WO2011063606A1 - 一种含加替沙星的眼用凝胶剂及其制备方法 - Google Patents
一种含加替沙星的眼用凝胶剂及其制备方法 Download PDFInfo
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- WO2011063606A1 WO2011063606A1 PCT/CN2010/001880 CN2010001880W WO2011063606A1 WO 2011063606 A1 WO2011063606 A1 WO 2011063606A1 CN 2010001880 W CN2010001880 W CN 2010001880W WO 2011063606 A1 WO2011063606 A1 WO 2011063606A1
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- water
- gatifloxacin
- group
- gel
- ophthalmic gel
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- 238000000691 measurement method Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
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- 230000000699 topical effect Effects 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the field of pharmaceutical preparations, and in particular to an ophthalmic preparation, and more particularly to an ophthalmic gel containing gatifloxacin and a preparation method thereof.
- the invention also relates to a method of treating an ocular infection.
- Gatifloxacin belongs to the fourth-generation fluoroquinolone anti-drug, developed by Japan Xinglin Company and transferred to BMS (Br i sob Myers Squibb) company's broad-spectrum antibacterial drug. In December 1999, the oral and intravenous injections of this product were approved by the US FDA, and the trade name was Tequin. Al lergan, Inc. announced on March 31 that the FDA has approved 0.3% ZYMARTM (Gatifloxacin Eye Drops) to be marketed in the United States.
- gatifloxacin Compared with the first three generations of quinolones, gatifloxacin has the following characteristics: First, the antibacterial activity against Gram-positive bacteria is 2 to 16 times to 32 times stronger than that of the first to third generations; This product has a strong inhibitory effect on pathogenic bacteria resistant to other antibiotics such as aminoglycosides and macrolides, and there is no cross-resistance between gatifloxacin and these antibiotics; gatifloxacin against chlamydia, Mycoplasma and other substances have strong activity; finally, gatifloxacin overcomes the side effects such as phototoxicity by introducing a methoxy group on C8, and the chemical structure is stable and the safety is greatly improved.
- Cipheral Patent Application Publication No. CN1448137A (Application No. 03113340. 1; Publication Date: October 15, 2003) discloses a gatifloxacin as a main component, supplemented with chitosan as a gel matrix and an isotonicity adjusting agent.
- chitosan a topical gel and an ophthalmic gel formulation prepared by using a pH adjusting agent, a preservative, a sterile water for injection, and the like, wherein the content of gatifloxacin is 0.1% -3 % by weight
- the content is 0.3% -3 % by weight; the invention not only has significant anti-infective function, but also accelerates wound healing and promotes epithelial growth.
- Gatifloxacin ophthalmic gel based on HPMC and a preparation method thereof, and gatisha Star is an active substance, and is prepared by using a hydrophilic polymer material hydroxypropylmethylcellulose (HPMC) as a substrate, a preservative, an isotonicity adjusting agent, a penetration enhancer, a pH adjuster and water.
- HPMC hydroxypropylmethylcellulose
- the preparation is suitable for treating eye infections such as orbital inflammation, sty, conjunctivitis, lacrimal inflammation, keratitis, corneal ulcer, trachoma; it is reported that the gel is a semi-solid fluid, easy to use, in the eye It has a long residence time, is not easy to lose, can maintain effective therapeutic concentration, enhance therapeutic effect, and has low toxicity and low irritation.
- eye infections such as orbital inflammation, sty, conjunctivitis, lacrimal inflammation, keratitis, corneal ulcer, trachoma
- eye infections such as orbital inflammation, sty, conjunctivitis, lacrimal inflammation, keratitis, corneal ulcer, trachoma
- the gel is a semi-solid fluid, easy to use, in the eye It has a long residence time, is not easy to lose, can maintain effective therapeutic concentration, enhance therapeutic effect, and has low toxicity and low irritation.
- the above known techniques still need to be improved in terms of improving the efficacy of
- the present inventors have found that gatifloxacin and a fine aqueous matrix carbomer can be made into a transparent carbomer ophthalmic gel, which overcomes the low bioavailability caused by the drug loss of the conventional eye drops and through the tears of the nose. Tube inflow leads to poor patient compliance, but the formulation causes irritation and damage to the cornea due to the need to add preservatives to the formulation.
- the object of the present invention is to provide an antibacterial drug replacement suitable for clinical application.
- Shaxing's ophthalmic gel The present inventors have surprisingly found that the combination of sodium hyaluronate and carbomer as a matrix for the preparation of gatifloxacin ophthalmic gel can effectively improve the performance of the formulation, for example, to reduce the local irritation of the formulation to the cornea.
- the present invention has been completed based on the above findings.
- a first aspect of the invention provides an ophthalmic gel comprising a therapeutically effective amount of gatifloxacin or a pharmaceutically acceptable salt thereof, a base shield and water, wherein the matrix is carbomer, carbomer and a mixture of one or more of hypromellose mixture, sodium hyaluronate, and the like.
- sodium hyaluronate is combined with the above matrix to prepare gatifloxacin ophthalmic gel.
- An ophthalmic gel according to any one of the first aspects of the invention, which comprises a therapeutically effective amount of gatifloxacin or a pharmaceutically acceptable salt thereof, carbomer, sodium hyaluronate, and water.
- Gatifloxacin or its pharmaceutically acceptable salt 0. 01-2. 0%, carbomer 0. 01-10. 0%, water suitable, added to 100%.
- Gatifloxacin or a pharmaceutically acceptable salt thereof 0. 01-2. 0%, carbomer 0. 05-4. 0%, hypromellose 0. 05-4. 0% water Appropriate amount added to 100%.
- Gatifloxacin or its pharmaceutically acceptable salt 0. 01-2. 0%, carbomer 0. 01-10%, sodium hyaluronate 0. 005-1. 0%, water amount, add to 100%.
- An ophthalmic gel according to any one of the first aspects of the present invention according to the weight of the gelling agent - / volume percentage, which contains:
- Gatifloxacin or its pharmaceutically acceptable salt 0.01-2.0%, carbomer 0.01-2.0%, sodium hyaluronate 0.005-0.5%, water suitable:, added to the painting.
- Gatifloxacin or its pharmaceutically acceptable salt 0.01-2.0%, carbomer 0.1-1.0%, sodium hyaluronate 0.01-0.1%, water suitable:, added to 100%.
- Gatifloxacin or a pharmaceutically acceptable salt thereof 0.1-2.0%, carbomer 0.1-1.0%, sodium hyaluronate 0.01-0.1%, water suitable:, added to drawing 0 according to any of the ophthalmic coagulants of the present invention
- the gatifloxacin or a pharmaceutically acceptable salt thereof is contained in an amount of from 0.1 to 2.0%, more specifically, from 0.1 to 1.0%, more specifically, 0.1 based on the weight/volume percentage of the gelling agent. Further, specifically, it is 0.1-0.3% or 0 ⁇ 1-0.2%, for example: 0.1%, 0.15°/. , 0.2%, 0.25%, or 0.3%.
- the content of the carbomer is, in particular, from 0.01 to 2.0%, more specifically from 0.1 to 1.0%, based on the weight/volume percentage of the gel. More specifically, it is 0.1-0.5%, such as 0.1%, 0.15%, 0.23 ⁇ 4, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5%.
- the content of the sodium hyaluronate is from 0.005 to 0.5%, more specifically, based on the weight/volume percentage of the gelling agent, more specifically, 01%. 0%, 0. 01%, 0. 02%, 0. 03%, 0. 04%, 0. 05%, 0. 01-0. 06%, for example: 0. 01%, 0. 02%, 0. 03%, 0. 04%, 0. 05% , or 0. 06 %.
- an ophthalmic gel according to any one of the first aspects of the present invention which further comprises a pH adjusting agent.
- the pH adjusting agent is selected from the group consisting of boric acid, borax, sodium hydroxide, hydrochloric acid, phosphate buffer solution, acetate buffer solution and the like. Either or a mixture thereof.
- the amount of the pH adjusting agent used in the formulation may vary due to various factors such as the type of pH adjusting agent and its strength, the formulation composition, the physical and chemical stability of the drug and the formulation.
- the pH of the preparation is adjusted with a suitable amount of pH adjuster before the preparation is fixed (to the final weight and / or volume). Adjustment, whereby the specific amount of the pH adjusting agent in the formulation can be easily determined.
- the pH is 6. 0-7.
- An ophthalmic gel according to any one of the first aspects of the present invention which further contains an osmotic pressure adjusting agent
- examples of the osmotic pressure adjusting agent usable in the present invention include, but are not limited to, propylene glycol, glycerin, sodium chloride, and mannitol. One or a mixture of them.
- the amount of the osmotic pressure regulating agent used in the formulation may vary depending on various factors such as the type of osmotic pressure adjusting agent and its strength, the formulation composition, the physical and chemical stability of the drug and the preparation, and the like.
- the amount of the osmotic pressure adjusting agent in the gelling agent of the present invention can be readily determined depending on the target osmotic pressure desired to be adjusted, for example, at a desired target osmotic pressure which is substantially isotonic or slightly hypertonic with body fluids.
- the osmotic pressure adjustment of the preparation with a suitable amount of osmotic pressure regulator before the preparation is fixed (to the final weight and / or volume)
- the specific amount of the osmotic pressure adjusting agent in the formulation can be easily determined.
- the ophthalmic gel of the present invention substantially comprises
- the amount of the osmotic pressure adjusting agent in the preparation can be initially determined by theoretical calculation based on the existing physical and chemical knowledge, for example, in the case of using sodium chloride as an osmotic regulator, sodium chloride is in the preparation. 9% (w/v), preferably 0. 88-0. 92% (w/v), more preferably about 0.9% (w/v) is more suitable of.
- Other types of osmotic pressure adjusting agents can also be readily determined by those skilled in the art by a combination of theory and practice.
- An ophthalmic gel according to any one of the first aspects of the present invention, which further comprises one or more bacteriostatic agents selected from the group consisting of phenylethyl alcohol, phenoxyethanol, decyl p-hydroxybenzoate, p-hydroxybenzoic acid Ethyl ester, propyl paraben, benzalkonium chloride, chlorobutanol, benzalkonium bromide, cetrimonium bromide.
- the bacteriostatic agent is one or more selected from the group consisting of phenoxyethanol, ethyl p-hydroxybenzoate, benzalkonium chloride, and chlorobutanol.
