CN1148810A - Medicinal composition for treating glaucoma - Google Patents
Medicinal composition for treating glaucoma Download PDFInfo
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- CN1148810A CN1148810A CN95193130A CN95193130A CN1148810A CN 1148810 A CN1148810 A CN 1148810A CN 95193130 A CN95193130 A CN 95193130A CN 95193130 A CN95193130 A CN 95193130A CN 1148810 A CN1148810 A CN 1148810A
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- 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
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- 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
- A61P27/06—Antiglaucoma agents or miotics
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Abstract
一种治疗青光眼的药物组合物，该组合物含有(±)-4-氨基-2-[4-(四氢化-2-糠酰)-1-哌嗪基]-6，7-二甲氧基喹唑啉或其药物上容许的酸加成盐和药物上容许的载体。A pharmaceutical composition for treating glaucoma, the composition comprising (±)-4-amino-2-[4-(tetrahydro-2-furfuryl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically permissible acid addition salt thereof and a pharmaceutically permissible carrier.
Description
Technical field
The present invention relates to the glaucomatous pharmaceutical composition of a kind of treatment, said composition can reduce intraocular pressure effectively and can not cause any side effect when low concentration.
Technical background
Glaucoma be a kind of be the disease of feature with unusual rising of intra-ocular pressure power (intraocular pressure), it can bring out many relevant symptoms such as eyes fatigability, blurred vision, ocular pain and vision weaken gradually, even has and cause the danger of losing one's sight.The patient that this disease is arranged, eyeball is hard as stone, thus be called " stone glaucoma (stone glaucoma) ", and the pupil degree of depth is blue color, so be called " blue color glaucoma (blue glaucoma) ".
In the eyeball, aqueous fluids (water quality body fluid) ceaselessly circulates to keep constant (intraocular pressure=10～21mmHg) of intraocular pressure.Intraocular pressure is that when any appearance was unusual in these factors, intraocular pressure will raise, and caused occurring glaucoma by controls such as the effects of the elasticity of the circulation of blood or lymph fluid, eyeball, the nerve that innervates.
When this be because ocular disease when comprising that iritis, wound or vitreous hemorrhage cause unusually, the glaucoma of generation is called secondary glaucoma.In most of the cases, the glaucoma that is difficult to treat is a primary glaucoma, and this glaucoma shows as the unusual of unknown cause.
Primary glaucoma can be divided into following three classes: (1) acute inflammation glaucoma, (2) primary open angle glaucoma, (3) congenital glaucoma.
In order to treat glaucoma, the various medicines of usefulness all are in order to prevent increasing or the intraocular pressure that increases being reduced of intraocular pressure.Hitherto knownly fall the intraocular pressure agent and comprise sympathomimetic such as epinephrine.It is active and impel angle closure (angleclosure) to have platycoria when epinephrine is used for NAG, causes that sometimes intraocular pressure increases sharply and makes hypertension and cause pigmentation of conjunctiva through regular meeting.
Parasympathomimetic agent such as pilocarpine have the activity of myosis, and can cause thus has dark sensation or unusual regulating action in the visual field.
But in recent years, B-adrenergic receptor blocker such as timolol are widely used for treating glaucoma, because they have the activity (" Drug therapy practice series " of restraining water quality body fluid and producing, glaucomatous Drug therapy, the 70-75 page or leaf, 1990 (Drug TherapyPractical Series, The Drug Treatment of Glaucoma, pp70-75,1990)).But this B-adrenergic receptor blocker it is reported side effect such as bradycardia, cardiac insufficiency and the asthma attack that causes system entirely, so there is the patient of this symptom can not take this class medicine.
Suggestion is arranged, α
1-adrenoreceptor blocker impels body fluid to flow out, Buna azoles piperazine (bunazosine) hydrochlorate can increase the choroid blood flow, thereby become the therapeutic agent (" Japanese ophthalmology association magazine " of a new effective low tension glaucoma, the 42nd volume, the 710-714 page or leaf, 1991 (Journalof Japanese Society of Ophthalmology, Vol.42pp.710～714,1991)).But during with this compounds for treatment of glaucoma, owing to its vasodilator activity, the symptom of conjunctival congestion and pupil contraction can appear unavoidably.
