CN103977008B - Gel for eye containing Dorzolamide and timolol and preparation method thereof - Google Patents
Gel for eye containing Dorzolamide and timolol and preparation method thereof Download PDFInfo
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- CN103977008B CN103977008B CN201310048824.1A CN201310048824A CN103977008B CN 103977008 B CN103977008 B CN 103977008B CN 201310048824 A CN201310048824 A CN 201310048824A CN 103977008 B CN103977008 B CN 103977008B
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Abstract
The invention belongs to field of pharmaceutical preparations, is related to a kind of gel for eye containing Dorzolamide and timolol and preparation method thereof.In particular it relates to a kind of gel for eye, which includes the Dorzolamide of effective dose or its officinal salt, timolol or its officinal salt, gel-type vehicle and water.The invention further relates to the purposes of the gel for eye.The gel for eye of the present invention is while active component consumption is reduced, it is achieved that the administering mode being administered once day, in conjunction with its high thixotropic, the characteristic of high clarity, substantially increases security and the compliance of clinical application.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of gel for eye and its system containing Dorzolamide and timolol
Preparation Method.The invention further relates to the purposes of the gel for eye.
Background technology
Glaucoma is generally defined as one group of threat and infringement optic nerve visual performance, and mainly being raised with pathologic intraocular pressure is had
The clinical syndrome of pass or illness in eye.The rising of intraocular pressure can bring the infringement of optic nerve function, be likely to result in optic nerve head with
And the irreversible infringement of visual performance.As taken treatment not in time, defect of visual field or total loss can be caused, is caused blind.
The main Types of glaucoma include primary（Including open-angle and keeping away angle-style）, Secondary cases, congenital and mixed glaucoma.
For the possible Etiologic Mechanism of glaucoma, effective measures clinically are exactly using different methods at present, reduce
Intraocular pressure, prevents and prevents the infringement of optic nerve, protects visual performance.The hypotensive agents thing of application mainly includes to intend choline at present
Drugs with function, B-adrenergic receptor antagonist, carbonic anhydrase inhibitor, alpha-2 adrenoceptor agonists and prostaglandin
Class medicine；Wherein B-adrenergic receptor antagonist is by blocking the β-adrenal gland on ciliary body non-pigmented epithelium cells
Element can acceptor come reduce aqueous humor generation, be most widely used hypotensive agents thing.Although clinically B-adrenergic receptor is short of money
It is effective for many patients that anti-agent is used for reducing the effect of intraocular pressure, but still suffers from many patients and is failed to respond to any medical treatment using this
Or insufficient effective phenomenon, and the characteristic such as the film stabilizing active based on this kind of medicine, easily occur increasing with administration time, effect
The phenomenon that fruit reduces.
Patent CN1066781A discloses a kind of containing carbonic anhydrase inhibitor and B-adrenergic receptor antagonist
Composition, it is adaptable to treat vasotonia disease and glaucoma.Reached better than using single work using the synergy of two kinds of medicines
The reducing iop of property composition.While reducing a day times for spraying, day is administered 2 times.U.S. FDA have approved Merck ＆ Co., Inc. within 1998
The product based on the exploitation of this patented technology（Dorzolamide hydrochloride-Timolol maleate eye drops）, day
Administration 2 times, for treating the ocular hypertensions such as open-angle glaucoma, is particularly suited for B-adrenergic receptor antagonist curative effect not
Sufficient ocular hypertension.Carbonic anhydrase inhibitor dorzolamide hydrochloride and B-adrenergic receptor antagonist timolol maleate
By synergy, reduce aqueous humor and generate, so as to effectively reduce the intraocular pressure of Bulbi hypertonia patient.
With the continuous development of field of pharmaceutical preparations, patient is required increasingly to the security of medicine and the compliance for using
High.The application of eye-gel preparation, can improve holdup time of the medicine in ocular, reduce dosage, reduce administration number of times,
Considerably increase security and the compliance of patient medication.However, as gel preparation composition is more complicated, different activity become
Divide with respective special nature（When particularly gel preparation is comprising various active composition）, this is high-quality ophthalmically acceptable solidifying for exploitation
Glue preparation brings unpredicted difficulty；Additionally, release of the active component from gel carrier and to intraocular infiltration also
It is difficult to predict or estimates.
The long-acting eye drops Timoptic-XE of timolol maleate that Merck ＆ Co., Inc. releases can improve eye biological utilisation
Spend and reduce administration number of times.Gel-type vehicle gellan gum used in the durative action preparation（Gelrite Gellan gum）, belong to one
Plant ion-sensitive type instant-type gel.Patent CN101278895A discloses a kind of preparation using the gel-type vehicle
The gel for eye use of active component.Patent CN102178644A discloses a kind of timolol maleate eye-gel preparation and its system
Preparation Method, with polyacrylic acid and HPMC as mixed-matrix, permissible when activity component concentration is for 0.1-0.7%
More full-bodied gel preparation is obtained, said preparation reduces the apparent Corneal trauma of active component timolol maleate, lead to
Spending the increase precorneal residence time increased the drug concentration in aqueous humor, it is achieved that when ordinary gel preparation increases medicine ocular and is detained
Between and improve bioavilability effect.
