HK1394A - Pharmaceutical composition for treating inflammation in the eye - Google Patents

Description

The subject of the invention is a medicinal product for the topical treatment of eye inflammation containing diclofenac sodium as an active substance and showing increased stability of formulation and very good tolerability in the eye.

The main treatment of more severe acute or chronic recurrent inflammation of the eye has been corticosteroids, but the immunosuppressive effect of these substances carries the risk of worsening the disease by bacterial or viral infection, which has recently led to the development and introduction of nonsteroidal anti-inflammatory drugs in ophthalmology.

Diclofenac sodium, known by the chemical name sodium-2- ((2,6-dichloranilino) phenylacetate, is a known non-steroidal anti-inflammatory; see DE-C 1543 639 and DE-C 1 793 592.

The substance has been used mainly in otolaryngology, gynecology, urology, paediatrics and rheumatology, but also has systemic applications in ophthalmology. A disadvantage of this use is that only relatively low levels of efficacy are obtained via the systemic pathway at the cortex, and it cannot be assumed that an increase in dose will also lead to a corresponding local increase in efficacy.

Topical application of diclofenac sodium to the eye should provide two advantages: first, the entire body is not burdened with the active substance to achieve a local effect, and second, a locally higher level of efficacy is achieved with an eye drop solution.

Sodium chloride and mannitide are referred to as isotonization additives. Solvents are called polyoxyethylene thioributan monolate, polyoxyethylene oxide-tetrahydroglyceride, polyoxyethylene glycol and α-cycloxyethylene and β-propyl vinyltromethrin. As eye preservatives, they are usually found in the form of methyl methyl methyl methyl, methyl methyl methyl methyl, methyl methyl methyl methyl, and methyl methyl methyl methyl, and methyl methyl methyl methyl, methyl, methyl, methyl, methyl, and methyl.

The addition of calcium or magnesium salts of physiologically compatible acids to reduce eye irritation by anti-inflammatory eye drops containing a non-steroidal anti-inflammatory with a carboxyl group in the molecule as the active substance is also described in JP-A-58/174309.

However, the formulations for eye drops described in JP-A-58/174310 and 58/174309 have significant drawbacks which make them unsuitable for use as finished medicinal products.

A major disadvantage of the known formulations is that they are unstable in the compositions described.

For eye drops, preservation of the preparations is also required in most European and other countries, i.e. protection against infestation and subsequent multiplication of microorganisms. While the prescription of preservatives is given in JP-A-58/174310, the prescription of preservatives is not suitable for the purpose in the formulations described, for the following reasons: benzalkonium chloride and cetylpyridinium chloride are incompatible with diclofenac sodium without the addition of a suitable solvent; their addition leads to precipitation in the preparation. In addition, the prescription of benzalkonium chloride with polyoxybutyrate, as contained in JP-A-517438/10 is proposed as a solution containing an incomplete solution of thiophenol. For example, the preparation of forbidden is only suitable for use in a solution with a pH of 7 to 78/A1743 and is not yet described as a preservative.

A further disadvantage of the known formulations is that calcium or magnesium salts must be added to prevent eye irritation by the active substance or by the preferred solvent β-cyclo-dextrin.

For the above reasons, the state of the art does not allow the production of eye drops containing diclofenac sodium that are stable and stored in accordance with the legal requirements and do not irritate the eye.

The purpose of the invention is therefore to formulate diclofenac sodium as eye drops which are stable enough for a finished product and which are preserved as required and well tolerated by the eye.

This problem is solved by the surprising finding that the use of certain stabilizers can achieve sufficient stabilization of the active substance and at the same time make it possible to use a preservative, since the stability and compatibility problems associated with its use are solved.

The invention is thus a sufficiently stable, preserved, well tolerated and effective medicinal product for the treatment of inflammation of the eye, containing an aqueous solution of diclofenac sodium, a buffer, an isotonic agent, a solvent and a preservative.

The addition of a special stabilizer to the aqueous preparation of diclofenac sodium intended for use as eye drops, in accordance with the invention, eliminates the difficulties associated with the known eye drops containing diclofenac sodium.

2-Amino-2-hydroxymethyl-1,3-propandiol (thromethamol) and its homologues up to 10 C atoms, in particular 5 to 7 C atoms, have been shown to be particularly suitable for the intended purpose.

Tromethamol and its homologs with up to 10, preferably 5 to 7, C atoms can also be illustrated by the general formula I: Other m, n, o (independently) an integer of at least 1 Sum of m, n and o 3 to 9, preferably 3 to 6 The primary preferred is 2-amino-2-hydroxymethyl-1,3-propandiol (trometamol), which corresponds to a compound of formula I with m = n = o = 1.

The addition of these stabilizers effectively prevents the decomposition of diclofenac sodium which would otherwise occur during storage. It also allows the use of a preservative which is required and required by law to prevent the contamination of the preparation by microorganisms in itself. In particular, the aqueous thiomersal, which is inherently unstable and has particularly favourable preservation properties, can be used in the formulation of the invention because it is indirectly co-stabilized by the stabilizer used. The stabilizer prevents the adsorption of the thiomersal at the stomach, thereby improving its shelf life. Finally, the invention has shown that no stimulant is necessary in the formulation of the invention, which is not necessary due to the presence of calcium or magnesium in the eye.

The individual components of the ophthalmic product of the invention are explained below.

The active substance diclofenac sodium is used in a concentration of 0.01 to 0.15%, preferably 0.05 to 0.11%, with a concentration of approximately 0.1% being particularly preferred.

The pH of the formulation is preferably 6.8 to 7.5 For example, boric acid, borates, phosphates and organic acids can be used as buffers, and boric acid is preferred, with the added stabilizer, e.g. trometamol, acting as the basic component of the buffer mixture.

Boric acid used as a buffer is preferably used in such quantities as to achieve isotonicity of the formulation at the same time.

Sodium chloride is not used for isotonisation of the preparation when thiomersal is used as a preservative to avoid compatibility problems with thiomersal.

A specific example of a particularly preferred solvent is reaction products from castor oil and ethylene oxide, e.g. the commercial product Cremophor EL®. Reaction products from castor oil and ethylene oxide have proven to be particularly good solvents with excellent eye compatibility. The concentration used is primarily directed to the concentration of the active substance. It is necessary to at least 60 times the concentration of the active substance to bring the active substance into solution. For example, the concentration of the solvent is 100 to 60 times the concentration of the active substance, especially the 5-fold concentration of the active substance.

A preservative must be contained in the preparations of the invention to prevent infection by microorganisms during the period of use. Due to its excellent preservation properties, sodium salt of 2- (ethylmercurithio) benzoic acid (thiomersal) is particularly preferred. It is used in a concentration of 0.002 to 0.02%, preferably 0.002 to 0.005 and in particular about 0.004%. Other known preservatives, such as benzalkonium chloride or cetylpyridinium chloride, can also be used in a concentration of 0.005 to 0.02%. Combinations of the above substances with edetric acid are also suitable.

The stabilizer is added to the preparation of the invention in a quantity of 0.05 to 5%, preferably 0.1 to 1.0%. In this quantity, the stabilizer, as mentioned, both stabilizes the active substance against chemical decomposition and stabilizes the thiomersal preservative against decomposition in aqueous solution. The compatibility of the other preservatives used in accordance with the invention, benzalkonium chloride and cetylpyridinium chloride, with the active substance is also further ensured by the stabilizer. If necessary, the amount of the solvent intermediate must be increased slightly when using these preservatives.

The preparation of the invention is prepared with water for injection and an osmolality of about 0.9 (301 mOsmol/kg) is established.

The product of the invention, due to its excellent chemical stability, can be stored for a long time even at room temperature and meets the requirements for its durability for such a product during therapeutic use.

The medicinal product of the invention is produced in a known manner by mixing and packaging all the components of the medicinal product in a homogeneous manner under sterile conditions.

The following examples of wording illustrate the invention:

Example 1

Example 2

Example 3

The formulations in examples 1, 2 and 3 are safe for 3-5 years at room temperature.

The tolerance of the eye drops was investigated in an eye irritation and toxicity study. The eye drop solution tested corresponds to formulation example 1. The test solution is applied to the eyelid bag five times a day for four weeks.

The following test scheme shall be used: Other The animals are examined for eye irritation twice daily, before the first and after the last daily application.

The results of the investigation can be summarised as follows: All rabbits did not show any local or systemic symptoms after four weeks of treatment with 50 μ l of 0.1% diclofenac Na-eye drop solution.

As a special test method for detecting increased tear flow due to local irritation, the Schirmer test is performed (see, for example, D. Vaughan and T. Asbury, Ophthalmology, Springer, Berlin et al. 1983):

The test shall be carried out in accordance with the following procedure:

The measurement shall be made in millimetres.

Group 1

Group 2

Observations and measurements obtained by the mirror test show that there are no differences between treated and control eyes that can be associated with the eye drops to be tested.

The differences observed can be considered as individual without biological or toxicological relevance.

In conclusion, the use of the eye drop solution containing diclofenac-Na, referred to in this patent as Example 1 of formulation, is safe for four weeks in rabbit eyes.

For the addition of trometamol, a 7-day study of eye irritation in rabbits was completed and two groups of six animals are used again:

The results of the two daily eye examinations, before the first and after the last application, show that trometamol is well tolerated in rabbit eyes.

The good tolerability shown in animal studies was also demonstrated in human clinical trials. 221 subjects are treated with eye drops that correspond to formulation example 1.

Overall, the results therefore suggest that the present formulation is a locally well tolerated solution for ophthalmological use.

Claims (9)

1. A medicament for the treatment of inflammations of the eye, comprising an aqueous solution of diclofenac sodium, a buffer, an isotonising agent, a solution aid and a preservative, characterised in that it comprises 2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up to 10 carbon atoms as stabiliser for the active ingredient and the preservative.
2. A medicament according to claim 1, characterised in that it comprises 2-amino-2-hydroxymethyl-1,3-propanediol (trometamol) as stabiliser.
3. A medicament according to claims 1 and 2, characterised in that it comprises the stabiliser in an amount of from 0.05 to 5 %.
4. A medicament according to claims 1 to 3, characterised in that it comprises a 0.01 to 0.15 % aqueous solution of diclofenac sodium.
5. A medicament according to claims 1 to 4, characterised in that it comprises the sodium salt of 2-(ethylmercurithio)-benzoic acid (thiomersal) as preservative.
6. A medicament according to claims 1 to 4, characterised in that it comprises benzalkonium chloride as preservative.
7. A medicament according to claims 1 to 4, characterised in that it comprises cetylpyridinium chloride as preservative.
8. A medicament according to claim 1, characterised in that it comprises a 0.05 to 0.11 % aqueous solution of diclofenac sodium, boric acid in an amount of 1.9 % as buffer and isotonising agent, a reaction product of castor oil and ethylene oxide in an amount of 5.0 % as solution aid, the sodium salt of 2-(ethylmercurithio)-benzoic acid (thiomersal) in an amount of from 0.002 to 0.005 % as preservative and 2-amino-2-hydroxymethyl-1,3-propanediol (trometamol) in an amount of from 0.1 to 1.0 % as stabiliser.
9. A process for the manufacture of a medicament according to claims 1 to 8, characterised in that all of the components of the medicament are mixed homogeneously, and filled, under sterile conditions.