DE2723936A1 - OPHTHALMIC SOLUTION FOR GLAUCOM TREATMENT - Google Patents

Description

The invention relates to a new ophthalmic solution. For the treatment of glaucoma z. Currently different Funds used e.g. B. a carbonic anhydrase inhibitor (internal medicine); injectable solutions against high osmotic pressure; injectable autonomic blocking agents; Miotics (ophthalmic solution), mydriatics (ophthalmic L. sung) or the like.) However, all of these agents have certain disadvantages. For example, the carboxylic anhydrase inhibitor causes gastrointestinal disorders, numbness in the limbs, difficulty breathing, drowsiness, dizziness, Uretralithiasis, acidosis, etc. with prolonged administration. Injections are usually used in acute cases administered and are not suitable for long-term treatment. Ophthalmic solutions of miotics cause local Side effects, especially darkness and abnormal attitudes of the field of vision, as well as systemic side effects in particular diarrhea, vomiting, etc. have mydriatics the disadvantage that, when administered to patients with narrow angle glaucoma, it causes blocked angle glaucoma aggravate. It is the object of the present invention to provide an ophthalmic solution for the treatment of glaucoma to create in which bupranolol is solubilized.

According to the invention, an ophthalmic solution for the treatment of glaucoma is created, which as an active ingredient Contains bupranolol of the following formula or a salt thereof:

CH ₃ I 0-CH ₂ CHCH ₂ NHC-CH ₃

Oh CH ₃

Cl

According to the invention, known compounds which are used under the name bupranolols for the treatment of angina pectoris and arrhythmia are used as the active ingredient . These active ingredients can be produced according to the method

709850/0913

U.S. Patent 3,309,406.

Bupranolols have a low solubility in water. Put them in an isotonic saline solution at room temperature a solubility less than 0.3% when the pH lies within an area that does not irritate the eye. The inventors tried to find pharmacological agents which are essentially non-toxic and increase the solubility of the bupranolols. It was determined, that the concentration of bupranolols in aqueous solutions can be increased if sodium carboxymethylcellulose is added to the solution or a combination of sodium carboxymethyl cellulose and a nonionic surfactant Agents with or without buffering agents incorporated as an adjuvant for solubilization. This is a stable Obtaining ophthalmic solution for glaucoma therapy.

Suitable nonionic surfactants include Polyoxyethylene glycol ether, such as polyoxyethylene lauryl ether, Polyoxyethylene oleyl ether; Esters of higher fatty acids with polyoxyethylene glycol, such as polyethylene glycol monolaurate, Polyethylene glycol monooleate; and polyoxyethylene sorbitol anhydride fatty acid esters, such as polyoxyethylene sorbitic anhydride monolaurate, polyoxyethylene sorbitic anhydride monooleate (e.g. polysorbate 80). It is particularly preferred to use polyethylene glycol monooleate or a polyoxyethylene adduct of the hydrogenated Castor oil fatty acid.

Suitable buffers include inorganic acids or salts same as sodium hydrogen phosphate, potassium hydrogen phosphate, Boric acid and sodium borate as well as organic acids and salts thereof, such as citric acid / sodium citrate, Tartaric acid / sodium tartrate.

The amount of sodium carboxymethyl cellulose is preferably in the range of about 0.25 to 1.0 %. If the nonionic surfactant is added, so

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its amount is preferably about 1 to 3%. If a buffering agent is added, the amount thereof is from 0 to 3 %. The solubility of the bupranolol is increased by adding this adjuvant through solubilization. The solubility of bupranolol hydrochloride at 25 ^° C. when using these additives was measured by ultraviolet absorption at 275 mm (in 0, In-HCl). The results are shown in Table 1. When the surface active agent is added, a solution of the surface active agent of the same concentration is used as a comparative solution because the ultraviolet absorption is interrupted.

Table 1 Adjuvant Adjuvant
concentration solubility
ν. Bupranclol
(mg / ml) standardized isotonic
solution 2.8 Polysorbate 80 (standardized
Isotonic solution) 3.0 6.6 Sodium carboxymethyl cellulose 0.5 14.7 Sodium carboxymethyl cellulose
Polysorbate 80 0.5
3.0 16.6 Sodium carboxymethyl cellulose
Polysorbate 80
K! .., PO. 0.5
3.0
0.8
0.56 18.6

Tnb "iie 1 clearly shows that an addition of sodium carboxymethyl cellulose the solubility of the bupranolol hydrochloride by 5 to 6.6 times compared to the isotonic Stancard solution elevated. The solubility of bupranolol hydrochloride at 5 ° C is 12.8 mg / ml and the ophthalmic one obtained Solution is stable at 5 C and the concentration of the active ingredient is satisfactory from the medical point of view.

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To test the stability of the aqueous solution obtained

the ophthalmic solution is at a temperature of 5 ⁰ C, 15 ⁰ C and 80 ⁰ C, as well as at room temperature and under normal room lighting, namely under the conditions mentioned in table 2. Then the bupranolol extracted with an organic solvent, which with

Water is immiscible and in the non-aqueous system

titrated. This procedure uses the bupranolols titrated after separation from the hydrolysis products.

