CN105434336B - Propranolol Hydrochloride external-use gel preparation and its preparation method and application - Google Patents
Propranolol Hydrochloride external-use gel preparation and its preparation method and application Download PDFInfo
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Abstract
The invention proposes Propranolol Hydrochloride external-use gel preparations and its preparation method and application, wherein Propranolol Hydrochloride external-use gel preparation includes: at least Propranolol Hydrochloride of 3 weight %.The Propranolol Hydrochloride external-use gel preparation is with good stability and transdermal characteristic, has significant curative effect to the infant hemangioma for treating and preventing located subcutaneously different depth.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, the present invention relates to Propranolol Hydrochloride external-use gel preparation and
Preparation method and use.
Background technique
Infant hemangioma is benign tumour caused by common endotheli ocytosis, and the disease incidence of infantile hemangiomas is about
It is 1.1%~2.6%, the position of appearance is in the majority with neck forehead, accounts for about 35%~60% and differs.Although most blood vessel
Tumor can spontaneous regression, but its paracmasis is very long, may continue 5~7 years.There are about 20% hemangioma can not spontaneous regression, and
It is also possible that multiple complications, such as ulcer, bleeding, infection etc..The hemangioma for betiding privileged sites, as periorbit, glottis,
Perineum easily causes dysfunction, growth restriction, and serious person's even energy life-threatening brings considerable distress to infant,
So being clinically intended to energetically treat in early days.The method for the treatment of infant hemangioma mainly has freezing, laser, mouth at present
Medication object and subcutaneous injection drug etc., but above-mentioned therapeutic modality has respective drawback and has different complication.
A kind of non-selective receptor blocking agent of the Propranolol as classics confirms there is treatment baby children by extensive
Angiomatous effect of youngster, it has now been found that it can pass through vasoconstriction, inhibition angiogenesis, promotion apoptosis of vascular endothelial cell
To promote angiomatous recession.But oral propranolol may cause the side effects such as low blood pressure, hypoglycemia, bradycardia, especially
There is potential adverse effect risk to infant's nervous system.To reduce clinically oral propranolol whole body system absorption band
The side effect that comes improves drug safety, and the administration of skin patient part, to improve local blood concentration will be a kind of effective technology
It improves.
Therefore, Propranolol still needs further to be studied.
Summary of the invention
The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, of the invention
One purpose is to propose the hydrochloric acid that a kind of medicament contg is high, percutaneous abilities are good, the quality of the pharmaceutical preparations is stable and skin irritation is small
Propranolol external-use gel preparation.
Currently, in the patent of Propranolol Hydrochloride correlation external preparation Propranolol Hydrochloride mass percent concentration range
Between 0.012%~10%, the Propranolol Hydrochloride percutaneous drug delivery formulation patent and document report of higher concentration there are no,
There is not the quality of the pharmaceutical preparations stability correlative study of Propranolol Hydrochloride content >=3%.
According to an aspect of the present invention, the invention proposes a kind of Propranolol Hydrochloride external-use gel preparations.According to this
The embodiment Propranolol Hydrochloride external-use gel preparation of invention includes: at least Propranolol Hydrochloride of 3 weight %.
The present inventor has been put forward for the first time the external preparation that Propranolol Hydrochloride content is 3 weight % or more.It needs
Illustrate, herein, if do not clearly stated, " the weight % " being previously mentioned is all based on " outside Propranolol Hydrochloride
With gel preparation " total weight.Clinically, hemangioma is based on its located subcutaneously depth and is divided into 3 classes: superficial patch type (65%),
Deeply in hypodermic type (15%) and mixed type (20%).It is deep to need carrier to have in hypodermic type and mixed type if transdermal medicine for treating
Better penetration capacity and bigger drug concentration can just play preferable curative effect.Therefore, the salt of embodiment according to the present invention
Sour Propranolol external-use gel preparation can be containing the up to Propranolol Hydrochloride of 3 weight % or more, thus, it is possible to further mention
High angiomatous therapeutic efficiency, especially mixed type and depth are in hypodermic type hemangioma.
According to an embodiment of the invention, the hydrochloric acid of the Propranolol Hydrochloride external-use gel preparation preferably 3-16 weight % is general
Naphthalene Luo Er.It further optionally, can also include the gel-type vehicle of 10-35 weight %；The transdermal penetration enhancer of 3-13 weight %；2-
The moisturizer of 12 weight %；The bacteriostatic agent of 0.02-0.2 weight %；And the water of surplus.It is surprisingly found by the inventors that the hydrochloric acid
Propranolol external-use gel preparation can effectively improve angiomatous therapeutic efficiency, especially mixed type and deeply in hypodermic type blood
Tuberculation, while excellent stability can also be shown.
