CN108403618A - A kind of imiquimod vaginal expansion plug and preparation method thereof - Google Patents
A kind of imiquimod vaginal expansion plug and preparation method thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
The present invention provides a kind of vaginal expansion plugs and its preparation method and application, the expansible plug includes imiquimod, hyaluronic acid, matrix and expandable expandable carrier, wherein expansible plug further includes the combination of functional oligose, preferably oligoisomaltose and oligomeric dragon gallbladder sugar.Vaginal expansion plug provided by the invention, the active ingredients such as imiquimod and hyaluronic acid are utilized by combination, it is synergistic, improve vaginal flora environment, the ingredients such as combination matching matrix, preservative, curing agent and thickener improve bioavilability, reduce the side effect of imiquimod, suppository comfort level is improved, intravaginal condyloma acuminatum can be effectively treated.
Description
Technical field
The invention belongs to vaginal suppository field, it is related to a kind of vaginal expansion plug and preparation method thereof, and in particular to Yi Zhongmi
Not special vaginal expansion plug of quinoline and preparation method thereof.
Background technology
Condyloma acuminatum be by human papilloma virus (HPV) infect caused by based on anus genital area hyperplastic lesions
The sexually transmitted disease to be showed seriously endangers women's health.HPV has different hypotypes, most often cause condyloma acuminatum have HPV6,
HPV11 is easy to live and reproduce under conditions of human body warm moist, therefore genitals and crissum are the positions most easily infected.
Suppository has the following advantages as a kind of common dosage form with other dosage form ratios：1) first pass effect of oral drugs can be avoided,
2) suppository can contact after filling in cavity with cavity mucomembranous surface, soften quickly, melt or dissolve in body temperature, be secreted with cavity
Liquid mixes, and is effectively increased contact area, 3) drug is not affected or less affected by the destruction of gastrointestinal tract pH value or enzyme.
Imiquimod is a kind of different ring imidazole quinoline amine drug of artificial synthesized non-nucleosides, belongs to small molecule immune adjusting
Agent, existing dosage form are confined to imiquimod cream, are that first external application of U.S. Food and Drug Administration's approval listing is controlled
The immunomodulator for treating genitals condyloma acuminatum, since imiquimod has immunological regulation, antitumor, anti-angiogenic and fibroplasia
It is interesting in recent years etc. a variety of effects.But single dosage form limitation is strong, can not effectively be directed to vagina administration, and excessively make
Red and swollen at smearing, rotten to the corn and bubble etc. with that can directly contribute, therefore limit its application.
CN106177007A disclose it is a kind of for treat high-risk HPV persistent infection cervical disease Chinese medicine suppository and
Preparation method, the Chinese medicine suppository include host agent and the pharmaceutically acceptable adjuvant that suppository is made, and host agent includes realgar 50-150
Part, 100-300 parts of the coptis or Berberine hydrochloride, 10-30 parts of alum, 5-15 parts of borneol.Traditional Chinese medicine ingredients contained by the suppository are complicated, treat
Imitate it is unstable, influence drug effect performance.CN1555264A discloses a kind of immune response modifier compound：Imidazole quinoline amine, imidazoles
Imidazole quinoline amine, thiazole and the-He oxazoles of pyridine amine, 6,7- condensed naphthenic base Imidazopyridine amine, 1,2- bridgings simultaneously-quinolinamine
It can be used for treating the illness of mucomembranous surface or lower part with pyridine amine, imidazoles naphthyridines and imidazolidine naphthyridines, method is in mucous membrane table
Apply these compounds of therapeutically effective amount in face.But it includes a variety of imidazole quinoline class compounds to combine species, and side effect is larger, is held
Easily cause the skin problems such as discomfort at medication.
Therefore it provides a kind of suppository of the treatment condyloma acuminatum of safety and stability is of great significance and wide foreground.
