MXPA06004276A - Antibiotic compositions - Google Patents

Abstract

The invention provides an antibiotic composition comprising coated micropellets and a method for preparing said antibiotic composition.

Description

ANTIBIOTIC COMPOSITIONS Field of the Invention The present invention provides an antibiotic composition comprising coated microgranules.

Background of the Invention Antibiotics, such as clarithromycin and erythromycin, have been used in the treatment of common pediatric infections of the middle ear and upper respiratory tract, as well as certain forms of pneumonia affecting the elderly. However, these antibiotics are extremely bitter, and even when dissolved in trace amounts in a liquid dosage form, they are often perceived as having an unpleasant taste. The administration of these antibiotics to children and the elderly presents a challenge, because these patients experience difficulty swallowing solid oral dosage forms. For these patients, antibiotics are usually provided in liquid forms, such as solutions, emulsions, and suspensions, which usually allow perceptible exposure of the antibiotic to the gustatory papilla. There is a need to mask the taste of these antibiotics in order to ensure patient compliance during therapy. Conventional taste masking techniques, such as the use of sweeteners, amino acids, and flavoring agents, often do not succeed in masking the taste of highly bitter drugs, and consequently, other techniques need to be exploited to effectively mask the taste. of these antibiotics. One technique involves the use of cation exchange resins, such as polymers of polysulfonic acid and polycarboxylic acid, to adsorb the amine drugs to mask the taste and for sustained release. However, this technique has limited applicability, and is not capable of masking the taste of highly bitter drugs. The coating of bitter drugs is another method that has been reported to mask the taste. This technique alone can be effective for moderately bitter drugs, or in products where the coated particles are formulated as aqueous preparations before administration, or formulated in a non-aqueous medium. This technique has its limitations, because the coating of fine particles is usually intense in technology, and the coated granules are easily broken by chewing and compression. Lipid-based microencapsulation is another technique used to mask the taste of drugs. This technique requires highly sophisticated hot melt granulation to produce fine particles, and can have adverse effects on heat sensitive molecules, or restrict drug release adversely. U.S. Patent No. 4,865,851 discloses cefuroxime axetil in the form of particles coated with an integral coating of lipid or a mixture of lipids. U.S. Patent No. 4,808,411 discloses a masked taste composition in the form of granules containing clarithromycin and a carbomer-acrylic acid polymer. It is believed that clarithromycin and carbomer are held together by both the ionic interactions between the amine group of clarithromycin and the carbonyl group of the carbomer, and by the gel properties of the carbomer. In addition, this complex is masked by coating. U.S. Patent No. 5,286,489 discloses a porous drug-polymer matrix formed by mixing one or more bitter-tasting active ingredients and a methyl-methacrylic ester copolymer in at least a 1: 1 ratio in weight of the active ingredient to the copolymer, effective to mask the taste of the drug. None of the examples disclosed in U.S. Patent No. 5,286,489 discloses the effect of these polymers on the release of the drug from the matrix. Although this drug-polymer matrix can result in good taste masking, the matrix can also retard the rate of drug release from the matrix to a degree that would be unacceptable for a conventional immediate release formulation. U.S. Patent No. 5,633,006 discloses a masked taste composition containing a bitter pharmaceutical agent such as azithromycin, an alkaline earth oxide such as magnesium oxide, and a pharmaceutically acceptable carrier. U.S. Patent No. 6,565,877 discloses a masked taste composition containing a bitter-tasting drug, such as clarithromycin, and a composition of two enteric polymers comprising a copolymer of methacrylic acid and a phthalate polymer, wherein the ratio of the methacrylic acid copolymer to the phthalate polymer is between 1: 9 or 9: 1. International Publication Number WO 03/082248 describes a pharmaceutical composition containing erythromycin A or a derivative thereof, such as clarithromycin, and alginic acid. International Publication Number WO 03/082241 describes a pharmaceutical composition containing micronized clarithromycin. Clarithromycin has a particle size of less than 35 microns.