- the bacteriostatic agent is a combination of phenoxyethanol and ethyl p-hydroxybenzoate.
- the bacteriostatic agent accounts for 0. 005 ⁇ 1% (w/v) of the total amount of the eye drops.
- the bacteriostatic agent accounts for the total amount of the eye drops. of 0. 01 ⁇ 0. 5% (w / v).
- the antibacterial agent comprises 0.1 ⁇ 0.5% of the total amount of the eye drops (w / v) 0 preferably, the The bacteriostatic agent accounts for the total amount of the eye drops 01. 0 ⁇ 1% (w/v). 5% (w/v)
- the bacteriostatic agent is 0. 01, 0. 1, or 0. 5% (w/v)
- An ophthalmic gel according to any one of the first aspects of the present invention which further comprises one or more surfactants selected from the group consisting of Tween, polyoxyethylene hydrogenated castor oil, and polyoxyethylene castor oil Classes such as, but not limited to, Tween-80, Tween-60, Tween-85, Tween-65, polyoxyethylene 60 hydrogenated castor oil, and the like.
- Tween-80, Tween-60, Tween-85, Tween-65, polyoxyethylene 60 hydrogenated castor oil, and the like O. 1-2% (w/v), more preferably 0. 01-5% (w/v), more preferably 0. 01-2% (w), in one embodiment, the ophthalmic gel of the present invention contains 0. 001-10% (w/v), preferably 0. 01-5% (w/v), more preferably 0. 01-2% (w /v), more preferably 0. 01-1% (w / v) of a surfactant.
- an ophthalmic preparation comprising the ophthalmic preparation according to any one of the first aspect of the present invention, wherein the ophthalmic preparation can also be prepared as a new ophthalmic gel.
- the ophthalmic gel can be adjusted in viscosity with a sodium chloride solution or a calcium chloride solution to undergo a phase transition in the physiological environment of the eye to obtain a clinically useful effect.
- a third aspect of the present invention provides a method for producing an ophthalmic gel according to any one of the first aspect of the present invention, which comprises using a proper amount of a polymer carbomer or carbomer and hydroxypropionin cellulose and sodium hyaluronate. After the water is completely swollen, the other components are dissolved in water, added to the gel matrix to form a gel matrix, and stirred uniformly, and the step of armoring.
- a third aspect of the invention provides a method for preparing an ophthalmic gel according to any of the first aspects of the invention, comprising the steps of:
- Iv) Mix the materials obtained by i i) and optional i i i), filter through microporous membrane, add to i) solution, add water to the total amount of the prescription, stir and hook, and get ready.
- an ophthalmic gel containing gatifloxacin is prepared by squeezing the carbomer substrate with an appropriate amount of water for injection and allowing to stand; and sterilizing 121 before use. C, 30 minutes or more; take appropriate amount of water for injection to add the auxiliary material; add the solvent, add it after hot melt, add osmotic pressure regulator, filter 0. 22 micron sterilization, the filtrate is added to the rubber phase, another water is taken, Add the main drug to dissolve, add and remove the bacteria by 0.22 micron filtration, stir evenly, adjust the pH value, make up the water for injection to the full amount, stir to make the uniform transparent gel.
- the gatifloxacin-containing ophthalmic gel which can be prepared according to the method of the present invention has a clear appearance, sterility, low irritation and low toxicity, and can provide a safe and effective ophthalmic preparation for clinical use.
- Still another aspect of the present invention relates to a method of treating an ocular infection, comprising the step of administering an effective amount of the ophthalmic gel of the present invention; specifically, the ocular infection is orbital inflammation, stye, conjunctivitis, Tear inflammation, keratitis, corneal ulcers, or trachoma.
- the phrase "in terms of weight/volume percent of the gelling agent” means 100 grams of the gelling agent, wherein the weight of the component contained is the weight/volume percent, ie, Indicates g/100ml, or expressed as % ⁇ ). In the present invention, % is weight/volume percentage unless otherwise specified.
- the ophthalmic gel of the present invention is an aqueous composition in which water is used as a medium or vehicle or vehicle or carrier for the composition.
- the ophthalmic solution of the present invention does not specifically indicate the percentage of water used as a percentage of the total weight of the ophthalmic solution, or the amount of water used is not specifically indicated in the preparation of the ophthalmic solution of the present invention, it is clear to those skilled in the art as an eye drop.
- the medium or vehicle or vehicle or vehicle of the formulation the amount of water is calculated by adding water to the total amount of the ophthalmic gel, which is in liquid preparations such as eye drops, injections or ophthalmic coagulation of the present invention.
- the measurement method generally used in the preparation of the glue.
- the bacteriostatic agent may be in any combination of one or more.
- the bacteriostatic agent is phenoxyethanol and p-hydroxyl a combination of ethyl benzoate; in a further embodiment, the bacteriostatic agent is a combination of phenoxyethanol and ethyl p-hydroxybenzoate in any ratio; in still further embodiments, the The microbial agent was a combination of phenoxyethanol and ethyl p-hydroxybenzoate in a weight ratio of 50:1.
- the bacteriostatic agent is a combination of phenoxyethanol and benzalkonium chloride; in a further embodiment, the bacteriostatic agent is phenoxyethanol and benzalkonium chloride in any ratio. Combination; In still further embodiments, the bacteriostatic agent is phenoxyethanol and benzalkonium chloride combined in a weight ratio of 50:1. In one embodiment, the bacteriostatic agent is a combination of chlorobutanol and benzalkonium chloride; in a further embodiment, the bacteriostatic agent is chlorobutanol and benzalkonium chloride.
- the bacteriostatic agent is chlorobutanol and benzalkonium chloride combined in a weight ratio of 10:1.
- the bacteriostatic agent is a combination of chlorobutanol and ethyl p-hydroxybenzoate; in a further embodiment, the bacteriostatic agent is chlorobutanol and p-hydroxybenzene. Ethyl citrate is combined in any ratio; in still further embodiments, the bacteriostatic agent is a combination of chlorobutanol and ethyl p-hydroxybenzoate in a weight ratio of 10:1.
- an ophthalmic gel made of sodium hyaluronate and carbomer is a pseudoplastic fluid having a property similar to that of human tears, and the viscosity of the preparation itself is drastically reduced during blinking, when blinking,
- the formulation restores its viscosity and prolongs the residence time of the drug on the ocular surface.
- This property allows the ophthalmic gel of the present invention to not cause "paste" and affect the visual object.
- Gels are generally multi-dose preparations, the addition of preservatives is essential, the stimulation and damage, and the combination of sodium hyaluronate and carbomer will greatly improve the pseudoplastic characteristics of the gel, making Kappa Mum has been sheared and thinned at a certain concentration.
- carbomer and sodium hyaluronate are used as a gel-based shield, and the polymer carbomer absorbs a large amount of water to form a semi-solid which is swollen and crosslinked, and can pass a covalent bond, hydrogen. Bond, van der Waals force, etc. cross-link with sodium hyaluronate, Cabo It is also resistant to autoclaving and maintains its release rate and appearance.
- An excellent ophthalmic gel matrix prepared by combining carbomer with sodium hyaluronate improves the bioavailability of the drug and reduces the stimulation and damage of the cornea by the bacteriostatic agent.
- Fig. 1 Time course of drug in tears after single-dose local administration of rabbit eyes: (State) Gatifloxacin eye drops group, ( ⁇ ) Gatifloxacin eye gel group.
- GTX represents Gatifloxacin.
- Fig. 2 Time course of drug in the cornea after single-dose local administration of rabbit eyes: ( ⁇ ) gatifloxacin eye drops group, ( ⁇ ) gatifloxacin eye gel group.
- Fig. 3 Time course of drug in aqueous humor after single-dose local administration of rabbit eyes: ( ⁇ ) Gatifloxacin eye drops group, (A) Gatifloxacin eye gel group.
- Fig. 4 Time course of three different gatifloxacin gel preparations in a single rabbit eye after topical administration in the cornea of rabbit eyes.
- Fig. 5 Time course of three different gatifloxacin gel preparations in a single rabbit eye after topical administration in rabbit aqueous humor. detailed description
- the invention generally and in the materials and test methods used in the test
- Gatifloxacin 4. 0g Carbomer 3. Og
- Preparation method Take the prescribed amount of carbomer and glycerin, add appropriate amount of water for injection, stir evenly, swell to form a gel matrix, and set aside. Take the prescription of triethanolamine and add appropriate amount of water for injection. Stir well and set aside. Take the prescription of gatifloxacin and add appropriate amount of injection. 7 Stir well and add propylene glycol. Mix the above three solutions. After filtering through 0.22 micron, add water to the full amount. Stir well and then fill. Comparative example 2
- Preparation method Take the prescribed amount of gatifloxacin, add appropriate amount of water for injection, stir to dissolve, take the prescribed amount of sodium hyaluronate into the above solution, swell, and then add the prescribed amount of benzalkonium bromide, sodium chloride and hydroxypropyl Base cyclodextrin, stirred and dissolved. Adjust the pH to 7 with boric acid, filter the solution through 0.22 ⁇ m, make up the water for injection to the full amount, stir evenly, and fill it.
- Test Example 1 Eye irritation test
- Drug-administered group Gatifloxacin ophthalmic gel prepared in Example 5
- Control group A blank control sample prepared by removing gatifloxacin was removed as in Example 5.
- Test method Four New Zealand rabbits were taken and the eyes of each animal were examined within 24 hours before the test. Animals with eye irritation, corneal defects and conjunctival injury could not be used for the test. Each animal's eyelashes were cut off, and each animal's right eye conjunctiva was dropped into a gatifloxacin ophthalmic gel solution, and an equal amount of blank sample was dropped into the left eye as a control. The nasolacrimal duct was compressed at each administration, and the rabbit eyes were passively closed for 10 seconds after administration, and then 2 % sodium fluorescein was added dropwise. The slit lamp was used to observe the local 1, 2, 4, 24, 48, and 72 hours after administration.
- the response was stimulated, and the cornea, iris, and conjunctiva were scored according to the scoring criteria (Table 1), and the average score was calculated.
- the administered eye was compared with the control eye, and the eye irritation of the drug was evaluated according to the criteria of Table 2.
- the results of the test face are shown in Table 3.
