WO2001045710A1

WO2001045710A1 - Pharmaceutical composition containing [1-{[1-(1,3-benzodioxol-5-ylmethyl)-1h-imidazol-5-yl]methyl}-4-(1-naphthyl)-1h-pyrrol-3-yl](4-methyl-1-piperazinyl)methanone

Info

Publication number: WO2001045710A1
Application number: PCT/KR2000/001510
Authority: WO
Inventors: Ae-Ri Kim; Jin-Hwa Lee; Jae-Hyeon Park; Sun-Hwa Lee; Sung-Hack Lee
Original assignee: LG Chemical Co Ltd
Current assignee: LG Corp
Priority date: 1999-12-22
Filing date: 2000-12-21
Publication date: 2001-06-28
Anticipated expiration: 2002-06-22
Also published as: KR20010063274A; AU2233701A

Abstract

The present invention relates to a pharmaceutical composition containing [1-{[1-(1,3-benzodioxol-5-ylmethyl)-1H-imidazol-5-yl]methyl}-4-(1-naphthyl)-1H-pyrrol-3-yl]-(4-methyl-1-piperazinyl)methanone, and more specifically, to the pharmaceutical composition containing the above compound in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable additive selected from acidifier, solubilizing aids or buffer. Formulations prepared from such pharmaceutical composition have remarkably improved dissolution rate and pharmacokinetic characteristics, as compared with those containing the free compound alone, and have excellent chemical stability, which are very useful as orally administrable or injectable formulations.

Description

Pharmaceutical composition containing [l-{[l-(l,3-benzodioxoI-5-ylmethyl)-lH- imidazol-5-yl]methyl}-4-(l-naphthyl)-lH-pyrrol-3-yI](4-methyl-l- piperazinyl)methanone

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition containing [1-{[1- (1,3 -benzodioxol-5 -ylmethyl)- 1 H-imidazol-5-yl] methyl } -4-( 1 -naphthyl)- 1 H-pyrrol-3 - yl](4-methyl-l-piperazinyl)methanone as represented by the following formula

More specifically, the present invention relates to the pharmaceutical composition containing the above compound in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable additive selected from acidifier, solubilizing aids or buffer

BACKGROUND ART

In order to develop a pharmacologically active compound into a medicine, various physicochemical properties, e g physicochemical stability, formulation procedures, dissolution rate, bioavailability, etc , of the compound must be considered and these properties must meet specific requirements (The Theory and Practice of Industrial

Pharmacy, 3^rd ed , 171-196, 1986, Lea & Febiger)

In many cases, sparingly water-soluble compounds have a low bioavailability That is, for the absorption of drugs orally administered as solid dosage forms into the gastrointestinal tracts, their dissolution into the molecules must be precedent However, since sparingly water-soluble compounds have a low dissolution rate, their absorption in vivo must be delayed, which results in the decrease of bioavailability (G S Banker, C T Rhodes, Modern Pharmaceutics, 3^rd ed , Chapter 4, Marcel Dekker, Inc ) In addition, both crystallinity and solubility of drugs are key factors for the design of injectable formulations Accordingly, such low solubility makes it difficult to prepare solutions having a desired concentration of drug and thus, makes it difficult to practically manufacture injectable formulations (G S Banker, C T Rhodes, Modern Pharmaceutics, 3^rd ed , Chapter 12, Marcel Dekker, Inc )

In order to solve the above-described problems due to a low solubility and bioavailability of a compound, it is conventional to convert the compound into appropriate salts, or to modify it into highly water-soluble derivatives, and thereby to enhance the bioavailability However, there still exist some compounds which cannot be converted into salts and in some cases, compounds in salt form have inappropriate properties for medicinal use Therefore, instead of such direct modification of pharmacologically active compounds, there have been many attempts to manufacture various formulations containing pharmaceutically acceptable additives as appropriate (Chakrabarti S , et al , Pharmazie, 1980, 5(10), 627-629, Effect of formulation on dissolution and bioavailability of phenytoin tablets)