However, the present inventor is found through experiments, when active component is comprising dorzolamide hydrochloride and timolol maleate,
And it is gel-type vehicle using the bioadhesive polyacrylic acid family macromolecule disclosed in CN102178644A, the macromolecular material
Gelling is lost completely, preparation viscosity is extremely low, is used cooperatively with which using HPMC, no matter in which kind of ratio
Under example, the gelling of polyacrylic acid matrix can not be all realized, and lose the characteristic of non-newtonian fluid, so as to lose using poly-
Acrylic polymer material loses gelling and the thixotroping of such biology viscosity matrix as the meaning of gel-type vehicle
Property, causing paste regards, and greatly reduces the compliance of dosing eyes.
Patent CN1144477A discloses a kind of ophthalmic composition of low-viscosity, with polyacrylic acid macromolecular material as base
Matter, S- timolol are active component.The patent notes, when activity component concentration is in the range of 0.1-0.5%, with poly- third
Olefin(e) acid macromolecule is tackifier, the beneficial effect of eye medicine combination be due to the effect of contained polymer concentration in composition,
Rather than the effect of viscosity, therefore, the invention provides a kind of eye medicine combination, its contain the polymer of enough high concentrations with
The formation of control polymer film on cornea.However, forming polymer film in ocular to need participation, the i.e. tear of ocular tear
Dilution under, change the concentration of topical remedy, so as to change the space structure of polymer, increase the ratio of linear polymer, from
And the interaction between polymer and mucoprotein is played, the anelasticity of preparation is improved, reaches the effect of similar instant-type gel.For
Different patient's ocular situations is different, and especially for the patient that lacrimal secretion is not enough, such preparation necessarily causes different medications
The drug effect difference of crowd, and the appearance character of composition, i.e. clear degree have a strong impact on the compliance that patient uses.
Additionally, listed at presentUsed in hydroxyethyl cellulose be tackifier, bioadhesive
Low, day is administered 2 times.
In a word, the said goods and patented technology all fail to solve for Dorzolamide and timolol to make long-acting composite preparation
Technical barrier（Particularly realize being administered once day）, accordingly, it would be desirable to develop new Dorzolamide-timolol gel for eye use, obtain more
The effect that good ocular is detained, realizes being administered once day.
Content of the invention
The present inventor has been obtained a kind of containing Dorzolamide and timolol by in-depth study and performing creative labour
Gel for eye, its with bioadhesive matrix as carrier, outward appearance clear, with high thixotropic, high drug permeability, by force
Eye anelasticity, overcomes active component to medium carrier viscosity and thixotropic impact, while overcoming medicine from hypothallus
To the restriction effect of corneal osmosis speed, the consumption of active component is considerably reduced, a day administration number of times is reduced, improves medicine
Security and compliance that thing is used, disclosure satisfy that the demand being administered once day.Thus provide following inventions：
One aspect of the present invention is related to a kind of gel for eye, and which includes the Dorzolamide of effective dose or its officinal salt
（Such as dorzolamide hydrochloride）, timolol or its officinal salt（Such as timolol maleate）, gel-type vehicle and water.
Gel for eye according to any one of the present invention, calculates (w/w) in percentage by weight, and which includes：
Dorzolamide or its officinal salt 0.5%-2.0%
Timolol or its officinal salt 0.05%-0.5%
Gel-type vehicle 0.3%-10%；
Or
Dorzolamide or its officinal salt 0.5%-1.5%
Timolol or its officinal salt 0.05%-0.3%
Gel-type vehicle 1.0%-8%；
Or
Dorzolamide or its officinal salt 0.5%-1.0%
Timolol or its officinal salt 0.05%-0.2%
Gel-type vehicle 1.5%-5%；
Or
Dorzolamide or its officinal salt 0.5%-1.0%
Timolol or its officinal salt 0.05%-0.2%
Gel-type vehicle 1.5%-3%.
Gel for eye according to any one of the present invention, wherein, the content of the Dorzolamide or its officinal salt is
0.5%-0.8%, 0.7%-1.0% or 0.6%-0.9%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%
(w/w).
Gel for eye according to any one of the present invention, wherein, the content of the timolol or its officinal salt
For 0.05%-0.15%, 0.10%-0.2% or 0.08%-0.18%, 0.05%, 0.06%, 0.07%, 0.08%,
0.09%th, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%
Or 0.20% (w/w).
Gel for eye according to any one of the present invention, wherein, the content of the gel-type vehicle is 1.5%-
2.5%th, 1.7%-2.6% or 2%-3%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%,
2.3%th, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3.0% (w/w).
Gel for eye according to any one of the present invention, wherein, the gel-type vehicle includes acrylate copolymer, glass
Glass acid sodium and polyvinyl alcohol；Specifically, the acrylate copolymer is Carbomer.
