LT3525B - Composition for ophthalmic use - Google Patents

Abstract

The present invention relates to a composition for the topical administration of bispilocarpic acid diesters to the eye in the form of an aqueous solution, which includes cyclodextrin and optionally a viscosity and enhancing and pH-adjusting agent.

Description

The present invention relates to a composition for topical ophthalmic treatment which contains as active ingredient a pilocarpine derivative, namely a bispilocarpic acid diester. The object of the invention is to eliminate or at least reduce some of the disadvantages associated with the use of pilocarpine.

Pilocarpine is a medicine used to treat glaucoma, which relieves pressure in the eye by increasing the amount of chamber fluid that comes out of the eye. Pilocarpine's ability to relieve visceral pressure relies on its astringent action on the dorsal muscle, which increases the angle of the anterior chamber, which is important for the discharge of the mole fluid, and facilitates fluid leakage.

Pilocarpine is absorbed into the eye through the cornea. In the cornea, it is primarily absorbed by the dense epithelial layer of the eye surface, which is rich in cellular memban lipids (fats). However, pilocarpine is not highly lipid soluble, which causes it to penetrate relatively little into the corneal epithelium, which transports pilocarpine through the aqueous Stroma and corneal endothelium into the anterior chamber fluid. From the chamber fluid, pilocarpine easily reaches its site of action, i.e. cavity muscle.

Poor absorption into the inner part of the eye and short acting pilocarpine in the eye make it difficult to treat. Pilocarpine should be used at relatively high doses to improve and prolong the effects of the medicine. It follows that immediately after instillation, high concentrations of pilocarpine are reached in the fluid, iris, and ciliary muscle of the chamber, resulting in a strong Ηι I i, III IIBUI jjiLOiijHiHfl · · I I ί I MII! Because of this, flax puppy shrinkage (myiosis) and ocular accommodation for short-range vision. However, pilocarpine is rapidly excreted from the eye and is therefore administered 3 to 8 times daily depending on the patient. Each drop is accompanied by the aforementioned discomfort.

Efforts have been made to address the problem of poor absorption of pilocarpine by the use of prodrug pilocarpine derivatives, i.e. bispilocarpic acid diester (WO 92/09583). These derivatives are more lipid soluble than pilocarpine and are therefore better absorbed. In the corneal epithelium, they are degraded by enzymatic and chemical hydrolysis, resulting in the release of a pharmacologically active pilocarpine and an ineffective pro group. Since the pro-group is redundant with respect to the drug effect, it is important that the eye is exposed to as few pro-groups as possible. So, for this reason, it is also important to reduce the amount of the ophthalmic drug.

Being liposoluble compounds, bispilocarpic acid diesters (BDs) are readily absorbed into the corneal epithelial fatty film, which makes it important to control the rate of absorption of the drug into the corneal epithelium and to avoid sharp increases in concentration, including eye irritation.

Cyclodextrins are cyclic oligosaccharides of the general formula m = 6 a-CD m = 7 β-CD m = 8 γ-CD

CH ₂ OH | ^{/ (}

-N

OH H ί ιι. ι. ιι! ιηιι .U1IHI3I

3ίΜΙ · Ι · 1Ι I U I ΗΙΙί SUSU

LT 3525 Β

In said compounds, the free hydroxy group (s) may be etherified, for example by alkyl or hydroxyalkyl groups, or esterified. The same applies to branched or polymeric cyclodextrins.

Cyclodextrins are known to form adductive and inclusion complexes with many compounds, and drug complexes with cyclodextrins are known to improve, for example, drug solubility and stability. The improved solubility and stability of cyclodextrin complexes is related to the hydrophobicity of the inner cyclodextrin cavity.

It is an object of the present invention to provide an ophthalmic composition for use in the form of an aqueous solution of bispilocarpic acid diester in an aqueous solution that increases the total amount of drug that reaches the eye, prolongs the duration of drug exposure, and decreases its pronounced concentration and related side effects such as eye irritation. This composition would be sufficient to administer less times a day, which would be more comfortable for the sick.

In the present invention, it has been found that by forming a complex of bispilocarpic acid diester and cyclodextrin, the delivery of the drug to the cornea can be controlled.

Based on the favorable symmetric structure of guest molecules with more than one hydrophobic moiety, complexes other than 1: 1 can be formed, thereby enhancing the advantages of the cyclodextrin effect.

Thus, the present invention relates to a composition for topical ocular administration of a diisester of bispilocarpic acid in the form of an aqueous solution comprising cyclodextrin.

Cyclodextrin molecules form complexes with some, ιη ιι. ι ι ιι. irau · {ilLUKlil

MII: BU which precursor molecules in the composition while other molecules remain free in solution.

When drops of bispilocarpic acid diester are applied to the eyes, solution neutralization occurs in the area preceding the cornea. Neutralized bispilocarpic acid diester is more readily absorbed into the eye, resulting in a marked increase in the bispilocarpic acid diester concentration in the corneal epithelium, which causes eye irritation. Cyclodextrin prevents easy access to the neutral, free prodrug by complexing with a certain amount of the neutral drug. When the free precursor is absorbed in the eye, the cyclodextrin complex is released from the complex by equilibrium laws. Thus, the use of appropriate concentrations of cyclodextrin can reduce the marked increase in the concentration of the precursor in the corneal epithelium, reducing the associated degree of ocular irritation.

In a preferred embodiment, the amount of cyclodextrin is from 1 to 40% (w / v).

As a cyclodextrin compound, any pharmaceutically acceptable derivative of cyclodextrin, a-, p- or γ-type, may be used. Cyclodextrin may also be substituted at the 2-, 3-, or 6-position substituted. These derivatives are generally cyclodextrin ethers, preferably lower alkyls or lower hydroxyalkyls, e.g. methyl, ethyl, hydroxyethyl, hydroxypropyl, e.g. 2-Hydroxypropyl derivatives and esters, such as acylates, sulfonates, sulfates and phosphates, or mixed derivatives. The use of suitable branched cyclodextrins, such as their glucosyl and maltosyl derivatives or linear covalently linked oligomers and other linked or polymeric cyclodextrins or combinations thereof, can achieve increased water solubility and the required viscosity and adhesive properties. In general, hydroxy-substituted side chain derivatives exhibit improved solubility, viscosity and adhesive properties where required.

For economic reasons and for ease of preparation, β-cyclodextrin, preferably β-cyclodextrin, alkylated and / or hydroxyalkylated at the 2-, 3- and / or 6-position is used as cyclodextrin.

Good results are obtained with 2-hydroxypropyl-cyclodextrin (2-HP 1 -cyclodextrin).

According to a further embodiment of the invention, the viscosity-increasing substance may additionally be included in the composition, and the desired level of viscosity is achieved by using a material suitable for this purpose. Typical examples are cellulose derivatives such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, polyacrylic acids, chitosan, hyaluronic acid and 1.1. The amount of polymer to be added will depend upon the level of viscosity desired and the polymer used, and may be readily determined by one of ordinary skill in the art.

Thus, the viscosity inducing agent is used in an amount sufficient to achieve the proper thickness of the composition, which usually means a viscosity of 1 to 25000 mPas. Viscosity is measured with a Brookfield viscometer (type LVDV-III) at 22 ° C and a shear rate (D) of 1 s ' ^{1 for a} viscosity of 100 -25000 mPas and a shear rate of 60 s' ^{1 for a} viscosity of 1-100 mPas.

Of course, the amount depends on the type of substance used. When using the first of the aforementioned cellulose derivatives in soap (HPMC), a viscosity of about 10-150 mPas is achieved in an amount of 0.3-1%, most preferably in the range of 15-50 mPas.

The viscosity enhancer increases the duration of contact of the composition with the eye surface, thereby increasing the amount of drug absorbed, allowing it to work longer. The viscosity enhancer decreases the rate of neutralization of the acidic or weakly acidic composition on the surface of the eye, which in turn affects the uptake of the prodrug, since the solubility of BD in fat is the better the solution is. Thus, the delivery of the precursor can also be controlled to some extent in this way.

The compositions of the present invention may also include other excipients, such as protective agents such as quaternary ammonium compounds, e.g. benzalkonium chloride, benzyl alcohol, mercury salts, thiomersal, chlorhexidine, chlorobutanol and the like.

According to the present invention, the composition may further comprise a buffer. Phosphate buffers, borate buffers, acetate buffers and citrate buffers, or mixed buffers may be mentioned as suitable buffer systems for the present invention.

Buffers are typically used in a concentration range of 5 to 100 mM, depending on the desired pH and the desired buffer capacity. The choice of amount and type of buffer depends on the knowledge of one skilled in the art.

The use of buffer can enhance the above-mentioned retardation effect of neutralization of the composition on the eye surface, thereby avoiding undesirable initial sharp increases in pilocarpine concentration. In combination with cyclodextrin, the buffer can regulate the bound and free η ι,! . 13 L.IUU · L JUIJIIIIIIIIIIU ·· JiniHll.lil IN i 01111! ItlIJI ⁷ EN 3525 B balance of the prodrug.

The pH of the composition is preferably from 3 to 8 and particularly from about 5 to 7.

The composition of the present invention is preferably administered as an isotonic solution (corresponding to a 0.9% NaCl solution) and the tonicity can be adjusted using conventional substances used for this purpose such as sodium chloric, potassium chloride, glycerol, mannitol, sorbitol, xylitol, sodium borate, sodium acetate and the like.

Bispilocarpic acid diesters are primarily those described in WO Publication 92 / *) 9583 and 93/24466, the contents of which are incorporated herein by reference.

Namely, WO 92/09583 describes in detail the compounds of the general formula

where O u

A) Y is hydrogen or -CR, wherein R is water, C, C, b-alkyl, C ₂ -C ₁₈ alkenyl, C ₂ -C ₈ alkynyl optionally substituted with C ₃ -C ₇ cycloalkyl, or - C ₇ cycloalkenyl, optionally substituted aryl or aryl lower alkyl, and

W is a group of: »ιι, i. U u

Milium

-O-A-O-Z-Y '

O

II wherein Y 'has the meaning of hydrogen or -C-R' wherein R 'has the meaning of the above R group and R' may be the same as or different from R, A is optionally hydroxy or hydroxy-protected to replace C, - C ₁₈ -alkylite, C ₂ -C 6, -alkenylene, C ₂ -C ₁₈ -alkynylene which may be substituted by optionally substituted C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkenyl, aryl or aryl lower alkyl, or A is optionally substituted C ₃ - C ₇ cycloalkylene mouldboard C ₃ - C ₇ cycloalkenylene or arylene, or A is the previously mentioned alkylene, alkenylene or alkynylene fuel. s as part of a chain has a cycloalkylene, cycloalkenylene or arylene group as defined above and -Z-Y 'is

CK ₃ or

B) W is -OR where R has the meaning given above, Y is

O O II II

-C-B-C-Z'-OR ', wherein R' has the meaning as defined above, and B has the value defined above, and -Z'-OR 'is. .1, Uil ι Ι · Ι ί .uliniu

ΙΙ ·! Ι · Ι · .Ι

as well as salts of the above compounds with the addition of an acid.

Preferred compounds are e.g. diacyl bispilocarpates of formula IA) wherein acyl is lower alkyl (1-4C) -, lower cycloalkyl (3-6C) carbonyl or benzoyl, A is lower alkyl »: (2-6C), lower cycloalkylene (3-6C) or arylene, namely 0,0'-diacetyl, 0,0'-dipropionyl, O, O''-dibutyryl, 0,0'valeryl and 0,0'-dicyclopropylcarbonyl (1,4-5 (, 3- , 1,2-silylene) - and - (1,2-ethylene) -, - (1,3-propylene) -, - (1,4-butylene) -, - (1,5-pentylene) - and - (1,6) -hexylene) bispilocarpate, especially - (1,4-xylyylene) bispilol arpate, the alkylene groups may not be optionally substituted by hydroxy or protected by hydroxy or by one or two methyl groups.

Of these, mention may be made where A is ethylene or A is 1,3-propylene which at position 2 may be substituted by hydroxy, by the group Y-Ο-, where the value of Y is already explained or by one or two methyl groups.

A subset of the compounds of formula IB) are those compounds wherein W is OR ', wherein R' is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl and B is 1,2-phytylene,

1,3-propylene or 1,4-butylene.

Another preferred group of compounds of formula IB) is e.g. (dibenzyl) and (lower alkyl)

Ali III, I. U.I. III.HlLllhll KILmUM J UJJ bispilocarpates such as 0,0'-glutaryl, 0,0'isisuccinyl, Ο, Ο'-adipoyl (dibenzyl) - and - (lower alkali) bispilocarpate.

The following specific compounds may be mentioned:

O, O'-dipropionyl (1,4-xylylene) bispilocarpate

O, O'-Dibutyryl (1,4-xylylene) bispilocarpate

0,0'-Dicyclopropylcarbonyl (1,4-xylene) bis-pilocarpate

0,0'-dipropionyl (1,6-hexylene) bispilocarpate

0,0'-dibutyril (1,6-hexylene) bispilocarpate

0,0'-Dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate.

The present invention achieves sufficient drug absorption and longer duration of action by using lower amounts of the drug compared to pilocarpine, thereby reducing the number of times the drug is administered daily. The concentration of BD in the composition of the present invention may vary but is suitable from 0.05 to 4, preferably 0.5 to 2% by weight, based on pilocarpine base. Within recent BD concentrations, cyclodextrin concentrations are preferably 5 to 20% by weight.

The following examples illustrate the invention but are not intended to limit it.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dipropionyl (1,4-xylylene) bispilocarpate 24.4 mg

2-HP-p-Cyclodextrin 50.0 mg

NaCl 4.0 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

LUIIHIII! Ui III! UI

The active ingredient is present in a concentration of 1.0% and contains 5% (w / v) cyclodextrin. The pH of the solution is 5.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dipropionyl (1,4-xylylene) bispilocarpate

2-HP-p-cyclodextrin

NaCl

NaOH to pH

Aq. ster. to

24.4 mg

100.0 mg

2.5 mg 5.0

1.0 ml.

The concentration of the active ingredient is 1.0% and the concentration of cyclodextrin is 10% (w / v). The pH of the solution is 5.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dipropionyl (1,4-xylylene)

2-HP-p-cyclodextrin

NaCl

NaOH to pH

Aq. ster. to bispilocarpate 24.4 mg 150.0 mg

1.0 mg 5.0

1.0 ml.

The concentration of the active ingredient is 1.0% and the concentration of cyclodextrin is 15% (w / v). The pH of the solution is 5.

example imi! iii i, i j «

ΙΙ · 1 · Ι · Ί

The composition of the present invention was prepared with the following ingredients:

0,0'-Dipropionyl (1,4-xylylene) bispilocarpate 12.2 mg

2-HP-p-Cyclodextrin 50.0 mg

HPMC 6.5 mg

NaCl 5.5 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 0.5% and the concentration of cyclodextrin is 5% (w / v). The viscosity is 50 cps and the pH of the solution is 5.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dibutyryl (1,4-xylylene) bispilocarpate 6.3 mg

2-HP-p-Cyclodextrin 50.0 mg

NaCl 6.5 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 0.25% and the concentration of cyclodextrin is 5% (w / v). The pH of the solution is 5.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dicyclopropylcarbonyl (1,4-xylene)

bispilocarpate 12.5 mg 2-HP-β-cyclodextrin 75.0 mg NaCl 4.0 mg NaOH to pH 5.0 Aq. ster. to 1.0 ml The active ingredient concentration is 0.5%,

the concentration of cyclodextrin is 7.5% (w / v).

The pH of the solution is 5.

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dicyclopropylcarbonyl (1,4-xylene) bispilocarpate 25.0 mg

2-HP-β-cyclodextrin 150.0 mg

NaCl 0.6 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 15% Cyclodextrin The pH of the solution is 5.

is 1.0% while (w / v).

example

The composition of the present invention was prepared with the following ingredients:

0,0'-Dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate

2-HP-β-cyclodextrin

12.2 mg

100.0 mg ηιι ιι i. gin Jin ·

14th LT 3525 B NaCl 4.0 mg NaOH to pH 5.0 Aq. ster. to 1.0 ml. Active ingredient concentration is 0.5% o

the concentration of cyclodextrin is 10% (w / v). The pH of the solution is 5.

example

The composition according to the present invention was prepared as follows

Ingredients: 0,0'-Dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate 24.5 mg 2-HP-p-cyclodextrin 200.0 mg NaCl 1.0 mg NaOH to pH 5.0 Aq. ster. to 1.0 ml. Concentration of active ingredient is 1.0%, 0 20% cyclodextrin concentration weight / volume rio).

The pH of the solution is 5.

The compositions of the present invention (compositions of Examples 1-9) were compared on the one hand with the commercial pilocarpine formulation (Oftan Pilocarpine 2%; Comparative composition 1) and on the other hand with the compositions containing the same prodrug. in an aqueous solution without cyclodextrin (reference compositions 25).

> OII «II!« Mt: it · »

1. Rabbit myiosis in aqueous solution with cyclodextrin and degree of eye irritation.

μΐ of each of the tested formulations was instilled into the rabbit's eye and the degree of ocular irritation caused by the formulation was then evaluated. The eye was photographed at equal intervals. Myositis induced by the compositions tested was detected in negatives. At least 6 replicate assays were performed on all formulations. The results were calculated as follows:

(a) PPC (area under the curve; related to the amount of drug absorbed)

b) Maximum myiosis (maximal pupil constriction as a percentage of time 0)

c) Time required to reach maximum meiosis (t _ma ks)

d) Total time at which maximum myosis is> 3%

The results are shown in Tables 1 and 2 and Figs. 1A and 1B.

Liliu KIIIIH ·! , ΙΗΙΗΙΙΤΙ I I; I U IT ULilll

Composition Solution PPK0.360 min Max. t _ma ks. tmiosis> 3% irritation conc (%) (¾ min) myiosis (¾) (min) (min) half (x ± SE) (x ± SE) (x ± SE) (x ± SE)

+ 4- 4 * + + + + 1 +

O co <0 04 10th CM CM co m IO +1 +1 +1 +1 +1 +1 00 h * (O 05 CO to co co h- b- T " CM 04 CM co

to +1 co

to rf · CO v- CM rf CM +1 +1 +1 +1 CO CO CM CO CM 0 CO co t— Ύ " Ύ— V- *

co CM t— T ^- CM 04 +1 +1 +1 +1 +1 +1 CO co co rf O CM T " V " T " 04

co rf CO v to b- b- 05 co to rf CM rf co Co5 rf +1 +1 +1 +1 +1 +1 co CO O) co co rf co to co 0 o> to CM T— co 0 co T "  »" CM • CM co co

o to o o p to CM o O

CM

CL CL CO (0 to (0 E E > n > O O Ό Ό Ό * Ό N N N N • » > 1 > > 7 σ> O) > > > > > » > t cd cd cd cd r — i 1 — i cl CL CL Q_ cd cd Q_ CL 1— CM CO rf

+ + + + + + + + + +

Ii tl II II c

• H o>

c_ • H * o cd

c.

• Φ c

c • H to co

I o «co

Λ

CO cd

E

Ή c

• H

O)

L.

• H

Ό

CO

O) • H <

<o <0 </)

E • H

C • H

O)

C_ • H σ

o5

H to

a.

to o

2d

C_

O)

E • H to

4- »to

ZJ

2d

U

Φ

E to> N

LAJ ω «-H + | Λ ε χ ά ° - +

• 4 *

4+ +

4 · 4 * 4- 4- 4- + 4- + 4- + + 4- + + + 4 ·

4-4- + + 4- I +

O LO xr V— 05 to V- CO 05 CM CO rf co CM co co χί * xT 41 41 + i +1 +1 +1 41 41 41 o 00 m CO CM σ> CO LO LO rj · V CO co b. LO O CM T ^- CM CM CM CM CM CM CM CM

to +1 co h-

CO 00 O Tf CO CM O T " CM CM Ί— CO CO 41 41 41 41 m 41 41 41

S S o s s co cS

LLI

Φ

N CO O + J • H X

E

o <D C LAJ CO • rd > O E 00 +1 O_ <λ ° X Q_ '-

O <λ ° f — i CJ • CL O u c • r4 o H 2d

• Φ CJ 'L' Ί r-d • H Φ O 4- » • H C N Φ O i-4 O ►H E O »—1 id

CO CM r · CM r— CM T " CM 41 41 41 +1 41 41 41 41 41 LO T— O CM M 05 co O CM n— t— T " T " V "

co LO T " co r— 00 co b » τί * g O co CO Etc. h- M- S 05 CM LO CM o LO 41 41 41 4t +1 +1 41 41 41 CO CM Tf T— h- v— CO M CO CO CO CO co T " b- CM b · LO CO b- o 00 CO CM co t— CM T * " T " CM CM T " T— T "

IO m to o CM CM CM LO O LO CM O O O 0 O

τ- CO V io ο CL to O ω co O W to H E > » E > » > » E O O XJ O Ό Ό O Ό Ό N 2d N N 2d N N • > 1 • > » > 1 O) CJ) > D) > > CJ) > >, > 1 > 1 CJ >> CJ C5 CJ CJ i-4 rH CL r — i CL CL r4 CL CL cj CJ cj CJ Q_ Q_ LO £ L CO b- Q_ co 05 i

li II o

E • H

C • H cn

U • H

Ό

LO

Eye irritation: no +

++

+ ii c:

• H ii JLII

The results show that:

(a) The compounds are absorbed into the cornea from an aqueous solution of cyclodextrin and release pilocarpine in a controlled manner, causing meiosis.

b) A composition containing 1% of the prodrug and cyclodextrin (Example 3) achieves 1.9 times the ocular absorption (PPC) of pilocarpine compared to 2% of commercial pilocarpine (reference composition 1) and even 2.4 times better overall absorption than 0.5% of a single prodrug (Comparative Composition 2) at similar or lesser degree of eye irritation.

The amount of precursor material absorbed from the cyclodextrin solution depends on the constant complexation of the precursor with the cyclodextrin molecule. Complexation constants, in turn, are important in physicochemical precursors and properties. The ratio of precursor to concentration is also relevant to the fraction of complex and free precursor.

c) A composition containing 1% of the prodrug in cyclodextrin solution causes significantly longer miosis compared to comparative composition 1 (Examples 2 and 3:

1.8 times longer), as well as comparisons with Comparative Composition 2 (Examples 2 and 3: 1.5 times longer).

d) The maximum meiosis induced by the compositions of the present invention is less than the maximum meiosis induced by Comparative Composition 1, despite the fact that the total amount of drug absorbed is twice that of Comparative Composition 1.

Lower maximal miosis indicates that the compositions of the invention may reduce pilocarpine concentration peaks, thereby reducing side effects in the eye.

cyclodextrin cyclodextrin

e) Maximum miosis with the compositions of the present invention is achieved three times later than Comparative Composition 1. Likewise, maximum miosis with the cyclodextrin containing composition is achieved later (1.5 times later) than when administering the prodrug in an aqueous triple without cyclodextrin (Comparative Composition 2). . This indicates a lower rate of absorption of the precursor from the cyclodextrin complex.

f) The use of the cyclodextrin-containing compositions of the present invention, particularly according to Example 3, can substantially reduce the degree of ocular irritation caused by the aqueous solution of the prodrug, while providing increased drug absorption and prolonged miosis.

(g) Compounds are absorbed approximately 1.3 times better with a viscous cyclodextrin solution and 1.2 times longer than the corresponding molecules of the prodrug substance in a cyclodextrin solution without a viscosity enhancing agent (Table 1).

FIG. The change (%) in diameter of sample 1A is shown as a function of time with respect to composition 1 and 2, as well as with respect to composition of example 3. FIG. The duration of eye irritation of 1B is shown for the same compositions as FIG. 1 A.

Claims (11)

DEFINITION OF INVENTION A composition for topical ocular administration of a bispilocarpic acid diester in aqueous solution, characterized in that it comprises cyclodextrin. 2. The composition of claim 1, wherein the cyclodextrin comprises from 1% to 40% (w / v) of the total composition. 3. The composition of claim 1 or 2, wherein the cyclodextrin is selected from the group consisting of unsubstituted and substituted lower alkyl and lower hydroxyalkyl p-cyclodextrins. Composition according to any one of the preceding claims, characterized in that it further comprises a viscosity enhancing agent. 5. The composition of claim 4, wherein the viscosity enhancing agent is selected from the group consisting of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, polyacrylic acids, chitosan acids, chitosan. 6. The composition of claim 4, wherein the viscosity enhancing agent is present in an amount such that the viscosity is in the range of 1 to 250,000 mPa.s. 7. The composition of claim 1, wherein the composition is an isotonic solution. 8. The composition of claim 1, further comprising a buffer. 9. The composition of claim 8, wherein the buffer is selected from the group consisting of phosphate buffers, borate buffers, acetate buffers, and citrate buffers or mixed buffers, preferably citrate buffers. Composition according to any one of the preceding claims, characterized in that it has a pH of 3 to 8, preferably 5 to 7. The composition according to any one of the preceding claims, wherein the diester of the bispilocarpic acid is 0.0'-diacyl (1,4-xylene) bispilocarpate, wherein the acyl is selected from the group consisting of lower alkyl or lower cycloalkylcarbonyls. , such as 0,0'-dipropionyl, 0,0'-dibutyryl or 0,0'-dicyclopropylcarbonyl (1,4-xylylene) - or propionyl, 0,0'-dibutyryl or carbonyl (1). , 6-hexylene) -bispilocarpate.