CN102335115A - Preparation and application of clindamycin phosphate in-situ gel - Google Patents
Preparation and application of clindamycin phosphate in-situ gel Download PDFInfo
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- CN102335115A CN102335115A CN2010102357231A CN201010235723A CN102335115A CN 102335115 A CN102335115 A CN 102335115A CN 2010102357231 A CN2010102357231 A CN 2010102357231A CN 201010235723 A CN201010235723 A CN 201010235723A CN 102335115 A CN102335115 A CN 102335115A
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Abstract
Relating to the field of medical technologies, the invention provides a new dosage form of clindamycin phosphate, i.e. preparation and application of temperature sensitive and pH sensitive clindamycin phosphate in-situ gel. The gel is characterized by preparation and application of the gel that is a solution under a nonphysiological state and is gel through phase transition under a physiological state. The temperature sensitive and pH sensitive clindamycin phosphate gel is finally prepared with Poloxamer 407 (F127 for short) and Poloxamer 188 (F68 for short) in a proper ratio. The pH sensitive in situ gel is prepared by Carbopol 980 and Poloxamer F127 in a proper ratio. The gel has viscosity of less than 1100mpa.s under a nonphysiological condition and viscosity of greater than 2500mpa.s under a physiological condition with pH of 4.5. The gel prolongs the detention time of clindamycin phosphate in the vagina and improves the bioavailability and curative effects, thus boasting good application prospects.
Description
Technical field
The present invention relates to the novel form of a kind of vagina medicinal thing of clindamycin phosphate, it is being solution at non-physiological state, and physiological status changes gel mutually into.Exactly it is the method for preparing and the clinical indication of clindamycin phosphate temperature and the responsive gel of pH.Said preparation has prolonged medicine greatly in the vagina holdup time, has improved bioavailability and curative effect, and application promise in clinical practice is arranged.
Background technology
The clinical G that is mainly used in of clindamycin phosphate
+With the microbial female genital tract of anaerobism and pelvic infection and abdominal cavity infection, be one of the choice drug of treatment bacterial vaginosis.At present, the domestic vagina preparation of having produced and having gone on the market has tablet, suppository, membrane, capsule and jelly.At present, it is very fast, easy to use that traditional vaginal preparation such as effervescent tablet etc. discharge medicine, steady quality; The mechanization degree of producing is higher, but is easy to leak, thereby medicine is short in the site of action holdup time; Cause effective dose to reduce, effective time is short, and brings inconvenience to user.After suppository gets into vagina, need 10～15min fusion and/or foaming, can reach the covering of maximum area.The effervescent vaginal suppository has combined both advantages, does not need special apparatus, can cover the cervix uteri mouth rapidly, but is merely rapid release product (in 5～10min onset), and effective time short (scarcely surpassing 30min) discharges soon, and dosage is high, is prone to reveal.Vaginal gel is a carrier with the hydrophilic high molecular material often, and better biocompatibility is arranged, and is semi-solid preparation, but reduce administration number of times, but dosage is wayward the action time of prolong drug.
Vagina has following characteristics with situ-gel: 1. have unique the hydrophilic three-dimensional net structure and the favorable tissue compatibility; 2. unique solution-gel conversion character make its have concurrently preparation simple, easy to use, compare with ordinary preparation, can the Long contact time vaginal mucosa, and contact area is bigger, easy to use
[1],, 3. overcome low shortcoming of bioavailability and the uppity shortcoming of vaginal gel dosage the release time that has prolonged medicine with agents area advantages such as particularly strong, holdup time of mucous membrane tissue affinity is long.Also there is not at present the preparation listing of situ-gel.
PH responsive type situ-gel is because of the difference of inside and outside environment (pH value) takes place to change mutually.This system is low viscous liquid usually external, and the dispersity or the conformation of administration post polymerization thing change, and become semisolid gel state [2].Situ-gel is easy to produce, viscosity and also sharply rising of adhesion in vivo after the use, and the holdup time is long, and the release of may command medicine.The clindamycin phosphate situ-gel external be a kind of liquid, get into vagina after, normal person's vagina pH is in the scope of 4.0-4.7, mean temperature is about 37 ℃～37.8 ℃.When pH＞4.5, just can be diagnosed as vaginitis.Because suffer from the difference of colpitic pH value, liquid is transformed into semi-solid, reach the effect of slow controlled release.