However, if various additives employed in formulation interact with a principal agent, even though they are pharmaceutically acceptable, they cannot but have the limit in use Further, since an additive is likely to have different effects depending upon the employed principal agent, the selection of an optimum additive depending upon the employed drug is very important (Howard C Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 1995, 99-154, Williams & Wilkins)

As previously explained, even though a drug has good pharmacological effects in vitro, to exhibit the desired effects in humans, it is important to manufacture it into orally or parenterally administrable formulations of good characteristics. Practically, whether or not such formulations can be obtained is a key factor for the successful development of drugs

[ 1 - { [ 1 -( 1 ,3-benzodioxol-5-ylmethyl)- lH-imidazol-5-yl]methyl } -4-( 1 -naphthyl)- lH-pyrrol-3-yl](4-methyl-l-piperazinyl)methanone as represented by the above formula (1) , or pharmaceutically acceptable salts, hydrates, solvates and isomers thereof are known to have anticancer activity (Korean Patent Laid-Open No 98-31512 and PCT WO9928315-A) Therefore, said compound is expected to be useful as a novel anticancer agent The compound has good crystallinity and chemical stability, but has merely low solubility Moreover, it is difficult to prepare the compound into salts having desirable properties and thus, is difficult to obtain its useful formulations In particular, in case of oral administration to dogs, its bioavailability has been shown to be extremely low In addition, it cannot be manufactured into liquid dosage forms having a desired concentration of drug and thus, has difficulty in use as injectable formulations.

DISCLOSURE OF THE INVENTION

The present inventors have performed extensive studies to develop a novel pharmaceutical composition suitable for oral or parenteral administration of the compound of the formula (1). As a result, they invented the pharmaceutical composition containing a compound of the formula (1) in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable additive, i e pharmaceutically acceptable acidifier, solubilizing aids or buffer Particularly, they found out that solid dosage forms prepared from the present pharmaceutical composition have remarkably improved dissolution rate and pharmacokinetic characteristics, as compared with those containing no additive and are very useful as orally administrable formulations, and thus, completed the present invention An object of the present invention is to provide a novel pharmaceutical composition containing [ 1 - { [ 1 -( 1 , 3 -benzodioxol-5 -ylmethyl)- 1 H-imidazol-5 -yl]methyl } -4- (l-naphthyl)-lH-pyrrol-3-yl](4-methyl-l-piperazinyl)methanone, which has excellent dissolution properties, pharmacokinetic characteristics and chemical stability.

In order to attain the above-described object, the present invention provides a pharmaceutical composition containing [l-{[l-(l,3-benzodioxol-5-ylmethyl)-lH-imidazol- 5-yl] methyl } -4-( 1 -naphthyl)- 1 H-pyrrol-3 -yl](4-methyl- 1 -piperazinyl)methanone as represented by the following formula:

in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable additive selected from the group consisting of acidifier, solubilizing aids and buffer.

More specifically, one aspect of the present invention provides an orally administrable pharmaceutical composition containing the compound of the formula (1) in free form, or hydrates or solvates thereof and a pharmaceutically acceptable acidifier or solubilizing aids. Another aspect of the present invention provides an injectable pharmaceutical composition containing the compound of the formula (1) in free form, or hydrates or solvates thereof and a pharmaceutically acceptable buffer or solubilizing aids.

The pharmaceutical composition according to the present invention may further contain another pharmaceutically acceptable additive selected from diluent, flavor, lubricant, suspending agent, disintegrating agent, isotonic agent, stabilizer, preservative or mixtures thereof.

The present pharmaceutical composition can be manufactured into solid or semisolid dosage forms such as powder, tablets, dispersions, capsules or suppositories and the like, or liquid dosage forms such as solutions, suspensions, emulsions and the like.

Hereinafter, the present invention will be more specifically explained.

