WO1995031200A1 - Pharmaceutical composition for treating glaucoma containing terazosin - Google Patents

Pharmaceutical composition for treating glaucoma containing terazosin Download PDF

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Publication number
WO1995031200A1
WO1995031200A1 PCT/JP1995/000920 JP9500920W WO9531200A1 WO 1995031200 A1 WO1995031200 A1 WO 1995031200A1 JP 9500920 W JP9500920 W JP 9500920W WO 9531200 A1 WO9531200 A1 WO 9531200A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
intraocular pressure
terazosin
pharmaceutically acceptable
glaucoma
Prior art date
Application number
PCT/JP1995/000920
Other languages
English (en)
French (fr)
Inventor
Takahiro Ogawa
Takaaki Deguchi
Katsuhiro Inada
Original Assignee
Senju Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Priority to EP95918186A priority Critical patent/EP0759756A1/en
Priority to KR1019960706564A priority patent/KR970703149A/ko
Priority to BR9507732A priority patent/BR9507732A/pt
Priority to AU24201/95A priority patent/AU2420195A/en
Priority to JP7529508A priority patent/JPH10500130A/ja
Publication of WO1995031200A1 publication Critical patent/WO1995031200A1/en

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

Definitions

  • 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.
  • Glaucoma is a disease characterized by an abnormally high pressure 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.
  • intraocular pressure the pressure within the eyeball
  • 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.
  • the eyeball hardens like stone so it is called “stone glaucoma”
  • the depth of the pupil looks blue so it is called “blue glaucoma”.
  • 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 intraoc ⁇ lar pressure rises and glaucoma develops.
  • the resulting glaucoma is termed secondary glaucoma.
  • therapeutically problematic glaucoma is primary glaucoma, which manifests abnormalities for unknown cause.
  • Intraocular pressure reducing agents include sympathomimetic drugs such as epinephrine. 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 conjunctiva.
  • Parasympathomimetic drugs such as pilocarpine have miotic activity and thereby cause a sensation of darkness or abnormal regulation in the visual field.
  • ⁇ -adrenergic blocking agents such as timolol have been extensively used for the treatment of glaucoma because they have inhibitory activity against production of the aqueous humor (Drug Therapy - Practical Series, The Drug Treatment of Glaucoma, pp.70 to 75, 1990).
  • ⁇ -adrenergic blocking agents have been reported to cause systemic side effects such as bradycardia, cardiac insufficiency and asthma onset, and they cannot therefore be administered to patients with such symptoms .
  • ⁇ -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.
  • 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).
  • 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 (mmHg) as ordinate. Each value represents mean ⁇ S.E. (the number of animals is 10).
  • the symbol “a” designates physiological saline
  • the symbols “b” , “c", “d”, “e” and “f” designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloride, respectively.
  • 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.
  • Fig. 3 is 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).
  • the symbol "a” designates physiological saline
  • the symbols "b”, “c”, “d”, "e” and “f” designate 0.003 %, 0.01 %, 0.03 %, 0.1 % 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 their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate (the number of animals is 10).
  • the symbols "a” and “g” designate physiological saline 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 % timolol maleate ophthalmic solution when they were instilled into eyes of 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 determined using intraocular pressure before instillation as a baseline value.
  • the symbols "b”, “c”, “d”, “e” and “f” designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloride, respectively, and the symbol “g” designates 0.5 % timolol maleate ophthalmic solution.
  • the symbols “*l” and “*2” designate p ⁇ 0.05 and p ⁇ 0.01 (vs timlol maleate), respectively, which were analyzed using Dunnett's test.
  • 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 .
  • the present inventors have found that terazosin hydrochloride described in the above publications has unexpectedly excellent intraocular pressure reducing activity and few side effects, while it is effective at lower concentrations.
  • 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.
  • 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 formula :
  • 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.
  • the hydrochloride i.e., terazosin hydrochloride
  • terazosin hydrochloride dihydrate is more preferable.
  • 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.
  • 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 carriers, excipients, diluents, etc., and processed according to known methods into preparations for parenteral application such as ophthalmic solutions, ophthalmic ointments, injectable solutions, etc., or preparations for oral administration such as tablets, capsules, granules, etc.
  • the composition may contain various type of additives which are conventionally formulated into ophthalmic solutions, 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, tartrate buffers, acetate buffers, a ino 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 su h as sodium chloride, etc.
  • the preservatives include, for example, benzalkonium chloride, benzethonium chloride, p-hydroxybenzoic acid esters such as methyl and ethyl hydroxybenzoates, etc. , benzyl alcohol, phenethyl alcohol, sorbic acid or its salts, thimerosal, chlorobutanol, etc.
  • the solubilizers include, for example, cyclodextrins and their derivatives, water-soluble polymers such as polyvinylpyrrolidone and the like, surfactants, 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- ethylcellulo ⁇ e, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and their salts, etc.
  • the chelating agents include, for example, sodium edetate, sodium citrate, condensed sodium phosphate, etc. 5
  • purified lanolin, petrolatum, plastibase, liquid paraffin, polyethylene glycol, etc. are suitably employed as an ophthalmic ointment base.
  • composition of the 1.0 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 invention can be used for treating glaucoma in mammals such 15 as humans, dogs, cats, rabbits, horses, cattle, etc.
  • the dose of the pharmaceutical composition of the present invention varies depending upon the route of administration, symptoms, age and body weight of a patient, etc. and, when it is used in the form of an ophthalmic 20 solution for an adult patient with glaucoma, for example, it is desirable that an ophthalmic solution containing as the active 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 1.0 w/v %, is applied at a dose of one to several drops once to six times a day according to the severity of the symptoms.
  • the pharmaceutical composition of the present invention may contain one or more other therapeutic agent for glaucoma, unless it is contrary 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 objective of the present invention.
  • An ophthalmic solution was prepared according to the following prescription by a conventional method:
  • An ophthalmic solution was prepared according to the following prescription by a conventional method:
  • An ophthalmic solution was prepared according to the following prescription by a conventional method:
  • Ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method: Terazosin hydrochloride dihydrate 0.36 g
  • An ophthalmic ointment was prepared according to the following prescription by a conventional method: Terazosin hydrochloride dihydrate 3.6 g
  • 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% aqueous solution of terazosin hydrochloride, 0.01% aqueous solution of terazosin hydrochloride, 0.03% aqueous solution of terazosin hydrochloride, 0.1% aqueous solution of terazosin hydrochloride, and 0.3% aqueous solution of terazosin hydrochloride, respectively).
  • Physiological saline was used as a control.
  • Fig. 1 Time-course changes of intraocular pressure after instillation of each test drug and physiological saline are shown in Fig. 1 (for treated eyes) and in Fig. 2 (for non- treated eyes) .
  • topical application of the 0.3 % aqueous solution of terazosin hydrochloride significantly decreased intraocular pressure, and the decrease was maintained 30 minutes to 6 hours after instillation and reached a peak decrease in intraocular pressure of 7.3 mmHg one hour after instillation.
  • terazosin hydrochloride produced a concentration-dependent and 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.
  • Acute toxicity test of terazosin hydrochloride in mice, rats and dogs The acute toxicity (expressed as a value of 50% lethal dose (LD 50 )) of terazosin hydrochloride administered via oral, subcutaneous and intravenous routes was examined in ICR mice and Wistar rats. The lethal dose of terazosin hydrochloride in oral administration was also examined 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. The results are shown in Table 1 Table 1
  • the animals were weighed and the food consumption was determined weekly.
  • the cornea was observed weekly using a test paper impregnated with fluorescein.
  • the pharmaceutical composition of the present invention can advantageously be used for the treatment of various types of glaucoma because of its excellent intraocular pressure reducing activity at a low concentration and its low toxicity.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/JP1995/000920 1994-05-18 1995-05-15 Pharmaceutical composition for treating glaucoma containing terazosin WO1995031200A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP95918186A EP0759756A1 (en) 1994-05-18 1995-05-15 Pharmaceutical composition for treating glaucoma containing terazosin
KR1019960706564A KR970703149A (ko) 1994-05-18 1995-05-15 테라조신을 함유하는 녹내장 치료용 약학 조성물(pharmaceutical composition for treating glaucoma containing terazosin)
BR9507732A BR9507732A (pt) 1994-05-18 1995-05-15 Composição farmacêutica para o tratamento de glaucoma
AU24201/95A AU2420195A (en) 1994-05-18 1995-05-15 Pharmaceutical composition for treating glaucoma containing terazosin
JP7529508A JPH10500130A (ja) 1994-05-18 1995-05-15 テラゾシンを含有する緑内障治療用医薬組成物

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
WO1995031200A1 true WO1995031200A1 (en) 1995-11-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/000920 WO1995031200A1 (en) 1994-05-18 1995-05-15 Pharmaceutical composition for treating glaucoma containing terazosin

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EP (1) EP0759756A1 (enrdf_load_stackoverflow)
JP (1) JPH10500130A (enrdf_load_stackoverflow)
CN (1) CN1148810A (enrdf_load_stackoverflow)
AU (1) AU2420195A (enrdf_load_stackoverflow)
BR (1) BR9507732A (enrdf_load_stackoverflow)
CA (1) CA2187361A1 (enrdf_load_stackoverflow)
HU (1) HUT76468A (enrdf_load_stackoverflow)
PL (1) PL317190A1 (enrdf_load_stackoverflow)
TW (1) TW304879B (enrdf_load_stackoverflow)
WO (1) WO1995031200A1 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006061A1 (fr) * 2001-07-13 2003-01-23 Kissei Pharmaceutical Co., Ltd. Compositions de medicaments pour usage ophtalmologique
EP1410808A4 (en) * 2001-07-02 2009-07-29 Santen Pharmaceutical Co Ltd MEDIUM FOR THE PROTECTION OF THE SEHNERV WITH ALPHA 1 RECEPTOR BLOCKER AS AN ACTIVE SUBSTANCE

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104840436B (zh) * 2015-06-11 2017-12-05 刘磊 药物组合物
WO2017002846A1 (ja) * 2015-06-30 2017-01-05 株式会社ニデック 視機能測定装置、および視機能測定プログラム
CN112439071B (zh) * 2019-09-04 2022-05-20 武汉科福新药有限责任公司 透皮促渗组合物及其在噻吗洛尔制剂中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128332A (ja) * 1989-07-12 1991-05-31 Eisai Co Ltd α↓１―ブロッカー点眼剤
EP0436726A1 (en) * 1989-08-03 1991-07-17 Eisai Co., Ltd. Method of photostabilizing eyewash
EP0534706A1 (en) * 1991-09-25 1993-03-31 Merck & Co. Inc. Quinazolinones and pyridopyrimidinones useful as angiotensin II antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128332A (ja) * 1989-07-12 1991-05-31 Eisai Co Ltd α↓１―ブロッカー点眼剤
EP0436726A1 (en) * 1989-08-03 1991-07-17 Eisai Co., Ltd. Method of photostabilizing eyewash
EP0534706A1 (en) * 1991-09-25 1993-03-31 Merck & Co. Inc. Quinazolinones and pyridopyrimidinones useful as angiotensin II antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALEXANDER F. KHOURY: "Alpha-blocker therapy of hypertension", JAMA, vol. 266, no. 3, 17 July 1991 (1991-07-17), pages 394 - 398 *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 337 (C - 0862) 27 August 1991 (1991-08-27) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1410808A4 (en) * 2001-07-02 2009-07-29 Santen Pharmaceutical Co Ltd MEDIUM FOR THE PROTECTION OF THE SEHNERV WITH ALPHA 1 RECEPTOR BLOCKER AS AN ACTIVE SUBSTANCE
WO2003006061A1 (fr) * 2001-07-13 2003-01-23 Kissei Pharmaceutical Co., Ltd. Compositions de medicaments pour usage ophtalmologique

Also Published As

Publication number Publication date
HUT76468A (en) 1997-09-29
CA2187361A1 (en) 1995-11-23
BR9507732A (pt) 1997-08-19
HU9603158D0 (en) 1997-01-28
EP0759756A1 (en) 1997-03-05
JPH10500130A (ja) 1998-01-06
PL317190A1 (en) 1997-03-17
AU2420195A (en) 1995-12-05
TW304879B (enrdf_load_stackoverflow) 1997-05-11
CN1148810A (zh) 1997-04-30

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