The macromolecular material poloxamer is the ABA block polymer that polyoxyethylene (PEO) and polyoxypropylene (PPO) are formed.In solution, generating with hydrophobicity PPO block is kernel, is wrapped in the globular micelle of hydrophilic PEO shell, and its gelation mechanism is considered to the result that tangles each other and pile up along with between temperature rising micelle.Concentration is high more, and the volume fraction of the shared solution of polymer is just big more, micelle quantity and each other contact and the probability that tangles all increase, thereby phase transition temperature presents concentration dependent, and is lower than a certain concentration and then no longer forms gel.
Carbomer belongs to acrylic polymer, and it contains a large amount of carboxyls (being about 56%～68%), when pH value less than 4 the time, carboxyl dissociates hardly, polymer disperses in water and swelling, but does not dissolve, and shows very low stickiness.Inorganic base or organic base can make carboxyl dissociate, and the repulsive interaction between negative charge causes strand to expand, stretch, and the carbomer of low concentration forms clear and bright solution, and when concentration was big, strand tangled each other to form and has certain intensity and elastic translucent gel.PH value is 6～12 o'clock, and the gel viscosity that carbomer forms is maximum.So, merge and use HPMC, reduce the consumption of carbomer.
Summary of the invention
The purpose of this invention is to provide vagina and use situ-gel with adaptation phase transition temperature and pH value,
The responsive vagina of pH is with the prescription screening of situ-gel.Screen the substrate of suitable pH responsive type vagina, investigate its agglomerative mechanism that influences with situ-gel, thus the optimum prescription of screening, and preparation clindamycin phosphate pH responsive type vagina is used situ-gel.Use punctate opacity of the cornea design-effect surface method to obtain optimization prescription and the preparation technology of the responsive vagina of pH with situ-gel.
The objective of the invention is to realize: 1. responsive to temperature type: medicine or the microgranule or the cyclodextrin clathrate that are loaded with medicine are dissolved in a small amount of distilled water through following scheme; Taking by weighing an amount of poloxamer (Poloxamer 407) (being called for short F127) and poloxamer 188 (abbreviation F68) again joins in the above-mentioned solution under ice bath and stirring condition; Deepfreeze is saved to the clarification uniform solution; Add an amount of antiseptic, regulate pH and osmotic pressure.2. pH responsive type: medicine or the microgranule or the cyclodextrin clathrate that are loaded with medicine are dissolved in a small amount of distilled water; Taking by weighing an amount of carbomer 980 again joins in the above-mentioned solution under ice bath and stirring condition with HPMC; Deepfreeze is saved to the clarification uniform solution, adds an amount of antiseptic.
(1) research of clindamycin phosphate thermosensitive in situ gel
1. the investigation of gelation temperature
Can temperature sensing in situ gel rubber gelling be one of index of this dosage form evaluation near body temperature.The gelation temperature of this The effects, because of the ratio of F127 and F68 in the poloxamer prescription is different, gelation temperature is different, so regulate gelation temperature through adjusting both ratios.Ratio and gained experimental result such as the table 1,2 of F127 and F68 in the prescription solution:
Table 1. different proportion F127 is to the investigation (n=3) of gelation temperature, gelling time
Table 2. different proportion F68 is to the investigation (n=3) of gelation temperature, gelling time
Assay method (gradient method): punching in the middle of the rubber stopper of cillin bottle, insert precision thermometer (precision is 0.1), put into cillin bottle to magnetic agitation; The prescription solution that will suit is then poured in the cillin bottle of oven dry; Cover the stopper of cillin bottle, the thermometer mercury ball is immersed in the poloxamer solution fully magnetic agitation; When treating that viscosity is big; The mercury ball of thermometer is immersed in the poloxamer solution fully (during the course, with the temperature of common thermometer control water-bath, guarantee the thermometer programming rate be about 1 ℃/2min).When being heated to stirrer when not rotating, at this moment its programming rate that slows down ceaselessly takes out cillin bottle; It is tilted about 60 °, when solution does not take place to flow, write down this temperature, parallel doing three times; Average, this mean temperature promptly is designated as phase transition temperature (gelation temperature).
The result: the gelation temperature of numbering 1～4 is respectively 39.8 ℃, 36.2 ℃, 34.1 ℃, 31.8 ℃
The gelation temperature of numbering 5～8 is respectively 34.8 ℃, 34.4 ℃, 34.1 ℃, 33.6 ℃
Conclusion: the result shows that F68 can improve gelation temperature; When F68 content is identical, increases its gelation temperature with F127 content and reduce.