On the other hand, beta-Adrenergic agonists can be used for this patient, but conventional beta-Adrenergic agonists such as salbutamol (sulbutamol) otherwise do not reach gratifying activity unless take in high concentration.Their high concentration administration can cause tangible conjunctival congestion, and successive administration then is impossible.
As mentioned above, do not find the satisfied medicine of the effective down treatment glaucoma of a kind of above-mentioned few side effects and low concentration so far as yet.
In addition, in recent years, it is reported (±) 4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6, the acid-addition salts, particularly its hydrochlorate (being called minipress herein) that 7-dimethoxyquinazoline (being called prazosin (terazosin) herein) and medicine thereof are allowed is useful decompression medicine (JP-A 52-48678).In addition, it is reported that minipress dihydrate water solublity is relatively poor, much more stable than minipress (anhydrous) in aqueous solution, thereby be more suitable in parenterai administration (JP-B2-31078).
Brief description
Fig. 1 shows after various trial drugs or normal saline splash into the eyes of the calm rabbit of normal pegmentation, and intraocular pressure is situation over time.Time after splashing into (hour) make abscissa, intraocular pressure (mmHg) is as vertical coordinate.Each value is represented average ± S, E (number of animals is 10).Among Fig. 1, code name " a " is a normal saline, and " b ", " c ", " d ", " e " and " f " are respectively 0.003%, 0.01%, 0.03%, 0.1% and 0.3% prazosin hydrochloride aqueous solution.Code name " * 1 " and " * 2 " are represented p＜0.05 and p＜0.01 (with respect to matched group) respectively, and these values are analyzed with the Dunnett test method(s).
Fig. 2 shows behind one of every kind of trial drug or the calm rabbit eyes of normal saline injection normal pegmentation, and the intraocular pressure of its another eyes (non-processing) is situation of change in time.(time after splashing into (hour) make abscissa, intraocular pressure (mmHg) is a vertical coordinate.Each value is represented average+S.E. (number of animals is 10).Among Fig. 2, code name " a " is a normal saline, and " b ", " c ", " d ", " e " and " f " are respectively 0.003%, 0.01%, 0.03%, 0.1% and 0.3% prazosin hydrochloride aqueous solution.
Fig. 3 shows behind the eyes of various trial drugs or the calm rabbit of normal saline injection normal pegmentation, and rabbit eye pupil bore dia is situation of change in time.Time after splashing into (hour) make abscissa, pupil diameter (mm) is made vertical coordinate.Each value is represented average ± S.E. (number of animals is 10).Among Fig. 3, code name " a " is a normal saline, and " b ", " c ", " d ", " e " and " f " are respectively 0.003%, 0.01%, 0.03%, 0.1% and 0.3% prazosin hydrochloride aqueous solution.
Fig. 4 has shown that its intraocular pressure is situation over time behind the eyes of 0.5% timolol (timolol) maleate eye solution or the calm rabbit of normal saline injection normal pegmentation.Time after splashing into (hour) make abscissa, intraocular pressure (mmHg) is made vertical coordinate (number of animals 10).Code name among Fig. 4 " a " and " g " represent normal saline and 0.5% Timolol eye solution respectively.
Fig. 5 has shown that it falls the active situation of intraocular pressure after various trial drugs and 0.5% thiophene Cor Equi peace maleate eye solution splashes into the eyes of the calm rabbit of normal pegmentation.Vertical coordinate representative splashes into after 8 hours area (AUC) (mmHg time) under the time graph from the beginning.Make baseline value with the intraocular pressure before splashing into when determining AUC.Among Fig. 5, code name " b ", " c ", " d ", " e " and " f " represent 0.003%, 0.01%, 0.03%, 0.1% and 0.3% prazosin hydrochloride aqueous solution respectively, and 0.5% Timolol eye solution represented in code name " g ".Code name " * 1 " and " * 2 " are represented p＜0.05 and p＜0.01 (with respect to Timolol) respectively, and these values are with the analysis of experiments of Dunnett.