The present invention provides a pharmaceutical composition containing [1-{[1- (1,3 -benzodioxol-5-ylmethyl)- 1 H-imidazol-5 -yljmethyl } -4-( 1 -naphthyl)- 1 H-pyrrol-3 -yl] (4-methyl-l-piperazinyl) methanone as represented by the above formula (1) in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable acidifier, solubilizing aids or buffer.

In the present invention, an orally administrable pharmaceutical composition containing the compound of the formula (1) in free form, or hydrates or solvates thereof and a pharmaceutically acceptable acidifier or solubilizing aids is included. In a preferable embodiment, the pharmaceutically acceptable acidifier is selected from the group consisting of tartaric acid, citric acid and alginic acid. The pharmaceutically acceptable acidifier is preferably contained in a ratio of 0.1 to 4 equivalents, more preferably, 0.2 to 1 equivalent, with respect to 1 equivalent of the compound of the formula (1) in free form. In another preferable embodiment, the pharmaceutically acceptable solubilizing aids are surfactants, which are selected from the group consisting of sodium lauryl sulfate, Poloxamer®(polyefhylene polypropylene glycol), Tween® 80(polyoxyethylene20 sorbitan mono-oleate), Tween® 60(polyoxyethylene20 sorbitan monostearate), Tween® 40(polyoxyethylene20 sorbitan monopalmitate) or Tween® 20(polyoxyethylene20 sorbitan monolaurate). The pharmaceutically acceptable solubilizing aids are preferably contained in 0.1 to 1000 parts by weight, more preferably, 1 to 500 parts by weight, based on 1 part by weight of the compound of the formula (1) in free form. In the present invention, an injectable pharmaceutical composition containing the compound of the formula (1) in free form, or hydrates or solvates thereof and a pharmaceutically acceptable buffer or solubilizing aids is also included In a preferable embodiment, the pharmaceutically acceptable buffer is selected from the group consisting of glycine-hydrochloric acid buffer, acetic acid-acetate buffer, citric acid-citrate buffer, phosphoric acid-phosphate buffer and mixtures thereof The pharmaceutically acceptable buffer is preferably contained at an amount to adjust a concentration of the compound of the formula (1) in free form to 1 to 100 mg/ml, more preferably, 10 to 50 mg/ml Such employment of the buffer enables the manufacture of injectable formulations containing the compound of the formula (1), in spite of its extremely low solubility In another preferable embodiment, solubilizing aids are selected from the group as described above and are contained at the content ratio as described above

In another preferable embodiment, the pharmaceutical composition according to the present invention further comprises another pharmaceutically acceptable additive selected from the group consisting of diluent, flavor, lubricant, suspending agent, binder, disintegrating agent, isotonic agent, stabilizer, preservative and mixtures thereof Specifically, the pharmaceutically acceptable additive may be solid or liquid Solid additive may be employed in powder, tablets, dispersions, capsules, suppositories, etc In particular, tablets, powder or capsules are preferable for oral administration In this case, one or more solid additives such as diluent, flavor, lubricant, suspending agent, binder or disintegrating agent may be employed Preferable disintegrating agent is microcrystalline cellulose, crospovidone or starch Preferable binder is microcrystalline cellulose, starch, povidone (PVP, polyvinylpyrrohdone), hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, alginic acid or gelatin Preferable lubricant is magnesium stearate, talc, calcium stearate, silica or solid polyethylene glycol Preferable diluent is calcium carbonate, microcrystalline cellulose, dextrose, galactose, kaolin, mannitol, sugar, starch, calcium phosphate or dextrin Liquid additive may be employed in liquid dosage forms such as solutions, suspensions, emulsions and the like In this case, one or more liquid additives such as isotonic agent, stabilizer, preservative or flavor may be employed Solutions and emulsions may further contain solvent, solubilizer, emulsifier (e g water, ethyl alcohol, isopropyl alcohol, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, oil such as cottonseed oil, peanut oil, cornseed oil, olive oil, castor oil, almond oil or sesame oil, glycerol, polyethylene glycol, sorbitan fatty acid ester, or mixtures thereof), or preservative (e g methyl paraben, propyl paraben, sodium benzoate or sorbic acid) Suspensions may further contain liquid diluent (e g water, ethyl alcohol, propylene glycol, polyethylene glycol), suspending agent (e g alginic acid, carbomer, carboxymethyl cellulose, microcrystalline cellulose, aluminum monostearate, bentonite, agar, tragacanth), injectable esters such as ethyl oleate, or mixtures thereof