Gel for eye according to any one of the present invention, calculates (w/w), wherein in percentage by weight：
Carbomer 0.1%-5%
Sodium hyaluronate 0.1%-3%
Polyvinyl alcohol 0.1%-7%；
Or
Carbomer 0.2%-3%
Sodium hyaluronate 0.3%-2%
Polyvinyl alcohol 0.2%-5%；
Or
Carbomer 0.3%-2%
Sodium hyaluronate 0.4%-1.5%
Polyvinyl alcohol 0.4%-2%；
Or
Carbomer 0.5%-1%
Sodium hyaluronate 0.5%-1%
Polyvinyl alcohol 0.5%-1.5%.
Gel for eye according to any one of the present invention, wherein, the content of the Carbomer is 0.5%-0.8%,
0.7%-1.0% or 0.6%-0.9%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% (w/w).
Gel for eye according to any one of the present invention, wherein, the content of the sodium hyaluronate is 0.5%-
0.8%th, 0.7%-1.0% or 0.6%-0.9%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% (w/w).
Gel for eye according to any one of the present invention, wherein, the content of the polyvinyl alcohol is 0.5%-
1.0%th, 1.0%-1.5% or 0.7%-1.2%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%,
1.2%th, 1.3%, 1.4% or 1.5% (w/w).
Gel for eye according to any one of the present invention, wherein：
The Carbomer is selected from any one or more in carbomer 934, Carbomer974 and Carbopol, preferably card ripple
Nurse 980；
Selected from the sodium hyaluronate that molecular weight is 50W-150W, preferred molecular weight is the glass of 80W-120W to the sodium hyaluronate
Glass acid sodium；
The polyvinyl alcohol is 200-2000 selected from the degree of polymerization, and alcoholysis degree is more than 78% polyvinyl alcohol, preferably poly- second
Enol 1799.
Gel for eye according to any one of the present invention, which is also containing at least one nonionic surfactant；Tool
Body ground, which is HS15, such as nonionic surfactantHS15.
Gel for eye according to any one of the present invention, wherein, calculates (w/w) in percentage by weight, described non-
The content of ionic surface active agent is 0.5%-15%, 0.5%-10% or 0.5%-5%, 0.5%-2%, 2%-
5%th, 1%-3%, 0.5%-1%, 1%-5%, 1%-2% or 2%-3% (w/w).
Gel for eye according to any one of the present invention, its pH are 5.0-8.0, preferably 6.0-7.0.
Gel for eye according to any one of the present invention, which is also comprising following（1）-（3）Any one of or
Multinomial：
（1）PH value regulator, its are selected from any one or more in NaOH and hydrochloric acid；
（2）Osmotic pressure regulator, its are selected from any one or more in propane diols, glycerine, mannitol and sorbierite；
（3）Bacteriostatic agent, its are selected from benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, Phenoxyethanol, benzyl carbinol and para hydroxybenzene
Any one or more in formic acid esters；Any one or more preferably in benzalkonium chloride and ethyl-para-hydroxybenzoate；Specifically
Ground, the content of the bacteriostatic agent are the 0.001-0.05%, preferably 0.005-0.03% of gel gross mass.
The gel of the present invention is a kind of waterborne compositions, wherein uses water as the solvent of said composition.Although this
Bright gel does not specifically note that water used accounts for the percentage of gel gross weight, or when inventive gel agent is prepared
The amount of used water is not specifically noted, but, it will be apparent to those skilled in the art that the medium as gel or solvent, the water
Amount adds to gel full dose with water to calculate.
Another aspect of the present invention is related to the preparation method of the gel for eye any one of the present invention, including following
Step：
1）Prepare the mixed-matrix of Carbomer and polyvinyl alcohol；
2）The aqueous solution obtained in other compositions in addition to gel-type vehicle is mixed with sodium hyaluronate matrix；
3）By step 1）With step 2）In product mix；
Specifically, comprise the steps：
) Carbomer, sodium hyaluronate, polyvinyl alcohol is fully swelling with appropriate water respectively, dissolving, sterilizing, standby；
) will) the Carbomer matrix of gained mixed with polyvinyl alcohol matrix, standby；
) by after pH adjusting agent suitable quantity of water dissolved dilution, filtration sterilization, with) mixed-matrix of gained mixes,
Standby；
) Dorzolamide or its officinal salt, timolol or its officinal salt are dissolved in appropriate water, add optionally
Bacteriostatic agent, osmotic pressure regulator, dissolving, filtration sterilization, standby；
) by) and the sodium hyaluronate matrix of gained with) solution of gained mixes；
) will) and) mixing of the material of gained, benefit adds water to full dose and stirs and obtain final product.
Certainly, those skilled in the art know, it is also possible to using water for injection, the step of so as to eliminate filtration sterilization, these
All within protection scope of the present invention.
The method that the filtration sterilization can be known using those skilled in the art, filtered for example with 0.22 μm of filter membrane
Bacterium.
The invention further relates to according to obtained in preparation method above gel for eye.
