CN116139249A - Cyclosporine suspension eye drops and preparation method thereof - Google Patents

Cyclosporine suspension eye drops and preparation method thereof Download PDF

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Publication number
CN116139249A
CN116139249A CN202211726145.0A CN202211726145A CN116139249A CN 116139249 A CN116139249 A CN 116139249A CN 202211726145 A CN202211726145 A CN 202211726145A CN 116139249 A CN116139249 A CN 116139249A
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cyclosporine
suspension eye
percent
eye drops
suspension
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Inventor
廖园
张黎
牟东升
周小顺
刘文双
李进
饶敦艳
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Wuhan Conform Pharmaceutical Co ltd
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Wuhan Conform Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses cyclosporine suspension eye drops, which comprise the following components in percentage by weight: 0.05 to 0.1 percent of cyclosporine, 0.05 to 1.4 percent of bioadhesive material, 0.75 to 3 percent of propylene glycol, and buffer salt to adjust the pH value to 6.0 to 8.0, and purified water is added to 100 percent; wherein the cyclosporine is an aqueous dispersion of cyclosporine nanocrystals. The invention can prolong the residence time of the medicine in eyes and increase the distribution of eye tissues of the medicine, thereby improving the medicine effect.

Description

Cyclosporine suspension eye drops and preparation method thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to cyclosporine suspension eye drops and a preparation method thereof.
Background
Cyclosporin, also called cyclosporin a (i.e., cycloporine or cycloporine, abbreviated as CsA), is a nonpolar cyclic oligopeptide drug composed of 11 amino acid residues, and is soluble in organic solvents and hardly soluble in water. The composition is mainly used for organ transplantation, anti-rejection treatment after bone marrow transplantation and treatment of autoimmune diseases. Research at home and abroad shows that the composition can inhibit aggregation of inflammatory cells and release of inflammatory factors, reduce infiltration of lacrimal gland and conjunctival tissue lymphocytes, inhibit apoptosis of ocular surface tissues such as lacrimal gland and conjunctival goblet cells and play a role, so that cyclosporin can be applied to eyes as a local immunomodulator, treat keratoma and conjunctivitis, inhibit cornea transplantation rejection and the like.
There are 3 cyclosporin preparations currently available on the market for treating dry eye, one is 0.05% cyclosporin fat emulsion eye drops developed by Allergan company
Figure BDA0004030033410000011
The product is a first drug for treating xerophthalmia, and has the main defects of slow onset of action, possibly up to 6 months for onset of action, and the administration frequency of certain patients is increased from standard twice daily to three to four times daily, and the burning sensation is higher, so that the severe xerophthalmia patients can stop taking medicines after being treated for several months due to adverse reactions and/or inconvenient administration. Better drug delivery systems are sought to increase cyclosporin concentration in the keratoconjunctiva. The second is 0.1% cyclosporin emulsion eye drop +.>
Figure BDA0004030033410000012
Preservative-free formula eye drops for reducing twice-a-day administration to once-a-day administration for the first timeThe cationic emulsion technology is utilized to increase the residence time of the medicine in eyes and the distribution of the eye tissues of the medicine, so that the cyclosporine has better bioavailability and long-acting property in the tear film. The third is cyclosporine micelle eye drop developed in Indian pharmacy +.>
Figure BDA0004030033410000013
The formulation uses a non-cationic surface-active polymer, with +.>
Figure BDA0004030033410000014
There are two differences, namely, the increase of cyclosporin concentration, which is the highest concentration of cyclosporin approved in the United states until now, and the contrast to +.>
Figure BDA0004030033410000015
The nano micelle aqueous solution can improve the bioavailability of hydrophilic tissues and increase the onset of action. In order to obtain more obvious curative effect, the two latter products adopt cyclosporine (0.09-0.1%) with larger concentration, and the carrier is changed at the same time, so that the higher the concentration of the drug is, the better the drug effect can be improved, but the disadvantage is that the adverse reaction is also less well controlled. There is therefore a need for better drug delivery systems based on lower cyclosporin formulation levels to increase cyclosporin concentration in the keratoconjunctiva and thereby improve drug efficacy.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and providing a cyclosporine suspension eye drop with better drug delivery effect by using low concentration cyclosporine and a preparation method thereof.
