阅读说明：本技术 一种眼用组合物及其制备方法和应用 (Ophthalmic composition and preparation method and application thereof ) 是由 李勇 王静 李晴晴 王稳定 于 2021-08-20 设计创作，主要内容包括：本发明公开了一种眼用组合物及其制备方法和应用,涉及眼用组合物。一种眼用组合物,为透明水包油乳化液剂型,乳滴平均粒径小于100nm,90%粒径不大于200nm,包括下列重量份的各组分：所述组合物总质量的0.1%-4.0%的第一表面活性剂,述组合物总质量的0.001%-0.1%的十六烷基二甲基苄基氯化铵(CKC),所述组合物总质量0.5%-2%的油相,所述组合物总质量的0.001%-0.25%的pH调节剂,所述组合物总质量的1.0%-3%的渗透压调节剂,余量为水。本发明解决了阳离子水包油型乳剂眼用组合物的透明度问题,眼部刺激性低,提高了患者使用的依从性。(The invention discloses an ophthalmic composition, a preparation method and application thereof, and relates to an ophthalmic composition. An ophthalmic composition in the form of a transparent oil-in-water emulsion having an average particle size of the emulsion droplets of less than 100nm and a 90% particle size of no more than 200nm, comprising the following components in parts by weight: the composition comprises, by weight, 0.1% -4.0% of a first surfactant, 0.001% -0.1% of hexadecyldimethylbenzyl ammonium chloride (CKC), 0.5% -2% of an oil phase, 0.001% -0.25% of a pH regulator, 1.0% -3% of an osmotic pressure regulator and the balance water. The invention solves the transparency problem of the cationic oil-in-water emulsion ophthalmic composition, has low eye irritation and improves the compliance of patients.)

1. An ophthalmic composition, which is a transparent oil-in-water emulsion dosage form, has an average emulsion droplet size of less than 100nm and a 90% particle size of not more than 200nm, and comprises the following components in parts by weight:

a first surfactant in an amount of 0.1-4.0% by total mass of the composition,

cetyl dimethyl benzyl ammonium chloride accounting for 0.001-0.1 percent of the total mass of the composition,

an oil phase accounting for 0.5 to 2 percent of the total mass of the composition,

0.001-0.25% of pH regulator based on the total weight of the composition,

an osmotic pressure regulator accounting for 1.0-3% of the total mass of the composition,

the balance being water.

2. The ophthalmic composition as claimed in claim 1, wherein the first surfactant is selected from the group consisting of polyethylene glycol and polyoxyethylene hydrogenated castor oil, which comprises one or two of polyethylene glycol 400, polyethylene glycol 600, PEG-20 hydrogenated castor oil, PEG-35 hydrogenated castor oil, and PEG-40 hydrogenated castor oil at any ratio.

3. An ophthalmic composition according to claim 1 or 2, wherein the first surfactant is polyethylene glycol 400 and/or PEG-35 hydrogenated castor oil.

4. An ophthalmic composition according to claim 1 or 2, wherein the oily phase comprises light mineral oil, and/or heavy mineral oil, and/or medium chain triglycerides, and/or castor oil.

5. An ophthalmic composition according to claim 1 or 2, wherein the pH adjusting agent is tromethamine.

6. An ophthalmic composition according to claim 1 or 2, wherein the tonicity modifier is glycerol, propylene glycol, sorbitol and/or mannitol.

7. A process for the preparation of the ophthalmic composition according to any one of claims 1 to 6, comprising the steps of: respectively heating the oil phase and the water phase of the emulsion to 75-85 ℃, slowly pouring the oil phase into the water phase under the condition of rapid mechanical stirring, continuously stirring for 15-25 minutes, carrying out high-shear homogeneous mixing for at least 30 minutes to reduce oil drops as much as possible, adding a pH regulator, and carrying out a high-pressure micro-jet homogenization process to prepare the emulsion.

8. Use of the ophthalmic composition of any one of claims 1-6 as a pharmaceutical carrier in the manufacture of a medicament for dry eye.

9. Use of the ophthalmic composition of any one of claims 1 to 6 for the preparation of artificial tears.

10. Use of an ophthalmic composition prepared according to the method of claim 7 in the preparation of an artificial tear.

Technical Field

The invention relates to an ophthalmic composition, in particular to a transparent emulsion type ophthalmic composition, a preparation method and application thereof.

Background

Dry eye is the most common ocular surface disease in clinic at present, is a disease causing eye discomfort due to the reduction of tear film stability and unbalance of ocular surface environment, and can be accompanied with symptoms such as eye tissue damage and the like. According to survey, the incidence rate of xerophthalmia in China is up to 21.0-30.0%, and serious people can cause obvious vision reduction to influence normal work and life of people. Therefore, dry eye disease is receiving more and more attention, and also attracts higher attention of ophthalmology clinical workers.

