than 2.0%.
Based on as above analyzing, according to prescription described in embodiment 1-3 of the present invention and the minoxidil external application prepared by technique
Under acceleration conditions, the data after storing 12 months show that its stability is significantly better than commercially available emulsifiable paste, i.e., by this hair to spray
Bright prescription and technique is remarkably reinforced the stability of minoxidil external preparation, and the production of impurity E is significantly pressed down
System, so that the present invention has prominent substantive distinguishing features and marked improvement, and there is practicality.
Embodiment
Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this area
Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
The minoxidil spray of embodiment 1 prepares (unit：g)
Prescription：
Preparation technology：
Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in propane diols, it is molten to obtain minoxidil propane diols
Liquid, it is standby；
Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；
Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, solution ph is adjusted to 6.5-7.0 with NaOH solution,
For NaAc_HAc buffer solution, resulting solution need to be isotonic with ammonium sulfate obtained by step 2；
Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in the ethanol of part, obtains the ethanol solution of lipid；
Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe
In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；
Step 6：Take blank liposomes liquid solution obtained by step 5, be placed in bag filter, the step of being placed in 100 times of volumes three gained
In NaAc_HAc buffer solution, stirring, 30min changes solution once, continuously changed 3 times, and it is molten that liposome is taken out from bag filter
Liquid,
This step is used to build the pH gradient between intraliposomal aqueous phase and outer aqueous phase, and outer aqueous phase pH is 6.5-7.0, interior aqueous phase pH
About 1.0-2.0, it is standby to obtain liposome solutions；
Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken,
It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried
Your alcohol plastid solution of promise ground, the minoxidil in this step in propylene glycol solution exists with molecular state, due to amino in molecule
Nitrogen-atoms exists for meta-alkalescence, in the presence of aqueous phase pH gradient inside and outside liposome, is passively enriched in the relatively low liposomes of pH
In interior aqueous phase；
Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot
That alcohol plastid external spraying agent.
Claims (7)
- A kind of 1. externally-applied medicinal composition containing minoxidil, by main ingredient minoxidil, lecithin, cholesterol, propane diols, sulphur Sour ammonium, glacial acetic acid, sodium hydroxide, purified water composition, said composition are further prepared into externally applied spray as follows：Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in propane diols, it is molten to obtain minoxidil propane diols Liquid, it is standby；Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, be acetic acid-vinegar with NaOH solution adjustment solution ph Sour sodium cushioning liquid, resulting solution need to be isotonic with ammonium sulfate obtained by step 2；Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in ethanol in proper amount, obtains the ethanol solution of lipid；Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；Step 6：Blank liposomes liquid solution obtained by taking step 5, is placed in bag filter, is placed in Acetic acid-sodium acetate obtained by step 3 In cushioning liquid, stirring, 30min changes solution once, continuously changes 3 times, liposome solutions are taken out from bag filter, standby；Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken, It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried Your alcohol plastid solution of promise ground；Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot That alcohol plastid external spraying agent；Characterized in that, step 3 resulting solution pH value is 6.5-7.0, and it is isotonic with step 2 gained ammonium sulfate.
- 2. a kind of externally-applied medicinal composition containing minoxidil as claimed in claim 1, it is characterised in that the propane diols is dense Spend for 15%-45%.
- A kind of 3. externally-applied medicinal composition containing minoxidil as claimed in claim 1, it is characterised in that unit dose minot Your content of ground is 1.0%-3.0%.