Inventor has found in the course of the research, in the process for preparation of Propranolol Hydrochloride gel, Propranolol Hydrochloride
Concentration increase can be such that the viscosity of formulation products is remarkably decreased, and the phenomenon that matrix flocculation or layering occur, be unable to satisfy clinical use
The demand of drug stabilisation.It therefore, can effectively treat deep in hypodermic type and the hemangioma of mixed type to reach, the present invention is from increasing
Big drug transit dose improves preparation stability, improves drug effect etc. and sets out, grinds to the novel form of Propranolol Hydrochloride
Study carefully, the Propranolol Hydrochloride external-use gel preparation with above-mentioned prescription being prepared, said preparation appearance is creamy white semisolid
Gel, pH value 4.0-6.5, the mean droplet size after gel dilutes 100 times is 200-700nm.Inventor has found the system
The advantages that agent has good transdermal characteristic, stability and carries concentration height, small to skin irritation, easy to use, especially to baby
Child's mixed type and deep there is significant therapeutic effect in hypodermic type hemangioma.
According to a particular embodiment of the invention, above-mentioned Propranolol Hydrochloride external-use gel preparation may include: 6-14 weight
Measure the Propranolol Hydrochloride of %；The gel-type vehicle of 14-23 weight %；The transdermal penetration enhancer of 4-10 weight %；6-10 weight %'s
Moisturizer；The bacteriostatic agent of 0.04-0.1 weight %；And the water of surplus.Thus, it is possible to further increase outside Propranolol Hydrochloride
Angiomatous therapeutic efficiency, especially mixed type are treated with gel preparation and deep in the angiomatous therapeutic efficiency of hypodermic type, simultaneously
The stability of preparation can also be further increased.
According to a particular embodiment of the invention, the gel-type vehicle is selected from poloxamer 237, Pluronic/Lutrol F 108, pool Lip river
At least one of husky nurse 407.Thus, it is possible to further increase, Propranolol Hydrochloride external-use gel preparation for treating is angiomatous to be controlled
Curative effect rate, especially mixed type and depth can also further increase the steady of preparation in the angiomatous therapeutic efficiency of hypodermic type
It is qualitative.
According to a particular embodiment of the invention, the transdermal penetration enhancer be selected from Laurocapram, isopropyl myristate,
At least one of menthol.Thus, it is possible to further increase, Propranolol Hydrochloride external-use gel preparation for treating is angiomatous to be controlled
Curative effect rate, especially mixed type and depth can also further increase the steady of preparation in the angiomatous therapeutic efficiency of hypodermic type
It is qualitative.
According to a particular embodiment of the invention, the moisturizer is at least one in propylene glycol, glycerol and sorbierite
Kind, it is preferable that the moisturizer is propylene glycol.Thus, it is possible to further increase Propranolol Hydrochloride external-use gel preparation for treating
Angiomatous therapeutic efficiency, especially mixed type and depth can also be mentioned further in the angiomatous therapeutic efficiency of hypodermic type
The stability of high preparation.
According to a particular embodiment of the invention, the bacteriostatic agent be selected from sorbic acid, methylparaben, propylben and
At least one of sodium benzoate, it is preferable that the bacteriostatic agent is sorbic acid.Thus, it is possible to further increase the general naphthalene Lip river of hydrochloric acid
Your the angiomatous therapeutic efficiency of external-use gel preparation for treating, especially mixed type and deep in the angiomatous therapeutic efficiency of hypodermic type,
The stability of preparation can also be further increased simultaneously.
According to an embodiment of the invention, the pH value of the Propranolol Hydrochloride external-use gel preparation is 4.0-6.5, the salt
Drop after sour 100 times of Propranolol external-use gel preparation diluent has the average grain diameter of 200-700nm.Thus, it is possible into one
Step improves the angiomatous therapeutic efficiency of Propranolol Hydrochloride external-use gel preparation for treating, especially mixed type and deeply in hypodermic type blood
The therapeutic efficiency of tuberculation, while the stability of preparation can also be further increased.