- test results show that this product is administered once and is not irritating to rabbit eyes.
- Test method Four New Zealand rabbits were taken and the eyes of each animal were examined within 24 hours before the test. Animals with eye irritation, corneal defects and conjunctival injury could not be used for the test.
- the administration method and the dose are the same as single administration, 6 times a day, 7 days of continuous administration, local irritant response before 1, 2, 4, 24, 48, 72 hours before and after the last administration.
- the cornea, the iris, and the conjunctiva were scored according to the scoring standard (Table 1), and the average score was calculated.
- the administered eye was compared with the control eye, and the eye irritation of the drug was evaluated according to the criteria of Table 2. The test results are shown in Table 4.
- Acetonitrile HPLC grade, batch number: 509124, TEDIA, USA
- methanol HPLC grade, batch number: UN1230, Merck, Germany
- dichloromethane chromatographically pure, Tianjin Comemi Chemical Reagent Development Center.
- Gatifloxacin reference substance content 97. 2%, China National Institute for Biological Products).
- Gatifloxacin ophthalmic gel (GTX-Gel) prepared by the method of Example 5. 1. 3 control drugs
- GTX-ED gatifloxacin eye drops
- Real sputum group (gel group): Gentified the gatifloxacin ophthalmic gel with a clean glass eye stick 0. 050g, gently apply it to the sacral conjunctiva on the side of the rabbit, gently close the sputum 30s;
- control group eye drops group: 50 ⁇ l of each of the rabbits' conjunctival sputum was added with a micro-sampler, and the sputum was gently closed for about 30 s.
- Each group was 5, 15, 30, 45, 60, 90, 120, 180, 240 after administration.
- the filter paper strips removed in the glass test tube were placed in the upper conjunctiva for 10 s, and the weight of the tears was accurately weighed out immediately.
- Using a topical anesthetic eye drop quickly use a 26G lmL injection needle to puncture the anterior chamber from the upper limbus, draw aqueous humor, and accurately draw the aqueous humor ⁇ into a stoppered centrifuge tube.
- Excessive sodium pentobarbital was injected into the ear vein, and the corneal tissue was taken out.
- the filter paper was blotted dry, placed in a glass test tube, accurately weighed, and all samples were stored at -60. Store in a refrigerator and thaw at room temperature before use for processing.
- Tear Add the mobile phase to the tube containing the tear filter strip, shake for 1 min, 4500 rpm, centrifuge for 15 min, and the supernatant can be injected into the liquid crystal.
- Corneal sample Take a precisely weighed cornea, cut into a test tube, add 1. OmL of water, use a tissue homogenizer (Fluko, Germany) 25000 rpm to grout lmin, take 200 ⁇ corneal sentence slurry, then add dichloro Methane 2. OmL, the rest of the treatment method is the same as the treatment of aqueous samples.
- the concentration of tears in the gatifloxacin ophthalmic gel group at each time point of 15 - 45 min was compared with the tifloxacin eye drops group by t-test. The results were significantly different (p ⁇ 0.05).
- the area under the drug concentration-time curve in tears from 0 to 360 min is:
- AUCGTX-Gel/AUCGTX-ED 1.2.
- Table 5 Drug concentration of gatifloxacin in rabbit tears, cornea and aqueous humor
- the concentration of the drug in the cornea after a single administration of gatifloxacin ophthalmic gel and gatifloxacin eye drops is shown in Table 5 and fig.
- the concentration of the drug in the cornea was maintained at 5-120 min, and the concentrations were 25.91 ⁇ 6.30, 30 ⁇ 63 ⁇ 12.32, 23.87 ⁇ 7.37, 14.53 ⁇ 5.31, 10.25 ⁇ 2.69, respectively. 10.04 ⁇ 3.10 and 7.42 ⁇ 1.79 g / g, respectively, the corresponding time points of the gatifloxacin eye drops group were 1.9, 2.3, 3.2, 2.1, 2.0, 3.1 and 2.1 times.
- the corneal drug concentration at each time point of 5 - 300 min and the gatifloxacin eye drops group were used for t-test, and the results were significantly different (p ⁇ 0.01).
- the drug concentration results in the aqueous humor after single administration of gatifloxacin ophthalmic gel and gatifloxacin eye drops are shown in Table 5 and fig. Gatifloxacin and the gel group reached a peak concentration at 90 min, which was 2.39 ⁇ 1.03 The gatifloxacin eye drops reached a peak concentration of 0.94 ⁇ 0.69 g/mL at 60 min. The gatifloxacin ophthalmic gel maintained a high concentration in the aqueous humor at 5-12 Omin, which was 3.8, 2.5, 4.4, 2.9, 1.9, 4.4 at the corresponding time points of the gatifloxacin eye drops group. And 2.5 times.
- the gatifloxacin ophthalmic gel group was significantly different from the gatifloxacin eye drops group at the time of 5 - 360 min except for 180 min, and there was a significant difference ( P ⁇ 0.05).
- the area under the drug concentration-time curve in 0-360 min of aqueous humor is:
- AUCGTX-Gel/AUCGTX-ED 2.8.
- Acetonitrile HPLC grade, batch number: 509124, TEDIA, USA
- Methanol HPLC grade, batch number: UN1230, Merck, Germany
- Dichlorodecane chromatographically pure, Tianjin Comemi Chemical Reagent Development Center.
- Gatifloxacin reference substance (content 97. 2%, China National Institute for Biological Products).
- Example 5 was prepared.
- the gatifloxacin ophthalmic gel was accurately weighed with a clean glass eye stick. 0. 050g, gently applied to the sacral conjunctiva on the side of the rabbit, and gently closed the sputum for about 30 s; each group was administered after administration. 5, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes, rinse the ocular surface with a large amount of normal saline (not less than 10ml per eye), dry cotton balls to wipe off residual liquid, quickly use 26G
- the ImL injection needle penetrates the anterior chamber from the upper limbus, draws aqueous humor, and accurately draws the aqueous humor into a test tube.
- the water is immersed in a room temperature of 100 ⁇ l, dichlorohydrin 2. 0 mL, vortexing Lmin, centrifuge at 3000 rpm for 5 min, discard the upper aqueous layer, and the organic layer at 40. Under C heating, dry with nitrogen, add 100 ⁇ L of mobile phase before the measurement, vortex for 1 min, 4500 rpm, centrifuge for 15 min, take the supernatant into HPLC, calculate the sample concentration according to the peak area external standard method. .
- Corneal sample Take a precisely weighed cornea, cut into a test tube, add 1. OmL of water, homogenize with a tissue homogenizer (Fluko, Germany) at 25000 rpm for 1 min, take 200 ⁇ corneal slurry, then add dichloropurine Alkane 2. OmL, the rest of the treatment method is the same as the treatment of aqueous samples.
- sample treatment the aqueous humor and corneal samples were treated separately. The supernatant was injected into HPLC, and the chromatogram and peak area were recorded. The external standard method was used to determine the tears and the room. Drug concentration in water and corneal samples.
- the peak time in the cornea of rabbits in group A, B and C was 15 min; the peak concentration was 36 ⁇ 28 ⁇ 8. 86 ⁇ 8/ ⁇ 1, respectively. 24. 35 ⁇ 3. 65 ⁇ 8 / ⁇ 1, 21. 69 ⁇ 6. 37 g / ml, wherein the peak concentration of group A was significantly higher than that of group B and C.
- the experimental group "the area under the drug concentration-time curve" (AUC. - 36 . rain )
- the maximum, 2867. 60 (g/ml) * min, was 1.36 times and 1.55 times of the B and C groups, respectively, indicating that the bioavailability of the group A in the cornea was higher than the other two groups.
- Min is the largest, consistent with the concentration of the drug in the cornea, which is 353.3% (ml)/min, which is 1, 45 times and 1.51 times of the B and C groups, respectively, indicating that the group A preparation is in the aqueous humor.
- the utilization rate is higher than the other two groups.
- the peak concentration of each group in the cornea was the highest in group A, followed by group B and group C.
- the bioavailability of each group in the cornea was highest in group A, followed by group B and group C.
- the peak concentration of each group in the aqueous water was the highest in group A, followed by group B and group C.
- the bioavailability of each group in aqueous water was highest in group A, followed by group B and group C. It is indicated that:
- the Gatifloxacin gel preparation of the experimental group A can be compared with other test preparations during the examination time. Rabbit corneal corneal tissue and aqueous humor reached higher concentrations, and the amount of drugs entering the cornea and aqueous humor was greater.
- the gatifloxacin ophthalmic gel prepared by the invention is combined with carbomer and sodium hyaluronate as a gel matrix; the test results show that the peak concentration in the cornea and aqueous humor is The bioavailability was significantly higher than that of the control drug group B (carbomer was used as the gel matrix alone) and the control drug group C (sodium hyaluronate alone as the gel matrix).