The present invention by gel-type vehicle component with appropriate water-swellable completely after form gel-type vehicle, other components are according to specific
Dissolving and order by merging mix with gel-type vehicle after can obtain high thixotropic with suitable viscosity（Non-Newton fluid characteristic）、
The eye-gel preparation of high clarity, changes the preparation method of conventional eye-gel preparation, be not using each component powders or
The method that the aqueous solution is directly mixed with gel-type vehicle one by one or jointly.The restriction of theory is not limited to, the present invention is by specific mixed
Conjunction order, first prepares partial gel matrix, and reaches optimal linear condition, to protect high thixotropic bioadhesive base
Effective group of matter；Mix with specific partial gel matrix after will be water-soluble for other non-gel-type vehicle compositions, become with shielding activity
Impact of the electric charge for dividing to biological adherent stroma.
Another aspect of the invention be related to any one of gel for eye prepare treatment and/or prevention and/auxiliary
The purposes helped in the medicine for the treatment of glaucoma or drop intraocular pressure；Specifically, the glaucoma be primary, Secondary cases, congenital
Or mixed glaucoma；Specifically, the primary glaucoma is that primary open-angle or primary keep away angle-style glaucoma.
Another aspect of the invention is related to the side of a kind for the treatment of and/or prevention and/auxiliary treatment glaucoma or drop intraocular pressure
Method, the step of including gel for eye using the present invention of effective dose；Specifically, the glaucoma be primary, Secondary cases,
Congenital or mixed glaucoma；Specifically, the primary glaucoma is that primary open-angle or primary keep away angle-style green light
Eye.
The specific dosage of the gel for eye of the present invention can be by physician in view active component Dorzolamide or which is pharmaceutically acceptable
The factors such as the age of the specified volume of salt, timolol or its officinal salt and patient, sex, body weight, the state of an illness are determining.This
The gel for eye of invention can be realized being administered once day.
The explanation of part term according to the present invention is presented herein below.These explanation be in order to understand the present invention, be not to this
The protection domain of invention is limited.
Term " effective dose " refers to prevent and/or treat and/or auxiliary treatment glaucoma, or reduces the effective agent of intraocular pressure
Amount.
The content of each component in the gel, refers in terms of gel 100g, the weight of the component included in which
Grams is the w/w percentage, i.e., usual represented g/100g, or is expressed as % (w/w).In the present invention, such as
Not otherwise indicated, % is w/w percentage.
In the present invention, the metering to Dorzolamide or its officinal salt, if specializing in terms of base or salt
Shape meter, then all in terms of base Dorzolamide.
In the present invention, the metering to timolol or its officinal salt, if specializing in terms of base or
Salt shape meter, then all in terms of base timolol.
Term " gel-type vehicle " is the gel base of application herein to forming the general name of the auxiliary material of gel-like matrix
Matter includes polyacrylic compounds, sodium hyaluronate and polyvinyl alcohol.
The preparation of the present invention can be placed on and be suitable in any required doser of eye-drops preparations.The device can be eye
With delivery system, such as sterilize ophthalmically acceptable aluminum pipe or multiple tube, plastic bottle etc..
The beneficial effect of the invention
The invention provides a kind of suitable clinical practice, increase Dorzolamide-timolol eye of the patient using compliance
With gel preparation and preparation method thereof.The inventors discovered that, based on Dorzolamide and the chemical property of timolol, considerably increase
Using high thixotropic bioadhesive gel-type vehicle for carrier difficulty, it is possible to be medicine charge effect make gel-type vehicle lose
Gelling and thixotropy is gone, and mixed-matrix and/or the specific preparation method of particular types and ratio has been used, can be not
Under the premise of change matrix is thixotropic, the compound eye-gel preparation that a kind of clarity is good, anelasticity is strong is obtained.The present inventor enters
One step finds, adds a kind of specific nonionic surfactant, can significantly improve activity and become in described gel preparation
Divide the interaction with gel-type vehicle, so as to speed of the medicine from carrier to corneal osmosis is improved, and obtain preferably clarification
Degree, while improve in preparation with special role and the less composition of consumption（Bacteriostatic agent）Stability.Obtained based on the present invention
Dorzolamide-timolol the gel for eye use for obtaining, while active component consumption is reduced, it is achieved that the administration side that day is administered once
Formula, in conjunction with its high thixotropic, the characteristic of high clarity, substantially increases security and the compliance of clinical application.
Description of the drawings
Fig. 1：Gel rheological curve.
Fig. 2：Timolol maleate concentration in aqueous humor.
Fig. 3：Dorzolamide hydrochloride concentration in aqueous humor.
Fig. 4：Give the varieties of intraocular pressure of rabbit in 24h after Dorzolamide timolol eye-drops preparations.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Unreceipted concrete in embodiment
Condition person, the condition that advises according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, are
Can by city available from conventional products.
Embodiment 1：The preparation of gel for eye 1
Gel for eye 1 is prepared according to corresponding prescription proportioning in table 1 below.
