WO1995000143A1

WO1995000143A1 - Composition for ophthalmic use

Info

Publication number: WO1995000143A1
Application number: PCT/FI1994/000269
Authority: WO
Inventors: Tomi Järvinen; Arto Urtti; Pekka Suhonen; Pekka Peura; Kari Lehmussaari; Timo Reunamäki; Sakari Alaranta; Olli Oksala; Esko Pohjala; Hannu HANHIJÄRVI
Original assignee: Leiras Oy
Priority date: 1993-06-24
Filing date: 1994-06-17
Publication date: 1995-01-05
Also published as: AU6973094A; EE9400039A

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 a viscosity enhancing agent and a buffer, and which has a pH of 3-6.

Description

Composition for ophthalmic use

The present invention relates to a composition for the topical treatment of the eye, which as the active ingre¬ dient contains a pilocarpine derivative, specifically a bispilocarpic acid diester. The object of the invention is to eliminate or at least reduce some of the disadvantages associated with the adminstration of pilocarpine.

Pilocarpine is a drug which is used for the treatment of glaucoma, which drug lowers the ocular pressure by increasing the flow of chamber fluid from the eye. The intraocular pressure reducing effect of pilocarpine is based on the ciliary muscle contracting effect of the drug, by widening the angle of the anterior chamber which is important from the viewpoint of the outflow of the chamber fluid and the outflow of the fluid is facilitated.

Pilocarpine is absorbed into the eye through the cornea. In the cornea it is first absorbed in the dense epithelium layer on the eye surface containing cell membrane lipids (fats) in abundance. However, pilocarpine is not very lipid soluble, wherefore it penetrates relatively little into the corneal epithelium, which delivers pilocarpine through the aqueous stro a and endothelium of the cornea into the fluid of the anterior chamber. From the chamber fluid, pilocar¬ pine has easy access to its action site, the ciliary muscle.

The low absorption into the inner parts of the eye and the short duration of action of pilocarpine administered into the eye, cause difficulties in drug treatment. In order to improve and prolong the action of the drug, pilocarpine must be used in relatively big doses. From this follows that shortly after administration, peak pilocarpine levels are obtained in the chamber fluid, in the iris and the ciliary muscle which lead to a strong contraction of the pupil (miosis) and adaptation of the eye to seeing at close distance. Pilocarpine, however, leaves the eye rapidly and is therefore administered 3 to 8 times daily, depending on the patient. Each administration is followed by the afore¬ mentioned disadvantages.

Efforts have been aimed at solving the disadvantages relating to the poor absorption of pilocarpine, by using pilocarpine prodrugs, i.e. bispilocarpic acid diesters (WO 92/09583) . These derivatives are more lipid soluble than pilocarpine and thus provide an improved absorption. They degrade through enzymatic and chemical hydrolysis in the corneal epithelium to liberate the pharmaceutically effec- tive pilocarpine and the ineffective pro-moiety. As the pro-moiety is superfluous in view of the pharmaceutical effect, it is important that the eye is subjected to as small amounts of pro-moiety as possible. Thus it is of importance also for this reason to lower the amount of drug administered to the eye.

The bispilocarpic acid diesters (BD) , being very lipid soluble compounds, readily enter the fatty film of the corneal epithelium. It is thus of importance to be able to control the rate of absorption of drug into the corneal epithelium to avoid peak concentrations, which cause i.a. eye irritation.

The lipid solubility of the BD's is greatly pH dependant, being lowest at low pH's and increasing when reaching neutral values, when applied to the eye. Due to stability reasons, the BD's have to stored in acidic solution. The faster the pH of the tear fluid increases, the faster the lipid solubility increases, and consequently the faster and at higher concentration the BD's are absorbed into the corneal epithelium. By slowing down the neutralization of the tear fluid, the lipid solubility of the BD's increases at a slower rate making it possible to control the rate of absorption of drug into the cornea.

It is known to administer e.g. pilocarpine from a viscous solution, the aim of which having been to prolong the contact time of pilocarpine with the eye surface. However, such a composition does not control the rate of absorption of pilocarpine to the area of action, and thus does not substantially affect the action profile of pilocarpine.

