WO2021229278A1

WO2021229278A1 - Concentrated liquid non-steroidal antiandrogen solution and method for preparing the solution

Info

Publication number: WO2021229278A1
Application number: PCT/IB2020/055416
Authority: WO
Inventors: Andres GOLD
Original assignee: Novocap S.A; BAENA AGUDELO, Monica
Priority date: 2020-05-13
Filing date: 2020-06-09
Publication date: 2021-11-18
Also published as: AR118925A1

Abstract

Disclosed is a concentrated liquid non-steroidal antiandrogen solution, containing 80-140 mg enzalutamide or apalutamide per gram of solution, which comprises copovidone and caprylocaproyl polyoxylglycerides as excipients. Also provided is a production method wherein a mixture of copovidone and caprylocaproyl polyoxylglycerides is prepared, then a non-steroidal antiandrogen is added to the mixture, maintaining stirring at 100°C or more until a solution is formed.

Description

CONCENTRATED LIQUID SOLUTION OF NON-STEROID ANTIANDROGENS AND PROCEDURE TO PREPARE THE SOLUTION.

The present invention relates to a concentrated liquid solution of non-steroidal antiandrogens and a process for obtaining it. More specifically the solution comprises a non-steroidal antriandrogen selected from enzalutamide and apalutamide, and comprises copovidone and caprylocaproyl polyoxylglycerides as excipients. The solution of the present invention is suitable for filling capsules for oral administration.

BACKGROUND OF THE INVENTION.

Nonsteroidal antiandrogens are used as drugs to treat prostate cancer. These include enzalutamide and apalutamide.

Enzalutamide and apalutamide are substances that act through an antagonistic effect on cellular androgen receptors, that is, they have an anti-androgenic effect by blocking the action of the male sex hormone. Its use was authorized by the US FDA and later by the European Medicines Agency.

The physicochemical characteristics and structure of enzalutamide and apalutamide are very similar.

The IUPAC name of enzalutamide is 4- (3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl) -2-fluoro-N- methylbenzamide.

The IUPAC name of apalutamide is (4- [7- (6-cyano-5-trifluoromethylpyridin-3-yl) -8-oxo6-thioxo-5,7-diazaspiro [3.4] oct-5 yl] -2-fluoro- N-methylbenzamide).

Enzalutamide and apalutamide have very low solubility in water, the products currently on the market use formulations designed to increase the solubility of the active principle and thus allow a sufficient level of bioavailability.

Currently, in several countries around the world, a product containing enzalutamide as an active ingredient is marketed under the Xtandi brand. Xtandi is available as soft capsules containing 40 mg of enzalutamide and also as coated tablets containing 80 mg of enzalutamide. The daily dose of enzalutamide is 160 mg in a single dose, therefore treatment with Xtandi requires the patient to take 4 capsules of 40 mg or 2 tablets of 80 mg, per day.

Xtandi 40 mg softgels contain a liquid solution of enzalutamide in approximately 906 mg of solvent. In this way, each Xtandi capsule It contains 40 mg of enzalutamide dissolved in approximately 946 mg of solution, the concentration being 42.3 mg of enzalutamide for each gram of solution. On the other hand, Xtandi 80 mg tablets are formulated as tablets containing a solid dispersion of enzalutamide in the polymer hypromellose acetate succinate (HPMCAS).

A product containing apalutamide as an active ingredient is marketed under the Erieada brand. Erieada is presented as coated tablets containing 60 mg of apalutamide. The daily dose of apalutamide is 240 mg in a single dose, therefore treatment with Erieada requires the patient to take 4 tablets per day. Erieada tablets contain a solid dispersion of apalutamide in HPMCAS.

For both enzalutamide and apalutamide, the solid dispersion in HPMCAS must be manufactured by the high-temperature extrusion process, a method known as "hot-melt extrusion, or by solvent evaporation, a method known as" spray drying. " These production methods are expensive and require the use of specific equipment. Additionally, for the active principle to remain in an amorphous state in the solid dispersion, a significant amount of HPMCAS must be used in relation to the amount of active principle. Thus tablets containing a solid dispersion are bulky.