Preparation method：(1) by the Carbomer of recipe quantity, sodium hyaluronate, polyvinyl alcohol, swelling with appropriate water for injection, sterilizing
Standby；(2) Carbomer matrix and polyvinyl alcohol matrix are fully mixed, standby；(3) appropriate NaOH is taken, with water-soluble in right amount
Solution, is mixed with the mixed-matrix of (2) gained after 0.22 μm of filtration sterilization, standby；(4) 40ml50-80 DEG C of water for injection is taken, according to
Secondary dissolving dorzolamide hydrochloride, timolol maleate, glycerine, ethyl hydroxy benzoate, 0.22 μm of filtration sterilization, standby；(5) will (1) gained
Sodium hyaluronate matrix mix with (4) resulting solution；(6) (5) resulting material will mix with (3) resulting material, mend water for injection
To 100g, stir, if necessary pH value is finely adjusted to 6.5.
Embodiment 2-4：The preparation of gel for eye 2-4
Gel for eye 2-4 is prepared according to corresponding prescription proportioning in table 1.
Preparation method reference implementation example 1.
Table 1：Prescription proportioning
| Component | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Dorzolamide hydrochloride | 0.56g | 0.56g | 1.11g | 2.22g |
| Timolol maleate | 0.68g | 0.34g | 0.14g | 0.068g |
| Carbopol | 0.5g | 0.5g | - | - |
| Carbomer974 | - | - | 0.6g | 0.7g |
| Sodium hyaluronate | 0.7g | 0.5g | 0.6g | 0.6g |
| Polyvinyl alcohol | 1.1g | 0.7g | 1.0g | 1.2g |
| Propane diols | - | - | 1.4g | 0.9g |
| Glycerine | 1.8g | 2.0g | - | - |
| Benzalkonium chloride | - | 0.01 | - | 0.005 |
| Ethyl hydroxy benzoate | 0.03 | - | 0.03 | 0.02 |
| NaOH | In right amount | In right amount | In right amount | In right amount |
| Water for injection is added to | 100g | 100g | 100g | 100g |
Embodiment 5-8：The preparation of gel for eye 5-8
Gel for eye 5-8 is prepared by corresponding prescription proportioning in table 2.
Table 2：Prescription proportioning
Preparation method：(1) by the Carbomer of recipe quantity, sodium hyaluronate, polyvinyl alcohol, swelling with appropriate water for injection, sterilizing
Standby；(2) Carbomer matrix and polyvinyl alcohol matrix are fully mixed, standby；(3) appropriate NaOH is taken, with water-soluble in right amount
Solution, is mixed with the mixed-matrix of (2) gained after 0.22 μm of filtration sterilization, standby；(4) 40ml50-80 DEG C of water for injection is taken, according to
Secondary dissolving dorzolamide hydrochloride, timolol maleate, glycerine, ethyl hydroxy benzoate,HS15,0.22 μm of filtration sterilization, standby
With；(5) the sodium hyaluronate matrix of (1) gained is mixed with (4) resulting solution；(6) (5) will mix with (3) resulting material resulting material
Close, water for injection is mended to 100g, stir, if necessary pH value is finely adjusted to 6.8.
Comparative example 1：Compare the preparation of gel for eye 1
Prepare by corresponding prescription proportioning in table 3 and compare gel for eye 1.
Table 3：Prescription proportioning
| Component | Comparative example 1 |
| Dorzolamide hydrochloride | 1.11g |
| Timolol maleate | 0.14g |
| Carbopol | 1.0g |
| Glycerine | 2.0g |
| Ethyl hydroxy benzoate | 0.03 |
| NaOH | In right amount |
| Water for injection is added to | 100g |
Preparation method：(1) the Carbomer of recipe quantity is swelling with appropriate water for injection, sterilize standby；(2) 40ml50-80 is taken
DEG C water for injection, successively dissolving dorzolamide hydrochloride, timolol maleate, glycerine, ethyl hydroxy benzoate, NaOH, 0.22 μm
Filtration sterilization, standby；(3) the matrix of (1) gained is mixed with (2) resulting solution, water for injection is mended to 100g, stir, necessary
When pH value is finely adjusted to 6.8.
Comparative example 2：Compare the preparation of gel for eye 2
Prepare by corresponding prescription proportioning in table 4 and compare gel for eye 2.
Table 4：Prescription proportioning
| Component | Comparative example 2 |
| Dorzolamide hydrochloride | 1.11g |
| Timolol maleate | 0.34g |
| Sodium hyaluronate | 1.2g |
| Glycerine | 2.0g |
| Ethyl hydroxy benzoate | 0.03 |
| NaOH | In right amount |
| Water for injection is added to | 100g |
Preparation method：(1) the sodium hyaluronate of recipe quantity is swelling with appropriate water for injection, sterilize standby；(2) 40ml50- is taken
80 DEG C of water for injection, dissolves dorzolamide hydrochloride, timolol maleate, glycerine, ethyl hydroxy benzoate, NaOH, 0.22 μ successively
M filtration sterilization, standby；(3) the matrix of (1) gained is mixed with (2) resulting solution, water for injection is mended to 100g, stir, must
PH value is finely adjusted to 6.8 when wanting.