- A kind of 4. externally-applied medicinal composition containing minoxidil as claimed in claim 1, it is characterised in that unit formulation prescription Composition is as follows：
- A kind of 5. externally-applied medicinal composition containing minoxidil as claimed in claim 1, it is characterised in that unit formulation prescription Composition is as follows：
- A kind of 6. externally-applied medicinal composition containing minoxidil as claimed in claim 1, it is characterised in that unit formulation prescription Composition is as follows：
- 7. any externally-applied medicinal composition containing minoxidil as described in claim 1-6, it is characterised in that by walking as follows Suddenly it is further prepared into external spraying agent：Step 1：Take minoxidil bulk drug to crush, cross 100 mesh sieves, be dissolved in recipe quantity propane diols, obtain minoxidil the third two Alcoholic solution, it is standby；Step 2：Take ammonium sulfate to be dissolved in purified water, obtain ammonium sulfate；Step 3：Take glacial acetic acid to be dissolved in purified water, obtain acetum, solution ph is adjusted to 6.5-7.0 with NaOH solution, For NaAc_HAc buffer solution, resulting solution and ammonium sulfate obtained by step 2 are isotonic；Step 4：Recipe quantity lecithin is taken, cholesterol is dissolved in the ethanol of part, obtains the ethanol solution of lipid；Step 5：The ethanol solution of lipid obtained by step 4 is taken to be injected into step under the conditions of 60 DEG C of stirring in water bath with syringe In two gained ammonium sulfates, cross 200nm miillpore filters three times, obtain blank liposome solutions；Step 6：Take blank liposomes liquid solution obtained by step 5, be placed in bag filter, the step of being placed in 100 times of volumes three gained In NaAc_HAc buffer solution, stirring, 30min changes solution once, continuously changed 3 times, and it is molten that liposome is taken out from bag filter Liquid, this step are used to build the pH gradient between intraliposomal aqueous phase and outer aqueous phase, and outer aqueous phase pH is 6.5-7.0, interior aqueous phase pH About 1.0-2.0, it is standby to obtain liposome solutions；Step 7：Liposome solutions obtained by step 6,60 DEG C of water-baths, stirring, minoxidil propylene glycol solution obtained by step 1 is taken, It is added in a manner of syringe injects along chamber wall in liposome solutions obtained by step 6, insulated and stirred 30min, medicine rice must be carried Your alcohol plastid solution of promise ground, the minoxidil in this step in propylene glycol solution exists with molecular state, due to amino in molecule Nitrogen-atoms exists for meta-alkalescence, in the presence of aqueous phase pH gradient inside and outside liposome, is passively enriched in the relatively low liposomes of pH In the sulfuric acid solution of interior aqueous phase；Step 8：Take and medicine minoxidil alcohol plastid solution is carried obtained by step 7, it is filling in suitable glass spray bottle, for minot That alcohol plastid external spraying agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711066389.XA CN107595777A (en) | 2017-11-02 | 2017-11-02 | A kind of externally-applied medicinal composition containing minoxidil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711066389.XA CN107595777A (en) | 2017-11-02 | 2017-11-02 | A kind of externally-applied medicinal composition containing minoxidil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107595777A true CN107595777A (en) | 2018-01-19 |
Family
ID=61084766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711066389.XA Pending CN107595777A (en) | 2017-11-02 | 2017-11-02 | A kind of externally-applied medicinal composition containing minoxidil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107595777A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108354904A (en) * | 2018-05-21 | 2018-08-03 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing amantadine hydrochloride |
| CN108420792A (en) * | 2018-05-21 | 2018-08-21 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing Oseltamivir phosphate |
| CN115006712A (en) * | 2022-06-28 | 2022-09-06 | 广州汇元医药科技有限公司 | Minoxidil lipid nanoparticle microneedle and preparation method and application thereof |
| CN115475168A (en) * | 2022-10-18 | 2022-12-16 | 湖北工业大学 | Minoxidil-containing pharmaceutical composition, and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424038A (en) * | 2002-12-25 | 2003-06-18 | 南昌弘益科技有限公司 | Preparation process for minoxidil spraying agent for treating bald and phalacrosis |
| CN1857268A (en) * | 2005-04-30 | 2006-11-08 | 深圳市天和医药科技开发有限公司 | Minoxidil solution and preparing method of minoxidil liniment tablet |
| CN101108167A (en) * | 2007-08-03 | 2008-01-23 | 南京师范大学 | Method for preparing hydrochloric acid berberine long circulation liposome with ammonium sulphate gradient method-film evaporation method |
