CN106176758B - A kind of externally-applied medicinal composition - Google Patents
A kind of externally-applied medicinal composition Download PDFInfo
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- CN106176758B CN106176758B CN201610427628.9A CN201610427628A CN106176758B CN 106176758 B CN106176758 B CN 106176758B CN 201610427628 A CN201610427628 A CN 201610427628A CN 106176758 B CN106176758 B CN 106176758B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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Abstract
The present invention relates to a kind of externally-applied medicinal compositions, it is characterised in that contains timolol and allantoin simultaneously, wherein timolol can be the form of free alkali, be also possible to the form of any salt of pharmaceutically acceptable.The composition preparation is with good stability and transdermal characteristic, has significant curative effect to infant hemangioma.
Description
Technical field
The pharmaceutical composition comprising timolol and allantoin that the present invention relates to a kind of, more particularly refers to hydrochloric acid thiophene Lip river
The compound external-use cream or gelling agent of that, timolol maleate and allantoin.
Background technique
Infant hemangioma (Infantile hemangioma, IH) is a kind of Childhood most common benign tumour,
Neonatal Morbidity is 10%-12%, male to female ratio 1:3-1:5.It is divided into superficial type, deep type generally according to lesions position and mixes
Mould assembly；It is divided into proliferative phase, paracmasis and recession completion phase according to pathological development process.The typical clinical manifestations of infant hemangioma
It is fast breeding in 1 year after birth, gradually slowly subsides later.
Although infant hemangioma can voluntarily subside, there is about 10% infant ulcer, infection, pain occur, or even lose
The severe complications such as bright, asphyxia；Separately because it is apt to occur in Head And Face, the serious psychological burden of infants ' parents is made.Currently,
The proliferation and recession mechanism of infant hemangioma are not yet completely clear, also without radical cure method in treatment.
According to angiomatous position, size, range, depth (Superficial hemangioma, deep vessels tumor, mixed type hemangioma),
By stages, function effect and to the different factor such as psychological impact of infant, the selection for the treatment of method is not also identical: smaller, place
In the hemangioma of stationary phase or paracmasis can using etc. it is to be seen；Local topical ointment can be used in Superficial hemangioma；Deep blood
Steroid hormone, pingyangmycin intratumor injection treatment can be used in tuberculation；Multiple, severe or the rapid hemangioma first choice mouth of growth
Hormone or propranolol in treatment are taken, interferon subcutaneous injection treatment also can be used when treatment is invalid；Angiomatous first choice is controlled in early days
Treatment scheme does not recommend operative treatment generally.
But above therapeutic effect is different, and systemic administration side reaction is big, to infant and parents of hospitalized children psychology, physiology and warp
Great burden is brought in Ji.
In recent years, topical remedy's external curing hemangioma obtains relatively satisfactory effect, and medication is convenient and avoids as far as possible
Whole body side reaction.In the research of therapeutic agent, from France doctor Leaute-Labreze C etc., in June, 2008 in " new English
Glan medical journal " on report for the first time Propranolol for the disease treatment after, the method causes scholars' immediately
Concern opened up a new way for angiomatous treatment, has started beta-receptor blocking agent and has treated the angiomatous beginning.
In recent years, other beta-receptor blocking agents such as timolol, acebutolol, atenolol is in treatment infant hemangioma
Aspect also shows that huge potentiality, curative effect are constantly confirmed.
2010, it is similarly timolol maleate (Timolol Maleate) eye drops of beta-receptor inhibitor, is reported
It road can external curing superficial type infant hemangioma；Separately having document report to deliver in December, -2013 in May, 2008 largely has
Beta-receptor blocking agent is closed, timolol local topical treats the domestic and foreign literature of infant hemangioma.
Additive of the allantoin as daily chemical products not only can promote the outermost water absorbing capacity of skin, hair, Er Qieyou
Help the hydrophilic power of keratoprotein molecule.Therefore, it can improve and wet skin, assign skin, hair and lip with soft, rich
In elasticity, gloss and anti-dry, anticracking.With flexibility, elasticity and the light for promoting epithelial cell growth, cutin-softening increase skin
The effect in pool.