The percentage of bupranolol hydrochloride in

the aqueous solution (%) is shown in Table 2.

Table 2

composition camp
conditional
worked Storage duration (days) 0.5 1 30th Bupranolol 1.0% 5 ° C 0 98. 7 Na-CMC 0.5% 15 ° C 100.0 100. 7 Polysorbate 80 3.0% Room-
temp. Il 98.2 KH ₂ PO ₄ 0.8% 80 "C
5InBIeT-
illuminate
tion Il 98.9 97.5 - Na ₂ HPO ₄ 0.56% ti 99.3 Il

Note: A measured value of more than 100.0 % is based on an incorrect measurement.

It can be seen from the results in Table 2 that the aqueous solution is stable on storage. A change the appearance does not occur and, in particular, no crystals are precipitated. The effective dose the drug used in glaucoma treatment is in the range

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from 0.2 to 1.5%, and preferably O, from 5 to 1, O% and especially about 1.0%. It is necessary to maintain normal intraocular pressure during Gl aucorn therapy. Otherwise, there will be disorders of the eye function. The following test shows that normal intraocular pressure can be maintained longer when a 1% solution is used than when a 0.2% solution or a 0.5% solution is used.

It is possible with the glaucoma agent according to the invention combine other drugs or other adjuvants.

To produce the agent according to the invention for glaucoma treatment, the active ingredient is mixed with the non-ionic surface-active agent or with the mixture of the non-ionic surface-active agent and the sodium carboxymethyl cellulose and the mixture is ^{melted at about 80 °} C. on a hot water bath and pure water of the same temperature is gradually added to cause solubilization with stirring. It is then cooled to room temperature. A buffering agent for isotonicization and pH adjustment is added and, if necessary, a preservative can also be added and dissolved in the solution. The desired solution of the desired concentration is obtained by dilution with pure water.

The application of the glaucoma agent according to the invention leads neither to a miosis nor to a mydriasis and side effects, e.g. B. Darkness or abnormal setting of the Field of view are not created. The agent according to the invention is therefore particularly suitable for treatment for blocked-angle glaucoma, or to treat wide-angle glaucoma. Since the inventive Agents that can be applied topically will have systemic side effects that occur with the conventional application of

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Acetasclamide, avoided. The agent according to the invention has a low toxicity. The acute toxicity of bupranolol hydrochloride is given in Table 3 as the LD, - _O value (mg / kg).

T ^ abelle 3 Would have
i
t η
f Rabbit fur
chen dogs Mice
t Ii). ? Laboratory animal
(Gender) i V. 'i ■ f 7K ^. 0 IiU). 0 intravenous
injection . ') (. 7.0 4 7. (i ] O (OK V (i. 0 subcutaneous
injection ", 0 I) IH. 0 / ι '). υ ■ ΠΗ.0 subcutaneous
Close injection 5 UV. 0 oral dose attempt

The ophthalmic tests are carried out using the ophthalmic solution of bupranolol hydrochloride in 5 patients with primary open angle glaucoma where the intraocular pressure is essentially the same in the right and left eyes. In the ophthalmic test, about 35 μl of each ophthalmic solution of 1 %, 0, Γ> % or 0.2% bupranolol hydrochloride were instilled in each eye as a test eye, while the other eye is used for comparison. The tonometry is performed using an aplanation tonometer to measure the intraocular pressure of the test eye and the reference eye before and after the ophthalmic test at equal time intervals. The results are summarized in the table. The maximum ratio of reduction in the intraocular pressure means the ratio of reduction of in ^tr: les iiren pressure <Test eye to the intraocular pressure of the V. , I cvi c hsauges.

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ORtGiNAL INSPECTED

j 3 Concentration
tion of the ι
ophthalm.
solution
(%) Tabel 4th minimal
effective
Conc
tration
3 (%) i 0.20 Again
position d.
intraocular
ren pressure
after d.Senk.
mdophthalm ^
Solution (h ~ l) test 1 ι 0. 1 S i
I. j
1 0.5 Duration
d. lowering
effect d.
ophthalm.
solution
(min) maximum
relationship
d. lowering
d.intraocu-
laren pressure! '< U. ^ 04 2 t 4th 0.2 5 50 0. 56 0.15 1 210 0.2- 0. 5 25th 0.0a j 0.0036 5 0.2 4 80 0.36 0. 10 1 250 0. 18 0. 5 0 0.08 0.0042 0.2 5 ^ 0 0. 59 0.16 1 320 0.30 0.5 70 0.12 0.0046 0.2 -1 2 0 0.34 1 310 0.22 0.5 120 0.09 0.0038 0.2 600 0.68 300 0.46 ü5 0.11

CO CD CO

As Table 4 shows, the effect of the ophthalmic persists Bupranolol solution in the case of a 1% solution 420 to 600 min on and in the case of a 0.5% solution 210 to 320 min and in the case of a 0.2% solution 0 to 120 min the decrease in intraocular pressure is 34 to 68% in the case of the 1% solution; 18 to 46% in the case of the 0.5% solution and 8 to 12% in the case of the 0.2% solution Solution. The minimum effective concentration can be calculated from this data and is 0.1 to 0.2%. Man recognizes that among the various solutions with a concentration of 0.2, 0.5 and 1%, the 1% solution is the most effective Medicine used to treat glaucoma.