In the research process of Propranolol Hydrochloride external-use gel preparation, inventors have found that containing when Propranolol Hydrochloride
When amount is near or above 3 weight %, gel-type vehicle (such as card pool nurse gel) can generate layering since flocculation occurs.Invention
People discovery, if using cellulose material as gel-type vehicle when (such as hydroxypropyl methyl cellulose), containing approach or it is super
Cross the gel of the Propranolol of 3 weight % after placing one month sample appearance can in non-uniform milky, occur matrix,
The phenomenon that water, penetrating agent layering.And the concentration of Propranolol is higher, and the stability of gel-type vehicle is poorer.Inventor is unexpected
Ground discovery, when using poloxamer as gel-type vehicle, by selecting specific penetrating agent (such as Laurocapram, nutmeg
Sour isopropyl ester, menthol etc.), the Poloxamer solution of hydrochloric Propranolol can be made to become milky from clear viscous liquids
Semi-solid gel, and when the content of Propranolol is up to 16%, using poloxamer was the gel preparation of matrix at 24 months
Long-time stability investigate in it is still very stable.In addition, inventor is it was unexpectedly observed that when using specific penetrating agent, due to
Poloxamer gel matrix viscosity under the action of penetrating agent dramatically increases, therefore, it is possible to reduce the dosage of gel-type vehicle avoids
Because gel-type vehicle concentration it is excessive caused by drug diffusion coefficient reduce, the problem of transdermal effect difference.Implementation according to the present invention
Example, Propranolol Hydrochloride gel preparation prepared by the present invention carry out partial size test after diluting 100 times, and average grain diameter is in 200-
700nm range, in addition, penetrating absorption result also demonstrates that the external gel preparation has excellent transdermal effect.
According to the second aspect of the invention, the general naphthalene Lip river of hydrochloric acid described in preceding embodiment is prepared the invention also provides a kind of
The method of your external-use gel preparation.The method packet for preparing Propranolol Hydrochloride external-use gel preparation of embodiment according to the present invention
It includes: being heated after Propranolol Hydrochloride, bacteriostatic agent and water are mixed, to obtain lysate；It is added into the lysate
Gel-type vehicle is simultaneously stirred to being swollen, to obtain the first mixture；Transdermal penetration enhancer and moisturizer are mixed, to obtain second
Mixture；It is stirred after second mixture is mixed with first mixture, to obtain the general naphthalene Lip river of the hydrochloric acid
That external-use gel preparation.
Inventors have found that mentioned-above Propranolol Hydrochloride external-use gel system can be effectivelyed prepared using this method
Agent.As previously mentioned, the present inventor has been put forward for the first time the external preparation that Propranolol Hydrochloride content is 3 weight % or more.
It should be noted that, in this document, " the weight % " being previously mentioned is all based on " the general naphthalene Lip river of hydrochloric acid if do not clearly stated
The total weight of that external-use gel preparation ".Clinically, hemangioma is divided into 3 classes: superficial patch type based on its located subcutaneously depth
(65%), deep in hypodermic type (15%) and mixed type (20%).It is deep to be needed in hypodermic type and mixed type if transdermal medicine for treating
Carrier has better penetration capacity and bigger drug concentration that can just play preferable curative effect.Therefore, implementation according to the present invention
The Propranolol Hydrochloride external-use gel preparation of the method preparation of example can contain the Propranolol Hydrochloride of up to 3 weight % or more,
Thus, it is possible to further increase angiomatous therapeutic efficiency, especially mixed type and depth is in hypodermic type hemangioma.
According to an embodiment of the invention, the method for preparing Propranolol Hydrochloride external-use gel preparation may include: by salt
After sour Propranolol and bacteriostatic agent mixing and water is added, is heated under water bath condition, to obtain lysate；To the lysate
Middle addition gel-type vehicle, stirring is to being swollen, to obtain the first mixture；Transdermal penetration enhancer and moisturizer are mixed, so as to
To the second mixture；Second mixture is added into first mixture, mechanical stirring is uniform, described to obtain
Propranolol Hydrochloride external-use gel preparation.
Inventors have found that the obtained Propranolol Hydrochloride external application of preparation method by using the embodiment of the present invention is solidifying
Mean droplet size after 100 times of glue preparation diluent is 200-700nm.It is dense with good transdermal characteristic, stability and load medicine
The advantages that degree is high, small to skin irritation, easy to use especially has to infant's mixed type and deeply in hypodermic type hemangioma aobvious
The therapeutic effect of work.
In addition, according to a particular embodiment of the invention, the churned mechanically speed is 100-6000rpm, mixing time
It is 6-15 minutes.It is possible thereby to which Propranolol Hydrochloride external-use gel preparation is made to form more small drop, and then significantly mention
Its high transdermal characteristic, and then reach raising and treat mixed type and deeply in the angiomatous effect of hypodermic type.
It will be appreciated by those skilled in the art that front is with regard to advantage and spy described in Propranolol Hydrochloride external-use gel preparation
Point, the equally applicable method for preparing Propranolol Hydrochloride external-use gel preparation, details are not described herein.
