CA2187361A1 - Pharmaceutical composition for treating glaucoma containing terazosin - Google Patents
Pharmaceutical composition for treating glaucoma containing terazosinInfo
- Publication number
- CA2187361A1 CA2187361A1 CA002187361A CA2187361A CA2187361A1 CA 2187361 A1 CA2187361 A1 CA 2187361A1 CA 002187361 A CA002187361 A CA 002187361A CA 2187361 A CA2187361 A CA 2187361A CA 2187361 A1 CA2187361 A1 CA 2187361A1
- Authority
- CA
- Canada
- Prior art keywords
- intraocular pressure
- pharmaceutical composition
- terazosin
- pharmaceutically acceptable
- glaucoma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical composition for treating glaucoma which comprises ()-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
Description
2 1 8 7 3 6 1 r~"l. ~ ,520 Pharmaceut~cal composition for treating glaucoma contaln'lng terazos~n TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for treating glaucoma which has a potent intraocular pressure lowering effect at low concentrations without causing any side effects.
BACKGROUND MT
~,laucoma is a disease characterized by an abnormally high ~ ,stiuLe within the eyeball (intraocular pressure) which provokes various associated symptoms, such as fatigability in the eye, blurred vision, pain in the eye and gradually impaired vision, eventually leading to the risk of loss of vision. In patients with this disease, the eyeball hardens like stone so it is called "stone glaucoma ', and the depth of the pupil looks blue so it is called "blue glaucoma .
In the eyeball, a watery fluid (aqueous humor) c$rculates invariably to maintain a constant pressure within the eye (intraocular pressure = 10 to 21 mmHg). This is controlled by the circulation of blood or lymph, resilience of the eyeball, action of the innervated nerve, etc., and when either of such factors becomes abnormal, the intraocular pressure rises and glaucoma develops.
Wo 95/31200 r~l/J. ,~ . ~0 2!87~61 When 6uch Ahnnrr-l ity is caused by ophthalmic diseases including iritis, wounds or vitreous hemorrhage, the resulting glaucoma is termed secondary glaucoma. In most cases, therapeutically problematic glaucoma is primary glaucoma, which manifests Ahnorr~lities for unknown cause.
Primary glaucoma falls into the following three categories: (1) inflammatory glaucoma whose progress is acute, ~ 2 ) simple glaucoma whose progress is chronic and ( 3 ) congenital glaucoma.
In order to treat glaucoma, heretofore, various drugs have been used to prevent a rise in intraocular pressure or reduce increased intraocular pressure. Intraocular pressure reducing agents known so far include sympathomimetic drugs such as ~rin~rhrine. Epinephrine has mydriatic activity and prompts angle closure when applied to narrow angle glaucoma, and sometimes causes a rapid increase in intraocular pressure and often produces an increase in blood pressure and pigmentation in the con~unctiva.
Parasympathomimetic drugs such as pilocarpine have miotic activity and thereby cause a sensation of darkness or abnormal regulation in the visual field.
In recent years, furthermore, ,~-adrenergic blocking agents such as timolol have been extensively used for the treatment of glaucoma because they have inhibitory activity 25 against production of the aqueous humor ( Drug Therapy -WO 95/3l200 2 1 8 7 3 6 1 r~l~J
Practical Series, The Drug Treatment of Glaucoma, pp.70 to 75, 1990 ) . Such ,~-adrenergic blocking agents, however, have been reported to cause systemic side effects such a6 bradycardia, cardiac insufficiency and asthma onset, and they cannot therefore be administered to patients with such symptoms.
It is suggested that t~-adrenergic blocking agents promote the a~[ueous outflow, and buna20sine hydrochloride can increase the choroidal blood flow and become a potential novel therapeutic agent against low tension glaucoma (Journal of Japanese Society of Ophthalmology, vol.42 pp.710 to 714, 1991). When this compound is used for the treatment of glaucoma, however, the con~unctival hyperemia and miosis owing to its vasodilatory activity are inevitable.
On the other hand, ~-adrenergic stimulants are expected to be given to such patients, but conventional ~-adrenergic stimulants such as sulbutamol fail to exhibit satisfactory activity unless applied at high concentrations.
Their administration at high concentrations causes marked conjunctival hyperemia, and their continuous administration is regarded as impossible.
As described above, no satisfactory therapeutic agents for glaucoma that have few side effects described above and are effective at a low concentration have so far been f ound .
WO 95/31200 E ~_l/JI .7i.'t j20 21~73~1 ~
By the way, in recent year9, Lt has been reported that ( + ) -4-amino-2- [ 4 - ( tetrahydro-2-furoyl ) -1 -piperazinyl ] -6,7-dimethoxyquinazoline (hereinafter referred to as terazosin ) and its pharmaceutically acceptable acid addition salts, particularly its hydrochloride salt (hereinafter referred to as terazosin hydrochloride), are useful as hypotensive agents (JP-A 52-48678). In addition, it is reported that terazosin hydrochloride dihydrate is less water-soluble but far more stable in an aqueous solution than terazosin hydrochloride (anhydride), and thus is more suitable for parenteral administration (JP-B 2-31078 ) .
BRIEF DESCRIPTIO~S OF DRAWINGS
Fig. 1 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when each test drug or physiological saline was instilled to their eyes.
Time (hour) after instillation is plotted as abscissa and intraocular pressure (mm~}g) as ordinate. Each value represents mean + S.E. (the number of animals is 10). In Fig.
1, the symbol ~ a~ designates physiological saline, and the symbols "b", "c, "d", e" and "f" designate 0.003 %, 0.01 %, 0 . 03 %, 0 .1 ~ and 0 . 3 % aqueous solutions of terazosLn hydrochloride, respectively. The symbols "*1' and ~*2~
designate p<0.05 and p<0.01 (vs Control), respectively, which were analyzed using Dunnett ' s test .
.~
~ WO9~/31200 218736! r~llJ.'~.21~
.
Fig. 2 is a graph showing time-course changes of intraocular pressure of fellow (non-treated) eyes of normal pigmented rabbits when each test drug or physiological saline was instilled into one of their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate. Each value represents mean + S.E. (the number of animals is 10). In Fig. 2, the symbol "a"
designates physiological saline, and the symbols 'b~, ''c~, '-d", 'e" and "f" designate 0.003 %, 0.01 %, 0.03 ~, 0.1 % and 0 . 3 % aqueous ~olutions of terazosin hydrochloride, respectively .
Fig. 3 i8 a graph showing time-course changes of pupil diameter in normal pigmented rabbits when each test drug or physiological saline was instilled into their eyes. Time (hour) after instillation is plotted as abscissa and pupil diameter (mm) as ordinate. Each value represents mean ~ S.E.
(the number of animals is 10). In Fig. 3, the symbol ''a"
designates physiological saline, and the symbols "b', "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 9s and 0 . 3 % aqueous solutions of terazosin hydrochloride, respectively .
Fig. 4 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when 0.5%
timolol maleate ophthalmic solution or physiologically saline was instilled into thei:c eyes. Time (hour) after instillation Wo 95/31ZO0 , r~l/J. ,~ S~O
2~ 8736:1 --is plotted as abscissa and intraocular pressure (mmHg ) as ordinate (the number of animals is 10 ) . In Fig . 4, the symbols "a~' and "g'' designate physiological 9aline and 0.5 %
timolol maleate ophthalmic solution, respectively.