2. the investigation of gelling time
Temperature sensing in situ gel rubber, gelling ability also are one of important indicators of this dosage form evaluation.After situ-gel got into human body, gelling ability was investigated through gelling time, and the scale effect gelling time of F127 and F68 is regulated gelling time so regulate both ratios in the poloxamer prescription solution.Ratio and the gained gelling time of F127 and F68 are seen table 1,2 in the prescription solution
Assay method: 2mL poloxamer solution is put into cillin bottle, stir poloxamer solution, make the solution internal temperature even with magnetic agitation; Earlier it is preheated to 20 ℃, is positioned in 37 ℃ of waters bath with thermostatic control manual time-keeping immediately again; When treating that solution does not take place to flow fully, record the time, repeat 3 times; The averaging of income value is and changes required time mutually, i.e. gelling time.
The result: the gelling time of numbering 1-4 is respectively 6 ' 07 ", 4 ' 16 ", 2 ' 01 ", 1 ' 10 "
The gelling time of numbering 1-4 is respectively 2 ' 23 ", 2 ' 07 ", 2 ' 00 ", 1 ' 51 "
Conclusion: the result shows, F127 and F68 are consistent to the influence of gelling time with the influence to gelation temperature, and the increase of both content has all prolonged the agglomerative time, and the increase of F68 content is to gelling time influence little than F127.
3. the optimization of prescription
The consumption of investigation selection F127, F68 consumption are as the investigation factor on the trial test basis.Design according to punctate opacity of the cornea
[6]Principle, every factor is established five levels, representes (two factor punctate opacity of the corneas design α=1.414) with code value-α ,-1,0,1, α.The practical operation physical quantity of code value representative is seen table 3, and experimental design and effect value are seen table 4.
Table 3 factor code level and corresponding physical quantity
This experiment is that the gelation temperature (T) with temperature sensing in situ gel rubber is an index, and the gelation temperature that optimizes blank gel is 36 ℃ a prescription.
Table 6 experimental design and effect value
3.1 model match
Using statistica7.0 software is that dependent variable carries out the analysis of binomial nonlinear fitting equation to each factor with the gelation temperature.Binary binomial fit equation is:
Y=101.516-4.3532X
1-0.63703X
2+ 0.038652X
1X
1-0.03719X
2X
2+ 0.05806X
1X
2, degree of fitting (R) is 0.9951.According to monobasic binomial fit equation Y=75.3719-2.2999X
1+ 0.742858X
2-0.05064X
2X
2, calculate best X
2Value (F68) is 7.4%, fixing best X
2Value when gelation temperature is 36 ℃, calculates best X
1(F127) value is 17.26%.
Fig. 1 gelation temperature (T) is to X
1(F127) and X
2(F68) prediction effect surface
3.2 fitting result
Binomial nonlinear equation degree of fitting is higher, finally draws: when gelation temperature was 36 ℃, blank gel best prescription was: F127 (17.26%), F68 (7.4%).
3.3 optimize the prescription checking
According to blank temperature sensing in situ gel rubber best prescription: F127 (17.26%), F68 (7.4%) prepares three batches, measures the gelation temperature of prescription.The confirmatory experiment result: the prediction gelation temperature is 36 ℃, and average true gelation temperature is 36.2 ℃, deviation (%)=(36.2-36)/36=0.56%.The result shows that the mathematical model that punctate opacity of the cornea design-effect surface optimization is set up has good predictability, selected process conditions favorable reproducibility.
4. the preparation of pastille prescription
The clindamycin phosphate of different proportion is added in the best blank gel prescription, investigate the dissolving situation of blank gel clindamycin phosphate.Experimental design and result such as table 5:
The dissolving situation of the clindamycin phosphate of table 5 different proportion in blank gel
The result: mass fraction is that 0.1%, 0.2% dissolving is complete, considers the factor of drug loading simultaneously, so in poloxamer prescription solution, be 0.2% to add clindamycin phosphate with mass fraction.