The technical scheme adopted by the invention is as follows:
the cyclosporine suspension eye drops comprise the following components in percentage by weight: 0.05 to 0.1 percent of cyclosporine, 0.05 to 1.4 percent of bioadhesive material, 0.75 to 3 percent of propylene glycol, and buffer salt to adjust the pH value to 6.0 to 8.0, and purified water is added to 100 percent; wherein the particle size of the cyclosporine is 100-500 nm.
The particle size of the medicinal particles of the cyclosporine suspension eye drops is less than or equal to 500nm, and the cyclosporine nanocrystallization treatment can effectively improve the solubility and dissolution rate of the medicament and improve the bioavailability of the medicament. However, after the cyclosporine particle diameter is changed, the drug particles are liable to be affected in the agglomeration adsorption fluidity, and the stability of the drug needs to be maintained. Therefore, a large number of experiments and researches prove that the biological adhesive material and the propylene glycol are compounded to jointly wrap the drug particles, so that the cyclosporine can be dispersed more uniformly in the suspension, the drug stability is good, and the better pharmacological effect can be exerted at the size of less than or equal to 500nm. In addition, the bioadhesive material and propylene glycol are adopted to wrap the drug particles, so that the interaction of the drug and mucin in tear can be avoided, the drug is prevented from being cleared by tear, the drug particles can reach keratoconjunctiva more successfully, meanwhile, the residence time of the drug particles in eyes can be prolonged, the chance of the drug entering cornea and other eye tissues is increased, the drug absorption time is prolonged, and the curative effect is improved.
Preferably, the bioadhesive material is selected from one or more of 0.3-0.9% by weight of polycarbophil, 0.05-0.3% by weight of tyloxapol, 0.1-0.5% by weight of poloxamer 407, and 0.4-0.5% by weight of carbomer 974P.
Further, the components also comprise 2% -3% of glycerol.
Further, the composition further comprises sodium chloride.
Further, the components also comprise 0.01 to 0.1 percent of EDTA-2Na.
Preferably, the buffer salt is selected from the group consisting of a citric acid/sodium citrate buffer pair, a boric acid/sodium borate buffer pair.
The invention also discloses a preparation method of the cyclosporine suspension eye drops, which comprises the following steps: preparing cyclosporine nanocrystal aqueous dispersion by adopting a homogenizing method or a wet grinding method; preparing a bioadhesive material solution: taking about 50% of the prescription amount of purified water, adding bioadhesive materials into the cut edges, shearing at 5000rpm for 5min to completely swell, sterilizing at 121 ℃ for 15min, and then placing to about 40 ℃ for standby; mixing cyclosporine nanocrystal water dispersion with bioadhesive material solution, adding prescribed amount of propylene glycol, uniformly mixing, supplementing water to full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
The invention has the beneficial effects that:
1. the cyclosporine suspension eye drops prepared by the invention can be administered once a day;
2. the cyclosporine suspension eye drops prepared by the invention do not contain surfactant and emulsifying agent, and have better eye drop administration comfort.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are only some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by one of ordinary skill in the art without undue burden on the person of ordinary skill in the art based on embodiments of the present invention, are within the scope of the present invention. The reagents in the following examples are all conventional products commercially available. The examples were conducted under conventional conditions, except that the specific conditions were not specified.
Example 1
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporin 0.05%, polycarbophil 0.5%, propylene glycol 1.0%, citric acid/sodium citrate buffer pair to adjust PH to 7.0, purified water to 100%; wherein the particle size of the cyclosporine is 300nm.
The preparation method comprises the following steps: preparing an aqueous cyclosporine nanocrystal dispersion by a high pressure homogenization process (high pressure homogenizer, pressure 600 bar); taking about 50% of the prescription amount of purified water, adding a bioadhesive material while shearing, sterilizing at 121 ℃ for 15min after swelling completely, and standing to 40 ℃ for later use; uniformly mixing the cyclosporine nanocrystal aqueous dispersion with the bioadhesive material solution, adding the prescribed amount of propylene glycol, and adding citric acid/sodium citrate to adjust the pH to 7.0; supplementing water to the full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
Example 2
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporine 0.06%, tyloxapol 0.15%, propylene glycol 0.75%, 2% glycerol, citric acid/sodium citrate buffer pair to adjust pH to 7.0, purified water added to 100%; wherein the particle size of the cyclosporine is 400nm.
