CN107854470B

CN107854470B - Acatadine composition, preparation method and application thereof

Info

Publication number: CN107854470B
Application number: CN201610846751.4A
Authority: CN
Inventors: 周晶晶; 于艳春; 吴娟; 郭婷婷; 杨波; 郭亚兵
Original assignee: WUHAN WUYAO TECHNOLOGY Co Ltd
Current assignee: WUHAN WUYAO TECHNOLOGY Co Ltd
Priority date: 2016-09-21
Filing date: 2016-09-21
Publication date: 2020-03-27
Anticipated expiration: 2036-09-21
Also published as: CN107854470A

Abstract

The application discloses an alcaftadine composition, which contains 0.005-10% (w/v) alcaftadine, 0.001-10% (w/v) nonionic surfactant and other proper amounts of pharmaceutically acceptable excipients and water for injection. The composition can ensure that the alcaftadine is fully dissolved in the aqueous solution and improve the stability of the alcaftadine in the aqueous solution while not increasing the excessive feeding of the main drug alcaftadine, and compared with the eye drops sold in the market, the eye drops with the prescription of the invention have no irritation and good safety. The application also discloses a preparation method of the alcaftadine composition, and the method is reasonable in process, simple and easy to implement.

Description

Acatadine composition, preparation method and application thereof

Technical Field

The application relates to an alcaftadine composition, and belongs to the technical field of medicines.

Technical Field

Allergic conjunctivitis, also known as allergic conjunctivitis, is a hypersensitivity reaction of the conjunctiva to external allergens. Mainly comprises I type allergic reaction and IV type allergic reaction, wherein allergic conjunctivitis caused by the I type allergic reaction is the most common. Allergic conjunctivitis caused by type I allergic reaction is in immediate form, and mainly refers to the allergic conjunctivitis including seasonal allergic conjunctivitis, perennial allergic conjunctivitis, giant papillary conjunctivitis, vernal keratoconjunctivitis, ectopic keratoconjunctivitis, etc.; allergic conjunctivitis caused by type IV allergy is delayed, and mainly comprises vesicular conjunctivitis.

The most common symptom of allergic conjunctivitis is itching of eyes, almost all patients with allergic conjunctivitis can have the allergic conjunctivitis, but the itching of eyes is not a specific symptom, the itching degrees of allergic conjunctivitis and eyes of different subtypes are different, wherein the vernal keratoconjunctivitis usually shows the most obvious symptoms, other more common symptoms comprise lacrimation, burning sensation, photophobia, secretion increase and the like, most secretions are mucus and are sticky and filamentous, and some more serious allergic conjunctivitis, such as vernal keratoconjunctivitis and atopic keratoconjunctivitis, can sometimes have vision loss.

If the allergic conjunctivitis is not treated in time, the allergic conjunctivitis is easy to repeatedly attack, and brings various troubles to the life of people: for example, (1) when allergic conjunctivitis occurs, the patient feels itching in the eyes, so that the attention of the patient cannot be concentrated, and the work and life of people are seriously influenced. Children can affect the academic industry. (2) The patient can be cured in a short term due to the influence on the vision, and the general allergic conjunctivitis has no influence on the vision, but certain vernal keratoconjunctivitis and atopic conjunctivitis can cause corneal complications and even harm the vision, and the serious patient can cause blindness. (3) Affecting the quality of life of people. Itching, pain, edema, etc. due to allergic conjunctivitis. Can affect the psychology and life of the patient. Causing a reduction in the quality of life of the patient and their family. (4) Other allergic diseases can be caused. The allergic conjunctivitis patients are allergic constitution, so that other allergic diseases such as allergic rhinitis and allergic asthma can be caused by the allergic conjunctivitis, and the burden of the patients is further increased. (5) Strictly speaking, the allergic reaction causes not only allergic conjunctivitis but also affects other parts of the eye, so that more eye diseases are manifested, with some serious consequences.