Comparative example 3：Compare the preparation of gel for eye 3
Prepare by corresponding prescription proportioning in table 5 and compare gel for eye 3.
Table 5：Prescription proportioning
| Component | Comparative example 3 |
| Dorzolamide hydrochloride | 2.22g |
| Timolol maleate | 0.68g |
| Hydroxyethyl cellulose 250M | 0.5g |
| Glycerine | 2.0g |
| Ethyl hydroxy benzoate | 0.03 |
| NaOH | In right amount |
| Water for injection is added to | 100g |
Preparation method：(1) the hydroxyethyl cellulose of recipe quantity is swelling with appropriate water for injection, sterilize standby；(2) take
40ml50-80 DEG C of water for injection, dissolves dorzolamide hydrochloride, timolol maleate, glycerine, ethyl hydroxy benzoate, hydroxide successively
Sodium, 0.22 μm of filtration sterilization, standby；(3) the matrix of (1) gained is mixed with (2) resulting solution, water for injection is mended to 100g, stir
Uniformly, if necessary pH value is finely adjusted to 6.8.
Experimental example 1：Colloidal nature and rheological properties comparative experiments
1. laboratory sample
Gel for eye 5 prepared by embodiment 5.
Comparison gel for eye 1 prepared by comparative example 1.
Comparison gel for eye 2 prepared by comparative example 2.
Comparison gel for eye 3 prepared by comparative example 3.
2. experimental technique
From from formulation aesthetics, the gel preparation outward appearance clear of 5 gained of embodiment, with suitable viscosity and bullet
Property.1 gained formulation aesthetics of comparative example are muddy, and viscosity is extremely low.Comparative example 2 and the gel preparation outward appearance clarification of 3 gained of comparative example, have
There is certain viscosity.
Using viscosity method（25 DEG C of 4# rotors of LVDV-II rotational viscometer）Determine embodiment 5 and comparative example 1-3's
Viscosity.
3. experimental result
As shown in Figure 1.
From figure 1 it appears that the Dorzolamide timolol gel for eye use that the present invention is provided, is had compared with comparative example 1-3
There are diverse rheological charactristicses, by using the mixed gel matrix of particular types and usage ratio, make bioadhesive
It is higher that gel-type vehicle maintains significant non-Newton fluid characteristic, i.e. thixotropy, energy while preparation viscosity is increased substantially
Enough meet patient's compliance of clinical practice, paste is not produced regarding grade ill-effect.
Experimental example 2：Pharmacokinetics comparative experiments
1. laboratory sample and animal used as test
Gel for eye 5 prepared by embodiment 5.
Gel for eye 6 prepared by embodiment 6.
Comparison gel for eye 3 prepared by comparative example 3.
Healthy Japan large ear rabbit 18, male and female half and half, be randomly divided into three groups, per group 6.
2. experimental technique
The aqueous humor pharmacokinetics of two kinds of active components is investigated using microdialysis method.
Operation consent instills ofloxacin eye drops to rabbit intraocular in 4 days, to eliminate inflammation of eye section.During operation, conjunctiva is betted
Penetrating lidocaine injection carries out local anaesthesia, is fixed in rabbit box, struts eyelid with eye speculum, starts operation.Use pin
Head does penetrability puncture at the corneal limbus of canthus position, and microdialysis probe is derived by pin hole, pumps syringe needle, adjusts the position of probe
Putting makes dialysis window be totally immersed in aqueous humor just, and probe two ends are fixed in nose grain husk side and the tail of the eye respectively.Oxygen fluorine is instilled at wound
Husky star eye drops prevents infection.Through 2 day convalescence, start internal pharmacokinetic studies after window heals completely.
3. experimental result
Measurement result is shown in Fig. 2-3.Pharmacokinetic parameter is shown in Table 6.
Table 6：Pharmacokinetic parameter in aqueous humor
As can be seen that the Dorzolamide timolol gel for eye use of present invention offer from Fig. 2-3, by increasing capacitance it is possible to increase medicine exists
The holdup time of eye, the as shown by data in table 6, two kinds of work in the Dorzolamide timolol gel for eye use aqueous humor that the present invention is provided
Under the medicine time graph of property composition, area AUC is significantly improved, the Increased Plasma Half-life of medicine, embodiment 6 compared with Example 5,
IncreasedSH15, can improve medicine further to the infiltration in aqueous humor, improve eye bioavilability.
Experimental example 3：External Corneal trauma comparative experiments
1. laboratory sample
Gel for eye 5 prepared by embodiment 5.
Gel for eye 6 prepared by embodiment 6.
2. experimental technique
Healthy Japan large ear rabbit is put to death, the complete cornea of separation.Cornea is fixed on diffusion cell, cornea interior surface
Towards acceptance pool, acceptance pool is full of with physiological saline.The gel for eye use of embodiment 5 and embodiment 6 is given in cornea upper surface,
Under simulation physiological condition, body outer osmotic is carried out.Timolol maleate medicine is determined in set time point respectively from acceptance pool sampling
Thing concentration（Assay method is shown in American Pharmacopeia USP34-NF29 Timolol maleate eye drops content assaying method, page 4443）
With dorzolamide hydrochloride drug concentration（Assay method is shown in American Pharmacopeia USP34-NF29 dorzolamide hydrochloride content assaying method, the
Page 2630）, calculate cumulative release drug concentration.
