LT3524B - Composition for ophthalmic use - Google Patents

Abstract

The present invention relates to a composition of local bispilocarpine acid diester usage for eyes in the form of a water solution, which also includes an agent and buffer of pH 3-6 for increasing the viscosity of the composition.

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 is based on its astringent action on the dorsal muscle, which increases the anterior chamber angle, which is important for chamber fluid outflow, and facilitates fluid outflow.

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 action of 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 chamber fluid, iris, and ciliary muscle, resulting in a strong ii. IIL II. II

Ellillll HB. [HUfllJlU I .I.IIIULII JS1IMII pupil contraction (miosis) 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 (BD) are readily absorbed into the adipose tissue of the corneal epithelium, which is why it is important to control the rate of absorption of the drug into the corneal epithelium and avoid sharp increases in concentration, which irritates the eye.

The fat solubility of BD is highly pH-dependent, with a low solubility at low pH and increases with near-neutral pH values with ocular administration. For stability reasons, BDs should be stored in acidic solution. The faster the pH of the lacrimal fluid increases, the more rapidly the lipid solubility of BD increases, which results in a faster and higher concentration of corneal epithelium. By slowing down the neutralization of the tear fluid, the solubility of BD in fat increases more slowly, thereby creating conditions to control «1IIL II. II!

JIIHIUI BUDI IIIUnilHlH

I L1IUEI.il .ΙΗΙΙΙΙΙΙ ,, ΙΙ rate of absorption in corneal epithelium.

Usual are for example. pilocarpine in viscous solution, thereby increasing the time of contact of pilocarpine with the eye surface. However, such a composition does not control the rate of surface absorption of pilocarpine, so that the mode of action of pilocarpine is not substantially altered.

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 sharp 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.

Thus, it is an object of the present invention to provide a composition for topical ocular administration of a di-bispilocarpic acid diester in the form of an aqueous solution comprising a viscosity enhancing agent and a buffer having a pH of 3-6.

The use of a viscosity enhancing agent in the composition of the present invention achieves a controlling or decreasing effect on the rate of neutralization on the surface of the eye, while increasing the amount of drug delivered to the eye and prolonging its duration of action. Thus, a viscosity enhancing agent improves the absorption profile of a drug by eliminating concentration peaks and sustaining elevated concentrations for longer. This effect is exacerbated by the use of a buffering agent which further reduces any eye irritation occurring after ingestion of larger volumes of the viscosity enhancing agent.

II.

1ΙΙΙΒ ttlllill UIIHIIjm i imu omui cellulose, cellulose,

Thus, by controlling the viscosity and tear pH in the tear fluid by the composition of the invention, it is possible to both reduce the peak concentration of the drug in the corneal epithelium and to provide increased drug delivery with less eye irritation.

The desired level of viscosity is achieved by the use of a suitable material for this purpose. Typical examples are cellulose derivatives such as hydroxypropylmethyl sodium carboxymethyl cellulose, methyl polyvinylpyrrolidone, polyvinyl alcohols, dextrans, polyacrylic acids, chitosan, hyaluronic acid and the like. The amount of polymer to be added depends on the level of viscosity desired and the polymer used, and can be easily predicted with sufficient knowledge in the art.

Thus, the viscosity inducing agent is used in an amount sufficient to achieve a suitable 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.

The amount will, of course, vary with the agent used. In the case of the first mentioned cellulose derivative (HPMC), a content of 0.3-1% results in a viscosity of approximately 10-150 mPas, preferably 15-50 mPas.

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.

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According to the invention, any system which provides the desired pH and which is pharmacologically acceptable can be used as 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.

Conventionally used buffers depend on the desired pH and desired buffering properties, concentrations ranging from 5 to 100 mM. The choice of the amount and type of buffer depends on the knowledge of the worker in the field.

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

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 chloride, potassium chloride, glycerol, mannitol, sorbitol, xylitol, sodium borate, sodium acetate and the like.

Bispilocarpic acid diesters are primarily those described in WO 92 92953 and 93/24466, the contents of which are incorporated herein by reference.

Namely, W0 Publication 92/09583 defines among others compounds having the general formula

CH.

N

O

Y w

(I)

11,1111:! L 11!

UI · II Diliu HIIIHUHJI.il i ItlUElilI JI.EIUI ⁶ LT 3524 B where O n

A) Y is hydrogen or -CR where R is hydrogen, C! C ₁₈ -alkyl, C ₂ - Ci ₈ -alkenyl, C ₂ - C ₈ alkynyl, optionally substituted with C ₃ - C ₇ cycloalkyl, or Cg - C ₇ cycloalkenyl, aryl or an optionally substituted aryl or lower alkyl, and

W is a group

-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 substituted C, -C _18- alkylene, C ₂ -C ₁₈ -alkenylene, C ₂ -C ₁₈ -alkynylene which may be optionally substituted with C ₃ -C ₇ -cycloalkyl or C ₃ -C ₇ -cycloalkenyl, aryl or aryl lower alkyl, or A is optionally substituted C ₃ -C ₇ -cycloalkylene or C ₃ -C ₇ -cycloalkenylene or arylene, or A is the aforementioned alkylene, alkenylene or alkynylene having a cycloalkylene, cycloalkenylene or arylene group as defined above and -Z-Y 'is

nu, «ιιιι u, m m imu. Kinu ι · π iiijui .11 liliimiil! JHIIUI or

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

O O II II

-C-B-C-Z'-OR ', where R' has the meaning as defined above, and B has the value defined above, and -Z'-OR 'is

OR ¹

CH as well as the 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) - or lower cycloalkyl (3-6C) carbonyl or benzoyl, A is lower alkylene (2-6C), lower cycloalkylene (3-6C) or arylene , namely, 0.0'-diacetyl, 0.0'-dipropionyl, O, O'-dibutyryl, 0.0'valeryl and O, O'-dicyclopropylcarbonyl (1,4-1,3-, 1, 2-xylene) - and - (1,2-ethylene) -, - (1,3-propylene) -, - (1,4-butylene) -, - (1,5-pentylene) - and - (1,6-hexylene) bispilocarpate, especially - (1,4-xylylene) bispilocarpate, alkylene groups may not be optionally substituted by hydroxy or.

I IH1I MII protected by hydroxy or 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-ethylene,

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

Another preferred group of compounds of formula IB) is e.g. (dibenzyl) and (lower alkyl) bispilocarpates such as O, O'-glutaryl, 0,0-disisuccinyl, Ο, Ο'-adipoyl (dibenzyl) -, and - (lower alkyl) bispilocarpate.

The following specific compounds may be mentioned:

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

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

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

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

O, O'-Dibutyryl (1,6-hexylene) bispilocarpate

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

The present invention achieves sufficient drug absorption and longer duration of action by using lower amounts of the drug relative to pilocarpine, thereby reducing the number of times per day the drug is administered. The concentration of BD in the composition of the present invention may vary but is suitable from 0.05 to 2% by weight, preferably from 0.25 to 1%, based on pilocarpine base.

The following examples illustrate the invention but are not intended to limit the same. The active substance is pilocarpine base (w / v).

UBUI. litu 11, Example III iuiui iiunjm (Compare)

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

0,0'-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 to pH 5.0

Aq. ster. to 1.0 ml.

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

example (Comparison)

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

0,0'-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 to pH 5) , 0

Aq. ster. to 1.0 ml.

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

example (Comparison)

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

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

Ml. K III ll. II

UI 41111 lllllLJIL

I WI1 HA »

HPMC

NaCl

NaOH

Aq. ster to pH to

5.0 mg 6.5 mg 5.0

1.0 ml.

The concentration of the active ingredient is 0.5% and its viscosity is 25 mPas. The pH of the solution is 5.

example (Comparison)

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

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

HPMC 6.5 mg

NaCl 6.5 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

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

example (Comparison)

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

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

HPMC 8.5 mg

NaCl 6.5 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

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

Ι.ΙΙΙίί II; II;

DilIllU IIU..IIII 1UHI1IJ.1U1.U. I ΙΙΙΗΚΙΙ UIII1H1 ¹¹ EN 3524 Example B

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

0,0'-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 to pH 5.0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 0.5% and that of the buffer is 10 mM. The viscosity is 50 mPas and 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 12.2 mg

Citric acid monohydr. 1.2 mg

Sodium citrate dihydr. 4.3 mg

HPMC 6.5 mg

NaCl 4.8 mg

NaOH to pH 5.0

Aq. ster. to 1.0 ml.

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

example

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

0,0'-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 to pH 5.0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 0.5% and that of the buffer is 50 mM. The viscosity is 50 mPas and 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 12, 2 mg Citric acid monohydr. 1, , 2 mg Sodium citrate dihydr. 4, , 3 mg HPMC 8, , 5 mg NaCl 6, , 0 mg NaOH to pH 5, , 0

Aq. ster. to 1.0 ml.

The concentration of the active ingredient is 0.5% and that of the buffer is 20 mM. The viscosity is 115 mPas and 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 12.2 mg. BU: U III. JEIII · IIUL1 · fflUilILUU I lt · Eli £ 9111.11 ¹³ LT 3524 B

Citric acid monohydr. 4, , 3 mg Sodium citrate dihydr. 16, , 0 mg HPMC 8, , 5 mg NaCl 1, , 0 mg NaOH to pH 5, , 0

Aq. ster. to 1.0 ml.

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

example

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

0,0'-Dibutiril (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 to pH 5.0 Aq. ster. to 1.0 ml.

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

example

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

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

Citric acid monohydr.

2.5 mg

0.6 mg m: m :: u ii: mum mi.ii iiiihljiu i iliuis isiiji ¹⁴ LT 3524 B

Sodium citrate dihydr. 2.1 mg

HPMC 5.0 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 that of the buffer is 10 mM. The viscosity is 25 mPas and the pH of the solution is 5.

example

The composition of the present invention was prepared with 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 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 that of the buffer is 10 mM. The viscosity is 25 mPas and the pH of the solution is 5.

The formulations of the present invention (formulations according to Example 610) were compared, on the one hand, with the commercial pilocarpine formulation (Oftan Pilocarpine 2%; Comparative Composition 1), on the other, and with the formulation containing the same prodrug in aqueous solution. without viscosity increasing agent and buffer (comparative formulation

2) as well as the compositions of Examples 1-5 using

IBI UII .. II III, ιιιι m nu u iiiuiii, 11.11 i m · iii take the same tests and under the same conditions.

Rabbit-induced myosis 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 maximal meiosis (t _max )

(d) Total time to maximum myosis of> 3%

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

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m. iii nu

Composition Solution PPK _o .36o min Max. max. t _m i _0Z >> 3% irritation ⁸ conc (%) (% min) myiosis (%) (min) (min) semi (x ± SE) (x ± SE) (x ± SE) (x ± SE) with the eyes closed

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The results show that:

The compositions of the invention are absorbed from the viscous buffer solution into the cornea to a much greater extent than Comparative Compositions 1 and 2 and Examples 1 and 2, and result in longer miosis than said Comparative Compositions. In spite of the greater amount of drug absorbed, the degree of solution-induced eye irritation is reduced even to Comparative Composition 1 and Examples 1 and 2, and in particular to that of Comparative Compositions 3-5 of comparable absorbency.

Thus, the use of the solutions of the invention can increase the total amount of pilocarpine absorbed and extend the duration of myosis compared to comparative formulations 1 and 2 and examples 1 and 2, avoiding the possibility of increased absorption of ocular irritation. - Generally speaking, the ratio of drug absorbed to degree of irritation is improved compared to all comparator compounds.

The buffered viscous compositions of the invention cause prolonged myiosis with a well-tolerated degree of eye irritation. On the other hand, the total amount of drug absorbed increases. Because precursors are effectively absorbed into the cornea, lower concentrations and less frequent drug administration can be achieved, which will reduce systemic side effects and make patients more comfortable.

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Claims (10)

DEFINITION OF INVENTION CLAIMS 1. A composition for topical ocular administration of a bispilocarpic acid diester in aqueous solution, characterized in that it comprises a viscosity enhancing agent and a buffer maintaining the composition at a pH of 3 to 6. Composition according to claim 1, characterized in that it comprises a viscosity increasing agent in an amount such that the viscosity is between 1 and 25000 mPa.s. 3. The composition of claim 1, wherein the viscosity enhancing agent is selected from the group consisting of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans, polyacrylic acids, chitosan acids. 4. The composition of claim 3 wherein the viscosity enhancing agent is hydroxypropylmethylcellulose (HPMC). Composition according to claim 1, characterized in that it has a pH of 4.5 to 5.5. 6. The composition of claim 1, wherein the buffer is selected from the group consisting of phosphate buffers, borate buffers, acetate buffers, and citrate buffers, or mixed buffers. 7. The composition of claim 6, wherein the buffer is a citrate buffer at a concentration of 5-100 mM. 8. The composition of claim 1, wherein the composition is an isotonic solution. «, Ηΐίΐιι m Ulini B11 1IL..HU mum iuiu 9. A composition according to any one of the preceding claims wherein the bispilocarpic acid diester is 0.0'-diacyl (1,4-xylene) bispilocarpate, wherein the acyl is selected from the group consisting of lower alkyl or lower cycloalkylcarbonyl. 10. The composition of claim 1, wherein the diester of the bispilocarpic acid is 0.0dipropionyl, 0.0'-dibutyryl or O, O'-dicyclopropylcarbonyl (1,4-xylene) - or (1,6- hexilen) bispilocarpate. mum i: iii ui u ·· ii m: U .UI. UI. 1/1 Changes in pupil diameter (%) FIG. 1 Time (min) x = Comparison comp.1 o = Compare. comp.2 ® = Example 6 composition = Example 8 composition