Fig. 5 is a graph showing intraocular pressure reducing activity of each test drugs and 0.5 96 timolol maleate ophthalmic solution when they were instilled into eyes o~
normal pigmented rabbits. The ordinate represents areas under curve of time (AUC) (mmHg-time) from the first instillation to 8 hours after then. AUC was detPrminPtl using intraocular pressure before instillation as a baseline value. In Fig. 5, the symbols "b", '-c", d-, 'e- and "f desLgnate 0.003 %, 0.01 96, O . 03 %, O .1 % and O . 3 % aqueous solutions of terazosin hydrochloride, respectively, and the symbol "g" designates 0.5 96 timolol maleate ophthalmic solution . The symbols ' *l " and "*2" designate p~O . 05 and p<0 . 01 (vs timlol maleate), respectively, which were analyzed using Dunnett's test.
DISCLOSURE OF INVENTION
The present inventors conducted intensive research to find a drug that has no defects (side effects) of conventional drugs as mentioned above and has intraocular pressure reducing activity at low concentrations. As a result, the present inventors have found that terazosin hydrochloride described in the above publications has ~ WO 9~131200 2 1 ~3 7 3 6 1 r~ 20 unexpectedly excellent intraocular pressure reducing activity and few side effects, wh~ - it is effective at lower concentrations. Thus, the present invention has been completed .
The present invention is to provide a novel and useful pharmaceutical composition for treating glaucoma that is free from the above defects (side effects) and has potent intraocular pressure reducing activity at low concentrations.
That is, the present invention provides a pharmaceutical composition for treating glaucoma which comprises (+)-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline (i.e., terazosin) of the f ormula:
CH30~`~N ~~ 0~
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloride, sulfate, etc., and those with organic acids such as maleate, tartrate, citrate, etc. Among the salts, the hydrochloride WO 95/31200 r~,l,J~ ~ n .20 (i.e., terazo6in hydrochloride) is preferable, and terazosin hydrochloride dihydrate is more preferable.
Physicochemical properties and production process of terazosin or its pharmaceutically acceptable acid addition salts used as an active ingredient of the pharmaceutical composition of the present invention are described, for ex~mple, in the above-mentioned JP-A 52-48678.
Since the pharmaceutical composition of the present invention, as demonstrated by the test examples below, has an excellent intraocular pressure reducing effect at low concentrations and has low toxicity, it can be used as an effective drug in the treatment of various types of glaucoma.
In using terazosin or its pharmaceutically acceptable acid addition salt as an active ingredient of the pharmaceutical composition, such active ingredient can usually be mixed with per se known pharmacologically acceptable c~rriers, excipients, diluents, etc., and processed according to known methods into preparations for parenteral application such as ophthalmic solutions, ophthalmic ointments, in~ectable solutions, etc., or preparations for oral administration such as tablets, capsules, granules, etc.
When the pharmaceutical composition of the present invention is used in the form of an ophthalmic solution, for example, the composition may contain various type of additives which are conventionally formulated into ophthalmic solutions, WO~5/31200 ~ ~ 8 ~3 P~l/J~. _'t ~G
_ g _ such as buffers, isotonizing agents, preservativeS, solubilizers ( stabilizers ), pH regulating agents, thickening agents , chelating agents , etc ., as far as they would not affect adversely the objective of the present invention.
The buffers include, for example, phosphate buffers, borate buffers, citrate buffers, tartr~te buffers, acetate buffers, amino acids, etc.
The isotonizing agents include, for example, sugars such as sorbitol, glucose, mannitol, etc., polyhydric alcohols such as glycerol, polyethylene glycol, propylene glycol, etc., and salts such as sodium chloride, etc.
Thepreservativesinclude, forexample, b~n7~lk--nium chloride, benzethonium chloride, p-hydroxybenzoic acid esters such as methyl and ethyl hydroxybenzoates , etc ., benzyl alcohol, phenethyl alcohol, sorbic acid or its salts, th i -- - usal, chlorobutanol, etc .
Thesolubilizers (stabilizers) include, forexample, cyclodextrins and their derivatives, water-soluble polymers such as polyvinylpyrrolidone and the like, surf actants, etc .
The pH regulating agents include, for example, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc.
The thickening agents include, for example, hydroxy-ethylcellulose, hyd, U~y~Lu~?ylcellulose, methylcellulose, W09~200 j ~? l 8~36~ /J.~ 52o ~
llydlu~y~L~J~ylmethylcellulosel carboxymethylcellulose and their salts, etc.
The chelating agents include, for example, sodium edetate, 60dium citrate, condensed sodium phosphate, etc.
When the pharmaceutical composition of the present invention is used as an ophthalmic ointment, purified lanolin, petrolatum, plastibase, liquid paraffin, polyethylene glycol, etc. are suitably employed as an ophthalmic ointment base.
Furthermore, the rh~ r~utical composition of the present invention can also be used in the form of preparations for oral administration such as tablets, capsules, granules, etc., or in the form of injectable solutions.
The pharmaceutical composition of the present Lnvention can be used for treating glaucoma in mammals such as humans, dogs, cats, rabbits, horses, cattle, etc.
The dose of the pharmaceutical composltion of the present invention varies depending upon the route of 2dministration, symptoms, age and body weight of a patient, etc. and, when it is used in the form of an ophthalmic solution for an adult patient with glaucoma, for example, it is desirable that an ophthalmic solution containing as the ac~ive ingredient terazosin or its pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 3.0 w/v %, preferably ranging from about 0.01 to l.0 w/v ,~
~ wo~s/3l2no 2 736 ~ ~ llV ~s~o %, is applied at a dose of one to several drops once to six times a day according to the severity of the symptoms.
When the pharmaceutical composition of the present invention is used in the form of an ophthalmic ointment, it is desirable that an ophthalmic ointment containing as the active ingredient terazosin or it5 pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 10 w/w ~, preferably ranging from 0.01 to 1.0 w/w 96, is applied once to f our times or so a day according to the 6everity of the symptoms.
The pharmaceutical composition of the present invention may contain one or more other therapeutic agent for glaucoma, unless it is contrar}~ to the objective of the present invention.
The pharmaceutical composition of the present invention may contain other drugs having different efficacies, unless it is contrary to the ob ~ective of the present invention .
The following examples and test examples further illustrates the present invention in detail and clarify the effects of the present invention, but are not to be understood to limit t~e scope of this invention.
WO95/31200 2-1 8 73~1 r~llJ~
EXA~PLES
ExamPle Ophthalmic solution An ophthalmic solutlon was prepared according to the following prescription by a conventional method.
Terazosin hydrochloride dihydrate 0.12 g (0.1 g when calculated in terms of terazosin) Conc . glycerol 2 . 6 g Sodium acetate 0.1 g B~n7~1kr-nium chloride ~ 0 005 g Dilute hydrochloric acid - Appropriate amount (pE~ 6.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml.