Invention content
In view of the deficiencies of the prior art and actual demand, the present invention provides a kind of imiquimod vaginal expansion plug and its system
Preparation Method.
For this purpose, the present invention uses following technical scheme：
In a first aspect, the present invention provides a kind of imiquimod vaginal expansion plug, the expansible plug includes imiquimod, transparent
Matter acid, matrix and expandable expandable carrier, the parts by weight of each ingredient of expansible plug are：
Imiquimod category imidazole quinoline class compound, is a Small molecule immunodulators, can induce internal cell factor
Antiviral activity is generated, it is more effectively to induce alpha-interferon (IFN-α) and α-tumornecrosisfactor (TNF-α) etc. in vivo and in vitro
Kind cell factor, starts immune system fight adventitious viruses in human body.
Hyaluronic acid is as modulators of cytokine activity, the ability of regulation and control with special cell factor, to inhomogeneity
The herpesviral of type and bacterial strain, HIV, cytomegalovirus have significant high activity.Imiquimod is applied in combination and hyaluronic acid can
With synergy, promote the two Function, while the addition of hyaluronic acid can mitigate the issuable secondary work of imiquimod
With alleviation cavity discomfort is such as red and swollen, itch, cusalgia etc..
It is a discovery of the invention that secondary work can be effectively prevent by the composition that the parts by weight and composition transparent matter acid are prepared
With generation, and suppository obtained can be used safely in intravaginal administration under the composition and preparation method, for treating vagina
Condyloma acuminatum.
The imiquimod is 15-30 parts, for example, can be 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22
Part, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts or 30 parts.
The hyaluronic acid is 10-26 parts, for example, can be 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17
Part, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts or 26 parts.
The matrix is 80-220 parts, for example, can be 80 parts, 82 parts, 84 parts, 85 parts, 87 parts, 89 parts, 90 parts, 94 parts,
95 parts, 98 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts,
155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, 195 parts, 200 parts, 205 parts, 210 parts, 205
Part, 206 parts, 208 parts or 220 parts.
The expandable carrier is 50-300 parts, for example, can be 50 parts, 55 parts, 60 parts, 70 parts, 80 parts, 90 parts, 100 parts,
110 parts, 120 parts, 130 parts, 140 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 180 parts, 190 parts, 200 parts, 210
Part, 220 parts, 230 parts, 240 parts, 250 parts, 260 parts, 270 parts, 280 parts, 290 parts or 300 parts.
Preferably, the expansible plug further includes functional oligose.
Functional oligose is the low polymerization sugar for forming branch or branch by glucosides key connection by 2-10 monosaccharide, people
Without the enzyme system of hydrolysis function oligosaccharide in body enteron aisle, therefore they cannot be digested absorption and to be directly entered big enteral excellent
It is first that Bifidobacterium utilizes, is the proliferation factor of Bifidobacterium, usually as the preferred prebiotics of food service industry, present invention hair
Existing, it can directly be that vagina beneficial bacterium Bifidobacterium supplies nutrition, and is not utilized by harmful bacteria that functional oligose is added in suppository,
And then increase accounting of the beneficial bacterium in vaginal environment, vaginal flora environment is adjusted, vagina immunity and self-healing ability are improved,
Drug effect is assisted to play.
Preferably, the parts by weight that the functional oligose accounts for the expansible plug are 5-20 parts, for example, can be 5 parts, 6
Part, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts or 20 parts, preferably
10-15 parts.
Preferably, the functional oligose include stachyose, it is raffinose, milk ketose, oligofructose, xylo-oligosaccharide, low
Appointing in poly- galactolipin, oligoisomaltose, iMOS, oligomeric dragon gallbladder sugar, soyabean oligosaccharides or chitosan oligomer
It anticipates a kind of or at least two combinations, the combination for example can be the combination of raffinose and oligofructose, xylo-oligosaccharide and low
The combination of the combination of poly- galactolipin, oligoisomaltose and oligomeric dragon gallbladder sugar, stachyose, oligoisomaltose and soyabean oligosaccharides
Combination, the combination of xylo-oligosaccharide, galactooligosaccharide, oligoisomaltose and iMOS, preferably oligomeric different wheat
The combination of bud sugar and oligomeric dragon gallbladder sugar.
