CN103202833A - Pharmaceutical composition of olopatadine or salts of olopatadine, and preparation method thereof - Google Patents

Abstract

The invention discloses a pharmaceutical composition of olopatadine or a salt thereof for treating allergic conjunctivitis and a preparation method thereof. The composition mainly contains olopatadine or its salt, polycarbophil or polycarbophil salt or carbomer. Its preparation method firstly fully swells polycarbophil or polycarbophil salt or carbomer with appropriate amount of pure water, and then adds olopatadine or its salt and other auxiliary materials.

Description

A kind of pharmaceutical composition of olopatadine or its salt and preparation method thereof

technical field

The invention relates to a pharmaceutical composition of olopatadine or a salt thereof for treating allergic conjunctivitis and a preparation method thereof

Background technique

A doxepin derivative represented by olopatadine is a mast cell stabilizer with antihistamine activity. For the prevention or treatment of allergic eye disease. The marketed product Olopatadine Hydrochloride Eye Drops, the trade name is Patanol, its ingredients are mainly composed of Olopatadine Hydrochloride, bacteriostatic agent, and pH regulator. 3 to 4 times a day, once every 6 to 8 hours. Its side effects include headache, fatigue, blurred vision, burning or stinging sensation, cold syndrome, dry eyes, foreign body sensation, congestion, allergies, keratitis, eyelid edema, nausea, pharyngitis, itching, rhinitis, sinusitis, and taste perversion wait. As conventional sterile pure aqueous eye drops, due to the existence of the corneal barrier, the inversion of tear fluid on the surface of the eyeball, etc., the eye drops show low bioavailability. Therefore, frequent dosing has to be done in order to maintain normal local efficacy. This has caused two problems, one is damage to the eye caused by the use of preservatives in conventional eye drops, and the other is adverse reactions caused by antihistamine active substances. the

In order to prevent antihistamine drugs from acting on the whole body, reduce damage to the eyes, and enable the drug to stay in the eyes for a longer period of time, continuously release the drug to the eyes, look for non-toxic and non-irritating drugs that can prolong the stay of the drug in the eyes Time for the druggable substance to become the key to solving the problem. the

Contents of the invention

The object of the present invention is to provide a sustained-release ophthalmic preparation capable of prolonging the residence time of olopatadine or its salt in the eye. The ophthalmic preparation mainly consists of olopatadine or its salt and polycarbophil or polycarbophil salt or carbomer. The adhesion of polycarbophil and its salt or carbomer can greatly improve the retention of drugs in the eyes, and slowly release drugs under the action of tear erosion and body temperature, which can not only reduce the number of administrations, Systemic side effects of the drug can also be avoided, thereby improving the bioavailability and curative effect of the drug. the

It has been reported in the literature that when carbomer is used in the scalp drug delivery system of progesterone, since the skin keratin filaments are surrounded by amorphous sulfur-rich proteins, the thiol polymer can make the drug through the exchange of disulfide bonds. The total adhesive force of the compound is significantly greater than the contrast preparation made with PVP, HPMC, showing that the carbomer series polymer has unique bioadhesive force (Pharm Res, 2001, 18, 211.). the

Ugwoke et al conducted a study on the bioavailability of nasal administration of apomorphine mucoadhesive drug delivery system in rabbits, using carbomer, polycarbophil and lactose to make drug powder preparations respectively. It was found that f and MRT of the former two were significantly greater than that of the latter, and had equal AUC values to subcutaneous injection. It is shown that carbomer polymers can increase the drug residence time and reduce the clearance of cilia through the bioadhesion at the nasal cavity absorption site (Eur J Pharm Sci, 1999, 9, 213.). the

Bron et al. found in their research that 0.2% carbomer has similar safety compared with 1.4% polyvinyl alcohol, and carbomer preparations can reduce the number of ocular administrations (Eur J Ophthalmol, 1998, 8, 81 .). People such as Nagarsenker prepared cationic and neutral liposomes of tropicamide, and at the same time neutral liposomes were dispersed in polycarbophil gel to make neutral liposome gels, rabbit eyes Pupil dilation was recorded after administration. The time-lapse curve of relative mydriasis intensity shows that after administration of neutral liposome gel, tmax is significantly greater than the aqueous solution of drug; the AUC of gel after drug administration is the same as that of cationic liposome and neutral liposome gel , This result shows that the real reason for the increase of AUC is that the viscosity of polycarbophil rather than liposome encapsulates the drug (Int J Pharm, 1999, 190, 63.). the

In summary, the use of carbomer and polycarbophil in skin, mucous membrane, and eye drug delivery systems has the characteristics of low irritation, long surface residence time, and improved bioavailability of drugs, and can be used as a gel and emulsion bases. the

Based on the above research results, in order to prolong the residence time of olopatadine hydrochloride in the eyes, acrylic acid polymer carbomer or polycarbophil and salts thereof can be used to prepare ophthalmic pharmaceutical compositions. the

A pharmaceutical composition of olopatadine or its salt for the treatment of allergic conjunctivitis provided by the present invention is characterized in that the composition mainly contains olopatadine or its salt, polycarbophil or polycarbamide Boffi salt or carbomer. The composition contains 0.1% olopatadine or its salt (calculated as olopatadine), and 0.02-2% (w/v) polycarbophil or polycarbophil salt or carbomer . The salt of olopatadine contained in the composition refers to hydrochloride. The composition contains an antioxidant capable of stabilizing polycarbophil or polycarbophil salt or carbomer, and the antioxidant is selected from edetate disodium, sodium thiosulfate or sodium citrate, preferably edetate disodium acid. The content of edetate disodium in the composition is 0.005-0.05%. the