Moisturizing and repair
Allantoin is widely used in skin-care cosmetics, especially the health care of infant and sensitive skin, to thick
Rough skin has good moisturizing effect, and skin smooth can be made plump.Allantoin has repair while moisturizing.
It can obviously improve the moisture loss between epidermis using the skin care item containing 0.5% allantoin, mitigate red and swollen phenomenon.
Moisture-keeping function
Allantoin, which has, promotes skin, and the water absorbing capacity of the outermost layer tissue of hair reduces moisture loss, there is skin emolliency
It is elastic, glossy and prevent chapped skin and other effects.
Allantoin has as drug and promotes cell growth, quickening wound healing, the physiological functions such as cutin-softening albumen,
It is the good consolidant and antiulcer agents of skin trauma.It can be used as alleviating and treating xerodermia, scaling skin illness, skin
Skin ulcer, digestive tract ulcer and inflammation, acne have good therapeutic effect.
In document published at present, the report that timolol and allantoin are used in combination there are no.
Summary of the invention
The present invention provides a kind of new externally-applied medicinal composition, pharmaceutical composition of the invention contain timolol and
Allantoin.
The present invention also provides a kind of new external preparation, external preparation of the invention contains timolol and allantoin drug
Composition.
Timolol can be the form of free alkali in the present invention, be also possible to the shape of any salt of pharmaceutically acceptable
Formula.It is preferred that timolol maleate, hydrochloric acid timolol.
Preferred timolol and allantoin mass ratio are 1:0.1-1:10 in pharmaceutical composition of the present invention.More preferable thiophene Lip river
You and allantoin mass ratio are 1:0.1-1:5.
External preparation of the invention, the preferably effective content of timolol are 0.1-5%.
External preparation of the invention can be semisolid external preparation, be also possible to externally used solution agent.It is semisolid outer
It can be gelling agent, ointment, cream with preparation.
It is preferred that external preparation of the invention is gelling agent.
The basic composition of inventive gel agent includes: gel-forming high molecular material, moisturizer, preservative and water.Gel
High molecular material is formed to play the role of gel forming and carry medicine；It is high that natural polymer, semi-synthetic macromolecule and synthesis can be divided into
Molecule three classes: 1. natural polymer: starch, alginate etc.；2. semi-synthetic macromolecule: modified cellulose and modified starch, such as
Carboxymethyl cellulose, methylcellulose etc.；3. synthesizing macromolecule: carbomer, polyacrylic etc.；Moisturizer plays holding moisture
With the effect of wet skin, there are commonly glycerol, the low molecule alcohol of propylene glycol: preservative plays the role of corrosion-resistant, keeps solidifying
Glue is not by the pollution of microorganism, and there are commonly oxybenzene esters etc..
In inventive gel agent formed gelling agent high molecular material be preferably selected from carbomer (carbopol) quasi polymer,
Hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyethylene glycol (PEG), carboxymethyl cellulose (CMC) class, hyaluronic acid
Mixture more than sodium or both and the two；Wherein the property of can choose add moisturizer, moisturizer be selected from propylene glycol, glycerol,
The low molecule alcohols such as ethyl alcohol, benzyl alcohol, benzyl carbinol and diethylene glycol monoethyl ether (Transcutol P), the poly- second of caprylic capric
Mixture more than glycol glyceride (Labrasol) or both and the two.
It is preferred that external preparation of the invention is cream.
When external preparation of the invention is cream, the ingredient of composition cream oil phase is preferably selected from, atoleine, tristearin
Mixing more than acid, oleic acid, vaseline, beeswax, stearin, cetostearyl alcohol, methyl-silicone oil or both and the two
Object.The emulsifier of composition cream is preferably selected from lauryl sodium sulfate, odium stearate, Crodaret, poly- mountain
Pear ester, glycerol polyethylene glycol -75- stearate, pegoxol 7 stearate, carbomer (carbopol) quasi polymer, or
Mixture more than both or both.
Creatively timolol and allantoin are used in combination by the present invention, and semisolid external preparation (such as gel is made
Agent, ointment, cream etc.), as a result researcher greatly improves thiophene it has surprisingly been found that due to joined allantoin
Luo Er external curing hemangioma curative effect, and overcome since bring adverse reaction problem is used for a long time in external preparation, it improves
The compliance of patient, significantly improves the quality of life of infant patient, is very beneficial for the active treatment of this kind of disease,
With huge economic and social benefit.