According to the third aspect of the invention we, the invention proposes the Propranolol Hydrochloride external-use gels described in preceding embodiment
Preparation is for treating and preventing the purposes in hemangioma.In other words, the invention proposes salt according to an embodiment of the present invention
The purposes of sour Propranolol external-use gel preparation in medicine preparation, the drug is for treating hemangioma.It is according to the present invention
Embodiment, the hemangioma are hemangioma under Infant, it is preferable that hemangioma is superficial type blood vessel under the Infant
Tumor, mixed type hemangioma and depth are in the angiomatous at least one of hypodermic type.
According to a particular embodiment of the invention, hemangioma can be superficial type hemangioma, mixed type under the Infant
Hemangioma is with deep in the angiomatous at least one of hypodermic type.Propranolol Hydrochloride external-use gel preparation due to its drugloading rate height, and
With good transdermal characteristic, therefore it can be adapted for various types of hemangiomas, especially to mixed type hemangioma and deeply subcutaneous
Type hemangioma has good therapeutic effect.And then it effectively compensates for existing most Propranolol Hydrochloride dosage form and is unable to reach pair
The defect of located subcutaneously deeper hemangioma cure.
According to an embodiment of the invention, technical solution of the present invention has the advantages that
1, Propranolol Hydrochloride external-use gel preparation according to an embodiment of the present invention, can efficiently solve containing high salt concentration
The unstable problem of sour Propranolol external preparation.
2, poloxamer in Propranolol Hydrochloride external-use gel preparation according to an embodiment of the present invention, penetrating agent, moisturizer,
And the water of drug containing forms the nanosized liquid droplets that average grain diameter is 200~700nm and is easy to enter tissue fluid through keratoderma
Accelerate drug absorption, sample has good transdermal effect and drug transit dose, can be applied to treat located subcutaneously different depth
Infant hemangioma, for not type hemangioma patient provide effectively, toxic side effect is small, clinical compliance is high treatment choosing
It selects.
3, Propranolol Hydrochloride external-use gel preparation according to an embodiment of the present invention can efficiently inhibit angiomatous growth to make
Hemangioma subsides, and skin irritation is small.
Detailed description of the invention
Fig. 1 is that according to one embodiment of present invention, Laurocapram coagulates solution appearance and property to the poloxamer of drug containing
Shape influence diagram, a are that the poloxamer of hydrochloric Propranolol coagulates 407 sticky drug solutions, and b is after Laurocapram is added in a
The change of gel-type vehicle viscosity and character.
Fig. 2 is that Propranolol Hydrochloride external-use gel prepared by embodiment according to the present invention 1 dilutes the nano fluid after 100 times
Drip grain size distribution.
2 sample treatment metastomium mixed type hemangioma effect picture of Fig. 3 embodiment according to the present invention, a are photograph before treatment
Piece, b are photo after being treated 20 days with the present invention.
Specific embodiment
The embodiment of the present invention is described below in detail, these embodiments are exemplary, it is intended to it is used to explain the present invention, and
It is not considered as limiting the invention.
Embodiment 1
It weighs 4g Propranolol Hydrochloride and 0.05g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
15g poloxamer188 is added after being completely dissolved, mechanical stirring makes complete swelling；6g Laurocapram and 8g propylene glycol separately are taken,
Stirring makes it dissolve each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, at 500 revs/min
Mechanical agitation under, stir 10 minutes, be made Propranolol Hydrochloride external-use gel preparation (prescription total amount is based on 100g).It is solidifying
Glue preparation is in uniform milky, semi-solid gel shape, and pH value 5.24, mean droplet size is 306.6nm after 100 times of dilution.Sample
After placing one month under the conditions of product are in sealing appliance, 25 DEG C ± 2 DEG C: appearance and character, pH value, the partial size nothing of sample are obvious
Variation.
Embodiment 2
It weighs 10g Propranolol Hydrochloride and 0.05g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
15g poloxamer188 is added after being completely dissolved, mechanical stirring makes complete swelling；6g Laurocapram and 8g propylene glycol separately are taken,
Stirring makes it dissolve each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, at 500 revs/min
Mechanical agitation under, stir 10 minutes, be made Propranolol Hydrochloride external-use gel preparation (prescription total amount is based on 100g).It is solidifying
Glue preparation is in uniform milky, semi-solid gel shape, and pH value 5.17, mean droplet size is 301.9nm after 100 times of dilution.Sample
After placing one month under the conditions of product are in sealing appliance, 25 DEG C ± 2 DEG C: appearance and character, pH value, the partial size nothing of sample are obvious
Variation.