Cumulative release drug concentration computing formula：
C cumulative release drug concentration；
CiDrug concentration in the acceptance pool of each time point practical measurement；
ViEach point in time sampling volume；
CtDrug concentration in the acceptance pool of t time practical measurement；
V0The volume of acceptable solution in acceptance pool.
3. experimental result
The results are shown in Table 7.
Table 7：The external permeability of rabbit cornea（n=5）
From table 7, in external cornea permeability test, in same time, nonionic surfactant
HS15 makes medicine in gel increase through the amount of cornea, i.e., apparent infiltration rate is improved, especially for timolol maleate,
Effect is more notable, it may be possible to due toHS15 change the interaction between active component and gel-type vehicle and
The effect that brings.
Experimental example 4：Pharmacodynamics comparative experiments
1. laboratory sample
Gel for eye 5 prepared by embodiment 5.
Gel for eye 6 prepared by embodiment 6.
Comparison gel for eye 3 prepared by comparative example 3.
2. experimental technique
Healthy nothing 3g/L Carbomer solution 0.2ml is injected respectively in eye illness Japan large ear rabbit 40, camera oculi anterior, make
Become ocular hypertension model, intraocular pressure maintains 28mmHg.Model rabbits are randomly divided into model control group, 3 treatment group of comparative example, reality
5 treatment group of Shi Li and 6 treatment group of embodiment (n=10).1 times/day of model group physiological saline eye droppings；3 treatment group of comparative example is with comparing
2 times/day of 3 eye droppings of example；Embodiment 5 is with 6 treatment group of embodiment respectively with embodiment 5 and 1 times/day of 6 eye droppings of embodiment.First administration
Afterwards, measure intraocular pressure during 4 groups of rabbit 0,1,4,8,12,16,20,24h with Tonopen intraocular pressure pen respectively, and compare between being organized
Analysis.
3. experimental result
As shown in Figure 4.
Figure 4, it is seen that the Dorzolamide timolol gel for eye use that the present invention is provided, dense active component is reduced
After degree, the drop intraocular pressure effect close with comparative example 3 can be reached, and intraocular pressure in 24h, can be maintained stable.
Experimental example 5：Stability experiment
1. laboratory sample
Gel for eye 5 prepared by embodiment 5.
Gel for eye 6 prepared by embodiment 6.
2. experimental technique
Example 5 and 6 gained gel for eye use of embodiment, in 30 DEG C ± 2 DEG C of temperature, the bar of relative humidity 65% ± 5%
Place under part, respectively at 0 month, 3 months, 6 months, 9 months, 12 months nonactive to the content of active component and feature become
Point（Bacteriostatic agent）Content detected.
Timolol maleate assay method is shown in American Pharmacopeia USP34-NF29 Timolol maleate eye drops containing measurement
Determine method, page 4443；Dorzolamide hydrochloride assay method is shown in American Pharmacopeia USP34-NF29 dorzolamide hydrochloride content assaying method,
Page 2630；Bacteriostatic agent assay method is shown in the inspection method of preservative in Chinese Pharmacopoeia version Gernebcin eye drops in 2010, the
Page 365.
3. experimental result
The results are shown in Table 8.
Table 8：Active component and the stability data of feature non-active ingredient content
Data from table 8 can be seen that the Dorzolamide timolol gel for eye use of present invention offer have good steady
Qualitative, nonionic surfactantHS15 causes the stability of bacteriostatic agent ethyl hydroxy benzoate to improve further.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor all in the present invention
Within the scope of shield.The four corner of the present invention is given by claims and its any equivalent.
Claims (27)
1. a kind of gel for eye, its include the Dorzolamide of effective dose or its officinal salt, timolol or its officinal salt, solidifying
Gel matrix and water；Wherein, the gel-type vehicle includes acrylate copolymer, sodium hyaluronate and polyvinyl alcohol；The acrylic acid gathers
Compound is Carbomer；
Wherein, calculate in percentage by weight, the gel for eye includes：
Carbomer 0.5%-1%
Sodium hyaluronate 0.5%-1%
Polyvinyl alcohol 0.5%-1.5%.
2. gel for eye according to claim 1, wherein, Dorzolamide officinal salt is dorzolamide hydrochloride.
3. gel for eye according to claim 1, wherein, timolol officinal salt is timolol maleate.
4. gel for eye according to claim 1, is calculated in percentage by weight, and which includes：
Dorzolamide or its officinal salt 0.5%-2.0%
Timolol or its officinal salt 0.05%-0.5%
Gel-type vehicle 1.5%-10%.
