CN105147595B - Pemirolast Potassiu temperature sensitive hydrogel and preparation method thereof - Google Patents
Pemirolast Potassiu temperature sensitive hydrogel and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of Pemirolast Potassiu temperature sensitive hydrogels and preparation method thereof, it is the aqueous solution being in a liquid state at 20 27 DEG C being mainly made of Pemirolast Potassiu, poloxamer188, PLURONICS F87 and osmotic pressure regulator, can be widely used for the eye-drops preparations for the treatment of allergic conjunctivitis and conjunctivitis catarrhalis aestiva.Pemirolast Potassiu temperature sensitive hydrogel of the present invention is liquid at normal temperatures, it instills in eye and forms semi-solid gel state, it is adhered to cornea and conjunctival sac surface, delay drug release, it can not only solve the problems, such as that the conventional eye drop solutions eye residence time is short, bioavilability is not high, the problem that common eye-gel preparation spreadability is poor, dosage is not easy to control is also overcomed, while Ocular irritation caused by using the dosage forms such as emulsifiable paste can be avoided.
Description
Technical field
The present invention relates to medicinal temperature sensitive hydrogels, and in particular to a kind of Pemirolast Potassiu temperature sensitive hydrogel
And preparation method thereof.
Background technology
Pemirolast Potassiu (English name：Pemirolast potassium；Chemical name：9- methyl -3- (1H-TETRAZOLE -5-
Base) -4H- pyridos [1,2-a] pyrimidin-4-one sylvite) it is a kind of mast cell membrane stabilizer, histamine, white can be effectively inhibited
The release of the inflammatory mediators such as triolefin.1977, Pemirolast Potassiu was developed by Shi Guibao companies of the U.S. as oral antasthmatic.
1999, U.S. FDA ratified pemirolast potassiumeye drops (trade name：Alamast it) lists.Pemirolast potassiumeye drops are in clinic
On be widely used in the treatment of allergic conjunctivitis and conjunctivitis catarrhalis aestiva.
Currently, Pemirolast Potassiu drop eye-drops preparations is eye drops.Due to blink and eye movement etc., conventional eye drip
The liquid eye residence time is short, bioavilability is relatively low." temperature-sensitive gel preparation " is energy after one kind is administered with solution state
It is undergone phase transition immediately with the variation of temperature in agents area, the preparation of semi-solid gel is converted by liquid.For example, ophthalmically acceptable temperature
It is solution state to spend sensitive gels at room temperature, can be undergone phase transition within the eye in time after administration in conjunctival sac in liquid form,
Form semi-solid gel.
Currently, the still not no report about Pemirolast Potassiu temperature sensitive hydrogel.
Invention content
In view of the deficiencies of the prior art, it is an object of the present invention to provide one kind can be widely used for treatment anaphylaxis conjunctiva
Scorching and conjunctivitis catarrhalis aestiva eye-drops preparations Pemirolast Potassiu temperature sensitive hydrogel；Another object of the present invention is
The preparation method of above-mentioned Pemirolast Potassiu temperature sensitive hydrogel is provided.
Pemirolast Potassiu temperature sensitive hydrogel of the present invention is mainly by Pemirolast Potassiu, poloxamer188, pool Lip river
The aqueous solution of husky nurse 188 and osmotic pressure regulator composition being in a liquid state at 20-27 DEG C, each component are a concentration of：
And 3<The concentration ratio of poloxamer188 and PLURONICS F87<3.7.
In the Pemirolast Potassiu temperature sensitive hydrogel, the concentration of main ingredient Pemirolast Potassiu is preferably 0.0009-
0.002g/ml。
Poloxamer188 and PLURONICS F87 are the important auxiliary material of the thermo-sensitive gel preparation, shadow as pharmaceutical carrier
Its phase transition temperature is rung, and then influences rate of release of the Pemirolast Potassiu in medication environment.Wherein, the concentration of poloxamer188
Preferably 0.15-0.30g/ml, more preferably 0.19-0.21g/ml；The concentration of PLURONICS F87 is preferably 0.04-0.10g/
Ml, more preferably 0.05-0.07g/ml.And 3<The concentration ratio of poloxamer188 and PLURONICS F87<3.7, it is preferable that 3.1<
The concentration ratio of poloxamer188 and PLURONICS F87<3.5, it is highly preferred that 3.2<Poloxamer188 and PLURONICS F87
Concentration ratio<3.4.