ExamPle 2 ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method:
~erazosin hydrochloride dihydrate 0 . 036 g (0.03 g when calculated in terms of terazosin) Sodium chloride o 9 g Sodium acetate ~ 0.1 g Polyvinylpyrrolidone o . 5 g Benzalkonium chloride 0 . 01 g Dilute hydrochloric acid Appropriate amount WO95131200 21 87361 r~l/J~
(pH 4.0) Sterile purif ied water was added to the above ingredients to a final volume of 100 ml.
ExamPle 3 Ophthalmic solution An ophthalmic solution was prepared according to the follo~ing prescription by a conventional method:
Terazosin hydrochloride dihydrate 0 . 36 g (0.3 g -zn calculated in terms of terazosin) Sodium chloride 0 . 9 g Dibasic sodium phosphate 0.1 g Sodium edetate 0. 05 g ~n~ nium chloride 0.01 g Sodium hydroxide Appropriate amount (pH 7.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml.
Exam~le 4 Ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method:
Terazosin hydrochloride dihydrate 0 . 36 g (0.3 g when calculated in terms of terazosin) Conc . glycerol 2 . 6 g 25 Sodium acetate 0.1 g WO 95MI200 2 1 8 7 3 6 1 I~-I/J~ ~e~t ~t~
BPn7~1knnium chloride 0.005 g Dilute hydrochloric acid : Appropriate amount (pH 6.0) Sterile purified water was added to the above ingredients to a flnal volume of 100 ml.
Example 5 Ophthalmic ointment An ophthalmic ointment was prepared according to the following prescription by a conventional method-Terazosin hydrochloride dihydrate 3 . 6 g (3.0 g when calculated in terms of terazosin) Liquid paraffin ' 1. 0 g White petrolatum Appropriate amount Total amount 100 g Test ExamPle 1 Intraocular pressure reducing effect of terazosin hydronh 1 nrirl.o dihydrate instilled into one of the eyes in individual pigmented rabbits having normal intraocular pressure and its effect on the intraocular pressure of the fellow (untreated) eyes: ~
Sixty male pigmented rabbit5 (Dutch belted rabbits ), weighing about 2 kg were confirmed that they have no ocular ~hnnrr-lities, and then were bred in a breeding room maintained at a temperature of 24 . 4 + 4 C and a humidity of 25 55 ~ 15 96. Each of them was given 100g of solid food (Labo WO9S/31200 1~lIJ. ''t 92(~
1~ 218736~
RG-RO, manu~actured by Nihon Nohsan kogyo R.R. ) per day and allowed free access to tap water as drinking water.
As the test drugs, the following aqueous solutions were used: aqueous solutions of terazosin hydrochloride dihydrate containing terazosin at concentrations of 0 . 003 w/v%, 0.01 w/v%, 0.03 w/v%, 0.1 w/v% and 0.3 w/v% (referred to as the 0 . 003~6 aqueous solution of terazosin hydrochloride, 0.01% aqueous solution of terazosin hydrochloride, 0.03%
aqueous solution of terazosin hydrochloride, O.lX aqueous solution of terazosin hydrochloride, and 0.396 aqueous solution of terazosin hydrochloride, respectively). Physiological saline was used as a control.
Sixty rabbits bred a6 ~ ri h~d above were divided into 8iX groups each consisting of 10 rabbits. 50 1ll of one of the test drugs or physiological saline was applied to one eye of each rabbit, and the other eye was left untreated.
Before instillation and 0.5, 1, 2, 4, 6 and 8 hours after instillation, intraocular pressure of both eyes of each animal was determined using pneumatonograph (manufactured by Alcon Co.; hereinafter referred to as "PTG" ) .
Time-course changes of intraocular pressure af ter instillation of each test drug and physiological saline are shown in Fig. 1 (for treated eyes) and in Fig. 2 (for non-treated eyes ) .
WO 95/31200 ~ ~, P_~/J1 . _.'t 3~0 ~ 2`1~7~61 AE is evident from the results shown in Fig. 1, topical application of the 0. 3 % aqueous solution of terazosin hydrochloride signif icantly decreased intraocular pressure, and the decrease was malntained 30 minutes to 6 hours after instillation and reached a peak decrease in intraocular pressure of 7 . 3 mmHg one hour after instlllation . A
significant decrease in intraocular pressure was observed from 30 min to 4 hours after instillation of the 0 . l % aqueous solution of terazosin hydrochloride, and the maximum decrease in intraocular pressure, 6.0 mmHg, was obtained one hour after instillation . Topical application of the 0 . 03 % aqueous solution of tera20sin hydroch~oride signif s cantly decreased intraocular pressure 30 minutes to 2 hours after instillation, and the maximum decrease, 5.9 mmHg was achieved one hour after instillation. Intraocular pressure was significantly reduced by the 0 . 01 % aqueous solution of terazosin hydrochloride one hour after instillation, and the maximum decrease in intraocular pressure was 4.1 mmHg. The maximum decrease in intraocular pressure, 2 . 2 mmHg, was found 30 min after instillation of the 0 . 003 % aqueous solution of terazosin hydrochloride, but the decrease was not significant.
As is apparent from the results shown in Fig. 2 (for non-treated eyes), no significant change was observed in intraocular pressure of the untreated eyes of the animals in any group treated with the test drug. Therefore, it may be .
~ WO 95131200 2 1 8 7 3 6 1 r~l,JA C ~ ~s~o concluded that terazosin hydrochloride does not affect the other non-treated eyes.
Test ExamPle 2 Ef fect of terazosin hydrochloride dihydrate instillation on pupil diameter in pigmented rabbits:
In each of the sixty rabbits which were given 50 ,ul of each test drug or physiological saline to one eye (with the other untreated) under Test Example l, the pupil diameter was measured for both eyes using a micrometer caliper before instillation and 0.5, l, 2 and 4 hours after topical application of each test drug or physiological saline.
Changes in pupil diameter in the eyes treated with each test drug and physiological saline are shown in Fig. 3.
As is evident from the results shown in Fig. 3, the pupil diameter of the eyes treated with each of the test drugs varied within a normal range, and no significant change in the pupil diameter was found in any groups. Therefore, it can be concluded that terazosin hydrochloride has no effect on the pupil diameter.
Test ExamPle 3 Comparison of a reduction of intraocular pressure caused by instillation of terazosin hydrochloride dihydrate with that caused by a positive control drug ( 0 . 5 % timolol maleate ophthalmic solution) in pigmented rabbits with normal intraocular pressure:
WO 95131200 2 1 8 7 3 6 ~ --_ 18 --In each of ten rabbits bred in the same manner as that described in the above Test ~xample l, 0.5% timolol maleate ophthalmic solution (50 Ill) as a positive control drug was applied to one eye and physiological saline (50 ~Ll) to the other eye. The intraocular pressure wa6 measured for both eyes using ~TG before instillation and 0.5, l, 2, 4, 6 and 8 hours after topLcal application of each solution. The results are shown in Fig. 4.
As is apparent from the results shown in Fig. 4, instillation of the positive control, 0.5% timolol maleate ophthalmic solution, caused only a slight degree of maximum decrease (2.5 mmHg) in intraocular pressure one hour after application, while no signif icant change was observed in the intraocular pressure in comparison with that for physiological 6aline-treated eyes.