The invention is explained in more detail below with reference to production examples.

Production example 1

0.5 g Bupranololhydrochlorid and 'Λ g polysorbate 80 (nonionic surfactant), and 0.2 ¹ S g sodium carboxymethylcellulose are mixed under heating, and thereafter they are gradually added with stirring about 80 ml of distilled water is added to bring about dissolution. Then add 0.8 g of KH ₂ PO ₄ and 0.56 g of Na _{3 HPO 4.} The solution is diluted to 100 ml with distilled water. Then the solution is filtered off to give an ophthalmic L _o s mg of pH 6, O to 7.0.

Production example 2

1 g of bupranolol hydrochloride, 3 g of polysorbate 80 and 0.5 g of sodium carboxymethyl cellulose are mixed with heating and then about 80 ml of distilled water is gradually added with stirring to cause dissolution. Then 0.8 g of KH ₂ PO ₄ and 0.56 g of Na ₃ HPO _{4 are} added and the resulting solution is then treated further as in preparation example 1. This gives an ophthalmic solution of pH 6.0 to 7.0.

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Production example 3

1 g of bupranolol hydrochloride, 3 g of polysorbate 80 and 0.5 g Sodium carboxymethyl cellulose is mixed with heating and then about 80 ml of distilled water is gradually added with stirring to cause dissolution. Then 2.9 g of disodium citrate (1,5 hydrate) are dissolved in the resulting solution. 9 ml of an aqueous solution are also added Solution of In-NaOH is added and the solution is treated according to the method of Preparation Example 1 further. Man receives an ophthalmic solution of pH 6.0 to 7.0.

Production example 4

1 g of bupranolol hydrochloride, 3 g of polysorbate 80 and 0.5 g of sodium carboxymethyl cellulose are mixed with heating and about 80 ml of distilled water are added under Stir added gradually to induce dissolution. 1.8 g of boric acid and 0.11 g of sodium borate (ΙΟ-hydrate) are then dissolved in it, whereupon the solution according to Preparation Example 1 is treated further. You get a ophthalmic solution from pH 6.0 to 7.0.

Production example 5

1 g of bupranolol hydrochloride, 3 g of polyoxyethylene adduct of the hydrogenated fatty acid of castor oil (50 moles of ethylene oxide adduct) and 0.5 g of sodium carboxymethyl cellulose are mixed with heating and about 80 ml of distilled water are gradually added with stirring to bring about dissolution. 0.8 g of KH ₂ PO ₄ and 0.56 g of Na ₂ HPO _{4 are} then dissolved in the solution, whereupon the resulting solution is treated further as in preparation example 1. An ophthalmic solution of pH 6.0 to 7.0 is obtained.

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Claims (10)

PATENT CLAIMS {\\ Ophthalmic solution for glaucoma treatment, marked determined by a content of bupranolol of the formula (I) or a salt of the same as an active ingredient: (> -tMl> CHCH> NnOCIIi Ci 2. Ophthalmic solution according to claim 1, characterized in that that the bupranolol is solubilized with sodium carboxymethyl cellulose as an adjuvant. 3. Ophthalmic solution according to one of claims 1 or 2, characterized in that the bupranolol with a non-ionic surfactants as an adjuvant is solubilized. 4. Ophthalmic solution according to one of claims 1 to 3, characterized in that the bupranolol is solubilized with a buffer as an adjuvant. 5. Ophthalmic solution according to claim 3, characterized in that the non-ionic surface-active agent is a polyoxyethylene sorbitol anhydride ester. 6. Ophthalmic solution according to claim 4, characterized in that the buffer is potassium hydrogen phosphate and disodium hydrogen phosphate is. 7. A method for preparing the ophthalmic solution according to any one of claims 1 to 6, characterized in that one bupranolol with sodium carboxymethyl cellulose solubilized. 7 0 9 8 f »η / Q 9 1 3 ORIGINAL INSPECTED 8. The method according to claim 7, characterized in that the bupranolol with sodium carboxymethyl cellulose and a nonionic surfactant solubilized. 9. rfahren according to any one of claims 7 or 8, characterized in that the solubilized bupranolol with sodium carboxymethyl cellulose and a buffer. 10. The method according to any one of claims 7 to 9, characterized in that that the bupranolol with sodium carboxymethyl cellulose, a non-ionic surface-active Agent and a buffer solubilized. 7098 5 Π / 091 'i