It in the prior art, is to be configured to aqueous pharmaceutical using timolol as main ingredient or ordinary gel agent uses；Existing skill
There are some unsurmountable defects for timolol external medicine preparation in art, have seriously affected using and pushing away for the drug
Extensively.
Firstly, solution action time it is short, it is easy trickling and be difficult to stay in lesion portion, dosage is unable to control, and is unfavorable for essence
Really administration；When applied to mouth week, eye circumference lesion, easy inflow entrance is interior, intraocular, and causes potential systemic adverse reactions；So molten
Liquor is apparently not the preferred form of administration of infant hemangioma treatment.
Secondly, the dosage forms such as common gelling agent and emulsifiable paste, although solution can be overcome to be administered, drug warp
Cross percutaneous drug delivery to treat hemangioma, the crucial step that drug plays drug effect is: (1) skin is that drug is penetrated into blood
The size of the barrier organ that tuberculation works, the amount that drug percutaneous skin absorbs is the angiomatous main pass of timolol external curing
Key factor；(2) angiomatous treatment is a long-term process, and generally contiguous administration time continues at 6 months or more.External application cream
The long-time services such as cream, gel, solution would generally bring rubefaction, itch, decortication even to fester etc. symptoms, especially baby children
Youngster patient, they bear a pretty, delicate skin, and anti-irritation is weak；Pruitus, fester be patient interrupt treatment principal element, seriously affect
The treatment of patient is arrived.
Researcher of the present invention is by verification experimental verification it has surprisingly been found that (1) medicine group of the present invention containing allantoin
It closes and preparation, the amount of the percutaneous absorbtion of drug timolol is significantly improved than control prescription, this is exactly of the present invention containing urine
The curative effect of medication of Bursin preparation improves reason for it.(2) while improving the curative effect of drug, allantoin can increase and promote
Into the hydratability of epidermis cement matrix, and keratin is directly acted on, the ability for making it combine water increases, and becomes skin
It is smooth, wetting and it is flexible, have the function of pacifying skin well.
Therefore timolol and allantoin are applied in combination, and not only act as the effect for increasing timolol Transdermal absorption, more
It is of importance that having simultaneously for long-term administration bring irritation, dry skin, ulcer is overcome and alleviating and pacify well work
With greatly improving the compliance of patient's medication, improve the quality of life of infant patient.
Pharmaceutical composition and external preparation of the invention can be prepared using the common method of pharmacy.
General preparative methods in a kind of specific embodiment of the present invention are briefly outlined below, the technique ginseng under specific prescription
Number has been not excluded for possibility adjusted.
The preparation method of gelling agent: taking carbomer, and appropriate purified water is added to stir evenly, and keeps carbomer fully dispersed；Separately take hydrogen-oxygen
Change sodium to be dissolved in purified water, be gradually added into carbomer suspension, adjusts pH to 4-9 range, form gel；Pharmaceutical composition with
And remaining component is added by several times, stirs evenly to obtain the final product.
The preparation method of cream: the oil and oil-soluble ingredients in prescription are heated to 80 DEG C or so at oily molten together
Liquid (oily phase), it is separately that pharmaceutical composition and water-soluble component is soluble in water and be heated to 80 DEG C at aqueous solution (water phase) together.
When oil is mutually mixed with water, water phase is added in oily phase.After stirring 30 minutes, continue to be cooled to room temperature under stirring to obtain the final product.
The effect of present composition external medicine preparation mainly passes through Drug Percutaneous Absorption comparative study, pharmacodynamics pair
It is embodied than three aspects such as research and the verifying of clinical efficacy.
Drug Percutaneous Absorption comparative study
It is tested using the vertical diffusion cell of the Franz of improvement, using in vitro miniature swine skin as absorption barrier, skin is solid
It is scheduled between supply pool and reception tank, by keratoderma towards supply pool side, it is (straight that tested preparation is uniformly coated in supply pool
Diameter 2.0cm).It is compared using the concentration that HPLC measurement drug penetrates, to illustrate the meaning of the present composition.It is tied by test
Fruit can be seen that the composite preparation containing allantoin, the drug concentration of the Transdermal absorption of timolol can be made to improve several
One times.Therefore the therapeutic effect of drug is substantially increased.Thus novelty and feasibility of the invention are demonstrated.