Methods for producing a solid dispersion of enzalutamide are described in WO 2014/043208. These methods involve the use of flammable organic solvents such as acetone or the high temperature extrusion procedure (See Example 11 of the aforementioned document, hot melt extrusion procedure).

In the application WO 2016 / 090098A1 (Aragón Pharmaceuticals) solid dispersion compositions of apalutamide (RNA-509) in the HPMCAS polymer are disclosed using the spray drying method with solvents such as acetone, and also the hot melt extrusion method. In patent document WO 2019/008426 a method is described for producing an enzalutamide granulate where, prior to granulation, the enzalutamide is dissolved in an organic solvent.

Patent document WO 2019/155416 refers to a process for micronizing enzalutamide from wet milling (nanosuspension). Once ground, it is dried and encapsulated.

All the procedures mentioned in the previous paragraphs are complex, require specialized high-cost equipment and in some cases use dangerous substances such as organic solvents.

Patent document WO 2018/037310 describes an enzalutamide solution for oral administration based on Labrasol (caprylocaproyl polyoxylglycerides), polyethylene glycol and other excipients. The examples presented in the document correspond to diluted solutions containing 160 mg in 5 ml (equivalent to 32 mg / g concentration). There is no indication of how to increase the concentration of enzalutamide in this solution.

Patent document WO 2015/022349 Al (Hans Jurgen MIKA et al.) Describes formulations containing a concentrated liquid solution of enzalutamide using two solvents. In this patent application several formulations are taught that reach a maximum concentration of 82 mg of enzalutamide per gram of solution. These formulations contain diethylene glycol monoethyl ether (also known as 2- (2-ethoxyethoxy) ethanol or by its trademark, Transcutol) as a solvent. The amount of Transcutol used to dissolve enzalutamide is 730 mg per capsule, equivalent to 73% of the weight of the solution. This high amount of Transcutol represents a serious problem since diethylene glycol monoethyl ether is a very strong solvent and its use as an excipient in formulations for oral administration is not approved by the FDA. On the other hand, Transcutol has a flash point of 96 ° C. In this way, the compositions containing Transcutol cannot be processed at high temperatures since the vapors that are generated represent a high risk of flammability. Due to the extremely low water solubility of enzalutamide and apalutamide, their absorption from the oral route is very low. In order to be administered orally, it is necessary to use a formulation that increases the solubility of the active principle. A viable alternative to guarantee oral absorption is to administer the active ingredients formulated as a solution, or as capsules containing a solution.

It is necessary to have a method that allows the production of a concentrated solution of enzalutamide or apalutamide that uses excipients approved for oral use and that can be produced simply and quickly, without risks to the safety of workers.

BRIEF DESCRIPTION OF THE INVENTION

A concentrated liquid solution of non-steroidal antiandrogens is provided comprising between 80 mg and 140 mg of enzalutamide or apalutamide per gram of solution, between 70 mg and 160 mg of copovidone per gram of solution, and between 700 mg and 850 mg of polyoxylglycerides. of caprylocaproil per gram of solution.

A process is provided to prepare the concentrated liquid solution comprising the following steps:

(a) prepare a mixture of copovidone and caprylocaproyl polyoxylglycerides, the amount of copovidone being between 70 mg and 160 mg per gram and the amount of caprylocaproyl polyoxylglycerides between 700 mg and 850 mg per gram,

(b) add to the mixture a non-steroidal antriandrogen keeping the stirring and the temperature at 100 ° C or higher. The nonsteroidal antriandrogen can be enzalutamide or apalutamide.

The use of the solution is provided for preparing a medicament in the form of a soft capsule or a rigid capsule for oral administration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a concentrated liquid solution of non-steroidal antiandrogens, for example, of active principles such as enzalutamide or apalutamide, suitable for producing capsules for oral administration of high dose and reduced size. The liquid solution of the present invention makes it possible to reach a concentration of up to 140 mg of active principle for each gram of solution.

The procedure consists of dispersing the active principle in a mixture of copovidone and caprylocaproyl polyoxylglycerides and shaking the dispersion while maintaining temperature control, the critical parameters being: (a) the amount of copovidone and caprylocaproyl polyoxylglycerides and (b) the temperature to which the solution is prepared.