Embodiment 3
It weighs 16g Propranolol Hydrochloride and 0.05g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
15g poloxamer188 is added after being completely dissolved, mechanical stirring makes complete swelling；6g Laurocapram and 8g propylene glycol separately are taken,
Stirring makes it dissolve each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, at 500 revs/min
Mechanical agitation under, stir 10 minutes, be made Propranolol Hydrochloride external-use gel preparation (prescription total amount is based on 100g).It is solidifying
Glue preparation is in uniform milky, semi-solid gel shape, and pH value 4.89, mean droplet size is 307.5nm after 100 times of dilution.Sample
After placing one month under the conditions of product are in sealing appliance, 25 DEG C ± 2 DEG C: appearance and character, pH value, the partial size nothing of sample are obvious
Variation.
Embodiment 4
It weighs 13g Propranolol Hydrochloride and 0.06g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
14g poloxamer188 is added after being completely dissolved, mechanical stirring makes complete swelling；6g menthol and 10g propylene glycol separately are taken, is stirred
Mixing makes it dissolve each other completely, and obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, at 2000 revs/min
It under mechanical agitation, stirs 8 minutes, is made Propranolol Hydrochloride external-use gel preparation (prescription total amount is based on 100g).Gel
Preparation is in uniform milky, semi-solid gel shape, and pH value 4.88, mean droplet size is 284.9nm after 100 times of dilution.Sample
After placing one month under the conditions of in sealing appliance, 25 DEG C ± 2 DEG C: the appearance and character of sample, pH value, partial size become without obvious
Change.
Embodiment 5
It weighs 12g Propranolol Hydrochloride and 0.06g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
17g poloxamer188 is added after being completely dissolved, mechanical stirring makes complete swelling；Separately take 8g isopropyl myristate and 10g sweet
Oil, stirring so that it is dissolved each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, 1000 turns/
It under the mechanical agitation of minute, stirs 10 minutes, Propranolol Hydrochloride external-use gel preparation is made, and (prescription total amount presses 100g
Meter).Gel preparation is in uniform milky, semi-solid gel shape, and pH value 5.14, mean droplet size is after 100 times of dilution
327.3nm.After being placed one month under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C: the appearance and character of sample, pH value, grain
Diameter has no significant change.
Embodiment 6
It weighs 10g Propranolol Hydrochloride and 0.04g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
20g Pluronic/Lutrol F 108 is added after being completely dissolved, mechanical stirring makes complete swelling；Separately take 8g Laurocapram and 10g the third two
Alcohol, stirring so that it is dissolved each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, 1500 turns/
It under the mechanical agitation of minute, stirs 10 minutes, Propranolol Hydrochloride external-use gel preparation is made, and (prescription total amount presses 100g
Meter).Gel preparation is in uniform milky, semi-solid gel shape, and pH value 5.47, mean droplet size is after 100 times of dilution
362.7nm.After being placed one month under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C: the appearance and character of sample, pH value, grain
Diameter has no significant change.
Embodiment 7
It weighs 14g Propranolol Hydrochloride and 0.05g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
22g Pluronic/Lutrol F 108 is added after being completely dissolved, mechanical stirring makes complete swelling；8g menthol and 6g glycerol separately are taken, stirring makes
It dissolves each other completely, and obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, in 500 revs/min of machinery
It under stirring condition, stirs 12 minutes, is made Propranolol Hydrochloride external-use gel preparation (prescription total amount is based on 100g).Gel preparation
In uniform milky, semi-solid gel shape, pH value 5.32, mean droplet size is 401.9nm after 100 times of dilution.Sample is close
In envelope utensil, after placing one month under the conditions of 25 DEG C ± 2 DEG C: the appearance and character of sample, pH value, partial size have no significant change.
Embodiment 8
It weighs 8g Propranolol Hydrochloride and 0.05g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
12g Pluronic/Lutrol F 108 and 6g poloxamer188 are added after being completely dissolved, mechanical stirring makes complete swelling；Separately take 6g nutmeg
Isopropyl propionate and 6g glycerol, stirring make it dissolve each other completely, obtained solution are added to the gel base dissolved with Propranolol Hydrochloride
It in matter, under 500 revs/min of mechanical agitation, stirs 10 minutes, Propranolol Hydrochloride external-use gel preparation (place is made
Square total amount is based on 100g).Gel preparation is in uniform milky, semi-solid gel shape, and pH value 5.29, drop is flat after 100 times of dilution
Equal partial size is 483.6nm.After being placed one month under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C: the appearance and property of sample
Shape, pH value, partial size have no significant change.