DISCLOSURE OF INVENTION
The present inventor has carried out having discovered extensively and profoundly a kind of medicine, and this medicine does not have the shortcoming (side effect) of above-mentioned conventional medicine and have the intraocular pressure lowering activity under low concentration.As a result of, the present inventor finds that the described prazosin hydrochloride of above-mentioned publication has the active and side effect seldom of excellent intraocular pressure lowering of unanticipated, and it is still effective when low concentration simultaneously.Thereby finished the present invention.
The invention provides a kind of new glaucomatous pharmaceutical composition of the treatment with useful, said composition does not have above-mentioned shortcoming (side effect) and have very strong intraocular pressure lowering activity when low concentration.
That is to say, the invention provides the glaucomatous pharmaceutical composition of a kind of treatment, said composition comprise as shown in the formula (±)-4-amino-2-[4-(tetrahydrochysene-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline (being prazosin).
Or the carrier of allowing on acid-addition salts of allowing on its medicine and the medicine.
The acid-addition salts of allowing on the medicine comprises the salt that forms with mineral acid example hydrochloric acid, sulphuric acid etc. and and the salt that forms such as organic acid such as maleic acid, tartaric acid, citric acid.In these salt, preferably hydrochlorate (being prazosin hydrochloride), more preferably prazosin hydrochloride dihydrate.
Being used for the physico-chemical property of the acid-addition salts of allowing on the prazosin of pharmaceutical composition active component of the present invention or its medicine and production method describes in that for example above-mentioned JP-A52-48678 is existing.
As following experimental example confirmed, because pharmaceutical composition of the present invention has the excellent intraocular pressure effect of falling when low concentration, and toxicity was low, thereby can be used as the glaucomatous active drug of treatment all kinds.
The acid-addition salts of allowing on prazosin or its medicine is during as active ingredient in pharmaceutical, usually the carrier of allowing on the medicine that can this active component and this area is known, excipient, diluent etc. mix, and be processed into preparation that various non-intestinals use such as eye solution, ophthalmic ointment, injection etc. in accordance with known methods, perhaps make oral formulations such as tablet, capsule, granule etc.
When pharmaceutical composition of the present invention is when using with the form of eye solution, the additive that said composition adds in the time of can containing various conventional eye formulations prepared from solutions, as buffer agent, isotonic agent, antiseptic, solubilizer (stabilizing agent), PH regulator, thickening agent, chelating agen etc., they should be as far as possible to the negatively influencing that do not have of the object of the invention.
Buffer agent comprises for example phosphate buffer, borate buffer, citrate buffer agent, tartrate buffer agent, acetate buffer, aminoacid etc.
Isotonic agent for example comprises saccharide such as Sorbitol, glucose, mannitol etc., polyhydric alcohol such as glycerol, Polyethylene Glycol, propylene glycol etc. and salt such as sodium chloride etc.
Antiseptic comprises for example Benasept, the Benzene Chloride first and second oxygen amine, p-Hydroxybenzoate such as methyl hydroxybenzoate and ethyl ester etc., benzylalcohol, phenethanol, sorbic acid and salt thereof, thimerosal, methaform etc.
Solubilizer (stabilizing agent) comprises for example cyclodextrin and derivant, water-soluble polymer such as polyvinyl pyrrolidone etc., surfactant etc.
The PH regulator comprises for example hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide etc.
Thickening agent comprises for example hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof etc.
Chelating agen comprises for example edetate sodium, sodium citrate, condensed phosphoric acid sodium etc.
When pharmaceutical composition of the present invention was used as ophthalmic ointment, free wool fat, vaseline, plastic matrix (plastibase), liquid paraffin, Polyethylene Glycol etc. were fit to do the base material of ophthalmic ointment.
In addition, the form of form that pharmaceutical composition of the present invention also can oral formulations such as tablet, capsule, granule etc. or injection is used.
Pharmaceutical composition of the present invention can be used for treating the glaucoma of mammal such as people, Canis familiaris L., cat, rabbit, horse, cattle etc.
