JPH05505605A - Use of 5-transprostaglandin F↓2α as an intraocular pressure-lowering agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to means for lowering or maintaining intraocular pressure, and more particularly to pharmaceutically acceptable means for reducing or maintaining intraocular pressure. administration of a composition comprising 5-trans prostaglandin F2α in a carrier that can The present invention relates to methods and compositions for lowering or maintaining intraocular pressure.

Background of the invention The compositions and methods of the invention are useful in treating glaucoma, an eye disease characterized by elevated intraocular pressure. This is especially useful in theory.

Based on its etiology, glaucoma is classified as primary or secondary. For example, Primary glaucoma (congenital glaucoma) in humans is open angle or acute or chronic closed angle glaucoma. One of the closed angles. Secondary glaucoma is caused by a pre-existing eye disease such as glaucoma. Resulting from pancreatitis, intraocular tumors or enlarged cataracts.

The basic cause of primary glaucoma is still unknown. Increased intraocular pressure is due to closure of aqueous humor outflow. The cause is blockage. In chronic open-angle glaucoma, the anterior chamber and its anatomical structures Appears normal, but drainage of aqueous humor is obstructed. acute or chronic angle closure In Schlemm's canal, the anterior chamber is shallow, the angle of passage is narrow, and the iris is trabecular at the entrance to Schlemm's canal. It will disturb the net. Dilation of the pupil pushes the base of the iris forward, opposite the angle; It causes pupillary block and therefore sudden onset of the disease. Eyes with a narrow anterior chamber angle They are susceptible to acute angle-closure glaucoma of varying severity.

Secondary glaucoma occurs when the flow of aqueous humor from the posterior layer into the anterior chamber and then into Schlemm's canal is obstructed. caused by something being done. Inflammatory diseases in the anterior chamber are completely manifested in the bulging iris. Obstruct aqueous fluid drainage by creating posterior synechiae and block the drainage canal with exudate Will. Other common causes are intraocular tumors, enlarged cataracts, and central retinal vein occlusion. , trauma to the eye, surgery and intraocular hemorrhage.

Considering all types together, glaucoma affects approximately 2% of all people over the age of 40. , and is asymptotic for many years before progressing until vision is rapidly impaired.

If surgery is not required, topical β-adlerseptal antagonists have traditionally been used to treat glaucoma. It has been selected as a therapeutic drug.

It has been reported that certain eicosanoids and their derivatives have intraocular pressure-lowering activity. and is recommended for use in the management of glaucoma. eicosanoids and Derivatives contain a number of biologically important compounds such as prostaglandins and their Contains derivatives. Prostaglandin is a block with a structural formula represented by the following formula: It is described as a derivative of stanoic acid.

Various types are available depending on the structure and substituents in the alicyclic ring of the brostanic acid skeleton. Prostaglandins are known. Another classification is the general type of prostaglandins The number of unsaturated bonds in the side chain indicated by the subscript after it [e.g. Grandin E+ (PGE+), Prostaglandin E! (PGE,)) and based on the configuration of substituents in the alicyclic ring represented by α or β ([e.g. For example, prostaglandin F, α (PGF, α)].

Prostaglandins were long thought to be strong agents that increase intraocular pressure, but However, evidence accumulating in recent IO years suggests that prostaglandins is a highly effective intraocular pressure-lowering agent and is actually suitable for the long-term management of glaucoma. It has been shown that there are some (for example, Pito, El, Set (B ito, L, Z, ) Biological Protection W ith Prostaglandins Cohen, E B Edited by M. (Cohen, K.lt), Boca Raton , Fuller (Fla), CRC Breath Co., Ltd., 1985. p, 231-252; and Bitol, Z, Applied Pharma cology in the Medical Treatment of G la floating shield high S, Trance, M, (Drance, S, K) and Neufeld , knee, naughty.

(Neufald, A,)L), - N.Y., Grune & Grune & 5tratton, 1984, p. 477-505 reference). Such prostaglandins include PGF2α, PGF, α, PGE, and certain fat-soluble esters of such compounds, such as C1-C, alkyl esters. Included are esters such as l-isopropyl ester.

Although the exact mechanism is still unclear, recent experimental results suggest that prostaglandin The decrease in intraocular pressure caused by ginseng causes the outflow of the oveoscleral membrane. [Nilsson et al. , Investophthalmol.