(2) pH responsive type clindamycin phosphate vagina is with the preparation of situ-gel
2.1Carbopol choice of base
At present, the kind of the host material of preparation gel has a variety of, like cellulose family, and polyacrylic, polyvinyl alcohol (PVA) or the like.Wherein, polyacrylic is representative with carbomer (Carbopol), and its gel-type vehicle that makes has the characteristics of water-soluble base, to skin and mucosa nonirritant
[4]
Wherein Carbopol 980 is more suitable for doing gel than the Carbopol of other models, so the main matrix material of Carbopol980 as the responsive gel of pH selected in decision for use.
In order to strengthen the gel strength of Carbopol 980, select HPMC (K4M) and Carbopol 980 compatibilities for use.
2.2Carbopol the screening of consumption
The responsive vagina of ideal pH is little with gel delivery system (pH4.0, T25 ℃) viscosity under non-physiological condition, can free-flow, can satisfy the property injected of its vagina; And the bigger gel of formation intensity takes place to change mutually in intravaginal in (pH4.5, T37.5 ℃) under physiological condition, delays drug release.Therefore be the screening that evaluation index is carried out Carbopol and HPMC consumption with flow of solution property, gel strength.
According to the preliminary experiment result, compound concentration is a series of Carbopol solution of 0.2%～1.2% (w/v).Above-mentioned solution is used 1.0mol/L NaHCO
3Solution is adjust pH to pH4.0 ± 0.05, pH4.5 ± 0.05 respectively, the flowability of perusal solution and gelling ability.Non-physiological condition current downflow property handy " 1 " expression, not handy " 0 " expression, gelling ability handy " 1 " expression under the physiological condition, not handy " 0 "
[5]Expression is in order to select the consumption of Carbopol.
The flowability and the gelling ability (n=3) of table 2-1 variable concentrations Carbopol aqueous solution
2-1 can know that 0.3% Carbopol has good mobility under non-physiological condition by table, and under physiological condition, gelling ability is preferably arranged, so preferred concentration is that 0.3% Carbopol is as the blank substrate of the responsive vagina of pH with gel.
2.3pH value changes the relation with the 0.3%Carbopol solution viscosity
0.3%Carbopol solution is used 1.0mol/L NaHCO
3Solution is transferred pH to 3.15,3.36,3.50,3.84,3.95,4.11,4.33,4.50,4.65 respectively, presses the viscosity measurement method and measures the variation of its viscosity with pH.The result is shown in Fig. 2-1.
The viscosity of Fig. 2-10.3%Carbopol solution is with pH variation relation figure
Can know that by Fig. 2-1 0.3% Carbopol has descended just gelling at non-physiological condition (pH4.0).
2.4Carbopol screening with poloxamer 407 (F127) consumption
2-1 can know according to table: 0.3% Carbopol has good mobility under non-physiological condition, and under physiological condition, gelling ability is preferably arranged; And literature survey can be known: contain 0.3%Carbopol and 14%F127 (w/w) but mixed solution free-flow under pH4.0 and 25 ℃ of conditions
[6]So find through preliminary experiment: behind 0.4% Carbopol and the F127 compatibility, under non-physiological condition, good mobility is arranged, and under physiological condition, gelling ability is preferably arranged also.So select for use 0.3% Carbopol and 0.4% Carbopol further to screen.
2.4.10.3%Carbopol/F127 compatibility and 0.4% Carbopol/F127 compatibility
According to the preliminary experiment result, compound concentration is 0.5%, 1.0%, 2.0%, 4.0%, 6.0%, 8.0%, 10.0% F127 aqueous solution, and add 0.3%Carbopol respectively; Compound concentration is 0.5%, 1.0%, 1.5%, 2.0% in addition, 2.5%, 3.0%, 3.5% F127 aqueous solution, and add 0.4%Carbopol respectively, each solution stirring is until dissolving fully.Above-mentioned two groups of solution are used 1.0mol/L NaHCO
3Solution is tone pitch to pH4.0 ± 0.05, pH4.5 ± 0.05 respectively, perusal flow of solution property and gelling ability.Non-physiological condition current downflow property handy " 1 " expression, not handy " 0 " expression, gelling ability handy " 1 " expression under the physiological condition, not handy " 0 " expression is in order to select the consumption of F127.
The flowability and the gelling ability (n=3) of table 2-20.3%Carbopol and variable concentrations F127 aqueous solution
By table 2-3 data; Combine experimental phenomena to observe again; High density F 127 is better than the F127 and the 0.3%Carbopol solution of low concentration with the flowability of 0.3%Carbopol solution under physiological condition (pH4.5); So, can get rid of the consumption of 0.3%Carbopol through the experimental result of these seven prescriptions.