A kind of preparation method of the pharmaceutical composition of olopatadine or its salt that is used for the treatment of allergic conjunctivitis provided by the present invention is characterized in that polycarbophil or polycarbophil salt is firstly mixed with appropriate amount of pure water Or carbomer is fully swollen, and then add olopatadine or its salt and other auxiliary materials. the

Detailed ways

The following typical embodiments are used to illustrate the present invention. Simple replacements or improvements made by those skilled in the art are within the technical solutions protected by the present invention. the

Example 1:

Preparation prescription of the present invention is made up of following components:

Preparation Process:

1) Under sterile conditions, carbomer and appropriate amount of water for injection are fully swollen at room temperature to obtain solution 1;

2) After dissolving olopatadine hydrochloride and benzalkonium chloride with appropriate amount of water for injection respectively, they were combined to obtain solution 2;

3) Dissolving mannitol, sodium chloride, edetate disodium, and poloxamer in an appropriate amount of water for injection in sequence to obtain solution 3;

4) Combine Solution 1, Solution 2, and Solution 3 under sterile conditions, mix them evenly through a high-speed homogenizer, adjust the pH value to 5-7 with 1M sodium hydroxide solution, and add water for injection to the total amount;

5) After sterilization, cool to room temperature, and dispense into sterilized eye drop bottles under aseptic conditions. the

Example 2:

Preparation prescription of the present invention is made up of following components:

Preparation Process:

1) Under sterile conditions, polycarbophil and an appropriate amount of water for injection are fully swollen at room temperature to obtain solution 1;

2) After dissolving olopatadine hydrochloride and benzalkonium bromide with appropriate amount of water for injection respectively, they were combined to obtain solution 2;

3) Dissolving mannitol, sodium chloride, disodium edetate, and polysorbate 80 in an appropriate amount of water for injection in sequence to obtain solution 3;

4) Combine Solution 1, Solution 2, and Solution 3 under sterile conditions, mix them evenly through a high-speed homogenizer, adjust the pH value to 5-7 with 1M sodium hydroxide solution, and add water for injection to the total amount;

5) After sterilization, cool to room temperature, and dispense into sterilized eye drop bottles under aseptic conditions. the

Embodiment 3: Rabbit eye residence time experiment

Objective: The length of ocular residence time is an important index to measure ophthalmic sustained-release eye drops. The residence time in the eyes of rabbits was compared. the

Preparation of the test product: Add 0.05% sodium fluorescein to the product prepared in Example 1 and Example 2 and commercially available Patanol (olopatadine hydrochloride eye drops, Alcon Company) . the

Method: 18 healthy rabbits were selected and divided into three groups on average. The rabbits were fixed with their heads, their lower eyelids were lifted, and the conjunctival sac was pulled into a ring shape, and fluorescein was dripped into the conjunctival sacs of the left eyes of the three groups of rabbits respectively. 20 μL each of the sodium product of Example 1, Example 2, and commercially available Patanol was dropped into 20 μL of Patanol containing fluorescein sodium as a control group. After administration, the eyes of the rabbits were passively closed for 10 seconds, placed in a rabbit clip and observed with a slit lamp, and the intensity of the fluorescent layer on the surface of the cornea and the conjunctival sac of the rabbits was observed at regular intervals. The time when the continuous fluorescent layer on the inner surface of the conjunctival sac disappeared was defined as the ocular residence time. The experimental results are shown in the table in Fig. 1 . the

Analysis: During the observation, it was found that Patanol was difficult to stay on the cornea of rabbits, and part of it flowed out from the corner of the eye. After the products of Example 1 and Example 2 were dripped into the conjunctival sac, they were evenly distributed on the conjunctiva and cornea. Compared with the control group, the products of Example 1 and Example 2 have increased the ocular retention time by 2 to 3 times, showing that the pharmaceutical composition containing olopatadine prepared according to the present invention has good ocular retention The results are shown in Figure 2. the

Description of drawings

Fig. 1 is the rabbit eye residence time data of embodiment 1 group, embodiment 2 group and Patanlo control group; Fig. 2 is the rabbit eye according to embodiment 1 group, embodiment 2 group and Patanlo control group Dwell time histogram. the

Claims (8)

1. one kind is used for the treatment of the olopatadine of anaphylaxis conjunctivitis or the Pharmaceutical composition of its salt, it is characterized in that said composition mainly contains olopatadine or its salt, Polycarbophil or Polycarbophil salt or carbomer.

2. Pharmaceutical composition according to claim 1 is characterized in that said composition contains 0.1% olopatadine or its salt (content calculates with olopatadine).

3. according to claim 1 and 2 described Pharmaceutical compositions, it is characterized in that the salt that said composition contains olopatadine is hydrochlorate.

4. Pharmaceutical composition according to claim 1 is characterized in that said composition contains Polycarbophil or Polycarbophil salt or the carbomer of 0.02～2% (w/v).

5. Pharmaceutical composition according to claim 1 is characterized in that said composition contains the antioxidant that can stablize Polycarbophil or Polycarbophil salt or carbomer.

6. according to claim 1 and 5 described Pharmaceutical compositions, it is characterized in that the antioxidant that said composition contains is selected from disodium edetate, sodium thiosulfate or sodium citrate, preferred disodium edetate.

7. according to claim 1,5 and 6 described Pharmaceutical compositions, it is characterized in that said composition contains 0.005～0.05% disodium edetate.

8. the preparation method of the described Pharmaceutical composition of claim 1 is characterized in that at first using an amount of pure water with Polycarbophil or Polycarbophil salt or the abundant swelling of carbomer, adds olopatadine or its salt and other adjuvants again.

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