It is a discovery of the invention that oligoisomaltose is best in vagina pH environment stability inferiors, utilized convenient for Bifidobacterium intake；
The hygroscopicity of oligomeric dragon gallbladder sugar is strong, can effectively keep moisture, prevents suppository dry and astringent.
Preferably, the weight ratio of the oligoisomaltose and oligomeric dragon gallbladder sugar is (3-8):(1-5), such as can be 3:
1、4:3、3:5、5:3、6:5、7:4 or 8:3, preferably 5:3.
It is a discovery of the invention that be combined under the ratio can be synergistic for oligoisomaltose and oligomeric dragon gallbladder sugar, it is double
The proliferative conditions of discrimination bacillus are best, and activity is best, the cure rate highest of condyloma acuminata of vagina.
Preferably, the matrix includes Acrawax, natural acid ester, lipoidis matrix, water-soluble base, hydrogen
In carburetion or distillate oil any one or at least two combination, the combination for example can be Acrawax and water-soluble
The combination of property matrix, the combination of natural acid ester and hydrogenated oil and fat, the combination of lipoidis matrix and distillate oil, synthetic fatty acid
Ester, the combination of natural acid ester and water-soluble base or the combination of lipoidis matrix, water-soluble base and hydrogenated oil and fat, preferably
For the combination of Acrawax, natural acid ester and water-soluble base.
Preferably, the weight ratio of the Acrawax, natural acid ester and water-soluble base is (3-8):(1-
5):(1-3), such as can be 3:2:2、3:1:3、4:3:1、5:3:2、5:4:1、6:3:2、7:4:3 or 8:5:3, preferably 5:
3:2。
It is a discovery of the invention that Acrawax, natural acid ester and water-soluble base are combined according to the ratio
The comfort level during suppository use can be improved, reduce foreign body sensation, while making drug distribution evenly, improve bioavilability.
Preferably, the Acrawax be mixed fatty glycerides, it is propylene glycol stearate, fixed oil, hemizygous
At any one in fatty glyceride, semi-synthetic cocounut oil ester, Witepsol, semi-synthetic palm grease or semi-synthetic fruit of a cubeb litsea tree ester
Kind or at least two mixture, the mixture for example can be the mixture of mixed fatty glycerides and fixed oil, firmly
The mixture or semi-synthetic cocounut oil ester, Witepsol and semi-synthetic mountain of resin acid propylene glycol ester and semi-synthetic fatty glyceride are grey
The mixture of sub- ester.
Preferably, the natural acid ester is to appoint in oleum sapii, spicebush oil, fennel fat, Ke Kemu fat or cocoa butter
It anticipates a kind of or at least two mixtures, the mixture for example can be the mixture of oleum sapii and Ke Kemu fat, spicebush oil
With the mixture or spicebush oil of Ke Kemu fat, the mixture of fennel fat and cocoa butter.
Preferably, the lipoidis matrix is lanolin and/or lanonol, preferably lanonol.
Preferably, the water-soluble base is polyethylene glycol 1450, polyethylene glycol 3350, Macrogol 4000, poly- second two
In alcohol 6000, glycerin gelatine, polyoxyl 40 stearate or poloxamer any one or at least two mixture, institute
State mixture for example and can be polyethylene glycol 1450 and the mixture of polyethylene glycol 3350, Macrogol 4000 and glycerin gelatine
The mixture of mixture, Macrogol 6000 and poloxamer, Macrogol 6000, glycerin gelatine and polyoxyethylene monostearate
The mixture of ester, polyethylene glycol 1450, polyethylene glycol 3350, Macrogol 4000 and poloxamer mixture, it is preferably poly-
The mixture of ethylene glycol 1450 and polyethylene glycol 3350.
