Ophthalmic spray combined preparation for relieving blepharoptosis and red eye

Abstract

The invention relates to an ophthalmic spray combined preparation for relieving blepharoptosis or relieving red eyes from blepharoptosis. The ophthalmic spray combined preparation is characterized by comprising the following components in percentage by mass: 0.01-1.15% of an alpha-adrenergic receptor agonist, 0.01-1.15% of an emulsifier, 0.01-1.15% of an emulsifier and the balance of water. 0.1% to 0.3% of sodium hyaluronate; 0.01%-2% of an osmotic pressure regulator; the liquid medicine further comprises a pH buffering agent, wherein the concentration of the pH buffering agent is 0.002 M to 0.16 M; the thickening agent is one or a combination of more of hydroxyethyl cellulose, polyvinyl alcohol and povidone, and the mass percent of the vitamin A derivative and the vitamin E derivative is 0.01%-0.2%. The spray preparation comprises a spraying device, and the spray particle size ranges from 5 mu m to 500 mu m, preferably ranges from 5 mu m to 100 mu m, and more preferably ranges from 10 mu m to 30 mu m.

Description

Technical Field

[0001] The invention relates to an ophthalmic pharmaceutical preparation, in particular to an ophthalmic spray combination preparation for relieving ptosis or alleviating red eyes caused by ptosis. Background Art

[0002] Ptosis refers to a type of eyelid disease caused by congenital developmental abnormalities or acquired diseases, which manifests as drooping of one or both upper eyelids, which are significantly lower than the normal position. It is a common disease in ophthalmology, and the main cause is partial or complete dysfunction of the muscles that lift the upper eyelid (levator palpebrae superioris and / or Muller muscle). Because the muscles in the eyelids of the elderly begin to degenerate, this disease is more common in the elderly and is one of the most common eyelid disorders. In mild cases, ptosis only affects the appearance of the eyes and does not affect vision; in severe cases, the pupil is partially or completely blocked, which can affect normal vision and seriously affect daily life such as driving and reading. The main treatment drugs for ptosis are α-adrenergic receptor agonists such as oxymetazoline, but while acting on the levator palpebrae superioris and / or Muller muscle to lift the upper eyelid, it can also cause side effects such as conjunctivitis, eye irritation, and red eyes.

[0003] On the other hand, ocular administration is the main route of administration for the treatment of local ocular diseases. Compared with systemic administration, it is more conducive to drug accumulation in the eye and can reduce systemic adverse reactions. The physiological structure of the eye can be divided into the anterior segment and the posterior segment. For anterior segment diseases, therapeutic drugs exert their efficacy through the cornea, conjunctival epithelium or blood-aqueous humor barrier; while for posterior segment diseases, when therapeutic drugs are administered locally and non-invasively, they still need to further cross multiple internal barriers such as the lens and vitreous body or the ocular-retinal barrier. Therefore, posterior segment diseases are traditionally treated with local vitreous injections, subconjunctival injections and other repetitive invasive treatments.

[0004] Eye drops are currently the most commonly used dosage form for the treatment of eye diseases in clinical practice, but they quickly drain from the surface of the eye, and the drug bioavailability is usually less than 5%. Common adverse reactions to topical eye drops include conjunctival congestion, dry eyes, blurred vision, and pain from medication irritation. New complex eye drug delivery systems such as nanoparticles, micelles, liposomes, in situ gels, and nanoemulsions, as well as eye drug delivery technologies such as implants and contact lenses, can significantly improve drug bioavailability and reduce adverse drug reactions; however, such preparations and drug delivery technologies are complex, and the R&D and commercialization costs are high.