Pharmacodynamics comparative study
It establishes the tumor model of nude mice: taking the HemSC and HUVEC of originally culture, while after being digested with pancreatin, taking 1 × 106
A HemSC+5 × 105A HUVEC is suspended in the Matrigel of 200 μ L, is transferred to every nude mice back side and is injected into 200 μ L
Matrigel i.e. 1.5 × 106A cell injects weekly 17 beta estradiols of 1 0.1mg/ only, after modeling successfully after 2 weeks, carries out
Pharmacodynamics test, MAIN OUTCOME MEASURES are the size of gross tumor volume.
Pharmacodynamic test result confirms: and the object preparation without allantoin compares, simultaneously containing timolol and allantoin
Composite preparation has surprising therapeutic effect on pharmacodynamics model, and medication effect greatlys improve, this also with it is transdermal
The result of test matches, and also provides the support of experimental data for novelty of the invention and feasibility.
The verifying of clinical efficacy
We choose the infant for suffering from superficial type infant hemangioma at 25 1 ~ 6 monthly ages, are to composite preparation
Phase 3 months external medications.The result shows that in 25 cases, no an example occurs that knurl local skin is rubescent, husking, skin
Skin ulceration, ulcer or severe total reaction.20 patient vessel's tumor symptoms completely disappear, although remaining 5 symptom is without complete
Subside, but has and significantly improve.All infants ' parents are very satisfied to therapeutic effect and side effect evaluation.At the beginning of this
The clinic trial of step demonstrates novelty and feasibility of the invention from clinical angle.
It is described in detail below by specific embodiment.The present invention is not limited only to following embodiment.
Embodiment 1.
Preparation process: by oil and oil-soluble ingredients (atoleine, stearic acid, the glycerol monostearate in prescription
Ester) it is heated to 80 DEG C or so together at oil solution (oily phase), it is separately that water-soluble component (glycerol, sodium hydroxide) is soluble in water and one
It rises and is heated to 80 DEG C at aqueous solution (water phase).When oil is mutually mixed with water, water phase is added in oily phase.It, will after stirring 30 minutes
Timolol maleate, allantoin, ethyl hydroxy benzoate, sequentially add, continue stirring 30 minutes, be cooled under stirring room temperature to get
Timolol maleate cream.
Embodiment 2.
Preparation process: together by the oil and oil-soluble ingredients (methyl-silicone oil, stearic acid, cetostearyl alcohol) in prescription
75 DEG C or so are heated at oil solution (oily phase), separately by water-soluble component (timolol maleate, propylene glycol, allantoin, glycerol
Polyethylene glycol -75- stearate, ethyl hydroxy benzoate) it is soluble in water and be heated to 70 DEG C together at aqueous solution (water phase).Oily Xiang Yushui
When mixing, after stirring 30 minutes, it is cooled to room temperature with stirring to get timolol maleate cream.
Embodiment 3.
Preparation process: the oil and oil-soluble ingredients (atoleine) in prescription are heated to 30 DEG C or so into oil solution
(oily phase), separately by water-soluble component (HPMC, timolol maleate, propylene glycol, allantoin, polyoxyethylene sorbitan monoleate, oxybenzene first/the third
Ester) it is soluble in water and be heated to 30 DEG C together at aqueous solution (water phase).Oil is mutually mixed with water, to get horse after stirring 30 minutes
Carry out sour timolol cream.
Embodiment 4.
Preparation process: the oil and oil-soluble ingredients (atoleine) in prescription are heated to 30 DEG C or so into oil solution
(oily phase), separately by water-soluble component (Crodaret, timolol maleate, propylene glycol, allantoin, oxybenzene first/
Propyl ester) it is soluble in water and be heated to 30 DEG C or so together at aqueous solution (water phase), water phase and oil mix, and stir 30 minutes；Card
It is 4-6 that wave nurse, which is scattered in after water with sodium hydroxide adjusting pH, is also added in the above mixture, it is equal to continue stirring mixing in 30 minutes
To get timolol maleate emulsion-type gel after even.
Embodiment 5.
Preparation process: it is 4-6 that carbomer dispersion, which is adjusted pH with sodium hydroxide after water, and it is spare to form gel；By prescription
Middle timolol maleate, allantoin, glycerol, Nipasol are soluble in water；The aqueous solution of the mixture is added to spare
In gel, mixing stirs 30 minutes to get Timoptic-XE agent.
Embodiment 6.
Preparation process: it is spare that sodium carboxymethylcellulose is dissolved in water formation gel；By timolol maleate, urine in prescription
Bursin, propylene glycol, diethylene glycol monoethyl ether, ethyl hydroxy benzoate are soluble in water；The aqueous solution of the mixture is added to spare
In gel, mixing stirs 30 minutes to get Timoptic-XE agent.
Embodiment 7.
Preparation process: by oil and oil-soluble ingredients (Labraso, diethylene glycol in prescription
Single ethylether) 60 DEG C or so are heated at oil solution (oily phase), separately by water-soluble component (hydrochloric acid timolol, allantoin, polyoxy
Ethylene hydrogenation castor oil, ethyl hydroxy benzoate) it is soluble in water and be heated to 60 DEG C together at aqueous solution (water phase).It is oily mutually mixed with water phase
It closes, to get timolol maleate cream after persistently stirring 45 minutes.
Embodiment 8.
Novelty and feasibility in order to further illustrate the present invention, we will be in pharmaceutical composition of the present invention and embodiment
External preparation carried out penetrating absorption measurement, after the allantoin in composition and preparation prescription is removed, carry out as a comparison
Comparability test, it was demonstrated that the Transdermal absorption facilitation to timolol of allantoin.
Penetrating absorption method
It is tested using the vertical diffusion cell of the Franz of improvement, this law is topical preparation more typical in current document
External permeability research method.Diffusion cell is made of supply pool and reception tank, by skin be fixed on supply pool and reception tank it
Between, by keratoderma towards supply pool side, tested preparation (diameter 2.0cm) is uniformly coated in supply pool.Add in reception tank
Enter the receiving liquid of 7ml, magnetic stir bar, mixing speed 300rpm, temperature (37 ± 0.5) DEG C are put into reception tank bottom groove.
After starting test, in 0,1,2,4,6,8,10h timing sampling, 3ml receiving liquid is drawn every time, mends the receiving liquid of equivalent, mistake immediately
Drug concentration is measured using HPLC after filter.
Instrument
Percutaneous dispersion test instrument (TK-12B type), the triumphant scientific and technological trade Co., Ltd of Shanghai armour；The vertical diffusion of the Franz of improvement
Pond (effective transmission area 3.14cm2, reception tank volume 7ml), the triumphant scientific and technological trade Co., Ltd of Shanghai armour.
Experimental animal skin
Miniature swine skin (BaMa miniature pig), gender: the age: male 2.0 months, is taught by third army medical university's experimental animal
Room offer is provided.
Test result
With embodiment 5 for basic prescription, the penetrating absorption result of different proportion composition is determined.Wherein Malaysia
The content of sour timolol immobilizes for 0.5%, determines timolol maleate: allantoin ratio is 0.5:0(i.e. anuria
Bursin group), 0.5:0.05,0.5:0.1,0.5:0.3,0.5:0.5, the composition penetrating absorption result of 0.5:1.0,0.5:2.5.
As a result as follows:
The preparation of composition it can be seen from test result containing allantoin can make the transdermal suction of timolol
The drug concentration of receipts increases substantially.When timolol maleate: allantoin ratio is Transdermal absorption when being increased to 0.5:0.3
Drug concentration be almost doubled；It is further added by the concentration of allantoin later, still can continue the medicine for improving Transdermal absorption
Object concentration, but increasing degree is slowed down.Therefore the composition containing allantoin substantially increases the therapeutic effect of drug.By
This demonstrates novelty and feasibility of the invention.