The reduction of intraocular pressure caused by topical application of each tes~ drug or O.S % timolol maleate ophthalmic solution in pigmented rabbits with normal intraocular pressure were compared in terms of areas under curves (AUC) of time from the first instillation to 8 hours after then, with the intraocular pressure before topical application being def ined as a baseline value . The results are shown in Fig. 5.
As is clear from the results shown in Fig. 5, terazosin hydrochloride produced a concentration-~iPr~n-~pnt and ~ WO9~/31200 2 1 ~ 7 3 6 I Y~IIJ.~ O
significant reduction of intraocular pressure in pigmented rabbits with normal intraocular pressure within the range of concentrations from 0 . 003% to 0 . 3% . The intraocular pressure reducing activity at the concentration of 0.1% proved to be higher than that of the 0 . 5% timolol maleate ophthalmic solution .
Test ~xample 4 ( l ) Acute toxicity test of terazosin hydrochloride in mice, rats and dogs:
The acute toxicity (expressed as a value of 50%
lethal dose (LD50) ) of terazosin hydro-~hl nri~P administered via oral, subcutaneous and intravenous routes was PY~m; nPrl in ICR mice and Wistar rats. The lethal dose of terazosin hydrochloride in oral administration was also PYr~m; nPd in beagle dogs.
Terazosin hydrochloride suspended in tragacanth was given orally to mice and rats by an oral gavage. Mice and rats were also treated with terazosin hydrochloride dissolved in physiological saline by subcutaneous or intravenous injection into the tail vein using a syringe. In addition, gelatin capsules packed with terazosin hydrochloride were used for oral administration to dogs.
W095131200 2 1 8 73 6 1 ~ J.~ iO
The results are shown in Table l.
Table l LD,; (m /kg) l,ethal dose g (mg/kg) mouse rat dor male female male female male female administration >8000 >8000 >8000 >8000 700 700 administration 1523 956 1163 1050 - -Intriveinous 237 262 350 361 - -(2) Test for ocular local toxicity of terazosin hydrochloride dihydrate toplcally applied in the f orm of 0.03%, 0.1% and 0.3% ophthalmic solution for 28 consecutive days in rabbits:
Twenty-four male Japanese white rabbits (6 rabbits per group) were used for this experiment. As a test drug, 0.03% terazosin hydrochloride ophthalmic solution, O.l %
terazosin hydrochloride ophthalmic solution, and O . 3%
terazosin hydrochloride ophthalmic solution were used. As a control, physiological saline was used. Each of the test drugs or physiological saline was instilled into the ri~ht eye at a dose of one drop (0.05 ml) four times a day at 3-hour intervals for 28 consecutive= days. Thus, their ocular toxicity was evaluated in terms of the items mentioned below.
In each rabbit, the left eye was not treated.
Wl>95/31200 21 8~,36~ ~lIJ.~ ~o .
Observation was done on the following items ( 1 ) to (6):
( 1 ) Death and general conditions;
All the animals were observed daily for death and general conditions.
( 2 ) Measurement of body weight and food consumption;
The animals were weighed and the food consumption was de~Prmi nerl weekly .
The present invention relates to a pharmaceutical composition for treating glaucoma which has a potent intraocular pressure lowering effect at low concentrations without causing any side effects.
BACKGROUND MT
~,laucoma is a disease characterized by an abnormally high ~ ,stiuLe within the eyeball (intraocular pressure) which provokes various associated symptoms, such as fatigability in the eye, blurred vision, pain in the eye and gradually impaired vision, eventually leading to the risk of loss of vision. In patients with this disease, the eyeball hardens like stone so it is called "stone glaucoma ', and the depth of the pupil looks blue so it is called "blue glaucoma .
In the eyeball, a watery fluid (aqueous humor) c$rculates invariably to maintain a constant pressure within the eye (intraocular pressure = 10 to 21 mmHg). This is controlled by the circulation of blood or lymph, resilience of the eyeball, action of the innervated nerve, etc., and when either of such factors becomes abnormal, the intraocular pressure rises and glaucoma develops.
Wo 95/31200 r~l/J. ,~ . ~0 2!87~61 When 6uch Ahnnrr-l ity is caused by ophthalmic diseases including iritis, wounds or vitreous hemorrhage, the resulting glaucoma is termed secondary glaucoma. In most cases, therapeutically problematic glaucoma is primary glaucoma, which manifests Ahnorr~lities for unknown cause.
Primary glaucoma falls into the following three categories: (1) inflammatory glaucoma whose progress is acute, ~ 2 ) simple glaucoma whose progress is chronic and ( 3 ) congenital glaucoma.
In order to treat glaucoma, heretofore, various drugs have been used to prevent a rise in intraocular pressure or reduce increased intraocular pressure. Intraocular pressure reducing agents known so far include sympathomimetic drugs such as ~rin~rhrine. Epinephrine has mydriatic activity and prompts angle closure when applied to narrow angle glaucoma, and sometimes causes a rapid increase in intraocular pressure and often produces an increase in blood pressure and pigmentation in the con~unctiva.
Parasympathomimetic drugs such as pilocarpine have miotic activity and thereby cause a sensation of darkness or abnormal regulation in the visual field.
In recent years, furthermore, ,~-adrenergic blocking agents such as timolol have been extensively used for the treatment of glaucoma because they have inhibitory activity 25 against production of the aqueous humor ( Drug Therapy -WO 95/3l200 2 1 8 7 3 6 1 r~l~J
Practical Series, The Drug Treatment of Glaucoma, pp.70 to 75, 1990 ) . Such ,~-adrenergic blocking agents, however, have been reported to cause systemic side effects such a6 bradycardia, cardiac insufficiency and asthma onset, and they cannot therefore be administered to patients with such symptoms.
It is suggested that t~-adrenergic blocking agents promote the a~[ueous outflow, and buna20sine hydrochloride can increase the choroidal blood flow and become a potential novel therapeutic agent against low tension glaucoma (Journal of Japanese Society of Ophthalmology, vol.42 pp.710 to 714, 1991). When this compound is used for the treatment of glaucoma, however, the con~unctival hyperemia and miosis owing to its vasodilatory activity are inevitable.
On the other hand, ~-adrenergic stimulants are expected to be given to such patients, but conventional ~-adrenergic stimulants such as sulbutamol fail to exhibit satisfactory activity unless applied at high concentrations.
Their administration at high concentrations causes marked conjunctival hyperemia, and their continuous administration is regarded as impossible.
As described above, no satisfactory therapeutic agents for glaucoma that have few side effects described above and are effective at a low concentration have so far been f ound .
WO 95/31200 E ~_l/JI .7i.'t j20 21~73~1 ~
By the way, in recent year9, Lt has been reported that ( + ) -4-amino-2- [ 4 - ( tetrahydro-2-furoyl ) -1 -piperazinyl ] -6,7-dimethoxyquinazoline (hereinafter referred to as terazosin ) and its pharmaceutically acceptable acid addition salts, particularly its hydrochloride salt (hereinafter referred to as terazosin hydrochloride), are useful as hypotensive agents (JP-A 52-48678). In addition, it is reported that terazosin hydrochloride dihydrate is less water-soluble but far more stable in an aqueous solution than terazosin hydrochloride (anhydride), and thus is more suitable for parenteral administration (JP-B 2-31078 ) .
BRIEF DESCRIPTIO~S OF DRAWINGS
Fig. 1 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when each test drug or physiological saline was instilled to their eyes.
Time (hour) after instillation is plotted as abscissa and intraocular pressure (mm~}g) as ordinate. Each value represents mean + S.E. (the number of animals is 10). In Fig.
1, the symbol ~ a~ designates physiological saline, and the symbols "b", "c, "d", e" and "f" designate 0.003 %, 0.01 %, 0 . 03 %, 0 .1 ~ and 0 . 3 % aqueous solutions of terazosLn hydrochloride, respectively. The symbols "*1' and ~*2~
designate p<0.05 and p<0.01 (vs Control), respectively, which were analyzed using Dunnett ' s test .
.~
~ WO9~/31200 218736! r~llJ.'~.21~
.
Fig. 2 is a graph showing time-course changes of intraocular pressure of fellow (non-treated) eyes of normal pigmented rabbits when each test drug or physiological saline was instilled into one of their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate. Each value represents mean + S.E. (the number of animals is 10). In Fig. 2, the symbol "a"
designates physiological saline, and the symbols 'b~, ''c~, '-d", 'e" and "f" designate 0.003 %, 0.01 %, 0.03 ~, 0.1 % and 0 . 3 % aqueous ~olutions of terazosin hydrochloride, respectively .
Fig. 3 i8 a graph showing time-course changes of pupil diameter in normal pigmented rabbits when each test drug or physiological saline was instilled into their eyes. Time (hour) after instillation is plotted as abscissa and pupil diameter (mm) as ordinate. Each value represents mean ~ S.E.
(the number of animals is 10). In Fig. 3, the symbol ''a"
designates physiological saline, and the symbols "b', "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 9s and 0 . 3 % aqueous solutions of terazosin hydrochloride, respectively .
Fig. 4 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when 0.5%
timolol maleate ophthalmic solution or physiologically saline was instilled into thei:c eyes. Time (hour) after instillation Wo 95/31ZO0 , r~l/J. ,~ S~O
2~ 8736:1 --is plotted as abscissa and intraocular pressure (mmHg ) as ordinate (the number of animals is 10 ) . In Fig . 4, the symbols "a~' and "g'' designate physiological 9aline and 0.5 %
timolol maleate ophthalmic solution, respectively.
Fig. 5 is a graph showing intraocular pressure reducing activity of each test drugs and 0.5 96 timolol maleate ophthalmic solution when they were instilled into eyes o~
normal pigmented rabbits. The ordinate represents areas under curve of time (AUC) (mmHg-time) from the first instillation to 8 hours after then. AUC was detPrminPtl using intraocular pressure before instillation as a baseline value. In Fig. 5, the symbols "b", '-c", d-, 'e- and "f desLgnate 0.003 %, 0.01 96, O . 03 %, O .1 % and O . 3 % aqueous solutions of terazosin hydrochloride, respectively, and the symbol "g" designates 0.5 96 timolol maleate ophthalmic solution . The symbols ' *l " and "*2" designate p~O . 05 and p<0 . 01 (vs timlol maleate), respectively, which were analyzed using Dunnett's test.
DISCLOSURE OF INVENTION
The present inventors conducted intensive research to find a drug that has no defects (side effects) of conventional drugs as mentioned above and has intraocular pressure reducing activity at low concentrations. As a result, the present inventors have found that terazosin hydrochloride described in the above publications has ~ WO 9~131200 2 1 ~3 7 3 6 1 r~ 20 unexpectedly excellent intraocular pressure reducing activity and few side effects, wh~ - it is effective at lower concentrations. Thus, the present invention has been completed .
The present invention is to provide a novel and useful pharmaceutical composition for treating glaucoma that is free from the above defects (side effects) and has potent intraocular pressure reducing activity at low concentrations.
That is, the present invention provides a pharmaceutical composition for treating glaucoma which comprises (+)-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline (i.e., terazosin) of the f ormula:
CH30~`~N ~~ 0~
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloride, sulfate, etc., and those with organic acids such as maleate, tartrate, citrate, etc. Among the salts, the hydrochloride WO 95/31200 r~,l,J~ ~ n .20 (i.e., terazo6in hydrochloride) is preferable, and terazosin hydrochloride dihydrate is more preferable.
Physicochemical properties and production process of terazosin or its pharmaceutically acceptable acid addition salts used as an active ingredient of the pharmaceutical composition of the present invention are described, for ex~mple, in the above-mentioned JP-A 52-48678.
Since the pharmaceutical composition of the present invention, as demonstrated by the test examples below, has an excellent intraocular pressure reducing effect at low concentrations and has low toxicity, it can be used as an effective drug in the treatment of various types of glaucoma.
In using terazosin or its pharmaceutically acceptable acid addition salt as an active ingredient of the pharmaceutical composition, such active ingredient can usually be mixed with per se known pharmacologically acceptable c~rriers, excipients, diluents, etc., and processed according to known methods into preparations for parenteral application such as ophthalmic solutions, ophthalmic ointments, in~ectable solutions, etc., or preparations for oral administration such as tablets, capsules, granules, etc.
When the pharmaceutical composition of the present invention is used in the form of an ophthalmic solution, for example, the composition may contain various type of additives which are conventionally formulated into ophthalmic solutions, WO~5/31200 ~ ~ 8 ~3 P~l/J~. _'t ~G
_ g _ such as buffers, isotonizing agents, preservativeS, solubilizers ( stabilizers ), pH regulating agents, thickening agents , chelating agents , etc ., as far as they would not affect adversely the objective of the present invention.
The buffers include, for example, phosphate buffers, borate buffers, citrate buffers, tartr~te buffers, acetate buffers, amino acids, etc.
The isotonizing agents include, for example, sugars such as sorbitol, glucose, mannitol, etc., polyhydric alcohols such as glycerol, polyethylene glycol, propylene glycol, etc., and salts such as sodium chloride, etc.
Thepreservativesinclude, forexample, b~n7~lk--nium chloride, benzethonium chloride, p-hydroxybenzoic acid esters such as methyl and ethyl hydroxybenzoates , etc ., benzyl alcohol, phenethyl alcohol, sorbic acid or its salts, th i -- - usal, chlorobutanol, etc .
Thesolubilizers (stabilizers) include, forexample, cyclodextrins and their derivatives, water-soluble polymers such as polyvinylpyrrolidone and the like, surf actants, etc .
The pH regulating agents include, for example, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc.
The thickening agents include, for example, hydroxy-ethylcellulose, hyd, U~y~Lu~?ylcellulose, methylcellulose, W09~200 j ~? l 8~36~ /J.~ 52o ~
llydlu~y~L~J~ylmethylcellulosel carboxymethylcellulose and their salts, etc.
The chelating agents include, for example, sodium edetate, 60dium citrate, condensed sodium phosphate, etc.
When the pharmaceutical composition of the present invention is used as an ophthalmic ointment, purified lanolin, petrolatum, plastibase, liquid paraffin, polyethylene glycol, etc. are suitably employed as an ophthalmic ointment base.