[0005] Therefore, it is of great significance to develop a combination drug preparation that can be used for ptosis while reducing its side effects. The spray preparation atomizes the drug solution into small particles (5-500μm) and sprays it on the eyes, reducing drug loss during ocular administration, reducing irritation, and greatly increasing the bioavailability of the drug; and through device design, it reduces microbial contamination during use, avoids adding antibacterial agents to the prescription, and reduces irritation to patients. At the same time, combined with compound drugs, it can be used for ptosis while reducing its side effects such as eye redness, relieve visual fatigue, and enhance eye protection. Summary of the invention

[0006] The present invention aims to provide an ophthalmic spray preparation that can both treat ptosis and reduce red eyes. The purposes of the present invention are: (1) to provide a compound preparation that can both treat ptosis and reduce its side effects such as red eyes; (2) the spray device can prevent microbial contamination during use, so the preparation does not contain antibacterial agents, reducing eye irritation; (3) the preparation is an ophthalmic spray, and compared with traditional eye drops, the spray particle size is small, which reduces the outflow of the drug solution and improves the bioavailability; (4) by adjusting the type and content of excipients, the spray performance is adjusted to enhance eye protection.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] An ophthalmic spray preparation for reducing side effects of ptosis, comprising the following components in percentage by mass:

[0009] α-adrenergic receptor agonists 0.01%-1.15%;

[0010] Sodium hyaluronate 0.1%-0.3%;

[0011] Osmotic pressure regulator 0.01%-2%;

[0012] Also includes a pH buffer, wherein the concentration of the pH buffer is 0.002M-0.16M;

[0013] It also includes a thickener with a mass percentage of 0.01%-6.5%, wherein the thickener is one or a combination of cellulose derivatives, carbomers, polyvinyl alcohols, polyethylene glycols, dextran, and povidones, wherein the cellulose derivatives include methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc., the carbomers include Carbopol 941, Carbopol 934, Carbopol AQUA SF-1, Carbopol ETD 2020, etc., the polyvinyl alcohols include PVA05-88, PVA17-88, PVA24-88, etc., the polyethylene glycols include PEG-200, PEG-400, PEG-600, PEG-800, etc., and the povidones include PVP K30, PVP K60, PVPK90, etc.;

[0014] It also includes vitamin A and its derivatives and / or vitamin E and its derivatives, with a mass percentage of 0.01%-0.2%;

[0015] The spray preparation includes a spray device, and the spray particle size is 5-500 μm, preferably 5-100 μm, and more preferably 10-30 μm. The relevant contents in the above technical solution are explained as follows:

[0016] 1. In the above scheme, the α-adrenaline receptor agonist includes but is not limited to: one or a combination of oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, xylometazoline, cilazoline, brimonidine, apraclonidine, apraclonidine, methoxyamine, midodrine, metaraminol, phenylephrine, amiphrine, SDZ-NVI-085, dexmedetomidine, guanfacine, guanabenz, guanoxabenz, tirtonidine, methyldopa, epinephrine, methylnorepinephrine, norepinephrine, and lofexidine, wherein the above ingredients all include their respective pharmaceutically acceptable salts.

[0017] 2. In the above scheme, the α-adrenaline receptor agonist is one or more of oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, xylometazoline or their respective pharmaceutically acceptable salts.

[0018] 3. In the above scheme, the α-adrenaline receptor agonist is oxymetazoline or a pharmaceutically acceptable salt thereof.

[0019] 4. In the above scheme, the α-adrenaline receptor agonist is preferably oxymetazoline hydrochloride; relative to the total weight of the pharmaceutical composition, its mass ratio ranges from 0.01% to 1.15%.

[0020] 5. In the above scheme, the α-adrenaline receptor agonist further includes one or a combination of brimonidine, apraclonidine, apraclonidine or their respective pharmaceutically acceptable salts.

[0021] 6. In the above scheme, the α-adrenaline receptor agonist further included is brimonidine or a pharmaceutically acceptable salt thereof.

[0022] 7. In the above scheme, the α-adrenaline receptor agonist further included is preferably brimonidine tartrate, and its mass ratio ranges from 0.01% to 0.15% relative to the total weight of the pharmaceutical composition.

[0023] 8. In the above scheme, the pharmaceutical composition further comprises sodium hyaluronate, and the mass ratio ranges from 0.1% to 0.3% relative to the total weight of the pharmaceutical composition.

[0024] 9. In the above scheme, the relative molecular mass range of the sodium hyaluronate is 3kDa-2200kDa; further, preferably 500kDa-1500kDa.