Embodiment 1,2,3,4,6 represents the different dosage forms of composition, as follows to the result of its skin permeation test in vitro measurement
Table, comparison prescription are the prescription that allantoin is free of in corresponding embodiment:
The preparation of the composition containing allantoin in all embodiments it can be seen from test result, can make thiophene
The drug concentration of the Transdermal absorption of Luo Er improves almost more than one times, therefore substantially increases the therapeutic effect of drug.Thus it demonstrate,proves
Novelty and feasibility of the invention is illustrated.
Preliminary pharmacodynamic study has been carried out to the composition prescription in embodiment 4 and 5 simultaneously.
The foundation of experimental hemangioma nude mice model: taking the HemSC and HUVEC of originally culture, while after being digested with pancreatin,
Take 1 × 106A HemSC+5 × 105A HUVEC is suspended in the Matrigel of 200 μ L, is transferred to every nude mice back side and is injected into 200 μ
LMatrigel i.e. 1.5 × 106A cell, injects weekly 17 beta estradiols (100 μ L DMSO dissolution) of 1 0.1mg/ only, and 2 weeks
Nude mice is put to death afterwards, observes its tumor formation effect, HE dyeing and SP method immunohistochemistry Glut-1 are carried out to transplanting tumor tissue
It is detected with CD31, whether verifying hemangioma model constructs success.After modeling successfully, pharmacodynamics test, MAIN OUTCOME MEASURES are carried out
For the size of gross tumor volume.
30 mouse for being successfully established hemangioma model are divided into 3 groups, respectively blank control group (abbreviation blank group), solidifying
Glue administration group 1(embodiment 4), gel delivery group 2(prescription with embodiment 4, but without allantoin).
Blank control group (abbreviation blank group): without any processing.
Gel: after hemangioma model construction 2 weeks, being uniformly applied to knurl surface by gel delivery group, thickness about 1mm,
Gently massage is until drug absorption, and 1 time/d；Knurl remained on surface drug matrices gently are wiped before applying outside every time, drug is filled
Divide and absorbs；Continuous processing 2 weeks；It observes the 20th day.
It is animal packet and test result (gross tumor volume size) below:
The above test result of embodiment 4 and embodiment 5 confirms: and the object preparation without allantoin compares, and contains simultaneously
The composite preparation of timolol and allantoin has surprising therapeutic effect on pharmacodynamics model, and medication effect is very big
Ground improves, this also matches with the result of penetrating absorption, also provides experimental data for novelty of the invention and feasibility
It supports.
Embodiment 9.
In order to verify novelty and feasibility of the invention, we choose 25 1 ~ 6 monthly ages with superficial type infant's blood
The infant of tuberculation, acquirement parent are known and license, has carried out preliminary clinic trial to 4 preparation of embodiment, has carried out 3 by a definite date
The external medication of the moon evaluates curative effect with visual analogue scales, and records adverse reaction.
The result shows that there is rubescent knurl local skin, husking, skin ulceration, ulcer or tight in no an example in 25 cases
General reaction again.20 patient vessel's tumor symptoms completely disappear, although remaining 5 symptom without subsiding completely, has very greatly
The improvement of degree.All infants ' parents are very satisfied to therapeutic effect and side effect evaluation.
This preliminary clinic trial demonstrates novelty and feasibility of the invention from clinical angle.
Bibliography
1. the progress China Dispensary of the local topical timolol such as Wang Xia treatment infant hemangioma, 2014,25
(44) : 4212
2. the randomized double-blind prediction that the timolol maleate external-use gel such as Chou Ya Jing treats superficial type infant hemangioma
Property clinical research organizational project and reconstructive surgery magazine, 2014,10 (4): 203
3. a kind of long-acting preparation capable of permeating skin of timolol of the big of Zheng family and its application Chinese invention patent in hemangioma,
CN104274390
4. in the external application Propranolol such as Li Qian and timolol treatment infant's haemangioma of facial region curative effect comparative observation
State's aesthetic medicine, 2014,23 (3): 221
5. the progress China aesthetic medicine of the hemangioma external medication such as clock benefit duckweed, 2013,22 (3): 229
/
6. the big equal infant hemangioma drug therapy of Zheng family summarizes China Oral and Maxillofacial Surgery magazine, 2014,12 (1):
1。
Claims (9)
1. a kind of externally-applied medicinal composition, it is characterised in that containing timolol and allantoin, wherein timolol and allantoin
Mass ratio is 1:0.1-1:10.