The flowability and the gelling ability (n=3) of table 2-30.4%Carbopol and variable concentrations F127 aqueous solution
2-4 can know that 0.4%Carbopol/0.5%-3.0%F127 has good mobility under non-physiological condition by table, and under physiological condition, gelling ability is preferably arranged.So 0.4%Carbopol/0.5%-3.0%F127 is the prescription of further studying.
2.4.2F127 consumption changes the relation with the Carbopol/F127 solution viscosity
Preparation is 0.4%Carbopol and 0.1%F127,0.5%F127,0.9%F127,1.75%F127, five groups of solution of 3.0%F127 of consumption fixedly, use 1.0mol/L NaHCO
3Solution is transferred to physiological condition pH to 4.5 ± 0.05 respectively, presses the viscosity measurement method and measures the consumption variation of its viscosity with F127.The result is shown in Fig. 2-2.
Fig. 2-2Carbopol/F127 solution viscosity is with the consumption variation relation figure of F127
Found by preliminary experiment: viscosity is stronger greater than the gelling ability of the Carbopol/F127 solution of 2500mPas down at physiological condition (4.5,37.5 ℃ of pH).Consider that simultaneously viscosity is unfavorable for too greatly sprawling, though the too little gelling gel of viscosity receives vaginal secretion buffering corrosion speed faster, so preferred Carbopol (0.4%)/F127 (0.5%) is final prescription.
2.5 other compositions are to the influence of the responsive gel viscosity of pH
Clindamycin phosphate is added in optimizing prescriptions Carbopol (0.4%)/F127 (0.5%) mixed solution that has prepared, be prepared into the Carbopol/F127 solution that contains clindamycin phosphate.
Above solution is used 1.0mol/L NaHCO
3Solution is transferred pH to 3.32,3.60,3.78,4.00,4.10,4.27,4.35,4.50,4.65 respectively, measures the variation of its viscosity with pH.The result is shown in Fig. 2-4.
Other compositions of Fig. 2-3 are to the influence (n=3) of the responsive gel viscosity of pH
2.6 the responsive vagina of punctate opacity of the cornea design pH is write out a prescription with situ-gel substrate
[7,8,9]
On the basis of preliminary experiment and the investigation of single factor, choose Carbopol (X
1) and F127 (X
2) two factors are for investigating object, according to the principle of punctate opacity of the cornea design, each factor 5 levels of getting prepare the responsive gel of pH, and the factor level table is seen table 2-4.
Table 2-4 factor level table
2.6.1 model match and prediction
Measure the viscosity of Carbopol/F127 mixed solution under pH4.0 ± 0.05 and pH4.5 ± 0.05 condition respectively according to above factor level table; With the gel viscosity as dependent variable; Respectively each level of each factor (independent variable) is carried out multiple linear regression and binomial match, equation is following:
Multiple linear regression: V
3=b
0+ b
1* X
1+ b
2* X
2
Binomial match: V
3=b
0+ b
1* X
1+ b
2* X
2+ b
3* X
1 2+ b
4* X
2 2+ b
5* X
1* X
2
With this mathematical model is that three-dimensional dependent variable (response surface) is described on the basis, by the dependent variable face and combine preliminary experiment to choose preferable prescription, prepares gel by best prescription, carries out forecast analysis.
The responsive gel three-dismensional effect face figure (pH4.5) of Fig. 2-4pH
Table 2-5 EXPERIMENTAL DESIGN and viscosity measurement result
Quadratic polynomial match (pH 4.5):
Z＝47.9568+3510.92×X
1+1862.13×X
2+4441.69×X
1 2+1275.5
1×X
1×X
2-3003.6×X
2 2
(R＝0.9043)
By finding in the preliminary experiment: viscosity is during less than 1100mPas, and gel is better mobile; Viscosity is during greater than 2500mPas, and the gel gelling ability is good.
Because each prescription viscosity under physiological condition (pH4.5) does not have significant difference all less than 1100mPas between 13 data, the gel flowability of all prescriptions is all better.It is above with individual quadratic polynomial preferably to locate the 0.4%Carbopol/0.5%F127 substitution, meets that viscosity is less than 1100mPas under the non-physiological condition, and viscosity is finally write out a prescription so confirm 0.4%Carbopol/0.5%F127 greater than 2500mPas under the physiological condition.