It is a discovery of the invention that when polyethylene glycol 1450 and polyethylene glycol 3350 being selected to combine as matrix, it can good branch
Suppository shape is supportted, hardness is moderate, does not interfere the release of drug component to be played with drug effect, improves suppository usage comfort.
Preferably, the weight ratio of the polyethylene glycol 1450 and polyethylene glycol 3350 is (1-4):1, such as can be 1:1、
2:1、3:1 or 4:1.
Preferably, the hydrogenated oil and fat is appointing in hydrogenated vegetable oil, hydrogenated groundnut, rilanit special or cotmar
It anticipates a kind of or at least two mixtures, the mixture for example can be the mixture of hydrogenated vegetable oil and rilanit special,
The mixture of the mixture or hydrogenated vegetable oil of hydrogenated groundnut and cotmar, hydrogenated groundnut and rilanit special.
Preferably, the distillate oil is fractionating palm oil and/or fractionated coconut oil.
Preferably, the matrix further include in preservative, curing agent or thickener any one or at least two group
It closes, such as can be the combination of preservative and curing agent, the combination of preservative and thickener, the combination of curing agent and thickener,
Or the combination of preservative, curing agent and thickener.
It is a discovery of the invention that matrix includes preservative, curing agent and thickener, and the preservative, curing agent and increasing
Thick dose be combined according to the parts by weight can be not corrupt with stable pharmaceutical ingredient, keeps suppository hardness moderate, dimensional stability
It is indeformable.
Preferably, the matrix includes the increasing of 5-10 parts of preservative, 1-12 parts of curing agent and 15-30 in parts by weight
Thick dose.
The preservative is 5-10 parts in parts by weight, such as can be 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts.
The curing agent is 1-12 parts in parts by weight, for example, can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8
Part, 9 parts, 10 parts, 11 parts or 12 parts.
The thickener is 15-30 parts in parts by weight, for example, can be 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20
Part, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts or 30 parts.
Preferably, the preservative includes any one in sorbic acid, cinnamic acid or vanilate or at least two
Combination, it is described combination for example can be sorbic acid and cinnamic acid combination, the combination of mountain sodium sulphate and vanilate, cinnamic acid and
The combination of vanilate, the combination of sorbic acid, cinnamic acid and vanilate, preferably sorbic acid.
Preferably, the curing agent include in Chinese wax, cetanol, stearic acid or Brazil wax any one or at least
Two kinds of combination, the combination for example can be the combinations of Chinese wax and cetanol, and the combination of stearic acid and Brazil wax is stearic
The combination of acid and Brazil wax, Chinese wax, cetanol and stearic combination, preferably cetanol and stearic combination.
It is a discovery of the invention that cetanol and stearic acid, which is applied in combination, can stablize suppository formulation, suitable stiff, cetanol are maintained
The effect stablized, thickened is had both with stearic acid, is conducive to the raising of drug effect performance and bioavilability.
Preferably, the cetanol and stearic weight ratio are (2-5):(1-4), such as can be 2:1、3:2、4:1、
5:4、2:3 or 5:3.
Preferably, the thickener includes arbitrary in glycerin monostearate, sodium alginate, furcellaran or aluminum stearate
It is a kind of or at least two mixture, the mixture for example can be the mixture of glycerin monostearate and sodium alginate,
The mixture of the mixture of sodium alginate and furcellaran, furcellaran and aluminum stearate, glycerin monostearate, sodium alginate and hard
The mixture of the mixture of resin acid aluminium, preferably sodium alginate and furcellaran.
Preferably, the weight ratio of the sodium alginate and furcellaran is (1-3):1, such as can be 1:1、2:1 or 3:1.
Preferably, the expandable carrier includes any one in sliver, non-woven fabrics or elastomer or at least two
Combination, the combination for example can be sliver and non-woven fabrics or sliver and elastomer, preferably sliver.
Second aspect, the present invention provides a kind of method preparing imiquimod vaginal expansion plug as described in relation to the first aspect,
Include the following steps：
(1) preparation of drug containing matrix：
A) each component in matrix is placed in by formula ratio in water-bath and is mixed, oil phase is made；
B) mixed liquor of imiquimod and hyaluronic acid will be contained as Aqueous dispersions in the oil phase of step a), obtained pre-
Lotion；
C) pre-emulsion for obtaining step (b) carries out fast film emulsification, obtains drug containing matrix；
(2) drug containing matrix is poured into bolt mould, is inserted into expandable carrier, suppository is made in attachment sizing.
Preferably, the step a) further includes following steps：By preservative, curing agent and thickener and matrix other components
It is collectively disposed in water-bath, mixes；
Preferably, the mixed liquor in step b) further includes functional oligose.
Compared with prior art, the present invention has the advantages that：
(1) imiquimod and hyaluronic acid is applied in combination in the present invention, and synergistic, antiviral effect is notable, passes through adjusting
The proportioning of each component reduces the side effect of imiquimod and is effectively increased antiviral activity, imiquimod is prepared as suppository,
Effectively treatment intravaginal condyloma acuminatum；
(2) functional oligose is applied in combination in the present invention, and Effective multiplication intravaginal profitable strain Bifidobacterium enhances vagina
Self-healing ability and immunity inhibit the growth and breeding of pathogenic bacteria；
(3) combination formula of matrix of the present invention can effectively facilitate drug and play drug effect, in preservative, curing agent and increasing
It can make vaginal expansion plug dimensional stability under thick dose of cooperation, release drug speed is gentle, maintains affected part part blood concentration average,
Improving curative effect reduces side effect.
Specific implementation mode
Further to illustrate the present invention technological means and its effect taken, below by way of specific implementation mode come into
One step illustrates technical scheme of the present invention, but the present invention is not limited in scope of embodiments.
Embodiment 1
Preparation method：
(1) preparation of drug containing matrix：
A) each component in matrix is placed in by formula ratio in water-bath and is mixed, oil phase is made；
B) mixed liquor of imiquimod and hyaluronic acid will be contained as Aqueous dispersions in the oil phase of step a), obtained pre-
Lotion；
C) pre-emulsion for obtaining step (b) carries out fast film emulsification, obtains drug containing matrix；
(2) drug containing matrix is poured into bolt mould, is inserted into expandable carrier, suppository is made in attachment sizing.
Embodiment 2
The preparation method is the same as that of Example 1.
Embodiment 3
The preparation method is the same as that of Example 1.
Embodiment 4
The preparation method is the same as that of Example 1.
Embodiment 5
The preparation method is the same as that of Example 1.
Embodiment 6
The preparation method is the same as that of Example 1.
Embodiment 7
The preparation method is the same as that of Example 1.
Embodiment 8
The preparation method is the same as that of Example 1.
Embodiment 9
The preparation method is the same as that of Example 1.
Embodiment 10
The preparation method is the same as that of Example 1.
Embodiment 11
The preparation method is the same as that of Example 1.
Embodiment 12
The preparation method is the same as that of Example 1.
Embodiment 13
The preparation method is the same as that of Example 1.
Embodiment 14
The preparation method is the same as that of Example 1.
Embodiment 15
The preparation method is the same as that of Example 1.
Embodiment 16
The preparation method is the same as that of Example 1.
Embodiment 17
The preparation method is the same as that of Example 1.
Embodiment 18
The preparation method is the same as that of Example 1.
Embodiment 19
The preparation method is the same as that of Example 1.
Embodiment 20
The preparation method is the same as that of Example 1.
Embodiment 21
The preparation method is the same as that of Example 1.