[0025] 10. In the above scheme, the pharmaceutical composition further includes a thickener, which includes but is not limited to one or more of the following: cellulose derivatives, carbomers, polyvinyl alcohols, polyethylene glycols, dextran, and povidones; the cellulose derivatives include methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc., the carbomers include carbomer 941, carbomer 934, carbomer AQUASF-1, carbomer ETD 2020, etc., the polyvinyl alcohols include PVA05-88, PVA17-88, PVA24-88, etc., the polyethylene glycols include PEG-200, PEG-400, PEG-600, PEG-800, etc., and the povidones include PVP K30, PVP K60, PVP K90, etc.

[0026] 11. In the above solution, the mass ratio of the thickener relative to the total weight of the pharmaceutical composition is in the range of 0.01%-6.5%.

[0027] 12. In the above scheme, the pharmaceutical composition may further include an osmotic pressure regulator, which includes but is not limited to one or more of the following: potassium chloride, calcium chloride, sodium chloride, magnesium chloride, glycerol, mannitol, and glucose.

[0028] 13. In the above scheme, the mass ratio of the osmotic pressure regulator to the pharmaceutical composition is in the range of 0.01%-2%.

[0029] 14. In the above scheme, the pharmaceutical composition may further include a pH buffer, which includes but is not limited to one or more of the following: citrate, borate, acetate, and phosphate.

[0030] 15. In the above scheme, the mass ratio of the pH buffer relative to the total weight of the pharmaceutical composition is in the range of 0.002M-0.16M.

[0031] 16. In the above scheme, the pH buffer may be borate, and the mass ratio of borate to the total weight of the pharmaceutical composition ranges from 0.05M to 0.16M.

[0032] 17. In the above scheme, the pH buffer may also be citrate, and the weight ratio of citrate to the total weight of the pharmaceutical composition ranges from 0.002M to 0.02M.

[0033] 18. In the above scheme, the pharmaceutical composition may further include a pH adjuster, including but not limited to one or more of the following: hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide.

[0034] 19. In the above scheme, the pH adjuster is hydrochloric acid or sodium hydroxide, and the pH range of the pharmaceutical composition is adjusted to 5.0-7.0, preferably 5.8-6.3.

[0035] 20. In the above scheme, the pharmaceutical composition may further include vitamin A and its derivatives, vitamin E and its derivatives, and the vitamin A and its derivatives, vitamin E and its derivatives include but are not limited to one or more of the following: vitamin A palmitate, retinol, retinoic acid, retinyl acetate, tocopherol, and tocotrienol.

[0036] 21. In the above scheme, the mass ratio of vitamin A and its derivatives, vitamin E and its derivatives relative to the total weight of the composition is in the range of 0.01%-0.2%.

[0037] 22. In the above scheme, the pharmaceutical composition can be filled into a device that prevents the invasion of microorganisms during administration, and the device is known in the art.

[0038] 23. In the above solution, the device for preventing microbial invasion during drug administration can be the OPEN EYE SPRAY eye spray device produced by Aeropump.

[0039] 24. In the above scheme, the device for preventing microbial invasion during drug administration can also be the APFPlus antibacterial spray pump eye spray device produced by Aptar.

[0040] 25. In the above scheme, the spray particle size is 5-500 μm, preferably 5-100 μm, more preferably 10-30 μm.

[0041] 26. In the above scheme, the pharmaceutical composition used can be prepared into a spray as well as a solution, suspension, oil, gel, emulsion, liposome, ointment, long-acting or sustained-release preparation, other types of solid or semi-solid preparation, and applied to the symptoms of ptosis and eye redness.

[0042] The working principle of the present invention is that the drug can act on the α-adrenergic receptors in the Muller muscle of the upper eyelid, stimulate its contraction, and lift the upper eyelid; at the same time, it can constrict blood vessels and relieve the symptoms of conjunctival redness. Vitamin A derivatives such as vitamin A palmitate, retinol, retinoic acid, and retinol acetate have physiological functions such as maintaining vision, normal secretion of mucosal epithelium and lacrimal glands, and protecting the cornea. Vitamin E derivatives such as tocopherol and tocotrienol have strong antioxidant effects and can provide protection for the ocular mucosa; further adding such drug adjuvants can enhance eye protection, reduce the irritation that may be caused by medication, and provide patients with long-term medication benefits.