2.7 the preparation technology of the responsive gel for eye use of clindamycin phosphate pH
With the Carbopol of recipe quantity and F127 respectively at being sprinkling upon distilled water (H under the stirring condition
2O [Carbopol]: H
2O [Carbopol]=4: 1) on the liquid level; Placement is spent the night; Make its abundant aquation swelling respectively; Again Carbopol solution and F127 solution are mixed in and continue abundant aquation swelling under the stirring condition, after slowly join with the clindamycin phosphate of recipe quantity, under stirring condition and to make dissolving fully, NaHCO in the Carbopol/F127 solution
3Regulate pH, process the responsive gel for eye use of 20mg/mL clindamycin phosphate pH.This gel is free-pouring liquid state under non-physiological condition, when in the following time of physiological condition of pH4.5, is the gel with suitable viscosity.
Description of drawings
Fig. 1 is that gelation temperature (T) is to X
1(F127) and X
2(F68) prediction effect surface
The viscosity of Fig. 2-10.3%Carbopol solution is with pH variation relation figure
Fig. 2-2Carbopol/F127 solution viscosity is with the consumption variation relation figure of F127
Other compositions of Fig. 2-3 are to the influence (n=3) of the responsive gel viscosity of pH
The responsive gel three-dismensional effect face figure (pH4.5) of Fig. 2-4pH
The specific embodiment
The temperature sensitive vagina of embodiment 1 clindamycin phosphate is with the preparation of gel
[prescription] clindamycin phosphate 0.1g
F127 21.4g
F68 9.6g
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate, uses dissolved in distilled water, and stirring condition slowly adds the F127 and the F68 of recipe quantity down, adding distil water to capacity, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright uniform solution.The said preparation phase transition temperature is 35 ± 2 ℃.
The temperature sensitive vagina of embodiment 2 clindamycin phosphates is with the preparation of gel
[prescription] clindamycin phosphate 0.1g
F127 17.2g
F68 7.4g
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate, uses dissolved in distilled water, and stirring condition slowly adds the F127 and the F68 of recipe quantity down, adding distil water to capacity, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright uniform solution.The said preparation phase transition temperature is 36 ± 0.2 ℃.
The responsive vagina of embodiment 3 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.1%
Carbomer 980 0.4%
Poloxamer F127 0.5%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 4 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.4%
Poloxamer F127 0.5%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 5 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.2%
Poloxamer F127 0.5%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 6 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.6%
Poloxamer F127 0.5%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 7 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.4%
Poloxamer F127 3.0%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 8 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.4%
Poloxamer F127 2.0%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
The responsive vagina of embodiment 9 clindamycin phosphate pH is with the preparation of gel
[prescription] clindamycin phosphate 0.3%
Carbomer 980 0.4%
Poloxamer F127 1.0%
Adding distil water is to full dose 100g
[method for making] got clindamycin phosphate and used the recipe quantity dissolved in distilled water, and stirring condition slowly adds the carbomer 980 of recipe quantity down to be preserved with the F127 deepfreeze, makes abundant swelling, until forming clear and bright uniform solution.Viscosity＜the 1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
Claims (9)
1. clindamycin phosphate (clindamycin phosphate is called for short Clin) situ-gel is characterized in that: for liquid, be transformed into gel after the administration mutually under this situ-gel room temperature condition and the non-physiological condition.The Clin situ-gel comprises temperature-sensitive situ-gel and pH sensitive in-situ gel, and wherein Clin concentration is 0.1-0.3%.
2. the described Clin temperature-sensitive situ-gel of claim 1, it is characterized in that: its composition is by percentage to the quality: Clin 0.1%-5%, poloxamer F127 16%-20%, poloxamer F68 5%-10%; Aqueous solution 65%-78.9%, 35 ± 2 ℃ of said preparation phase transition temperatures.
3. the described Clin temperature-sensitive situ-gel of claim 1, it is characterized in that: poloxamer F127 accounts for 21.4%, and poloxamer F68 accounts for 9.6%, and the said preparation phase transition temperature is 35 ± 2 ℃.Poloxamer F127 accounts for 17.26%, and poloxamer F68 accounts for 7.4%, and the said preparation phase transition temperature is 36 ± 0.2 ℃.