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Description
一种含加替沙星的眼用凝胶剂及其制备方法 技术领域
本发明属于药物制剂领域, 具体地, 涉及一种眼用制剂, 更 具体地, 涉及一种含有加替沙星的眼用凝胶剂及其制备方法。 本 发明还涉及一种治疗眼部感染的方法。 技术背景
加替沙星属于第四代氟喹诺酮类抗 @药, 由日本杏林公司研 制开发并转让给 BMS (Br i so卜 Myers Squibb)公司的广谱抗菌药 物。 1999年 12月本品口服和静脉注射剂获美国 FDA批准上市, 商品名为 Tequin。 Al lergan, Inc公司 3月 31 日宣称, FDA已批 准 0. 3%的 ZYMAR™ (加替沙星滴眼液)在美国上市。
加替沙星与前三代喹诺酮类药物相比, 主要有以下特点, 首 先, 对革兰氏阳性菌的抗菌活性较第一代至第三代品种强 2 ~ 16 倍至 32倍; 第二, 本品对氨基糖苷类、 大环内酯类等其他抗生素 有耐药的病原菌有很强的抑制作用, 而且加替沙星与这些抗生素 之间无交叉耐药性; 加替沙星对衣原体、支原体等有很强的活性; 最后,加替沙星由于在 C8上引入了甲氧基基团,从而克服了光毒 等副作用, 化学结构稳定, 安全性也大大提高。
中国专利申请公开 CN1448137A (申请号: 03113340. 1 ; 公开 日: 2003年 10月 15 日)公开了一种以加替沙星为主要成份, 辅 以壳聚糖为凝胶基质及等渗调节剂、 pH调节剂、 防腐剂、 灭菌注 射用水等, 制成的外用凝胶及眼用凝胶剂型, 其中加替沙星的含 量为 0. 1 % -3 % (重量), 壳聚糖的含量为 0. 3 % -3 % (重量); 该发 明既具有显著的抗感染功能, 又具有加速创伤愈合、 促进上皮生
长和抑制疤痕组织形成及緩释、 长时间维持局部治疗药物浓度等 功能; 并且可用于治疗烧烫伤、 皮肤感染、 毛嚢炎、 疖肿、 脓疱 病、 外伤感染、 湿疹感染、 妇科阴道炎、 宫颈炎和眼科细菌性结 膜炎、 角膜炎、 角膜溃疡、 眼部手术后预防感染和促进伤口愈合 及病毒性結、 角膜炎、 干燥性结、 角膜炎等疾病。 中国专利申请 公开 CN1562030A (申请号: 200410020427. 4; 公开日: 2005年 1 月 12日)公开了一种以 HPMC为基质的加替沙星眼用凝胶剂及其制 备方法, 以加替沙星为活性物质, 以亲水性高分子材料羟丙基甲 基纤维素(HPMC)为基质, 同时加入防腐剂、 等渗调节剂、 渗透促 进剂、 pH调节剂及水而制得。将加替沙星溶解于水,再加入基质、 防腐剂、 等渗调节剂、 渗透促进剂搅拌溶解, 用 pH 调节剂调节 pH为 5-9, 溶液通过微孔滤膜过滤再从滤器上加水至总量; 该制 剂适用于治疗眼睑炎、 麦粒肿、 结膜炎、 泪嚢炎、 角膜炎、 角膜 溃疡、 沙眼等眼部感染; 据报导, 该凝胶剂为流动的半固体, 使 用方便, 在眼内停留时间长, 不易流失, 能维持有效治疗浓度, 增强治疗效果, 且毒性低、 刺激性小。 然而以上公知技术在提高 药物疗效、延长滞留时间、 降低对眼的刺激性等方面仍有待改善。
因此, 本领域仍然需要有新的加替沙星眼用制剂特别是眼用 凝胶剂以克服现有加替沙星眼用制剂的缺陷。 发明内容
本发明人发现,加替沙星与优良的水性基质卡波姆可以制成的 透明的卡波姆眼用凝胶,克服了传统滴眼剂的药物流失引起的生物 利用度低及通过鼻泪管流入口导致患者顺应性差的问题,但是由于 制剂中需要加入防腐剂而使制剂对角膜会产生刺激性和损害。
本发明的目的在于提供一种适合临床应用的含有抗菌药加替
沙星的眼用凝胶剂。 本发明人令人惊奇地发现, 将玻璃酸钠与卡波 姆组合作为基质制备加替沙星眼用凝胶剂, 可以有效改善制剂的性 能例如降低制剂对眼角膜的局部刺激性。本发明基于上述发现而得 以完成。
为此, 本发明第一方面提供了一种眼用凝胶剂, 其包含治疗有 效量的加替沙星或其药用盐、 基盾和水, 其中基质为卡波姆、 卡波 姆与羟丙甲纤维素混合物、 玻璃酸钠等一种或多种的混合物。 其中 玻璃酸钠与上述基质组合制备加替沙星眼用凝胶剂。
根据本发明第一方面任一项的眼用凝胶剂,其包含治疗有效量 的加替沙星或其药用盐、 卡波姆、 玻璃酸钠、 和水。
根据本发明第一方面任一项的眼用凝胶剂,按该凝胶剂的重量
/体积百分数计, 其中包含:
加替沙星或其药用盐 0. 01-2. 0%, 卡波姆 0. 01-10. 0%, 水 适 , 加至 100%。
根据本发明第一方面任一项的眼用凝胶剂 按该凝股剂的重-
/体积百分数计, 其中包含:
加替沙星或其药用盐 0. 01-2. 0%, 卡波姆 0. 05-4. 0%, 羟丙甲纤维素 0. 05-4. 0% 水 适量 加至 100%。
根据本发明第一方面任一项的眼用凝胶剂 按该凝股剂的重-
/体积百分数计, 其中包含:
加替沙星或其药用盐 0. 01-2. 0%, 卡波姆 0. 01-10%, 玻璃酸钠 0. 005-1. 0%, 水 适量, 加至 100%。
根据本发明第一方面任一项的眼用凝胶剂,按该凝胶剂的重-
/体积百分数计, 其中包含:
加替沙星或其药用盐 0.01-2.0%, 卡波姆 0.01-2.0%, 玻璃酸钠 0.005-0.5%, 水 适: , 加至画。
根据本发明第一方面任一项的眼用凝胶剂 按该凝胶剂的重量
/体积百分数计, 其中包含:
加替沙星或其药用盐 0.01-2.0%, 卡波姆 0.1-1.0%, 玻璃酸钠 0.01-0.1%, 水 适: , 加至 100%。
根据本发明第一方面任一项的眼用凝胶剂 按该凝胶剂的重量
/体积百分数计, 其中包含:
加替沙星或其药用盐 0.1-2.0%, 卡波姆 0.1-1.0%, 玻璃酸钠 0.01-0.1%, 水 适: , 加至画 0 根据本发明的任一项眼用凝聚剂, 按该凝胶剂的重量 /体积百 分数计, 具体地, 所述加替沙星或其药用盐的含量为 0.1-2.0%, 更 具体地, 为 0.1-1.0%, 进一步具体地, 为 0.1-0.5, 更进一步具体 地, 为 0.1-0.3%或 0· 1-0.2%, 例如: 0.1%、 0.15°/。、 0.2%、 0.25%、 或 0.3%。
根据本发明的任一项眼用凝聚剂 , 按该凝胶剂的重量 /体积百 分数计, 具体地, 所述卡波姆的含量为 0.01-2.0%, 更具体地, 为 0.1-1.0%,进一步具体地,为 0.1-0.5%,例如 0.1%、 0.15 %、 0.2¾、 0.25%, 0.3%、 0.35%、 0.4%、 0.45%、 或 0.5%。
根据本发明的任一项眼用凝聚剂, 按该凝胶剂的重量 /体积百 分数计, 具体地, 所述玻璃酸钠的含量为 0.005-0.5%, 更具体地,
为 0. 01-0. 1%,进一步具体地,为 0. 01-0. 06%,例如: 0. 01%、 0. 02%、 0. 03%, 0. 04%, 0. 05%、 或 0. 06 %。
根据本发明第一方面任一项的眼用凝胶剂,按该凝胶剂的重量
/体积百分数计, 其中包含:
加替沙星或其药用盐
卡波姆
羟丙曱纤维素
玻璃酸钠
水
根据本发明第一方面任一项的眼用凝胶剂, 其中还含有 pH值 调节剂。 在本发明第一方面眼用凝胶剂的一个实施方案中, 所述的 pH值调节剂选自硼酸、 硼砂、 氢氧化钠、 盐酸、 磷酸盐緩冲溶液、 醋酸盐緩沖溶液等中的任一种或者为它们的混合物。 根据本发明, 所述的 pH值调节剂在制剂中的使用量会因多种因素而改变, 所述 因素例如 pH值调节剂类型及其强度、 处方组成、 药物和制剂的物 理和化学稳定性等, 本领域技术人员理解, 该 pH值调节剂在本发 明凝胶剂中的量可以容易地根据希望调节的目标 pH值来确定, 例 如在希望的目标 pH值为 6. 5-7. 5的情况下, 在混合了大部分的物 料特别是除水以外的所有处方成分之后, 在制剂定容 (到最终重量 和 /或体积)之前, 用适宜量的 pH值调节剂对制剂进行 pH值调节, 由此可以容易地确定 pH值调节剂在制剂中的具体用量。 在本发明 第一方面眼用凝胶剂的一个实施方案中, 所述眼用凝胶剂的 pH值 为 4. 5-9. 5, 优选的 pH值为 5. 5-8. 5, 更优选的 pH值为 6. 0-8. 0, 再更优选的 pH值为 6. 0-7. 5。