In the present invention, the ratio of the concentration of the concentration and PLURONICS F87 of poloxamer188 is extremely important, Dang Boluo
When the concentration ratio of husky nurse 407 and PLURONICS F87≤3, the thermo-sensitive gel preparation does not generate gelling when temperature is higher than 27 DEG C；
When the concentration ratio of poloxamer188 and PLURONICS F87 >=3.7, the thermo-sensitive gel preparation generates phase transformation at room temperature
It is frozen into gel, does not meet formulation requirements.
In the Pemirolast Potassiu temperature sensitive hydrogel, the addition of osmotic pressure regulator makes the hydrogel and tear
Liquid has identical or higher osmotic pressure.Hypertonic solution is crossed due to absorbing moisture, so that ocular tissue is dehydrated, is dry and generation discomfort
Feel；Hypotonic solution can then make cornea tissue expand and cause pain.The conditioning agent that oozes can be selected from sodium chloride, glucose, sweet
Oil, polyethylene glycol, propylene glycol.A concentration of 0.005-0.1g/ml of the osmotic pressure regulator, preferably 0.01-0.08g/ml,
More preferably 0.04-0.06g/ml.
The pH value of the Pemirolast Potassiu temperature sensitive hydrogel of the present invention is 6-8.
The Pemirolast Potassiu temperature sensitive hydrogel of the present invention also may include other pharmaceutic adjuvants, such as preservative, wetting
Agent and/or buffer.These pharmaceutic adjuvants are not to the essential characteristics of Pemirolast Potassiu temperature sensitive hydrogel, such as phase transformation
Temperature has an impact.Other described pharmaceutic adjuvants can be selected from the auxiliary material well known in the art that can be used for eye-drops preparations.For example, anti-
Rotten agent can be selected from quaternary ammonium salt, such as benzalkonium chloride, benzalkonium bromide；Cationic surfactant；Alcohols, such as benzyl alcohol, trichlorine uncle
Butanol；Esters, oxybenzene ester；Sorbic acid (potassium) etc., preferably quaternary ammonium salt.Wetting agent can be selected from glycerine, ethyl alcohol, propylene glycol etc.；It is slow
Fliud flushing can be selected from phosphate buffer, borate buffer solution.The concentration of these pharmaceutic adjuvants is not particularly limited, as long as it contains
Amount can make it play corresponding effect.
In a specific embodiment, Pemirolast Potassiu temperature sensitive hydrogel of the invention also includes anti-corrosion
Agent, a concentration of 0.0001-0.02ml/ml of preservative, more preferably 0.0002-0.0005ml/ml.
In a further preferred embodiment, Pemirolast Potassiu temperature sensitive hydrogel of the invention includes the phonetic department of pyrrole
Special potassium, poloxamer188, PLURONICS F87, mannitol and benzalkonium bromide, each component it is a concentration of
Pemirolast Potassiu：0.0009-0.002g/ml
Mannitol：0.01-0.08g/ml
Poloxamer188：0.19-0.21g/ml
PLURONICS F87：0.05-0.07g/ml
Benzalkonium bromide：0.0002-0.0005ml/ml
And 3.2<The concentration of concentration/PLURONICS F87 of poloxamer188<3.4.
In a most preferred embodiment, Pemirolast Potassiu temperature sensitive hydrogel of the invention includes
Pemirolast Potassiu：0.001g/ml
Mannitol：0.05g/ml
Poloxamer188：0.20g/ml
PLURONICS F87：0.06g/ml
Benzalkonium bromide：0.0003ml/ml.
