JPS5833202B2 - Gankayoushiyohouno Anteikahou - Google Patents

Description

[Detailed description of the invention] TECHNICAL FIELD This invention relates generally to methods for stabilizing ophthalmic formulations.

1-[4-(1-pyrrolidinyl)-2butynyl]-2-pyrrolidinone or 1-(2oquino-1-pyrrolidino)-4-(1-pyrrolidino)-budo-2-yne having the formula is "oxotremorine" It is a compound known as.

Oxotremorine is known as ``tremoline'', and oxidation of the 2-position carbon atom of one of the pyrrolidine rings leads to 1,1'-(2-butynylene).
It is a metabolite of dipyrrolidine.

These compounds are highly active muscarinic tertiary amines that are conventionally used to study cholinergic effects in both the peripheral and central nervous systems.

Tremoline and especially its metabolite oxotremorine have been used as pharmacological tools in screening anti-parkinnon active compounds due to the appearance of symptoms similar to parkinnon syndrome when they are administered intravenously.

A second compound similar to oxotremorine has the formula i
-C4-(1-a3-pyrrolidinyl)=2-butynyl-2-pyrrolidinone.

For convenience, the above compound will be referred to as "dehydro-oxotremorine" in the following description.

A number of methods are known for the production of oxotremorine and dehydro-oxotremorine and are described, for example, in U.S. Pat.・Communications J 5
(4), 276-279.1961 and in the Journal of Medicinal Chemistry J8, 274° 1965.

Oxotremorine also has peripheral cholinergic effects when administered intravenously (US Pat. No. 34,441).
(See Specification No. 71).

British Patent No. 10, equivalent to US Patent No. 3,444,185
No. 79467 states that when oxotremorine is administered intravenously to animals, a rapid and transient decrease in arterial pressure occurs, and when administered intraperitoneally to anesthetized rats, it causes a progressive decrease in arterial pressure. It has been reported that a long-lasting and persistent drop in blood pressure occurs.

US Pat. No. 3,354,178 further discloses aminoalkynes as central nervous system stimulants.

Glaucoma is an eye condition characterized by increased intraocular pressure.

If untreated, the condition eventually results in irreversible retinal damage and blindness.

Common treatments for glaucoma include pilocarpine and/or
It is done by administering epinephrine several times a day.

The disadvantages of pilocarpine are that it can irritate the user's eyes, and as a natural substance it is susceptible to changes in its composition. Long-term pilocarpine treatment usually requires a dose adjustment to maintain its medicinal activity over time. ie up to 4% concentration is required.

In many cases of long-term treatment with pilocarpine, the drug becomes ineffective.

However, problems such as those mentioned above have been met by the difficulty in combining the active compound with a topical ophthalmological pharmaceutical carrier sufficient to maintain the pH of the resulting composition between about 4.0 and 7.5. It has been found that the present invention relates to a process for the preparation of highly stable topical ophthalmic compositions containing an active compound having a formula selected from the group consisting of: It was done.

Oxotremorine and dehydro-oxotremorine can each be produced by any suitable method, such as those described above.

As will be apparent to those skilled in the art, non-toxic acid addition salts of oxotremorine and dehydro-oxotremorine may also be prepared.

It will therefore be understood that their conventional pharmaceutically acceptable acid addition salts are included within the scope of this invention.

Many physiologically and pharmaceutically acceptable salts can be used in the present invention.

Examples of acids suitable for forming salts with oxotremorine or dehydro-oxotremorine include fumarate, citric acid, hydrochloric acid, nitric acid, sulfuric acid and tartaric acid.

Suitable ophthalmic carriers are known to those skilled in the art and all such known conventional carriers may be used in the present invention.

The particular carrier may be in the form of a sterile ophthalmic cartilage, cream, gel, solution or dispersion, with solutions being preferred.

Suitable carriers may also include sustained release polymers, for example chelating agents and stabilizing agents such as EDTA.

Antioxidants such as sodium bisulfite, sodium thiosulfite, 8-hydroxyquinoline or ascorbic acid may also be used.

Non-toxicity is maintained primarily by conventional ophthalmic preservatives such as chlorbutanol, benzalkonium chloride, cetylpyridium chloride, phenylmercuric salts, thimerosal, phenethyl alcohol, etc. for aqueous formulations. and generally from about 0.001 to
It is used in amounts varying over about 0.1% by weight.

Common preservatives for ointments include methyl and propylparabens.

Typical ointment bases include white petrolatum and mineral oil or liquid petrolatum.

However, preservative aqueous carriers are preferred.

The solutions may be administered manually to the eye in a suitable dosage form, such as eye drops, or by means of a suitable droplet or spray device.

Suitable ophthalmic carriers or stabilizers include sterile,
Included are substantially isophoric aqueous solutions containing small amounts, ie, up to about 5% by weight, of hydroxypropylmethyl-cellulose, polyvinyl alcohol, carboxymethylcellulose, hydroxyethylcellulose, glycerin, EDTA, sodium bisulfite, and ascorbic acid.

Generally, a dosage level of 1 to 2 drops of the aforementioned aqueous solution applied 1 to 4 times per day will be a suitable dosage.

Generally, the concentration of oxotremorine or dehydro-oxotremorine will be from about 0.001% to about 0.5%, preferably from about 0.05% to 0.25%, and advantageously from about 0.05% to 0. .1% (wt,/v, % calculated on free base).

The method by which the ophthalmic solution is stabilized is such that the solution is stabilized by about 4.
This is based on the fact that it has been found to be extremely stable at a pH of 0 to 7.5.

Above this pH range, stability rapidly decreases to approximately pH 4.
Below 0, the solution becomes too acidic and may irritate and sting the user's eyes.

The foregoing solutions of this invention contain suitable amounts of borate, carbonate,
phosphate, tris(hydroxymethylaminomethane),
p by buffers such as acetate and citrate buffers.
H may be maintained between about 4.0 and 7.5.

The following examples illustrate how the invention may be practiced.

However, it should be understood that these examples are included for illustrative purposes and that the invention is not limited to the particular materials or conditions described in the examples.

Example 1 Formulations A-C were prepared by combining the base formulation with various concentrations of oxotremorine ranging from 0.0055% to 0.25% as follows.

Formulations A-C were stability tested at room temperature for the indicated times.

The data obtained from this test are shown in Table 1 below.

According to the table above, at room temperature and pH of about 6.7, all of the above formulations are very stable for long periods of time, with a concentration of about 5%
It is shown that only the following decrease in activity occurred.

Example 2 ☆ ☆ Contains about 0.1% oxotremorine and has a pH of 5~
Five (phosphate) buffer solutions ranging from 9.5 to 9.5 were prepared and accelerated stability studies were performed at 45° C. for the indicated times.

The data obtained from this test are displayed in Table 2 below.

According to the results of the above tests, the actual decrease in activity is approximately 7.5
This is shown to occur at pHs above.

Example 3 Example 2 is repeated except that the stability results are evaluated for stability over 0.5 to 3 years at 23<0>C.

The results are shown in Table 3 below. Table 3 above shows that oxotremorine has high stability in solutions with a pH of about 4 to 7.5.

Example 4 Examples 1-3 are repeated, except that dehydro-oxotremorine is used instead of oxotremorine.

Comparable results are obtained.

Example 5 This example shows rabbit intraocular pressure (I) assessed by miosis.
Comparison of the effect of pilocarpine (a drug commonly used in the treatment of glaucoma) with that of oxotremorine and dehydro-oxotremorine on OP).

Seven New Sealant expelled rabbits were used.

These are suppressed and a pre-measured amount (0.05T
Ll) was instilled into one eye by folding the eyelids 5 times to minimize drug leakage.

Compounds were prepared in isomorphic phosphate buffer (pH 7.4) at the indicated concentration.
) given as.

The untreated eye served as the control.

The evaluation was based on the following scale.

Scale 0 - No contraction 1 - Slight contraction Early medium contraction 5 - Severe contraction (pinpoint) The data obtained from the above tests are shown in Table 4 below.

According to Table 4 above, oxotremorine and dehydro-oxotremorine are actually 1/100 of pilocarpine.
It is clearly shown that it is comparable to pilocarpine at a concentration of ~1/200.

Claims (1)

Claims: An active compound having the formula
containing an active compound having the above formula, or a pharmaceutically acceptable acid addition salt thereof, characterized in that it is combined with a topical ophthalmic pharmaceutical carrier containing sufficient buffering agents to maintain A method for stabilizing a topically administrable ophthalmic composition.