The dosage of pharmaceutical composition of the present invention depends on age of route of administration, symptom, patient and body weight etc., for example when suffering from glaucomatous adult with eye solution form administration, eye solution has the concentration range of the acid-addition salts of allowing on active component prazosin or its medicine to be generally about 0.001～3.0w/v%, be preferably about 0.01～1.0w/v%, the order of severity according to the state of an illness, application dosage is every day 1 to 6 time, each 1 to several.
When pharmaceutical composition of the present invention uses with the form of ophthalmic ointment, the concentration range of the acid-addition salts of being allowed on the active component prazosin that ophthalmic ointment contains or its medicine is generally about 0.001～10w/w%, be preferably 0.01～1.0w/w%, according to severity extent, preferably with once a day or about 4 times dosage use.
Pharmaceutical composition of the present invention can contain one or more other glaucoma treatment medicine, and condition is conflict to be arranged with purpose of the present invention.
Pharmaceutical composition of the present invention can contain the medicine of other different efficacies, and condition is conflict to be arranged with purpose of the present invention.
The following examples and test example will further describe the present invention and clear and definite effect of the present invention, but can not be interpreted as limitation of the scope of the invention.
Embodiment
Eye solution
Eye solution is to prepare by conventional method by following prescription:
Prazosin hydrochloride dihydrate 0.12g
(when calculating, being 0.1g) by prazosin
Concentrated glycerin 2.6g
Sodium acetate 0.1g
Benasept 0.005g
Dilute hydrochloric acid is an amount of
(PH6.0) with aseptic purify waste water add in the above-mentioned prescription to final volume be 100ml.
Eye solution
Press surface compositions and prepare eye solution by conventional method:
Prazosin hydrochloride dihydrate 0.036g
(when calculating, being 0.03g) by prazosin
Sodium chloride 0.9g
Sodium acetate 0.1g
Polyvinyl pyrrolidone 0.5g
Benasept 0.01g
Dilute hydrochloric acid is an amount of
(PH4.0)
With aseptic purify waste water add in the above-mentioned prescription to final volume be 100ml.
Embodiment 3
Ophthalmic solution
Prepare eye solution by following prescription by conventional method:
Prazosin hydrochloride dihydrate 0.36g
(when calculating, being 0.3g) by prazosin
Sodium chloride 0.9g
Sodium hydrogen phosphate 0.1g
Edetate sodium 0.05g
Benasept 0.01g
Sodium hydroxide is an amount of
(PH7.0)
With aseptic purify waste water add in the mentioned component to final volume be 100ml.
Ophthalmic solution
Prepare eye solution according to following prescription by conventional method:
Prazosin hydrochloride dihydrate 0.36g
(when calculating, being 0.3g) by prazosin
Concentrated glycerin 2.6g
Sodium acetate 0.1g
Benasept 0.005g
Dilute hydrochloric acid is an amount of
(PH6.0)
With aseptic purify waste water add in the mentioned component to final volume be 100ml.
Embodiment 5
Ophthalmic ointment
Prepare ophthalmic ointment by following prescription by conventional method:
Prazosin hydrochloride dihydrate 3.6g
(when calculating, being 3.0g) by prazosin
Liquid paraffin 1.0g
White vaseline is an amount of
Total amount 100g
Test example 1
The prazosin hydrochloride dihydrate inject behind the eyes of each pigmentation rabbit with normal intra-ocular tension the intraocular pressure effect of falling and to the intrinsic pressure influence of another pairing (being untreated) eye:
Select 60 about 2kg of body weight for use and confirm the unusual male pigmentation rabbit (Dutch belted rabbit) of no eyes, then it is raised in 24.4 ± 4 ℃ of temperature maintenances and humidity are 55 ± 15% receptacle.Each rabbit feeds with 100g food (LaboRG-RO, NihonNohsan Koggo K.K. produces) and allows it arbitrarily obtain tap water and make drinking water every day.
The medicine of test is following aqueous solution: containing prazosin concentration is the aqueous solution (being called 0.003% prazosin hydrochloride aqueous solution, 0.01% prazosin hydrochloride aqueous solution, 0.03% prazosin hydrochloride aqueous solution, 0.1% prazosin hydrochloride aqueous solution and 0.3% prazosin hydrochloride aqueous solution) of the prazosin hydrochloride dihydrate of 0.003w/v%, 0.01w/v%, 0.03w/v%, 0.1w/v% and 0.3w/v%.Normal saline is with comparing.
