AQUEOUS PHARMACEUTICAL PREPARATION

Abstract: The present invention relates to a new pharmaceutical preparation for local application comprising an aqueous solution of 11β-hydroxy-­ 16α,17α,21-trimethyl-▴¹,⁴-pregnadiene-3,20-dione and a β-cyclodextrine derivative.

Description: The present invention relates to a new pharmaceutical preparation for local application comprising an aqueous solution of 11β-hydroxy-16α,17α,21-trimethylΔ¹ ,4 -pregnadiene-3,20-dione (hereinafter called Org 6216 or the Steroid) and a β-cyclodextrine derivative. More particularly the said new composition is particularly useful for ophthalmological purposes, viz. for the treatment of infections in or at the eyes. In general, 11β-hydroxy steroids (corticosteroids) including the Steroid are known for their potent local anti-inflammatory activity, see for example US patent 3,947,478. Moreover, Org 6216 did not expose any significant systemic effect when administered locally. However, it is also generally known that most corticosteroids when applied to the eyes are held responsible for an unacceptable increase of intra ocular pressure (I.O.P.) which render them absolutely unsuitable for any ophthalmological application. Fortunately, however, it was recently found that contrary to other corticosteroids Org 6216 did not increase I.O.P., so that also an ophthalmological application of Org 6216 could be considered. Org 6216, however, has one significant drawback which hitherto blocked virtually any practical application namely its extremely poor solubility in aqueous systems. For local application in the form of injection preparations, eye-drops, ear-drops, nose-sprays or the like the desired concentration of in water could not be obtained. For topical application in the form of a gel, foams, cream or ointment (on water basis) large amounts of the Steroid were necessary in order to have very small amounts penetrated through the skin. In general it is known that α,β and τ-cyclodextrins may form inclusion complexes with various organic or inorganic compounds and as a result may increase the solubility of these compounds. See e.g. the review article of Saenger in Angewandte Chemie Int. Ed. 19, 344 (1980). It is Applicant's own experience and supported by literature data that the solubility of a compound in water may increase very roughly by a factor 2-500 provided said compound is able to form an inclusion-complex with one of the cyclodextrins. Org 6216, however, would not benefit from such increase because its original solubility in water of approximately 5x10⁻⁴ mg/ml would most ideally increase at most up to a level of about 0.1 mg/ml which is still insufficient for local administration of Org 6216 in general and more in particular for ophthalmological application. Practical solubility tests carried out with α,β and τ-cyclodextrin only confirmed this expectation. Surprisingly, however, it was found that an inclusion complex formed between Org 6216 and 2,6dimethyl-β-cyclodextrin increased the solubility of the Steroid in water from the original level of 5x10⁻⁴ mg/ml up to a level of about 10 mg/ml, which means an increase of the solubility with the unexpectedly high factor of 10,000. This increase of Org 6216 solubility in water renders a practical application of the Steroid possible in pharmaceutical preparations for local administration and especially in ophthalmological preparations. The present invention therefore encompasses a pharmaceutical preparation for local administration, and especially an ophthalmological preparation comprising an aqueous solution of 11β-hydroxy-16α,17α,21-trimethyl-Δ¹ ,4 - pregnadiene-3,20-dione (the Steroid, Org 6216) and a partially alkylated β-cyclodextrin. A partially alkylated β-cyclodextrin is a derivative of β-cyclodextrin (or cyclohepta amylose) in which one or more hydroxy groups are alkylated. Examples of such partially alkylated β-cyclodextrins are the 2 hydroxypropyl, 6-methyl, 2,3-dimethyl and in particular the 2,6-dimethyl-β-cyclodextrin. The solubility of Org 6216 in water increases with increasing concentrations of partially alkylated β-cyclodextrin until this solubility reaches its level-off phase or maximal level. This maximal level is obtained using relatively large amounts of partially alkylated β-cyclodextrins, roughly 0.2-0.3 mmol. partially alkylated β-cyclodextrin per mililiter water. The maximal solubility of Org 6216 in water using 2,6-dimethyl-β-cyclodextrin as the solubilizing agent amounts to about 9-10 mg/ml; at this level the 2,6-dimethyl-β-cyclodextrin concentration required is about 0,28 millimol per ml. A further increase of the cyclodextrin concentration contributes less effectively to a further improvement of the Steroid's solubility. The graph shows the increase of the solubility of Org 6216 with increasing 2,6-dimethyl-β-cyclodextrin concentrations. The solubility studies were performed according to the method described below which is well known in the litrature. Excess amounts of Org 6216 were added to aqueous solutions of 2,6-dimethyl-β-cyclodextrin. These suspensions were shaken at room temperature for 5 days followed by an equilibration period of 3 days at room temperature. Then an aliquot was centrifuged and the supernatant was filtered through a 0.45 µm membrane filter (Millipore: HV4, Millex™). The samples were analysed with the Perkin Elmer Lambda 5 UV/VIS spectrophotometer. The absorbance was read and compared with a blanc and standard calibration curve. From these data the concentration of Org 6216 dissolved in water was calculated. After calculation of the amount of steroid dissolved, a phase-solubility diagram was constructed by plotting the dissolved amounts of Org 6216 as a function of the concentration of 2,6-dimethyl-β-cyclodextrin (see Graph). From the curve obtained the complex stability constant K was calculated using the formula: K = slope S o (1-slope) S o = saturation concentration of Steroid without 2,6-dimethyl-β-cyclodextrin. slope = the slope of the initial part of the curve. This complex-stability constant K is also a measure for the solubility of Org 6216 in water. The higher this complex-stability constant, the better is the stability of the complex and the higher is the solubility in water. For comparative purposes the unexpected increase of solubility of Org 6216 in water using 2,6-dimethyl-β-cyclodextrin, is compared with other more common cyclodextrins. The results are described in the following table: Besides the essential ingredients Org 6216, partially methylated β-cyclodextrin and water, the pharmaceutical preparation according to the invention may contain other active substances and/or pharmaceutical auxiliaries. The preparation may optionally contain for example, preservatives, viscosity increasing agents, agents for rendering the solution isotonic, buffers for adapting the desired pH, surfactants etc., as well as the usual pharmaceutically acceptable carriers and/or diluents. As already said the preparation according to the invention may be used for all kinds of local administration, e.g. as injection preparation, intranasal preparation, ear-drops, topical preparation (gel, ointment, foam, cream), but is preferably used for ophthalmological purposes. A preparation for local administration is a preparation that is locally active and does not exert a significant systemic effect. The concentration of Org 6216 in the pharmaceutical preparation according to the invention may vary somewhat depending upon the way of administration. The usual concentration, however, varies between 1 and 10 mg and more particularly between 5 and 10 mg per mililiter water. For ophthalmological purposes where usually only one or two drops are applied the concentration of ORG 6216 is preferably as high as possible, viz. about 9-10 mg per ml water. prepare oil phase and water phase separately at elevated temperatures then, add oil phase to water phase and homogenize.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A pharmaceutical preparation for local administration comprising an aqueous solution of 11-β-hydroxy-16α,17α, 21-trimethyl-δ¹ ,4 -pregnadiene 3,20-dione and a partially alkylated β-cyclodextrin. 2. Preparation according to claim 1 comprising 2,6-dimethyl-β-cyclodextrin as the partially alkylated β-cyclodextrin. 3. Preparation according to claim 1 or 2 intended for opthalmological purposes. 4. Preparation according to claim 3 comprising 5-10 mg of 11-β-hydroxy-16α,17α, 21-trimethyl-δ¹ ,4 -pregnadiene 3,20-dione per ml water. Claims for the following Contracting Sates : GR, SP 1. A process of manufacturing a pharmaceutical preparation for local administration comprising dissolving 11-β-hydroxy-16α,17α, 21-trimethyl-δ¹ ,4 -pregnadiene 3,20-dione into an aqueous solution containing a partially alkylated β-cyclodextrin. 2. The process according to claim 1 wherein 2,6-dimethyl-β-cyclodextrin is the partially alkylated β-cyclodextrin. 3. The process of claim 1 or claim 2 wherein said pharmaceutical preparation is intended for opthalmological purposes. 4. The process according to claim 3 wherein the resulting pharmaceutical preparation comprises 5-10 mg of 11-β-hydroxy-16α,17α, 21-trimethyl-δ¹ ,4 -pregnadiene 3,20-dione per ml water.

Inventors: BRINKS, GERRIT JOHANNES, EGBERINK, JOHANNES GERHARDUS JOSEPH
Applicants: AKZO N.V.
Application year: 1989
Main classification: A61K31
IPC codes: A61K47, A61K9, A61P29, A61K31, A61P27