Embodiment 22
The preparation method is the same as that of Example 1.
Embodiment 23
The preparation method is the same as that of Example 1.
Embodiment 24
The preparation method is the same as that of Example 1.
Embodiment 25
The preparation method is the same as that of Example 1.
Embodiment 26
The preparation method is the same as that of Example 1.
Embodiment 27
The preparation method is the same as that of Example 1.
Embodiment 28
The preparation method is the same as that of Example 1.
Embodiment 29
The preparation method is the same as that of Example 1.
Embodiment 30
The preparation method is the same as that of Example 1.
Embodiment 31
The preparation method is the same as that of Example 1.
Comparative example 1
The preparation method is the same as that of Example 1.
Comparative example 2
The preparation method is the same as that of Example 1.
Comparative example 3
The preparation method is the same as that of Example 1.
Comparative example 4
The preparation method is the same as that of Example 1.
Comparative example 5
The preparation method is the same as that of Example 1.
Comparative example 6
The preparation method is the same as that of Example 1.
Clinical test
One, research method
Research approach is with reference to related " the gynemetrics's genital inflammation of Ministry of Health of the People's Republic of China's new drug clinical guidance principle
The clinical verification of local application " content and formulate.
1. testing case：It accepts patient totally 93 for medical treatment, makes a definite diagnosis HPV6 the infected 29, HPV11 the infected through gynecologial examination
32, HPV16 the infected 17, HPV18 the infected 15, the age, exclusion gestation and nursing period suffered between 18-49 Sui
Person；
2. diagnostic criteria：
Symptom：Intravaginal itch, cusalgia, the pink colour in tufted hyperplasia or white papillule shape wart；
Laboratory examination：With vagina or uterine neck wart tissue smear, pap staining, it is seen that Empity veside cell and dyskeratosis are thin
Born of the same parents occur simultaneously；Above spinous layer and there is Empity veside cell in stratum granulosum, is the important evidence for diagnosing HPV infection；Using anti-HPV
HPV antigens in the antibody test pathological tissues of albumen；Specific analysis, high sensitivity, side are done using PCR
Just rapid；
3. grouping and administration：The vagina that 93 patients with condyloma acuminatum are given to embodiment 1-31 and comparative example 1-6 respectively is swollen
Swollen bolt, administration are 7 days as one therapeutic course once a day；
4. observation item
4.1 therapeutic observations
(1) symptom；
(2) gynecologial examination：Including vulva, vagina, uterine neck and vaginal fluid inspection；
(3) laboratory examination：To vaginal fluid inspection, including under mirror, smear, PCR detection；
4.2 safety observations
(1) general physical examination project；
(2) blood, urine, feces routine test；
(3) heart, Liver and kidney function inspection；
4.3 adverse reactions are observed
Any abnormal symptom occurred during medication, sign, laboratory examination all answer serious analysis, carefully differentiate；
5. efficacy assessment standard：
Recovery from illness：Symptom disappears, and gynecologial examination and laboratory examination are normal；
It is effective：Symptom is substantially reduced, and gynecologial examination and laboratory examination are clearly better；
Effectively：Symptom is mitigated, and gynecologial examination and laboratory examination are improved；
In vain：It is unchanged before relatively being treated after treatment；
6. treatment results：After 4 courses for the treatment of are administered in patient, therapeutic effect is as shown in table 1.