Vis, Sci, 28 (separate volume), 284 (1987)).

The isopropyl ester of PGF, α, probably moves more efficiently through the cornea. However, it has a significantly stronger intraocular pressure-lowering effect than the original compound. It is shown. In 1987, the compound was declared “the most potent yet reported.” [For example, Pitot, L, Z (Bit□ .

L, Z, ), Arch, Ophthalmol, 105. 1036 (19 87) and Siebold et al., Prodrug 5. 3 ( (1989)].

Although prostaglandins appear to have no significant intraocular side effects, Such compounds in particular PGF2α and its prodrugs e.g. Topical ocular use of l-isopropyl ester of The feeling always accompanies me. Conditions related to increased intraocular pressure, such as in the treatment of glaucoma. The clinical potential of rostaglandin is severely limited by these side effects.

Contemporaneous-pending series transferred to Allergan Inc. U.S. patent applications for improved intraocular pressure reduction with no or very few side effects. Prostaglandin esters with lower activity are disclosed. Concurrently pending rice National Patent Application No. 386.835 (July 27, 1989) -prostaglandins such as 11-pivaloyl, 11-acetyl, 11- Regarding isobutyryl, 11-valeryl and 11-isovaleryl PGF, α.

Intraocular hypotensive 15-acyl prostaglandins are disclosed in co-pending U.S. patent application no. No. 57,394 (filed May 25, 1989). Similarly, professional 11.15-19,15- and 9,11-diesters of staglandins and For example, ll.

15-dipivaloyl PGFtα is known to have intraocular pressure lowering activity. same Currently pending U.S. Patent Applications No. 385,645, No. 386,312 and No. No. 386.834 (see all issues dated July 27, 1989). The entire disclosure of the patent application is expressly incorporated herein by reference.

Outline of the invention The present invention provides a method for treating glaucoma and elevated intraocular pressure in a pharmaceutically acceptable vehicle. The present invention relates to the use of 5-trans prostaglandin F, α blended into.

Quite surprisingly, the 5-6 double bond is trans than the natural cis configuration. Transprostaglandin F2α has significantly lower side effects, especially ocular surface hyperemia. It has remarkable intraocular pressure-lowering activity. Therefore, 5-trans prostaglandin F , α is associated with various ocular hypertension symptoms such as open-angle glaucoma, angle-closure glaucoma, and ocular hypertension. Sword (episode), suitable for treatment after surgery and laser trellis excision. It is an excellent preoperative aid.

In another aspect of the present invention, 5-transprostagra represented by the following formula (I) Eyes comprising a therapeutically effective amount of gin F, α or a salt thereof in a pharmaceutically acceptable excipient. Topically administrable pharmaceutical compositions for the treatment of elevated pressure are provided. Treatment effective The amount is usually within the range of approximately 0.0001% to 5%. Optionally, compositions of the invention The article further includes co-solvents, pH buffers, thickeners, antibiotics or other advantageous auxiliaries. .

According to another aspect of the invention, 5-trans prostaglandin PGF, α or administering a therapeutically effective amount of a pharmaceutically acceptable salt thereof to a mammal with elevated intraocular pressure; The present invention provides a method for treating high intraocular pressure.

In another aspect, the present invention provides a non-toxic ophthalmically acceptable liquid vehicle. PGF2α or a pharmaceutically acceptable drug thereof, packaged in a container suitable for metered administration. The present invention relates to an ophthalmic solution containing a therapeutically effective amount of vine salt.

In yet another aspect, the present invention provides a container selected for applying the contents of the container in metered form; and Ophthalmic solution defined therein Relating to pharmaceutical products containing.

Further features and advantages of the invention will be apparent from the detailed description of the preferred embodiments that follows. This will become clear when considered together with the examples and appended claims.

Detailed description of the invention The present invention uses PGFtα and pharmaceutically acceptable salts thereof as intraocular pressure lowering agents. Regarding the use of. PGF, α, has the following structural formula (I).

In the formula below, the thick solid line bond indicates the β position. This is the broken line bond of the hydroxyl group. This indicates that the substituents are in the α configuration.

As mentioned above, PGF in humans and other mammals when administered topically to the eye. It has been established that 2α lowers intraocular pressure. However, prostaglandins Topical administration of F, α can reduce, for example, conjunctival hyperemia, stinging and Patients may experience side effects such as foreign body sensation that range from no to unacceptable. depending on the amount of pressure and the dosage required to produce sufficient pressure regulation. moreover, Prostaglandin F, α may also cause a temporary increase in intraocular pressure.

According to the present invention, an intraocular pressure-lowering agent containing 5-trans prostaglandin F, α is provided. It is provided. 5-transpros in which the 5-6 double bond is in the trans configuration Taglandin F2α has been shown to reduce side effects, especially ocular surface hyperemia. It has the same intraocular pressure-lowering activity as natural prostaglandin F2α. Additionally, the dosage , based on its action, 5-transprostaglandin F,α has been shown to be useful in the treatment of glaucoma. It is less likely to cause an increase in intraocular pressure, which is an undesirable side effect.

The PGFtα compound of formula (I) is in the free acid form. However, As will be apparent to those skilled in the art, any of a variety of suitable salts may also be used in the ophthalmic formulations of the present invention. The vine is used for compounding. Therefore, for the carboxylic acid group at the C-position of formula (I), : A is -OH, forming the free acid, or -OR, in which R is various The anionic component of any pharmaceutically acceptable salt may be used. pharmaceutically acceptable A salt is any salt that retains the activity of the original compound, and which is administered any harm or disadvantage in the patient in whom it is administered and in the context in which it is administered. It does not have the desired effect.

Suitable pharmaceutically acceptable salts are derived from either organic or inorganic bases.

Such salts contain monovalent or polyvalent ions. Of particular interest are inorganic cations. Examples are sodium, potassium, calcium, magnesium and zinc.

Organic salts include amines, especially ammonium salts such as mono-, di- and trialkyl salts. Can be made with amines or ethanolamines. Salt also has caffeine, Can be formed with tromethamine and similar molecules. Acid addition salts form from amines Any inorganic or organic acid can be used when prepared. Preferred salt is chlorinated water salts, sulfates, phosphates and salts of simple organic acids of 2 to 6 carbon atoms, -acids or is either a diacid. Quaternary ammonium compounds can be used with alkylating agents such as iodine. Vine prepared from methyl uride etc.

The pharmaceutical composition contains 5-trans PGF, α or a pharmaceutically acceptable thereof as an active ingredient. combining a therapeutically effective amount of an acid addition salt with a conventional ophthalmically acceptable pharmaceutical excipient; and can be prepared by formulating unit dosage forms suitable for topical ocular use. can. A therapeutically effective amount typically ranges from about 0.0001 to about 5% (w/v) of the liquid formulation. ), preferably about 0.001 to about o, i% (w/v).

For ophthalmological use, preferred solutions are prepared using saline as the primary vehicle. It will be done. The pH of such ophthalmic solutions can be adjusted between 6.5 and 7.2 using a suitable buffer system. Preferably maintained. The formulation also contains conventional pharmaceutically acceptable preservatives and Stabilizers may also be included.

Preferred preservatives for use in the pharmaceutical compositions of the present invention are limited to: However, benzalkonium chloride, chlorobutanol, thimerosal, vinegar phenylmercuric acid and phenylmercuric nitrate. Similarly, various preferred vehicles used in the ophthalmic formulation of the present invention. These vehicles include: Polyvinyl alcohol, povidone, hydroxypropyl medicinal Chillcellulose, poloxamer, carboxymethylcellulose, hydroxyethyl cellulose and pure water.

Tonicity adjusting agents may be added as necessary or convenient. These include salt, Sodium chloride, potassium chloride, mannitol and glycerin, or other Suitable ophthalmically acceptable tonicity modifiers include, but are not limited to: Various buffers and means for adjusting the You can use it as long as it vines. Therefore, buffering agents include acetate buffer, citrate buffer, There are buffers, phosphate buffers and borate buffers. Requires use of acids or bases The pH of these formulations may be adjusted accordingly.

Similarly, ophthalmically acceptable antioxidants for use in the present invention include Examples include, but are not limited to, sodium metabisulfite, sodium thiosulfate, Cetylcysteine, butylated hydroxyanisole and butylated hydroxyl There is Luen.

Other excipients that may be included in ophthalmic formulations include chelating agents. Preferred chelating agent is disodium edentate, but other chelating agents may also be substituted. is used with this.

The above components may generally be used in the following amounts: Component Amount (%W/v) Active ingredient: approx. 0.001-5 Preservative 0-0.10 Vehicle θ ~ 40 Tonicity regulator 1-10 Buffer 0.01-10 pH adjuster: appropriate amount pH 4,5-7,5 Antioxidant: as needed Purified water up to 100% if necessary Practical dosage of the active compound of the invention is Depending on the particular compound and the condition to be treated, selection of the appropriate dosage is within the skill of the art. It is sufficient that it is within the knowledge of the individual.

The ophthalmic formulations of the present invention can be administered in a suitable dosage form to facilitate administration to the eye; For example, it is conveniently packaged in a container equipped with a dripping section. Volume suitable for drip administration The vessel is usually made from a suitable plastic material that is inert and non-toxic, and generally has a temperature of about 0. Contains 5 to about 15 μl solution.

The invention will be more fully elucidated by the following examples.

Example 5-Trans prostaglandin F, α and prostaglandin F, α experiments Dissolve the amount in 2% (w/v) Na, COs and adjust the pH to 7.0 with 0.1N HCl. It was knotted. Experimental rabbits were treated with either 0.01%, 0.1% or 1% solution. Three treatments of 6-8 animals each were treated by adding one drop to the sphere surface. 5-trans prostaglandin F,α and prostaglandin F2α obtained for both. Time of administration and its 0.5. 1. 2. 3.　4 and and 6 hours later, an indenter-type compressed air tonometer (pneunmtonomet) was used. Intraocular pressure was measured by ry). Visually assess ocular surface hyperemia and detect any ocular surface hyperemia that is not present. It was stated that either it exists or exists to some extent. The following data were obtained.

Obtained with 5-trans prostaglandin F, α and prostaglandin F, α A comparison of these data shows that they have essentially equal potency as intraocular pressure-lowering agents. I understand that. However, prostaglandin F, α-induced intraocular pressure decrease occurs on the ocular surface. 5-trans prostaglandis occurs with a high incidence of facial hyperemia, whereas 5-transprostagrange F2α was similar at low (0.01%) and moderate doses (0.1%). of intraocular pressure reduction is achieved with minimal ocular surface hyperemia or at the 0.1% dose. There is no ocular surface hyperemia. Furthermore, based on the dose-effect curve, 5-tran Sprostaglandin F and α have effects that are considered undesirable in glaucoma treatment. It is.

It has a much lower intraocular pressure elevating effect.

Although the invention has been described with respect to certain preferred embodiments, these embodiments These are intended to specifically illustrate the present invention, and are not intended to limit it. For those skilled in the art Other obvious embodiments are also within the scope of the invention. Therefore, the scope of the invention is It is to be determined solely by reference to the claims appended hereto.

Summary book The present invention provides means for lowering or maintaining intraocular pressure, particularly in a pharmaceutically acceptable carrier. administering a composition comprising 5-trans prostaglandin F2α to the eye. METHODS AND COMPOSITIONS FOR LOWERING OR MAINTAINING PRESSURE.

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Claims (6)

[Claims] 1. The following formula (I) mixed with a non-toxic ophthalmically acceptable vehicle: There are academic formulas, tables, etc.▼ Therapeutic efficacy of 5-trans PGF2α represented by or a pharmaceutically acceptable salt thereof for lowering or maintaining intraocular pressure, containing an effective amount in a unit dosage form suitable for ocular topical use. pharmaceutical composition. 2. The composition according to claim 1, wherein the compound is 5-trans PGF2α. thing. 3. A therapeutically effective amount of 5-trans PGF2α or a pharmaceutically acceptable salt thereof is administered to the eye. A method of treating ocular hypertension comprising administering to a mammal with elevated intraocular pressure. 4. The method according to claim 3, wherein the compound is 5-trans PGF2α. . 5. Mixed with a non-toxic ophthalmically acceptable liquid vehicle, in a volume suitable for metered administration. Treatment with 5-trans PGF2α or a pharmaceutically acceptable salt thereof packaged in a container A dosing solution containing an effective dose. 6. a container selected for applying the contents of the container in metered form; and 5-trans PGF2α or mixed with a toxic ophthalmically acceptable liquid vehicle. and an ophthalmic solution in said container containing a pharmaceutically acceptable salt thereof.