A process has been developed that allows enzalutamide or apalutamide to be dispersed in a mixture of copovidone and caprylocaproyl polyoxylglycerides, the preferred amount of copovidone being between 70 mg and 160 mg per gram and the preferred amount of caprylocaproyl polyoxylglycerides between 700 mg and 850 mg per gram, after heating the dispersion applying a temperature of 100 ° C or more, a stable concentrated liquid solution is formed, which does not recrystallize even after cooling the solution. It can also be expressed as a ratio between the amount of copovidone and the amount of caprylocaproyl polyoxylglycerides, the minimum ratio being approximately 8.2% (corresponding to 70 mg / 850mg) and the maximum ratio being approximately 22.8% (corresponding at 160mg / 700mg).

The solution of the present invention has a viscosity that allows filling in conventional capsule filling machines. For a liquid solution to be filled into capsules using conventional machines it must have a viscosity between 50 and 5000 centipoise (cP), ideally between 100 and 2500 cP. Liquids with viscosity less than 100 cP increase the risk of leakage and liquids with viscosity greater than 2500 cP do not allow capsule filling equipment to operate at high speed. The solution of the present invention can be heated to reduce its viscosity and allow the capsules to be filled at a higher machine speed. It is important to note that hard gelatin capsules allow filling liquids with a temperature of up to 70 ° C, temperatures higher at the time of filling can cause deformations in the capsules and, therefore, are not recommended.

When we refer to capsules, we mean any conventional capsule suitable for oral administration, either soft capsule or hard capsule, both gelatin, hypromellose or pullulan. By "copovidone" we mean the copolymer of vinylpyrrolidone and vinyl acetate in a ratio of 60:40, also known as copolymer or PVP / VA copolymer. It is a yellowish-white powder that is marketed under the brand names Kollidon VA64 (manufactured by BASF, Germany) and Plasdone S630 (manufactured by Ashland, USA).

By "caprylocaproyl polyoxylglycerides" we mean a substance that is liquid at room temperature mainly composed of monoesters and diesters of caprylic acid and capric acid with polyethylene glycol. The substance is known by the following names (synonyms): caprylic / capric glycerides of PEG-8, caprylocaproyl polyoxyl-8 glycerides and caprylocaproyl macrogol-8 glycerides. It is marketed under the brand names Labrasol (manufactured by Gattefosse, France) and Acconon MC8-2 (manufactured by Abitec, United States).

This invention is best illustrated by the following examples, which should not be construed as limiting the scope thereof. On the contrary, it should be clearly understood that other embodiments, modifications and equivalents thereof may be resorted to, which after reading the present description, may suggest to those skilled in the art without departing from the spirit of the present invention and / or scope of the annexed claims.

Examples

Example 1: Evaluation of the preparation temperature

A test was designed to know the effect of temperature in the preparation of the enzalutamide solution. 4 tests were prepared using 1.60 grams of enzalutamide and 18.40 g of excipients to form 20.00 g of solution with a concentration of 80 mg of enzalutamide for each gram of solution. The amount of copovidone was 120 mg / g and the amount of caprylocaproyl polyoxylglycerides was 800 mg / g. The only factor that was changed in each test was the temperature at which the dispersion was maintained during the stirring time.

The following materials were used: enzalutamide (Laurus Labs.), Kollidon VA64 brand copovidone (BASF) and Acconon MC8-2 brand caprylocaproyl polyoxylglycerides (Abitec). Preparation procedure: Kollidon VA64 was incorporated into Acconon MC8-2 and stirred for 10 minutes at the temperature indicated in each test. Then, enzalutamide was added to the mixture and it was kept stirring for 24 hours at the indicated temperature.

Table 1. Evaluation of the preparation temperature

By using a preparation temperature of 100 ° C or higher, it was possible to form a concentrated solution containing 80 mg of enzalutamide for each gram of solution. Making the solution at 115 ° C reduced the stirring time required to form a solution by about half. With the solution of Example 1-C, 30 rigid gelatin capsules were manually filled, at a rate of 500 mg of solution per capsule. Capsugel brand capsules model Coni-Snap size 0 were used. The capsules were manually sealed with a gelatin band and packed in 2 high-density polyethylene bottles with screw caps. One bottle was kept at room temperature and the other was kept in a refrigerator at a temperature of 5 ° C. After 30 days it was verified that all the capsules remained in perfect condition, flexible, without cracks or loss of content, and that the enzalutamide remained in solution without precipitates, even in the capsules kept in the refrigerator.

