WO2004062692A1

WO2004062692A1 - Formulation of poorly water-soluble active substances

Info

Publication number: WO2004062692A1
Application number: PCT/EP2004/050012
Authority: WO
Inventors: Maria A.E. Van Der Heijden-Van Beek
Original assignee: Solvay Pharmaceuticals B.V.
Priority date: 2003-01-13
Filing date: 2004-01-12
Publication date: 2004-07-29

Abstract

The present invention relates to a formulation with enhanced bio-availability consisting of a thermodynamically stable liquid or semisolid solution of the poorly water-soluble biologically active substance of the general formula wherein: R1 is a selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a (C1-C6)alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1 C6)-alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 is a biolabile ester forming group; or a pharmaceutically acceptable salt thereof; characterised in that said formulation is consisting of a) said substance or a pharmaceutically acceptable salt thereof in an amount of up to 50% of the total weight of the formulation, and b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said non-ionic hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16 . The invention further relates to a method for the preparation of said formulation and the use thereof in the prevention and/or treatment of diseases.

Description

Formulation of poorly water-soluble active substances.

The present invention relates to formulations of benzazepin -, benzoxazepin- and benzothiazepin- N -acetic acid compounds, a method for the preparation of said formulations and the use thereof in the prevention and/or treatment of diseases

The above mentioned compounds are known from EP 0733642, EP 0830863,

WO00/48601 an WO01/03699

EP 0733642 is related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency EP 0830863, WO00/48601 and WO01/03699 are related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages indu ced by adπamycin and comparable anti-cancer drugs, respectively

The above mentioned active substances have a poor bio-availability due to the poor solubility in the gastric fluid Even when these substances are applied in the form of a salt and when they are solved in a buffer, they precipitate in the gastric fluid The precipitate formed is very difficult to solubilize again, leading to a low overall bioavai bility

The problem of poor solubility and poor bioavailability is known for a large number of active substances In order to solve this problem several methods were developed, such as micronization, inclusion in cyclodextnnes, the use of inert water-soluble carriers, the use of self -emulsifying mixtures of (digestible) oil and surfactant wherein the oil is the main solvent for the active ingredient (EP0517412, US 6,096,338), the use of solid dispersions (WO 00/00179), or nanocrystalline or amorphous forms of an active substance The effect of the above mentioned methods on the bio -availability often depends on the properties of the active substance involved Further the dosage forms developed until now have often drawbacks, such as poor thermodynamic stability, critical or difficult production processes or poor batch-to-batch reproducibi ty Moreover these methods are often not applicable for the improvement of the bioavaihbility of benzazepin-, benzoxazepin- and benzothiazepin- N-acetic acid compounds, as said compounds, even when they have been formulated in a sophisticated way, often precipitate in the gastric fluid due to the presence of a carboxy group It is the objective of the present invention to provide a formulation for the poorly soluble benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid compounds mentioned above, with a significant increase in bio-availability compared with said active substance in a traditionally formulated form. It is a further objective of the present invention to provide a formulation which does not precipitate in the gastric fluid and which can be prepared using normal formulation procedures and equipment, so that no large investments are necessary.

These objectives can be achieved, according to the present invention, by a formulation with enhanced bio-availability consisting of a thermodynamically stable liquid or semisolid solution of the poorly water-soluble biologically active substance of the general formula

(i) wherein:

Ri is a selected from the group consisting of (C₁-C₆)alkoxy(C₁-C₆)alkyl which may be substituted by a (CrC_B)alkoxy, phenyl-(C C₆)-alkyl and phenyloxy-(C_r

C₆)-alkyl wherein the phenylgroup may be substituted with (C ι-C₆)alkyl, (CrC₆)- alkoxy or halogen, and naphtyl-(C_rC₆)-alkyl, R₂ and R₃ are both independently hydrogen or halogen,

R₄ is a biolabile ester forming group; or a pharmaceutically acceptable salt thereof; characterised in that said formulation is consisting of a) said substance or a pharmaceutically acceptable salt thereof in an amount of up to 20% of the total weight of the formulation, and b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30 °C, selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said non -ionic hydrophilic surfactants having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16. Preferred pharmaceutically active salts of the active substances according to the present invention are bivalent metal salts. Even more preferred are calcium salts.