The preparation method of the Pemirolast Potassiu temperature sensitive hydrogel of the present invention, includes the following steps：
(1) Pemirolast Potassiu, poloxamer188, PLURONICS F87 and osmotic pressure regulator are added in distilled water, are stirred
It mixes, it is spare；
(2) solution obtained in step (1) is swollen at 4-10 DEG C, until obtaining the solution of clear.
Wherein
In step (1), add together with Pemirolast Potassiu, poloxamer188, PLURONICS F87 and osmotic pressure regulator
What is entered can also have other pharmaceutic adjuvants, such as preservative, wetting agent and/or buffer.Each mutual addition of pharmaceutic adjuvant is suitable
Sequence is not particularly limited.
Pemirolast Potassiu temperature sensitive hydrogel of the present invention can be used as eye-drops preparations.The Pemirolast Potassiu temperature sensitivity
Hydrogel is liquid at room temperature, instills in eye and forms semi-solid gel state, is adhered to cornea and conjunctival sac surface, prolongs
Slow drug release, can not only solve the problems, such as that the conventional eye drop solutions eye residence time is short, bioavilability is not high, also overcome general
The problem that logical eye-gel preparation spreadability is poor, dosage is not easy to control, while can avoid caused by using the dosage forms such as emulsifiable paste
Ocular irritation.
Description of the drawings
Fig. 1 is the accumulative figure of vitro release of the Pemirolast Potassiu temperature sensitive hydrogel prepared according to embodiment 4.
Specific implementation mode
For a further understanding of the present invention, with reference to specific embodiment, the present invention is described in detail, it should be appreciated that under
It states embodiment to be intended to illustrate, not limit the invention.
Instrument and material used by experiment：
FA2004 electronic analytical balances (Shanghai Shun Yuhengping instrument companies, 200g/0.1mg)；UV-160A type ultraviolet spectrometries
Photometer (Japanese Shimadzu Corporation)；TS-200B types constant-temperature table (Changzhou Nuo Ji Instrument Ltd.)；
Pemirolast Potassiu (Lunan Beite Pharmaceutical Co., Ltd.；Lot number：140101, detected through HPLC, purity 99.9%)；
Poloxamer188 (BASF Corp. of Germany, lot number：WPNI566B)；PLURONICS F87 (BASF Corp. of Germany, lot number：
WPHC625E)；Other reagents are that analysis is pure.
Bibliography：
(Zhang Jianqiang, Yang Fang, Yao Jie wait development [J] the China antibiotic of Ciprofloxacin Lactate instant gel for eye to document
Magazine, 2010,35 (4)：It 292-313) reports, 40 μ L of each droplet of solution type eye-drops preparations volume average out to, tear in conjunctival sac
Volume is 7 μ L.It is diluted just between without tear with the mixed process of tear after temperature sensitive hydrogel is added dropwise in conjunctival sac
It forms gel and re-forms gel between the two after being first thoroughly mixed with tear.Therefore, suitable temperature sensitive hydrogel,
Liquid condition is should be at room temperature, with simulation tear 40:7 (V/V) still can be (in conjunctival sac warm less than 35 DEG C after being thoroughly mixed
Degree) temperature generate gelling.The ingredient of artificial tears is simulated used in following embodiment：Including 2.18g sodium bicarbonates,
6.78g sodium chloride, 0.084g calcium chloride dihydrates and 1.38g potassium chloride.
It indicates：
The Pemirolast Potassiu temperature sensitive hydrogel exists>27 DEG C and<35 DEG C of a temperature spot becomes half from liquid
Solid-state, forms gel, and the temperature spot is phase transition temperature (the also referred to as gelling temperature of Pemirolast Potassiu temperature sensitive hydrogel
Degree).In the present invention, environment temperature when " phase transition temperature " refers to the Pemirolast Potassiu temperature sensitive hydrogel complete gelation
Degree.