The preparation method comprises the following steps: wet milling method is adopted
Figure BDA0004030033410000041
The grinding medium is zirconia beads or polystyrene resin coated beads with high crosslinking degree, and the particle size is 400 mu m; ) Preparing an aqueous cyclosporine nanocrystal dispersion; preparing a bioadhesive material solution: taking about 50% of the prescription amount of purified water, adding bioadhesive materials, standing and swelling completely, sterilizing at 121 ℃ for 15min, and standing to 40 ℃ for later use; uniformly mixing the cyclosporine nanocrystal aqueous dispersion with a bioadhesive material solution, propylene glycol and glycerin, and adding citric acid/sodium citrate to adjust the pH to 7.0; supplementing water to the full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
Example 3
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporine 0.07%, poloxamer 4070.3%,1.5% propylene glycol, citric acid/sodium citrate buffer pair to adjust PH to 7.0, purified water to 100%; wherein the particle size of the cyclosporine is 320nm.
The preparation method comprises the following steps: wet milling method is adopted
Figure BDA0004030033410000042
Grinding medium is zirconia beads or polystyrene resin coated beads with high crosslinking degree, and the particle size is 400 mu m); taking about 50% of the prescription amount of purified water, adding a bioadhesive material while shearing, sterilizing at 121 ℃ for 15min after swelling completely, and standing to 40 ℃ for later use; uniformly mixing the cyclosporine nanocrystal aqueous dispersion with the bioadhesive material solution, adding the prescribed amount of propylene glycol, and adding citric acid/sodium citrate to adjust the pH to 7.0; supplementing water to the full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
Example 4
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporine 0.08%, bioadhesive material 0.9% polycarbophil and carbomer 974p0.4%, propylene glycol 2.0%, boric acid/sodium borate buffer pair adjusted PH to 7.0, purified water added to 100%; wherein the particle size of the cyclosporine is 200nm.
The preparation method comprises the following steps: wet milling method is adopted
Figure BDA0004030033410000043
Grinding medium is zirconia beads or polystyrene resin coated beads with high crosslinking degree, and the particle size is 200 mu m); taking about 50% of the prescription amount of purified water, adding a bioadhesive material while shearing, sterilizing at 121 ℃ for 15min after swelling completely, and standing to 40 ℃ for later use; uniformly mixing the cyclosporine nanocrystal aqueous dispersion with a bioadhesive material solution and propylene glycol, and adding boric acid/sodium borate to adjust the pH to 7.0; supplementing water to the full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
Example 5
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporin 0.1%, carbomer 974P 0.5%, propylene glycol 3.0%, 0.05% EDTA-2Na, boric acid/sodium borate buffer pair adjusted pH to 7.0, purified water added to 100%; wherein the particle size of the cyclosporine is 100nm.
The preparation method comprises the following steps: wet milling method is adopted
Figure BDA0004030033410000051
Grinding medium is zirconia beads or polystyrene resin coated beads with high crosslinking degree, and the particle size is 200 mu m); preparing a bioadhesive material solution: taking about 50% of the prescription amount of purified water, adding a bioadhesive material while shearing, sterilizing at 121 ℃ for 15min after swelling completely, and standing to 40 ℃ for later use; uniformly mixing the cyclosporine nanocrystal aqueous dispersion with the bioadhesive material solution and propylene glycol, and adding EDTA-2Na with a prescription amount; adding boric acid/sodium borate to adjust the pH to 7.0; supplementing water to the full amount, and stirring for 30min; and (5) filling to obtain the cyclosporine suspension eye drops.
Comparative example 1
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporine 0.05%, carboxymethylcellulose sodium 1.2%, propylene glycol 1.0%, citric acid/sodium citrate buffer pair to adjust PH to 7.0, purified water to 100%; wherein the particle size of the cyclosporine is 300nm.
Comparative example 2
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporin 0.05%, polycarbophil 0.5%, propylene glycol 1.0%, citric acid/sodium citrate buffer pair to adjust PH to 7.0, purified water to 100%; wherein the particle size of the cyclosporine is 1um.
Comparative example 3
A cyclosporine suspension eye drop, which comprises the following components in percentage by weight: cyclosporin 0.05%, polycarbophil 0.5%, citric acid/sodium citrate buffer pair to adjust PH to 7.0, purified water to 100%; wherein the particle size of the cyclosporine is 300nm.