The most preferred active substances according to the present invention are 3-[1-{2'- (ethoxycarbonyl)}-4'-phenylbutyl]cyclopentan-1-carbonylamino]-2,3,4,5-tetrahydro-2- oxo-1 H-1 -benzazepin -1 -acetic acid, preferably in its 3S,2'R form and 3-[1-{2'- (ethoxycarbonyl)}-4'-naphtylbutyl]cyclopentan-1-carbonylamino]-2,3,4,5-tetrahydro-2- oxo-1 H-1 -benzazepin-1 -acetic acid, also preferably in its 3S,2'R form.

The following definitions are provided to facilitate understanding of certain terms used within the framework of the present application.

Thermodynamically stable refers to the absence of significant physical or chemical changes of the product that might affect the quality of the product during storage . With poorly water-soluble is meant that the aqueous solubility of the active substance is less than 1 in 1000. This means that according to the pharmacopoeial definitions substances that are categorised as "very slightly soluble", "practically insoluble" and "insoluble" are included in this definition (USP 24/NF 19 (Jan 10, 2000), page 10) The term non-ionic hydrophilic surfactant refers to those amphiphilic substances that are soluble in water (they have higher HLB values), posses surface activity and are not ionised in aqueous solutions (H. Auterhoff, Worterbuch der Pharmazie, Wissenschafliche Verlagsgesellschaft GmbH, Stuttgart 1981 , 192) With HLB value is meant a value on a scale from 0 to 20, that is assigned to each surfactant based on the relative proportions of the hydrophilic and hydrophobic part of the molecule. Oil soluble surfactants have low HLB values, whereas water soluble surfactants have higher HLB values. The HLB value is calculated as:

HLB = 20(1 -M_o/M) In which M is the molecular weight of the molecule and M₀ is the molecular weight of the hydrophobic part of the molecule. The term semi-solid means a system that behaves as a solid material at ambient conditions, but will change to a system that behaves as a liquid due to a change in the physical conditions of the system, e.g. the application of stress on the material or a rise in temperature. Semi-solids, just as normal solids, retain their shape as long as no outside forces are applied, but unlike normal solids they are easily deformed on application of outside forces. In the framework of the present invention the term semi -solid is related to the mixture of the active substance and the the non -ionic hydrophilic surfactant ingredient, as this mixture may be liquid but often is in a semi -solid form.

With the term derived from a thermodynamically stable liquid or semi-solid solution is meant that the formulation no longer comprises the stable liquid or semi -solid solution in its original state, but that due to further steps, e.g. absorption on a carrier or dissolution in a diluent, the original liquid or semi -solid solution state is lost.

The non-ionic hydrophilic surfactant ingredient is selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said surfactants having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16. Polyoxyethylene glycol polysorbates are commercially available from ICI Inc., and are known under the trademark Tween®. For the present invention Tween® 80 i s preferred. Non hydrogenated polyoxyethylene castor oil derivatives are commercially available from the BASF Corporation under the trademark Cremophor®. The most preferred compound for the present invention is Cremophor® EL.

It has surprisingly been found that the above combination of active substances and non-ionic hydrophilic surfactant leads to a very stable formulation at a low ratio between the non-ionic hydrophilic surfactant and the active substance, compared with the prior art. The formulation also has a high solubility in gastro -intestinal fluids, remaining soluble even in the highly acidic gastric environment, and a high bioavailibility. The ratio between the active substance in the formulation and the non -ionic hydrophilic surfactant is between 1 : 1 and 1 : 8 by weight, preferably between 1 : 3 and 1 : 6 and most preferred is 1 : 5.

The active substance can be used in an amount between about 0.01 and 50% by weight, more preferably in an amount between 0.1 and 30% by weight, even more preferably in an amount between 1 and 25% and most preferred in an amount between about 10 and 25% of the total weight of the formulation .