4. the described Clin temperature-sensitive situ-gel of claim 1, it is characterized in that: wherein polyoxyethylated content is not less than 60% in the poloxamer F127 molecule, and mean molecule quantity is between 5000-16000.Polyoxyethylated content is not less than 70% in the poloxamer F68 molecule, and mean molecule quantity is between 5000-16000.
5. the described Clin temperature-sensitive situ-gel of claim 1 method for preparing is characterized in that: get clindamycin phosphate, use dissolved in distilled water; Stirring condition slowly adds the F127 and the F68 of recipe quantity down; Adding distil water is to capacity, and deepfreeze is preserved, and makes abundant swelling; Until forming clear and bright uniform solution, promptly get.
6. the described Clin pH of claim 1 sensitive in-situ gel, it is characterized in that: carbomer 980 accounts for 0.2-0.6%, and said preparation is gelling during at physiological condition pH4.5 when non-physiological condition good fluidity pH4.5.
7. the described Clin pH of claim 1 sensitive in-situ gel; It is characterized in that: contain 0.4% carbomer 980 in the prescription; Contain 0.5--3.0% poloxamer F127 simultaneously, the viscosity＜1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
8. the described Clin pH of claim 1 sensitive in-situ gel; It is characterized in that: contain 0.4% carbomer 980 in the prescription; Contain 0.5% poloxamer F127 simultaneously, the viscosity＜1100mpa.s of said preparation when non-physiological condition, the viscosity＞2500mpa.s when physiological condition pH4.5.
9. Clin pH sensitive in-situ gel method for preparing according to claim 1; It is characterized in that: weighing Carbopol (0.4%) and F127 (0.5%) and clindamycin phosphate (0.1-0.3%); Place volumetric flask, adding distil water is placed in the refrigerator more than the swelling 24h.
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| CN2010102357231A CN102335115A (en) | 2010-07-17 | 2010-07-17 | Preparation and application of clindamycin phosphate in-situ gel |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010102357231A CN102335115A (en) | 2010-07-17 | 2010-07-17 | Preparation and application of clindamycin phosphate in-situ gel |
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| CN102335115A true CN102335115A (en) | 2012-02-01 |
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| CN2010102357231A Pending CN102335115A (en) | 2010-07-17 | 2010-07-17 | Preparation and application of clindamycin phosphate in-situ gel |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335121A (en) * | 2010-07-21 | 2012-02-01 | 胡容峰 | Preparation and application of pH sensitive in situ gel for vagina |
| CN103211752A (en) * | 2012-01-20 | 2013-07-24 | 胡容峰 | Preparation and application of in-situ gel used for nystatin pH sensitive type vagina |
| CN103371964A (en) * | 2012-04-16 | 2013-10-30 | 胡容峰 | Preparation and application of gynecological pH-sensitive situ gel for vagina |
| CN112569196A (en) * | 2020-12-30 | 2021-03-30 | 海南海神同洲制药有限公司 | Clindamycin phosphate vaginal tablet and preparation process thereof |
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|---|---|---|---|---|
| CN1593386A (en) * | 2004-06-30 | 2005-03-16 | 上海复康医药科技发展有限公司 | Temperature sensitive gel formulation for in situ vagina uses |
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- 2010-07-17 CN CN2010102357231A patent/CN102335115A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1593386A (en) * | 2004-06-30 | 2005-03-16 | 上海复康医药科技发展有限公司 | Temperature sensitive gel formulation for in situ vagina uses |
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| HONG-RU LIN ET AL.: ""Carbopol/ pluronic phase change solutions for ophthalmic drug delivery"", 《JOURNAL OF CONTROLLED RELEASE》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335121A (en) * | 2010-07-21 | 2012-02-01 | 胡容峰 | Preparation and application of pH sensitive in situ gel for vagina |
| CN103211752A (en) * | 2012-01-20 | 2013-07-24 | 胡容峰 | Preparation and application of in-situ gel used for nystatin pH sensitive type vagina |
| CN103371964A (en) * | 2012-04-16 | 2013-10-30 | 胡容峰 | Preparation and application of gynecological pH-sensitive situ gel for vagina |
| CN112569196A (en) * | 2020-12-30 | 2021-03-30 | 海南海神同洲制药有限公司 | Clindamycin phosphate vaginal tablet and preparation process thereof |
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Application publication date: 20120201 |