| CN101129378A (en) * | 2007-07-24 | 2008-02-27 | 西安交通大学 | Medicament spraying agent used for accelerating growth of hair |
| CN107115300A (en) * | 2017-05-04 | 2017-09-01 | 方达医药技术（苏州）有限公司 | A kind of application process of tangential flow systems in ammonium sulphate gradient prepares liposome |
-
2017
- 2017-11-02 CN CN201711066389.XA patent/CN107595777A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424038A (en) * | 2002-12-25 | 2003-06-18 | 南昌弘益科技有限公司 | Preparation process for minoxidil spraying agent for treating bald and phalacrosis |
| CN1857268A (en) * | 2005-04-30 | 2006-11-08 | 深圳市天和医药科技开发有限公司 | Minoxidil solution and preparing method of minoxidil liniment tablet |
| CN101129378A (en) * | 2007-07-24 | 2008-02-27 | 西安交通大学 | Medicament spraying agent used for accelerating growth of hair |
| CN101108167A (en) * | 2007-08-03 | 2008-01-23 | 南京师范大学 | Method for preparing hydrochloric acid berberine long circulation liposome with ammonium sulphate gradient method-film evaporation method |
| CN107115300A (en) * | 2017-05-04 | 2017-09-01 | 方达医药技术（苏州）有限公司 | A kind of application process of tangential flow systems in ammonium sulphate gradient prepares liposome |
Non-Patent Citations (3)
| Title |
|---|
| 吴川彦等: "HPLC-Q-TOF-MS法对米诺地尔及凝胶有关物质的分析", 《中国药师》 * |
| 方亮: "《全国高等医药院校药学类第四轮规划教材 药剂学 第3版》", 31 March 2016 * |
| 杨明: "《药剂学》", 29 July 2016 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108354904A (en) * | 2018-05-21 | 2018-08-03 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing amantadine hydrochloride |
| CN108420792A (en) * | 2018-05-21 | 2018-08-21 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing Oseltamivir phosphate |
| CN115006712A (en) * | 2022-06-28 | 2022-09-06 | 广州汇元医药科技有限公司 | Minoxidil lipid nanoparticle microneedle and preparation method and application thereof |
| CN115006712B (en) * | 2022-06-28 | 2024-01-09 | 广州汇元医药科技有限公司 | Minoxidil lipid nanoparticle microneedle and preparation method and application thereof |
| CN115475168A (en) * | 2022-10-18 | 2022-12-16 | 湖北工业大学 | Minoxidil-containing pharmaceutical composition, and preparation method and application thereof |
| CN115475168B (en) * | 2022-10-18 | 2024-02-13 | 湖北工业大学 | Minoxidil-containing pharmaceutical composition and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107595777A (en) | A kind of externally-applied medicinal composition containing minoxidil | |
| CN102871956B (en) | Propranolol hydrochloride gel for treating infant superficial hemangioma | |
| CN105434337B (en) | Propranolol Hydrochloride Submicron Emulsion gel and its preparation method and application | |
| CN106955277A (en) | A kind of transdermal drug delivery system of alcohol liposome containing hyaluronic acid and preparation method and application | |
| WO2024082819A1 (en) | Hyaluronic acid liposome assembly, and preparation method therefor and use thereof | |
| CN111195230B (en) | Method for preparing flexible liposome | |
| CN109069418A (en) | topical composition comprising tacrolimus | |
| CN102525930B (en) | Lipoic acid liposome injection | |
| CN102988257B (en) | Liposome sun-screening skin care product | |
| Parmar et al. | Preparation and evaluation of ethosomal gel of clotrimazole for fungal infection by mechanical dispersion method | |
| CN101474144A (en) | Tetracaine hydrochloride lipidosome gel and preparation method thereof | |
| US20150037269A1 (en) | Topical compositions for treatment of excessive sweating and methods of use thereof | |
| CN107638304B (en) | Alpha-arbutin composition with high skin cell permeability and preparation method and application thereof | |
| CN102579437A (en) | Tacrolimus composition containing alcohol and preparation method of tacrolimus composition | |
| CN110448519B (en) | Flexible liposome of human fibroblast regulation culture solution and preparation method and application thereof | |
| CN114681403B (en) | Minoxidil delivery body with high drug loading and encapsulation efficiency, gel and preparation thereof | |
| CN108721604B (en) | Thymosin beta-4 ethosome and preparation process thereof | |
| US20140343159A1 (en) | Formulation of small adrenergic agonist salt forms in organic solvents | |
| CN113952272B (en) | Freckle-removing wrinkle-removing skin-moisturizing emulsion composition and preparation method thereof | |
| CN114767738A (en) | Sanbai soup transfersome and preparation method thereof | |
| CN114569507A (en) | Moisturizing emulsion and preparation method thereof | |
| CN111281851A (en) | PH-targeted flexible nanoliposome with acne removing effect and preparation method thereof | |
| CN114452257B (en) | Selenium disulfide foam agent for skin care and preparation method thereof | |
| CN100493530C (en) | Method for preparing coated magnolia fargesii volatile oil nano liposome nasal drops | |
| CN100450484C (en) | Imiquimod turbid liquor and gelling agent thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180119 |
|
| RJ01 | Rejection of invention patent application after publication |