GB1564454A - Antiglaucomatous ophtalmic solution - Google Patents
Antiglaucomatous ophtalmic solution Download PDFInfo
- Publication number
- GB1564454A GB1564454A GB22965/77A GB2296577A GB1564454A GB 1564454 A GB1564454 A GB 1564454A GB 22965/77 A GB22965/77 A GB 22965/77A GB 2296577 A GB2296577 A GB 2296577A GB 1564454 A GB1564454 A GB 1564454A
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- United Kingdom
- Prior art keywords
- solution
- ophthalmic solution
- antiglaucomatous
- preparation
- added
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
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- Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
(54) ANTIGLAUCOMATOUS OPHTHALMIC SOLUTION
(71) We, KAKEN CHEMICAL CO., LTD., a Japanese company of
No. 28--8, 2-chome, Honkomagome, Bunkyo-ku, Tokyo, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to a novel opthalmic solution. For the purpose of therapy to glaucoma, carbonic anhydrase inhibitor (internal medicine); high osmotic pressure solution (injectable); autonomic blocking agent (injectable); miotic (ophthalmic solution) and mydriatic (ophthalmic solution) have been used.
However, they have certain disadvantages.
For example, the carbonic anhydrase inhibitor causes gastorintestinal disorder, limb numbness, difficulty of breathing, drowsiness, dizziness, urethralithiasis and acidosis, on administration for a long term. The injection is usually applied for acute attacks and is not suitable for long term administration.
The ophthalmic solution of miotic causes local side-effects of darkness or abnormal adjustment of visual field, and systematic side-effects of diarrhoea and vomiting.
The disadvantage of mydriatic is that, when used in patients with narrow-angle glaucoma, it aggravates blocked-angle glaucoma.
The present invention provides an antiglaucomatous ophthalmic solution which comprises an aqueous solution of a bupranolol having the formula
or a salt thereof as an active ingredient and sodium carboxymethyl cellulose as a solubilizing adjuvant.
The active ingredients are known compounds which are called bupranolols and are used for therapy against angina pectoria and arhythmia.
The active ingredients can be produced by the process disclosed in U.S. Patent
No. 3,309,406.
Bupranolols have low solubility in water which is less than 0.3 wt.% at room temperature in an isotonic solution for example with NaCI in a pH range which would not cause any ocular irritation.
We have studied the preparation of pharmacological compositions which are substantially non-toxic and in which the solubility of the bupranolols is increased,
As a result, we have found that the concentration of the bupranolols in aqueous solutions can be increased by incorporating sodium carboxymethyl cellulose, and optionally also a nonionic surfactant with or without a buffer agent as adjuvants for solubilization whereby a stable ophthalmic solution suitable for therapy against glaucoma can be obtained.
Suitable nonionic surfactants include polyoxyethyleneglycol ethers such as polyoxyethylene lauryl ethers and polyoxyethylene oleyl ethers; polyoxyethyleneglycol higher fatty acid esters such as polyethyleneglycol monolaurate and polyethyleneglycol monooleate; and polyoxyethylenesorbitan fatty acid esters such as polyoxyethylenesorbitane monolaurate and polyoxyethylenesorbitane monooleate (e.g. Polysorbate 80). It is especially preferable to use polyethylene glycol monooleate or polyoxyethylene hydrogenated castor oil.
Suitable buffer agents include inorganic acids or salts thereof such as sodium hydrogen phosphate, potassium hydrogen phosphate boric acid and sodium borate; and organic acids and salts thereof such as citric acid, sodium citrate, tartaric acid and sodium tartrate.
The amount of sodium carboxymethyl cellulose is preferably in a range of 0.25 to 1.0% by weight.
When the nonionic surfactant is added, the amount of the nonionic surfactant is preferably in a range of 1 to 3% by weight.
When the buffer agent is added, the amount of the buffer agent is in a range of o to 3% by weight.
The solubility of the bupranolol is increased by adding these adjuvants for solubilization.
For example, the solubilities of the bupranolol hydrochloride at 250C with and without these adjuvants were measured by ultraviolet absorptions at 275 mm (in 0. lN-HCl). The results are shown in Table 1. When the surfactant was added, a solution of the surfactant having the same concentration was used as a blank, because the ultraviolet absorption was interrupted.
TABLE 1
Adjuvant Solubility of concentration bupranolol Adjuvant (wt. So) (mg/ml) Standard isotonized solution ~ 2.8 Polysorbate 80 (Standard isotonized solution) ('Polysorbate is a registered trade mark) 3.0 6.6 Sodium carboxymethyl cellulose 0.5 14.7 Sodium carboxymethyl cellulose 0.5 16.6 Polysorbate 80 3.0 Sodium carboxymethyl cellulose 0.5 Polysorbate 80 3.0 18.6 KH2PO4 0.8 Na2HPO4 0.56 Table 1 clearly shows that the addition of sodium carboxymethyl cellulose causes an increase m the solubility of bupranolol hydrochloride to a level 5 to 6.6 times higher than that of the standard isotonized solution.
The solubility of bupranolol hydrochloride at 50C was 12.8 mg/ml, the ophthalmic solution was stable at 50C and the concentration was satisfactory from the viewpoint of the medical effect.
In order to test the stability of the resulting aqueous solution, the ophthalmic solutions were stored at temperatures of 50C, 150 , 80"C and room temperature and under room light for the terms shown in Table 2 and then, the bupranolol was extracted with an organic solvent which is not miscible with water and titrated in a non-aqueous titration.
In accordance with the method, bupranolols can be titrated after separating from the hydrolyzed compounds of the bupranolol.
The percentages by weight of bupranolol hydrochloride in the aqueous solution are shown in Table 2.
TABLE 2
Condition De zs for storage (days) of Composition storage 0 0.5 1 30 Bupranolol 1.0% 50C 100.0 ~ 98.7 Na-CMC 0.5% 150C ,, 100.7 Polysorbate 80 3.0% room ,, 98.2 temp.
KH2PO4 0.8% 800C ,, 98.9 97:5 - Na2HPO4 0.56% room ,, 99.3 light Note: more than 100.0% is an experimental error.
From the results of Table 2, it was found that the aqueous solution was stable for storage. Change of appearance such as precipitation of crystals were not found.
The effective dose of the medicine for glaucoma is in a range of 0.2 to 1.5% preferably 0.5 to 1.0% and especially about 1.0% by weight.
It is necessary to maintain normal intraocular pressure during the therapy against glaucoma. Otherwise, the function of eye is disordered.
The following test clearly indicates that application of a 1 wt.% solution makes it possible to maintain the normal intraocular pressure longer than that of a 0.2 or 0.5 wt.% solution.
It is possible to include other medicines or other adjuvants in the composition of the invention.
In a preferred preparation of the composition for treatment of glaucoma, the active ingredient is mixed with the sodium carboxymethyl cellulose or the mixture of the nonionic surfactant and sodium carboxymethyl cellulose and the mixture is melted at about 80"C on a hot water bath and pure water at the same temperature is gradually added to solubilize the active ingredient with stirring and the mixture is cooled to room temperature.
A buffer agent as the isotonizing and pH adjusting agent is added to it and, if necessary, a preservative agent is added to dissolve in it and the mixture is diluted with pure water to obtain a composition of the desired concentration.
The medicine for glaucoma of the invention does not cause miosis or mydriasis whereby the side-effects of darkness and abnormal adjustment of visual field are not caused. Accordingly, it can be advantageously used for both blocked-angle glaucoma and wide-angle glaucoma.
The side-effects of systemic symptoms caused by the conventional medicine acetasolamide are not caused, the medicine of the invention can be topically applied.
The medicine of the invention has low toxicity.
