WO2002013789A1

WO2002013789A1 - Pharmaceutical composition containing 1'-[4-[1-(4-fluorophenyl)-1h-indole-3-yl] -1-butyl]-spiro[isobenzofuran-1(3h),4'-piperidine]

Info

Publication number: WO2002013789A1
Application number: PCT/DK2001/000540
Authority: WO
Inventors: Ken Liljegren
Original assignee: H. Lundbeck A/S
Priority date: 2000-08-15
Filing date: 2001-08-14
Publication date: 2002-02-21
Also published as: AR030453A1; AU2001279607A1

Abstract

The present invention relates to a pharmaceutical composition comprising a solution of 1'-[4-[1-(4-fluorophenyl)1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4'-piperidine] in a liquid, semi-solid or solid solvent system comprising polyethylene glycol and an amount of co-solvent.

Description

PHARMACEUTICAL COMPOSITION CONTAINING l'-[4-[l-(4-FLUOROPHENYL lH-]NDOLE-3-YL]-l-BUTYL]-SPIRO[ISOBENZOF^

Field of invention

The present invention relates to a pharmaceutical composition containing l'-[4-[l-(4- fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzofirran-l(3H),4'-piperidine] as the active ingredient. In particular, the present invention relates to a solution of the active ingredient, which is contained in a capsule.

Background of the Invention

International Patent Publication No. WO 92/22554 describes a series of sigma receptor ligands useful for the treatment of a range of psychic and neurological disorders.

In particular, International Patent Publication No. WO 92/22554 discloses the compound 1'- [4- [ 1 -(4-fluorophenyl)- lH-indole-3 -yl]- 1 -butyl] -spiro [isobenzofuran 1 (3H),4 ' - piperidine] having the formula

which is the subject of the present invention. This compound was shown in Perregaard, J. et al. J Med. Chem. 1995, 38, 11, p. 1998-2008 to be a potent and selective sigma ligand, in particular a sig ^ ligand. The anxiolytic potential of the compound was tested in the black/white exploration test in rats, which is an animal model predictive for effect in the treatment of generalised anxiety disorder and it was found to be active over a large dose range. Results of further tests in models of generalised anxiety disorder are reported in J Pharmacol.Exp.Ther. 1997, 283, No. 2. Further, WO 00/15225 and WO 99/51229 describe the use of the compound of formula I for the treatment of depression and panic attacks.

In general, the compound of formula I and pharmaceutically acceptable salts thereof have a poor aqueous solubility, although the hydrohalogenides of the compound of formula I have improved aqueous solubility compared to other salts of the compound.

It has also been found that the bioavailabihty of the compound of formula I shows a high degree of variation when the compound is administered in the form of a conventional tablet prepared by simple compression of the active ingredient and pharmaceutically acceptable excipients.

Micronisation of the compound of formula I was expected to improve bioavailabihty, but was found not to markedly improve the bioavailabihty of the compound. In addition, it was found that food intake had a pronounced effect on the bioavailabihty of the compound, which leads to undesirable variations of the blood serum level of the active compound.

It has now been found that certain liquid or semi-solid solutions of the compound of formula I in a polyethylene glycol phase provide improved bioavailabihty of the compound.

Description of the Invention

The present invention relates to a pharmaceutical composition of the compound of formula I comprising a solution of the compound of formula I or a pharmaceutically acceptable salt thereof in a liquid, semi-solid or solid solvent system comprising polyethylene glycol and optionally a solubility enhancer.

In a preferred embodiment, the pharmaceutical composition of the invention comprises a solution of the compound of formula I in a solvent system comprising polyethylene glycol and up to 20 % w/w of a solubility enhancer. In particular, the present invention relates to such solutions, which are contained in a capsule.

The molecular weight of the polyethylene glycol used affects the properties of the resulting solution of the invention. Thus, polyethylene glycol having an average molecular weight from about 200-800 daltons, preferably from about 400-600, produces a solution, which is liquid. Polyethylene glycol, having an average molecular weight from about 800-10.000, preferably from about 2.000- 8.000, produces a solution, which is semi-solid, and polyethylene glycol, having an average molecular weight between about 10.000-100.000, preferably about 15.000-60.000 produces a solution, which is solid at room temperature.

In particular, the present invention relates to solutions as above wherein the solvent system is liquid at room temperature.

In particular, the polyethylene glycol is selected from polyethylene glycols with an average molecular weight of 400-600 (PEG 400 - PEG 600).

Thus, the present invention also relates to such liquid solutions, which may be contained in a soft capsule, preferably a soft gelatine capsule, or in a modified hard gelatine capsule..

Many solvents are not suitable for filling in gelatine capsules because they degrade the capsule material. Concentrations of water above few percent will dissolve the gelatine capsule, and other hydrophilic solvents such as alcohols also interfere with the capsule material.