根据本发明第一方面任一项的眼用凝胶剂, 其中还含有渗透压 调节剂, 可用于本发明渗透压调节剂的实例包括但不限于丙二醇、 甘油、 氯化钠和甘露醇等中的一种或它们的混合物。 根据本发明,
所述的渗透压调节剂在制剂中的使用量会因多种因素而改变,所述 因素例如渗透压调节剂类型及其强度、 处方组成、 药物和制剂的物 理和化学稳定性等, 本领域技术人员理解, 该渗透压调节剂在本发 明凝胶剂中的量可以容易地根据希望调节的目标渗透压来确定, 例 如在希望的目标渗透压为与体液基本上等渗或稍高渗的情况下, 在 混合了大部分的物料特别是除水以外的所有处方成分之后,在制剂 定容 (到最终重量和 /或体积)之前, 用适宜量的渗透压调节剂对制 剂进行渗透压调节, 由此可以容易地确定渗透压调节剂在制剂中的 具体用量。 在一个实施方案中, 本发明的眼用凝胶剂大体上含有
0-15. 0% (w/v)、 优选 0. 01-10% (w/v)、 更优选 0. 01-5% (w/v)、 再 更优选 0. 05-2% (w/v)的渗透压调节剂。此外,还可才艮据已有的物理 化学知识通过理论计算来初步确定渗透压调节剂在制剂中的用量, 例如, 在以氯化钠为渗透压调节剂的情况下, 氯化钠在制剂中的浓 度在 0. 85%- 0. 95% (w/v) , 优选 0. 88-0. 92% (w/v) , 更优选约 0. 9% (w/v)时是比较合适的。 其它类型的渗透压调节剂也可容易地 通过理论与实践结合而由本领域技术人员容易地确定。
根据本发明第一方面任一项的眼用凝胶剂, 其中还含有一种或 多种选自以下的抑菌剂: 苯乙醇、 苯氧乙醇、 对羟基苯甲酸曱酯、 对羟基苯甲酸乙酯、 对羟基苯甲酸丙酯、 苯扎氯铵、 三氯叔丁醇、 苯扎溴铵、 西曲溴铵。 在进一步的实施方案中, 所述的抑菌剂是选 自苯氧乙醇、 对羟基苯曱酸乙酯、 苯扎氯铵、 三氯叔丁醇中的一种 或多种。 在再进一步的实施方案中, 所述的抑菌剂是苯氧乙醇和对 羟基苯曱酸乙酯的组合。 在更进一步的实施方案中, 所述的抑菌剂 占该滴眼液总量的 0. 005 ~ 1% (w/v)„ 优选的, 所述的抑菌剂占该 滴眼液总量的 0. 01 ~ 0. 5% (w/v)。 优选的, 所述的抑菌剂占该滴眼 液总量的 0. 1 ~ 0. 5% (w/v) 0 优选的, 所述的抑菌剂占该滴眼液总
量的 0. 01 ~ 0. 1% (w/v)。 优选的, 所述的抑菌剂占该滴眼液总量的 0. 01、 0. 1、 或 0. 5% (w/v)
根据本发明第一方面任一项的眼用凝胶剂, 其中还含有一种或 多种选自以下的表面活性剂: 吐温类、 聚氧乙烯氢化蓖麻油类、 和 聚氧乙烯蓖麻油类, 例如但不限于吐温- 80、 吐温 -60、 吐温 -85、 吐温 -65、 聚氧乙烯 60氢化蓖麻油等。 在一个实施方案中, 本发明 的眼用凝胶剂含有 0. 001-10% (w/v) , 优选 0. 01-5% (w/v)、 更优选 0. 01-2% (w/v)、 再更优选 0. 01-1% (w/v)的表面活性剂。
本发明第二方面提供了一种眼用制剂,其包含本发明第一方面 任一项所述的眼用凝 剂, 该眼用制剂也可以制备成为一种新的眼 用即型凝胶,该眼用凝胶剂可以用氯化钠溶液或氯化钙溶液调整其 粘度,在眼睛生理环境中发生相转变,以获得某种临床适用的效果。
本发明第三方面提供了本发明第一方面任一项所述眼用凝胶 剂的制备方法, 其包括将高分子卡波姆或卡波姆和羟丙曱纤维素与 玻璃酸钠用适量的水溶胀完全后,将其他组分用水溶解后加入至凝 胶基质中形成凝胶基质, 并搅拌均匀, 和璀装的步骤。
本发明第三方面提供了本发明第一方面任一项所述眼用凝胶 剂的制备方法, 其包括以下步骤:
i)使高分子基质 (例如卡波姆)用适量水溶胀, 溶解, 灭菌, 备用; 玻璃酸钠用适量水溶胀, 备用;
i i)用适量水与加替沙星和玻璃酸钠溶液混合, 加入任选的表 面活性剂和渗透压调节剂, 使所得混合物溶解;
i i i)将任选的抑菌剂和 pH调节剂溶解于适量水中;
iv)使以上 i i)和任选的 i i i)所得的物料混合, 经微孔滤膜过 滤,加至 i)项溶液中, 补加水至处方全量,搅拌均勾, 濯装, 即得。
在本发明第三方面制备方法的一个实施方案中,可以按如下步
骤制备含有加替沙星的眼用凝胶剂:取卡波姆基质用适量注射用水 溶胀, 静置; 临用前灭菌 121。C , 30分钟以上; 取适量注射用水将 辅料等加入溶解; 取增溶剂, 热融后加入, 加入渗透压调节剂, 过 滤 0. 22微米除菌, 滤液加入至胶相中, 另取水适量, 取主药加入 溶解, 经 0. 22微米过滤除菌加入, 搅拌均匀, 调整 pH值后, 补注 射用水至全量, 搅拌使成均 透明凝胶。
根据本发明方法可以制得的含有加替沙星的眼用凝胶剂,其外 观澄明、 无菌、 刺激性低、 毒性低, 可以为临床提供一种安全、 有 效的眼用制剂。
本发明的还一方面涉及一种治疗眼部感染的方法, 包括给与有 效量的本发明的眼用凝胶剂的步骤; 具体地, 所述眼部感染为眼睑 炎、 麦粒肿、 结膜炎、 泪嚢炎、 角膜炎、 角膜溃疡、 或沙眼。
下面对本发明的各个方面以及它们的益处作进一步的描述。 如本文所用的, 短语"按该凝胶剂的重量 /体积百分数计 "是指 以该凝胶剂 100ml计, 其中所包含的组分的重量克数即为该重量 / 体积百分数, 即通常所表示的 g/100ml, 或表示为%^^)。 在本发 明中, 如未另有指明, %均为重量 /体积百分数。
本发明的眼用凝胶剂为一种水性组合物,其中使用水作为该组 合物的介质或溶媒或赋形剂或载体。尽管本发明的滴眼液没有具体 指出所用的水占滴眼液总重量的百分数, 或者在配制本发明滴眼液 时没有具体指出所用水的量, 但是, 本领域技术人员清楚, 作为滴 眼用制剂的介质或溶媒或赋形剂或载体, 该水的量是以水加至眼用 凝胶剂全量来计算的, 这在液体制剂例如滴眼液、 注射液或本发明 的眼用凝胶剂的配制过程中一般采用的计量方式。
在本发明的眼用凝胶剂中, 所述的抑菌剂可以是一种或多种的 任意组合。 在一个实施方案中, 所述的抑菌剂是苯氧乙醇和对羟基
苯甲酸乙酯的组合; 在进一步的实施方案中, 所述的抑菌剂是苯氧 乙醇和对羟基苯曱酸乙酯以任意比例的组合; 在再进一步的实施方 案中, 所述的抑菌剂是苯氧乙醇和对羟基苯甲酸乙酯以重量比 50: 1的比例组合。 在一个实施方案中, 所述的抑菌剂是苯氧乙醇和苯 扎氯铵的组合; 在进一步的实施方案中, 所述的抑菌剂是苯氧乙醇 和苯扎氯铵以任意比例的组合; 在再进一步的实施方案中, 所述的 抑菌剂是苯氧乙醇和苯扎氯铵以重量比 50: 1的比例组合。 在一个 实施方案中, 所述的抑菌剂是三氯叔丁醇和苯扎氯铵的组合; 在进 一步的实施方案中, 所述的抑菌剂是三氯叔丁醇和苯扎氯铵以任意 比例的组合; 在再进一步的实施方案中, 所述的抑菌剂是三氯叔丁 醇和苯扎氯铵以重量比 10: 1的比例组合。 在一个实施方案中, 所 述的抑菌剂是三氯叔丁醇和对羟基苯曱酸乙酯的组合; 在进一步的 实施方案中, 所述的抑菌剂是三氯叔丁醇和对羟基苯曱酸乙酯以任 意比例的组合; 在再进一步的实施方案中, 所述的抑菌剂是三氯叔 丁醇和对羟基苯曱酸乙酯以重量比 10: 1的比例组合。
根据本发明,玻璃酸钠与卡波姆为基质制成的眼用凝胶剂为假 塑性流体, 具有与人类泪液功能类似的性质, 在瞬目时制剂的本身 粘度急剧降低, 不眨眼时, 制剂恢复其粘性, 延长药物在眼表的滞 留时间,这种性质使得本发明的眼用凝胶剂不会引起"糊视"而影响 视物。 凝胶剂一般为多剂量制剂, 防腐剂的加入是必不可少的, 本 刺激和损害, 而且玻璃酸钠与卡波姆的联合使用, 会大大改善凝胶 剂的假塑性特征, 使得卡波姆在一定浓度时更已被剪切稀化。
不受理论的限制,本发明中使用卡波姆与玻璃酸钠合用作为凝 胶基盾, 高分子卡波姆吸收大量水分后形成的溶胀交联状态的半固 体, 可通过共价键、 氢键、 范得华力等方式与玻璃酸钠交联, 卡波
姆还可以耐受热压蒸汽灭菌, 并且保持其释药速率及外观形状不 变。 让卡波姆与玻璃酸钠合并使用制的一种优良的眼科用凝胶基 质, 提高了药物的生物利用度, 降低抑菌剂对角膜的刺激和损害。