Embodiment 9
It weighs 6g Propranolol Hydrochloride and 0.08g sorbic acid adds suitable quantity of water, make it with the obtained mixture of heating water bath
19g poloxamer 237 is added after being completely dissolved, mechanical stirring makes complete swelling；Separately take 7g Laurocapram and 10g sorb
Alcohol, stirring so that it is dissolved each other completely, obtained solution is added in the gel-type vehicle dissolved with Propranolol Hydrochloride, 1000 turns/
It under the mechanical agitation of minute, stirs 12 minutes, Propranolol Hydrochloride external-use gel preparation is made, and (prescription total amount presses 100g
Meter).Gel preparation is in uniform milky, semi-solid gel shape, and pH value 5.71, mean droplet size is after 100 times of dilution
582.4nm.After placing one under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C: the appearance and character of sample, pH value, partial size
It has no significant change.
Above-described embodiment shows to stablize according to the gel preparation character of composition used in the present invention and content preparation, especially
It still is able to obtain physical and chemical performance stable gel rubber system in the case where drug concentration height, is suitable as effective drug
Preparation, and due to foring nano-scale particle in system, be conducive to drug and adhere to and penetrate in skin surface.
Validity in order to further illustrate the present invention, is prepared for comparing embodiment
Comparative example 1
Weigh Propranolol Hydrochloride 4g, carbomer 3g, geraniol 5g, propylene glycol 10g, Tween-60 1.0g, ethyl hydroxy benzoate
1.0g, surplus are water (prescription total amount is based on 100g), prepare Propranolol Hydrochloride gel.
Comparative example 2
Weigh Propranolol Hydrochloride 3g, hydroxypropyl methyl cellulose 3g, propylene glycol 10g, polyoxyethylene sorbitan monoleate 1g, laurel nitrogen Zhuo
Ketone 5g, sorbic acid 0.05g, surplus are water (prescription total amount is based on 100g).Under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C
After placing one month: sample appearance is in uneven milky, the phenomenon that matrix, water, penetrating agent layering occurs, preparation is unstable.
Comparative example 3
Weigh Propranolol Hydrochloride 4g, octadecyl alcolol 6.5g, stearic acid 6.5g, single bi-tristearin 6.5g, liquid stone
Wax 5g, propylene glycol 9g, Laurocapram 6g, glycerol 9g, polyoxyethylene sorbitan monoleate 2g, ethylparaben 0.1g, surplus are that (prescription is total for water
Amount is based on 100g).After placing one month under the conditions of sample is in sealing appliance, 25 DEG C ± 2 DEG C: sample appearance is creamy white cream
Shape does not occur the phenomenon that matrix, water layer.
Embodiment 10
In vitro transdermal test
It is 280~350g male SD rat skin of abdomen as the barrier layer of penetrating absorption using weight.By intact unbroken
Skin is fixed between reception tank and supply pool (skin inner layer is towards reception tank).Diffusion cell parameter: effective diffusion area
3.14cm2, receive pool volume about 8.0ml, magnetic stirring speed 600rpm.It is full of physiological saline in reception tank, excludes bubble,
Stirring is opened, and constant temperature is to (37.0 ± 0.5) DEG C.Distinguish even spread sample about 0.5g (n=6) to skin surface, in 1,2,
4,6,8,10,12h absorption receiving liquid 5ml, and supplement physiological saline 5ml.The reception through 0.45 μm of membrane filtration is measured with HPLC
The concentration of Propranolol Hydrochloride in liquid.
Propranolol Hydrochloride unit area is calculated as follows accumulates transdermal amount:
Physiological saline volume in reception tank；Ci: the 1st
It is secondary to previous sample when receiving liquid drug concentration；Cn: receiving liquid drug concentration when the sub-sampling；m0: sample theory claims sample
Amount；M: the practical sample weighting amount of sample.
Drugs through skin amount percentage calculation formula: (drug accumulation transit dose ÷ is initially supplied to medication amount in pond) ×
100%
The gel preparation of emulsifiable paste and the Examples 1 to 9 preparation prepared using comparing embodiment 3 carries out penetrating absorption as sample.
The gel preparation penetrating absorption result (n=6) of 1 comparing embodiment 1 of table and 3 samples and Examples 1 to 9 preparation
Test result shows: 1. sample provided by the invention has good transdermal effect.In transdermal evaluation in 12 hours
79% or more drug in middle Examples 1 to 9 has all penetrated skin barrier layer.2. of the invention under the same conditions in medicament contg
There is the sample of preparation better transdermal effect (to be shown in Table 1 sample of comparing embodiment 1 in 3, comparing embodiment 3 and embodiment
Transdermal result).3. the highly concentrated sample of drug containing provided by the invention can penetrate more medication amounts, can for hypodermic type and
The treatment of mixed type hemangioma provides higher local blood concentration.
Embodiment 11
Long-term stable experiment
It in 10ml aluminum pipe and seals external-use gel preparation prepared by Examples 1 to 9 is filling, it is steady at 25 DEG C ± 2 DEG C
After being placed 24 months in qualitative investigation case, checks the appearance of sample and character and measure the content of drug, after 100 times of preparation diluent
Average grain diameter, preparation pH value with it is freshly prepared when parameter compare.