The aim of the present invention is to provide a composi¬ tion for ophthal ological use in the form of an aqueous solution of a bispilocarpic acid diester, which provides for an increase in the total amount of drug delivered to the eye, for a prolonged duration thereof, while simul¬ taneously reducing its peak concentration and associated side effects, for example eye irritation. By means of the composition the number of daily administration times may be reduced, which leads to improved patient compliance.

The object of the present invention is thus to provide a composition for the topical administration of bispilocarpic acid diesters to the eye in the form of an aqueous solu¬ tion, which is characterized in that it includes a vis- cosity enhancing agent and a buffer, and exhibits a pH of 3 - 6.

By using, according to the invention, a viscosity enhancing agent in the composition, a neutralization rate controlling or reducing effect on the eye surface is obtained, with a simultaneous increase in the amount of drug being taken up by the eye, and a prolongation of its duration of action. The viscosity enhancing agent thus improves the profile of absorption of drug, cutting peak concentrations and leading to higher long-term profiles. The effect is further pronounced by the use of a buffering agent, which further reduces any eye irritation following increased drug uptake caused by the viscosity enhancing agent.

Thus by regulating the viscosity and the pH profile of the tear fluid by means of the composition of the invention, it is possible both to cut the peak concentrations of the drug in the corneal epithelium and also provide for increased drug uptake in combination with less eye irritation.

The viscosity is adjusted to the desired level with a substance suitable for the purpose. Typical examples are the cellulose derivatives, such as hydroxypropylmethylcel- lulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, poly- acrylic acids, chitosans, hyaluronic acid etc. The amount of polymer to be added depends on the desired viscosity level, and on the polymer used, and can be easily deter¬ mined by a person skilled in the art.

The viscosity enhancing agent is thus used in an amount to provide a suitable thickness to the composition, which preferably means a viscosity of 1 - 25000 mPas. The vis¬ cosity is measured with a Brookfield viscosimeter (type LVDV-III) at a temperature of 22 °C and a shear rate (D) of 1 s^"1 for viscosities of 100 - 25000 mPas, and a shear rate of 60 s"¹ for viscosities of 1 - 100 mPas.

The amount naturally varies according to the agent used. When using the first mentioned cellulose derivative (HPMC) and amount of 0.3 - 1 % gives a viscosity of appr. 10 - 150 mPas, a preferable range being 15 - 50 mPas.

The compositions according to the invention may also include further adjuvants, for example preservatives, such as quaternary ammonium compounds, e.g. benzalkonium chlori- de, benzyl alcohol, mercury salts, thiomersal, chlor- hexidine, chlorobutanol or the like. According to the invention, as buffer, any system giving the desired pH and being pharmaceutically acceptable, can be used.

As suitable buffering systems according to the invention may be mentioned phosphate buffers, borate buffers, acetate buffers and citrate buffers, or mixed buffers.

The buffers are usually used, depending on the desired pH and buffering capacity desired, in concentrations of 5 to 100 mM. The choice of amount and kind of buffer lies within the knowledge of the person skilled in the art.

The pH of the composition is 3 - 6, preferably pH 4.5 to 5.5.

The composition according to the invention is preferably used in the form of an isotonic solution (corresponding to a 0.9 % NaCl-solution) and the tonicity may be varied by using substances conventionally used for this purpose, such as sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, xylitol, sodium borate, sodium acetate and the like.

The bispilocarpic acid diesters are preferably those compounds which are disclosed in the WO-publications 92/- 09583 and 93/24466, the contents of which are included here for reference.

Specifically the WO-publication 92/09583 broadly claims i.a. compounds of the general formula

wherein 0 w

A) Y is hydrogen or -C-R, wherein R is hydrogen, Cι-C₁₈- alkyl , C₂-Cι₈-alkenyl , C₂-C_lg-alkynyl , optionally substituted G_j-C_j-cycloalkyl or C₃-C₇-cycloalkenyl , optionally substitu¬ ted aryl or aryl lower alkyl , and W is the group

-O-A-O-Z-Y '

O ii wherein Y' has the meaning of hydrogen or the group -C- R', wherein R' has the meaning of R above, whereby R* can be the same as or different from R, A is optionally hydroxy or protected-hydroxy substituted C,-C,_g-alkylene, C₂-C,_g- alkenylene, C₂-C,₈-alkynylene, which may be substituted by optionally substituted C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl, aryl, or aryl lower alkyl, or A is optionally substituted C₃-C₇-cycloalkylene or C₃-C₇-cycloalkenylene or arylene, or A is the aforementioned alkylene, alkenylene, or alkynyle- ne, which as a chain member contains the afore defined cycloalkylene, cycloalkenylene or arylene group, and -Z-Y¹ is

or

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

O O -C-B-C-Z'-OR' , wherein R' has the meaning given above and B has the meaning given for A above, and -Z'-OR' is

as well as the acid addition salts of the said compounds.

Preferred compounds are e.g. the diacyl bispilocarpates according to formula IA) , wherein acyl is lower alkyl(1- 4C)- or lower cycloalkyl(3-6C)-carbonyl or benzoyl, A is lower alkylene(2-6C) , lower cycloalkylene(3-6C) or arylene, specifically 0,0'-diacetyl-, O,0'-dipropionyl-, 0,0'- dibutyryl-, 0,0'-valeryl- and O,0'-dicyclopropylcarbonyl (1,4-, 1,3-, 1,2-xylylene)- and -(1,2-ethylene)-, -(1,3- propylene)-, -(1,4-butylene)-, -(1,5-pentylene)- and -(1,6- hexylene) bispilocarpate, especially -(1,4-xylylene) bispilocarpate, the alkylene groups optionally being substituted with hydroxy or protected hydroxy, or with one or two methyl groups. - Of these can be mentioned those wherein A is ethylene, or A is 1,3-propylene, which can be substituted in its 2-position with hydroxy, the group Y-O- wherein Y has the meaning given, or with one or two methyl groups.

A subgroup of the compounds of the formula IB) is formed by the compounds, wherein W is OR', wherein R' has the meaning of C_j-^-alkyl or C₃-C₆-cycloalkyl, and B is 1,2-ethylene, 1,3-propylene or 1,4-butylene.

Another preferred group of compounds of the formula IB) is comprised of e.g. the (dibenzyl) and (dilower alkyl) bis¬ pilocarpates, such as 0,0'-glutaryl-, 0,0'-disuccinyl-, O,0'-adipoyl (dibenzyl)- and -(dilower alkyl) bispilocar¬ pate.

Specifically the following compounds may be mentioned: O,0'-dipropionyl (1,4-xylylene) bispilocarpate O,O'-dibutyryl (1,4-xylylene) bispilocarpate O,0'-dicyclopropylcarbonyl (1,4-xylylene) bispilocarpate O,0'-dipropionyl (1,6-hexylene) bispilocarpate 0,0'-dibutyryl (1,6-hexylene) bispilocarpate

O,0'-dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate.

According to the invention it is possible to achieve sufficient drug absorption and prolonged duration of action with smaller amounts of drug as compared to pilocarpine and thus to reduce the number of daily administration times. The concentration of the BD's in the composition according to the invention may vary, but is suitably from 0.05 to 2 weight %, preferably 0.25 to 1 weight %, calculated as the pilocarpine base.

The following Examples illustrate the invention, but are not intended to limit the same. The active agent refers to pilocarpine base (in w/v) . Example 1 (Reference)

A composition was made having the following ingredients:

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

Citric acid monohydr. 1.2 mg

Sodium citrate dihydr. 4.3 mg

NaCl 4.8 mg

NaOH ad pH 5.0 Aq. ster. ad 1.0 ml.

The concentration of active ingredient (pilocarpine) is 0.5 % and that of the buffer 20 mM. The pH of the solution is 5.

Example 2 (Reference)

A composition was made having the following ingredients:

O,0'-Dipropionyl (1,4-xylylene) bispilocarpate 12.2 mg Citric acid monohydr. 4.3 mg

Sodium citrate dihydr. 16.0 mg

NaCl 1.0 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 75 mM. The pH of the solution is 5.

Example 3 (Reference) A composition was made having the following ingredients:

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

HPMC 5.0 mg

NaCl 6.5 g NaOH ad pH 5.0

Aq. ster. ad 1.0 ml. The concentration of active ingredient is 0.5 % and its viscosity is 25 mPas. The pH of the solution is 5.

Example 4 (Reference) A composition was made having the following ingredients:

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

HPMC 6.5 mg

NaCl 6.5 mg NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and its viscosity 50 mPas. The pH of the solution is 5.

Example 5 (Reference)

A composition was made having the following ingredients:

O,0'-Dipropionyl (1,4-xylylene) bispilocarpate 12.2 mg HPMC 8.5 mg

NaCl 6.5 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and its viscosity 115 mPas. The pH of the solution is 5.

Example 6

A composition according to the invention was made having the following ingredients:

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

Citric acid monohydr. 0.6 mg

Sodium citrate dihydr. 2.1 mg

HPMC 6.5 mg NaCl 5.5 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml. The concentration of active ingredient is 0.5 % and that of the buffer 10 mM. The viscosity is 50 mPas and the pH of the solution is 5.

Example 7

O,0'-Dipropionyl (1,4-xylylene) bispilocarpate 12.2 mg Citric acid monohydr. 1.2 mg

Sodium citrate dihydr. 4.3 mg

HPMC 6.5 mg

NaCl 4.8 mg

NaOH ad pH 5.0 Aq. ster. ad 1.0 ml

The concentration of active ingredient is 0.5 % and that of the buffer 20 mM. The viscosity is 50 mPas and the pH of the solution 5.

Example 8

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

Citric acid monohydr. 2.9 mg

Sodium citrate dihydr. 10.7 mg

HPMC 6.5 mg

NaCl 3.1 mg NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 50 mM. The viscosity is 50 mPas and the pH of the solution is 5. Example 9

O,0'-Dipropionyl (1,4-xylylene) bispilocarpate 12.2 mg Citric acid monohydr. 1.2 mg Sodium citrate dihydr. 4.3 mg HPMC 8.5 mg NaCl 6.0 mg NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 20 mM. The viscosity is 115 mPas and the pH of the solution is 5.

Example 10

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

Citric acid monohydr. 4.3 mg

Sodium citrate dihydr. 16.0 mg

HPMC 8.5 mg NaCl 1.0 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 75 mM. The viscosity is 115 mPas and the pH of the solution is 5.

Example 11

A composition according to the invention was made having the following ingredients: 0,0'-Dibutyryl (1,4-xylylene) bispilocarpate 12.5 mg Citric acid monohydr. 0.6 mg Sodium citrate dihydr. 2.1 mg HPMC 5.0 mg NaCl 5.5 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 10 mM. The viscosity of the solution is 25 mPas and the pH of the solution is 5.

Example 12

0,0'-Dicyclopropylcarbonyl (1,4-xylylene) bispilocarpate 12.5 mg

Citric acid monohydr. 0.6 mg Sodium citrate dihydr. 2.1 mg

HPMC 5.0 mg

NaCl 5.5 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The concentration of active ingredient is 0.5 % and that of the buffer 10 mM. The viscosity is 25 mPas and the pH of the solution is 5.

Example 13

A composition according to the invention was made having the following ingredients

0,0'-Dicyclopropylcarbonyl (1,6-hexylene) bispilocarpate 12.2 mg

Citric acid monohydr. 0.6 mg

Sodium citrate dihydr. 2.1 mg HPMC 5.0 g

NaCl 5.5 mg

NaOH ad pH 5.0

Aq. ster. ad 1.0 ml.

The compositions according to the invention (compositions according to the Examples 6-10) were compared on the one hand to a commercial pilocarpine formulation (Oftan Pilocarpine 2%; reference composition 1) and on the other hand to a composition of the same prodrug in an aqueous solution without viscosity enhancing agent and buffer (reference composition 2) , as well as to the compositions of Examples 1-5, in the same tests and under the same conditions.

Miosis and the degree of eve irritation in rabbit

25 μl of each of the compositions to be tested were intro¬ duced in a rabbit eye, whereafter the degree of eye irritation caused by the composition was evaluated. The eye was photographed at regular intervals. The miosis caused by the tested compositions was determined from the negatives. With all compositions, at least 6 parallel tests were run. From the results was calculated:

a) AUC (area under curve; relates to the amount of drug absorbed) b) Maximum miosis (maximum contraction of the pupil in percentages, compared to time 0) c) Time to reach maximum miosis (t^) d) Total time during which maximum miosis is > 3 %

The results are shown in Table 1 and in Fig. 1. Table I.

Composition Cone, of AL'C₀_₃₆₀ --i_n Max. 'max ττtk>sls>3% irritation⁸ solution (% min) miosis, (%) (min) (min) eye eye

(%) (x±S.E.) (x±S.E.) (x±S.E.) (x±S.E.) closed half-open

Ref. comp. 1 2.0 1588 ± 471 21 ± 3 43 ± 5 154 ± 20 + +++

Ref. comp. 2 0.5 1258 ± 273 13 + 2 73 ± 24 188 ± 28 +++ ++++

Example 1 0.5 1432 ± 494 12 ± 2 48 ± 6 202 ± 48 - +++

Example 2 0.5 1545 ± 316 13 ± 1 93 ± 20 184 ± 29 + ++

Example 3 0.5 3735 + 334 16 ± 1 105 ± 31 330 ± 11 ++ ++++

Example 4 0.5 3505 + 460 19 ± 2 88 ± 17 322 ± 30 +++ ++++

Example 5 0.5 3778 ± 658 20 + 2 98 ± 12 302 ± 29 ++++ ++++ I

Example 6 0.5 3326 ± 388 17 ± 2 58 ± 14 316 ± 16 + +++ i Example 7 0.5 2552 ± 411 15 ± 2 125 ± 14 275 ± 28 + ++++

Example 8 0.5 2280 ± 434 14 ± 1 96 ± 23 262 ± 38 - +++

Example 9 0.5 2923 ± 326 18 ± 1 90 ± 21 273 ± 34 +++ +-I-++

Example 10 0.5 1725 ± 492 14 ± 1 58 ± 17 226 ± 36 ++ ++++

Viscous vehicle = = 115 mPas + 75 mM citr.buff. + ++++

Eye-irritation: no irritation = -

< 0.5 min = +

0.5 - 1 min = ++

1 - 3 min = +++

> 3 min = ++++

The results show:

The compositions according to the invention are absorbed from a viscous buffered solution into the cornea to a much higher degree compared to that of the reference compositions 1 and 2, and of Examples 1 and 2, and give rise to a longer miosis than the said reference compositions. Irrespective of the increased absorbed amount of drug, the degree of eye irritation caused by the solution is reduced, even to the level of the reference composition 1 and those of Examples 1 and 2, and especially it is reduced compared to the reference compositions of Examples 3-5 of comparable degree of absorption.

With the solutions according to the invention it is thus possible to increase the total amount of pilocarpine absorbed and prolong the duration of miosis compared to the reference compositions 1 and 2 and those of Examples 1 and 2, without accompanying eye irritation due to the increased absorption. - Generally it can be said that the ratio of drug absorbed to the degree of irritation is improved compared to all reference compounds.

The buffered viscous compositions according to the invention result in a long lasting miosis combined with a well tolerable degree of eye irritation. On the other hand, the total amount of drug absorbed is increased. As the prodrugs are effectively absorbed into the cornea, smaller concentrations and fewer times of administration may be used, resulting in lesser systemic side effects and better patient compliance.

Claims

1. Composition for the topical administration of bispilo¬ carpic acid diesters to the eye in the form of an aqueous solution, characterized in that it includes a viscosity enhancing agent and a buffer, the pH of the composition being 3-6.

2. Composition according to claim 1, characterized in that it contains the viscosity enhancing agent in an amount sufficient to give a viscosity of 1 - 25000 mPas.

3. Composition according to claim 1, characterized in that the viscosity enhancing agent is selected from the group consisting of hydroxypropylmethylcellulose, sodium car- boxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, polyacrylic acids, chitosans, and hyaluronic acid.

4. Composition according to claim 3, characterized in that the viscosity enhancing agent is hydroxypropyl methylcellulose (HPMC) .

5. Composition according to claim 1, characterized in that its pH is 4.5 - 5.5.

6. Composition according to claim 1, characterized in that the buffer is selected from the group consisting of phos¬ phate buffers, borate buffers, acetate buffers and citrate buffers, and mixed buffers.

7. Composition according to claim 6, characterized in that the buffer is a citrate buffer in a concentration of 5 - 100 mM.

8. Composition according to claim 1, characterized in that it is an isotonic solution.

9. Composition according to any one of the preceeding claims, characterized in that the bispilocarpic acid diester is a 0,0'-diacyl (1,4-xylylene) bispilocarpate, wherein acyl is selected from the group consisting of lower alkyl- or lower cycloalkylcarbonyl.

10. Composition according to claim 1, characterized in that the bispilocarpic acid diester is O,0'-dipropionyl, 0,0'- dibutyryl or 0,0'-dicyclopropylcarbonyl (1,4-xylylene) or (1,6-hexylene) bispilocarpate.