Table 1
As can be seen from Table 1, imiquimod vaginal expansion plug to condyloma acuminata of vagina caused by a variety of HPV Subtypes all
There is good therapeutic effect.Comparing embodiment 1 is with comparative example 1-6 it is found that imiquimod and hyaluronic acid combine synergy, in the parts by weight
The lower best results of number proportioning, side effect caused by effectivelying prevent imiquimod possible.Comparing embodiment 1 and embodiment 6-13 can be with
Find out, functional oligose according to the parts by weight and matches gained expansible plug to the active promoting function of therapeutic effect
Curative effect is best, improves vagina immunity and self-healing ability by adjusting vaginal flora, reduces the influence of side effect.Comparing embodiment
1 can be seen that matrix species and composition ratio and controls imiquimod vaginal expansion plug with embodiment 14-25, embodiment 29-31
The influence of therapeutic effect treats condyloma acuminatum best results under the matrix species and composition and ratio.Comparing embodiment 1 and reality
It applies a 26-28 and can be seen that the positive effect that preservative, curing agent and thickener play suppository drug effect, maintain suppository good
Form makes drug branch uniformly improve bioavilability.
Crowd's test evaluation
The vaginal expansion plug of Example and comparative example carry out use feeling evaluation test, select 100 patients with condyloma acuminatum into
Row stage contrast test, period are 15 days, use comparative example vaginal expansion plug within first 7 days, begin to use implementation after stopping a day
Example vaginal expansion plug.Respectively from being to generate side effect such as red and swollen, itch, and commented for the use of process comfort level
Point, questionnaire is filled according to use feeling, for standards of grading using 5 points of systems, 1 point is worst for effect, and 5 points are best results, are adjusted
It looks into and the results are shown in Table 2.
Table 2
As can be seen from Table 2, imiquimod is applied in combination with hyaluronic acid, and cooperation functional oligose can be reduced effectively
The side effect of imiquimod reduces the symptoms such as red and swollen itch, and matrix species and combination matching used in the present invention can improve miaow
The not special vaginal expansion plug usage comfort of quinoline, reduces patient and repels.Comparing embodiment 1 and comparative example 1-6 is it is found that imiquimod is used
Amount can be used safely in intravaginal administration in range of the present invention, not generate side effect.Comparing embodiment 1 and embodiment 6-
31 as can be seen that the influence of matrix species and combination matching to the safety of imiquimod vaginal expansion plug and usage comfort.
To sum up, imiquimod vaginal expansion plug of the invention utilizes imiquimod and hyaluronic acid and work(by combination
Energy property oligosaccharide, coordinates best matrix species and proportioning, reduces the side effect of imiquimod itself, while making to assist between each component
Same-action improves suppository curative effect and usage comfort, can effectively treat intravaginal condyloma acuminatum.
Applicant states that the present invention illustrates the method detailed of the present invention, but the present invention not office by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implement.Technical field
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, the selection etc. of concrete mode, all fall within protection scope of the present invention and the open scope.
Claims (10)
1. a kind of imiquimod vaginal expansion plug, which is characterized in that the expansible plug includes imiquimod, hyaluronic acid, matrix
Parts by weight with expandable expandable carrier, each ingredient of expansible plug are：
2. vaginal expansion plug according to claim 1, which is characterized in that the expansible plug further includes functional oligose；
Preferably, the parts by weight that the functional oligose accounts for the expansible plug are 5-20 parts, preferably 10-15 parts；
Preferably, the functional oligose includes stachyose, raffinose, milk ketose, oligofructose, xylo-oligosaccharide, oligomeric half
It is any one in lactose, oligoisomaltose, iMOS, oligomeric dragon gallbladder sugar, soyabean oligosaccharides or chitosan oligomer
Kind or at least two combination, the preferably combination of oligoisomaltose and oligomeric dragon gallbladder sugar；
Preferably, the weight ratio of the oligoisomaltose and oligomeric dragon gallbladder sugar is (3-8):(1-5), preferably 5:3.
3. vaginal expansion plug according to claim 1 or 2, which is characterized in that the matrix includes Acrawax, day
In right aliphatic ester, lipoidis matrix, water-soluble base, hydrogenated oil and fat or distillate oil any one or at least two combination,
The combination of preferably synthetic aliphatic ester, natural acid ester and water-soluble base；
Preferably, the weight ratio of the Acrawax, natural acid ester and water-soluble base is (3-8):(1-5):(1-
3), preferably 5:3:2.