Alcaftadine acts as a tricyclic histamine H1 receptor antagonist and mast cell stabilizer, and reduces allergic reactions by inhibiting histamine release from mast cells and arresting histamine action. In addition, the alcaftadine also has the effects of reducing chemotaxis and inhibiting eosinophil activity. This makes it obvious that alcaftadine has therapeutic effect on various symptoms of ocular allergy such as redness of the eye, edema of the conjunctiva, and eyelid swelling, etc. due to other similar drugs. The structural formula of alcaftadine is as follows:

foreign clinical studies show that 0.25 percent of alcaftadine eye drops are taken by patients once a day, and the red swelling of eyes caused by allergic conjunctivitis can be reduced. At present, the eye drops are sold and used in developed countries in Europe and America, so that the clinical use is safer, the toxic and side effects are small, and the compliance of patients is good.

As is well known, the formulation of ophthalmic solutions typically requires filter sterilization through a filter membrane and is a necessary step. Acatadine is found to be a poorly soluble drug, being practically insoluble in water. The acatadine which is not completely dissolved is easily trapped or adsorbed by the filter membrane in the filtering process, so that the final liquid medicine content is seriously reduced and is not qualified. Although the method can be compensated by increasing the feeding amount and the dissolving temperature, the method causes the waste of raw materials and the increase of the content of related substances, and also greatly increases the production cost. In addition, aqueous alcaftadine solutions are also unstable, especially under heat and light conditions. Certain degradation impurities also occur in aqueous solutions of alcaftadine during storage and standing, and the presence of these degradation impurities can affect the toxicological profile of the formulation.

Accordingly, the present invention has been made to overcome the above-mentioned shortcomings of the prior art.

Disclosure of Invention

The inventor of the invention finds that the solubility of the alcaftadine is greatly improved and the alcaftadine can be completely dissolved under the normal condition under the condition of containing the nonionic surfactant in the research and development process of the prescription of the alcaftadine eye drops, thereby solving the problem of raw material waste caused by excessive feeding in the preparation process. In addition, the inventor also finds that the alcaftadine eye drops prepared by adding the nonionic surfactant are more stable than the alcaftadine eye drops without adding the nonionic surfactant, and the stability of the alcaftadine eye preparations is improved.

Therefore, according to one aspect of the invention, the alcaftadine composition is provided, and the alcaftadine composition can ensure that the alcaftadine is fully dissolved in an aqueous solution and improve the stability of the alcaftadine in the aqueous solution while the dosage of the main drug alcaftadine is not increased, so that the aim of safely and effectively treating pruritus related to allergic conjunctivitis is fulfilled.

In order to achieve the purpose, the following technical scheme is adopted in the application:

an alcaftadine composition comprising 0.005-10% (w/v) alcaftadine and 0.001-10% (w/v) nonionic surfactant.

Preferably, the alcaftadine composition comprises 0.1-0.4% (w/v) of alcaftadine and 0.05-5% (w/v) of a nonionic surfactant.

More preferably, the alcaftadine composition comprises 0.25% (w/v) of alcaftadine and 0.5% (w/v) of a nonionic surfactant.

Preferably, the alcaftadine composition further comprises a solvent and other pharmaceutically acceptable excipients other than a non-ionic surfactant.

Reference herein to percent (w/v) is to weight to volume ratio, and more specifically to the weight (g) of each component of the acatadine compositions of the present application as a percentage of the total volume (mL) of the final solution.

Preferably, the nonionic surfactant is polyethylene glycol-12-hydroxystearate.

Preferably, the pharmaceutically acceptable excipient comprises at least one of an osmotic pressure regulator, a bacteriostatic agent, a stabilizer and a solvent.

Preferably, the osmolality adjusting agent comprises at least one of sodium chloride, glucose, mannitol, glycerol, propylene glycol and boric acid.