Polyethylene glycols do not dissolve the gelatin capsule material and may therefore be used as a vehicle in gelatin capsule formulations. However, it is important that a suitable amount of the active ingredient can be completely dissolved in a volume of solvent small enough to be contained in a capsule of a size, which is acceptable to patients. It may thus be necessary to add a solubility enhancer or co-solvent to the polyethylene glycol phase to obtain complete dissolution of the active ingredient. The solubility enhancers or co-solvents useful according to the invention are suitably more hydrophilic than the polyethylene glycol used and such an enhancer could suitably be a short chain alcohol. Such solubility enhancers will typically be less compatible with the gelatin capsule material than the polyethylene glycol. However, according to the present invention, it has been found that the amount of solubility enhancer to be added to the solution may be kept below the amount, which causes degradation, etc. of the gelatin capsule.

Suitable solubility enhancers or co-solvents used according to the invention are propyleneglycol, ethyleneglycol, glycerol, sorbitol, transcutol and low molecular alcohols. In a particular embodiment, the solubility enhancer is propyleneglycol, sorbitol, ethanol and /or glycerol.

The amount of solubility enhancer, which may be added to the polyethylene glycol phase without causing degradation of the gelatine capsule, will depend on the solubility enhancer chosen. Suitably, the amount of solubility enhancer is kept below 20% w/w.

When propylene glycol is used as the solubility enhancer, the amount of solubility enhancer is suitably up to 10% w/w, preferably about 5% w/w.

Peroxidation of the polyethylene glycol may lead to oxidation of the active ingredient, as well as oxidation of the gelatin in the capsule shell causing gelatin cross-linking, and it may be preferred to add an antioxidant to the composition of the invention.

The antioxidant used may be any antioxidant, which is pharmaceutically acceptable. Suitably the antioxidant is selected from alpha-tocopherol, BHA (2-tert-butyl-4-methylphenol) or BHT (2,6-di-tert-butyl-4-methylphenol), propylgallate, ascorbylpalmitate and other antioxidants well-known in the art.

Metal ion chelators such as sodium EDTA or citric acid may also be employed. According to a preferred embodiment of the invention, the pharmaceutical composition of the invention comprises a hydrohalogenide of the compound of formula I, preferably the hydrochloride (hereinafter referred to as compound II).

In a particular embodiment, the present invention relates to a pharmaceutical composition comprising 1 ' - [4- [ 1 -(4-fluorophenyl)- lH-indole-3yl] - 1 -butyl] -spiro [isobenzo-furan- 1 (3H),- 4'-piperidine] hydrochloride, PEG 400, about 5% w/w propylene glycol and an antioxidant. The solutions according to the invention may contain up to 27 mg/ml of compound II.

In general, the solutions of the invention are prepared by heating the polyethylene glycol, the solubility enhancer, the antioxidant and other excipients in a vessel fitted with an agitator. The active ingredient is added and the mixture is stirred until the active ingredient is completely dissolved. When the polyethylene glycol in question is a liquid at room temperature, it is not strictly necessary to apply heating, but heating to about 40 °C will allow a rapid dissolution of the active ingredient.

Liquid formulations are suitably filled in capsules, such as soft gelatin capsules, available from RP.Scherer, Banner Pharmacaps or Capsugel or modified hard gelatin capsules available from Shionogi Qualicaps, while solutions, which are semi-solid or solid when cooled to room temperature, may be filled in two-piece hard gelatin capsules available from Shionogi Qualicaps, Capsugel and others. Highly concentrated solutions that are solid at room temperature have the additional utility of being suitable for conversion into tablets.

The liquid solution of the invention may be introduced into the soft gelatin capsule using encapsulation equipment and techniques known in the art, such as those described in US patent No. 4.772.472, US 4.894.978 and WO 96/41622.

Encapsulation in hardshell capsules may be carried out using conventional techniques.

The solutions of the invention are most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 μg/kg to lOmg/kg body weight, preferably 25 μg/day/kg to 1.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body weight.

The solutions of the invention may also be administered orally as liquids.

In the following, the invention is illustrated by way of examples.

Example 1

Soft gelatin capsule containing compound II in a polyethylene glycol phase.

Composition of fill material:

PEG 400 93.97% w/w Propyleneglycol 4.95% w/w

Compound II 1.08% w/w

PEG 400 and propyleneglycol are heated to 40 °C. Compound II is added and the mixture is stirred until the active compound is completely dissolved.

The liquid is then filled in soft gelatin capsules. The capsule is sealed.

Example 2

Soft gelatin capsule containing compound II in a polyethylene glycol phase.

Composition of fill material:

PEG 400 93.48% w/w Propyleneglycol 4.95% w/w

Butylhydroxytoluene (BHT) 0.49% w/w

Compound II 1.08% w/w PEG 400, propyleneglycol and BHT are heated to 40 °C. Compound II is added and the mixture is stirred until the active compound is completely dissolved.