Table 2 applies 24 months stability parameters of external-use gel preparation of the preparation of example 1~9 compared with freshly prepared sample
Test result shows that Examples 1 to 9 sample provided by the invention is moderately good, can satisfy clinical application stability
Requirement.
Embodiment 12
Animal efficacy test and skin irritation observation
1. experimental design
Experimental animal is divided into five groups, and every group animal 7 (n=7), including hemangioma group (not giving any drug), compare
Sample (the hydrochloric Propranolol of sample (hydrochloric Propranolol 4%) administration group, the preparation of embodiment 1 prepared by embodiment 1
4%) sample (saliferous of sample (the hydrochloric Propranolol 10%) administration group, the preparation of embodiment 3 that prepared by administration group, embodiment 2
Sour Propranolol 16%) administration group.Every group of animal is by hemangioma position for percutaneous administration of the solidifying of equal quality in addition to hemangioma group
Glue.
2. establishing hemangioma model
Take hemangioma stem cell (HemSC) about 5 × 106It is a to be suspended in 200 μ l matrigels and culture medium mixed liquor (1:1)
In, it is inoculated into 6 week old nude mice dorsal scs, tumor formation after seven days.The execution of hemangioma group is taken into knurl after seven days.Remaining four groups are pressed agent
Amount design administration, 1 times/day, successive administration seven days, and whether observation skin there is red and swollen and fash daily, puts to death after seven days naked
Mouse takes out hemangioma knurl.
3. Testing index
Knurl is subjected to histotomy, 200 times of light are sliced under the microscope after HE dyeing, calculate cell and blood under each visual field
Lumen number.
4. test result is shown in Table 3
3 Examples 1 to 3 of table and 1 pharmacodynamic parameter of comparing embodiment and skin irritation observation result (n=7)
Test result shows: the sample that 1. embodiment of the present invention 1~3 provides can effectively inhibit angiomatous life
It is long, and skin irritation is small.2. 1 sample of embodiment provided by the invention is to angiomatous inhibition under the conditions of same medicament contg
Effect is significantly better than 1 sample of comparing embodiment.3. the high sample of Propranolol Hydrochloride content provided by the invention inhibits hemangioma
Effect it is more preferable, the infant hemangioma patient for the subcutaneous different depth of clinical treatment provides more selections.
Embodiment 13
Clinical drug effect and safety observations
The superficial type hemangioma 6 through clinical definite is collected, wherein male 2, female 4, the age 2 months~3 years old.It will implement
1 sample of example, which is uniformly applied to give at hemangioma, treats.Mixed type hemangioma 3 for collecting clinical definite, wherein male 1, female 2
Example, the age 3 months~2 years old, 2 sample of embodiment is uniformly applied to give at hemangioma and is treated.Successive administration 20 days, observation was treated
Effect, and monitor the blood pressure, blood glucose, heart rate of patient.
As a result: 1. either superficial type or mixed type hemangioma upon administration the 3rd day or so hemangioma color by scarlet
It deepens and gradually atrophy.Superficial type hemangioma almost all atrophy after administration 20 days, patient part color is normal close to recovery,
The close recovery from illness of patient part.After mixed-blood type hemangioma is administered 20 days, the hemangioma atrophy on surface, area become smaller, subcutaneous protrusion
Knurl gradually becomes flat, protrusion area and substantially reduces, and patient part improves significant.Show that the present invention is aobvious to blood vessel curative effect
It writes.2. not observing medicine-feeding part redness or broken skin phenomenon during administration, do not monitor that oral propranolol patient is common yet
Blood pressure, blood glucose, heart rate abnormal phenomenon.Show that the present invention has good safety.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field
The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel
And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, modifies, replacement and variant.
Claims (14)
1. a kind of Propranolol Hydrochloride external-use gel preparation, characterized by comprising:
At least Propranolol Hydrochloride of 3 weight %,
Drop after described 100 times of Propranolol Hydrochloride external-use gel preparation diluent has the average grain diameter of 200-700nm,
The Propranolol Hydrochloride external-use gel preparation further includes:
The gel-type vehicle of 10-35 weight %, the gel-type vehicle are selected from poloxamer；
The transdermal penetration enhancer of 3-13 weight %, the transdermal penetration enhancer are selected from Laurocapram, isopropyl myristate, peppermint
At least one of brain；
The moisturizer of 2-12 weight %；
The bacteriostatic agent of 0.02-0.2 weight %；And
The water of surplus.