Example 2: Evaluation of the amount of copovidone

A test was designed to know the effect of the amount of copovidone in the preparation of the enzalutamide solution. In each example 2 grams of enzalutamide and 18 g of excipients were used to form 20 g of solution with an enzalutamide concentration of 100 mg / g. Increasing amounts of copovidone were tested from 0 mg / g to 257 mg / g.

The following materials were used: enzalutamide (Laurus Labs.), Kollidon VA64 brand copovidone (BASF) and Acconon MC8-2 brand caprylocaproyl polyoxylglycerides (Abitec).

Manufacturing procedure: Kollidon VA64 was incorporated into Acconon MC8-2 and stirred for 10 minutes. The set amount of enzalutamide was added to the mixture and stirred at 115 ° C for an additional 40 minutes.

Table 2. Evaluation of the amount of copovidone

In Examples 2-B and 2-C a solution with the desired characteristics was obtained with an enzalutamide concentration of 100 mg / g. The amount of copovidone used in these examples was 70 mg / g and 160 mg / g. Caprylocaproyl polyoxylglycerides accounted for 830 mg / g and 740 mg / g, respectively. Example 2-C had a high viscosity at room temperature, however, heating the solution to a temperature between 30 ° C and 40 ° C reduced the viscosity allowing adequate encapsulation.

Example 3: Evaluation of Enzalutamide concentration

Four tests were designed to verify the characteristics of the solution when increasing the concentration of enzalutamide. The following enzalutamide concentrations were tested: 120 mg / g, 130 mg / g, 140 mg / g, and 150 mg / g. In the 4 tests, a constant relationship between copovidone and caprylocaproyl polyoxylglycerides was maintained, the amount of copovidone being 16.3% of the weight of caprylocaproyl polyoxylglycerides.

The following materials were used: enzalutamide (Laurus Labs.), Kollidon VA64 brand copovidone (BASF) and Acconon MC8-2 brand caprylocaproyl polyoxylglycerides (Abitec). Manufacturing procedure: Acconon MC8-2 and Kollidon VA64 were mixed and stirred for 10 minutes. The set amount of enzalutamide was added to the mixture and it was stirred at 115 ° C for an additional 40 minutes.

Table 3. Evaluation of the concentration of enzalutamide

In Examples 3-A, 3-B and 3-C, a solution with the desired characteristics was obtained. The maximum concentration obtained was 140 mg of enzalutamide for each gram of solution.

Example 4. Preparation of the concentrated solution

Using the same elaboration procedure of Example 3, the following formulas were tested in order to verify the maximum and minimum amounts of copovidone and caprylocaproyl polyoxylglycerides.

In all cases, transparent solutions suitable for encapsulation were obtained.

Example 5: Preparation of concentrated enzalutamide solution and filling of capsules

A 8.402 kg batch of solution was produced containing 800 g of enzalutamide (equivalent to 95.2 mg / g). A temperature controlled stainless steel reactor with a process capacity of up to 15 liters was used. In order to improve the stability of the active principle, antioxidants were added.

Table 4. Solution batch. Scaling up

Manufacturing procedure: Kollidon VA64 was incorporated into Acconon MC8-2 and stirred for 10 minutes at a temperature of about 115 ° C. The set amount of enzalutamide was added to the mixture and stirred for an additional 20 minutes maintaining a temperature of around 115 ° C. Total preparation time 30 minutes. It was allowed to cool to room temperature and it was verified that the appearance is that of a colorless or slightly yellow transparent solution, free of suspended particles.

Encapsulation Procedure: The obtained solution was heated to a temperature of around 30 ° C to reduce the viscosity and allow a higher encapsulation speed. Approximately 9900 hard gelatin capsules size No. 00 were filled with 840.20 mg of solution each (equivalent to 80 mg of enzalutamide per capsule). A Dott brand encapsulator was used. Bonapace In-Cap 3000 model equipped with liquid dispenser. The capsules were kept in stainless steel trays and checked for leaks. The capsules were then sealed by applying a colorless gelatin band to the junction of the body and the cap. A Dott brand machine was used for sealing. Bonapace model BD-3000. The sealed capsules were packed in aluminum / aluminum strips.