The liquid is then filled in soft gelatine capsules. The capsule is sealed.

Example 3

Hard gelatin/PEG capsule containing compound II in a polyethylene glycol phase.

Composition of fill material:

PEG 400 93.48% w/w

Propyleneglycol 4.95% w/w Butylhydroxytoluene (BHT) 0.49% w/w

Compound II 1.08% w/w

PEG 400, propyleneglycol and BHT are heated to 40 °C. Compound II is added and the mixture is stirred until the active compound is completely dissolved.

The liquid is then filled in hard gelatine/PEG capsules (Shionogi Qualicaps®) and sealed by banding.

Example 4

Hard gelatin capsule containing micronized compound of formula II.

Composition of fill material:

Lactose monohydrate, 325 mesh 68.82% w/w Cetylpyridinium chloride 30.00% w/w

Compound II (micronized) 1.18% w/w Micronized compound II was prepared by milling in an Alpine Laboratory Universal Mill

100 UPZ-II fitted with a 4-row stud disc milling unit. Milling at 18.000 rpm decreases the average particle size to 6 microns (measured by laser diffraction).

Micronized compound II is mixed with lactose monohydrate, 325 mesh (filler) and cetylpyridinium chloride (wetting agent).

The powder mix is then filled in hard gelatin capsules.

Example 5

Solution of a complex of cyclodextrine and compound II in water.

Composition containing 2.7 mg compound II /mL solution:

2-Hydroxypropyl-beta-cyclodextrine 14.34% w/w

Purified water 85.40% w/w

Compound II 0.26% w/w

Hydroxypropyl-beta-cyclodextrine is added to purified water and stirred until completely dissolved. Compound II is added and the mixture is stirred until compound II is completely dissolved.

The liquid is then filled in glass vials and heat sterilised.

Example 6

The bioavailabihty of the formulations according to the invention was compared to a formulation containing micronized compound II (Example 4) and an aqueous solution of 2- hydroxypropyl-beta-cyclodextrine complex with compound II (Example 5).

The three formulations were administered to Beagle dogs of about 12 kg body weight and 3- 4 years old. 5 mg of the compound of formula II was administered to each dog. The concentration of the compound of formula I in the blood was determined, whereafter C„ t_max and AUC were calculated.

The 2-hydroxypropyl-beta-cyclodextrin complex solution was administered by oral gavage, whereas other formulations were administered orally in the gelatine capsules.

The results obtained are shown in table 1 :

Table 1

As shown in table 1, the formulation containing micronized compound II has a much lower bioavailabihty compared to the two other formulations. The formulation according to Example 5 has a good bioavailabihty but uses water as a solvent and it is therefore not suitable for filling in capsules. Thus, the formulation according to the invention provides improved bioavailabihty and may be contained in capsules suitable for oral administration.

Claims

1. A pharmaceutical composition of l'-[4-[l-(4-fluorophenyl) lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan-l(3H),4'-piperidine] comprising a solution of r-[4-[l-(4-fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan-l(3H),4'- piperidine] or a pharmaceutically acceptable salt thereof in a liquid, semi-solid, or solid solvent system comprising polyethylene glycol and optionally a co-solvent.

2. A solution according to claim 1, which is contained in a capsule.

3. A solution according to claims 1-2, wherein the solvent system is liquid at room temperature.

4. A solution according to claims 1-2 wherein the polyethylene glycol is PEG 400 - PEG 600.

5. A solution according to claims 2-4, wherein the solution is contained in a capsule, preferably a soft gelatin capsule.

6. A solution according to claim 1, which contains up to 20% w/w of a co-solvent.

7. A solution according to claims 1-7, wherein the co-solvent is selected from propyleneglycol, sorbitol, ethanol and /or glycerol.

8. A solution according to claim 7, wherein the co-solvent is polyethylene glycol and the amount of co-solvent is up to 10% w/w, preferably 5% w/w.

9. A solution according to claims 1- 8, wherein the solution contains a hydrohalogenide of 1 '-[4-[l-(4-fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan-l(3H),4'- piperidine], preferably the hydrochloride.

10. A solution according to claim 9 comprising 1 '-[4-[l-(4-fluorophenyl)-lH-indole-3 yl]-l-butyl]-spiro[isobenzo-furan-l(3H),4'-piperidine] hydrochloride, PEG 400, about 5 % w/w propylene glycol and an antioxidant.

11. A solution according to claim 9, wherein the pharmaceutical composition contains up to 27mg/ml of -[4-[l-(4-fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan- l(3H),4'-piperidine] hydrochloride.

12. A solution according to claim 1, wherein the solution contains an antioxidant and/or a metal chelator.