The artificial tears are the most commonly used medicine for treating xerophthalmia, namely, the imitated artificial tears form a new tear film on the surfaces of eyeballs so as to maintain the health of the surfaces of the eyes and relieve uncomfortable symptoms. At present, the ophthalmic clinical choice of artificial tears is more, such as polyvinyl alcohol, methylcellulose, sodium hyaluronate, polyvinylpyrrolidone, polyacrylic acid and the like. However, as the main components of the eye cream are aqueous solutions, the eye cream is easy to evaporate quickly after the eye cream is spread, and the tear film is destroyed instantly, so the eye cream needs to be used for 5 to 6 times every day, and the compliance of patients is poor; in addition, long-term use is prone to produce dependency and further disturb the function of ocular surface tissue.

In order to solve the above problems of the water-soluble artificial tears, artificial tears for treating dry eye syndrome using an emulsion as a carrier have been developed, which can improve the viscosity of a liquid medicine and increase the retention time on the ocular surface, thereby enhancing and prolonging the medicinal effect and action time.

However, the artificial tears using emulsion as carrier have some disadvantages in use and popularization, for example, lipid nano-emulsion artificial tears, because the emulsion is milky white and maintains milky and opaque state when being used, may cause the problem of visual field obstruction and is not good for applying to eyes.

In order to solve the above problems of the prior art, the present inventors have developed a transparent oil-in-water ophthalmic composition which is more suitable for ocular use and has improved comfort of use.

Disclosure of Invention

The object of the present invention is to provide an ophthalmic composition.

It is another object of the present invention to provide a method for the preparation of an ophthalmic composition.

It is a further object of the present invention to provide the use of ophthalmic compositions.

The invention is realized by the following technical scheme:

an ophthalmic composition in the form of a transparent oil-in-water emulsion having an average particle size of the emulsion droplets of less than 100nm and a 90% particle size of no more than 200nm, comprising the following components in parts by weight:

a first surfactant in an amount of 0.1-4.0% by total mass of the composition,

cetyl dimethyl benzyl ammonium chloride (CKC) in an amount of 0.001-0.1% by weight of the total composition,

an oil phase accounting for 0.5 to 2 percent of the total mass of the composition,

0.001-0.25% of pH regulator based on the total weight of the composition,

an osmotic pressure regulator accounting for 1.0-3% of the total mass of the composition,

the balance being water.

Further, the first surfactant is polyethylene glycol and/or polyoxyethylene hydrogenated castor oil, and specifically comprises: any one or two of polyethylene glycol 400, polyethylene glycol 600, PEG-20 hydrogenated castor oil, PEG-35 hydrogenated castor oil and PEG-40 hydrogenated castor oil in any proportion, wherein the PEG-35 hydrogenated castor oil and/or the polyethylene glycol 400 are preferred.

The oil phase comprises light mineral oil, and/or heavy mineral oil, and/or medium chain triglyceride, and/or castor oil.

The pH regulator is tromethamine.

The osmotic pressure regulator is glycerol, propylene glycol, sorbitol and/or mannitol.

The preparation method of the ophthalmic composition comprises the following steps: respectively heating the oil phase and the water phase of the emulsion to 75-85 ℃, slowly pouring the oil phase into the water phase under the condition of rapid mechanical stirring, stirring for 15-25 minutes, carrying out high-shear homogeneous mixing for at least 30 minutes to reduce oil drops as much as possible, adding a pH regulator, and carrying out a high-pressure micro-jet homogenization process to prepare the emulsion.

The invention discloses application of the ophthalmic composition in preparing artificial tears.

The invention also discloses application of the ophthalmic composition as a medicine carrier in preparation of a medicine for xerophthalmia.

The transparent emulsion type ophthalmic composition of the present invention uses two surfactants, wherein the first surfactant is preferably PEG-35 hydrogenated castor oil and/or polyethylene glycol 400, etc., and CKC is used as the second surfactant, i.e., the present invention uses the combination of the two surfactants to replace the artificial tear thickeners such as polyvinyl alcohol, methyl cellulose, sodium hyaluronate, etc., in the market, and the mixture of mineral oil, castor oil, etc. is used as the emulsion oil phase. The two surfactants are beneficial to prolonging the detention time of the tear film on the dry eye surface, avoiding the trouble of frequent administration, mineral oil and the like are used, a lipid layer can be formed on the corneal surface, the effects of stabilizing the tear film and preventing water evaporation are achieved, when the composition is prepared, the composition is heated, stirred and mixed and then homogenized, the average particle size of emulsion droplets is less than 100nm, and the 90% particle size is not more than 200 nm.

Compared with the prior art, the invention has the following advantages:

(1) the problem of transparency of the cationic oil-in-water emulsion ophthalmic composition is solved;

(2) no preservative is used, so that the eye irritation is reduced, and the use compliance of patients is improved;

(3) can improve the solubility of ophthalmic drugs suitable for the system, and can be used as carriers of ophthalmic drugs.

Detailed Description

The present invention is further illustrated by the following examples.

Example 1

Compositions were prepared according to the components shown in table 1 to obtain four compositions of group 1, group 2, group 3, and group 4, respectively.

