WO2017166888A1

WO2017166888A1 - Eyedrop and preparation method and application thereof

Info

Publication number: WO2017166888A1
Application number: PCT/CN2017/000180
Authority: WO
Original assignee: 广东中科药物研究有限公司
Priority date: 2016-03-30
Filing date: 2017-02-17
Publication date: 2017-10-05
Also published as: CN105769758B; CN105769758A

Abstract

An eyedrop prepared using a biphenylacetate or a biphenylacetic acid. A technical study showed that the pH level must be controlled within a specific range. A hydroxybenzoate ester is selected as an antimicrobial agent. The invention is stable and improves a local anti-inflammatory effect.

Description

Eye drop liquid and preparation method and application thereof

Technical field

The invention relates to an eye drop prepared by using biphenyl acetate and the application thereof, and the preparation method of the biphenyl acetate tromethamine eye drop is illustrated as an example.

Background technique

Biphenylacetic acid as an anti-inflammatory analgesic drug was marketed in Japan, Italy and other countries in 1993. It is used for analgesic and anti-inflammatory effects such as osteoarthritis, frozen shoulder, tenosynovitis, periorbital inflammation, muscle pain and soft tissue injury, and after alleviating trauma. Swelling pain. However, since biphenylacetic acid is insoluble in water, it can only be used as a topical drug, which seriously affects the promotion and use of the drug. In Japan, there was a biphenyl ethyl acetate injection emulsion (insoluble in water) for clinical analgesia. Recently, due to the clinical occurrence of shock, the manufacturer has withdrawn the variety from the market, and re-examination of clinical studies shows that Allergies are one of the main causes of shock, and soy lecithin, an excipient for injectable emulsions, may be one of allergens. Moreover, as an emulsion, the product has disadvantages such as poor stability, complicated production process, and unsafe factors caused by macromolecular excipients. Our company has found through experiments that biphenylacetate tromethamine salt (hereinafter, aniline fenbutanol is substituted for benzacetamide tromethamine salt) has better water solubility and safety than other salts, and is suitable for preparation into an injection solution. Based on the anti-inflammatory effect of aniclofen, we developed the eye drops. However, in the research and development of eye drops, it was found that the eye drops prepared by the use of nigroprofen must be in a certain pH range. It is able to maintain stable properties and has strict requirements for bacteriostatic agents. Aniline is a white crystalline powder, slightly soluble in water and dissolved in a dilute alkali solution. The degradation test in the quality standard of the drug substance shows that the product is relatively stable in general high temperature, high humidity, acid solution and alkali solution. It is also relatively stable in a general concentration of hydrogen peroxide solution, and is not stable under severe conditions such as strong acid, strong alkali and strong oxidation. Therefore, anhydrous sodium carbonate is used as a solubilizer to promote the dissolution of nigroprofen; and the pH of the anilinoprofen eye drops is maintained at about 7.5, maintaining the relative stability of the flexiphene, and the effect on the cornea is mild and non-irritating. The addition of the surfactant poloxamer 407 can prolong the retention time of the drug in the cornea and improve the bioavailability of the drug; the sodium chloride is added to adjust the osmotic pressure so that the osmotic pressure is consistent with the intraocular pressure; and a small amount is added. Disodium edetate is used as a metal ion chelating agent; since aniline is incompatible with benzalkonium chloride, hydroxyethyl ester is used as a preservative, and the application range of hydroxyphenylethyl ester is just at pH 7-9. The antibacterial efficacy test verified its inhibition The effect of the bacteria; the influencing factors test showed that the product is relatively stable to high temperature and illumination; by examining the effects of different packaging materials on the stability of aniline fentanyl eye drops, the results show that the compatibility of phenamifofen eye drops with different packaging materials They are all better, so the polypropylene packaging eye drops bottle, which is the common packaging material for general eye drops, is selected as the inner packaging material of this product. The above research results show that the above-mentioned formulated nigroprofen eye drops are relatively stable.

Invention disclosure

The eye drops prepared by the present invention have an active ingredient of nigroprofen (biphenylacetate tromethamine). Its chemical formula is:

The molecular formula is C ₁₈ H ₂₃ NO ₅ and the molecular weight is 333.14.