4. vaginal expansion plug according to claim 3, which is characterized in that the Acrawax is that fatty acid mixed is sweet
Grease, propylene glycol stearate, fixed oil, semi-synthetic fatty glyceride, semi-synthetic cocounut oil ester, Witepsol, semi-synthetic palm fibre
In palmitic acid grease or semi-synthetic fruit of a cubeb litsea tree ester any one or at least two mixture；
Preferably, the natural acid ester is any one in oleum sapii, spicebush oil, fennel fat, Ke Kemu fat or cocoa butter
Kind or at least two mixture；
Preferably, the lipoidis matrix is lanolin and/or lanonol, preferably lanonol.
5. vaginal expansion plug according to claim 3, which is characterized in that the water-soluble base be polyethylene glycol 1450,
Polyethylene glycol 3350, Macrogol 4000, Macrogol 6000, glycerin gelatine, polyoxyl 40 stearate or poloxamer
In any one or at least two mixture, the preferably mixture of polyethylene glycol 1450 and polyethylene glycol 3350；
Preferably, the weight ratio of the polyethylene glycol 1450 and polyethylene glycol 3350 is (2-4):1；
Preferably, the hydrogenated oil and fat is any one in hydrogenated vegetable oil, hydrogenated groundnut, rilanit special or cotmar
Kind or at least two mixture；
Preferably, the distillate oil is fractionating palm oil and/or fractionated coconut oil.
6. according to claim 1-5 any one of them vaginal expansion plugs, which is characterized in that the matrix further include preservative,
In curing agent or thickener any one or at least two combination；
Preferably, the matrix includes 5-10 parts of preservative, the thickener of 1-12 parts of curing agents and 15-30 in parts by weight.
7. vaginal expansion plug according to claim 6, which is characterized in that the preservative include sorbic acid, cinnamic acid or
In vanilate any one or at least two combination, preferably sorbic acid；
Preferably, the curing agent includes any one in Chinese wax, cetanol, stearic acid or Brazil wax or at least two
Combination, preferably cetanol and stearic combination；
Preferably, the cetanol and stearic weight ratio are (2-5):(1-4)；
Preferably, the thickener includes any one in glycerin monostearate, sodium alginate, furcellaran or aluminum stearate
Or at least two mixture, the preferably combination of sodium alginate and furcellaran；
Preferably, the weight ratio of the sodium alginate and furcellaran is (1-3):1.
8. according to claim 1-7 any one of them vaginal expansion plugs, which is characterized in that the expandable carrier include sliver,
In non-woven fabrics or elastomer any one or at least two combination, preferably sliver.
9. a kind of method preparing the vaginal expansion plug as described in claim any one of 1-8, which is characterized in that including walking as follows
Suddenly：
(1) preparation of drug containing matrix：
A) each component in matrix is placed in by formula ratio in water-bath and is mixed, oil phase is made；
B) mixed liquor of imiquimod and hyaluronic acid will be contained as Aqueous dispersions in the oil phase of step a), obtains pre- breast
Liquid；
C) pre-emulsion for obtaining step (b) carries out fast film emulsification, obtains drug containing matrix；
(2) drug containing matrix is poured into bolt mould, is inserted into expandable carrier, suppository is made in attachment sizing.
10. according to the method described in claim 9, it is characterized in that, the step a) further includes following steps：By preservative,
Curing agent and thickener are collectively disposed at matrix other components in water-bath, are mixed；
Preferably, the mixed liquor in step b) further includes functional oligose.
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| CN201810386193.7A CN108403618A (en) | 2018-04-26 | 2018-04-26 | A kind of imiquimod vaginal expansion plug and preparation method thereof |
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| CN201810386193.7A CN108403618A (en) | 2018-04-26 | 2018-04-26 | A kind of imiquimod vaginal expansion plug and preparation method thereof |
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