The active substance may be formulated in its acid form or in the form of a pharmaceutically acceptable salt. Bivalent metal salts such as magnesium, calcium, zinc or iron salts are preferred. The most preferred salt is a calcium salt. The present invention can be used in two main classes of embodiments. In the first class of embodiments the formulated product in a concentrate d form is filled into a soft or hard gelatin capsule, or, after having been absorbed on a carrier, into a hard gelatin capsule.

In the second class of embodiments the formulation is diluted further with a diluent to form a drop formulation or a drinkable solution.

When necessary both embodiments of the formulation according to the present invention may also comprise auxiliary materials that are needed to obtain a good formulation. Examples of auxiliary materials that can be used are coloring agents, preservatives such as methylparahydroxybenzoate and propylparahydroxybenzoate , a suitable aroma or an artificial sweetener. Examples of suitable coloring agents, aromas and sweeteners are well known in the art.

In the first class of embodiment the formulation may contain, apart from the active substance and the non -ionic hydrophilic surfactant ingredient, a fatty or oily diluent or a mixture of these diluents. Said diluent or mixture of diluents is preferably selected from the group consisting of polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene 600 (PEG 600), Labrasol^R (mixture of caprylocaproyl Macrogol-8 glycerides) oleic acid, peanut oil, sesam oil, soy bean oil, ethyloleate, isopropylmyristate and Miglyol 812. The diluent or mixture of diluents may be used in such art amount that the desired weight of the formulation to fill into the capsule is reached.

When the formulation is absorbed on a carrier the following carriers may be used: Cab-O-Sil, Accurel Powder and Avicel, si licified Avicel, Kollidon CL and all other acceptable pharmaceutical fillers and desintegrants.

The diluent or mixture of diluents used in the second class of embodiments are miscible with water and are suitable for oral purposes. Therefore the diluent or mixture of diluents is preferably selected from the group consisting of ethanol, glycerol, propylene glycol, PEG 200, PEG 400, PEG 600, and water. The most preferred diluent is water. The amount of diluent or mixture of diluents may be used in such an amount that the desired weight of the formulation that is needed for a drinkable or drop formulation is reached. Preferably the amount is between 20% and 98% of the total weight of the formulation. When a drop formulation is required the solution normally wi II be diluted till a preferred final concentration of between 5 and 100 g active substance per liter. For an oral liquid formulation the solution will have a most preferred concentration of between 1 and 50 g active substance per liter.

The present invention is also related to a method of preparing the formulations according to the present invention. In order to prepare the formulation according to the first class of embodiments, a method is used that is characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined above, at between 50-80°C to dissolve the active substance and b) the resulting mixture is optionally mixed with a diluent and/or auxiliary materials. The mixing of the non-ionic hydrophilic surfactant and the active substance preferably takes place at a temperature of between 70 and 75 ^CC, and the resulting mixture is optionally mixed with the diluent at a preferred temperature of between 60 and 80°C. The resulting mixture can be filled into a soft or hard gelatine capsule. When the carrier-absorbed formulation has to be prepared the resulting mixture is first absorbed on the carrier, e.g. by spraying of the mixture on the carrier, followed by filling of the carrier -absorbed formulation into the hard gelatine capsule.

In order to prepare the formulation according to the second class of embodiments, a method is used that is characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined above, at between 50-80°C and b) the resulting mixture is mixed with a diluent and optionally with the auxiliary materials . The mixing and dissolving of the non-ionic hydrophilic surfactant and the active substance preferably takes place at a temperature of between 70 and 75°C, and the resulting mixture is mixed with the diluent at a preferred temperature of between 60 and 80 °C followed by cooling to ambient temperature while stirring. In this way a drinkable solution or a drop formulation is obtained.

The following examples are only intended to further illustrate the invention, in more detail, and therefore these examples are not deemed to restrict the scope of the invention in any way. Example 1. Liquid/semisolid filled capsule

A quantity of a surfactant together with the poorly water soluble active substance is composed. The compositions are given in Table 1 for liquid filled capsules which contain 50 mg active substance. The effect of the amount and the effect of type of surfactant on the release of the active substance from the liquid filled capsule determines the bioavailability of the drug.