The use of anhydrous sodium carbonate as a solubilizer promotes the dissolution of nigroprofen and maintains the pH of the flexionoside eye drops at around 7.5, maintaining the relative stability of the flexiphene, and acting mildly on the cornea without irritation. Adding the surfactant poloxamer 407, can prolong the retention time of the drug in the cornea, and improve the bioavailability of the drug; adding sodium chloride to adjust the osmotic pressure, so that the osmotic pressure is consistent with the intraocular pressure; and adding a small amount Disodium edetate is used as a metal ion chelating agent; since aniline is incompatible with benzalkonium chloride, hydroxyethyl ester is used as a preservative to ensure the sterility requirements of aniline fentanyl eye drops in accordance with the national pharmacopoeia. Standard, in the design and research stage, the prescription mainly contains nigroprofen, poloxamer 407, hydroxyethyl ester, sodium chloride, anhydrous sodium carbonate, disodium edetate and other raw materials; in the selection of raw materials Sodium chloride and anhydrous sodium carbonate are all injection-grade aseptic auxiliary materials. Poloxamer 407, disodium edetate and hydroxyphenylethyl ester are selected as pharmaceutical excipients with national approval number; Liquid Production process using the production process of internationally accepted sterilization filtration, under production conditions of GMP, one hundred clean production zone, production of aniline to ensure good quality drops ketoprofen. The specification is determined according to the pharmacodynamic concentration screening test of aniline fentanyl eye drops, and the effective concentration is determined to be 0.1%. 1 mg of aniline is contained per 1 ml of phenamifofen eye drops, and reference is made to the similar drug that has been marketed in Japan. The specification of Lofin Eye Drops is 5ml: 5mg, so we tentatively set the product size to 5ml: 5mg. Similarly, other salts of biphenylacetic acid, sodium salt, ammonium salt, potassium salt, diethylamine, guanamine salt, etc. are used, and the pH value and the selection of the bacteriostatic agent are the same. It is also possible to dissolve the biphenyl acetic acid in a certain concentration of sodium carbonate solution, and the pH and the bacteriostatic agent are selected in the same manner. Hydroxyphenyl ethyl ester can be used

Replacement with methylparaben, propylparaben and hydroxybutyrate.

The best way to implement the invention

Example 1 Preparation of Biphenylacetate Eye Drops

prescription

[1] Dissolve anhydrous sodium carbonate with a small amount of water for injection, add a prescribed amount of nigroprofen, and stir to completely dissolve. Dissolve the hydroxyethyl ester with a small amount of water for injection and boil it to dissolve completely. Dissolve poloxamer 407 with 50% of the prescribed amount of water for injection, add dissolved sodium carbonate and nigroprofen, add sodium chloride and disodium edetate, stir to dissolve, and finally add dissolved Hydroxyphenyl ethyl ester, add water for injection to the full amount, stir evenly. The bacteria were sterilized by filtration through a 0.22 μm microporous membrane.

[2] pH value, osmotic pressure and main drug content of the test solution.

[3] After passing the test, use 5ml polypropylene medicinal eye drops bottle to pack and seal in a hundred-level environment, and 5ml of liquid medicine per bottle.

Example 2 Selection of PH Value

Weigh 5.01g of nigroprofen, add 1000ml of water for injection, then add an appropriate amount of anhydrous sodium carbonate, stir it to completely dissolve it, cool it to 5 parts after cooling, then add water to 5000ml after cooling, adjust the pH value to 7.0, 7.5, 8.0, 8.5, 9.0, 1000ml each, stir well, filter and sterilize by 0.22μm microporous membrane, and then potting in 5ml polypropylene pharmaceutical eye drops bottle, 5ml per bottle ,seal. The quality inspection results are shown in Table 1.

Table 1 Quality inspection results of samples under different pH values and the same sterilization conditions

It can be seen from the table that when the pH value is 7.0 during sample preparation, the sample is not dissolved in the aqueous solution, dissolved by heating, and solid precipitates after cooling. There is no abnormality in the preparation of other samples, appearance characteristics and pH value before and after sterilization. There was no change in the substance and content. No precipitation of crystals was observed at room temperature and in cold storage (2-8 °C), indicating that the sample has good physical and chemical properties within this pH range, according to the pH range suitable for human eyes. We have a pH range of 7.0 to 8.0, and the pH is generally controlled to about 7.5 in the formulation process.

Example 3 Selection of preservatives

Eye drops are multi-dose preparations, which cannot be kept sterile during use, and nigrofiprofen itself does not have sufficient antibacterial activity. Therefore, suitable effective bacteriostatic agents should be added to prevent the preparation from being stored and used during normal use. Microbial contamination and reproduction that may occur can cause the drug to deteriorate and cause harm to the user. The bacteriostatic agent added to the eye drops is not only required to be effective, but also requires rapid action to achieve bacteriostatic action in the interval between two uses of the patient. Foreign eye drops are most commonly used in quaternary ammonium salts. We first use benzalkonium chloride to add eye drops. The solution immediately turbid and replaced with benzalkonium bromide. The same result indicates that quaternary ammonium salts and aniline are used. Fen is not compatible. Then we chose hydroxyphenyl esters, which are effective at pH 7~9. The eye drops we prepared are just within this pH range.

Weigh 5.03g of nigroprofen, add 1000ml of water for injection, then add an appropriate amount of anhydrous sodium carbonate, stir it to dissolve completely, add hydroxyphenylethyl ester, then add cooling and then dilute to 5000ml with water for injection, 0.22μm After the microporous membrane filter was sterilized, it was potted in a 5 ml polypropylene pharmaceutical eye drop bottle, and each bottle was filled with 5 ml and sealed. After the addition of hydroxyethyl ester, the eye drops were still a colorless clear liquid, and remained clear and transparent after 10 days of storage. The quality inspection results are shown in Table 2.

Table 2 Quality inspection results of different preservatives

Example 4 Experimental study on the effects of different concentrations of biphenyl acetate tromethamine on eye drops in guinea pigs

120 guinea pigs, except the vehicle control group (10), the other groups were prepared according to the methods reported in the literature to prepare an animal model of allergic conjunctivitis. 1 Sensitization: Each guinea pig was intraperitoneally injected with OVA (ovalbumin albumin) suspension (OVA 0.1 mg and AL (OH) ₃ 5 mg, dissolved in 1 mL of normal saline), and each injection of the vehicle control group was injected physiologically. 1 ml of saline was injected again after 14 days. 2 Model evaluation and grouping: On the 7th day after the completion of intraperitoneal injection, a passive skin immune response (PCA) test was performed to determine that the OVA-IgE antibody titer was elevated for successful modeling. 80 randomly selected animals were randomly divided into model group, and the dosage of biphenyl acetate tromethamine series eye drops was 1-6 (concentration: 0.04%, 0.08%, 0.16%, 0.32%, 0.48%, 0.96%). The pranoprofen eye drop control group, the model control group, and the vehicle control group, a total of 9 groups, each group of 10, male and female. 3 Excitation and administration: OVA saline dilution (5 mg/mL) was dropped into the conjunctival sac of the double eye with a micro-applicator, 20 μL per eye, once a day, once every other day for one week. At the same time, each group of eyes was given 20 μL per eye for the corresponding liquid, once a day for one week, and the model group and the vehicle control group were given physiological saline. 4 symptom observation and index measurement:

Ocular symptom observation and scoring: After 30 minutes of the last antigen challenge, the guinea pig eye symptoms were scored with a slit lamp. The scoring criteria were as follows: A. Conjunctival hyperemia (referring to the conjunctiva and bulbar conjunctiva): normal blood vessel 0 points; blood vessels Congestion was bright red 1 point; blood vessel congestion was dark red, blood vessels were difficult to distinguish 2 points; diffuse hyperemia was purple red 3 points.

B. Conjunctival edema: no 0 points; slight edema (including nictitating membrane) 1 point; obvious edema, with partial eyelid valgus 2 points; edema to the eyelid nearly half closed 3 points; edema to the eyelids mostly closed 4 points. C. Secretion: no 0; a small amount of secretion 1 point; secretions make the eyelids and eyelashes wet or stick 2 points; secretions make the entire eye area damp or stick 3 points. The result of the scoring is a cumulative score of 3 points, which is the total score of congestion, edema, and secretion score. Scratch reaction count: 20 μ n was observed continuously after antigen challenge, and the number of scratches was recorded. The eye scratching reaction was defined as the guinea pig forelimb moving to the eye more than 2 times.

test results:

2.1 eye symptom observation score

The results of the trials (Table 1) showed that the symptom scores of the model group were significantly higher than those of the vehicle control group (p<0.001), and the symptom scores of the medication groups were lower than those of the model group (p<0.05 or p<0.01 or 0.001). The dose of biphenyl acetate tromethamine series eye drops 2 to 6 was superior to the pranoprofen eye drops group (p<0.05 or p<0.01 or 0.001).

2.2 scratch response count

The results of the test (Table 3) showed that the number of sputum responses in the model group was significantly higher than that in the vehicle control group (p<0.001), and the number of sputum responses in the guinea pigs in each group was lower than that in the model group (p<0.05). Dingtriol series eye drops dose 2 to dose 6 were superior to pranoprofen eye drops group (p<0.05 or p<0.01 or 0.001).

Table 3 Effect of biphenyl acetate tromethamine series eye drops on complication of conjunctivitis and sputum response in guinea pigs

Compared with the model group: *p<0.05, **p<0.01, ***p<0.001

Comparison with pranoprofen eye drops: #p<0.05,##p<0.01,###p<0.001

Test Conclusions:

Different concentrations of biphenyl acetate tromethamine series of eye drops have a good effect on the conjunctivitis symptoms of guinea pigs, and are superior to pranoprofen eye drops.

Claims

A biphenyl acetate eye drop characterized by:

(1) the active ingredient contains biphenylacetic acid or biphenyl acetate;

(2) PH value is 7-8;

(3) The bacteriostatic agent is hydroxyethyl ester or methylparaben or hydroxypropylpropyl or hydroxyphenyl butyl ester.
A biphenyl acetate tromethamine eye drop, characterized by:

(1) the active ingredient contains biphenyl acetate tromethamine salt;

(2) PH value is 7-8;

(3) The bacteriostatic agent is hydroxyethyl ester or methylparaben or hydroxypropylpropyl or hydroxyphenyl butyl ester.
A biphenyl acetate tromethamine eye drop, characterized by:

(1) the active ingredient contains biphenyl acetate tromethamine salt;

(2) PH value is 7-8;

(3) The bacteriostatic agent is hydroxyphenylethyl ester.
The eye drops according to claims 1-3, which contain a concentration of 0.04-1% of biphenylacetic acid or biphenylacetate.
Use of an eye drop according to claims 1-3 for the preparation of a medicament for the treatment of a local inflammatory response.