The above dosage forms may also contain buffering salts, colorant, preservative, flavor, e g peppermint oil or eucalyptus oil, or sweetener, e g aspartame or saccharin The dosage forms may contain another pharmacologically active compound in addition to the compound of the formula (1) They may be prepared according to the known processes, for example, a conventional process comprising the step of mixing the active compound with the additives

Solid dosage forms prepared from the pharmaceutical composition containing [1- { [ 1 -( 1 , 3 -benzodioxol-5-ylmethy 1)- 1 H-imidazol-5 -yl] methyl } -4-( 1 -naphthyl) - 1 H-pyrrol-3 - yl](4-methyl-l-piperazinyl)methanone of the present invention have much better dissolution rate and pharmacokinetic characteristics than those containing no additive As a result of dissolution test in 37 °C water, capsules containing the free compound alone had extremely low dissolution rate and thus, only less than 10% was dissolved even after 75 minutes In contrast, in case of tablets prepared from the present pharmaceutical composition, almost 100% of the free compound was dissolved after 75 minutes In addition, as a result of in vivo absorption test by oral administration to dogs, tablets and capsules prepared from the present pharmaceutical composition had 6 to 8 5-fold increased maximal plasma concentration of drug as compared with capsules containing the free compound alone AUC (Area Under the Curve) was also 10-fold increased and a high plasma concentration of drug was maintained for a long time Tablets prepared from the present pharmaceutical composition retained 95% or more of the principal agent even after 55 days at 50 °C and 70 °C, respectively Accordingly, it was confirmed that the additives as employed in the present invention do not interact with the principal agent and thus, the stable pharmaceutical composition can be obtained Further, because the solubility of the compound of the formula (1) is 0 5 mg/ml or less, it was difficult to prepare aqueous solutions containing the compound at a concentration of more than 0.5 mg/ml But, according to the present invention, solutions containing 50 mg/ml of drug can be prepared by the employment of glycine-hydrochloric acid buffer

As described above, solid dosage forms as well as solutions can be conveniently prepared from the pharmaceutical composition of the present invention In particular, such solid dosage forms are excellent in view of dissolution rate, pharmacokinetic characteristics and chemical stability Therefore, the present pharmaceutical composition is very useful as orally administrable or injectable formulations

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 is a dissolution curve of solid dosage forms prepared from the present pharmaceutical composition containing the compound of the formula (1)

Fig 2 is a graph showing the changes in the plasma concentration of drug by oral administration of solid dosage forms prepared from the present pharmaceutical composition containing the compound of the formula (1) to dogs

BEST MODE FOR CARRYING OUT THE INVENTION

This invention will be better understood from the following examples However, one skilled in the art will readily appreciate the specific materials and results described are merely illustrative of, and are not intended to, nor should be intended to, limit the invention as described more fully in the claims, which follow thereafter

Examples 1-4: Preparation of Tablets

As orally administrable solid dosage forms, tablets were manufactured by preparing powder mixture from the compositions as shown in the following table 1

Table 1 Composition of tablets

(Comp Composition)

Examples 5-6: Preparation of Capsules

As orally administrable solid dosage forms, capsules were manufactured by preparing powder mixture from the compositions as shown in the following table 2, and filling it into gelatin capsules No 0 (Torpac, Inc , New Jersey)

Table 2 Composition of capsules

Example 7: Preparation of Solutions

0 3754 g of Glycine was mixed with 5 7 ml of 0 2 M hydrochloric acid solution and thereto was added distilled water to adjust the total volume to 100 ml to give glycine- hydrochloric acid buffer of pH 3 The free compound (1) was added thereto to adjust its concentration to 50 mg/ml to give solutions By the employment of the glycine- hydrochloric acid buffer, the sparingly water-soluble compound (1) could be formulated into homogeneous aqueous solutions

Comparative Example: Preparation of Capsules Capsules were prepared by filling 100 mg of the free compound (1) into gelatin capsules No 0 (Torpac, Inc )

Experimental Example 1: Dissolution Test of Solid Dosage Forms

The pharmaceutical composition containing the free compound (1) of the present invention was tested for the dissolution rate as follows

Dissolution test was carried out according to Basket method using tablets of compositions 1, 2 and 3 obtained from example 1 and capsules obtained from comparative example(USP 23, General Tests and Assays, <711> Dissolution, Apparatus 1) 500 ml of Distilled water was employed as the dissolving solvent and the temperature was constantly kept at 37 °C Basket was rotated at 50 rpm and after 15, 30, 45, 60 and 75 minutes, 1 ml of the solution was taken and filtered through 0 22 μm filter, respectively The free compound (1) contained in the filtrate was assayed by HPLC (Hewlett Packard, Series 1100) The results are shown in the following table 3 and Fig 1 Table 3 Dissolution rate

As shown in table 3 and Fig 1, in case of capsules containing the free compound (1) alone, only less than 10% was dissolved even after 75 minutes By contrast, in case of tablets of compositions 1, 2 and 3, almost 100% was dissolved after 75 minutes Consequently, tablets prepared from the pharmaceutical composition of the present invention were confirmed to have remarkably improved dissolution rate as compared with capsules containing the free compound alone

Experimental Example 2: In vivo Absorption Test by Oral Administration

The present pharmaceutical composition containing the free compound (1) was tested for in vivo absorbability by oral administration thereof as follows

Tablets of compositions 1, 2 and 4 obtained from example 1, capsules of composition 5 obtained from example 2, and capsules obtained from comparative example were employed in the experiment They were administered orally to Beagle Dogs(weight 9 to 12 kg) with a dose of 30 mg/kg as the free compound (1) At 0, 10, 20, 40, 60, 90, 120, 180, 240, 360 and 480 minutes after the oral administration, blood was gathered from the dogs The gathered blood was treated with 2-fold methanol and centrifuged to deproteinize Then, the free compound (1) in the blood was assayed by HPLC Plasma concentrations of drug with the lapse of time are shown in Fig 2 Each pharmacokinetic parameter, i e maximal concentration (C_max), maximal time (T_max) and AUC (Area Under the Curve), was calculated therefrom and the results are shown in the following table 4 Table 4: Pharmacokinetic parameters by oral administration to dogs

As shown in table 4, capsules containing the free compound (1) alone have the extremely low C_max of 0.51 μg/ml. By contrast, solid dosage forms prepared from compositions 1, 2, 4 and 5 have 3.64, 4.24, 3.10 and 4.35 μg/ml of C_max, respectively and thus, the maximal plasma concentration of drug was 6 to 8.5-fold increased. In addition, capsules obtained from the comparative example had only 100 μg.min/ml of AUC, but solid dosage forms prepared from compositions 1, 2, 4 and 5 had 927, 1126, 732 and 1056 μg.min/ml of AUC, respectively and thus, AUC was about 10-fold increased.

As shown in Fig. 2, solid dosage forms prepared from the present pharmaceutical composition have prolonged retention time of maximal plasma concentration as compared with those from the comparative example. Even after 480 hours, the plasma concentration was similar to the maximal concentration of the comparative example and thus, high plasma concentration of drug was maintained for a long time.

As described above, solid dosage forms prepared from the pharmaceutical composition of the present invention were confirmed to have remarkably improved pharmacokinetic characteristics compared with those containing the free compound only.