SUMMARY OF THE INVENTION The invention provides an antibiotic composition comprising coated microgranules, and optionally one or more excipients, wherein said coated microgranules comprise: (i) a core comprising at least one antibiotic; (ii) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (i¡¡) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns. According to another aspect, the invention provides an oral suspension comprising: (a) an antibiotic composition comprising coated microgranules and optionally one or more excipients, (b) additional excipients, and (c) a solvent, wherein said microgranules Coated comprise: (i) a core comprising at least one antibiotic; (i) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (iii) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns. According to another aspect, the invention provides a method for preparing an antibiotic composition comprising coated microgranules, and optionally one or more excipients, said method comprising: (A) mixing at least one antibiotic, and optionally one or more excipients, to form a premix; (B) adding a solvent, and optionally one or more excipients, to the premix formed in Step (A), and granulating in the presence of a propeller set at at least 50 revolutions per minute, to form a wet granulation; (C) drying the wet granulation, and optionally grinding and sieving the dried granules to form microgranules; and (D) coating the microgranules with an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (E) coating the microgranules of Step (D) with an outer coating comprising at least one enteric coating polymer to form coated microgranules, wherein these coated microgranules have an average particle size of about 100 microns to about 650 microns. The oral suspension of the invention is characterized by a lack of bitter taste.

Description of the Invention The invention provides an antibiotic composition comprising coated microgranules and optionally one or more excipients, wherein said coated microgranules comprise: (i) a core comprising at least one antibiotic; (i i) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (iii) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns. As used herein, "coated microgranules" refers to granules having an average particle size of about 100 microns to about 650 microns, preferably 200 microns to about 500 microns. More preferably, at least about 90 percent, preferably 95 percent of the coated microgranules, have a particle size of about 100 microns to about 650 microns, more preferably from about 200 microns to about 500 microns. Preferred antibiotics include the following: erythromycin; clarithromycin; f luoroquinolones, such as ciprofloxacin and norfloxacin; cephalosporin, such as cefuroxime and ceftriaxone; and tetracyclic antibiotics, for example chloramphenicol, chlorpromazine, etc. A combination of antibiotics can also be used. Preferably, the antibiotic is clarithromycin. The antibiotic preferably has a particle size of about 0.1 microns to about 100 microns, more preferably 5 microns to about 40 microns. The antibiotic is present in an amount of about 1 weight percent to about 80 weight percent, based on the total weight of the coated microgranule. Preferably, the antibiotic is present in an amount of about 5 weight percent to about 50 weight percent, more preferably from about 20 weight percent to about 35 weight percent, based on the weight total of the coated microgranule. Preferred cellulose polymers include the following: hydroxy-propyl-methyl-cellulose, hydroxy-propyl-cellulose, methyl-cellulose, ethyl-cellulose, carboxy-methyl-ethyl-cellulose, sodium carboxy-methyl-cellulose, and ethyl- carboxy-ethyl-cellulose. A combination of cellulose polymers can also be used. More preferably, the cellulose polymer is hydroxypropyl methyl cellulose or hydroxypropyl cellulose. Most preferably, the cellulose polymer is hydroxypropyl methyl cellulose. Preferred enteric coating polymers include the following: crosslinked poiivinyl pyrrolidone; non-crosslinked polyvinyl-pyrrolidone; hydroxy-propyl-methyl-cellulose phthalate, hydroxy-propyl-methyl-cellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxy-propyl-methyl-cellulose acetate succinate, cellulose acetate trimellitate, hydroxy-propyl-methyl-cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; starch acetate phthalate; poly-vinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate; methyl cellulose succinate; methyl cellulose phthalate succinate; methyl-cellulose italic acid half-ester; ethyl cellulose succinate; carboxymethyl amide; potassium methacrylate copolymer / di vi nyl-benzene; polyvinyl alcohols; poly oxyethylene glycols; polyethylene glycol; sodium alginate; galactomanone; carboxy-polymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with a monomer selected from the following: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate , methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, for example the series EUDRAGIT®-L and -S, such as L100-55, L30D55, L100, S100, L12.5, and S12.5 , available in Rohm; vinyl acetate poly; fats; oils; waxes; fatty alcohols; shellac; gluten; ethyl acrylate-maleic acid anhydride copolymer; maleic acid / vinyl methyl ether anhydride copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate-maleic acid anhydride; copolymer of croton ico-vinyl acetate acid; glutamic acid / glutamic acid ester copolymer; glycerol carboxymethyl ethyl cellulose mono-octanoate; polyarginin; poly (ethylene); Polypropylene); p or I i (ethylene oxide); poly (ethylene terephthalate); poly (vinyl isobutyl ether); polyvinylchloride); and polyurethane. A combination of enteric coating polymers can also be used. More preferably, the enteric coating polymer is selected from a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate. More preferably, the enteric coating polymer is poly (methacrylic acid, ethyl acrylate) 1: 1 (EUDRAGIT®-L30D-55 and EUDRAGIT®-L100-55). It is within the scope of the invention that the antibiotic compositions include one or more pharmaceutically acceptable excipients. Examples of these excipients are binders, diluents, plasticizers, anti-blocking agents, fillers, solvents, disintegrants, lubricants, surfactants, flavorings, sweeteners, stabilizers, anti-oxidants, anti-adherents, preservatives, skimmers, and pigments. A combination of excipients can also be used. These excipients are known to those skilled in the art, and therefore, only a limited number will be specifically referenced. Preferred binders include, but are not limited to, starches, e.g., potato starch, wheat starch, corn starch; gums, such as gum tragacanth, acacia gum, and gelatin; and polyvinylpyrrolidone, for example Povidone. A particularly preferred binder is polyvinyl pyrrolidone. Preferred plasticizers include, but are not limited to, esters of citric and tartaric acid (acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triethyl citrate); glycerol and glycerol-esters (glycerol diacetate and triacetate, acetylated monoglycerides, castor oil); esters of italic acid (dibutyl phthalate, diamyl phthalate, diethyl phthalate, dimethyl phthalate, dipropyl phthalate); di- (2-methoxy- or 2-ethoxy-ethyl) phthalate, ethyl-phthalyl glycolate, butyl-phthalyl-ethyl glycolate, and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of different chain lengths), adi ducks (diethyl adipate, di- (2-methoxy- or 2-ethoxy-etiio) adipate, benzophenone, di-ethyl and dibutyl sebacate, dibutyl succinate , dibutyl tartrate, diethylene glycol dipropionate, diacetate, dibutyrate, and ethylene glycol dipropionate, tributyl phosphate, tributyltin, polyethylene glycol sorbitan mono-oleate (polysorbates, such as Polysorbar 50), sorbitan mono-oleate. can use a combination of plasticizers A preferred plasticizer for use with the cellulose polymer is polyethylene glycol, such as polyethylene glycol 600. A preferred plasticizer for use with the enteric coating polymer is a combination of triethyl citrate and glycerol monostearate. Preferred include, but are not limited to, microcrystalline cellulose, starch, pregelatinized starch, modified starch, phosphine dihydrate dibasic calcium atoate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, dextrose, sucrose, lactose, mannitol, and sorbltol. A particularly preferred filler is lactose.