Table 1. Composition of liquid formulation in liquid filled capsules (Amounts are expressed in %)

*) (3S,2'R)-3-[1 -{2'-(ethoxycarbonyl)}-4'-phenylbutyl]cyc opentan-1 -carbonylamino]- 2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepin-1 -acetic acid, n.a.: not applicable

Preparation of the formulations.

The non-ionic hydrophilic surfactant, Tween® 80 or Cremophor® EL is heated to a temperature between 60 °C and 70 °C. The active substance is added and dissolved at said temperature. The resulti ng solution is filled into capsule size 1.

Dissolution testing.

Dissolution testing of the liquid/ semi-solid filled capsules is performed in artificial gastro-intestinal fluid of 37 °C using USP II apparatus using a paddle speed of 75 rpm. The dissolution is tested in a sequential range of increasing pH of the medium starting with 400 ml pH 2, prepared from 400 ml 0.01 N hydrochloric acid. One hour after starting the dissolution 15 ml of the medium is withdrawn and the pH of the buffer is changed into pH 4.5 by adding 88.5 ml 0.05 N glacial acetic acid and 211.5 ml 0.05 N sodium acetate solution. After 30 minutes 5 ml of the medium is withdrawn and the pH of the buffer is changed into pH 6.8 by adding 180 ml 0.2 N disodium hydrogen phosphate and 120 ml 0.2 N potassium dihydrogen phosphate. After 2 hours the dissolution test is stopped. The dissolution medium is continuously sampled and the absorption of the samples is detected by UV at two wavelengths, 240 nm and 267 nm using an optical path length of 2 mm.

The concentration of the surfactants in the dissolution medium affects the UV absorption, so the absorption of placebo compositions of the said formulations are simultaneously detected at 240 nm and 267 nm using an optical path length of 2 mm.

The amount of drug substance released from the liquid filled capsules is calculated from equation 1 in which A is the UV absorption, V is the volume of the dissolution

A ^{l %} medium expressed in ml, ' »» is the absorption coefficient of a 1 % w/w solution of the said active substance in the dissolution medium recorded through a optical path length of 1 cm, d is the dose or label claim expressed in mg and I is the optical path length in cm. The values for V andA ,' " are given in Table 2. The tolerance in the measurement is about 10%.

Table 2. Values for V and ^m in equation 1

Example 2. Oral Solution.

A formulation of a surfactant together with the poorly water soluble active compound is composed. The compositions for a batch size of 100 gram are given in Table 3 for an oral solution containing 10 mg/ml, calculated as acid. The amount and type of surfactant determines the release of the active substance from the liquid filled capsule, or the release of the active substance into the oral solution and prevents precipitation of the drug in an acidic environment. Table 3. Composition of an oral solution

*) (3S,2'R)-3-[1 -{2'-(ethoxycarbonyl)}-4'-phenylbutyl]cyclopentan-1 -carbonylamino]- 2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepin-1 -acetic acid, n.a.: not applicable

Preparation of the oral solution with water as the diluent.

The required quantity of purified water is heated to 70-75°C. Separately the active substance and the non-ionic surfactant are also heated to 70-75^QC while stirring, until complete dissolution of the active substance. The heated purified water is slowly (in approximately 10 minutes) added under stirring, normally resulting in a clear solution. When the solution is not clear after completion of the addition of water, it is stirred for an additional 10 minutes while heating at 70°C. The resulting solution is cooled down slowly in one hour to a temperature of 30 °C, while stirring and is ready for use.

Dissolution of the oral solution

The formulation obtained is tested according to the method describe d i n Example 1 and the release of the drug from the oral solution is given in Figure 1

Figure 1 clearly shows that the active substance remains dissolved in pH 2 (data from 0 up to 60 minutes), in pH 4.5 (the next 30 minutes) and pH 6.8 (data until end of test). That means that even in gastric environment the active substance will not precipitate.