Application example 1: examples 1 to 5 and comparative examples 1 to 3 stability test of eye drops
The eye drops prepared in examples 1 to 5 and comparative examples 1 to 3 were left for 3 months at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75.+ -. 5%, the appearance of the samples was observed, and the average particle size of the eye drops was measured, and the test results were shown in Table 1 below:
table 1: stability test results
Numbering device Traits (3) Average particle diameter
Example 1 Suspension liquid 336nm
Example 2 Suspension liquid 428nm
Example 3 Suspension liquid 355nm
Example 4 Suspension liquid 212nm
Example 5 Suspension liquid 105nm
Comparative example 1 Suspension liquid 415nm
Comparative example 2 Suspension liquid 1120nm
Comparative example 3 Suspension liquid 378nm
Application example 2: eye tissue distribution experiment of cyclosporine preparations of examples 1 to 5 and comparative examples 1 to 3
New Zealand white rabbits, weighing 1.7-2.4kg, dropping cyclosporine eye drops into eyes, grouping animals according to sampling time points, killing 2 animals in each group 20 minutes and 6 hours after administration, and collecting eye tissue samples. Cyclosporin concentration in tissues such as cornea, conjunctiva and tear is measured.
Table 2: concentration detection of cyclosporine in ocular tissue (ng/ml)
Figure BDA0004030033410000061
/>
In examples 1 to 5 of the present invention, the concentration of cyclosporin in the eye drops increases, and the concentration of the drug in the cornea and conjunctiva tends to increase, but the ratio of the increase of the concentration of the drug in the cornea and conjunctiva is lower than the ratio of the increase of the concentration of the cyclosporin, i.e., the bioavailability of the eye is higher at low concentrations. The invention discovers that when the particle size is not in the range of the invention or the bioadhesive material is replaced by sodium carboxymethylcellulose or propylene glycol is not contained, the stability of the cyclosporine suspension eye drops is poor, and the concentration of cyclosporine in tissues such as cornea, conjunctiva and the like is low.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (7)

1. The cyclosporine suspension eye drop is characterized by comprising the following components in percentage by weight: 0.05 to 0.1 percent of cyclosporine, 0.05 to 1.4 percent of bioadhesive material, 0.75 to 3 percent of propylene glycol, and buffer salt to adjust the pH value to 6.0 to 8.0, and purified water is added to 100 percent; wherein the particle size of the cyclosporine is 100-500 nm.
2. The cyclosporine suspension eye drops of claim 1, wherein the bioadhesive material is selected from one or more of the following polycarbophil 0.3-0.9%, tyloxapol 0.05-0.3%, poloxamer 4070.1-0.5%, carbomer 974P 0.4-0.5% by weight.
3. A cyclosporine suspension eye drop as in claim 1, wherein said composition further comprises 2% to 3% glycerin.
4. The cyclosporine suspension eye drop of claim 1, wherein said composition further comprises 0.05% to 0.9% sodium chloride.
5. A cyclosporine suspension eye drop according to claim 1, wherein said composition further comprises 0.01% to 0.1% edta-2Na.
6. The cyclosporine suspension eye drops of claim 1 wherein said buffer salt is selected from the group consisting of a citric acid/sodium citrate buffer pair, a boric acid/sodium borate buffer pair.
7. A process for the preparation of a cyclosporine suspension eye drop as claimed in any one of claims 1 to 6, comprising the steps of: preparing cyclosporine nanocrystal aqueous dispersion by adopting a homogenizing method or a wet grinding method; preparing a bioadhesive material solution: taking about 50% of the prescription amount of purified water, adding bioadhesive materials into the cut edges, shearing at 5000rpm for 5min to completely swell, sterilizing at 121 ℃ for 15min, and then placing to about 40 ℃ for standby; uniformly mixing the cyclosporine nanocrystal aqueous dispersion, a bioadhesive material solution and propylene glycol, supplementing water to a full amount, and stirring; and (5) filling to obtain the cyclosporine suspension eye drops.
CN202211726145.0A 2022-12-30 2022-12-30 Cyclosporine suspension eye drops and preparation method thereof Pending CN116139249A (en)

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