Furthermore, the rh~ r~utical composition of the present invention can also be used in the form of preparations for oral administration such as tablets, capsules, granules, etc., or in the form of injectable solutions.
The pharmaceutical composition of the present Lnvention can be used for treating glaucoma in mammals such as humans, dogs, cats, rabbits, horses, cattle, etc.
The dose of the pharmaceutical composltion of the present invention varies depending upon the route of 2dministration, symptoms, age and body weight of a patient, etc. and, when it is used in the form of an ophthalmic solution for an adult patient with glaucoma, for example, it is desirable that an ophthalmic solution containing as the ac~ive ingredient terazosin or its pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 3.0 w/v %, preferably ranging from about 0.01 to l.0 w/v ,~
~ wo~s/3l2no 2 736 ~ ~ llV ~s~o %, is applied at a dose of one to several drops once to six times a day according to the severity of the symptoms.
When the pharmaceutical composition of the present invention is used in the form of an ophthalmic ointment, it is desirable that an ophthalmic ointment containing as the active ingredient terazosin or it5 pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 10 w/w ~, preferably ranging from 0.01 to 1.0 w/w 96, is applied once to f our times or so a day according to the 6everity of the symptoms.
The pharmaceutical composition of the present invention may contain one or more other therapeutic agent for glaucoma, unless it is contrar}~ to the objective of the present invention.
The pharmaceutical composition of the present invention may contain other drugs having different efficacies, unless it is contrary to the ob ~ective of the present invention .
The following examples and test examples further illustrates the present invention in detail and clarify the effects of the present invention, but are not to be understood to limit t~e scope of this invention.
WO95/31200 2-1 8 73~1 r~llJ~
EXA~PLES
ExamPle Ophthalmic solution An ophthalmic solutlon was prepared according to the following prescription by a conventional method.
Terazosin hydrochloride dihydrate 0.12 g (0.1 g when calculated in terms of terazosin) Conc . glycerol 2 . 6 g Sodium acetate 0.1 g B~n7~1kr-nium chloride ~ 0 005 g Dilute hydrochloric acid - Appropriate amount (pE~ 6.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml.
ExamPle 2 ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method:
~erazosin hydrochloride dihydrate 0 . 036 g (0.03 g when calculated in terms of terazosin) Sodium chloride o 9 g Sodium acetate ~ 0.1 g Polyvinylpyrrolidone o . 5 g Benzalkonium chloride 0 . 01 g Dilute hydrochloric acid Appropriate amount WO95131200 21 87361 r~l/J~
(pH 4.0) Sterile purif ied water was added to the above ingredients to a final volume of 100 ml.
ExamPle 3 Ophthalmic solution An ophthalmic solution was prepared according to the follo~ing prescription by a conventional method:
Terazosin hydrochloride dihydrate 0 . 36 g (0.3 g -zn calculated in terms of terazosin) Sodium chloride 0 . 9 g Dibasic sodium phosphate 0.1 g Sodium edetate 0. 05 g ~n~ nium chloride 0.01 g Sodium hydroxide Appropriate amount (pH 7.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml.
Exam~le 4 Ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method:
Terazosin hydrochloride dihydrate 0 . 36 g (0.3 g when calculated in terms of terazosin) Conc . glycerol 2 . 6 g 25 Sodium acetate 0.1 g WO 95MI200 2 1 8 7 3 6 1 I~-I/J~ ~e~t ~t~
BPn7~1knnium chloride 0.005 g Dilute hydrochloric acid : Appropriate amount (pH 6.0) Sterile purified water was added to the above ingredients to a flnal volume of 100 ml.
Example 5 Ophthalmic ointment An ophthalmic ointment was prepared according to the following prescription by a conventional method-Terazosin hydrochloride dihydrate 3 . 6 g (3.0 g when calculated in terms of terazosin) Liquid paraffin ' 1. 0 g White petrolatum Appropriate amount Total amount 100 g Test ExamPle 1 Intraocular pressure reducing effect of terazosin hydronh 1 nrirl.o dihydrate instilled into one of the eyes in individual pigmented rabbits having normal intraocular pressure and its effect on the intraocular pressure of the fellow (untreated) eyes: ~
Sixty male pigmented rabbit5 (Dutch belted rabbits ), weighing about 2 kg were confirmed that they have no ocular ~hnnrr-lities, and then were bred in a breeding room maintained at a temperature of 24 . 4 + 4 C and a humidity of 25 55 ~ 15 96. Each of them was given 100g of solid food (Labo WO9S/31200 1~lIJ. ''t 92(~
1~ 218736~
RG-RO, manu~actured by Nihon Nohsan kogyo R.R. ) per day and allowed free access to tap water as drinking water.
As the test drugs, the following aqueous solutions were used: aqueous solutions of terazosin hydrochloride dihydrate containing terazosin at concentrations of 0 . 003 w/v%, 0.01 w/v%, 0.03 w/v%, 0.1 w/v% and 0.3 w/v% (referred to as the 0 . 003~6 aqueous solution of terazosin hydrochloride, 0.01% aqueous solution of terazosin hydrochloride, 0.03%
aqueous solution of terazosin hydrochloride, O.lX aqueous solution of terazosin hydrochloride, and 0.396 aqueous solution of terazosin hydrochloride, respectively). Physiological saline was used as a control.
Sixty rabbits bred a6 ~ ri h~d above were divided into 8iX groups each consisting of 10 rabbits. 50 1ll of one of the test drugs or physiological saline was applied to one eye of each rabbit, and the other eye was left untreated.
Before instillation and 0.5, 1, 2, 4, 6 and 8 hours after instillation, intraocular pressure of both eyes of each animal was determined using pneumatonograph (manufactured by Alcon Co.; hereinafter referred to as "PTG" ) .
Time-course changes of intraocular pressure af ter instillation of each test drug and physiological saline are shown in Fig. 1 (for treated eyes) and in Fig. 2 (for non-treated eyes ) .
WO 95/31200 ~ ~, P_~/J1 . _.'t 3~0 ~ 2`1~7~61 AE is evident from the results shown in Fig. 1, topical application of the 0. 3 % aqueous solution of terazosin hydrochloride signif icantly decreased intraocular pressure, and the decrease was malntained 30 minutes to 6 hours after instillation and reached a peak decrease in intraocular pressure of 7 . 3 mmHg one hour after instlllation . A
significant decrease in intraocular pressure was observed from 30 min to 4 hours after instillation of the 0 . l % aqueous solution of terazosin hydrochloride, and the maximum decrease in intraocular pressure, 6.0 mmHg, was obtained one hour after instillation . Topical application of the 0 . 03 % aqueous solution of tera20sin hydroch~oride signif s cantly decreased intraocular pressure 30 minutes to 2 hours after instillation, and the maximum decrease, 5.9 mmHg was achieved one hour after instillation. Intraocular pressure was significantly reduced by the 0 . 01 % aqueous solution of terazosin hydrochloride one hour after instillation, and the maximum decrease in intraocular pressure was 4.1 mmHg. The maximum decrease in intraocular pressure, 2 . 2 mmHg, was found 30 min after instillation of the 0 . 003 % aqueous solution of terazosin hydrochloride, but the decrease was not significant.
As is apparent from the results shown in Fig. 2 (for non-treated eyes), no significant change was observed in intraocular pressure of the untreated eyes of the animals in any group treated with the test drug. Therefore, it may be .
~ WO 95131200 2 1 8 7 3 6 1 r~l,JA C ~ ~s~o concluded that terazosin hydrochloride does not affect the other non-treated eyes.
Test ExamPle 2 Ef fect of terazosin hydrochloride dihydrate instillation on pupil diameter in pigmented rabbits:
In each of the sixty rabbits which were given 50 ,ul of each test drug or physiological saline to one eye (with the other untreated) under Test Example l, the pupil diameter was measured for both eyes using a micrometer caliper before instillation and 0.5, l, 2 and 4 hours after topical application of each test drug or physiological saline.
Changes in pupil diameter in the eyes treated with each test drug and physiological saline are shown in Fig. 3.
As is evident from the results shown in Fig. 3, the pupil diameter of the eyes treated with each of the test drugs varied within a normal range, and no significant change in the pupil diameter was found in any groups. Therefore, it can be concluded that terazosin hydrochloride has no effect on the pupil diameter.
Test ExamPle 3 Comparison of a reduction of intraocular pressure caused by instillation of terazosin hydrochloride dihydrate with that caused by a positive control drug ( 0 . 5 % timolol maleate ophthalmic solution) in pigmented rabbits with normal intraocular pressure:
WO 95131200 2 1 8 7 3 6 ~ --_ 18 --In each of ten rabbits bred in the same manner as that described in the above Test ~xample l, 0.5% timolol maleate ophthalmic solution (50 Ill) as a positive control drug was applied to one eye and physiological saline (50 ~Ll) to the other eye. The intraocular pressure wa6 measured for both eyes using ~TG before instillation and 0.5, l, 2, 4, 6 and 8 hours after topLcal application of each solution. The results are shown in Fig. 4.
As is apparent from the results shown in Fig. 4, instillation of the positive control, 0.5% timolol maleate ophthalmic solution, caused only a slight degree of maximum decrease (2.5 mmHg) in intraocular pressure one hour after application, while no signif icant change was observed in the intraocular pressure in comparison with that for physiological 6aline-treated eyes.
The reduction of intraocular pressure caused by topical application of each tes~ drug or O.S % timolol maleate ophthalmic solution in pigmented rabbits with normal intraocular pressure were compared in terms of areas under curves (AUC) of time from the first instillation to 8 hours after then, with the intraocular pressure before topical application being def ined as a baseline value . The results are shown in Fig. 5.
As is clear from the results shown in Fig. 5, terazosin hydrochloride produced a concentration-~iPr~n-~pnt and ~ WO9~/31200 2 1 ~ 7 3 6 I Y~IIJ.~ O
significant reduction of intraocular pressure in pigmented rabbits with normal intraocular pressure within the range of concentrations from 0 . 003% to 0 . 3% . The intraocular pressure reducing activity at the concentration of 0.1% proved to be higher than that of the 0 . 5% timolol maleate ophthalmic solution .
Test ~xample 4 ( l ) Acute toxicity test of terazosin hydrochloride in mice, rats and dogs:
The acute toxicity (expressed as a value of 50%
lethal dose (LD50) ) of terazosin hydro-~hl nri~P administered via oral, subcutaneous and intravenous routes was PY~m; nPrl in ICR mice and Wistar rats. The lethal dose of terazosin hydrochloride in oral administration was also PYr~m; nPd in beagle dogs.
Terazosin hydrochloride suspended in tragacanth was given orally to mice and rats by an oral gavage. Mice and rats were also treated with terazosin hydrochloride dissolved in physiological saline by subcutaneous or intravenous injection into the tail vein using a syringe. In addition, gelatin capsules packed with terazosin hydrochloride were used for oral administration to dogs.
W095131200 2 1 8 73 6 1 ~ J.~ iO
The results are shown in Table l.
Table l LD,; (m /kg) l,ethal dose g (mg/kg) mouse rat dor male female male female male female administration >8000 >8000 >8000 >8000 700 700 administration 1523 956 1163 1050 - -Intriveinous 237 262 350 361 - -(2) Test for ocular local toxicity of terazosin hydrochloride dihydrate toplcally applied in the f orm of 0.03%, 0.1% and 0.3% ophthalmic solution for 28 consecutive days in rabbits:
Twenty-four male Japanese white rabbits (6 rabbits per group) were used for this experiment. As a test drug, 0.03% terazosin hydrochloride ophthalmic solution, O.l %
terazosin hydrochloride ophthalmic solution, and O . 3%
terazosin hydrochloride ophthalmic solution were used. As a control, physiological saline was used. Each of the test drugs or physiological saline was instilled into the ri~ht eye at a dose of one drop (0.05 ml) four times a day at 3-hour intervals for 28 consecutive= days. Thus, their ocular toxicity was evaluated in terms of the items mentioned below.
In each rabbit, the left eye was not treated.
Wl>95/31200 21 8~,36~ ~lIJ.~ ~o .
Observation was done on the following items ( 1 ) to (6):
( 1 ) Death and general conditions;
All the animals were observed daily for death and general conditions.
( 2 ) Measurement of body weight and food consumption;
The animals were weighed and the food consumption was de~Prmi nerl weekly .
(3) Gross observation of the anterior ocul~: segment;
Based on the modified Draize method, gross observation of the anterior ocular segment was carried out weekly .
( 4 ) Corneal test The cornea was observed weekly using a test paper impregnated with f luorescein .
( 5 ) Evaluation of the corneal epithelium using a scanning electron microscope;
After instillation of each test drug, the morphology of the corneal epithelium was observed using a scanning electron microscope.
( 6 ) Evaluation of the cornea, con ~unctiva and retina using an optical microscope;
After instillation of ez~ch test drug, microscopic examinations of the cornea, con junctiva and retina were performed with an optical microscope.
WO95/31200 j r~l/J.,'. 15~0 2 1 8736 1 ~
As a result, ( 1 ) no dead animals and no abnormalities in general conditions, (2) no Ahnorr~lity in body weight and food consumption were observed in any of the groups which were treated with the 0 . 03%, 0 .1% and 0 . 3%
terazosin hydrochloride ophthalmic solutions during the period of application of these test drugs . ( 3 ) Gross observation of the anterior ocular segment revealed no abnormality related to any test drug, except that very slight redness of the con~unctiva, which was evaluated as normal, was observed in the treated eyes of some test animals. Furthermore, (4) corneal test, ( 5 ) evaluation of the corneal epithelium under a scanning electron microscope, and (6) evaluation of the cornea, con~unctiva and retina under an optical microscope also showed no i~hnc~ 1 ities related to any test drug .
The above results of the various tests demonstrated that the pharmaceutical composition of the present invention containing terazosin hydrochloride has no effect on the fellow (i.e., non-treated) eye or the pupil diameter, and has few side effects (toxicity) as well as excellent intraocular pressure reducing activity at a low concentration. The pharmaceutical composition of the present invention is thus a clinically very safe drug.
As described above, the pharmaceutical composition of the present invention can advantageously be used for the 25 treatment of various types of glaucoma because of its ~ WO95/31200 21 87361 r~l~J~ o~
_ 23 --r excellent intraocular pressure reducing activit~ at a low concentration and its low toxicity.