本发明提供的含有加替沙星的眼用凝胶剂与加替沙星滴眼液 进行的药效学比较中惊喜的发现: 在同等浓度的两制剂给药过程 中, 测量兔眼内加替沙星水平。 眼用凝胶剂给药后兔眼内药物浓度 要显著高于相同给药浓度的滴眼液。 即在达到同等治疗效果的情况 下, 本发明提供的眼用凝胶剂中加替沙星的浓度可以更小, 达到了 减小药物的毒副作用的目的。 附图说明
Fig. 1:兔眼单剂量局部给药后药物在泪液中的经时过程: (國) 加替沙星眼滴眼液组, (▲) 加替沙星眼凝胶组。 图中 GTX表示加 替沙星。
Fig. 2: 兔眼单剂量局部给药后药物在角膜中的经时过程: (■) 加替沙星眼滴眼液组, (▲) 加替沙星眼凝胶组。
Fig. 3: 兔眼单剂量局部给药后药物在房水中的经时过程: (■) 加替沙星眼滴眼液组, (A) 加替沙星眼凝胶组。
Fig. 4: 三种不同的加替沙星凝胶制剂单次兔眼局部给药后药 物在兔眼角膜中的经时过程。
Fig. 5: 三种不同的加替沙星凝胶制剂单次兔眼局部给药后药 物在兔眼房水中的经时过程。 具体实施方式
下面通过具体的实施例进一步说明本发明, 但是, 应当理解 为, 这些实施例仅仅是用于更详细具体地说明之用, 而不应理解
为用于以任何形式限制本发明。
本发明对试验中所使用到的材料以及试验方法进行一般性和
/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作 方法是本领域公知的, 但是本发明仍然在此作尽可能详细描述。 本领域技术人员清楚, 在下文中, 如果未特别说明, 本发明所用 材料和操作方法是本领域公知的。
1. Og
2. Og
20. Og
15. 6g
5. Og
0. 2g
补充至 1000ml 取处方量的卡波姆, 加入适量注射用水, 溶胀, 灭菌后备用; 取适量注射用水, 加入处方量的苯扎溴铵溶解, 加入硼砂形成抑 菌剂溶液; 另取处方量的聚氧乙烯 60氢化蓖麻油, 加入甘油, 相 互混溶, 与加替沙星混合均勾后, 再与抑菌剂溶液混合均匀, 经 0. 22微米过滤后加入至卡波姆中; 补注射用水至全量, 搅拌均匀 后, 濯装即可。 实施例 2
处方:
加替沙星 4. 0g
卡波姆 3. Og
2. Og
射替璃苯氧温油波丙 、 20. Og
15. 6g
钠钠星^水酯
吐温 5. Og
苯扎溴铵 素 0. 2g
注射用水 补充至 1000ml
制备工艺:
取处方量的卡波姆,羟丙甲纤维素,加入适量注射用水,溶胀, 灭菌后备用; 取适量注射用水, 加入处方量的苯扎溴铵溶解, 加入 硼酸形成抑菌剂溶液; 另取处方量的吐温, 加入甘油, 相互混溶, 与加替沙星混合均匀后, 再与抑菌剂溶液混合均匀, 经 0. 22微米 过滤后加入至卡波姆中; 补注射用水至全量, 搅拌均勾后, 灌装即 可。
4. 0g
3. 0g
0. lg
2. Og
8. Og
15. 6g
5. Og
0. 2g
补充至 1000ml
制备工艺:
取处方量的卡波姆、羟丙甲纤维素,加入适量注射用水,溶胀,
灭菌后备用; 取玻璃酸钠加入适量注射用水, 溶胀后备用; 取适量 注射用水, 加入处方量的羟苯乙酯溶解, 加入氢氧化钠形成抑菌剂 溶液; 另取处方量的吐温, 加入甘油, 相互混溶, 与加替沙星, 玻 璃酸钠溶液混合均匀后, 再与抑菌剂溶液混合均匀, 经 0. 22微米 过滤后加入至卡波姆中; 补注射用水至全量, 搅拌均匀后, 灌装即 可。 实施例 4
处方:
加替沙星 3. Og
卡波姆 4. Og
氯化钙 0. 30g
玻璃酸钠 0. 2g
氢氧化钠 8. Og
丙二醇 16. Og
羟苯乙酯 0. 2g
注射用水 补充至 l QOOml
制备工艺:
取处方量的卡波姆, 加入适量注射用水, 溶胀, 灭菌后备用; 取玻璃酸钠加入适量注射用水, 溶胀后备用; 取适量注射用水将氯 化钙溶解, 加入处方量的羟苯乙酯溶解, 加入氢氧化钠形成抑菌剂 溶液; 另取处方量丙二醇, 相互混溶, 与加替沙星, 玻璃酸钠溶液 混合均匀后, 再与抑菌剂溶液混合均匀, 经 0. 22微米过滤后加入至 卡波姆中; 补注射用水至全量, 搅拌均勾后, 灌装即可。
处硼加硼加玻羟玻羟卡卡注注丙丙 3. 5g
^砂射砂射替替璃二璃二苯苯波波 、 0. 6g
姆姆用用酸醇^醇沙沙乙乙
納納水星水星醋醋 9. Og
11. Og
0. 2g
补充至 1000ml
制备工艺:
取处方量的卡波姆, 加入适量注射用水, 溶胀, 灭菌后备用; 取玻璃酸钠加入适量注射用水, 溶胀后备用; 取适量注射用水, 加 入处方量的羟苯乙酯溶解, 加入硼砂形成抑菌剂溶液; 另取处方量 丙二醇, 相互混溶, 与加替沙星, 玻璃酸钠溶液混合均勾后, 再与 抑菌剂溶液混合均匀, 经 0. 22微米过滤后加入至卡波姆中; 补注射 用水至全量, 搅拌均匀后, '灌装即可。 实施例 6
1. Og
2. Og
0. 5g
20. Og
15. 6g
0. 3g
补充至 l QOOml
制备工艺:
取处方量的卡波姆, 加入适量注射用水, 溶胀, 灭菌后备用; 取玻璃酸钠加入适量注射用水, 溶胀后备用; 取适量注射用水, 加 入处方量的羟苯乙酯溶解, 加入硼砂形成抑菌剂溶液; 另取处方量
丙二醇, 相互混溶, 与加替沙星, 玻璃酸钠溶液混合均匀后, 再与 抑菌剂处硼加对对玻吐卡氯注溶液混合均匀, 经 0. 22微米过滤后加入至卡波姆中; 补注射
^化砂射替璃羟羟温波 、
用水至全量姆基基钠 T用酸沙, 搅拌均勾后, 灌装即可。
钠苯苯水星 G
甲曱
实施例 7 酸酸
丙乙
西酉
0. 5g
lg
0. lg
0. Olg
0. 02g
制备工艺:
取处方量的卡波姆, 加入适量注射用水, 溶胀, 灭菌后备用; 取玻璃酸钠加入适量注射用水, 溶胀后备用; 取适量注射用水, 加 入处方量的羟苯乙酯和羟苯丙酯溶解,加入硼 、适量形成抑菌剂溶 液; 另取处方量氯化钠、 加替沙星、 玻璃酸钠溶液和吐温以及适量 水, 混合均匀, 使溶解, 再与抑菌剂溶液混合均匀, 经 0. 22微米过 滤后加入至卡波姆中; 用适量硼酸(必要时可用适量氢氧化钠)调节 pH至约 7. 0, 补注射用水至全量, 搅拌均勾后, 灌装即可。
本领域技术人员可以理解, 尽管实施例 1-7中各组分的重量 单位是 g, 但是也可以理解为重量份, 即各组分之间分别满足实 施例 1-7中的处方中的比例就可以。
对照例 1
处方:
加替沙星 3g
丙二醇 90g
甘油 100g
卡波姆 10g
三乙醇胺 15g
注射用水 补充至 1000ml
制备方法: 取处方量卡波姆和甘油, 加入适量注射用水, 搅拌 均匀, 溶胀形成凝胶基质, 备用。 取处方量三乙醇胺加入适量注射 用水搅拌均匀 , 待用。 取处方量加替沙星加入适量注射用 7 搅拌均 匀后加入丙二醇, 将以上三种溶液混合, 经 0. 22微米过滤后补注 射用水至全量, 搅拌均勾后, 灌装即可。 对照例 2
处方:
加替沙星 3g
玻璃酸钠 2. 5g
苯扎氯铵 0. Olg
氯化钠 1. 5g
羟丙基 环糊精 3. 5g
硼酸 调节 pH为 7
注射用水 补充至 1000ml
制备方法: 取处方量的加替沙星加入适量注射用水, 搅拌使溶 解, 取处方量的玻璃酸钠加入上述溶液中, 溶胀, 依次加入处方量 的苯扎溴铵、 氯化钠及羟丙基 环糊精, 搅拌溶解。 用硼酸调节 pH至 7, 溶液经 0. 22微米过滤, 补注射用水至全量, 搅拌均匀后, 灌装即可。
试验例 1 : 眼刺激性试验
一、 材料
1.受试药物:
给药组: 釆用实施例 5制备的加替沙星眼用凝胶剂
对照组: 按实施例 5中除去加替沙星制备的空白对照样品。
2.动物:
家兔, 日本大耳白种, 体重 2. 6 ~ 3. Okg, 雌雄兼用, 由沈阳市 双义实验动物研究所提供。
二、 实验方法与结果:
1. 单次给药眼刺激试验
试验方法: 取新西兰种家兔 4只, 试验前 24小时内对每只动物 的双眼进行检查, 有眼睛刺激症状、 角膜缺陷和结膜损伤的动物不 能用于试猃。 将每只动物眼睫毛剪去, 将每只动物右眼结膜袭内滴 入加替沙星眼用凝胶剂 1滴, 左眼滴入等量的空白样品作为对照。 每次给药时压迫鼻泪管, 给药后让兔眼被动闭合 10秒, 然后滴入 2% 荧光素钠用裂隙灯观察给药后 1、 2、 4、 24、 48、 72小时的局部刺 激反应情况, 按照评分标准(表 1 )对角膜、 虹膜及结膜分别进行 评分, 算出平均分值, 给药眼与对照眼进行比较, 根据表 2标准评 价药物的眼刺激性。 试脸结果见表 3.