[0043] Due to the application of the above technical scheme, the present invention has the following advantages and effects compared with the prior art: (1) a compound preparation is provided, which can not only treat ptosis but also reduce its side effects such as red eyes; (2) the spray device can prevent microbial contamination during use, so the preparation does not contain antibacterial agents, reducing eye irritation; (3) the preparation is an eye spray, and compared with traditional eye drops, the spray particle size is small, which reduces the outflow of the drug solution and improves the bioavailability; (4) by adjusting the type and content of excipients, the spray performance can be adjusted to enhance eye protection.

[0044] The present invention also provides the use of the above-mentioned pharmaceutical preparation in treating eye diseases, wherein the eye diseases include but are not limited to ptosis, ptosis and red eye symptoms. The drug is administered by eye spray, avoiding local irritation of eye drops, improving patient compliance with medication, and increasing bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 For comparison with Test Example 6 Figure 1 (Upneeq oxymetazoline hydrochloride eye drops were applied to the left eye, and no product was applied to the right eye);

[0046] Figure 2 For comparison with Test Example 6 Figure 2 (The sample prepared in Example 20 was applied to the left eye, and no product was applied to the right eye). DETAILED DESCRIPTION

[0047] The present invention will be further described below in conjunction with the accompanying drawings and embodiments:

[0048] In the following examples, pH buffers (boric acid buffer, citrate buffer, acetate buffer, phosphate buffer) are embodied in the form of "boric acid + hydrochloric acid / sodium hydroxide", "citric acid + hydrochloric acid / sodium hydroxide", "acetic acid + hydrochloric acid / sodium hydroxide", and "phosphoric acid + hydrochloric acid / sodium hydroxide".

[0049] Example 1

[0050] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 0.05% of hydroxyethyl cellulose, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0051] Example 2

[0052] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0053] Example 3

[0054] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 1.5% of polyvinyl alcohol 05-88, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0055] Example 4

[0056] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 1.5% of polyvinyl alcohol 05-88, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0057] Example 5

[0058] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 5.8.

[0059] Example 6

[0060] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.02% of citric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0061] Example 7

[0062] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.1% oxymetazoline hydrochloride, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0063] Example 8

[0064] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0065] Example 9

[0066] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.3% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0067] Example 10

[0068] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.25% of apraclonidine hydrochloride, 0.025% of naphazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.02% of retinol, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0069] Embodiment 11

[0070] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.15% of epinephrine, 0.2% of tetrahydrozoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.02% of tocopherol, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0071] Example 12

[0072] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.125% of apraclonidine hydrochloride, 0.2% of xylometazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.02% of tocotrienol, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0073] Embodiment 13

[0074] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.1% of phenylephrine, 0.05% of cirazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 5% of povidone K30, 0.01% of retinoic acid, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0075] Embodiment 14

[0076] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.15% norepinephrine, 0.1% tramazoline, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% retinoic acid acetate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0077] Embodiment 15

[0078] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.15% brimonidine tartrate, 1% oxymetazoline hydrochloride, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0079] Example 16

[0080] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 0.01% of hydroxyethyl cellulose, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0081] Embodiment 17

[0082] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 0.01% of povidone K30, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide for adjusting pH to 6.3.

[0083] Embodiment 18

[0084] An ophthalmic drug spray preparation for ptosis and red eye ptosis comprises the following components in percentage by mass: 0.025% of brimonidine tartrate, 0.1% of oxymetazoline hydrochloride, 0.1% of sodium hyaluronate, 0.05% of boric acid, 0.02% of calcium chloride, 0.25% of potassium chloride, 0.225% of sodium chloride, 0.42% of glycerol, 0.01% of polyvinyl alcohol 05-88, 0.01% of vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust pH to 6.3.

[0085] Embodiment 19

[0086] A drug solution was prepared according to the following components in percentage by mass: 0.025% brimonidine tartrate, 0.1% oxymetazoline hydrochloride, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust the pH to 6.3; the drug solution was filled into a Softspray eye spray device produced by Medspray and the device was capped.

[0087] Embodiment 20

[0088] A drug solution was prepared according to the following components in percentage by mass: 0.025% brimonidine tartrate, 0.1% oxymetazoline hydrochloride, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust the pH to 6.3; the drug solution was filled into an APFPlus antibacterial spray pump eye spray device produced by Aptar and the cap was pressed.

[0089] Embodiment 21

[0090] A drug solution was prepared according to the following components in percentage by mass: 0.025% brimonidine tartrate, 0.1% oxymetazoline hydrochloride, 0.1% sodium hyaluronate, 0.05% boric acid, 0.02% calcium chloride, 0.25% potassium chloride, 0.225% sodium chloride, 0.42% glycerol, 5% povidone K30, 0.01% vitamin A palmitate, and hydrochloric acid / sodium hydroxide to adjust the pH to 6.3; the drug solution was filled into an OPEN EYE SPRAY eye spray device produced by Aeropump and the cap was pressed.

[0091] The main purpose of the thickener added in the present invention is to adjust the spray performance. Different spray effects can be achieved by adjusting the type, molecular weight and dosage of the thickener. Therefore, hydroxyethyl cellulose, povidone K30 and polyvinyl alcohol 05-88 are specifically described in the above embodiments. The combination of each thickener and the drug composition is not specifically listed, but the thickener mentioned in the present invention is added to the prescription and is expected to produce similar preparation performance.

[0092] Test Example 1:

[0093] Solutions were prepared according to Example 1, Example 2 and Example 3, respectively, and loaded into a spray device to measure the spray shape, atomized droplet size and particle size distribution.

[0094] The results suggest that the addition of hydroxyethyl cellulose, povidone, and polyvinyl alcohol thickeners can adjust the spray performance.

[0095] Spray shape characterization (vertical):

[0096] Example Spray Angle Spray width mm Example 1 26.8 28.5 Example 2 38.9 42.4 Example 3 29.1 31.3

[0097] Spray shape characterization (parallel):

[0098]

[0099] Droplet size and particle size distribution:

[0100]

[0101]

[0102] Test Example 2:

[0103] Sample solutions were prepared according to Example 2 and Example 5, and placed at 40° C. to examine the stability of the samples.

[0104] The results showed that the samples were relatively stable in the range of 5.8-6.3.

[0105]

[0106] Test Example 3:

[0107] Sample solutions were prepared according to Example 2 and Example 6, and placed at 40° C. to examine the stability of the samples.

[0108] The results showed that there was no significant difference in the impurity growth trend of samples prepared by boric acid / borax buffer system and citric acid / sodium citrate buffer system, and the stability was good.

[0109]

[0110] Test example 4:

[0111] Sample solutions were prepared according to Example 2, Example 7, and Example 8, and placed at 60° C. to investigate the stability of the samples. The results showed that there was no significant difference in the degradation impurities of the corresponding drug components in the compound and the two single prescription solutions, and the compound had good compatibility stability.

[0112]

[0113] Test Example 5: Red Eye;

[0114] Test plan:

[0115] Ten rabbits were randomly divided into two groups. Oxymetazoline hydrochloride eye drops with the brand name Upneeq (hereinafter referred to as Upneeq) and Example 20 were respectively administered to the right eyes of the rabbits in each group. The degree of conjunctival hyperemia of the test eyes was observed at different time points after administration.

[0116] Evaluation criteria:

[0117]

[0118] Test results:

[0119]

[0120] The results showed that the application of the trademark Upneeq eye drops caused conjunctival congestion and redness in some of the test rabbits, which lasted up to 10 minutes and disappeared; the application of Example 20 only caused conjunctival congestion and redness in a small number of test rabbits, and the duration was short, which disappeared in about 3 minutes. This suggests that the compound (Example 20) has the potential to reduce the side effects of the single oxymetazoline hydrochloride solution (i.e., the trademark Upneeq eye drops).

[0121] Test Example 6:

[0122] Subjects with ptosis and ocular redness were given brand Upneeq eye drops in the left eye and no product (e.g. Figure 1 ), 5 minutes after application, the subjects' two eyes were observed, and the ptosis of the left eye was significantly improved, but the redness of the eye corner increased.

[0123] The sample prepared in Example 20 was applied to the left eye of the same subject with ptosis and eye redness, and no product (such as Figure 2 ), 5 minutes after application, the subjects' two eyes were observed, and the ptosis of the left eye was significantly improved, while the red eye symptom almost completely disappeared.

[0124] Test Example 7: Palpebral fissure detection:

[0125] Test plan:

[0126] The Upneeq eye drops drug solution was randomly administered to one eye of the subject, and the Example 20 drug solution was administered to the other eye, and the palpebral fissure width was measured before, 30 minutes and 2 hours after drug administration.

[0127] Palpebral fissure measurement:

[0128] The height between the upper and lower eyelid margins was measured using a thin ruler (sagittally across the pupil center; unit: cm).

[0129] Test results:

[0130]

[0131] In subjects with ptosis, the average increase in palpebral fissure was 27.7% 2 hours after application of the brand Upneeq eye drops, and the average increase in palpebral fissure was 34.0% 2 hours after application of the pharmaceutical preparation of Example 20.

[0132] In normal subjects, the palpebral fissure increased by an average of 11.6% 2 hours after the application of the brand Upneeq eye drops, and the palpebral fissure increased by an average of 11.6% 2 hours after the application of the pharmaceutical preparation of Example 20.

[0133] The above results show that for patients with ptosis, both the trademark Upneeq eye drops and Example 20 have a significant effect on enlarging the eyelids. At the same time, the compound pharmaceutical preparation (Example 20) has a more obvious effect on enlarging the eyelids than the single 0.1% oxymetazoline solution (i.e., the trademark Upneeq eye drops), indicating that brimonidine tartrate and oxymetazoline hydrochloride have a synergistic effect.

[0134] From the above embodiments, especially embodiments 1, 2, 3, 4, 5, 6, 9, 16, 17, 18, 19, 20 and 21, we can find that the two active ingredients of brimonidine tartrate and oxymetazoline hydrochloride are used in combination, and the ratio is: 0.025% brimonidine tartrate and 0.1% oxymetazoline hydrochloride. This specific combination of compound drugs has strong stability, which not only ensures the efficacy, but also reduces the dosage of a single ingredient, effectively reducing side effects.

[0135] The following is a specific comparative test:

[0136] 1. Formula of the prior art

[0137] Comparison of prescriptions of marketed products

[0138]

[0139]

[0140] 2. This patent has determined through research the pH range within which the drug can exist stably.

[0141] According to the Upneeq instructions, the oxymetazoline hydrochloride in the oxymetazoline hydrochloride eye drops is stable within the pH range of 5.8-6.8.

[0142] The invention prepares compound preparation samples with different pH values ​​(5.8, 6.3, 6.8), and places the samples at 40°C and 60°C to examine the sample stability. According to the application data of the present invention (see the table below), in the compound preparation of the present invention, when the pH is 6.8, the stability impurity details of oxymetazoline hydrochloride in the compound preparation increase, and it is unstable at pH 6.8. However, at pH 5.8-6.3, the impurity growth of the compound components is small, and the sample is stable.

[0143] The present invention has determined through experimental research that the pH range in which the two components in the compound preparation can stably exist is 5.8-6.3, which is smaller than the range recorded in the specification.

[0144] Different pH formulations

[0145] materials Test Example 0078010 Test Example 0078011 Test Example 0078012 Brimonidine tartrate 0.025％ 0.025％ 0.025％ Oxymetazoline hydrochloride 0.01％ 0.01％ 0.01％ Boric acid / borax Adjust pH to 5.8 Adjust pH to 6.3 Adjust pH to 6.8

[0146] Stability test results of different pH samples at 40℃

[0147]

[0148] Stability test results of different pH samples at 60℃

[0149]

[0150]

[0151] 3. This patent has identified a new buffer salt system through research that can allow drugs to exist stably.

[0152] The buffer salt of Upneeq is citric acid-acetic acid, and the buffer salt of LUMIFY is boric acid-borax buffer system. In order to study the buffer system that can keep the two components stable, samples were prepared with different buffer systems and placed at 40℃ and 60℃ to investigate the stability of the samples. There was no significant difference in the impurity growth trend of the samples prepared by the boric acid / borax buffer system and the citric acid / sodium citrate buffer system. The impurities of the samples prepared by the sodium dihydrogen phosphate / disodium hydrogen phosphate buffer system increased significantly, and the stability of the solution was poor. Therefore, the boric acid / borax buffer system or the citric acid / sodium citrate buffer system can be used.

