MXPA98000688A - Obtaining preparations of quinolone derivatives with antibacterial activity, with flavor encubie - Google Patents

Abstract

The present invention relates to a process for obtaining preparations of quinolone derivatives with antibacterial activity, with covert taste, as well as for preparations obtainable by this process.

Description

Obtaining preparations of quinolone derivatives with antibacterial activity, with covert taste The present invention relates to a process for obtaining oral pharmaceutical preparations of quinolone derivatives with antibacterial activity, with covert taste.

It is known that substances with antibacterial activity that inhibit the bacterial gyrase of the quinolone group of substances are characterized by their own strongly bitter taste. In order to achieve sufficient acceptance by the patient, in the case of the administration of oral preparations of the substances this own taste must be disguised. As a rule, this is achieved by varnishing the tablets with a film. For therapy with quinolone derivatives with an abacterial activity, unit doses of 100 mg to 1,000 mg of the drug substance are necessary. The ingestion of solid dosage forms of such a large volume by swallowing presents great difficulties in the case of elderly patients and in patients with hindered swallowing and children, such that there is a need for an oral pharmaceutical form of acceptable taste, which It must not be swallowed entirely in solid form, but may be taken either suspended in a liquid or by chewing. The technologically simpler way and way to conceal an unpleasant taste is the addition of suitable flavors to a solution of the drug. However, in the case of quinolone derivatives with antibacterial activity this measure is insufficient, so that additional steps are necessary to conceal or neutralize the bitter taste. The methods known to date tend to prevent or at least decrease the dissolution of the quinolone derivatives with antibacterial activity, with a predominantly good solubility in the solvents used and in the saliva.