Examples of the disintegrants include: (i) natural starches, such as corn starch, potato starch, and the like, directly compressible starches, for example Sta-rx® 1500; modified starches, for example carboxymethyl starches and sodium starch glycolate, available as Primojel®, Explotab®, Explosol®, and starch derivatives, such as amylose; (i i) crosslinked polyvinyl pyrrolidones, for example crospovidones, such as Polyplasdone® XL and Kollidon® CL; (iii) alginic acid and sodium alginate; (iv) methacrylic acid / divinyl benzene copolymer salts, for example Amberlite® IRP-88; Y (v) cross-linked carboxymethyl cellulose, available as, for example, Ac-Di-Sol®, Primellose®, Pharmacel® XL, Explocel®, and Nymcel® ZSX. Additional disintegrants also include hydroxypropyl I-cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium, sodium starch glycolate, potassium polacrilin, polyacrylates, such as Carbopol®, magnesium aluminum silicate, and bentonite. Examples of the surfactants include: 1) the reaction products of a natural or hydrogenated castor oil and ethylene oxide. Hydrogenated castor oils with polyethylene glycol available under the registered trademark Cremophor are especially suitable, such as CREMOPHOR RH 40 and CREMOPHOR RH 60. Also suitable are polyethylene glycol castor oils, such as that available under the trade name CREMOPHOR EL. 2) Esters of polyoxyethylene sorbitan fatty acids, also called polysorbates, for example mono- and tri-lauryl-, palmityl-, stearyl-, and oleyl-esters of known and commercial type available under the registered trademark TWEEN. 20 [[polyoxyethylene sorbitan monolaurate (20)], 21 [[polyoxyethylene sorbitan monolaurate (4)], 40 [[polyoxyethylene sorbitan momoxystitate (20)], 60 [[polyoxyethylene sorbitan monostearate (20)] )], 65 [[polyoxyethylene sorbitan tristearate (20)], 80 [[polyoxyethylene sorbitan mono-oleate (20)], 81 [[polyoxyethylene sorbitan mono-oleate (5)], 85 [[trioleate of polyoxyethylene sorbitan (20)]. A preferred product of this class is TWEEN 80.