[0153] Different buffer system prescription composition

[0154]

[0155] Stability test results of different buffer system samples at 40℃

[0156]

[0157] Stability test results of different buffer system samples at 60℃

[0158]

[0159]

[0160] 4. Compared with the existing patent text, this patent introduces a new excipient, sodium hyaluronate (HA), which significantly improves the stability of the drug brimonidine tartrate in the compound preparation.

[0161] When HA was not contained in the system, the impurities of oxymetazoline hydrochloride and brimonidine tartrate increased significantly when the compound preparation was placed at 40°C for 3 months. When HA was added to the compound preparation and placed at 40°C for 3 months, the impurities of oxymetazoline hydrochloride and brimonidine tartrate did not increase significantly.

[0162] Therefore, the present invention significantly improves the drug stability in the compound preparation by adding HA to the compound preparation.

[0163] The following experiment proves its stability:

[0164] Prescriptions with and without sodium hyaluronate were prepared and placed at 40°C for 3 months. The stability of the products was compared as shown in the following table.

[0165] Formula composition with / without sodium hyaluronate

[0166] materials Test Example 0078014 Test Example 0078015 Brimonidine tartrate 0.025％ 0.025％ Oxymetazoline hydrochloride 0.01％ 0.01％ Sodium Hyaluronate NA 0.1％ Boric acid / borax Adjust pH to 6.3 Adjust pH to 6.3 Calcium chloride 0.02％ 0.02％ Potassium chloride 0.25％ 0.25％ Sodium chloride 0.225％ 0.225％ glycerin 0.42％ 0.42％

[0167] Results of stability study on formulations with / without sodium hyaluronate

[0168]

[0169]

[0170] 5. This patent has proved through experimental research that the two active ingredients of brimonidine tartrate and oxymetazoline hydrochloride have good compatibility and have compound drug properties.

[0171] Two single and compound samples were prepared and placed at 60°C to investigate the stability of the samples. There was no significant difference in the degradation of the corresponding drug components in the compound and the two single solution, indicating that the compound had good compatibility stability.

[0172] Different prescription compositions

[0173] materials Test Example 0078015 Test Example 0078017 Test Example 0078018 Brimonidine tartrate 0.025％ 0.025％ - Oxymetazoline hydrochloride 0.01％ - 0.01％ Sodium Hyaluronate 0.1％ 0.1％ 0.1％ Boric acid / borax Adjust pH to 6.3 Adjust pH to 6.3 Adjust pH to 6.3 Calcium chloride 0.02％ 0.02％ 0.02％ Potassium chloride 0.25％ 0.25％ 0.25％ Sodium chloride 0.225％ 0.225％ 0.225％ glycerin 0.42％ 0.42％ 0.42％

[0174] Stability test results of samples with different compositions at 60°C

[0175]

[0176] 6. This patent has found through research that the combined use of brimonidine tartrate and oxymetazoline hydrochloride can achieve a better therapeutic effect at a lower dosage.

[0177] As shown in the table below, the eye drops of the prior art brand Upneeq for treating ptosis have a dosage of 35 μg per administration, and the eye drops of the prior art brand LUMIFY for treating red eyes have a dosage of 8.25 μg per administration.

[0178] In the compound spray preparation of the present invention, in each administration dose, the dosage of oxymetazoline hydrochloride is 19.61 μg, and the dosage of brimonidine tartrate is 4.97 μg. Compared with the dosage of a single drug, the dosage of both drugs is significantly reduced, but the efficacy is significant.

[0179] By reducing the dosage, the side effects of oxymetazoline and brimonidine tartrate can be reduced; at the same time, the cost of the drug can be reduced.