In EP-A-0 551 820 this is achieved by microencapsulating the anhydrate of the basic form of these substances. As the wrapping materials, neutral water insoluble methyl and / or ethyl ester compounds or poly (methacrylic acid) quaternary ammonium compounds or mixtures thereof or ethylcellulose are used. In Biol. Pharm. Bull. (1993), 16 (2), 172-7 describes a microencapsulation of granular fines of sparfloxacin and hydroxypropylcellulose with lower substitution, using ethylcellulose and hydroxypropylmethylcellulose as wrapping materials. In EP-A-409 254 a similar process for the microencapsulation of particles of antibacterial agents of pyridonecarboxylic acid (especially enoxacin) and water-swellable agents based on ethylcellulose and water-soluble polymers is described. In these processes, the wrapping materials for microencapsulation are applied by spraying their solutions. It is inconvenient in this case that equipment constructed in a costly manner is necessary, and that a practical lower limit is set for the useful particle size of the granules to be coated - on the one hand, caused by the consumption of varnish, which grows supraproportionally as it decreases the particle size, and on the other hand by the increasing cohesiveness as the particle size decreases, which technically limits the possibilities of coating by means of spraying, due to the increasing tendencies to agglomeration. Thus, EP-A-0551 820 mentions the range of 100-500 μm as the preferred range for the microcapsules obtained. However, particles of 500 μm, applied as a suspension, can produce an unpleasant sandy sensation in the patient's mouth. In addition, the time required to spray-coat finer particles is high. JP 63 150220 describes a process that should also produce a product similar to a microencapsulation. A drug substance is mixed in the form of powder (for example enoxacin with powder coating material), for example with waxy substances, such as paraffin, stearic acid, beeswax, etc., or with polymers, substances suitable for the formation of films such as methacrylic acid copolymer, ethylcellulose, polystyrene, etc. Organic solvents are added to the mixture to dissolve the wrapping materials. After removing the solvent, a powder is again obtained. The use of flammable solvents, harmful to health or ecologically questionable, which must be recovered or disposed of in an expensive manner, is inconvenient in this process. There is also a residual amount in the product. It is common to all the methods described to date for the coating of active substance particles or granules of quinolone derivatives with antimicrobial activity to use liquid carriers as a means for dissolving or dispersing the wrapping materials. The invention has been based on the task of making available a method for obtaining orally administrable covertly-flavored pharmaceutical preparations, with a rapid release of active substance from quinolone derivatives with antibacterial activity, which does not present the drawbacks that are have cited the methods known in the literature, and also avoided the use of liquid vehicles as a means for dissolving or dispersing the wrapping materials. The release of at least 80% of a unit dose after 30 minutes in 900 ml of 0.1 N HCl is understood by rapid release of active substance. It has now been found, surprisingly, that the concealment of taste is even possible. without using liquid vehicles, if quinolone derivatives with antimicrobial activity, with higher fatty acids and, eventually, with other additives are mixed, the mixture is heated, and ground after cooling, to give a powder or granulate. Even after spraying, the product still has a sufficient concealment of flavor. ? Warm up? of the mixture can be carried out by customary methods. From the point of view of the process technique, the use of a high-speed heating mixer (such as, for example, the fluid mixer Henschel Fluid ischer F 4 or FM10) in which the mixtures are heated is preferred. by the heat of friction, and that offers in the same equipment the possibility of the crushing after the cooling. A high number of revolutions means a number of revolutions of at least 3,000 rpm The mixtures are heated to 30 ° C to 140 ° C, preferably to 40 ° C to 120 ° C, particularly preferably 50 ° C to 85 ° C. C. The invention also relates to preparations which can be obtained according to this process. Higher fatty acids are understood to mean 0 fatty acids with at least 10 C atoms. Suitable higher fatty acids are those having 10 to 22 carbon atoms. carbon, with fatty acids having 12 to 18 carbon atoms being particularly suitable for the process described, and mixtures of fatty acids can also be advantageously used, so that commercially available stearic acid, which is a mixture of approximately equal amounts of stearic acid and palmitic acid Another suitable additive is, for example, highly dispersed or dispersed silicon dioxide. Two of quinolone with antibacterial activity have as an essential structural feature l-ethyl-4-oxo-pyridine-3-carboxylic acid (see Auterhoff, Knabe, Hóltje, Lehrbuch der Pharmazeutischen Chemie, 13th edition, 5 1994, page 788). Levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, sparfloxacin or enoxacin are preferred. Especially preferred are levofoxacin and ofloxacin. The weight ratio of derivative or quinolone derivatives to acid or fatty acids is preferably 1: 0, 3 to 1: 4, especially preferably 1: 1 5 to 1: 2. The heat-treated and subsequently comminuted preparations according to the invention based on quinolone derivatives with antibacterial activity and higher fatty acids can be further processed to obtain medicaments such as, for example, sachets, chewable tablets or drinkable tablets. 1. Drinkable tablets A drinkable tablet is a pharmaceutical form which is intended to disintegrate in a glass of water in the course of 3 minutes, at most, with agitation, and form a suspension that can pass a mesh aperture screen of 0.715 mm. The drinkable tablets are offered as pharmaceutical form for medicinal substances of too high dosage, which would be difficult to swallow because of their large volume as conventional tablets. The special way of administration of the drinkable tablets in the form of suspension or solution requires a sufficient concealment of the taste of bad tasting medicinal substances. The drinkable tablets can be formulated with auxiliary substances which are also used for conventional tablets. Aromas, substances or sweeteners and, optionally, coloring substances are also typically added. Wet-granulation, dry granulation and direct tablet formation are useful preparation technologies. 2. Envelopes Envelopes are bags that contain at least one unit dose of a medicine in the form of powder or granules. For administration, the contents of a bag are suspended or dissolved in a glass of water. Suitable additives are, in addition to sugars and sugar substitutes, substances that increase viscosity, creep-regulating agents, aroma substances, coloring substances and optionally buffer substances. 3. Chewable tablets Chewable tablets are tablets that break with your teeth before you swallow them. Reasons for the use of this pharmaceutical form are also the problems that certain groups of patients have, in the case of quinolone derivatives with high dosage antibacterial activity, with the ease of swallowing tablets, film-coated tablets, capsules or conventional lozenges . The chewable tablets contain predominantly in most cases, in addition to other auxiliary substances customary for the preparation of tablets, sugar or sugar substitutes, and also flavorings. The release of the active substance is measured in a USP pallet apparatus, as described in the US Pharmacopoeia. USP23, page 1792, section 711, figure 2.

