NO179575B - Pharmaceutical preparation containing a physical form of the compound N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl-3-methoxybenzoyl] -2-methylbenzenesulfonamide - Google Patents

Description

The present invention relates to pharmaceutical agents. More particularly, it relates to a pharmaceutical preparation containing a particular physical form of a heterocyclic amide derivative.

European patent application publication number EP-A2-0199543 describes certain heterocyclic amide derivatives which antagonize the pharmacological actions of one or more of the arachidonic acid metabolites known as leukotrienes, for example , D and/or E4, which are known to be potent spasmogens (especially in the lungs), increase vascular permeability and to be implicated in the pathogenesis of asthma and inflammation (see J.L. Marx, Science, 1982, 215, 1380-1383) as well as of endotoxic shock (see J.A. Cook et al.,

J. Pharmacol. Exp. Ther., 1985, 235. 470) and traumatic shocks

(see C. Denzlinger et al., Science, 1985, 230, 330). The compounds are thus useful in the treatment of diseases where leukotrienes are involved and where antagonism of their action is desired. Such diseases include, for example, allergic lung disorders, such as asthma, hay fever and allergic rhinitis, as well as certain inflammatory diseases, such as bronchitis, ectopic and atopic eczema, psoriasis, as well as vasospastic cardiovascular disease, as well as endotoxic and traumatic shock states.

One of these heterocyclic amide derivatives described in EP-A2-0199543 is N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methyl-indol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide. This compound is described in Example 105 in the patent description and will hereafter be referred to as compound 1.

In recent clinical trials, compound 1 has been shown to be effective in the treatment of asthma when administered orally to asthmatics. This property of compound 1 that it is effective when administered peroral is unusual and highly desirable.

The pharmaceutical preparation used in the above-mentioned clinical trials was not entirely satisfactory and an improved formulation has been sought. As described in more detail below, it was necessary to solve a number of technical problems in order to obtain such a preparation.

Compound 1 has been shown to have relatively low solubility in water. There has therefore been a need for a pharmaceutical preparation suitable for peroral administration and which includes compound 1 in solid form.

It has been shown that compound 1 can be obtained in solid form as a material with a number of different physical properties, depending on the way it has been isolated and subsequently processed. This ability is due to the fact that compound 1 can exist in more than one physical form, at least one of which has little physical stability, and these physical forms can be obtained in mixtures. It has also been shown that different samples of compound 1 have different bioavailability in the solid state.

It is not particularly desirable to develop a formulation where a compound occurs in a mixture of physical forms that have different bioavailability, especially when one is physically unstable, since the effective dose of the compound cannot then be properly controlled. There has therefore been a need to find methods for producing physical forms of compound 1 which are virtually free of other physical forms.

Methods for the production of three physical forms of compound 1 almost free of other physical forms have now been found, and the physical stability and bioavailability of these three forms have been the subject of investigations. Two of these forms, hereafter referred to as forms B and X, have been shown to be physically stable, but have relatively little bioavailability. The third of the three forms, hereafter referred to as form A, has been shown to have relatively good bioavailability. However, it has also been shown that this physical form tends to transform into form B in the presence of water. This is an unfavorable characteristic of a material intended for formulation in a solid preparation, because granulation involves the use of water as an auxiliary substance in the mixing process. The tablets used in the above-mentioned clinical trials were prepared from form A by the wet granulation method, and were found to contain form B in an amount varying from approx. 25 to approx. 30%, calculated on the basis of the weight of compound 1.

There is therefore a need for a pharmaceutical preparation for peroral administration, which comprises compound 1 in a physical form which is virtually free of other physical forms, and which is physically stable, can be produced reproducibly and has good bio-availability.

It has now been shown that pharmaceutical preparations that meet these requirements can be obtained by choosing form A as the active ingredient and polyvinylpyrrolidone as an additional component.

The present invention therefore provides a pharmaceutical preparation which comprises, as active ingredient, a physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide ( previously referred to as form A) which is virtually free of other physical forms to such an extent that at least 90% by weight of said compound is in this physical form, and where the physical form has an infrared spectrum (0.5% in KBr) with sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm, and polyvinylpyrrolidone and a pharmaceutically acceptable carrier.

Form A has an X-ray powder diffraction pattern that has no clear peaks and is therefore amorphous.

It has been shown that preparations according to the invention have acceptable physical stability and can be produced reproducibly and with unexpectedly high bioavailability.

When in this description reference is made to form A as being virtually free of other physical forms, it is preferably meant that at least 90% by weight, preferably 95%, for example at least 96%, 97%, 98% or 99% of compound 1 occurs in this physical form.