Claims

1. A formulation with enhanced bio-availability consisting of a thermodynamically stable liquid or semisolid solution of the poorly water-soluble biologically active substance of the general formula

(I) wherein:

Ri is a selected from the group consisting of (C ι-C₆)alkoxy(C₁-C₆)alkyl which may be substituted by a (C_rC₆)alkoxy, phenyl-(C C₆)-alkyl and phenyloxy-(C

C₆)-alkyl wherein the phenylgroup may be substituted with (C_rC₆)alkyl, (C C₆)- alkoxy or halogen, and naphtyl-(C_rC₆)-alkyl,

R₂ and R₃ are both independently hydrogen or halogen,

R₄ is a biolabile ester forming group; or a pharmaceutically acceptable salt thereof; characterised in that said formulation is consisting of a) said substance or a pharmaceutically acceptable salt thereof in an amount of up to 50% of the total weight of the formulation, and b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said non -ionic hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16.

2. A formulation according to claim 1 , characterized in that the non -ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene glycol (80) sorbitan monooleate (Tween® 80) and the non-hydrogenated polyoxyethylene castor oil derivative Cremophor® EL.

3. A formulation according to claims 1 -2, characterized in that said pharmaceutically acceptable salt is a bivalent metal salt.

4. A formulation according to claim 3, characterized in that said bivalent metal salt is a calcium salt.

5. A formulation according to claims 1 - 4, characterized in that said poorly water- soluble active substance is 3-[1-{2'-(ethoxycarbonyl)}-4'-phenylbutyl]cyclopentan- 1 -carbonylamino]-2,3,4,5-tetrahydro-2 -oxo-1 H-1 -benzazepin-1 -acetic acid, preferably in its 3S,2'R form.

6. A formulation according to claims 1 - 4, characterized in that said poorly water- soluble active substance is 3-[1 -{2'-(ethoxycarbonyl)}-4'-naphtylbutyl]cyclopentan- 1 -carbonylamino]-2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepin-1 -acetic acid, preferably in its 3S,2'R form.

7. A formulation according to claims 1 -6, further characterized in that the formulation additionally comprises a fatty or oily diluent or a mixtures of these diluents and optionally auxiliary materials and wherein the ratio between said active substance and said non-ionic hydrophilic surfactant ingredient is between 1 :1 and 1 :8.

8. A formulation according to claims 7 wherein said diluent is a compound or a mixture of compounds selected from the group consisting of polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene 600 ( PEG 600), Labrasol^R (mixture of caprylocaproyl Macrogol-8 glycerides) oleic acid, peanut oil, sesam oil, soy bean oil, ethyloleate, isopropylmyristate and Miglyol 812.

9. A formulation according to claims 1 -8, absorbed on a carrier.

10. A soft or hard gelatin capsule comprising the formulation according to claims 1 -9.

11. A formulation according to claims 1 -6, further characterized in that the formulation additionally comprises a water miscible diluent or a mixture of water soluble diluents and optionally auxiliary materials and wherein the ratio between said active substance and said non-ionic hydrophilic surfactant ingredient is between 1 :1 and 1 :8.

12. A formulation according to claims 11 , wherein the diluent is a compound or a mixture of compounds selected from the group consisting of ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene 600 and water.

13. A formulation according to claim 12, wherein the diluent is water.

14. A formulation according to claim 7-13, characterized in that the ratio between said active substance and said non -ionic hydrophilic surfactant ingredient is between 1 : 3 and 1 : 6.

15. A formulation according to claims 7-14, wherein said optionally auxiliary materials are selected from the group consisting of coloring agents, preservatives, suitable aromas and sweeteners.

16. A method of preparing a formulation according to claims 1 -6, characterized in that the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined in claim 1 , at between 50 -80°C, preferably between 70 and 75 °C.

17. A method of preparing a formulation according to claims 7-15, characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined in claim 1 , at between 50 -80°C, preferably between 70 and 75 °C and b) the resulting mixture is mixed with said diluent and optionally with additional auxiliary materials, at a temperature between 60 -80°C.

18. A method according to claim 17, characterized in that the diluent is water.

19. A method of preparing a formulation according to claim 9, characterized in that a) the non -ionic hydrophilic surfactant ingredient is mixed with the active substance with the genera formula I as defined in claim 1 , at between 50-80°C, preferably between 70 and 75 °C and b) the resulting mixture is absorbed on a carrier.

20. Use of a formulation according to claims 1 -15 for the preparation of a medicament improvement of gastrointestinal blood flow, for the treatment of hypertension and for the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs.