CN102178644A - Timolol maleate (TM) eye gel and preparation method thereof - Google Patents
Timolol maleate (TM) eye gel and preparation method thereof Download PDFInfo
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- CN102178644A CN102178644A CN 201110113130 CN201110113130A CN102178644A CN 102178644 A CN102178644 A CN 102178644A CN 201110113130 CN201110113130 CN 201110113130 CN 201110113130 A CN201110113130 A CN 201110113130A CN 102178644 A CN102178644 A CN 102178644A
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Abstract
The invention provides timolol maleate (TM) eye gel and a preparation method thereof. One hundred grams of the eye gel comprises the following components by weight: 0.10-0.70g of TM, 0.10-2.0g of gel matrix, 0.2-5.0g of osmotic pressure regulator and the balance of water, wherein the gel matrix is a mixture of cellulose derivatives and carbopol and the weight ratio of cellulose derivatives to carbopol is 1:0.02-1, the cellulose derivatives comprise more than one of methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) and carboxymethyl cellulose (CMC), and the carbopol comprises one of polyacrylic acid (PAA), polyacrylate or crosslinking polyacrylic resin. Patients with glaucoma and ocular hypertension use the controlled-release TM eye preparation once a day; and the prescription of the eye preparation is free of preservatives, thus lowering stimulation to eyes and improving medication safety if the gel is used for a long term.
Description
Technical field
The present invention relates to the timolol maleate preparation.
Background technology
Timolol maleate is a kind of nonselective beta receptor blocker, does not have tangible endogenous to intend sympathetic activity drawn game anaesthetic effect, and cardiac muscle is not had direct repression.Timolol maleate eye drops is one of the most frequently used medicine of treatment glaucoma, to high intraocular pressure patient with the intraocular pressure of falling effect is normally arranged per capita, be applicable to primary open angle glaucoma, secondary glaucoma, ocular hypertension and part primary angle-closure glaucoma.For adopting other drug or the invalid glaucoma of operative treatment, also can use this product and treat.But timolol eye drop consumption is excessive or whole body absorbs more for a long time, also can produce tangible systemic side effects, as bradycardia, arrhythmia, bronchospasm etc.
The reducing iop of timolol maleate external eye drip is rapid-action, and 20～30 minutes intraocular pressures promptly began to descend after the administration, reached ceiling effect through 1～2 hour.But because the influence of nictation and lacrimal secretion, the retention time at eye after the ordinary eye drops administration is short, and the dose of absorption only accounts for the minimum part of dosage usually, and this just requires solution-type eye drop repetitively administered.Though the sustainable long period of the reducing iop of timolol maleate, the timolol eye drop on the domestic market still requires administration every day 2 times.On the other hand, high intraocular pressure is glaucoma patient especially, needs long-term prescription usually, and all contains antiseptic in the at present commercially available Timolol maleate eye drops.Studies show that in a large number the ophthalmic preparation that life-time service contains antiseptic can bring zest and harm to eyes inevitably.
Drugs approved by FDA a kind of of Merck ﹠ Co., Inc. its gel-type vehicle is the ion-sensitive Gellan gum with timolol instant gel (Timoptic-XE, gel formingsolution), and contain bromo geramine (0.012%) in this prescription and make antiseptic.The another kind of eye timolol instant gel of being produced by Alcon Universal Ltd. (Timolast, gel formingsolution), its gel-type vehicle is an albumen sensitivity xanthan gum, also contains bromo geramine (0.012%) in the prescription and makes antiseptic.Chinese patent CN101342176 discloses a kind of timolol maleate instant gel for eye, and its gel-type vehicle is selected from one or more in methylcellulose, ethyl cellulose, Polyethylene Glycol, polyacrylic acid and the sodium polyacrylate, and contains antiseptic in the prescription.Chinese patent CN1634071 discloses a kind of timolol gel for eye use, and its gel-type vehicle is cellulose derivative such as methylcellulose, hydroxypropyl cellulose, hypromellose etc.Chinese patent CN101401791 discloses a kind of Timolol liposome and preparation method thereof, its objective is to prolong the retention time of preparation in eye.Chinese patent CN101474146 discloses Timolol maleate eye drops of a kind of not bacteriostatic agent and preparation method thereof, but patent is the solution-type eye drop, and unresolved medicine is in short this problem of eye retention time.In a word, the said goods and patent all do not solve the zest problem of timolol maleate eye drop at eye retention time weak point and antiseptic life-time service simultaneously.
Summary of the invention
The purpose of this invention is to provide a kind of timolol maleate gel for eye and preparation method thereof, to overcome the above-mentioned defective that prior art exists.
Timolol maleate gel for eye of the present invention, in the 100g gel, contain the component of following weight:
Timolol maleate 0.10-0.70g, preferred 0.30～0.68g, most preferably 0.34～0.68g
Gel-type vehicle 0.10～2.0g, preferred 0.2～2.0g, most preferably 0.5～1.6g
Osmotic pressure regulator 0.2～5.0g, preferred 2.0～4.5g, most preferably 3.0～4.5g
Water is supplied 100g
Described gel-type vehicle is the mixture of cellulose derivative and carbopol, and weight ratio is:
Cellulose derivative: carbopol=1: 0.02～1;
Preferably: cellulose derivative: carbopol=1: 0.04～0.67;
Described cellulose derivative comprises a kind of or its combination in any in methylcellulose, hydroxy methocel, hypromellose, the carboxymethyl cellulose, preferred hypromellose (is called for short HPMC, down together), more preferably viscosity is the hypromellose of 1000～30000cP, as to block happy Kanggong department specification be products such as HPMC E4M or HPMC E10M;
Wherein, HPMC E4M viscosity is 4000cP, and HPMC E10M viscosity is 15000cP;
The test condition of HPMC viscosity is: in the time of 20 ℃, weight concentration is 2% hypromellose aqueous solution;
Described carbopol comprises a kind of in polyacrylic acid, polyacrylate or the crosslinked polypropylene acid resin, preferred crosslinked polypropylene acid resin (is called for short carbopol, down together), more preferably adopting viscosity is the carbopol of 2000-30000cP, is products such as carbopol 971 or carbopol 981 as the Lubrizol company standard;
The viscosity of carbopol 971 is 7000cP, and carbopol 981 viscositys are 6000cP;
The test condition of the viscosity of carbopol is: in the time of 20 ℃, weight concentration is 0.5% carbopol aqueous solution;
Cellulose derivative and carbopol can produce significant rheology synergism in aqueous solution.For example, during with hypromellose E4M/E10M aqueous solution and carbopol 971 aqueous solution, the viscosity of solution is significantly higher than the viscosity sum under the same concentrations separately, has significant rheology synergism, and is as shown in table 1 below.This shows, cellulose derivative and and carbopol in aqueous solution, can form the polymer interpenetration network gel, so the present invention realizes the slow releasing function of timolol with cellulose derivative and the carbopol combination substrate as gel.
The rheology synergism of table 1 hypromellose (HPMC) and carbopol (CP971) (k value adopts the BrookField viscosimeter to record)
In the table 1: 0.5%HPMC E4M represents to contain in the 100 gram solution 0.5 gram HPMC E4M; Contain 0.5 gram HPMC E4M and 0.04 gram CP 971 in 0.5%HPMC E4M and the 0.04%CP 971 expressions 100 gram solution.
Other implication is identical.
The preferred nonionic chemical compound of described osmotic pressure regulator is as mannitol, sorbitol, glucose, glycerol or propylene glycol etc.
Preferably, described timolol maleate gel for eye in the 100g gel, also comprises 0.01～0.05g, and the EDTA of preferred 0.02～0.03g or EDTA-2Na are as chelating agent, to improve stability of formulation.
Described gel prescription does not contain any antiseptic.Antiseptic has zest to eyes, especially may cause serious zest during life-time service.Therefore, timolol maleate sustain-released ophthalmic gels of the present invention does not contain antiseptic, is disposable unit dose package sterile preparation.
The preparation method of timolol maleate sustain-released ophthalmic gels of the present invention comprises the steps:
Hypromellose and carbopol respectively at soaked overnight in the water of gross weight 25～35%, are stirred the mixed solution that obtains hydroxypropyl methylcellulose and carbopol solution, standby;
With timolol maleate, osmotic pressure regulator and stabilizing agent, the water that adds gross weight 25～35%, stir dissolving down, microporous filter membrane filters, and then filtrate is joined in the hydroxypropyl methylcellulose and carbopol mixed solution of above-mentioned preparation, and adding weight concentration and be 3～15% NaOH solution, to transfer to pH be 6.0-7.5, adding the entry ad pond om then is 100 grams, stirring and evenly mixing, sterilization obtains the timolol maleate gel for eye.