60 rabbits of above-mentioned raising are divided into six groups, every group of 10 rabbits.The eyes of every rabbit are dripped) 50 μ l trial drug or normal saline, the another eyes are not then handled.Measure two eyes of each rabbit splashing into before and splash into intraocular pressure after afterwards 0.5,1,2,4,6 and 8 hour with breathing scanning device (Alcon company produces, and is called " PTG " herein).
Various trial drugs and normal saline splash into the back intraocular pressure over time situation shown in Fig. 1 (eyes of handling) and Fig. 2 (untreated eyes).
Result shown in Figure 1 clearlys show, local application 0.3% prazosin hydrochloride aqueous solution can significantly reduce intraocular pressure, all can keep intraocular pressure to reduce in 30 minutes to 6 hours after splashing into medicine, and reach intraocular pressure decline peak value 7.3mmHg in back 1 hour splashing into.Also can be observed the remarkable reduction of intraocular pressure in 30 minutes to 4 hours after splashing into 0.1% prazosin hydrochloride aqueous solution, and splashing into the maximum 6.0mmHg that reached intraocular pressure decline in back 1 hour.Local application 0.03% prazosin hydrochloride aqueous solution is splashing in back 30 minutes to 2 hours and can significantly reduce intraocular pressure, splashes into to reach decline maximum 5.9mmHg in back 1 hour.Splash into 0.01% prazosin hydrochloride aqueous solution after 1 hour intraocular pressure can significantly descend, intraocular pressure decline maximum is 4.1mmHg.Splash into behind the 0.003% prazosin hydrochloride aqueous solution and to find that intraocular pressure decline maximum was 2.2mmHg in 30 minutes, but it is not remarkable to descend.
Fig. 2 (eyes are untreated) display result obviously shows, the eyes that are untreated of any one group of animal of handling with trial drug, and its intraocular pressure does not all have obvious variation.So, can reach a conclusion, prazosin hydrochloride can not influence the untreated eyes of another.
Test example 2
Splash into of the influence of prazosin hydrochloride dihydrate to pigmentation rabbit pupil diameter:
An one eye in the test example 1 have been used the various trial drugs of 50 μ l or normal saline (the another eyes are untreated) 60 rabbits each only, respectively behind 0.5,1,2 and 4 hour before splashing into and behind various trial drugs of local application or the normal saline, with the pupil diameter of two eyes of miking.
Handle back eye pupil diameter variation as shown in Figure 3 with various trial drugs and normal saline.Result shown in Figure 3 shows that with the eyes that various trial drugs are handled, its pupil diameter changes, and does not find that any one group of its pupil diameter of rabbit has tangible change in normal scope.So, can reach a conclusion, prazosin hydrochloride does not have influence to pupil diameter.
Test example 3
Pigmentation rabbit with normal intra-ocular tension splash into behind the prazosin hydrochloride dihydrate caused intraocular pressure decline effect with the comparison that causes intraocular pressure decline effect after the positive drugs compared (0.5% Timolol ophthalmic solution):
Select 10 rabbits of raising by top test example 1 described method for use, the eyes of every rabbit are used 0.5% Timolol ophthalmic solution (50 μ l) as positive drugs compared, the another eyes then splash into normal saline (50 μ l).Measure the intraocular pressure of two eyes during before splashing into and behind the various solution of local application 0.5,1,2,4,6 and 8 hour with PTG.The result as shown in Figure 4.
Result shown in Figure 4 clearlys show, splash into positive drugs compared, 0.5% Timolol ophthalmic solution only causes slight maximum intraocular pressure decline (2.5mmHg) after using 1 hour, compare with the eyes of using the normal saline processing simultaneously, intraocular pressure does not have tangible change.
Caused intraocular pressure behind various trial drugs of pigmentation rabbit local application with normal intra-ocular tension or the 0.5% Timolol eye solution is descended and can splash into to splashing into back 8 hours area under curve (AUC) to come relatively from beginning with the time, and the intraocular pressure before the local application is as baseline value.The result as shown in Figure 5.