Preferably, the bacteriostatic agent comprises at least one of methylparaben, ethylparaben, propylparaben, benzyl alcohol, phenylethyl alcohol, sorbic acid, salicylic acid, chlorobutanol, benzalkonium chloride, benzalkonium bromide, thimerosal, or phenoxyethanol.

Preferably, the solvent comprises water for injection.

Preferably, the alcaftadine composition specifically comprises benzalkonium chloride, sodium dihydrogen phosphate, sodium chloride, edetate disodium and water for injection.

More preferably, the concentration of benzalkonium chloride in the alcaftadine composition is 0.001-0.01% (w/v) benzalkonium chloride, the concentration of monobasic sodium phosphate in the alcaftadine composition is 0.3-0.8% (w/v), the concentration of sodium chloride in the alcaftadine composition is 0.3-0.8% (w/v), the concentration of edetate disodium in the alcaftadine composition is 0.005-0.02% (w/v).

Most preferably, the alcaftadine composition consists of 0.25% (w/v) alcaftadine, 0.5% (w/v) polyethylene glycol-12-hydroxystearate, 0.005% (w/v) benzalkonium chloride, 0.54% (w/v) sodium dihydrogen phosphate, 0.62% (w/v) sodium chloride, 0.01% (w/v) disodium edetate, and water for injection.

Preferably, the alcaftadine composition has a pH of 6.0-7.0.

In addition, other pharmaceutically acceptable excipients mentioned in the alcaftadine compositions of the present application may also comprise other components commonly used in ophthalmic formulations, such as viscosity increasing agents, antioxidants, and the like.

The viscosity increasing agent is at least one selected from methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvidone, polyethylene glycol and polyvinyl alcohol.

The antioxidant is selected from at least one of vitamin C, vitamin E, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium sulfite, citric acid, tartaric acid, lecithin and amino acid.

According to another aspect of the invention, a preparation method of the alcaftadine composition is provided, and the method is reasonable in process, simple and feasible.

a method of preparing an alcaftadine composition, comprising the steps of:

(1) mixing the alcaftadine, the nonionic surfactant and a first solvent, and fully dissolving the alcaftadine to obtain a solution I, wherein the water for injection is preferably water for injection;

(2) optionally dissolving other pharmaceutically acceptable carriers in a second solvent to obtain a solution II; wherein the first solvent is the same as or different from the second solvent;

(3) mixing the solution I and the solution II in the presence of step (2) to obtain a solution III,

subjecting the solution I obtained in the step (1) or the solution III obtained in the step 3) to aseptic processing to obtain the composition.

Preferably, the filtration is performed using a 0.2 μm-0.45 μm microfiltration membrane for aseptic processing.

Most preferably, filtration is performed using a 0.2 μm to 0.22 μm microfiltration membrane for aseptic processing.

Preferably, the preparation method of the alcaftadine composition specifically comprises the following steps:

(1) dissolving the nonionic surfactant in water for injection, and then adding a prescription amount of alcaftadine to fully dissolve the alcaftadine to obtain a solution I;

(2) heating a proper amount of water for injection to boil, dissolving a pharmaceutically acceptable excipient in the water, and stirring to fully dissolve the excipient to obtain a solution II;

(3) cooling the solution II to room temperature, then combining the solution II with the solution I, and adding water for injection to obtain a solution III;

(4) adjusting the pH value of the solution III to 6.0-7.0, and filtering through a 0.22 mu m microporous filter membrane to obtain the alcaftadine composition.

In the step (3), the addition of the water for injection to the full amount means that the water for injection is added so that the alcaftadine composition reaches the specified total volume.

According to a further aspect of the present application, there is provided the use of an alcaftadine composition for the manufacture of a medicament for the treatment and/or prevention of clinical symptoms of, or mechanistic symptoms associated with, ocular allergy and/or ocular inflammation, wherein the symptoms are selected from at least one of allergic conjunctivitis, ocular itching, ocular redness, eyelid swelling, conjunctival edema, lacrimation, rhinitis, nasal congestion, rhinorrhea, ear pruritus, palate pruritus, sneezing, vascular permeability, reduced integrity of the tight junctions of the conjunctival epithelium, mast cell degradation.

Preferably, the alcaftadine composition is prepared into eye drops or an ophthalmic gel, preferably into eye drops.

Benefits that can be produced by the present application include, but are not limited to:

1) the alcaftadine composition provided by the application comprises 0.005-10% (w/v) alcaftadine, 0.001-10% (w/v) nonionic surfactant, and a proper amount of pharmaceutically acceptable excipient and water for injection. In the process of recipe research of the alcaftadine composition, the inventor of the invention finds that particularly, when 0.5% (w/v) of nonionic surfactant polyethylene glycol-12-hydroxystearate is added into the alcaftadine composition, the alcaftadine can be completely dissolved, the solubility is greatly improved, and the problem of raw material waste caused by excessive feeding in the preparation process is solved. In addition, the present inventors have also found that alcaftadine eye drops prepared by adding 0.5% (w/v) of nonionic surfactant polyethylene glycol-12-hydroxystearate are more stable than commercially available alcaftadine eye drops without adding nonionic surfactant. This demonstrates that the alcaftadine compositions provided herein have greater stability than prior art ophthalmic formulations of alcaftadine.

2) The preparation method of the alcaftadine composition has the characteristics of reasonable process, simplicity and feasibility; meanwhile, impurities generated in the preparation process or the storage process can be obviously reduced, and the stability of the composition is improved, so that the beneficial effects of improving the product quality and improving the curative effect are achieved.

3) According to the application of the alcaftadine composition in the preparation of the medicine for treating allergic conjunctivitis and related eye pruritus, the alcaftadine composition is free of irritation after being taken for multiple times according to experimental results; compared with the commercial alcaftadine eye drops, the pharmaceutical composition does not increase irritation, and the alcaftadine composition provided by the application has good safety.

Detailed description of the preferred embodiments

The present application will be described in detail with reference to examples, but the present application is not limited to these examples.

Unless otherwise specified, the raw material alcaftadine in the examples of the present application was synthesized according to the method described in patent application No. 201510448367.4, and the remaining adjuvants were commercially available.

Example 1

The preparation method of the alcaftadine composition comprises the following steps:

(1) weighing the nonionic surfactant according to the prescription amount, dissolving the nonionic surfactant in water for injection, adding the prescription amount of alcaftadine, and stirring to completely dissolve to obtain a solution I;

(2) heating a proper amount of water for injection to boil, dissolving pharmaceutically acceptable excipient in the water, and stirring to dissolve completely to obtain a solution II;

(3) cooling the solution II to room temperature, then combining the solution II with the solution I, and adding water for injection to full volume to obtain a solution III;

The specific composition of the alcaftadine composition is shown in the following table:

example 2

Different alcaftadine eye drops are prepared according to the following prescription and preparation process, and the content of alcaftadine before and after filtration is detected by adopting an HPLC method:

the preparation process comprises the following steps:

Table 1: prescription composition and measurement results

And (4) conclusion: from the above test results, it can be seen that formula 13 without the addition of the nonionic surfactant has a lower content before filtration and a lower content after filtration with the microporous membrane, indicating that the principal drug is not completely dissolved and is retained by the membrane after filtration; in addition, the content of the formula 7 added with the nonionic surfactant of polyethylene glycol-12-hydroxystearate (Solutol HS 15) is basically unchanged before and after the filtration of the microporous filter membrane, which indicates that the main drug is fully dissolved, compared with the formula added with other nonionic surfactants, the content of the alcaftadine is reduced less before and after the filtration, which indicates that the solubilizing effect of the polyethylene glycol-12-hydroxystearate (Solutol HS 15) on the alcaftadine is stronger than that of other nonionic surfactants, and therefore, the polyethylene glycol-12-hydroxystearate (Solutol HS 15) is preferably used as the cosolvent of the alcaftadine eye drops.