Timolol maleate gel for eye of the present invention can be used for the treatment of diseases such as high intraocular pressure and glaucoma, and dosage is generally 1 time/day, and each giving suffered from 1 of eye, and be concrete, can be determined by the doctor according to patient's the state of an illness, age etc.
The slow release timolol maleate ophthalmic preparation that the present invention provided be administered once in a kind of one day for glaucoma and high intraocular pressure patient, said preparation is slow-releasing gel used, but prolong drug is in the retention time of eye, reduce administration number of times and dosage, not only improve patient's compliance, and can reduce side effects of pharmaceutical drugs.Simultaneously, said preparation does not contain any antiseptic, adopts unit dose package, has reduced the zest of eye drop life-time service to eye, has improved the safety of medication greatly.
The present invention selects to produce the synergistic hypromellose of rheology and carbopol as mixed gel substrate, utilizes two kinds of macromolecular materials to form the polymer interpenetration network gels, preparation timolol maleate gel for eye.Because both have significant rheology synergism, lower consumption can produce full-bodied gel, thereby prolong drug is in the holdup time of eye, on the other hand, positively charged medicine timolol can form complex by electrostatic interaction with electronegative carbopol, thereby further delay the release of timolol, produce better slow releasing function, and reduce side effects of pharmaceutical drugs from gel.Simultaneously, gel for eye of the present invention does not contain antiseptic, thus when having reduced life-time service to the zest of eye, improved drug safety.
The specific embodiment
Below by specific embodiment to and the invention be described further.
Embodiment 1
Hypromellose E4M and carbopol 971 respectively at soaking liquid in the 30 gram waters for injection, are stirred, obtain solution, standby.
With timolol maleate, mannitol and EDTA-2Na, add injection water 30 grams, stir dissolving down, microporous filter membrane filters.
Filtrate is joined in the hypromellose and carbopol solution of above-mentioned preparation, adding weight concentration and be the pH that 10% NaOH solution transfers to system is 6.5, and to add the water for injection ad pond om be 100 grams, stirs, the irradiation method sterilization obtains the timolol maleate gel for eye.
Embodiment 2
Preparation method is with embodiment 1.
Embodiment 3
Preparation method is with embodiment 1.
Embodiment 4
Preparation method is with embodiment 1.
Embodiment 5
Preparation method is with embodiment 1.
Embodiment 6
Preparation method is with embodiment 1.
Embodiment 7
Preparation method is with embodiment 1.
Embodiment 8
The timolol maleate eye is exempted from the external permeability of cornea to family with sustained-release gel
Normal rabbits is put to death, separate complete cornea.Cornea is fixed on the diffusion cell, and cornea inboard (aqueous humor side) towards accepting the pond, accepts that acceptable solution is a normal saline in the pond.The timolol maleate eye of getting embodiment 1 places supply pool with sustained-release gel (TMG) 0.5 gram, sees through experiment under 37 ℃.Timolol maleate normal saline solution (TMS) with same concentrations compares.From accept the pond, get acceptable solution 0.2ml respectively at different time, replenish the normal saline of equal volume.The HPLC method is measured the concentration of timolol in the acceptable solution, and experimental result sees Table 2.
Table 2TMG and TMS are to the external permeability of tame rabbit cornea
By table 2 as seen, see through in the test at external cornea, in the identical time, the amount that medicine in the gel sees through cornea is few than aqueous solution, this mainly is because the diffusion velocity of medicine in gel is slow than aqueous solution, and have stronger electrostatic interaction between medicine and carbopol, thereby further delayed the diffusion of medicine and see through.
Embodiment 9
Family exempts from eye and gives behind the timolol sustained-release gel timolol concentrations in the tear
Get 6 of normal rabbits, be divided into two groups at random, 3 every group.The eye of getting embodiment 1 is administered to the experimental group rabbit in the eyes with sustained-release gel (TMG) 50 μ l, and matched group gives the timolol maleate normal saline solution (TMS) of same concentrations and dosage.Different time after administration places house to exempt from the conjunctival sac 30s with an amount of absorbent cotton and dips in and get tear, take by weighing tear weight, and with behind the mobile phase eluting, the concentration of timolol the results are shown in Table 3 in the HPLC method mensuration tear.
Table 3 family exempts from eye and gives the timolol concentrations in the different time tear behind TMS and the TMG
By table 3 as seen, family exempts from eye and gives behind the timolol sustained-release gel solution that timolol concentrations in the different time tear is significantly higher than the identical time, shows that solution can be removed rapidly, and the retention time significant prolongation of gel in eye.
Embodiment 10
Family exempt from eye give the timolol maleate eye with sustained-release gel after drug level in the aqueous humor
Get house and exempt from 12, be divided into two groups at random, 6 every group.The eye of getting embodiment 1 is administered to the experimental group rabbit in the eyes with sustained-release gel (TMG) 50 μ l, and matched group gives the maleic acid thiophene Ma Luoer normal saline solution (TMS) of same concentrations and dosage.Respectively at two rabbit of execution in 1,3 and 5 hour after the administration, get aqueous humor, the concentration with timolol in the HPLC method mensuration aqueous humor the results are shown in Table 4.
Table 4 rabbit eye gives the timolol concentrations in the aqueous humor behind TMS and the TMG
ND: do not detect timolol
By table 4 as seen, after the rabbit eye gave the timolol sustained-release gel, the drug level in the aqueous humor was significantly higher than the solution of identical dosage in the identical time, as give gel after 3 hours in the aqueous humor concentration of timolol be about 7 times of solution.This shows that gel helps medicine to see through the cornea absorption in the long retention time of eye, improves bioavailability.Gel has remarkable advantages than regular solution agent.
Embodiment 11
Family exempt from eye give the timolol maleate eye with sustained-release gel after drug level in the aqueous humor
Get house and exempt from 12, be divided into two groups at random, 6 every group.The eye of getting embodiment 3 is administered to the experimental group rabbit in the eyes with sustained-release gel (TMG) 50 μ l, and matched group gives the maleic acid thiophene Ma Luoer normal saline solution (TMS) of same concentrations and dosage.Experimental technique the results are shown in Table 5 with embodiment 10.
Table 5 rabbit eye gives the timolol concentrations in the aqueous humor behind TMS and the TMG
ND: do not detect timolol
By table 5 as seen, after the rabbit eye gives the timolol sustained-release gel, drug level in the aqueous humor is significantly higher than the solution of same dose, as give gel after 3 hours in the aqueous humor concentration of timolol be 0.2 μ g/ml, and give this moment to detect less than timolol in the rabbit aqueous humor of same concentrations and dosage solution.This shows that gel helps medicine to see through the cornea absorption in the long retention time of eye, improves bioavailability.Gel has remarkable advantages than regular solution agent.
Embodiment 12
Family exempt from eye give the timolol maleate eye with sustained-release gel after drug level in the aqueous humor
Get house and exempt from 12, be divided into two groups at random, 6 every group.The eye of getting embodiment 5 is administered to the experimental group rabbit in the eyes with sustained-release gel (TMG) 50 μ l, and matched group gives the maleic acid thiophene Ma Luoer normal saline solution (TMS) of same concentrations and dosage.Experimental technique the results are shown in Table 6 with embodiment 10.
Table 6 rabbit eye gives the timolol concentrations in the aqueous humor behind TMS and the TMG
ND: do not detect timolol
By table 6 as seen, after the rabbit eye gives the timolol sustained-release gel, in the identical time, drug level in the aqueous humor is significantly higher than the solution of same dose, as give gel after 5 hours in the aqueous humor concentration of timolol be molten 0.06 μ g/ml, and the detection of rabbit aqueous humor of solution that gives same concentrations and dosage this moment is less than timolol.This shows that gel helps medicine to see through the cornea absorption in the long retention time of eye, improves bioavailability.Gel has remarkable advantages than regular solution agent.
Claims (10)
1. the timolol maleate gel for eye is characterized in that, in the 100g gel, contains the component of following weight:
Described gel-type vehicle is the mixture of cellulose derivative and carbopol, and weight ratio is:
Cellulose derivative: carbopol=1: 0.02～1;
Described cellulose derivative comprises more than one in methylcellulose, hydroxy methocel, hypromellose, the carboxymethyl cellulose; Described carbopol comprises a kind of in polyacrylic acid, polyacrylate or the crosslinked polypropylene acid resin.
2. timolol maleate gel for eye according to claim 1 is characterized in that, contains the component of following weight:
Cellulose derivative: carbopol=1: 0.04～0.67.
3. timolol maleate gel for eye according to claim 2 is characterized in that, contains the component of following weight:
4. timolol maleate gel for eye according to claim 1 is characterized in that, described osmotic pressure regulator is mannitol, sorbitol, glucose, glycerol or propylene glycol.
5. timolol maleate gel for eye according to claim 2 is characterized in that, described osmotic pressure regulator is mannitol, sorbitol, glucose, glycerol or propylene glycol.
6. timolol maleate gel for eye according to claim 3 is characterized in that, described osmotic pressure regulator is mannitol, sorbitol, glucose, glycerol or propylene glycol.
7. according to each described timolol maleate gel for eye of claim 1～6, it is characterized in that the viscosity of described hypromellose is 1000～30000cP, described cross linked polyacrylate resin viscosity is 2000-30000cP;
The test condition of hypromellose viscosity is: in the time of 20 ℃, weight concentration is 2% hypromellose aqueous solution;
The test condition of the viscosity of crosslinked polypropylene acid resin is: in the time of 20 ℃, weight concentration is 0.5% carbopol aqueous solution.
8. timolol maleate gel for eye according to claim 7 is characterized in that, described cellulose derivative is HPMC E4M or HPMC E10M, and described carbopol is carbopol 971 or carbopol 981.
9. timolol maleate gel for eye according to claim 8 is characterized in that, in the 100g gel, also comprises stabilizing agent 0.01～0.05g, and described stabilizing agent is EDTA or EDTA-2Na.
10. according to the preparation method of each described timolol maleate gel for eye of claim 1～5, it is characterized in that, comprise the steps: hypromellose and carbopol respectively at soaked overnight in the water for injection of gross weight 25～35%, stir the mixed solution that obtains hydroxypropyl methylcellulose and carbopol solution, standby; With timolol maleate and osmotic pressure regulator and stabilizing agent, the water for injection that adds gross weight 25～35%, dissolving, filter, then filtrate is joined in the hydroxypropyl methylcellulose and carbopol mixed solution of above-mentioned preparation, adding weight concentration and be 3～15% NaOH solution, to transfer to pH be 6.0-7.5, and adding the entry ad pond om then is 100 grams, obtains the timolol maleate gel for eye.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102614109A (en) * | 2012-04-16 | 2012-08-01 | 上海现代药物制剂工程研究中心有限公司 | Active substance-contained gel composite based on multilayer liquid crystal framework and method for producing same |
| CN105663029A (en) * | 2016-01-13 | 2016-06-15 | 杭州市儿童医院 | Bioadhesion slow-release gel preparation for oral administration and preparation method thereof |
| CN106619573A (en) * | 2016-12-27 | 2017-05-10 | 广州中大南沙科技创新产业园有限公司 | Timolol maleate cubic liquid crystal nanoparticle eye drops and preparation method thereof |
| WO2019056751A1 (en) * | 2017-09-22 | 2019-03-28 | 沈阳兴齐眼药股份有限公司 | Ophthalmic sustained-release medicament delivery system and preparation method therefor |
| CN114073670A (en) * | 2020-08-11 | 2022-02-22 | 武汉科福新药有限责任公司 | Timolol maleate gel eye drops and preparation method thereof |
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| CN101474146A (en) * | 2009-01-06 | 2009-07-08 | 河北科技大学 | Timolol maleate eye drops without bacteriostatic agent and preparation method thereof |
| CN101618010A (en) * | 2008-07-03 | 2010-01-06 | 北京大学 | Aciclovir eye pH-sensitive in-situ gel and preparation method |
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| CN101185645A (en) * | 2007-11-21 | 2008-05-28 | 吉林大学 | Cromoglyn sodium gel eyedrop and preparation method |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102614109A (en) * | 2012-04-16 | 2012-08-01 | 上海现代药物制剂工程研究中心有限公司 | Active substance-contained gel composite based on multilayer liquid crystal framework and method for producing same |
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| CN105663029A (en) * | 2016-01-13 | 2016-06-15 | 杭州市儿童医院 | Bioadhesion slow-release gel preparation for oral administration and preparation method thereof |
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| WO2019056751A1 (en) * | 2017-09-22 | 2019-03-28 | 沈阳兴齐眼药股份有限公司 | Ophthalmic sustained-release medicament delivery system and preparation method therefor |
| CN114073670A (en) * | 2020-08-11 | 2022-02-22 | 武汉科福新药有限责任公司 | Timolol maleate gel eye drops and preparation method thereof |
| CN114073670B (en) * | 2020-08-11 | 2023-02-24 | 武汉科福新药有限责任公司 | Timolol maleate gel eye drops and preparation method thereof |
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