Experimental Example 3: Stability Test of Solid Dosage Forms

The present pharmaceutical composition containing the free compound (1) was tested for the stability as follows.

Tablets of compositions 2 and 3 prepared from example 1 were introduced into ovens at 50 °C and 70 °C and were kept for 17, 28 and 55 days, respectively. Then, residual free compound (1) in the tablets was assayed by HPLC and the results are shown in the following table 5.

Table 5: Stability

As shown in table 5, in case of storing tablets prepared from the present pharmaceutical composition at high temperatures of 50 °C and 70 °C for 55 days, 95% or more of compound (1) was retained. Accordingly, it was confirmed that the additives employed in the present invention do not interact with compound (1). As a result of stability test at a high temperature, solid dosage forms prepared from the composition of the present invention are expected to be stable at room temperature.

As explained above, solid dosage forms prepared from the pharmaceutical composition containing [ 1 - { [ 1 -( 1 ,3 -benzodioxol-5 -ylmethyl)- 1 H-imidazol-5 -yl] methyl } -4- (l-naphthyl)-lH-pyrrol-3-yl](4-methyl-l-piperazinyl)methanone as represented by the formula (1) of the present invention have remarkably improved dissolution rate and pharmacokinetic characteristics, as compared with those containing the free compound alone, and have excellent chemical stability, which are very useful as orally administrable formulations. Furthermore, according to the present invention, a high concentration of solutions, which are useful as injectable formulations, can be obtained.

Claims

WHAT IS CLAIMED IS:

1 A pharmaceutical composition containing [l-{[l-(l,3-benzodioxol-5-ylmethyl)-lH- imidazol-5-yl] methyl } -4-( 1 -naphthyl)- 1 H-pyrrol-3 -yl](4-methyl- 1 -piperazinyl) methanone as represented by the following formula

in free form, or hydrates or solvates thereof, in admixture with a pharmaceutically acceptable additive selected from the group consisting of acidifier, solubilizing aids and buffer

2 The orally administrable composition of claim 1, wherein the pharmaceutically acceptable additive is acidifier or solubilizing aids

3 The orally administrable composition of claim 2, wherein the acidifier is selected from th group consisting of tartaric acid, citric acid and alginic acid

4 The orally administrable composition of claim 2, wherein the acidifier is contained in a ratio of 0 1 to 4 equivalents with respect to 1 equivalent of the compound of the formula (1) in free from

5 The injectable composition of claim 1, wherein the pharmaceutically acceptable additive is buffer or solubilizing aids

6 The orally administrable or injectable composition of claim 2 or 5, wherein the solubilizing aids are selected from the group consisting of sodium lauryl sulfate, Poloxamer®(polyethylene polypropylene glycol), Tween® 80(polyoxyethylene20 sorbitan mono-oleate), Tween® 60(polyoxyethylene20 sorbitan mono stearate), Tween® 40(polyoxyethylene20 sorbitan monopalmitate) and Tween® 20(polyoxy ethyl ene20 sorbitan monolaurate).

7. The orally administrable or injectable composition of claim 2 or 5, which contains 0.1 to 1000 parts by weight of the solubilizing aids based on 1 part by weight of the compound of the formula (1) in free from.

8. The injectable composition of claim 5, wherein the buffer is selected from the group consisting of glycine-hydrochloric acid buffer, acetic acid-acetate buffer, citric acid- citrate buffer, phosphoric acid-phosphate buffer and mixtures thereof.

9. The injectable composition of claim 5, which the buffer is contained at an amount to adjust a concentration of the compound of the formula (1) to 1 to 100 mg/ml.

10. The pharmaceutical composition of claim 1, further comprising another pharmaceutically acceptable additive selected from the group consisting of diluent, flavor, lubricant, suspending agent, binder, disintegrating agent, isotonic agent, stabilizer, preservative and mixtures thereof.