EXAMPLE 2 Effect of the nonionic surfactant polyethylene glycol-12-hydroxystearate (Solutol HS 15) on the stability of Actadine eye drops

Samples were prepared according to the above-mentioned recipe 7 of example 1, and packaged on the market, and placed together with commercially available Lastacaft (acatadine) eye drops (surfactant-free Solutol HS 15) for influencing factor experiments and stability test investigation. The results are shown in tables 2 and 3 below:

table 2: the influence factor test investigation results of formula 7 and commercial samples in the example 1 of the invention

Table 3: stability test results of self-developed prescription and commercially available samples

Influence factors and stability test results show that the pH value, the properties, the visible foreign matters, related substances, the content and the like of the alcaftadine eye drop prepared according to the self-grinding prescription are in accordance with the regulations, while the related substances of the commercial preparation are obviously increased in the standing process, which indicates that the stability of the self-grinding prescription preparation added with the nonionic surfactant of polyethylene glycol-12-hydroxystearate (Solutol HS 15) is obviously higher than that of the commercial sample without the nonionic surfactant.

Example 3 Alcattadine eye drops toxicology test

First, test purpose

In the experiment, an acatadine eye drop test sample is subjected to a multi-dose eye irritation test (28 days), the condition of the eye irritation response of the test sample of the acatadine eye drop to rabbit eyes is observed, and the eye irritation response degree is evaluated according to the total eye irritation response integral and the histopathological examination result.

Second, test samples

Samples were prepared as described in formula 7 of example 1 above and packaged as commercially available with the following specifications: 3.0ml (pilot plant).

The content of the main drug, the content of related substances, the pH value, visible foreign matters and appearance inspection are all test samples with qualified quality according to the requirements of eye drops in the appendix of the second part of Chinese pharmacopoeia 2010 edition.

Third, test methods and procedures

4 quarantine-qualified ordinary-grade rabbits are selected, a homosomatic left-eye and right-eye self-contrast method is adopted, a product with the same volume and on the market is given to the left eye as a contrast, and a prescription 7 sample prepared in the embodiment 1 is given to the right eye. According to the clinical administration method, 1 drop (50 μ l) is continuously dropped into the eye 1 time per day

The medicine is taken for 28 days. The eyes were examined before each day and 1, 2, 4, 24, 48 and 72 hours after the last administration, and the ocular irritation intensity of the acatadine eye drop test sample was evaluated based on the ocular irritation response evaluation criterion and the ocular irritation evaluation criterion. The ocular irritation response score criteria are shown in table 4.

TABLE 4 eye irritation response score criteria

The stimulation response scores of the cornea, iris and conjunctiva of each animal at each observation time were summed to obtain a total score, which was divided by the number of animals to obtain the final score of the group, and the stimulation level was determined according to Table 3. The criteria for evaluation of eye irritation are shown in Table 5.

TABLE 5 evaluation criteria for eye irritation

Score value	Evaluation of
		0-3	Has no irritation
4-8	Mild irritation
		9-12	Moderate irritation
13-16	Severe irritation

Fourth, test results

Eyes were examined before each day and 1, 2, 4, 24, 48 and 72 hours after the last dose, no obvious eye irritation symptoms were seen in both eyes of 4 tested rabbits, no obvious difference was observed between each eye and the pre-test comparison and the bilateral comparison, and the irritation response scores were as shown in table 6.

TABLE 6 evaluation of Ocular irritation response of Alcattadine eye drops to test rabbits before daily administration

TABLE 6 continuation

Fifth, conclusion of the experiment

The detection result is calculated by score statistics, and the fact that the sample of formula 7 in the embodiment 1 of the invention has no irritation after being administered for multiple times is found; compared with the eye drops sold on the market, the eye drops do not increase the irritation, and the prescription of the invention has good safety.

Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.

Claims

1. An alcaftadine composition, characterized in that the alcaftadine composition consists of 0.1-0.4% w/v alcaftadine, 0.05-5% w/v nonionic surfactant, benzalkonium chloride, sodium dihydrogen phosphate, sodium chloride, disodium edetate and solvent; the nonionic surfactant is polyethylene glycol-12-hydroxystearate; the solvent is water for injection.

2. The alcaftadine composition of claim 1, wherein the alcaftadine composition comprises 0.25% w/v alcaftadine and 0.5% w/v nonionic surfactant.

3. The alcaftadine composition according to claim 1, wherein the concentration of the benzalkonium chloride in the alcaftadine composition is from 0.001-0.01% w/v, the concentration of the monobasic sodium phosphate in the alcaftadine composition is from 0.3-0.8% w/v, the concentration of the sodium chloride in the alcaftadine composition is from 0.3-0.8% w/v, and the concentration of the edetate disodium in the alcaftadine composition is from 0.005-0.02% w/v.

4. The alcaftadine composition of claim 3, wherein the alcaftadine composition consists of 0.25% w/v alcaftadine, 0.5% w/v polyethylene glycol-12-hydroxystearate, 0.005% w/v benzalkonium chloride, 0.54% w/v sodium dihydrogen phosphate, 0.62% w/v sodium chloride, 0.01% w/v edetate disodium, and water for injection.

5. A process for the preparation of the alcaftadine composition according to any of claims 1-4, characterized in that it comprises the steps of:

(1) mixing the alcaftadine, the nonionic surfactant and a first solvent, and fully dissolving the alcaftadine to obtain a solution I;

(2) dissolving other pharmaceutically acceptable carriers in a second solvent to obtain a solution II;

(3) mixing the solution I and the solution II to obtain a solution III,

subjecting said solution I obtained in said step (1) and said solution III obtained in said step 3) to aseptic processing to obtain said composition;

wherein the other pharmaceutically acceptable carriers are benzalkonium chloride, sodium dihydrogen phosphate, sodium chloride, disodium edetate;

wherein the first solvent and the second solvent are water for injection.

6. The method according to claim 5, wherein the filtration is performed using a 0.2 μm to 0.45 μm microporous membrane for aseptic treatment.

7. The method according to claim 6, wherein the filtration is performed using a 0.2 μm to 0.22 μm microporous membrane for aseptic treatment.

8. The method according to any one of claims 5 to 7, comprising in particular the steps of:

(1) dissolving the nonionic surfactant in water for injection, and then adding a prescription amount of alcaftadine to fully dissolve the nonionic surfactant to obtain a solution I;

(4) adjusting the pH value of the solution III to 6.0-7.0, and filtering the solution III through a 0.22 mu m microporous filter membrane to obtain the alcaftadine composition;

wherein the pharmaceutically acceptable excipient is benzalkonium chloride, sodium dihydrogen phosphate, sodium chloride, and edetate disodium.

9. Use of the alcaftadine composition of any one of claims 1-4 and/or the alcaftadine composition prepared according to the process of any one of claims 5-8 for the preparation of a medicament for treating and/or preventing clinical symptoms of or mechanistic symptoms associated with ocular allergy and/or ocular inflammation, wherein said symptoms are selected from at least one of allergic conjunctivitis, ocular itching, ocular redness, eyelid swelling, conjunctival edema, sneezing, rhinitis, nasal congestion, rhinorrhea, ear pruritus, palate pruritus, sneezing, vascular penetration, reduced integrity of the tight junctions of the conjunctival epithelium, mast cell degradation.

10. The use according to claim 9, wherein the alcaftadine composition is prepared as eye drops or an ophthalmic gel.

11. Use according to claim 10, characterized in that it is prepared as eye drops.