The acute toxicity test result of bupranolol hydrochloride is shown in Table 3 wherein the figures show LD, values (mgkg).
TABLE 3
Mouse Rat Rabbit Dog Test animal (sex) M F M F M M Intravenous injection 39.3 47.6 15.3 Subcutaneous injection 567.0 622.0 789.0 630.0 Intraperitoneal injection 106.0 96.0 Oral dose 369.0 329.0 518.0 749.0 895.0 438.0 Experiment.
The ophthalmic tests using the ophthalmic solution of bupranolol hydrochloride were carried out in 5 patients with primary open-angle glaucoma having substantially the same intraocular pressure in right and left eyes.
In the ophthalmic test, about 35 ,ul of each ophthalmic solution of 1%, 0.5% or 0.2% by weight of the solution of bupranolol hydrochloride was in each case dropped into one eye as the test eye and the other eye was used as a control eye.
Tonometry was carried out using an Aplanation tonometer to measure intraocular pressure of the test eyes and the control eyes before and after the ophthalmic test with time intervals.
The results are shown in Table 4. The maximum ratio of decrease of intraocular pressures means the ratio of decrease of intraocular pressure of the test eye to that of the control eye.
TABLE 4
Lasting time Recovery of of the lower- intraocul'ar ing effect pressure Concen- induced Maximum Minimum lowered tration of by the ratio of effective by the ophthalmic ophthalmic decrease of concen- ophthalmic solution solution intraocular tration solution Test (wt. Sc) (min.) pressure (wt. s (hr 1) 1 1 550 0.56 0.5 210 0.22 0.18 0.0042 0.2 25 0.08 2 1 480 0.36 0.5 250 0.18 0.20 0.0036 0.2 0 0.08 3 1 530 0.59 0,5 320 0.30 0.15 0.0042 0.2 70 0.12 4 1 420 0.34 0.5 310 0.22 0.10 0.0046 0.2 120 0.09 5 1 600 0.68 0.5 1 300 0.46 0.16 0.0038 0.2 65 0.11 As shown in Table 4, the effect of bupranolol ophthalmic solution lasted for 420 to 600 min. in the case of 1% solution, 210 to 320 min. in the case of a 0.5wt.% solution and 0 to 120 min. in the case of a 0.2wt,% solution.
The ratio of decrease of intraocular pressure was 34 to 68% in the case of a lwt.% solution; 18 to 46% in the case of a 0.5wt.% solution and 8 to 12% in the case of 0.2wt.%. The mininum effective concentration calculated from the data was 0.1 to 0.2wt.%.
As the result, it was found that a lwt.% solution was the most effective as the medicine for glaucoma among the ophthalmic solutions of 0.2, 0.5 and lwt% concentrations.
Preparation l.
0.5 g of bupranolol hydrochloride and 3 g of Polysorbate 80 (nonionic surfactant) and 0.25 g of sodium carboxymethyl cellulose were mixed with heating, about 80 ml of distilled water was gradually added with stirring to dissolve them, and 0.8 g of KH2PO4 and 0.56 g of Na2HPO4 were added to the solution. The solution was diluted with distilled water to a volume of 100 ml. The solution was filtered to prepare an ophthalmic solution (pH 6.O7.0).
Preparation 2.
l g of bupranolol hydrochloride, 3 g of Polysorbate 80 and 0.5 g of sodium carboxymethyl cellulose were mixed with heating, about 80 ml of distilled water was gradually added with stirring to dissolve them, and 0.8 g of KH2PO4 and 0.56 g of Na2HPO4 were added and dissolved and the solution was treated in accordance with the process of Preparation 1 to obtain an ophthalmic solution (pH 6.0 to 7.0).
Preparation 3.
A 1 g of bupranolol hydrochloride, 3 g of Polysorbate 80 and 0.5 g of sodium carboxymethyl cellulose were mixed with heating, about 80 ml of distilled water was gradually added with stirring to dissolve them, 2.9 g of disodium citrate (1.5 hydrate) was added and dissolved, and 9 ml of IN--NaOH aq. solution was further added and the solution was treated in accordance with the process of Preparation 1 to obtain an ophthalmic solution (pH 6.0 to 7.0).