5. gel for eye according to claim 1, is calculated in percentage by weight, and which includes：
Dorzolamide or its officinal salt 0.5%-1.5%
Timolol or its officinal salt 0.05%-0.3%
Gel-type vehicle 1.5%-8%.
6. gel for eye according to claim 1, is calculated in percentage by weight, and which includes：
Dorzolamide or its officinal salt 0.5%-1.0%
Timolol or its officinal salt 0.05%-0.2%
Gel-type vehicle 1.5%-5%.
7. gel for eye according to claim 1, is calculated in percentage by weight, and which includes：
Dorzolamide or its officinal salt 0.5%-1.0%
Timolol or its officinal salt 0.05%-0.2%
Gel-type vehicle 1.5%-3%.
8. the gel for eye according to any one of claim 1-7, wherein：
The Carbomer is selected from any one or more in carbomer 934, Carbomer974 and Carbopol；
The sodium hyaluronate is selected from the sodium hyaluronate that molecular weight is 50W-150W；
The polyvinyl alcohol is 200-2000 selected from the degree of polymerization, and alcoholysis degree is more than 78% polyvinyl alcohol.
9. gel for eye according to claim 8, wherein, the Carbomer is Carbopol.
10. gel for eye according to claim 8, wherein, the sodium hyaluronate for molecular weight for 80W-120W glass
Glass acid sodium.
11. gel for eye according to claim 8, wherein, the polyvinyl alcohol is polyvinyl alcohol 1799.
12. gel for eye according to any one of claim 1 to 7, its are also lived containing at least one non-ionic surface
Property agent.
13. gel for eye according to claim 12, wherein, the nonionic surfactant is polyethylene glycol -12-
Hydroxy stearic acid ester.
14. gel for eye according to claim 12, wherein, the nonionic surfactant is lived for non-ionic surface
Property agentHS15.
15. gel for eye according to claim 12, wherein, are calculated in percentage by weight, the non-ionic surface
The content of activating agent is 0.5%-15%.
16. gel for eye according to claim 12, wherein, are calculated in percentage by weight, the non-ionic surface
The content of activating agent is 0.5%-10%.
17. gel for eye according to claim 12, wherein, are calculated in percentage by weight, the non-ionic surface
The content of activating agent is 0.5%-5%.
18. gel for eye according to any one of claim 1 to 7, which is also comprising appointing in following (1)-(4)
One or more：
(1) pH of the gel for eye is 5.0-8.0；
(2) pH value regulator, which is selected from any one or more in NaOH and hydrochloric acid；
(3) osmotic pressure regulator, its are selected from any one or more in propane diols, glycerine, mannitol and sorbierite；
(4) bacteriostatic agent, its are selected from benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, Phenoxyethanol, benzyl carbinol and P-hydroxybenzoic acid
Any one or more in ester.
19. gel for eye according to claim 18, wherein, the pH of the gel for eye is 6.0-7.0.
20. gel for eye according to claim 18, wherein, the bacteriostatic agent is benzalkonium chloride and P-hydroxybenzoic acid
Any one or more in ethyl ester.
21. gel for eye according to claim 18, wherein, the content of the bacteriostatic agent is gel gross mass
0.001-0.05%.
22. gel for eye according to claim 18, wherein, the content of the bacteriostatic agent is gel gross mass
0.005-0.03%.
The preparation method of the gel for eye any one of 23. claims 1-22, comprises the steps：
1) mixed-matrix of Carbomer and polyvinyl alcohol is prepared；
2) aqueous solution obtained in other compositions in addition to gel-type vehicle is mixed with sodium hyaluronate matrix；
3) by step 1) and step 2) in product mix.
24. preparation methods according to claim 23, comprise the steps：
) Carbomer, sodium hyaluronate, polyvinyl alcohol is fully swelling with appropriate water respectively, dissolving, sterilizing, standby；
) will) the Carbomer matrix of gained mixed with polyvinyl alcohol matrix, standby；
) by after pH adjusting agent suitable quantity of water dissolved dilution, filtration sterilization, with) mixed-matrix of gained mixes, standby
With；
) Dorzolamide or its officinal salt, timolol or its officinal salt are dissolved in appropriate water, add optional suppression
Microbial inoculum, osmotic pressure regulator, dissolving, filtration sterilization, standby；
) by) and the sodium hyaluronate matrix of gained with) solution of gained mixes；
) will) and) mixing of the material of gained, benefit adds water to full dose and stirs and obtain final product.
Gel for eye any one of 25. claims 1-22 is preparing treatment and/or prevention and/auxiliary treatment green grass or young crops
Purposes in the medicine of light eye or drop intraocular pressure.
26. purposes according to claim 25, wherein, the glaucoma is primary, Secondary cases, congenital or mixed type
Glaucoma.
27. purposes according to claim 26, wherein, the primary glaucoma is that primary open-angle or primary are kept away
Angle-style glaucoma.
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| CN106214624A (en) * | 2016-08-22 | 2016-12-14 | 北京中燕瑞康医药科技开发有限公司 | For treating timolol maleate preparation and the application thereof of baby's Superficial hemangioma |
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