Table 5. Quality control of the capsules

Example 6: Accelerated stability study

The capsules packed in aluminum / aluminum strips obtained in Example 4 were subjected to a 6-month stability study under conditions of 40 ° C temperature and 75% relative humidity.

Table 6. Accelerated stability study results

Example 7: Preparation of the concentrated apalutamide solution

A 2.5 kg batch of solution was produced containing 350 g apalutamide (equivalent to 140 mg / g). A temperature-controlled stainless steel reactor with a process capacity of up to 5 liters was used. The amount of copovidone used was equivalent to 13% by weight of caprylocaproyl polyoxylglycerides (98.91 mg / g of copovidone and 760.86 mg / g of caprylocaproyl polyoxylglycerides).

Table 7.

Manufacturing procedure: Kollidon VA64 was incorporated into Acconon MC8-2 and stirred for 10 minutes at a temperature of about 100 ° C. The set amount of apalutamide was added to the mixture and stirred for an additional 20 minutes maintaining a temperature of about 100 ° C. Total preparation time 25 minutes. It was allowed to cool to room temperature and it was verified that the appearance is that of a colorless or slightly yellow transparent solution, free of suspended particles.

Encapsulation Procedure: The solution obtained can be encapsulated at room temperature. Approximately 2800 size Nr. 00 rigid gelatin capsules are filled with 857.14 mg of solution each (equivalent to 120 mg apalutamide per capsule) using the same encapsulation and sealing procedure of Example

Four.

The capsules were packed in plastic screw cap PVC containers without desiccant. After 3 months at room temperature, the capsules were in perfect condition with no cracks or liquid leaks. The apalutamide solution remained without color changes or the appearance of precipitated crystals.

The process of the present invention allows to produce quickly and simply, without using organic solvents or specialized high-cost equipment, High concentration liquid solutions of enzalutamide or apalutamide useful for producing capsules with liquid content with high doses of active ingredient.

The examples presented include the detailed description of the invention and the preferred embodiments. The descriptions and examples are included for illustrative purposes and are not intended to limit the scope of the invention, which is limited only by the following claims.

Claims

CLAIMS Having thus specially described and determined the nature of the present invention and the way in which it is to be carried out, it is declared to claim as property and exclusive right:

1. Concentrated liquid solution of a non-steroidal antiandrogen, characterized in that it comprises between 80 mg / g and 140 mg / g of the non-steroidal antiandrogen, between 70 mg / g and 160 mg / g of copovidone, between 700 mg / g and 850 mg / g of caprylocaproyl polyoxylglycerides and optionally other pharmaceutical excipients, wherein the non-steroidal antiandrogen is selected from the group consisting of enzalutamide and apalutamide.

2. The solution according to claim 1, characterized in that it comprises butylhydroxyanisole and butylhydroxytoluene as antioxidant excipients.

3. The solution according to claim 1, characterized in that when the non-steroidal anti-androgen is enzalutamide, the solution comprises between 90 mg / g and 100 mg / g of said non-steroidal anti-androgen.

4. The solution according to claim 1, characterized in that when the non-steroidal anti-androgen is apalutamide, the solution comprises between 130 mg / g and 140 mg / g of said non-steroidal anti-androgen.

5. A process for preparing the concentrated liquid solution of claim 1, characterized in that it comprises the following steps:

(a) preparing a mixture of copovidone and caprylocaproyl polyoxylglycerides, and

(b) add to the mixture a non-steroidal antriandrogen maintaining stirring at a temperature of 100 ° C or more, until a solution is formed.

6. The process according to claim 5, characterized in that the temperature is approximately 115 ° C.

The use of the solution of claim 1 to prepare a medicament in the form of capsules with liquid content comprising 80 mg of enzalutamide per capsule.

The use of the solution of claim 1 to prepare a medicament in the form of capsules with liquid content comprising 120 mg apalutamide per capsule.