Although polyethylene glycol (PEG) by itself does not function as a surfactant, a variety of polyethylene glycol fatty acid esters have useful surfactant properties. Among the monoesters of polyethylene glycol fatty acids, the most useful are the esters of lauric acid, oleic acid, and stearic acid. Among the surfactants of Table 1, the preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, laurate. of PEG-12, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 oleate. 3) Esters of polyoxyethylene fatty acids, for example esters of polyoxyethylene stearic acids of the known and commercial type available under the registered trademark MYRJ. 4) Polyoxyethylene-polyoxypropylene block copolymers and copolymers, for example of the known and commercially available type under the registered trademark PLURONIC, EMKALYX and POLOXAMER. Preferred products of this class are PLURONIC F68 and POLOXAMER 188. 5) Dioctyl sulphonate or di- [2-ethylhexyl] succinate. 6) Phospholipids, in particular lecithins. Suitable lecithins include, in particular, soybean lecithins. 7) Propylene glycol mono- and di-fatty esters, such as propylene glycol dicaprylate (also known and commercially available under the registered trademark MIGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, and propylene glycol stearate. 8) Polyoxyethylene alkyl esters, such as those commercially available under the registered trademark Brij, for example Brij 92V and Brij 35. 9) Esters of tocopherol, for example tocopheryl acetate and tocopheryl acid succinate. 10) Docusate salts, for example dioctyl sulfosuccinate or related compounds, such as di- [2-ethylhexyl] succinate]. A combination of surfactants can also be used.

Preferred sweeteners include, but are not limited to, artificial sweeteners such as rt ame, saccharin, and cyclamates; natural sweeteners such as sucrose, fructose, glucose, lactose, maltodextrin, and sodium glycolate; and mixtures of artificial and natural sweeteners, such as a mixture of aspartame and sucrose. Preferred flavors include, but are not limited to, cherry, strawberry, fruit punch, grape, cream, vanilla, chocolate, mocha, mint, cola, and the like. Preferred pigments include, but are not limited to, titanium dioxide, iron oxide, and vegetable dyes. Preferred diluents include, but are not limited to, dextrose, sorbitol, sucrose, lactose, mannitol, urea, potassium chloride, sodium chloride, gelatin, starch, methyl cellulose, ethyl cellulose, propyl cellous, hydroxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, silica, polyvinyl alcohol, polyvinyl pyrrolidone, and magnesium stearate. The antibiotic compositions of the invention are prepared using any of a wide variety of different methods well known to one of ordinary skill in the art. Antibiotic compositions are preferably prepared by mixing at least one antibiotic, and optionally one or more excipients, in the presence or absence of a solvent, to form a premix. The premix preferably is in the form of a solid dispersion or a homogeneous suspension. The premix preferably is subjected to high shear granulation, melt extrusion, wet granulation, or roll compaction, to form microgranules. The microgranules are preferably dried, or cooled in the case of melt extrusion, and optionally milled and / or sieved. The microgranules are coated with an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and an outer coating comprising at least one enteric coating polymer, to form the coated microgranules. In the case of high shear granulation, the high shear granulation preferably is conducted in the presence of a propeller set to at least 50 revolutions per minute. More preferably, the propeller is set at approximately 300 revolutions per minute. Most preferably, the high shear granulation is further conducted in the presence of a chopper which is preferably set at at least 1,000 revolutions per minute, and more preferably the chopper is set at approximately 2,400 revolutions per minute. In one embodiment of the invention, the antibiotic composition is prepared by a method comprising: (A) mixing at least one antibiotic, and optionally one or more excipients, to form a premix; (B) adding a solvent, and optionally one or more excipients, to the premix formed in Step (A), and granulating in the presence of a propeller set at at least 50 revolutions per minute, to form a wet granulation; (C) drying the wet granulation, and optionally grinding and sieving the dried granules to form microgranules; and (D) coating the microgranules with an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (E) coating the microgranules of Step (D) with an outer coating comprising at least one enteric coating polymer to form coated microgranules. Drying techniques include spray drying, fluid bed drying, flash drying, ring drying, micron drying, pan drying, vacuum drying, radiofrequency drying, and microwave drying. A preferred drying technique is in fluid bed. Types of mills include fluid energy mill, ball mill or rod mill, hammer mill, cutting mill, and oscillating granulator. More specifically, suitable mills include Quadro, Fryma, Glatt Quick, Sieve, Fluidaire, Fitzpatrick (Fitz mill), BTS mill, and Tornado. A preferred mill is a Fitz mill. The antibiotic compositions of the invention may be in the form of an oral suspension, capsule, caplet, powder, or tablet. In a preferred embodiment, the antibiotic compositions are in the form of an oral suspension. The oral suspension comprises: (a) an antibiotic composition comprising coated microgranules and optionally one or more excipients, (b) additional excipients, and (c) a solvent, wherein said coated microgranules comprise: (i) a core comprising less an antibiotic; (ii) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (iii) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns. The solvent for the oral suspension is preferably an aqueous solvent. The oral suspension in general is simply imbibed. In an alternative way, the oral suspension can be mixed with food or drinks. Examples of additional excipients are binders, diluents, plasticizers, anti-luting agents, fillers, solubilizing agents, disintegrants, lubricants, surfactants, flavors, sweeteners, stabilizers, antioxidants, anti-adherents, preservatives, skimmers, and pigments. A combination of additional excipients can also be used. Additional preferred excipients include sucrose, maltodextrin, potassium sorbate, silica, xanthan gum, titanium dioxide, and a flavoring.