Exemplary embodiments Example 1 shows the preparation of a base mixture of levofloxacin hemihydrate, with covert taste Levofloxacin hemihydrate 256.23 mg Stearic acid 211.00 mg Levofloxacin hemihydrate and stearic acid are mixed for 3 minutes in a heating mixer at a speed of 1000 rpm. The number of revolutions is then increased to 5,500 rpm. and stirring is continued until the temperature of the mixture mass reaches 75 ° C and said mass has acquired a structure in the form of granules. It is cooled to room temperature by cooling the jacket, and then the dough is ground by further mixing for 4 x 0.5 minutes at 5500 r.p.m., with additional cooling. A powder with a neutral taste is obtained. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 34.2% 91.2% after 15 minutes 47.1% 97.9% after 30 minutes 55.7 % 97.4% Example 2 shows the further elaboration of the covertly flavored base mixture of Example 1, to give a drinkable tablet Mixture of levofloxacin hemihydrate / stearic acid 467.23 mg Corn starch 243.77 mg Microcrystalline cellulose 200.00 mg Crospovidone micronized 50.00 mg Polyvinylpyrrolidone 5.00 mg The levofloxa-cino / stearic acid hemihydrate mixture, the corn starch, the microcrystalline cellulose, the micronized crospovidone and the polyvinylpyrrolidone are mixed, granulated with water, dried, and pressed through a 1 mesh screen. , 2 mm, and tablets are obtained with an eccentric tabletting machine. In the suspension of the drinkable tablet in 100 ml of tap water at room temperature, the bitter taste of the active substance is widely disguised. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 32.2% 96.4% after 15 minutes 47.4% 100% after 30 minutes 58.9% 100 % Example 3 shows the preparation of a drinking tablet of levofloxacin hemihydrate with palmitic acid as a superior fatty acid concealed from the taste, which had been prepared according to the process according to the invention: Levofloxacin hemihydrate 512.46 mg Palmitic acid 422.00 mg Microcrystalline cellulose 457.54 mg Crospovidone 150.00 mg Raspberry aroma 30.00 mg Aspartame 60.00 mg Levofloxacin hemihydrate and palmitic acid are prepared, as described in Example 1, to obtain a base mixture with covert taste. The microcrystalline cellulose, the crospovidone, the raspberry flavor and the aspartame are added and mixed, and the joint mixture is compacted and dry granulated through a 1.0 mm sieve. The dry granulate is made to obtain drinkable tablets.

The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 43.5% 100% after 15 minutes 58.9% 100% after 30 minutes 73, 9% 100% Example 4 shows the preparation of a norfloxacin drinkable tablet according to the process according to the invention, with stearic acid as a superior fatty acid to hide the taste. Norfloxacin is an example of a drug substance with lower solubility than levofloxacin.

Norfloxacin 500.00 mg Stearic acid 600.00 mg Corn starch 711.46 mg Microcrystalline cellulose 638.32 mg Crospovidone 146.22 mg Highly dispersed silicon dioxide 14.00 mg Peach aroma 30.00 mg Aspartame 40.00 mg Acesulfame K 20.00 mg Norfloxacin and stearic acid are prepared, in a manner analogous to Example 1, to obtain a base mixture with covert taste. Corn starch, microcrystalline cellulose, crospovidone, highly dispersed silicon dioxide, peach flavor, aspartame and acesulfa or K. are added to the base mixture, with an eccentric tabletting machine tablets are obtained from the joint mix.

The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 7.6% 94.9% after 15 minutes 16.5% 99.5% after 30 minutes 24% 100 % Example 5 shows the preparation of a drinkable tablet of ofloxacin according to the process according to the invention, with stearic acid as a superior fatty acid to hide the taste.