" room temperature " refers to 10 DEG C -30 DEG C to the present invention in the whole text.
" concentration " of the present invention Pemirolast Potassiu temperature sensitive hydrogel each component in the whole text refers to each component
Amount (in mass for solids fraction, unit g；By volume for liquid composition, unit ml) with the phonetic department of pyrrole at room temperature
The ratio between volume (ml) of special potassium temperature sensitive hydrogel aqueous solution.
Prepare embodiment 1
Precision weighs 0.1g Pemirolast Potassius bulk pharmaceutical chemicals, 20g poloxamer188s, 6g PLURONICS F87s and sets in conical flask,
Add 5% (g/ml) Osmitrol to 100ml, is swollen 24 hours after appropriate stirring at 4 DEG C up to Pemirolast Potassiu temperature
Sensitive aqueous gel.
Measure gelation temperature：Weigh as stated above Pemirolast Potassiu temperature sensitive hydrogel 4ml obtained in test tube
In, liquid is all placed in the water-bath water surface hereinafter, with 1 DEG C of min-1Speed heats, while constantly tilting test tube, when medicine in test tube
Temperature when liquid no longer flows is gelation temperature (also referred to as phase transition temperature).In this embodiment, Pemirolast Potassiu temperature obtained
The gelation temperature for spending sensitive aqueous gel itself is 28 DEG C；It is measured as stated above after being mixed with 0.7ml simulation artificial tears
Gelation temperature be 34 DEG C.
Prepare embodiment 2
Precision weighs 0.1g Pemirolast Potassius bulk pharmaceutical chemicals, 18.6g poloxamer188s, 6g PLURONICS F87s and sets conical flask
In, add 5% (g/ml) Osmitrol to 100ml, is swollen 20 hours after appropriate stirring at 4 DEG C up to Pemirolast Potassiu temperature
Spend sensitive aqueous gel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 30.0 DEG C；It is pressed after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the above method measures is 34.5 DEG C.
Prepare embodiment 3
Precision weighs 0.2g Pemirolast Potassius bulk pharmaceutical chemicals, 21g poloxamer188s, 6g PLURONICS F87s and sets in conical flask,
Add 1% (g/ml) sodium-chloride water solution to 100ml, is swollen 18 hours after appropriate stirring at 4 DEG C up to Pemirolast Potassiu temperature
Sensitive aqueous gel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 27.2 DEG C；It is pressed after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the above method measures is 30 DEG C.
Prepare embodiment 4
Precision weighs 0.1g Pemirolast Potassius bulk pharmaceutical chemicals, 20g poloxamer188s, 6g PLURONICS F87s and sets in conical flask,
0.03% (v/v) benzalkonium bromide aqueous solution is added, adds 5% (g/ml) Osmitrol to 100ml, in 4 DEG C after appropriate stirring
It is lower to be swollen 24 hours up to Pemirolast Potassiu temperature sensitive hydrogel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 28.5 DEG C；It is pressed after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the above method measures is 34.0 DEG C.
Prepare embodiment 5
Precision weighs 0.2g Pemirolast Potassius bulk pharmaceutical chemicals, 16g poloxamer188s, 5g PLURONICS F87s and sets in conical flask,
0.03% (v/v) benzalkonium bromide aqueous solution is added, adds 5% (g/ml) Osmitrol to 100ml, in 4 DEG C after appropriate stirring
It is lower to be swollen 22 hours up to Pemirolast Potassiu temperature sensitive hydrogel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 30 DEG C；By upper after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the method for stating measures is 34.9 DEG C.
Prepare embodiment 6
Precision weighs 0.15g Pemirolast Potassius bulk pharmaceutical chemicals, 23g poloxamer188s, 7g PLURONICS F87s and sets in conical flask,
0.02% (v/v) benzalkonium bromide aqueous solution is added, adds 5% (g/ml) Osmitrol to 100ml, in 4 DEG C after appropriate stirring
It is lower to be swollen 20 hours up to Pemirolast Potassiu temperature sensitive hydrogel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 27.1 DEG C；It is pressed after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the above method measures is 28 DEG C.
Prepare embodiment 7
Precision weighs 0.2g Pemirolast Potassius bulk pharmaceutical chemicals, 20g poloxamer188s, 6g PLURONICS F87s and sets in conical flask,
0.03% (v/v) benzalkonium bromide aqueous solution is added, adds 3% (g/ml) Osmitrol to 100ml, in 4 DEG C after appropriate stirring
It is lower to be swollen 24 hours up to Pemirolast Potassiu temperature sensitive hydrogel.
Gelation temperature is measured with embodiment 1, and gelation temperature is 28.7 DEG C；It is pressed after being mixed with 0.7ml simulation artificial tears
The gelation temperature that the above method measures is 34.3 DEG C.
Testing example 1
Vitro release measures：
Tear in conjunctival sac is constantly updated, while the behaviors such as rotation, blink of eyes can influence the release of drug.
(Zhang Jianqiang, Yang Fang, Yao Jie wait development [J] the China antibiotic of Ciprofloxacin Lactate instant gel for eye to no film dissolution model
Magazine, 2010,35 (4)：292-313) selection, the method are provided along with the drug release that gel erosion occurs for research
Generate the shear action of similar blink, the corrosion of water-soluable gel and medicine to gel surface under oscillating condition using simulation tear
Object release is synchronous to be carried out, and the real processes of instant gel for eye in vivo are met.
At 4 DEG C, ophthalmically acceptable thermo-sensitive gel about 4ml prepared by embodiment 4 is added in the test tube weighed in advance, by this
Container is placed in 35 DEG C of oscillator and preheats 5min, and polymer is made to form gel state completely.The artificial tear preheated in advance is added
As dissolution medium, the constant temperature oscillation 20min under the frequency of 75r/min pours out whole dissolution mediums, will hold liquid 2.4ml immediately
Device surfaces externally and internally blots, and weighs rapidly and records, and is reentered into oscillator inner equilibrium 5min, is supplemented artificial tears and continues to shake
Swing 20min.It operates repeatedly.Using measurement extinction under 357nm ultraviolet wavelengths after the dissolution medium poured out is diluted 10 times
Spend A.
The results are shown in Figure 1, and gel adds up corrosion amount and drug Cumulative release amount respectively returns the time, is as a result in
Good linear relationship meets zero order kinetics feature.Add up corrosion amount to gel with the Cumulative release amount of drug to return,
Equally it is in good linear relationship, the corrosion of drug release and gel is carried out with identical rate, shows that gel erosion is limitation
The principal element of drug release, it is semisolid gel that this, which shows the drug phase inversion of the present invention, can increase the drug in eye
The residence time in portion, to have the function that sustained release
Testing example 2
Influence factor is tested：
The Pemirolast Potassiu temperature sensitive hydrogel prepared according to embodiment 4 is packed into cillin bottle, is respectively placed in light (certainly
Under the conditions of right light and the fluorescent lamp that illumination is 4500Lx), high temperature (60 DEG C of insulating boxs) and low temperature (4 DEG C of refrigerators) are placed 10 days, point
It was not sampled in the 0th, 5,10 day, investigates Pemirolast Potassiu temperature sensitive hydrogel content, gelation temperature.The results show that by
After each experiment investigation of influence factor, the content and gelation temperature of Pemirolast Potassiu temperature sensitive hydrogel of the invention are without change
Change, properties of samples is stable, reliable, and concrete outcome is shown in Table 1.
1. influence factor test result of table
| Condition | Time (d) | Gelation temperature (DEG C) | Content (%) |
| Natural light irradiation | 0 | 28.5℃ | 100.00% |
| 5 | 28.5℃ | 100.12% | |
| 10 | 28.5℃ | 100.19% | |
| 4500Lx daylight light irradiations | 0 | 28.5℃ | 100.00% |
| 5 | 28.5℃ | 100.03% | |
| 10 | 28.5℃ | 100.02% | |
| High temperature (60 DEG C of insulating boxs) | 0 | 28.5℃ | 100.00% |
| 5 | 28.5℃ | 100.21% | |
| 10 | 28.5℃ | 100.15% | |
| Low temperature (4 DEG C of refrigerators) | 0 | 28.5℃ | 100.00% |
| 5 | 28.5℃ | 99.97% | |
| 10 | 28.5℃ | 100.01% |
Although with reference to particular embodiment, the present invention is described, those skilled in the art will recognize that
It is that without departing from spirit and scope of the present invention, the embodiment can be changed or be improved.
Claims (11)
1. a kind of Pemirolast Potassiu temperature sensitive hydrogel is mainly by Pemirolast Potassiu, poloxamer188, poloxamer
188 and osmotic pressure regulator composition the aqueous solution being in a liquid state at 20-27 DEG C, each component is a concentration of：
Pemirolast Potassiu 0.0009-0.002g/ml
Poloxamer188 0.19-0.21g/ml
PLURONICS F87 0.05-0.07g/ml
Osmotic pressure regulator 0.01-0.08g/ml
And 3.2<The concentration ratio of poloxamer188 and PLURONICS F87<3.4.
2. Pemirolast Potassiu temperature sensitive hydrogel according to claim 1, which is characterized in that the osmotic pressure is adjusted
Agent is selected from sodium chloride, glucose, glycerine, polyethylene glycol or propylene glycol.
3. Pemirolast Potassiu temperature sensitive hydrogel according to claim 1, which is characterized in that the osmotic pressure is adjusted
A concentration of 0.03-0.05g/ml of agent.
4. Pemirolast Potassiu temperature sensitive hydrogel according to claim 1, which is characterized in that also include preservative,
Preservative is selected from cationic surfactant, benzyl alcohol, anesin or oxybenzene ester.
5. Pemirolast Potassiu temperature sensitive hydrogel according to claim 1, which is characterized in that also include preservative,
Preservative is selected from benzalkonium chloride, benzalkonium bromide.
6. Pemirolast Potassiu temperature sensitive hydrogel according to claim 1, which is characterized in that also include wetting agent
And/or buffer, wetting agent are selected from glycerine, ethyl alcohol, propylene glycol；Buffer is selected from phosphate buffer, borate buffer solution.
7. a kind of Pemirolast Potassiu temperature sensitive hydrogel, it is characterised in that include Pemirolast Potassiu, poloxamer188, pool
Luo Shamu 188, mannitol and benzalkonium bromide, each component it is a concentration of：
Pemirolast Potassiu：0.0009-0.002g/ml
Mannitol：0.04-0.06g/ml
Poloxamer188：0.19-0.21g/ml
PLURONICS F87：0.05-0.07g/ml
Benzalkonium bromide：0.0002-0.0005g/ml
And 3.2<The concentration of concentration/PLURONICS F87 of poloxamer188<3.4.
8. Pemirolast Potassiu temperature sensitive hydrogel according to claim 7, which is characterized in that the concentration of each component
For：
Pemirolast Potassiu：0.001g/ml
Mannitol：0.05g/ml
Poloxamer188：0.20g/ml
PLURONICS F87：0.06g/ml
Benzalkonium bromide：0.0003g/ml.
9. a kind of preparation method of Pemirolast Potassiu temperature sensitive hydrogel described in claim 1, includes the following steps：
(1) Pemirolast Potassiu, poloxamer188, PLURONICS F87 and osmotic pressure regulator are added in distilled water, stirring is standby
With；
(2) solution obtained in step (1) is swollen at 4-10 DEG C, until obtaining the solution of clear.
10. preparation method according to claim 9 is additionally added other pharmaceutic adjuvants in step (1).
11. preparation method according to claim 10, wherein other described pharmaceutic adjuvants be selected from preservative, wetting agent and/
Or buffer.
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