Based on the modified Draize method, gross observation of the anterior ocular segment was carried out weekly .
( 4 ) Corneal test The cornea was observed weekly using a test paper impregnated with f luorescein .
( 5 ) Evaluation of the corneal epithelium using a scanning electron microscope;
After instillation of each test drug, the morphology of the corneal epithelium was observed using a scanning electron microscope.
( 6 ) Evaluation of the cornea, con ~unctiva and retina using an optical microscope;
After instillation of ez~ch test drug, microscopic examinations of the cornea, con junctiva and retina were performed with an optical microscope.
WO95/31200 j r~l/J.,'. 15~0 2 1 8736 1 ~
As a result, ( 1 ) no dead animals and no abnormalities in general conditions, (2) no Ahnorr~lity in body weight and food consumption were observed in any of the groups which were treated with the 0 . 03%, 0 .1% and 0 . 3%
terazosin hydrochloride ophthalmic solutions during the period of application of these test drugs . ( 3 ) Gross observation of the anterior ocular segment revealed no abnormality related to any test drug, except that very slight redness of the con~unctiva, which was evaluated as normal, was observed in the treated eyes of some test animals. Furthermore, (4) corneal test, ( 5 ) evaluation of the corneal epithelium under a scanning electron microscope, and (6) evaluation of the cornea, con~unctiva and retina under an optical microscope also showed no i~hnc~ 1 ities related to any test drug .
The above results of the various tests demonstrated that the pharmaceutical composition of the present invention containing terazosin hydrochloride has no effect on the fellow (i.e., non-treated) eye or the pupil diameter, and has few side effects (toxicity) as well as excellent intraocular pressure reducing activity at a low concentration. The pharmaceutical composition of the present invention is thus a clinically very safe drug.
As described above, the pharmaceutical composition of the present invention can advantageously be used for the 25 treatment of various types of glaucoma because of its ~ WO95/31200 21 87361 r~l~J~ o~
_ 23 --r excellent intraocular pressure reducing activit~ at a low concentration and its low toxicity.
Claims (6)
1. A pharmaceutical composition for treating glaucoma which comprises ()-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline of the formula:
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, which is an ophthalmic solution.
3. The pharmaceutical composition according to claim 1, which is an ophthalmic ointment.
4. A process for producing a pharmaceutical composition accordlng to claim 1, which comprises mixing ()-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
5. A method of treating glaucoma in a mammal in need thereof which comprises administering to such mammal an effective amount of ()-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.
6. Use of ()-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating glaucoma.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10367694 | 1994-05-18 | ||
| JP6/103676 | 1994-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2187361A1 true CA2187361A1 (en) | 1995-11-23 |
Family
ID=14360400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002187361A Abandoned CA2187361A1 (en) | 1994-05-18 | 1995-05-15 | Pharmaceutical composition for treating glaucoma containing terazosin |
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) |
Families Citing this family (5)
| 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 |
| EP1415666A4 (en) * | 2001-07-13 | 2005-02-02 | Kissei Pharmaceutical | Medicinal compositions for opthalmic use |
| CN104840436B (en) * | 2015-06-11 | 2017-12-05 | 刘磊 | Pharmaceutical composition |
| WO2017002846A1 (en) * | 2015-06-30 | 2017-01-05 | 株式会社ニデック | Visual function measurement device and visual function measurement program |
| CN112439071B (en) * | 2019-09-04 | 2022-05-20 | 武汉科福新药有限责任公司 | Transdermal penetration-promoting composition and application thereof in timolol preparation |
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 |
| EP0436726B1 (en) * | 1989-08-03 | 1993-10-20 | Eisai Co., Ltd. | Method of photostabilizing eyewash |
| US5256667A (en) * | 1991-09-25 | 1993-10-26 | Merck & Co., Inc. | Quinazolinones and pyridopyrimidinones |
-
1995
- 1995-05-15 CA CA002187361A patent/CA2187361A1/en not_active Abandoned
- 1995-05-15 JP JP7529508A patent/JPH10500130A/en active Pending
- 1995-05-15 PL PL95317190A patent/PL317190A1/en unknown
- 1995-05-15 AU AU24201/95A patent/AU2420195A/en not_active Abandoned
- 1995-05-15 WO PCT/JP1995/000920 patent/WO1995031200A1/en not_active Application Discontinuation
- 1995-05-15 CN CN95193130A patent/CN1148810A/en active Pending
- 1995-05-15 HU HU9603158A patent/HUT76468A/en unknown
- 1995-05-15 EP EP95918186A patent/EP0759756A1/en not_active Withdrawn
- 1995-05-15 BR BR9507732A patent/BR9507732A/en not_active Application Discontinuation
- 1995-05-18 TW TW084104919A patent/TW304879B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| HU9603158D0 (en) | 1997-01-28 |
| CN1148810A (en) | 1997-04-30 |
| WO1995031200A1 (en) | 1995-11-23 |
| PL317190A1 (en) | 1997-03-17 |
| BR9507732A (en) | 1997-08-19 |
| EP0759756A1 (en) | 1997-03-05 |
| AU2420195A (en) | 1995-12-05 |
| JPH10500130A (en) | 1998-01-06 |
| TW304879B (en) | 1997-05-11 |
| HUT76468A (en) | 1997-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5663205A (en) | Pharmaceutical composition for use in glaucoma treatment | |
| EP2163548B1 (en) | Prophylactic or therapeutic agent for age-related macular degeneration | |
| US20020045585A1 (en) | Cytoskeletal active agents for glaucoma therapy | |
| WO2003018057A1 (en) | Remedy for glaucoma comprising as the active ingredient compound having pi3 kinase inhibitory effect | |
| EP0672417A1 (en) | Reduction of elevated intraocular pressure | |
| CA2127519A1 (en) | Pharmaceutical composition useful for treating ophthalmological diseases | |
| CA2187361A1 (en) | Pharmaceutical composition for treating glaucoma containing terazosin | |
| EP0968716B1 (en) | Drugs for ameliorating ocular circulatory disorders | |
| AU677860B2 (en) | Composition for prophylaxis and treatment of myopia | |
| KR980008226A (en) | Prevention and treatment of visual dysfunction | |
| EP1225890B1 (en) | Rivastigmine for the treatment of ocular disorders | |
| US5308849A (en) | Method of reducing elevated intraocular pressure | |
| AU778148B2 (en) | 2-aminotetralin derivatives for the therapy of glaucoma | |
| EP0728480A1 (en) | Use of ifenprodil for treatment of elevated intraocular pressure | |
| KR100585299B1 (en) | Optic papillary circulation improving agents | |
| JPH04247036A (en) | Method for therapy for decreasing intraocular tension without generating miosis | |
| EP0561913B1 (en) | Use of pyridine derivatives in the treatment of ocular hypertension | |
| JP2741285B2 (en) | Glaucoma treatment | |
| EP0456988B1 (en) | Use of naproxen as mydriatic agent | |
| EP0607697A2 (en) | DILAZEP for reduction of elevated intraocular pressure | |
| JPH04134029A (en) | Glaucoma pemedy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |