HK1010080A - Preparation of concealed taste preparations of antibacterially active quinolone derivatives - Google Patents

Description

Preparation of taste masked formulation of antibacterial quinolone derivatives

The present invention relates to a process for preparing taste-masked quinolone derivative oral pharmaceutical preparations having antibacterial activity.

Quinolones are known to have an intrinsic, extremely bitter taste against inhibitors of the antibacterial activity of bacterial gyrases. When oral formulations of such substances are taken, this inherent bitter taste must be masked to be acceptable to the patient. In general terms, this is done by film coating the tablets. When the antibacterial quinolone derivative is used for treatment, a single dose of 100mg to 1000mg of the medicine is required. Swallowing solid pharmaceutical dosage forms of such a large volume presents great difficulties for the elderly and patients and children who have difficulty swallowing, and there is a need for oral pharmaceutical dosage forms which taste acceptable and which do not require swallowing the entire solid dosage form together, but which can be taken in liquid suspension or by chewing.

The simplest technical means of masking the unpleasant taste is to add a suitable flavouring to the solution of the drug. This is not suitable for the quinolone derivatives having antibacterial activity. Therefore, additional steps are required to mask or neutralize this bitter taste.

The techniques now known are aimed at preventing or at least reducing the solubility of the lyotropic antibacterial quinolone derivatives in the solvents used or in the saliva.

In EP-A-0551820, this is achieved by microencapsulating the dehydrate in the form of the base of these substances. As coating material, a water-soluble neutral methyl and/or ethyl ester compound or quaternary ammonium salt compound of polymethacrylic acid, or a mixture thereof, or ethylcellulose is used.

In biopharmaceutical gazette, (1993), 16(2), 172-7, a process for microencapsulation of fine particles of cilofloxacin and hydroxypropyl cellulose using low substituted ethylcellulose and hydroxypropyl methylcellulose as coating substances is described.

EP-A-409254 describes ｃA similar process, namely microencapsulation of pyridonecarboxylic acid antibacterial agents, in particular enoxacin, and water-swellable agents with ｃA mixture of ethylcellulose and water-soluble polymers.

In these microencapsulation processes, the coating substance is applied by spraying with a solution thereof. The disadvantage is that expensive assembly equipment is required and the applicable particle size of the coated particles is subject to severe restrictions. This is due on the one hand to the unexpected requirement of a reduced particle size, and on the other hand to the fact that a reduced particle size leads to an increased adhesion, which leads to an increased tendency to agglomerate, and thus technically limits the possibilities of spray coating.

Thus, EP-A-0551820 mentions that 100-500. mu.m is the preferred particle size range for the microcapsules obtained. However, the 500 μm particles used as a suspension cause unpleasant gritty feeling in the mouth of a patient. In addition, the time required to spray coat the fine particles is relatively long.

JP63150220 describes a process by which a product similar to microcapsules can be obtained. Powdered medicaments such as enoxacin are mixed with powdered coating substances such as wax substances, e.g. paraffin, stearic acid, beeswax, etc., or with polymers which form a film coating, e.g. methacrylic acid copolymers, ethylcellulose, polystyrene, etc. The mixture is treated with an organic solvent to dissolve the coating material. After removal of the solvent, a powdery substance is again obtained. The disadvantage of this process is that the solvents used are flammable, hazardous to health or pose ecological problems. These solvents must be recovered or disposed of by expensive methods. There is also a residue in the product.

The use of a liquid carrier as a medium for dissolving or dispersing the coating substance is common in all methods of coating existing, active compound particles or antibacterial active quinolone derivatives.

The object of the present invention is to provide a process for the preparation of orally administrable, taste-masked pharmaceutical preparations in which quinolone derivatives having antibacterial activity as active compounds are rapidly released, without the disadvantages described in the processes of the literature and without the use of liquid carriers as a medium for dissolving or dispersing the coating substances.

By rapid release of the active substance is meant a single dose release of at least 80% after 30 minutes in 900ml 0.1N HCl.

Surprisingly, it has now been found that taste masking is possible even without the use of a liquid carrier. The method comprises mixing the antibacterial quinolone derivative with higher fatty acid and optionally other additives, heating the mixture, cooling, and making into powder or granule. The product can suitably mask the taste even after pulverization. The heating of the mixture may be carried out according to conventional methods. From the viewpoint of the treatment process, it is preferable to use a heating mixer (e.g., Henschel liquid mixer FM4 or FM10) rotating at a high speed. In these mixers, heat is generated by friction, the mixture is heated and, in the same machine, after cooling, the mixture is comminuted. High speed rotation means a rotational speed of at least 3000 rpm. The mixture is heated to 30 ℃ to 140 ℃, preferably 40 ℃ to 120 ℃, particularly preferably 50 ℃ to 85 ℃.

The invention also relates to the formulations prepared by this method.

Higher fatty acids refer to fatty acids containing at least 10 carbon atoms.

Suitable higher fatty acids have from 10 to 22 carbon atoms, with fatty acids having from 12 to 18 carbon atoms being particularly suitable for the process. Mixtures of fatty acids may also be preferably used. For example, it is convenient to use commercially available stearic acid, which is a mixture of nearly equal amounts of stearic acid and palmitic acid. Suitable additives are also, for example, highly dispersed silica.

As a basic structural feature, the antibacterial quinolone derivatives include 1-ethyl-4-oxopyridine-3-carboxylic acid (see Auterhoff, Knabe, Holtje, ([ textbook of medicinal chemistry, 13 th edition, 1994, page 788)). Preferred are levofloxacin (levofloxacin), ofloxacin, ciprofloxacin, norfloxacin, siloxacin and enoxacin. More preferred are levofloxacin and ofloxacin.

The weight ratio of the quinolone derivative(s) to the fatty acid(s) is preferably 1: 0.3 to 1: 4, particularly preferably 1: 1 to 1: 2.

The formulation of antibacterial chemical quinolone derivative and higher fatty acid after heating and subsequent pulverization according to the present invention may be further formulated into medicines such as sachets, chewable tablets or soluble tablets.

1. Soluble tablet

A soluble tablet is a pharmaceutical dosage form that disintegrates in a cup of water when stirred for up to 3 minutes and forms a suspension that can pass through a 0.715mm mesh.

Soluble tablets require large doses for administration as a medicament. Because of their large size, they are difficult to swallow as conventional tablets. The particular mode of administration of soluble tablets in suspension or solution requires that the bad taste of the drug be properly masked.

Soluble tablet formulations can be prepared using the adjuvants used in conventional tablets. In general, flavoring agents, sweeteners and possibly coloring agents may also be added. The preparation techniques used are wet granulation, dry granulation and direct compression.

2. Small medicine bag

Sachets are pouches that typically contain a single dose of powdered or granular drug. For administration, the drug in the bag is suspended or dissolved in a glass of water. Suitable additives, in addition to sugar and sugar substitutes, are thickeners, glidants, flavors, colorants and possibly buffer substances.

3. Chewable tablet

Chewable tablets are tablets that are chewed prior to swallowing. The reason for using this pharmaceutical dosage form for large doses of the antibacterial quinolone derivative is the problem of swallowing in some patients with conventional tablets, film-coated tablets, capsules or coated tablets. Chewable tablets generally contain primarily sugar or sugar substitutes and flavoring agents in addition to conventional tablet adjuvants.

The release of the active substance is measured in a blade stirrer in the us pharmacopoeia, see us pharmacopoeia 23, page 1792, section 711, figure 2.

Examples example 1

Formulations of a base mixture of levofloxacin hemihydrate with masked taste were prepared.

Levofloxacin hemihydrate 256.23mg

Stearic acid 211.00mg

The levofloxacin hemihydrate was mixed with stearic acid in a heated mixer at 1000rpm for 3 minutes. The speed was then increased to 5500rpm and mixed until the temperature was increased to 75 ℃, the material was in a granular structure. The mixture was cooled to room temperature with mantle cooling and then comminuted by further mixing at 5500rpm while cooling within 4X 0.5 minutes. A powder with a natural taste is obtained.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

34.2% 91.2% after 5 minutes

47.1% 97.9% after 15 minutes

55.7% 97.4% after 30 minutes example 2

The taste-masked mixture of example 1 was further processed to give soluble tablets.

Levofloxacin hemihydrate

Stearic acid mixture 467.23mg

Corn starch 243.77mg

Microcrystalline cellulose 200.00mg

Micronized crospovidone 50.00mg

Polyvinylpyrrolidone 5.00mg

Levofloxacin hemihydrate/stearic acid mixture, corn starch, microcrystalline cellulose, micronized crospovidone, and polyvinylpyrrolidone were mixed, granulated with water, dried, pressed through a 1.2mm screen, and tabletted with an eccentric tableting machine.

The bitter taste inherent to the active compound is largely masked in 100ml of aqueous suspension of the soluble tablet at room temperature.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

32.2% after 5 minutes 96.4%

47.4% after 15 minutes 100%

After 30 minutes 58.9% 100% example 3

Levofloxacin hemihydrate soluble tablet products were prepared according to the process of the invention using palmitic acid as the taste masking higher fatty acid:

levofloxacin hemihydrate 512.46mg

Palmitic acid 422.00mg

Microcrystalline cellulose 457.54mg

Crospovidone 150.00mg

Raspberry flavor corrective 30.00mg

Saccharin 60.00mg

Levofloxacin hemihydrate and palmitic acid were processed as described in example 1 to give a base mixture with masked taste.

Mixing the above mixture with microcrystalline cellulose, crospovidone, raspberry flavor and saccharin, compacting the total mixture and dry granulating through a 1.0mm screen. The granules are made into soluble tablets.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

43.5% after 5 minutes 100%

58.9% to 100% after 15 minutes

73.9% after 30 minutes 100% example 4

The norfloxacin soluble tablets were prepared according to the process of the present invention using stearic acid as the taste-masking higher fatty acid. Norfloxacin is an example of a drug with lower solubility than levofloxacin.

500.00mg of norfloxacin

Stearic acid 600.00mg

Corn starch 711.46mg

Microcrystalline cellulose 638.32mg

Crospovidone 146.22mg

High dispersibility silica 14.00mg

Pear flavor corrective 30.00mg

Saccharin 40.00mg acetoacetate derivative (Acesulfam K) 20.00mg

Norfloxacin and stearic acid were treated in a similar manner to example 1 to give a taste-masked base mixture. Mixing corn starch, microcrystalline cellulose, crospovidone, high dispersibility silica, pear flavor, saccharin, and acetoacetic acid derivatives with the base mixture. The total mixture was tabletted with an eccentric tabletting machine.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

7.6% 94.9% after 5 minutes

16.5% 99.5% after 15 minutes

24% 100% after 30 min example 5

According to the process of the present invention, ofloxacin soluble tablets are prepared using stearic acid as the taste-masking higher fatty acid.

Ofloxacin 500.00mg

Stearic acid 600.00mg

Corn starch 711.46mg

Microcrystalline cellulose 638.32mg

Crospovidone 146.22mg

High dispersibility silica 14.00mg

Pear flavoring agent 30.00mg

Saccharin 40.00mg

Acetoacetic acid derivative 20.00mg

Ofloxacin and stearic acid were treated in a similar manner to example 1 to give a taste-masked base mixture. Corn starch, microcrystalline cellulose, crospovidone, high dispersibility silica, pear flavor, saccharin, and the acetoacetic acid derivative are mixed with the base mix, the total mix is compacted, granulated through a 1.0mm screen, and tableted with an off-center tableting machine.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

6.8% after 5 minutes 87.3%

14.4% after 15 minutes 100%

After 30 minutes 20.6% 100% of examples 6, 7, 8 and 9

Soluble tablets of levofloxacin hemihydrate were prepared using different waxy materials as taste masking agents.

Example 9101112 levofloxacin hemihydrate 512.45mg 512.45mg 512.45mg 512.45mg

Stearic acid 422.00 mg-

Stearyl alcohol-422.00 mg-

Hydrogenated Castor oil- -422.00 mg-Glycerol monostearate- -422.00 mg polyvinylpyrrolidone 2500010.00 mg 10.00mg 10.00mg 10.00mg

Corn starch 487.55mg 487.55mg 487.55mg 487.55mg

Microcrystalline cellulose 400.00mg 400.00mg 400.00mg 400.00mg micronized crospovidone 100.00mg 100.00mg

Levofloxacin hemihydrate was ground with stearic acid or stearyl alcohol or hydrogenated castor oil or glycerol monostearate in a mortar and heated in a drying oven at 80 ℃ for 1 hour. The mixture was cooled, pulverized and mixed with polyvinylpyrrolidone 25000, corn starch, microcrystalline cellulose and micronized crospovidone, the mixture was granulated with water, dried, passed through a 1mm screen and the granules compressed into tablets.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained: example 9101112

Release medium water 33.5% 64.3% 51.9% 61.6% after 5 minutes 46.4% 81.7% 76.1% 74.4% after 30 minutes 63.4% 90.6% 89.3% 81.5%

Release Medium 95.3% 91.6% 81.2% 85.1% after 0.1N HCl5 min 100% 99.4% 94.0% 93.8% after 30 min 100% 100% 98.6%

The soluble tablets of examples 9 to 12 were suspended in 100 water and evaluated for taste, only the taste of the soluble tablet of example 9 was suitably masked. Comparative example 1

Levofloxacin hemihydrate soluble tablets were prepared without the process of the present invention using palmitic acid as the higher fatty acid. Levofloxacin hemihydrate 512.46mg palmitic acid 422.00mg microcrystalline cellulose 807.54mg crospovidone 150.00mg raspberry flavoring agent 30.00mg saccharin 60.00mg

Levofloxacin hemihydrate, palmitic acid, microcrystalline cellulose, crospovidone, raspberry flavor and saccharin are mixed, compacted and dry granulated through a 1.0mm screen. The dry granules are formed into soluble tablets.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

89.9% 98% after 5 minutes

100% after 15 minutes

100% after 30 minutes

The inherent bitterness of the drug was perceived to be much stronger after suspending this soluble tablet in 100ml of water compared to the soluble tablet of example 3. Comparative example 2

The norfloxacin-soluble tablets were prepared without the process of the present invention and without the use of higher fatty acids.

500.00mg of norfloxacin

Corn starch 711.46mg

Microcrystalline cellulose 638.32mg

Crospovidone 146.22mg

High dispersibility silica 14.00mg

Pear flavor corrective 30.00mg

Saccharin 40.00mg

Acetoacetic acid derivative 20.00mg

Mixing norfloxacin, corn starch, microcrystalline cellulose, polyvinylpolypyrrolidone, high-dispersibility silica, pear flavor correctant, saccharin and acetoacetic acid derivatives, and making into tablet.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

40.1% 98.2% after 5 minutes

62.2% after 15 minutes 100%

73.2% after 30 minutes 100%

After suspending the soluble tablets of example 4 and comparative example 2 in 100ml of water, respectively, the following taste tests showed that: the preparation of example 4, which is taste-masked with the active compound according to the process of the invention, is free from bitter taste; rather than following the process of the present invention, the intrinsic bitterness of the compound in the formulation prepared according to comparative example 2 was determined very clearly. Comparative example 3

Ofloxacin soluble tablets are not prepared according to the process of the present invention, nor are higher fatty acids used.

Ofloxacin 500.00mg

Corn starch 711.46mg

Microcrystalline cellulose 638.32mg

Crospovidone 146.22mg

High dispersibility silica 14.00mg

Pear flavor corrective 30.00mg

Saccharin 40.00mg

Acetoacetic acid derivative 20.00mg

Ofloxacin, corn starch, microcrystalline cellulose, crospovidone, highly dispersible silica, pear flavor, saccharin, and acetoacetic acid derivatives are mixed and compressed into tablets.

The release of this active mixture was measured in a usp paddle stirrer and the following results were obtained:

release medium

900ml of Water 900ml of 0.1N HCl

89.9% after 5 minutes 95.4%

100% 97.4% after 15 minutes

100% after 30 minutes

After suspending the soluble tablets of example 5 and comparative example 3 in 100ml of water, respectively, the following taste tests showed that: the preparation of example 5, which is taste-masked with the active compound according to the process of the invention, is free from bitter taste; rather than following the process of the present invention, the intrinsic bitterness of the compound in the formulation prepared according to comparative example 3 was determined very clearly.

Claims (13)

1. A process for preparing antibacterial quinolone-derivative orally taken medicine with masked taste and quick release of active compound includes mixing quinolone derivative with at least one higher fatty acid and heating to raise the temp to 30-140 deg.C.

2. The method of claim 1, wherein the temperature is from 40 ℃ to 120 ℃.

3. The method of claim 1 or 2, wherein the temperature is from 65 ℃ to 85 ℃.

4. The process as claimed in one or more of claims 1 to 3, wherein the mixture is heated with a high number of revolutions of the hot mixer.

5. The process as claimed in one or more of claims 1 to 4, wherein the temperature is raised exclusively by frictional heating in the mixer.

6. The process as claimed in one or more of claims 1 to 5, wherein the weight ratio of the one or more quinolone derivatives to the one or more fatty acids is from 1: 0.3 to 1: 4.

7. The method of one or more of claims 1 to 6, wherein the fatty acid has at least 10 carbon atoms.

8. The process as claimed in one or more of claims 1 to 7, wherein the fatty acids contain from 10 to 18 carbon atoms.

9. The process as claimed in one or more of claims 1 to 8, wherein the antibacterial quinolone derivative used is a quinolone derivative such as levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, siloxacin or enoxacin.

10. The process as claimed in one or more of claims 1 to 9, wherein the antibacterial quinolone derivative is levofloxacin or ofloxacin.

11. Process according to one or more of claims 1 to 10, wherein the mixture of antibacterially active quinolone derivatives with higher fatty acids and, if desired, further additives is processed to give pharmaceutical dosage forms of the active compounds whose taste is to be masked, such as soluble tablets, chewable tablets, sachets and the like.

12. A formulation preparable by a process as claimed in claims 1 to 11.

13. A formulation according to claim 12 for use in the manufacture of a medicament for the treatment of bacterial infections.