2. pharmaceutical composition described in claim 1, which is characterized in that timolol be free alkali form or pharmaceutically can be with
The form of any salt received.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that timolol is selected from timolol maleate, hydrochloric acid thiophene
Luo Er.
4. the external preparation containing any one of claim 1-3 described pharmaceutical composition, it is characterised in that timolol in preparation
Effective content be 0.1-5%.
5. external preparation as claimed in claim 4 is selected from gelling agent, cream, other semisolid external preparations, externally used solution
Agent.
6. external preparation described in claim 5 is gelling agent, it is characterised in that the major auxiliary burden for forming gelling agent is selected from card wave
Nurse (carbopol) polymer, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyethylene glycol (PEG), carboxymethyl cellulose
Plain (CMC), Sodium Hyaluronate or the mixture more than both.
7. external preparation as claimed in claim 6, it is characterised in that can wherein add propylene glycol, glycerol, ethyl alcohol, benzyl alcohol,
Benzyl carbinol and diethylene glycol monoethyl ether, Labraso or the mixture more than both.
8. external preparation described in claims 5 is cream, it is characterised in that the ingredient of composition cream oil phase is selected from liquid
Body paraffin, stearic acid, oleic acid, vaseline, beeswax, stearin, methyl-silicone oil or the mixture more than both.
9. external preparation described in claims 5 is cream, it is characterised in that the emulsifier for forming cream is selected from 12
Sodium alkyl sulfate, odium stearate, Crodaret, polysorbate, glycerol polyethylene glycol -75- stearate, poly- second
Glycol -7- stearate, carbomer (carbopol) polymer or the mixture more than both.
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| CN201610427628.9A CN106176758B (en) | 2016-06-17 | 2016-06-17 | A kind of externally-applied medicinal composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610427628.9A CN106176758B (en) | 2016-06-17 | 2016-06-17 | A kind of externally-applied medicinal composition |
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| Publication Number | Publication Date |
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| CN106176758A CN106176758A (en) | 2016-12-07 |
| CN106176758B true CN106176758B (en) | 2019-07-23 |
Family
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| CN201610427628.9A Active CN106176758B (en) | 2016-06-17 | 2016-06-17 | A kind of externally-applied medicinal composition |
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| Country | Link |
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| CN (1) | CN106176758B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2621775A (en) * | 2019-09-04 | 2024-02-21 | Wuhan Conform Pharmaceutical Co Ltd | Transdermal permeation enhancing composition and application thereof in timolol preparation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107281094B (en) * | 2017-06-14 | 2018-05-15 | 上海奥科达生物医药科技有限公司 | A kind of timolol maleate Pharmaceutical composition and preparation method thereof |
| CN107970257A (en) * | 2017-12-22 | 2018-05-01 | 成都博创必成医药技术有限公司 | A kind of ear pharmaceutical composition, preparation method and applications and ear pharmaceutical preparation |
| CN111374937B (en) * | 2019-10-11 | 2023-04-18 | 郑州儿童医院 | Gel for infantile hemangioma and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040837A (en) * | 2013-01-13 | 2013-04-17 | 广东宏盈科技有限公司 | Ophthalmologic intraocular pressure reduction drug for external use |
| CN105106105A (en) * | 2015-08-14 | 2015-12-02 | 天津市聚星康华医药科技有限公司 | Application of external timolol preparations in treating infantile hemangioma and preparation method thereof |
-
2016
- 2016-06-17 CN CN201610427628.9A patent/CN106176758B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040837A (en) * | 2013-01-13 | 2013-04-17 | 广东宏盈科技有限公司 | Ophthalmologic intraocular pressure reduction drug for external use |
| CN105106105A (en) * | 2015-08-14 | 2015-12-02 | 天津市聚星康华医药科技有限公司 | Application of external timolol preparations in treating infantile hemangioma and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2621775A (en) * | 2019-09-04 | 2024-02-21 | Wuhan Conform Pharmaceutical Co Ltd | Transdermal permeation enhancing composition and application thereof in timolol preparation |
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| CN106176758A (en) | 2016-12-07 |
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