Preparation 4.
A 1 g of bupranolol hydrochloride, 3 g of Polysorbate 80 and 0.5 g of sodium carboxymethyl cellulose were mixed with heating, about 80 ml of distilled water was gradually added with stirring to dissolve them, and 1.8 g of boric acid and 0.11 g of sodium borate (10 hydrate) were added and dissolved and the solution was treated in accordance with the process of Preparation 1 to obtain an ophthalmic solution (pH 6.0 to 7.0).
Preparation 5.
A 1 g of bupranolol hydrochloride, 3 g of polyoxyethylene hydrogenated castor oil (50 moles of ethyleneoxide adduct) and 0.5 g of sodium carboxymethyl cellulose were mixed with heating, about 80 ml of distilled water was gradually added with stirring to dissolve them, and 0.8 g of KH2PO4 and 0.56 g of Na2HPO4 were added and dissolved and the solution was treated in accordance with the process of Preparation 1 to obtain an ophthalmic solution (pH 6.0 to 7.0).
WHAT WE CLAIM IS:
1. An antiglaucomatous ophthalmic solution which comprises an aqueous solution of a bupranolol having the formula I
or a salt thereof as an active ingredient and sodium carboxy-methyl cellulose as a solubilizing adjuvant.
2. An antiglaucomatous ophthalmic solution according to claim 1 also containing a nonionic surfactant as a solubilizing adjuvant.
3. An antiglaucomatous ophthalmic solution according to claim 2 wherein said nonionic surfactant is a polyoxyethylenesorbitan ester.
4. An antiglaucomatous ophthalmic solution according to claim 2 or claim 3 also containing a buffer agent as a solubilizing adjuvant.
5. An antiglaucomatous ophthalmic solution according to claim 4 wherein said buffer agent is potassium dihydrogen phosphate and/or disodium hydrogen phosphate.
6. An antiglaucomatous ophthalmic solution according to claim 1 substantially as herein described with reference to any one of Preparations 1 to 5.
7. A process for preparing an antiglaucomatous ophthalmic solution which comprises solubilizing a bupranolol having the formula I herein or a salt thereof in an aqueous medium with sodium carboxymethyl cellulose as a solubilizing agent.
8. A process according to claim 7 wherein the aqueous medium also contains a nonionic surfactant as an additional solubilizing agent.
9. A process according to claim 8 wherein the aqueous medium also contains a buffer agent as a further solubilizing agent.
10. A process according to claim 8 substantially as herein described with reference to preparations I to 5 herein.
11. An antiglaucomatous ophthalmic solution made by a process according to any one of claims 7 to 10.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (11)
1. An antiglaucomatous ophthalmic solution which comprises an aqueous solution of a bupranolol having the formula I
or a salt thereof as an active ingredient and sodium carboxy-methyl cellulose as a solubilizing adjuvant.
2. An antiglaucomatous ophthalmic solution according to claim 1 also containing a nonionic surfactant as a solubilizing adjuvant.
3. An antiglaucomatous ophthalmic solution according to claim 2 wherein said nonionic surfactant is a polyoxyethylenesorbitan ester.
4. An antiglaucomatous ophthalmic solution according to claim 2 or claim 3 also containing a buffer agent as a solubilizing adjuvant.
5. An antiglaucomatous ophthalmic solution according to claim 4 wherein said buffer agent is potassium dihydrogen phosphate and/or disodium hydrogen phosphate.
6. An antiglaucomatous ophthalmic solution according to claim 1 substantially as herein described with reference to any one of Preparations 1 to 5.
7. A process for preparing an antiglaucomatous ophthalmic solution which comprises solubilizing a bupranolol having the formula I herein or a salt thereof in an aqueous medium with sodium carboxymethyl cellulose as a solubilizing agent.
8. A process according to claim 7 wherein the aqueous medium also contains a nonionic surfactant as an additional solubilizing agent.
9. A process according to claim 8 wherein the aqueous medium also contains a buffer agent as a further solubilizing agent.
10. A process according to claim 8 substantially as herein described with reference to preparations I to 5 herein.
11. An antiglaucomatous ophthalmic solution made by a process according to any one of claims 7 to 10.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6225876A JPS52154528A (en) | 1976-05-31 | 1976-05-31 | Remedy for glaucoma |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1564454A true GB1564454A (en) | 1980-04-10 |
Family
ID=13194930
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB22965/77A Expired GB1564454A (en) | 1976-05-31 | 1977-05-31 | Antiglaucomatous ophtalmic solution |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS52154528A (en) |
DE (1) | DE2723936A1 (en) |
FR (1) | FR2353295A1 (en) |
GB (1) | GB1564454A (en) |
NL (1) | NL7705839A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0037622A2 (en) * | 1980-04-07 | 1981-10-14 | Alza Corporation | Drug delivery insert for controlled ocular therapy |
EP0458588A1 (en) * | 1990-05-22 | 1991-11-27 | R-Tech Ueno Ltd. | Treatment of ocular hypertension with a synergistic combination for ocular administration |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3125636A1 (en) * | 1981-06-30 | 1983-01-13 | Merck Patent Gmbh, 6100 Darmstadt | 1- (P-2-ISOPROPOXYETHOXYMETHYL-PHENOXY) -3-ISOPROPYLAMINO-PROPAN-2-OL FOR LOWERING THE EYE PRESSURE AND OPHTALMIC, CONTAIN THIS COMPOUND |
IT1163107B (en) * | 1983-02-15 | 1987-04-08 | Simes | PHARMACEUTICAL COMPOSITIONS AND THEIR USE IN GLAUCOMA TREATMENT |
IT1248014B (en) * | 1991-06-07 | 1995-01-05 | Inverni Della Beffa Spa | PROTRACTED OPHTHALMIC PREPARATIONS |
GR1001366B (en) * | 1992-10-16 | 1993-10-29 | Inverni Della Beffa Spa | Extended-release opthalmic preparations. |
-
1976
- 1976-05-31 JP JP6225876A patent/JPS52154528A/en active Pending
-
1977
- 1977-05-26 DE DE19772723936 patent/DE2723936A1/en active Pending
- 1977-05-27 FR FR7716290A patent/FR2353295A1/en active Granted
- 1977-05-27 NL NL7705839A patent/NL7705839A/en not_active Application Discontinuation
- 1977-05-31 GB GB22965/77A patent/GB1564454A/en not_active Expired
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0037622A2 (en) * | 1980-04-07 | 1981-10-14 | Alza Corporation | Drug delivery insert for controlled ocular therapy |
EP0037622A3 (en) * | 1980-04-07 | 1981-11-11 | Alza Corporation | Drug delivery insert for controlled ocular therapy |
EP0458588A1 (en) * | 1990-05-22 | 1991-11-27 | R-Tech Ueno Ltd. | Treatment of ocular hypertension with a synergistic combination for ocular administration |
US5208256A (en) * | 1990-05-22 | 1993-05-04 | R-Tech Ueno, Ltd. | Treatment of ocular hypertension with a synergistic combination for ocular administration |
Also Published As
Publication number | Publication date |
---|---|
FR2353295A1 (en) | 1977-12-30 |
DE2723936A1 (en) | 1977-12-15 |
FR2353295B1 (en) | 1982-11-05 |
NL7705839A (en) | 1977-12-02 |
JPS52154528A (en) | 1977-12-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee | ||
PCPE | Delete 'patent ceased' from journal |
Free format text: 4845,PAGE 62 |
|
PCNP | Patent ceased through non-payment of renewal fee |
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