Result shown in Figure 5 clearlys show, in 0.003% to 0.3% concentration range, prazosin hydrochloride to the pigmentation rabbit with normal intra-ocular tension can produce with concentration dependent, significantly the intraocular pressure effect falls.0.1% concentration fall that the intraocular pressure activity obviously is higher than 0.5% Timolol eye solution the intraocular pressure activity falls.
Test example 4
(1) prazosin hydrochloride is to the acute toxicity test of mice, rat and Canis familiaris L.:
Investigated prazosin hydrochloride to ICR mice and the Wistar rat acute toxicity after via oral, subcutaneous and intravenous route administration (with 50% lethal agent value (LD
50) expression).Also investigated the oral fatal dose of beagle (beagle dogs) prazosin hydrochloride.
Mice and rat are by the Tragacanth suspension of gavage per os feeding prazosin hydrochloride.Also prazosin hydrochloride can be dissolved in normal saline, with syringe to mice and rat skin lower injection or by the quiet notes of tail vein.In addition, can make the oral gelatine capsule that wraps up prazosin hydrochloride of Canis familiaris L..
The result is as shown in table 1:
Table 1
| ??????????????????LD 50(mg/kg) | Fatal dose (mg/kg) | |||||
| Mice | Rat | Canis familiaris L. | ||||
| Male | Female | Male | Female | Male | Female | |
| Oral | ???＞8000 | ?＞8000 | ??＞8000 | ?＞8000 | ????700 | ????700 |
| Subcutaneous administration | ????1523 | ???956 | ????1163 | ???1050 | ????- | ????- |
| Intravenously administrable | ????237 | ???262 | ????350 | ???361 | ????- | ????- |
(2) the eye local toxicity of rabbit local application 0.03%, 0.1% in continuous 28 days and 0.3% prazosin hydrochloride eye solution is tested:
24 male Japan rabbits (every group of six rabbits) are selected in this test for use.Trial drug is 0.03% prazosin hydrochloride eye solution, 0.1% prazosin hydrochloride eye solution and 0.3% prazosin hydrochloride eye solution.With normal saline in contrast.Various trial drugs or normal saline are splashed into the right eye of rabbit, and dosage is every day 4 times, is spaced apart 3 hours, each 1 (0.05ml), continuous 28 days.With following project evaluation eye toxicity.The left eye of every rabbit all is untreated.
Following (1) is observed to (6) are every:
(1) death and overall health of patients;
Observe death and the overall health of patients of all animals every day.
(2) measure body weight and appetite;
Weekly animal is weighed and definite its appetite.
(3) ophthalmic segment (anterior ocular segment) before the perusal
On the basis of improving the Draize method, ophthalmic segment before the perusal weekly.
(4) corneal test
Observe cornea with the reagent paper that has flooded luciferin weekly.
(5) check corneal epithelium with scanning electron microscope;
After splashing into various trial drugs, with scanning electron microscopic observation corneal epithelium form.
(6) with light microscopy cornea, conjunctiva and retina;
After splashing into various trial drugs, with optical microscope micro cornea, conjunctiva and retina.
The result is as follows: (1) no animal dead, and overall health of patients is no abnormal, and (2) any one group of animal with 0.03%, 0.1% and 0.3% prazosin hydrochloride eye solution-treated there is no the unusual of body weight and appetite during medication.(3) ophthalmic segment shows before the perusal, except the eyes conjunctiva that some experimental animal was handled is observed extremely slight the reddening (belonging to normal range).Do not see the abnormal phenomena relevant with any trial drug.In addition, the scanning electron microscope inspection of (4) corneal test, (5) corneal epithelium is not seen the abnormal phenomena relevant with any trial drug with (6) cornea, conjunctiva and amphiblestroid observation by light microscope yet.
Above-mentioned various result of the test proves, the pharmaceutical composition that the present invention contains prazosin hydrochloride matches eyes (eyes promptly are untreated) or pupil diameter to another does not have influence, almost is free from side effects (toxicity) and the excellent intraocular pressure activity of falling is arranged under low concentration.So pharmaceutical composition of the present invention is a kind of medicine as safe as a house clinically.
As mentioned above, pharmaceutical composition of the present invention is owing to there is the excellent intraocular pressure activity of falling under the low concentration, and toxicity is low, treats all kinds glaucoma so go for platform.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10367694 | 1994-05-18 | ||
| JP103676/94 | 1994-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1148810A true CN1148810A (en) | 1997-04-30 |
Family
ID=14360400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193130A Pending CN1148810A (en) | 1994-05-18 | 1995-05-15 | Medicinal composition for treating glaucoma |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0759756A1 (en) |
| JP (1) | JPH10500130A (en) |
| CN (1) | CN1148810A (en) |
| AU (1) | AU2420195A (en) |
| BR (1) | BR9507732A (en) |
| CA (1) | CA2187361A1 (en) |
| HU (1) | HUT76468A (en) |
| PL (1) | PL317190A1 (en) |
| TW (1) | TW304879B (en) |
| WO (1) | WO1995031200A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104840436A (en) * | 2015-06-11 | 2015-08-19 | 刘磊 | Medicine composition |
| CN114767688A (en) * | 2019-09-04 | 2022-07-22 | 武汉科福新药有限责任公司 | Transdermal penetration-promoting composition and application thereof in timolol preparation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2454544A1 (en) * | 2001-07-02 | 2003-01-16 | Santen Pharmaceutical Co., Ltd. | Optic nerve protecting agents containing .alpha.1 receptor blocker as active ingredient |
| WO2003006061A1 (en) * | 2001-07-13 | 2003-01-23 | Kissei Pharmaceutical Co., Ltd. | Medicinal compositions for opthalmic use |
| JPWO2017002846A1 (en) * | 2015-06-30 | 2018-05-24 | 株式会社ニデック | Visual function measuring device and visual function measuring program |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2824863B2 (en) * | 1989-07-12 | 1998-11-18 | エーザイ株式会社 | α ▲ Lower 1 ▼ -Blocker eye drops |
| DE69004066T2 (en) * | 1989-08-03 | 1994-02-17 | Eisai Co Ltd | METHOD FOR PHOTOSTABILIZING EYE WASHING SOLUTIONS. |
| US5256667A (en) * | 1991-09-25 | 1993-10-26 | Merck & Co., Inc. | Quinazolinones and pyridopyrimidinones |
-
1995
- 1995-05-15 EP EP95918186A patent/EP0759756A1/en not_active Withdrawn
- 1995-05-15 HU HU9603158A patent/HUT76468A/en unknown
- 1995-05-15 JP JP7529508A patent/JPH10500130A/en active Pending
- 1995-05-15 BR BR9507732A patent/BR9507732A/en not_active Application Discontinuation
- 1995-05-15 CA CA002187361A patent/CA2187361A1/en not_active Abandoned
- 1995-05-15 AU AU24201/95A patent/AU2420195A/en not_active Abandoned
- 1995-05-15 PL PL95317190A patent/PL317190A1/en unknown
- 1995-05-15 CN CN95193130A patent/CN1148810A/en active Pending
- 1995-05-15 WO PCT/JP1995/000920 patent/WO1995031200A1/en not_active Ceased
- 1995-05-18 TW TW084104919A patent/TW304879B/zh active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104840436A (en) * | 2015-06-11 | 2015-08-19 | 刘磊 | Medicine composition |
| CN104840436B (en) * | 2015-06-11 | 2017-12-05 | 刘磊 | Pharmaceutical composition |
| CN114767688A (en) * | 2019-09-04 | 2022-07-22 | 武汉科福新药有限责任公司 | Transdermal penetration-promoting composition and application thereof in timolol preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2187361A1 (en) | 1995-11-23 |
| BR9507732A (en) | 1997-08-19 |
| EP0759756A1 (en) | 1997-03-05 |
| WO1995031200A1 (en) | 1995-11-23 |
| PL317190A1 (en) | 1997-03-17 |
| TW304879B (en) | 1997-05-11 |
| HUT76468A (en) | 1997-09-29 |
| AU2420195A (en) | 1995-12-05 |
| HU9603158D0 (en) | 1997-01-28 |
| JPH10500130A (en) | 1998-01-06 |
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