Ofloxacin 500.00 mg Stearic acid 600.00 mg Corn starch 711.46 mg Microcrystalline cellulose 638.32 mg Crospovidone 146.22 mg Highly dispersed silicon dioxide 14.00 mg Peach aroma 30.00 mg Aspartame 40.00 mg Acesulfame K 20.00 mg -il- Ofloxacin and stearic acid are prepared, in a manner analogous to Example 1, to obtain a base mixture with covert taste. Maize starch, microcrystalline cellulose, crospovidone, highly dispersed silicon dioxide, peach flavor, aspartame and acesulfame K are added and mixed to the base mixture, the joint mixture is compacted, granulated through a sieve of 1.0 mm, and tablets are obtained with an eccentric tabletting machine. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 6.8% 87.3% after 15 minutes 14.4% 100% after 30 minutes 20.6% 100 % Examples 6, 7, 8 and 9 show the preparation of drinking tablets of levofloxacin hemihydrate using different waxy substances as flavoring agents.

Example 9 10 11 12 Levofloxacin hemihydrate 512.45 mg 512.45 mg 512.45 mg 512.45 mg Stearic acid 422.00 mg Stearyl alcohol 422.00 mg Hydrogenated castor oil 422.00 mg Glycerol monostearate 422.00 mg Polyvidone 25000 10.00 mg 10.00 mg 10.00 mg 10.00 mg Corn starch 487.55 mg 487.55 mg 487.55 mg 487.55 mg Microcrystalline cellulose 400.00 mg 400.00 mg 400.00 mg 400.00 mg Crospovidone micronized 100.00 mg 100.00 mg 100.00 mg 100.00 mg The levofloxacin hemihydrate and, respectively, the stearic acid, the stearyl alcohol, or the hydrogenated castor oil are stirred in a capsule and heated for 1 hour at 80 ° C in a drying oven. Allow to cool, mix the mixture and add Polyvidone 25000, corn starch, microcrystalline cellulose and micronized crospovi-dona. The mixture is granulated with water, dried, passed through a sieve with a 1 mm mesh opening, and the granulate is compressed to obtain tablets. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Example 9 10 11 12 Release medium: water after 33.5% 64.3% 51.9% 61.6% 5 minutes after 46.4% 81.7% 76.1% 74.4 % 15 minutes after 63.4% 90.6% 89.3% 81.5% 30 minutes Release medium: 0.1 N hydrochloric acid after 95.3% 91.6% 81.2% 85 , 1% 5 minutes after 100% 99.4% 94.0% 93.8% 15 minutes after 100% 100% 100% 98.6% 30 minutes After suspending the drinkable tablets of Examples 9 to 12 in each case in 100 ml of tap water and evaluating the taste, only for the drinkable tablets of Example 9 did a sufficient concealment of the taste result.

Comparative Example 1 shows the preparation of a levof loxacin hemihydrate tablet with palmitic acid as a higher fatty acid, which has not been prepared according to the process according to the invention.

Levof loxacin hemihydrate 512.46 mg Palmitic acid 422.00 mg Microcrystalline cellulose 807.54 mg Crospovidone 150.00 mg Raspberry scent 30.00 mg Aspartame 60.00 mg Levofloxacin hemihydrate, palmitic acid, cellulose are mixed microcrystalline, crospovidone, raspberry flavor and aspartame, are compacted and granulated dry through a 1.0 mm sieve. The dry granulate is made to obtain drinkable tablets. Determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 89.9% 98% after 15 minutes 100% 100% after 30 minutes 100% 100% After suspending the drinkable tablet in 100 ml of water, the bitter taste of the drug substance could be found much more strongly than in the case of the drinkable tablet of Example 3.

Comparative Example 2 shows the obtaining of a norfloxacin drinkable tablet which has not been prepared according to the process according to the invention and without using a higher fatty acid either.

Norfloxacin 500.00 mg Corn starch 711.46 mg Microcrystalline cellulose 638.32 mg Crospovidone 146.22 mg Highly dispersed silicon dioxide 14.00 mg Peach aroma 30.00 mg Aspartame 40.00 mg Acesulfame K 20.00 mg Norfloxacin, corn starch, microcrystalline cellulose, crospovidone, highly dispersed silicon dioxide, peach aroma, aspartame and acesulfame K are mixed and compressed into tablets. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 40.1% 98.2% after 15 minutes 62.2% 100% after 30 minutes 73.2% 100 % After suspending the drinkable tablets of Example 4 and Comparative Example 2 in each case in 100 ml of tap water, the following results were obtained in the taste test: the preparation of example 4 with the active substance with covert taste according to the process of according to the invention, it no longer exhibited any bitter taste, whereas the preparation not in accordance with the invention, according to Comparative Example 2, allowed to clearly recognize the bitter taste of the active substance itself.

Comparative Example 3 shows the obtaining of a drinkable tablet of ofloxacin which has not been prepared according to the process according to the invention and without using a higher fatty acid either.

Ofloxacin 500.00 mg Corn starch 711.46 mg Microcrystalline cellulose 638.32 mg Crospovidone 146.22 mg Highly dispersed silicon dioxide 14.00 mg Peach aroma 30.00 mg Aspartame 40.00 mg Acesulfame K 20.00 mg The ofloxacin, the corn starch, the crospovidone, the highly dispersed silicon dioxide, the peach aroma, the aspartame and the acesulfame K are mixed and compressed to obtain tablets. The determinations of the release of the active substance in a USP pallet apparatus yielded the following results: Release medium 900 ml of water 900 ml of 0.1 N hydrochloric acid after 5 minutes 89.9% 95.4% after 15 minutes 100% 97.4% after 30 minutes 100% 100% After suspending the drinkable tablets of Example 5 and Comparative Example 3 in each case in 100 ml of tap water, the following results were obtained in the taste test: the preparation of Example 5 with the active substance with covert taste according to the procedure of according to the invention no longer had any bitter taste, while the preparation not in accordance with the invention, according to Comparative Example 3 allowed to clearly recognize the unpleasant bitter taste of the active substance itself.

Claims (13)

1. Process for obtaining covertly-flavored pharmaceutical preparations, orally administrable, with a rapid release of active substance from quinolone derivatives with antibacterial activity, characterized in that the quinolone derivative is mixed with at least one higher fatty acid and at the same time , then it is carried by heating to a temperature of 30 ° C to 140 ° C.

2. Method according to claim 1, characterized in that the temperature rises to 40 ° C to 120 ° C.

3. Procedure according to with claim 1 or 2, characterized in that the temperature rises to 65 'C until 85'C.

Method according to one or more of claims 1 to 3, characterized in that a high-speed heating mixer is used for heating.

Method according to one or more of claims 1 to 4, characterized in that the temperature rise is achieved exclusively by the friction heat originating in the mixer.

Process according to one or more of claims 1 to 5, characterized in that the weight ratio of derivative or quinolone derivatives to acid or fatty acids is 1: 0.3 to 1: 4.

7. Process according to one or more of claims 1 to 6, characterized in that fatty acids with at least 10 carbon atoms are used.

8. Process according to one or more of claims 1 to 7, characterized in that fatty acids having 10 to 18 carbon atoms are used.

9. Process according to one or more of claims 1 to 8, characterized in that quinolone derivatives such as levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, sparfloxacin or enoxacin are used as quinolone derivatives with antibacterial activity.

10. Process according to one or more of claims 1 to 9, characterized in that levofloxane or ofloxacin are used as quinolone derivatives with antibacterial activity.

11. Process according to one or more of claims 1 to 10, characterized in that the mixture of quinolone derivative with antibacterial activity, higher fatty acids and, if appropriate, other additive substances is prepared in order to obtain pharmaceutical forms that require a taste concealer. the active substance, such as drinkable tablets, chewable tablets, sachets, etc.

12. Preparations that can be obtained according to the method according to claims 1 to 11.

13. Preparations according to claim 12 for obtaining a medicament for the treatment of bacterial infections.