The preparation according to the invention can have any conventional form suitable for oral administration, such as tablets, capsules or powder. Preferably it is in the form of tablets.

The active ingredient in the preparation suitably occurs in an amount of 1 to 90% by weight, calculated on the total weight of the preparation, for example from 10 to 50% by weight.

The polyvinylpyrrolidone is suitably included in an amount of at least 1% by weight, calculated on the basis of the total weight of the preparation. It can, together with the active ingredient, make up the entire total weight of the preparation. However, the preparation will also most often comprise at least one pharmaceutically acceptable carrier. For example, the polyvinylpyrrolidone can be present in an amount of 1 to 20% by weight, calculated on the basis of the total weight of the preparation and preferably amount to from 2 to 6% by weight.

Examples of suitable pharmaceutically acceptable carriers include, for example, sugar derivatives such as mannitol, lactose, sorbitol, glucose, sucrose, dextrose, fructose and xylitol, and cellulose derivatives such as microcrystalline cellulose, powdered cellulose and hydroxypropyl methylcellulose. Preferably, the preparation contains a sugar derivative, especially lactose, and a cellulose derivative, especially microcrystalline cellulose. The amount of sugar derivative present can, for example, be from 10 to 30% by weight, calculated on the basis of the total weight of the preparation. The amount of cellulose derivative present can, for example, amount to from 25 to 70% by weight, calculated on the total weight of the preparation.

The preparation may further contain one or more production aids, such as disintegrants, for example croscarmellose sodium, sodium starch glycolate and starch, as well as smoothing agents, for example magnesium stearate, stearic acid, talc and crushed vegetable stearin. The amount of explosive present can, for example, be in the range from 1 to 10% by weight, calculated on the basis of the total weight of the preparation. The amount of smoothing agent present can, for example, be from 0.25 to 2% by weight, calculated on the basis of the total weight of the preparation.

The preparation can be prepared by mixing the relevant ingredients according to conventional methods, for example by a granulation process.

A method for producing a pharmaceutical preparation consists of mixing form A, almost free of the other physical forms, with polyvinylpyrrolidone and water, and drying the resulting mixture.

The amount of water used will depend on the desired type of pharmaceutical preparation (e.g. tablet, capsule or powder) and on other ingredients that are mixed into the preparation. Appropriately, the weight ratio between water and form A will lie in the range from 0.1 to 100:1.

When the preparation is in the form of a tablet, the weight can be

the tablet suitably being in the range from 25 to 500 mg, such as from 50 to 250 mg, for example from 100 to 200 mg. The tablets can be uncoated or coated. The coating may be a conventional coating and may be applied by a conventional method.

A method for the preparation of form A, virtually free of other physical forms, consists in heating another physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl] -2-methylbenzenesulfonamide (previously referred to as form B) virtually free of other crystalline forms, and where the physical form is a monohydrate of N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3 -methoxybenzoyl]-2-methylbenzenesulfonamide which is crystalline has an infrared spectrum (0.5% in KBr) having sharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 858 cm"<1>, and an X-ray powder diffraction pattern with peaks at 20 = 10.0, 11.2, 14.6, 19.8 and 23.0°, at a temperature ranging from 90 to 125°C under reduced pressure.

The dehydration of form B is preferably carried out at a temperature in the range from 115 to 122°C.

The pressure during the dehydration of form B is preferably no more than 100 mbara, preferably no more than 50 mbara. For example, the pressure can range from 5 to 50 mbar.

Form B can be prepared almost free of other crystalline forms by crystallization from hot aqueous acetone. In particular, it can be prepared by dissolving a supply of compound 1 in aqueous acetone at a slightly higher temperature, adding more water, and then allowing the resulting mixture to cool. Preferably, the water is added quickly so that compound 1 initially separates as an oil. The material produced in this way has been shown to give form A in a particularly high degree of morphological purity.

The crystalline product can be dried at a slightly higher temperature, for example at approx. 60°C or lower. If it is desired to start from an impure supply of compound 1, it has proven advantageous to rub this impure supply with hot toluene/ethyl acetate before crystallization.

If form B is dried at a high temperature, for example above 60°C, a certain transformation to form A can occur. Material produced by drying form B at a temperature of approx. 60°C or lower, has been shown to be virtually free of other physical forms of compound 1.

Another method for producing form A, almost free of other physical forms of compound 1, consists in rapid evaporation of the solvent from a solution of compound 1. It can, for example, be produced by spray drying a solution of compound 1.

The solvent can be any liquid that dissolves compound 1 and can evaporate at a temperature lower than the melting point of form A. Examples of solvents include ketones, such as acetone, and nitriles such as acetonitrile, optionally in admixture with water. Aqueous acetone has proven to be a particularly suitable solvent.

The temperature at which the solvent evaporates should be lower than the melting point of form A. Suitably it is lower than 125°C, preferably lower than 120°C. If acetone is used as solvent, it has been established that significant amounts of crystalline material are obtained if the temperature is lower than 100°C. The temperature at which the solvent is evaporated can therefore, for example, be in the range from 100 to 125°C.

The solution of compound 1 is conveniently prepared by dissolving a crystalline form of compound 1, such as form B, in the solvent. A solution prepared in this way will contain a minimum of non-volatile impurities.

It will be clear from what has been stated above that aqueous acetone is a particularly advantageous solvent for the production of form A, which is almost free of other physical forms. It has also been shown that the content of the organic solvent in form A produced via form B by using this solution is very low. The solution may, for example, comprise from 5 to 15% by weight, preferably from 6 to 13% of compound 1. The solvent may comprise, for example, from 3 to 9% by weight, preferably from 4 to 8%, of water.

The advantages of the preparations according to the invention can be demonstrated by comparing its properties with corresponding preparations, where form A is replaced by form B or form X, and with a preparation comprising form A which does not contain polyvinylpyrrolidone.

Form X is a physical form of compound 1, which is crystalline, has an X-ray powder diffraction pattern with specific peaks at 29=8.1, 13.7, 16.4, 2 0.5 and 2 3.7° and an infrared -spectrum (0.5% in KBr) which has sharp peaks at 3 370, 167 0, 152 5, 1490, 1280, 890, 870 and 550 cm"<1>.

Form X can be prepared virtually free of other physical forms through a process which consists of dissolving a supply of compound 1 in hot aqueous acetone, reducing the volume of the resulting solution by evaporation, adding toluene and reducing the volume further by evaporation. If a relatively impure supply of compound 1 is to be used, it may be advantageous for the material to be rubbed out with hot toluene/ethyl acetate before the crystallization step.

Each of the forms A, B and X can be easily characterized,

for example through their X-ray powder diffraction pattern or by their infrared pattern.

For this purpose, infrared spectra were recorded here using a 0.5% dispersion of the sample material in a potassium bromide disk over the wavenumber range 4000 to 400 cm 1. Examples of infrared spectra for each of the forms X, A and B are shown in the figures 1, 2 and 3.

X-ray powder diffraction spectra were determined using 2 g of sample material placed in a standard Philips "deep pack" holder and scanned over the range 4-4 0° 28 counting for 4 seconds per point at 0.02° intervals, to produce a curve where distances are plotted against the intensity for this area. Examples of X-ray powder diffraction ion spectra for each of the forms X, A and B are shown in figures 4, 5 and 6.

The melting points of each of the forms A, B and X generally depend on their level of contamination. Form X thus has a typical melting point above 190°C, for example approx. 200°C; form A between 115°C and 140°C, for example approx. 124-132°C, and form B approx. 140-160°C, for example from 145 to 155°C. Form B has been shown to lose water at temperatures from approx. 60°C and has no sharp melting point.

As indicated above, form A has sufficient stability in preparations according to the invention. Under conditions of high relative humidity and higher temperatures, however, conversion of form A to form B has been shown to occur. Under certain circumstances, it may be desirable to store pharmaceutical preparations containing Form A in the presence of a suitable desiccant, such as silica gel. It may also be desirable to keep them in an airtight container, such as a foil pack.

The dose of compound 1 that is administered to a patient through a preparation according to the invention will depend on the degree of the disorder and on the patient's age and size. In general, the compound will be administered in a dose ranging from 0.1 to 10.0 mg/kg, for example from 0.2 to 5 mg/kg.

Acute toxicity studies of compound 1 to obtain LD5Q values have been carried out. In experiments on mice and rats, it has been found, for example, that the LD5Q value for compound 1 is >500 mg/kg.

(Reference) example 1

Preparation of form A

a) Preparation of an impure supply of compound 1

Methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)benzoate

(prepared as described in Example 4 of EP-A2-0199543) was converted to the free acid by treatment with aqueous sodium hydroxide. The free acid was then converted to the acid chloride by treatment with thionyl chloride in dichloromethane. The acid chloride was then reacted with o-toluenesulfonamide in dichloromethane in the presence of 2.2 equivalents of 4-dimethylaminopyridine to give the dimethylaminopyridine salt of 4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxy-benzoyl-2-methylbenzenesulfonamide .

A solution of the dimethylaminopyridine salt of 4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoyl-2-methylbenzenesulfonamide

(30 g) in 2-methoxyethanol (130 mL) and concentrated sodium hydroxide solution (3.2 mL) was placed in a nitrogen-purged flask containing 10% palladium on charcoal (3.3 g of a 60.9% watery pasta). The mixture was then stirred under a hydrogen atmosphere at a pressure of 3 bar for 2.5 hours. The mixture was then filtered through diatomaceous earth and washed with 2-methoxyethanol (37.5 mL).

Cyclopentyl chloroformate (9.2 mL) was added to the combined washings, and the mixture was allowed to stir under nitrogen overnight. The temperature was then adjusted to 30-33°C, whereupon 0.8M hydrochloric acid (68 mL) was added over 20 minutes with vigorous stirring. The mixture was then cooled to 15-20°C and stirred for 1 hour. The crude crystalline product was then filtered off, washed with water and dried at 50°C. It was then used in the next step.

b) Rubbing of impure compound 1

60 g (0.101 gmol) of the product from step a), toluene 240 ml (4

volumes) and ethyl acetate 150 ml (2.5 volumes) were slowly heated to the boiling point and 30 ml (0.5 volumes) of distillate collected to remove most of the liberated water. The mixture was refluxed for 1 hour (88-90°C) and then cooled to 10-15°C. After stirring for 3 hours at 10-15°C, the solid was filtered through glass sinter and washed with a 2:1 mixture of toluene (80 mL) and ethyl acetate (40 mL). The product was then dried to constant weight on the sinter filter to give 53.2 g of dry compound 1 (yield 91.5%)

c) Production of Form B

30.0 g of the product from step b), 210 ml of acetone and 12 ml of water

was placed in a 500 ml reaction flask. The mixture was then boiled under reflux for 15 minutes, whereupon at 45-50°C it was passed through a layer of diatomaceous earth on a glass sinter directly into a 500 ml reaction flask. The flask and sintered filter were washed with a mixture of acetone (60 mL) and water (3 mL). The combined liquids were then stirred in a water bath at approx. 40°C, during which water (120 ml) was added over 5 minutes.

The mixture first separated an oil, but then rapidly crystallized. The mixture was then cooled to 20°C over 1 hour, stirred for 2 hours at 15-20°C and then filtered. The product was washed with water (60 ml), dried as far as possible on the sinter filter and then dried in an air oven at 60°C (max.). The yield of Form B was 30.0 g (97%).

d) Production of Form A

The product from step c) (15.0 g) was placed in a 500 ml

round bottom flask which was then evacuated on a rotary evaporator to 20 mbar. The flask with contents was then immersed in an oil bath which had previously been heated to 118°C, and slowly rotated at this temperature for 6 hours. After cooling, the mass was crushed to give Form A as a white powder.

For large-scale production, Form A can be prepared as follows: 30 kg of the product from step c) is spread evenly over metal trays and heated to 120°C under vacuum in a 7m 2 vacuum oven for up to 24 hours. The pressure is usually approx. 20 mbara. After cooling (to 40°C or lower), the material is taken out of the oven and ground to give the desired shape A.

If desired, form A can be finely ground before use.

Production of Form X

The product from step b) (30.0 g, 0.0521 gmol) was dissolved in acetone (150 mL) and water (4.7 mL) by gently heating to boiling, after which the solution was passed through a sintered glass funnel. The filtrate was heated to the boiling point and 90 ml of distillate collected. The toluene (120 mL) was added and a further 75 mL of distillate collected. More toluene (120 mL) was added and another 75 mL of distillate collected. After boiling for an additional 1 hour under reflux, the mixture was cooled to 15-20°C and the product collected and washed with toluene (2 x 30 mL). The yield after drying on the sintered glass funnel was 29.5 g (98.3%).

(Reference) example 2

Alternative production of Form A

Form B (which can be obtained as described in Example 1) was dissolved in aqueous acetone to give an 8% by weight solution of compound 1 in 6% by weight aqueous acetone. This solution was then spray dried using a Niro Laboratory Minor spray dryer (from A/S Niro Atomizer, Gladsaxevej 3 05, DK-2860, Soeborg, Denmark). The solution was nebulized at a flow rate of 2 kg/hr with nitrogen under a flow rate of 6.6 kg/hr using a dual nozzle nebulizer. The drying gas used was nitrogen with a flow rate of 70 kg/hour with inlet/outlet temperatures of 215/120°C respectively. The produced Form A was collected on a bag filter.

Example 3

The components of the granulation material were wet granulated. The granules were then dried and ground. The dried, ground granules were then mixed with the other ingredients for the final mixture and pressed into tablets.

The weight percent of Form B occurring, based on the weight of Compound 1 occurring, was determined by X-ray analysis. For the 20 mg tablet, it was found to be <8%. For the 50 mg tablet, more sensitive X-ray methods were used. Weight percentage of Form B before formulation was determined to be 3% and after formulation to <3.2%. Note: In each of these examples, the polyvinylpyrrolidone used had a K value of 29-32. It is believed that any pharmaceutical grade polyvinylpyrrolidone, for example with a K value in the range of 10-100, will be suitable.

Example 4

Short-term stability test

Tablets prepared according to the procedure in Example 3 and containing 20 mg of form A were stored under different conditions for 1, 2 and 3 months. The tablets were then examined by X-ray diffraction to determine how much of the active ingredient had been converted to form B. The results are summarized in Table 1 below.

The tablets stored at room temperature and at 50°C were in white HD polyethylene bottles with metal caps. The tablets stored at 80% RH were exposed to air.

Connection example 1

The components for the granulation material were wet granulated. The granules were then dried and ground. The dried ground granules were then mixed with the other ingredients in the final mixture and pressed into tablets.

The percentage of compound 1 present as form B was determined by X-ray analysis before and after granulation. Before granulation, <1.5% of compound 1 was found to occur as form B. However, after granulation, 28% of compound 1 was found to be form B.

These results clearly show the improved stability of form A in preparations according to the invention.

Example 5

Size 0 gelatin capsule

Mix the active ingredient, polyvinylpyrrolidone, lactose and microcrystalline cellulose in a suitable mixer. Mix with purified water to a suitable consistency, dry and pass through a suitable mill. Mix with colloidal silicon dioxide and magnesium stearate. Place in two-piece size 0 gelatin capsules.

Prepare a 10% dispersion of the polyvinylpyrrolidone in purified water. Add the active ingredient and mix until uniform dispersion. Spray the mixture onto the granulated sugar using suitable equipment. The beads can be filled onto two-part capsules of size 1 or poured into a suitable bag.

Mix the active substance, polyvinylpyrrolidone and mannitol in a suitable mixer. Mix to a suitable consistency with purified water, dry and pass through a suitable sieve.

Comparative example 2

Comparison of the bioavailability of compound 1 in <p>re<p>arates prepared from form A with and without polyvinylpyrrolidone

24 healthy male subjects were randomly assigned to treatment groups. One treatment consisted of a single 50 mg tablet prepared as described in Example 3, and another in a single 50 mg tablet prepared as described in Comparative Example 1. During the course of the study, each subject received both preparations. During each treatment period, blood samples were periodically taken to determine the concentration of compound 1.

These results clearly demonstrate the improved bioavailability of compound 1 in preparations according to the invention.

Comparative example 3

Comparison of the bioavailability of compound 1 in preparations made with polyvinylpyrrolidone and forms A, B and X

Tablets containing 20 mg of Form A, Form B or Form X were prepared according to the following recipe.

Using a balanced cross-over design, each of 8 dogs received each of the three tablet forms. During the experimental period, blood samples were periodically taken from each animal and the concentration of compound 1 determined. The results are summarized below.

The results clearly show the superior bioavailability in preparations according to the invention, compared to preparations containing form B or form X.

Claims (6)

1. Pharmaceutical preparation, characterized in that it contains as active ingredient, a physical form of the compound N-[4-[5-(cyclopentyloxy-carbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide which is approximately free of other physical forms to such an extent that at least 90% by weight of said compound is in this physical form, and where the physical form has an infrared spectrum (0.5% in KBr) with sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm"<1>, and polyvinylpyrrolidone and a pharmaceutically acceptable carrier. 2. Preparation according to claim 1, characterized in that the active substance occurs in an amount of from 1 to 90% by weight, calculated on the basis of the total weight of the preparation. 3. Preparation according to claim 1 or 2, characterized in that the polyvinylpyrrolidone occurs in an amount of from 1 to 20% by weight, calculated on the basis of the total weight of the preparation. 4. Preparation according to claims 1 to 3, characterized in that the pharmaceutically acceptable carrier is selected from mannitol, lactose, sorbitol, glucose, sucrose, dextrose, fructose, xylitol, microcrystalline cellulose, powdered cellulose and hydroxymethyl cellulose. 5. Preparation according to claims 1 to 4, characterized in that it also comprises a production aid selected from croscarmellose sodium, sodium starch glycolate, starch, magnesium stearate, stearic acid, talc and powdered vegetable stearin. 6. Preparation according to claims 1 to 5, characterized in that it has the form of a tablet.