TABLE 1

The preparation method comprises the following steps:

1) dissolving PEG-35 hydrogenated castor oil and/or PEG 400 in the oil phase;

2) dissolving CKC, an osmotic pressure regulator glycerol and tromethamine in an aqueous phase;

3) respectively heating the water phase and the oil phase to appropriate temperature of 75-85 deg.C, slowly pouring the oil phase into the water phase under rapid mechanical stirring, continuously stirring for 20 min, adding water for injection to full volume, homogenizing and mixing under high shear for at least 30 min to reduce oil drop as much as possible, and adjusting pH to 6.2 with dilute hydrochloric acid.

PEG-35 hydrogenated castor oil can be replaced by PEG-20 hydrogenated castor oil or PEG-40 hydrogenated castor oil, PEG 400 can be replaced by PEG 200, it should be noted that the ophthalmic pharmaceutical composition provided by the present invention uses two different types of emulsifiers CKC in combination with polyoxyethylene hydrogenated castor oil and/or polyethylene glycol to replace the thickening agent and maintain low irritation, does not contain preservatives, and is also beneficial for application to eyes.

When a drug for dry eye is produced, the composition obtained by the above method is used as a drug carrier, an effective amount of a drug such as cyclosporin is added to the composition, and eye drops are produced under the conditions of autoclaving.

In the production of artificial tear, the composition obtained as described above is loaded into a suitable container and sterilized by autoclaving to prepare an artificial tear eye drop.

Example 2

Compositions were prepared according to the components shown in Table 2 to obtain four compositions of comparative group 1, comparative group 2, comparative group 3 and comparative group 4, respectively.

TABLE 2

The compositions of the 4 groups of compositions of example 1 and the 4 groups of comparative compositions of example 2 were prepared in the same manner and stored in a low density polyethylene plastic vial for 6 months at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 20. + -. 5%, and inspected for appearance by time sampling, and the test results are shown in Table 3:

TABLE 3

As can be seen from Table 3, the ionic agent CKC and polyoxyethylene hydrogenated castor oil and/or polyethylene glycol compound emulsion has excellent compatibility, and the appearance of the emulsion is transparent after long-term storage, is not changed after 6 months, and has good stability.

Example 3

Compositions were prepared according to the components shown in table 4, and 4 compositions were obtained, respectively.

TABLE 4

The preparation method comprises the following steps:

1) dissolving PEG-20 hydrogenated castor oil or PEG-40 hydrogenated castor oil or PEG 200 in the oil phase;

2) dissolving CKC, an osmotic pressure regulator glycerol and tromethamine in an aqueous phase;

3) respectively heating the water phase and the oil phase to appropriate temperature of 75-85 deg.C, slowly pouring the oil phase into the water phase under rapid mechanical stirring, continuously stirring for 20 min, adding water for injection to full volume, homogenizing and mixing under high shear for at least 30 min to reduce oil drop as much as possible, and adjusting pH to 6.2 with dilute hydrochloric acid.

The above 4 compositions were stored in a low density polyethylene plastic vial at 40 ℃. + -. 2 ℃ and 20. + -. 5% relative humidity for 3 months, and then sampled for appearance, and the test results are shown in Table 5:

TABLE 5

Components	Observation for 0 day	3 month appearance
			Group 5	Transparent emulsion	Transparent emulsion
Group 6	Transparent emulsion	Transparent emulsion
			Group 7	Transparent emulsion	Transparent emulsion
Group 8	Transparent emulsion	Transparent emulsion

The compositions in tables 1 and 4 above can also be used as eye drop drug carriers as usual.

Example 4

Pharmaceutical compositions were prepared according to the components shown in table 6 to obtain two compositions of group 9 and group 10, respectively.

TABLE 6

Components	Group 9	Group 10
			Cyclosporin A	0.10%	0
Tacrolimus	0	0.10%
			Medium chain triglycerides	1.0%	0.50%
CKC	0.001%	0.05%
			PEG-35 hydrogenated Castor oil	0.05%	1.0%
PEG 400	0.05%	0
			Tromethamine	0.071%	0.071%
Glycerol	2.50%	1%
			Water (W)	Balance of	Balance of

The preparation method comprises the following steps:

1) dissolving cyclosporin A or tacrolimus, PEG-35 hydrogenated castor oil and/or PEG 400 in the oil phase;

2) dissolving CKC, an osmotic pressure regulator glycerol and tromethamine in an aqueous phase;

3) respectively heating the water phase and the oil phase to appropriate temperature of 75-85 deg.C, slowly pouring the oil phase into the water phase under rapid mechanical stirring, continuously stirring for 20 min, adding water for injection to full volume, homogenizing and mixing under high shear for at least 30 min to reduce oil drop as much as possible, and adjusting pH to 6.2 with dilute hydrochloric acid.

The above 2 compositions were stored in a low density polyethylene plastic vial at 40 ℃. + -. 2 ℃ and 20. + -. 5% relative humidity for 3 months, and then sampled for appearance, and the test results are shown in Table 7:

TABLE 7

Components	Observation for 0 day	3 month appearance
			Group 9	Transparent emulsion	Transparent emulsion
Group 10	Transparent emulsion	Transparent emulsion

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention and the equivalent alternatives or modifications according to the technical solution and the inventive concept of the present invention within the technical scope of the present invention.