表 1 : 眼刺激反应评
眼刺激反应 分值 角膜混浊 (以〕 1:致密部位为准):
无混浊 0 散在或弥漫, |±混浊, 虹膜清晰可见 1 半透明区易分辨, 虹膜模糊不清 2 出现灰白色透明区, 虹膜细节不清, 瞳孔大小勉强看清 3
总积分 16 表 2: 眼刺激性评价标准
刺激激性 积分 无刺激性 0- -3 轻度刺激性 4—8 中毒刺激性 9- -12 强度刺激性 13- -16 次给药眼刺激试验检查结果(X±SD )
组别 动物数 ( n ) 刺激得分 对照组 4 0
给药组 4 0. 5
试验结果表明本品一次给药, 对家兔眼睛无刺激性。
2.多次给药对兔眼刺激性的观察
试验方法: 取新西兰种家兔 4只, 试验前 24小时内对每只动物 的双眼进行检查, 有眼睛刺激症状、 角膜缺陷和结膜损伤的动物不 能用于试验。 给药方法及剂量同单次给药, 每日给药 6次, 连续给 药 7日, 每日给药前及末次给药后 1、 2、 4、 24、 48、 72小时的局部 刺激反应情况, 按照评分标准(表 1 )对角膜、 虹膜及结膜分别进 行评分, 算出平均分值, 给药眼与对照眼进行比较, 根据表 2标准 评价药物的眼刺激性。 试验结果见表 4。
表 4: 多次给药眼刺激试验检查结果( X±SD )
组别 动物数 ( n ) 刺激得分 对照组 4 0
给药组 4 0
观察结果表明每次给药后家兔眼睛均无异常。 评分结果: 眼刺 激综合评分均为零,表明加替沙星眼用凝胶多次给药对兔眼无刺激 性。
三、 结论:
结果表明: 给药后给药组各只动物各时间点均未发现受试药物 对受试动物眼有明显刺激作用。对照组各只动物各时间点也未发现 给予赋形剂后对受试动物眼有明显刺激作用。 眼刺激性评价为无刺 激性。 各组各只动物给药及观察期间均未见烦躁、 嗜睡等异常行为 活动。
试猃例 2: 加替沙星眼用凝胶剂兔眼生物利用度研究
测定加替沙星眼用凝胶兔眼单次给药后不同时间的泪液、角膜 及房水中的药物浓度, 同时与加替沙星滴眼液兔眼单次给药后对应 时间点的药物浓度比较, 并比较眼部相对生物利用度。
1. 材料
1. 1主要试剂
乙腈(HPLC级,批号: 509124, TEDIA公司, 美国); 甲醇(HPLC 级, 批号: UN1230, Merck公司, 德国); 二氯甲烷(色谱纯, 天津 科密欧化学试剂开发中心) 。 加替沙星对照品 (含量 97. 2%, 中国 生物制品检定所) 。
1. 2实验药物
釆用实施例 5方法制备的加替沙星眼用凝胶剂 (GTX-Gel ) 。 1. 3对照药物
市售加替沙星滴眼液(GTX-ED, 规格: 0. 3% )
1. 4动物及分组
日本大耳白兔, 健康、 无眼疾, 雄性, 体重 2 ~ 2. 5kg (河南省 实验动物中心提供, 合格证号: SCXK (豫) 2005-0002 ) 。 完全随机 化分成实验组与对照组, 每组各 44动物, 每组动物随机分成 11个亚 组, 每亚组 4只动物共 8眼。
1. 5 给药及釆样
实猃组(凝胶组): 用洁净玻璃点眼棒精密称取加替沙星眼用 凝胶 0. 050g, 一次性轻轻涂入家兔下睑结膜嚢颞侧, 轻轻闭合双睑 约 30s;
对照组(滴眼液组): 用微量取样器分别给家兔双眼结膜嚢内 滴加替沙星滴眼液各 50μ1, 轻轻闭合双睑约 30s。
各组分别于给药后 5、 15、 30、 45、 60、 90、 120、 180、 240、
300和 360分钟用在玻璃试管内除皮的滤纸条置于上结膜嚢内 10s , 取出立即精密称取泪液的重量。 用表面麻醉剂滴眼, 迅速用 26G的 lmL注射针从上方角膜缘刺入前房, 抽取房水, 精密吸取房水 Ι ΟΟμΙ 置于具塞离心试管中。 耳缘静脉注射过量戊巴比妥钠, 处死, 剖取 角膜组织, 滤纸吸干水分, 置玻璃试管中, 精密称重, 所有样品均 储存于 -60。C冰箱内保存, 使用前室温解冻, 以备处理测定。
1. 6 样品的处理
泪液: 在盛吸有泪液滤纸条的试管内加入流动相, 振荡 lmin, 4500rpm, 离心 15min, 上清液即可注入液相色 i普仪中。
房水: 精密吸取房水 100μ1, 加入二氯甲烷 2. GmL, 涡旋振荡 lmin, 3000rpm离心 5min, 弃上层水层, 取下层有机层, 在 40。C加 热下, 以氮气吹干, 测定前精密加入流动相, 涡旋振荡 lmin , 4500rpm, 离心 15min,取上清液注入 HPLC中,按峰面积外标法计算, 求得样品药物浓度。
角膜样品:取精密称重的角膜,剪碎置于试管中,加入水 1. OmL, 用组织匀浆器(Fluko,德国 ) 25000rpm的转速勾浆 lmin,取 200μί 角膜句浆液, 然后加入二氯甲烷 2. OmL, 其余处理方法同房水样品 的处理。
1. 7 样品测定: 按 "样品的处理" 项下分别对泪液、 房水及角 膜样品进行处理后, 取上清液注入 HPLC中, 记录色谱图与峰面积, 外标法定量, 求得泪液、 房水及角膜样品中的药物浓度。
2. 结果
2. 1加替沙星眼用凝胶与加替沙星滴眼液的兔眼药动学分析及 眼部相对生物利用度
2. 1. 1 加替沙星眼用凝胶与加替沙星滴眼液在兔眼泪液中经 时过程
加替沙星眼用凝胶与加替沙星滴眼液单次给药后泪液中药物 浓度结果见表 5及 fig.1。 加替沙星眼用凝胶组在 15、 30和 45 和时 泪液中的药物浓度分别为 581.83 ±261.19、 147.46 ± 79.84和 87.07 土 88.87μδ/8,分别是替沙星滴眼液组对应时间点的 2.5、 3.4和 10.7 倍。 加替沙星眼用凝胶组在 15 - 45min各时间点的泪液药物浓度与 替沙星滴眼液组作 t-检验, 结果有显著性差异(p<0.05)。 在 0- 360min的泪液中药物浓度-时间曲线下面积为:
AUCGTX-Gel/AUCGTX-ED =1.2。
表 5: 加替沙星在兔眼泪液、 角膜和房水中的药物浓度
泪液中药物浓度 角膜中药物浓度 房水中药物浓度 时间 滴眼液组 凝肢组 滴眼液组 凝胶组 滴眼液组 凝胶组
(min) ( ml) ( ml) ml) ml) /ml) /ml)
(x 士 s) (x ± s) (x 土 s) (x 土 s) (x 士 s) (x ±s)
2543.11 1864.85 13.56 25.91 0.09 0.34
5
士 2231.39 土 636.70 ± 2.16 士 6.30** ±0.06 土 0.31*
581.63
124.17 0.35 0.89
15 -工μ 13.29 30.63
土 127.52 ±5.92 士 12.32** ±0.44 土 0.27*
261.19**
43.95 147.46 7.46 23.87 0.47 2.09
30
± 55.22 土 79.85** ±2.05 士 7.37** ±0.21 士 0.70**
8.12 87.07 6.80 14.53 0.81 2.33
45
±3.11 土 88.87* ±2.74 ±5.31** ±0.49 ±1.01**
9.31 10.53 5.04 10.25 0.94 1.80
60
±9.50 ±6.09 土 1.62 ±2.69** ±0.69 ± 0.89*
3.00 8.24 3.23 10.04 0.54 2.39
90
±2.82 土 5.29* ±0.49 ±3.10** ±0.21 土 1 03**
11.00 7.20 3.52 7.42 0.58 1.43
120
± 10.50 ±4.80 ±0.63 土 1.79** ± 0.39 土 0.56**
11.32 7.15 2.68 4.79 0.43 0.54
180
± 13.30 ±4.89 ±0.37 土 1.27** ± 0.28 土 0.27
6.28 2.95 2.18 3.61 0.12 0.48
240
±4.64 ±2.88 ±0.23 ±0.43** ±0.03 ±0.19**
1.57 8.95 2.28 3.37 0.04 0.38
300
±1.07 土 5.25** ±0.09 ±0.19** ±0.01 土 0.06**
1.16 7.08 2.37 2.68 0.05 0.26
360
±0.31 ±6.19* ±0.41 ±0.17 ±0.05 ± 0.13**
注: *为经 t检验, p<0.05; **为经 t检验, p<0.01;
2.2.2 加替沙星眼用凝胶与加替沙星滴眼液在兔眼角膜中经 时过程
加替沙星眼用凝胶与加替沙星滴眼液单次给药后角膜中药物 浓度结果见表 5和 fig.2。 加替沙星眼用凝胶组在 5-120min时, 在 角膜中药物维持较高的浓度, 浓度分别为 25.91 ±6.30、 30· 63土 12.32、 23.87 ±7.37、 14.53 ±5.31、 10.25 ±2.69、 10.04 ±3.10 和 7.42士 1.79 g/g, 分别是加替沙星滴眼液组对应时间点的 1.9、 2.3、 3.2、 2.1、 2.0、 3.1和 2.1倍。加替沙星眼用凝胶组在 5 - 300min 各时间点的角膜药物浓度与加替沙星滴眼液组作 t -检验, 结果有 显著性差异(p<0.01) 。 在 0 - 360min的角膜中药物浓度-时间曲 线下面积为: AUCGTX-Gel/AUCGTX-ED = 2.1。
2.2.3 加替沙星眼用凝胶与加替沙星滴眼液在兔眼房水中经 时过程
加替沙星眼用凝胶与加替沙星滴眼液单次给药后房水中药物 浓度结果见表 5和 fig.3。 加替沙星跟用凝胶组药物在 90min时达到 峰浓度, 为 2.39 ±1.03
加替沙星滴眼液组在 60min时药物 达到峰值浓度, 为 0.94 ±0.69 g/mL。 加替沙星眼用凝胶在 5- 12 Omin时药物在房水中维持较高的浓度, 浓度分别是加替沙星滴眼 液组对应时间点的 3.8、 2.5、 4.4、 2.9、 1.9、 4.4和 2.5倍。 加替 沙星眼用凝胶组在 5 - 360min各时间点除 180min外的房水药物浓度 与加替沙星滴眼液组作 t-检验结果, 有显著性差异(P<0.05) 。 在 0 - 360min的房水中药物浓度-时间曲线下面积为:
AUCGTX-Gel/AUCGTX-ED = 2.8。
2.2.4 加替沙星眼用凝胶与加替沙星滴眼液兔眼单次给药后 的药动学参数