2. Propranolol Hydrochloride external-use gel preparation according to claim 1 is, characterized by comprising: 3-16 weight %
Propranolol Hydrochloride.
3. Propranolol Hydrochloride external-use gel preparation according to claim 1, which is characterized in that the Propranolol Hydrochloride
The pH value of external-use gel preparation is 4.0-6.5.
4. Propranolol Hydrochloride external-use gel preparation according to claim 1, characterized by comprising:
The Propranolol Hydrochloride of 6-14 weight %；
The gel-type vehicle of 14-23 weight %；
The transdermal penetration enhancer of 4-10 weight %；
The moisturizer of 6-10 weight %；
The bacteriostatic agent of 0.04-0.1 weight %；And
The water of surplus.
5. Propranolol Hydrochloride external-use gel preparation according to claim 1 or 4, which is characterized in that the gel-type vehicle
For selected from least one of poloxamer 237, Pluronic/Lutrol F 108, poloxamer188.
6. Propranolol Hydrochloride external-use gel preparation according to claim 1 or 4, which is characterized in that the moisturizer is
Selected from least one of propylene glycol, glycerol and sorbierite.
7. Propranolol Hydrochloride external-use gel preparation according to claim 1 or 4, which is characterized in that the moisturizer is
Propylene glycol.
8. Propranolol Hydrochloride external-use gel preparation according to claim 1 or 4, which is characterized in that the bacteriostatic agent is
Selected from least one of sorbic acid, methylparaben, propylben and sodium benzoate.
9. Propranolol Hydrochloride external-use gel preparation according to claim 1 or 4, which is characterized in that the bacteriostatic agent is
Sorbic acid.
10. a kind of method for preparing the described in any item Propranolol Hydrochloride external-use gel preparations of claim 1-9, comprising:
It is heated after Propranolol Hydrochloride, bacteriostatic agent and water are mixed, to obtain lysate；
Gel-type vehicle is added into the lysate and stirs to being swollen, to obtain the first mixture；
Transdermal penetration enhancer and moisturizer are mixed, to obtain the second mixture；And
It is stirred after second mixture is mixed with first mixture, to obtain outside the Propranolol Hydrochloride
Use gel preparation.
11. the preparation method according to claim 10 for preparing Propranolol Hydrochloride external-use gel preparation, which is characterized in that
The stirring is carried out 6~15 minutes under the mixing speed of 100~6000rpm.
12. the purposes of the described in any item Propranolol Hydrochloride external-use gel preparations of claim 1-9 in medicine preparation, described
Drug is for treating hemangioma.
13. purposes according to claim 12, which is characterized in that the hemangioma is hemangioma under Infant.
14. purposes according to claim 12, which is characterized in that hemangioma is superficial type blood vessel under the Infant
Tumor, mixed type hemangioma and depth are in the angiomatous at least one of hypodermic type.
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| CN106619486B (en) * | 2016-11-03 | 2019-08-27 | 中国人民解放军第二军医大学 | Propranolol Hydrochloride gel and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1663560A (en) * | 2004-03-03 | 2005-09-07 | 杭州民生药业集团有限公司 | Transdermal drug administering system |
| CN102871956A (en) * | 2012-10-29 | 2013-01-16 | 中南大学湘雅医院 | Propranolol hydrochloride gel for treating infant superficial hemangioma |
-
2015
- 2015-04-03 CN CN201510158251.7A patent/CN105434336B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1663560A (en) * | 2004-03-03 | 2005-09-07 | 杭州民生药业集团有限公司 | Transdermal drug administering system |
| CN102871956A (en) * | 2012-10-29 | 2013-01-16 | 中南大学湘雅医院 | Propranolol hydrochloride gel for treating infant superficial hemangioma |
Non-Patent Citations (5)
| Title |
|---|
| Salt effects on the diffusion and release rate of propranolol from poloxamer 407 gels;Nivedita K. Pandit et al;《International Journal of Pharmaceutics》;19981231;第167卷;第183-189页 |
| Topical Propranolol Hydrochloride Gel for Superficial Infantile Hemangiomas;Lie WANG et al;《J Huazhong Univ Sci Technol》;20121231;第32卷(第6期);第923-923页 |
| 不同浓度***凝胶治疗婴幼儿血管瘤疗效观察;鲁阳春等;《中华实用儿科临床杂志》;20141031;第29卷(第19期);第1510页左栏第1段至第1513页左栏最后1段 |
| 盐酸***凝胶的制备与处方优化;张丽华等;《中国药房》;20150110;第26卷(第1期);第99页左栏第1段至第102页右栏最后1段 |
| 盐酸***凝胶的制备及其含量测定;张杰等;《中国药房》;20140402;第25卷(第13期);第1196-1198页 |
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