PL174170B1 - 3-substituted 2-oxyindolo-1-carboxylamide pharmaceutical preparations - Google Patents

Abstract

A pharmaceutical preparation comprising: (A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; and (B) at least one compound of formula (I) where R1, R2, and R3 are each independently hydrogen, fluoro, bromo, or chloro, or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to a pharmaceutical preparation containing a 3-substituted 2-oxindole-1-carboxamide with analgesic effect and in the treatment of disorders and diseases mediated by collagenase.

These carboxamides are useful as analgesics for use in mammals, such as humans, and for ameliorating or relieving pain during recovery from surgery or other trauma, or for relieving the symptoms of chronic diseases such as inflammation and associated pain. , rheumatoid arthritis and osteoarthritis as described in U.S. Patent Nos. 4,556,672 and 5,047,554. Carboxamides are also useful in the treatment of collagenase-mediated disorders and diseases such as bone resorption disorders, corneas, periodontal disease, and skin wounds and burns in mammals as described in U.S. Patent No. 5,008,283.

Carboxamides, as represented by the formula in the figure, are chemically unstable in water. It is known that the rate of hydrolytic degradation can be reduced by protecting unstable drugs, e.g. by isolating micelles in a hydrophobic core or shaping into a form with low activity towards water, with non-aqueous solvent based media, i.e. essential oils. Carboxamides, apart from their hydrolytic instability, are also susceptible to decomposition under the influence of oxygen in water, e.g. in aqueous and non-aqueous media, e.g. in oils, carriers. Oxidative instability can be reduced in saturated oils by the inclusion of antioxidants or the use of unsaturated oils in the formulation, which protect the drug by being self-oxidizing more easily. However, carboxamides of the formula shown are not readily stabilized in oils commonly used in pharmaceutical formulations, e.g. sesame oil, peanut oil, safflower oil, cottonseed oil.

Triglycerides commonly used in pharmaceutical preparations include cottonseed oil, castor oil, peanut oil, sunflower oil, and sesame oil. These are all natural fats / oils. Their use is known from EP 448 253. This specification does not mention the use of modified semisynthetic oils such as caprylic acid / capric triglyceride esters (Miglyols) for the formulation of a parenteral dosage form for humans and mammals (The Theory and Practice of Industrial Pharmacy). , Leon Lachman, Herbert A. Lieberman, Josheph L. Kanic, Lea & Febiger, 1988, Philadelphia). Miglyols are not natural oils. They are oils that have been chemically modified and as a result differ significantly from natural oils in their physicochemical properties, stability and toxicity and are therefore considered a separate class of excipients different from natural oils.

The subject of the invention is a pharmaceutical preparation containing a 3-substituted 2-oxsmdole-1-carboxamide of a compound of the formula shown in the figure.

wherein R1, R2 and R3 are, independently of each other, hydrogen, fluorine, bromine or chlorine, or a pharmaceutically acceptable salt thereof, which comprises (A) at least one fatty acid triglyceride or propylene glycol diester oil component, (B) at least one compound of the formula in which R 1, R 2 and R 3 are as defined above, and optionally auxiliary ingredients, according to the invention as an oil component of the triglyceride or diester type

174 170 propylene glycol fatty acids containing a modified neutral oil composed of glycerin or propylene glycol esterified fatty acids with an average chain length of Cs to C10, the ratio of wt.% (A) to wt.% (B) ranging from 5.6 up to 99.9.

The pharmaceutical preparation preferably comprises 85 to 99% by weight (A) and 0.1 to 15% by weight (B).

Preferably Ri, R2 and R3 in the formula are, independently of each other, a fluorine or chlorine atom.

Preferred carboxamide compounds are:

5- chl <^: ro-2, i ^ - ^ (^ ił ^ 2yc ^ i ^ c ^^ - ^ - to ^ i; c ^ - ^ - ((^ - tiiir ^^ / lcrl ^ ai ^ ^ ^ (^ o ^ n ^ lo) ii ^ (^ d ^ ol (^ ok ^ irboxamide,

6- chl <^ oro-5 -: ^^ ll ^ (^^^ o-2, ^ - ^ <dii ^ h ^ c ^ i ^ <^^^ - ^ - ^ c ^ l ^ .sco-- 3 - ((2-thien / lc ^ l <aidbco ^^ lc ^) iirc ^ (ol ^ o ^^ arboxamide and 6-chloro-5-fluorot2,3-dihydro-2-oxo-3- [2- ( 4-chloro) thienylcarbonyl] molar carboxamide.

The preparation according to the invention makes it possible to inhibit the action of collagenase, and thus allows the treatment of inflammatory diseases and has an analgesic effect.

Pharmaceutical preparations containing carboxamides of the formula shown in the figure and triglycerides of saturated fatty acids Cs to C10 and propylene glycol dieesters have been found to exhibit increased stability and longer shelf life. As a result of such a formulation, carboxamides are less prone to hydrolysis and oxidation which would spoil them and ultimately render them ineffective. Stabilizing the carboxamides in these formulations does not require the addition of an antioxidant or other stabilizing excipients, although the addition of a preservative may be advantageous at times.

The triglycerides used in the formulation according to the invention are neutral oils which are composed of medium chain length (Cs to C10) fatty acid esters, also known as fractionated coconut oil. These fatty acids are esterified with either glycerin or propylene glycol and are marketed under the name MIGLYOL® (e.g. MIGLYOL® 810, MIGLYOL® 812 and MIGLYOL® 840). Miglyols are also referred to as fractionated coconut oil fatty acid triglycerides or caprylic acid / capric acid triglycerides. Fractionated coconut oil is obtained from solid oils obtained from the dried solids of Cocos nucifera L endosperm by hydrolysis, fractionation of the released fatty acids and re-esterification with glycerin or propylene glycol. It consists of a mixture of short and medium chain saturated fatty acids, mainly caprylic and capric acids. Miglyol® is a trade name of Fractionated Coconut Oil or Caprylic Acid / Capric Triglycerides from Dynamit Nobel Ltd., Germany and UK. These substrates show resistance to oxidation and rancidity as well as excellent safety and biocompatibility. Moreover, due to the use of saturated acids, the oils do not produce peroxides or other free radicals that could destabilize the pharmaceutical ingredient they contain. The low water content also minimizes the hydrolysis of the carboxamide. In a preferred formulation, the carboxamide of formula illustrated is dispersed in an oily vehicle containing Miglyol® 812 and other oil-soluble additives described below to form a homogeneous suspension of the drug substance in the oily vehicle.

Other additives that may be present in the pharmaceutical preparations may include an anti-caking agent such as, for example, propylene glycol, polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, or aluminum stearate. The amount of anti-caking agent may be approximately from 0.05 to 5% by weight. The pharmaceutical preparation may also contain a preservative in an amount ranging from 0.5 to 2.0% by weight. Such preservatives may include, for example, phenol, benzyl alcohol, parabens, chlorobutanol, and benzyl benzoate. Gelling agents such as aluminum monostearate may also be incorporated into the pharmaceutical formulation in an amount ranging from 0.5 to 3.0% by volume.

174 170

It is also possible for the formulation according to the invention to contain (C) 0 to 5% by weight of an anti-caking agent and (D) 0 to 2.0% by weight of a preservative as auxiliary ingredient.

The stability of these pharmaceutical preparations can be assessed, for example, under accelerated aging conditions by subjecting carboxamide suspensions (6% by weight of drug substance) in glass vials to temperatures elevated to 70 ° C for up to nine weeks. During these stability tests, the levels of undamaged drug remaining in the formulation, as well as the hydrolytic degradation and oxidation products, were quantified by pressure liquid chromatography (HPLC). For determination, the suspension is diluted with methanol / triethylamine in a ratio of 100/1 by volume to obtain a final drug concentration of 0.6 to 1.2 mg / ml. This solvent dissolves the suspended drug to form a solution that can be directly injected into the HPLC column. In chromatography, the mobile phase is a 90/10 v / v methanol / water mixture. + 1% triethylamine, reversed-phase octadecasilane column and the flow rate is 1 ml / min. Drug detection is by ultraviolet absorbance at 46 nm. This study showed no actual degradation of the carboxamide in suspension after nine weeks.

In the case of using a compound of the formula shown in the figure or a salt thereof in human subjects, the daily dose will usually be prescribed by a physician. In addition, the dosage will vary depending upon the age, weight, and response of the individual patient, as well as the severity of the symptoms and the potency of the particular compound administered. However, in acute conditions, when administered for pain relief, the effective dose in most cases is 0.01 to 0.25 g as needed (e.g., once to four times a day. In chronic treatment, the effective dose is in most cases 0 0.01 to 0.5 g per day, preferably 0.1 to 0.25 g per day, in single or divided doses On the other hand, in some cases it may be necessary to use doses outside these limits.

Preferably, the pharmaceutical preparations according to the invention are parenteral preparations. The pharmaceutical preparations according to the invention can be prepared in the form of a compound of the formula shown in the figure (as an active ingredient) in a unit dose. Some examples of unit dosage forms are sterile suspensions for intramuscular, subcutaneous or intraarticular injection, sterile ophthalmic suspensions for topical ocular use, capsules for oral administration, rectal suppositories or topical lotions for use on the skin or scalp.

An example of a suitable pharmaceutical form for oral administration is soft gelatin capsules. Orally administered suspensions may be delivered, e.g., after encapsulating a suspension of the compound of formula illustrated in the figure in an oil, i.e., Miglyol® 812, in a soft gelatin capsule. A rectal suppository may be formulated by dispersing the carboxamide in a neutral oil, together with a compatible suppository base, such as cocoa butter or Whitepsol W35, having a melting point greater than body temperature. The product for topical application to the skin should contain carboxamide as an active ingredient suspended in a neutral oil, e.g. Miglyol® 812, and also contain one or more pharmaceutically inactive ingredients such as cetyl alcohol, stearic acid, propylene glycol, aluminum monostearate, benzyl alcohol, as diluents and preservatives. A parenteral formulation is preferably a suspension of the carboxamide in a neutral oil and may also contain non-pharmaceutically active ingredients such as benzyl alcohol as a preservative, aluminum monostearate as a gelling agent and propylene glycol as a dispersant.

The following examples illustrate the preparation of pharmaceutical preparations. Commercial reagents can be used without further purification.

174 170

EXAMPLE 1 800 ml of Miglyol 812 are heated to 45 ° C in a mixer equipped with an agitator and homogenizer. 10 g of benzyl alcohol are added to the oil while stirring (approximately 60-80 rpm). The oily solution is sterile filtered into a sterile blender equipped with a stirrer and homogenizer. 120 g of micronized, sterile carboxamide powder are dispersed in the oily phase with mixing. The suspension is homogenized at high speed for 10 minutes and then allowed to cool to room temperature with gentle agitation (60-80 rpm). The mixture is brought to a total batch size of 1000 g by adding the required amount of sterile Miglyol 812 to obtain a final concentration of 12% by weight of carboxamides in the finished formulation. The suspension is poured to sterile vials of lead glass with a capacity of 50 cm ^{3 of} type I, using an automatic filling. The vials are closed with Teflon-coated rubber stoppers and capped with an aluminum cap.

Example II. In a mixer equipped with a stirrer and homogenizer, ml of Miglyol 812 is heated to 45 ° C. 10 g of benzyl alcohol are added to the oil while stirring (60-80 rpm). The oily solution is sterile filtered into a sterile blender equipped with a stirrer and homogenizer. 20 g of sterile, powdered aluminum monostearate is added in portions to the oily solution while stirring to gel the oil. The gelled oil is allowed to cool to room temperature and set aside for six hours without stirring. 120 g of micronized, sterile carboxamide powder are then dispersed in the gelled oil with stirring. The slurry is made up to a total batch weight of 1000 grams by adding the required amount of sterile Miglyol 812 to achieve a final concentration of 12% by weight of carboxamide in the finished formulation. The suspension is sterilized into 50 cc Type I lead glass vials using an automatic filling apparatus. The vials are closed with Teflon-coated rubber stoppers and capped with an aluminum cap.

Example III. In a mixer equipped with a stirrer and homogenizer, 800 ml of Miglyol 812 are heated to 45 ° C. 10 g of benzyl alcohol is added to the oil with stirring (about 60-80 rpm). In the oil phase, 120 g of micronized sterile carboxamide powder are suspended with stirring. The suspension is homogenized at high speed for ten minutes and then allowed to cool to room temperature with gentle agitation (60-80 rpm). The slurry is brought to a total batch weight of 1000 grams by adding the required amount of Miglyol 812 to achieve a final concentration of 12% by weight of carboxamide in the finished formulation. The suspension is filled using an automatic filler into soft gelatin capsules for oral ingestion.

Example IV. 200 g of Miglyol 812 and 800 g of Whitepsol W35 are heated to 60 ° C in a mixer with a mixer and homogenizer. The carboxamide powder is dispersed into the resulting oil solution with stirring. The suspension is allowed to fill in the suppository forms and to solidify by cooling to room temperature.

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Claims (7)

Patent claims 1. A pharmaceutical preparation containing a 3-substituted 2-oxindole-1-carboxamide of the formula shown in the figure R wherein R1, R2 and R3 are, independently of each other, hydrogen, fluorine, bromine or chlorine, or a pharmaceutically acceptable salt thereof, which comprises (A) at least one fatty acid triglyceride or propylene glycol diester oil component, (B ) at least one compound of the formula shown in the figure, in which R1, R2 and R3 are as defined above and optionally auxiliary components, characterized in that the oil component of the triglyceride or propylene glycol diester type of fatty acids contains a modified neutral oil composed of esterified glycerin or propylene glycol of fatty acids with an average chain length of Cs to C10, wherein the ratio of wt.% (A) to wt.% (B) is in the range 5.6 to 99.9. 2. A formulation according to claim 1 The process of claim 1, comprising 85 to 99% by weight (A) and 0.1 to 15% by weight (B). 3. The formulation according to claim 1 The process of claim 1, wherein the excipient is 0.05 to 5% by weight of an anti-caking agent. 4. A formulation according to claim 1 The method of claim 1, wherein the anti-caking agent is propylene glycol, polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, or aluminum stearate. 5. The formulation according to claim 1 A preservative according to claim 1, wherein the excipient is 0.5 to 2.0% by weight of a preservative. 6. A formulation according to claim 1 The process of claim 5, wherein the preservative is phenol, benzyl alcohol, parabens, chlorobutanol, or benzyl benzoate. 7. A formulation according to claim 1 The process of claim 1, wherein the excipient is (C) 0 to 5% by weight of an anti-caking agent and (D) to 2.0% by weight of a preservative.