加替沙星眼用凝胶与加替沙星滴眼液组药物单次滴眼后泪液、 角膜和房水中的药物浓度数据分别用计算机进行拟合并计算得动 力学参数(例如可以使用 DAS2. 1. 1软件)见表 6。 凝胶组药物在角 膜和房水中的达峰时间被推迟。 加替沙星眼用凝胶组泪液、 角膜和 房水的药物浓度-时间曲线下面积分别明显大于加替沙星滴眼液 组。
表 6: 实验组与对照组单次滴目艮后兔眼药动学参数 (n=8)
3. 结论
本研究结果表明: 加替沙星眼用凝胶兔眼单次给药同滴眼液单 次给药比较, 药物在泪液中浓度 15-45min显著高于滴眼液组, 角膜 中的浓度在 5-300min显著高于滴眼液组,房水中的浓度在 5-360min ( 180min时除外)显著高于滴眼液组。 目艮部生物利用度显著提高。 结果见 f ig. 1-3。 试猃例 3: 三种不同的加替沙星眼用凝胶兔眼药动学的比较 测定不同方法制备的 3种加替沙星眼用凝胶制剂兔眼单次给药 后一定时间内各点角膜及房水中的药物浓度, 对 3种制剂在兔眼的 药动学进行比较。
1. 材料与方法
1. 1 主要试剂
乙腈(HPLC级,批号: 509124, TEDIA公司, 美国); 甲醇(HPLC 级, 批号: UN1230, Merck公司, 德国); 二氯曱烷(色谱纯, 天津 科密欧化学试剂开发中心) 。 加替沙星对照品 (含量 97. 2%, 中国 生物制品检定所) 。
1. 2 试验药物
A组: 实施例 5制备。
B组: 对照例 1制备。
C组: 对照例 2制备。
1. 3 动物及分组
日本大耳白兔, 健康、 无眼疾, 雄性, 体重 2 - 2. 5kg (河南省 实验动物中心提供, 合格证号: SCXK (豫) 2005-0002 ) 。 完全随机 化分成 A、 B、 C三组, 每组各 44动物, 每组动物随机分成 11个亚组, 每亚组 4只动物共 8眼。
1. 4 给药及采样
用洁净玻璃点眼棒精密称取加替沙星眼用凝胶 0. 050g,一次性 轻轻涂入家兔下睑结膜嚢颞侧, 轻轻闭合双睑约 30s; 各组分别于 给药后 5、 15、 30、 45、 60、 90、 120、 180、 240、 300和 360分钟后, 以大量生理盐水沖洗眼表(每眼不小于 10ml ), 干棉球拭去残余液 体, 迅速用 26G的 ImL注射针从上方角膜缘刺入前房, 抽取房水, 精 密吸取房水置于试管中。 耳缘静脉注射过量戊巴比妥钠, 处死, 剖 取角膜组织, 滤纸吸干水分, 置玻璃试管中, 精密称重, 所有样品 均储存于 -60。C冰箱内保存, 使用前室温解冻, 以备处理测定。
1. 5 样品的处理
房水: 精密吸取房水 100μ1, 加入二氯申烷 2. 0mL, 涡旋振荡
lmin, 3000rpm离心 5min, 弃上层水层, 有机层在 40。C加热下, 以 氮气吹干,测定前精密加入流动相 100 μ L,涡旋振荡 lmin, 4500rpm, 离心 15min, 取上清液注入 HPLC中, 按峰面积外标法计算, 求得样 品药物浓度。
角膜样品:取精密称重的角膜,剪碎置于试管中,加入水 1. OmL, 用组织匀浆器(Fluko,德国) 25000rpm的转速匀浆 lmin,取 200μί 角膜 浆液, 然后加入二氯曱烷 2. OmL, 其余处理方法同房水样品 的处理。
1. 6 样品测定: 按 "样品的处理" 项下分别对房水及角膜样品 进行处理后, 取上清液注入 HPLC中, 记录色谱图与峰面积, 外标法 定量, 求得泪液、 房水及角膜样品中的药物浓度。
2. 兔眼药动学分析
2. 1 加替沙星在角膜和房水中的经时过程
3种不同的加替沙星凝胶制剂单次给药后兔眼角膜和房水中药 物浓度的测定结果见 f ig.,4 - 5及表 7。
如 f ig. 4所示, 单次兔眼局部给药后, A、 B、 C组兔眼角膜中的 达峰时间均为 15min; 达峰浓度分别为 36· 28 ± 8. 86μ8/ηι1、 24. 35 ± 3. 65μ8/ιη1、 21. 69 ± 6. 37 g/ml , 其中, A组的达峰浓度显著高于 B、 C组。
如 f ig. 5所示, A、 B、 C各組给药后在兔眼房水中的达峰时间分 别为 45min、 45min、 60min; 达峰浓度分别为 3. 33 ± 0. 93 g/ml、 2. 21 ± 1· 19μ8/πι1、 2· 38 ± 0. 65 g/ml。 其中, A组的达峰浓度显著 高于 B组和 C组。 各组房水中加替沙星达峰浓度水平较角膜组织低, 但药物浓度的吸收和消除也比较緩慢。
表 7: 加替沙星在兔眼角膜和房水中的药物浓度
2. 2. 4 加替沙星眼用凝胶制剂兔眼单次给药后的药动学参数 分别用计算机拟合加替沙星眼用凝胶制剂单次给药后角膜和 房水中各时间点的药物浓度数据, 并利用梯形法、 Wanger-Nel son 法、 残数法计算得药物动力学参数, 见结果表 8。
角膜中 A实验组 "药物浓度 -时间曲线下面积" ( AUC。— 36。rain )
最大, 为 2867. 60 ( g/ml) * min , 分别是 B、 C组的 1. 36倍和 1. 55 倍, 表明 A组在角膜的生物利用度高于其余 2组。
房水中 A实驗组的 AUC。-36。min最大, 与角膜中药物的浓度情况一 致, 为 353. 3 ^g/ml) * min, 分别为 B、 C组的 1, 45倍和 1. 51倍, 表 明 A组制剂在房水中的生物利用度高于其余 2组。
表 8 : 实验组与对照组单次滴目艮后兔眼药动学参数 (n=8)
3. 结论
由上述药动学分析结果可知, 角膜中各组的达峰浓度 A组最高, 其次为 B组、 C组; 角膜中各组的生物利用度 A组最高, 其次为 B组、 C组。 房水中各组的达峰浓度 A组最高, 其次为 B组、 C组; 房水中各 组的生物利用度 A组最高, 其次为 B组、 C组。 表明: 在本研究中, 以相同的给药剂量及给药方式进行兔眼局部给药后, 在考察时间 内, A实验组加替沙星凝胶制剂与其他试猃制剂相比, 可在兔眼部 角膜组织及房水中达到更高的浓度,且进入角膜组和房水的药物的 量更多。
本发明制备的加替沙星眼用凝胶中联合应用卡波姆及玻璃酸 钠作为凝胶基质; 试验结果表明, 其在角膜及房水中的达峰浓度及
生物利用度均显著高于对照药物组 B (单独使用卡波姆为凝胶基质 ) 及对照药物组 C (单独使用玻璃酸钠为凝胶基质) 。 尽管本发明的具体实施方式已经得到详细的描述, 本领域技 术人员将会理解。 根据已经公开的所有教导, 可以对那些细节进 行各种修改和替换, 这些改变均在本发明的保护范围之内。 本发 明的全部范围由所附权利要求及其任何等同物给出。
Claims
1. 一种眼用凝胶剂, 其包含治疗有效量的加替沙星或其药用 盐、基盾和水,其中基质为卡波姆、卡波姆与羟丙曱纤维素混合物、 以及玻璃酸钠中的一种或多种。
2. —种眼用凝胶剂, 其包含治疗有效量的加替沙星或其药用 盐、 卡波姆、 玻璃酸钠、 和水。
3. 根据权利要求 2的眼用凝胶剂 按该凝胶剂的重量 /体积百 分数计, 其中包含:
4. 根据权利要求 2的眼用凝胶剂 按该凝胶剂的重量 /体积百 分数计, 其中包含:
5. 根据权利要求 2的眼用凝胶剂 按该凝胶剂的重量 /体积百 分数计, 其中包含:
6. 根据权利要求 2 的眼用凝胶剂 按该凝胶剂的重量 /体积百 分数计, 其中包含:
加替沙星或其药用盐 0. 1-2. 0%, 卡波姆 0. 1-1. 0%, 玻璃酸钠 0. 01-0. 1% , 水 适量, 加至 100%。
7. 根据权利要求 2 的眼用凝胶剂, 按该凝胶剂的重量 /体积百 分数计, 其中包含:
加替沙星或其药用盐 0. 01-2. 0%, 卡波姆 0. 05-4. 0%, 羟丙曱纤维素 0. 05-4. 0%, 玻璃酸钠 0. 005-1. 0%, 水 适量, 加至 100%。
8. 根据权利要求 1至 7中任一项的眼用凝胶剂,其中还含有 pH 值调节剂, 所述的 pH值调节剂选自硼酸、 硼砂、 氢氧化钠、 磷酸 盐緩冲溶液、 醋酸盐緩冲溶液中的一种或多种; 具体地, 所述眼用 凝胶剂的 pH值为 4. 5-9. 5。
9. 根据权利要求 1至 8中任一项的眼用凝胶剂,其中还含有渗 透压调节剂, 所述的渗透压调节剂选自丙二醇、 甘油、 氯化钠和甘 露醇等中的一种或多种; 具体地, 所述眼用凝胶剂含有 0-15. 0% (w/v)的渗透压调节剂。
10. 根据权利要求 1至 9中任一项的眼用凝胶剂, 其中还含有 一种或多种选自以下的抑菌剂: 苯乙醇、 苯氧乙醇、 对羟基苯曱酸 甲酯、 对羟基苯曱酸乙酯、 对羟基苯曱酸丙酯、 苯扎氯铵、 三氯叔 丁醇、 苯扎溴铵、 西曲溴铵; 具体地, 所述的柙菌剂占该滴眼液总 量的 0. 005 - 1% (w/v) 0
11. 根据权利要求 1至 10中任一项的眼用凝胶剂,其中还含有 一种或多种选自以下的表面活性剂: 吐温类、 聚氧乙烯氢化蓖麻油 类、 和聚氧乙烯蓖麻油类, 具体地, 选自吐温 -80、 吐温- 60、 吐温 -85、 吐温 -65、 和聚氧乙烯 60氢化蓖麻油; 具体地, 所述眼用凝 胶剂含有 0. 001-10% (w/v)的表面活性剂。
12. 权利要求 1至 11中任一项的眼用凝胶剂的制备方法,其包 括以下步骤:
i)使卡波姆用适量水溶胀, 溶解, 灭菌, 备用; 玻璃酸钠用适量水 溶胀, 备用;
Π)用适量水与加替沙星和玻璃酸钠溶液混合, 加入任选的表面活 性剂和渗透压调节剂, 使所得混合物溶解;
i i i)将任选的抑菌剂和 pH调节剂溶解于适量水中;
iv)使以上 Π)和任选的 i i i)所得的物料混合, 经微孔滤膜过滤, 加至 i)项溶液中, 补加水至处方全量, 搅拌均勾, 灌装, 即得。
13. 一种治疗眼部感染的方法, 包括给与有效量的权利要求 1 至 11 中任一项的眼用凝 _剂的步骤; 具体地, 所述眼部感染为眼 睑炎、 麦粒肿、 结膜炎、 泪嚢炎、 角膜炎、 角膜溃疡、 或沙眼。
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RU2669768C1 (ru) * | 2017-12-26 | 2018-10-16 | Илья Александрович Марков | Гелеобразные капли для лечения воспалительных заболеваний глаз, включая инфекционные, устойчивые к антибиотикам |
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