[0180] Comparison of dosage between the spray preparation and eye drops in the present invention

[0181]

[0182] The results show that the single dosage of the spray preparation of the present invention is lower than that of the eye drops of the trademark Upneeq and the eye drops of the trademark LUMIFY, but the achieved drug administration effect is not inferior to Upneeq and LUMIFY (Test Example 7 of the invention application text); the present invention further reduces the daily exposure of the drug for the spray preparation, reduces the possible safety risks of the drug, and does not reduce the effect of the drug.

[0183] Special note: In this patent, brimonidine tartrate and oxymetazoline hydrochloride can exist stably, which is the result of the combined effect of pH, buffer salt, and the newly introduced auxiliary material sodium hyaluronate, rather than a single influencing factor. In order to explain clearly, this patent focuses on data description.

[0184] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention.

[0185] The formulations involved in the above embodiments can also be prepared into solutions, suspensions, oils, gels, emulsions, liposomes, ointments, long-acting or sustained-release preparations, or other types of solid or semi-solid preparations.

[0186] All equivalent changes or modifications made according to the spirit and essence of the present invention should be included in the protection scope of the present invention.

Claims

1. An ophthalmic spray combination preparation for relieving ptosis and red eyes, characterized in that: The following components are included in mass percentage: α-adrenergic receptor agonists 0.01%-1.15%; Sodium hyaluronate 0.1%-0.3%; Osmotic pressure regulator 0.01%-2%; Also includes a pH buffer, wherein the concentration of the pH buffer is 0.002M-0.16M; It also includes a thickener with a mass percentage of 0.01%-6.5%, wherein the thickener is one or a combination of cellulose derivatives, carbomers, polyvinyl alcohols, polyethylene glycols, dextran, and povidones; Also includes 0.01%-0.2% by mass of vitamin A and its derivatives or / and vitamin E and its derivatives; The spray preparation comprises a spray device, and the spray particle size is 5-500 μm.

2. The eye spray combination preparation according to claim 1, characterized in that: The α-adrenaline receptor agonist is one or a combination of oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, xylometazoline, cilazoline, brimonidine, apraclonidine, apraclonidine, methoxyamine, midodrine, metaraminol, phenylephrine, amiphrine, SDZ-NVI-085, dexmedetomidine, guanfacine, guanabenz, guanoxabenz, tirtonidine, methyldopa, epinephrine, methylnorepinephrine, norepinephrine, and lofexidine, and the above drugs include their corresponding pharmaceutically acceptable salts.

3. The eye spray combination preparation according to claim 2, characterized in that: The α-adrenaline receptor agonist is oxymetazoline hydrochloride and / or brimonidine tartrate.

4. The eye spray combination preparation according to claim 3, characterized in that: The α-adrenaline receptor agonist is 0.1% by mass of oxymetazoline hydrochloride and 0.025% by mass of brimonidine tartrate.

5. The ophthalmic spray combination preparation according to claim 1, characterized in that: The relative molecular weight of the sodium hyaluronate is in the range of 3 kDa-2200 kDa, and the mass percentage is 0.1%-0.3%.

6. The eye spray combination preparation according to claim 1, characterized in that: The osmotic pressure regulator is one or a combination of potassium chloride, calcium chloride, sodium chloride, magnesium chloride, glycerol, mannitol, and glucose, and the mass percentage is 0.01%-2%.

7. The ophthalmic spray combination preparation according to claim 1, characterized in that: The pH buffer is one or a combination of borate buffer, citrate buffer, acetate buffer, and phosphate buffer, with a molar concentration of 0.002M-0.16M, and the pH range is adjusted to 5.0-7.

0.

8. The eye spray combination preparation according to claim 1, characterized in that: The cellulose derivatives include methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; the carbomers include Carbopol 941, Carbopol 934, Carbopol AQUA SF-1, and Carbopol ETD2020; the polyvinyl alcohols include PVA05-88, PVA17-88, and PVA24-88; the polyethylene glycols include PEG-200, PEG-400, PEG-600, and PEG-800; and the povidones include PVP K30, PVP K60, and PVP K90.

9. The eye spray combination preparation according to claim 1, characterized in that: The product is filled in a spray drug delivery device and the spray particle size produced is 5-500 μm.

10. Use of the ophthalmic spray combination preparation according to any one of claims 1 to 9 for treating ptosis or alleviating the red eye symptom caused by ptosis.

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