Examples Example 1 Preparation of a Clarithromycin Composition.

Clarithromycin, lactose, starch, and croscarmellose sodium were mixed in a high-shear VG5 Glatt 2.5-liter granulator for 5 minutes, with a propeller set at 350 revolutions per minute, and a chopper set at 2,000 revolutions per minute. Separately, the polyvinyl pyrrolidone was mixed with water at room temperature until it dissolved. The polyvinyl pyrrolidone solution was added over a period of 3 minutes to the mixture containing clarithromycin, and was mixed in the granulator at 250 milliliters / minute in the above positions. The mixture in the granulator was continued for an additional 3 minutes in the above positions, to form wet granules. The wet granules were unloaded and placed on a tray, which was placed in an oven at 55 ° C for 4 hours to form dry granules. The dried granules were sieved through the US Standard Screen of mesh numbers 30, 40, 50, and 80. The granules collected on the 30 mesh were milled using a Quadro Co mill equipped with a # 62 screen to form microgranules. The microgranules were subjected to the screening procedure as described above, and the particle size distribution was summarized in Table 1. The yield of the remaining microgranules on the Sizes Nos. 40 to 80 was determined at 83.5 percent, based on the total amount of redients.

Table I Example 2: Preparation of a Composition of Clarithromycin.

Clarithromycin, lactose, starch, and Ac-Di-Sol were mixed in a 2.5-liter high-shear DG5 Glatt granulator for 5 minutes with a helix set at 300 revolutions per minute, and the chopper set at 2,400 revolutions per minute. Separately, the polyvinyl pyrrolidone was mixed with water at room temperature until it dissolved. The polyvinylpyrrolidone solution was added over a period of 3 minutes to the mixture containing clarithromycin, and was mixed in the granulator at 250 milliliters / minute in the above positions. The mixture in the granulator was continued for an additional 3 minutes in the above positions to form wet granules. The wet granules were unloaded and placed on a tray, which was placed in an oven at 55 ° C for 4 hours, to form dry granules. The dried granules were sieved through US Standard Sieve with 30, 40, 50, and 80 meshes. The granules collected on the 30 mesh were milled using a Fitzpatrick mill equipped with a # 65 sieve to form microgranules. The microgranules were subjected to the sieving procedure as described above, and the particle size distribution was summarized in Table II. The yield of the remaining pellets on Sizes Nos. 40 to 80 was determined at 81.15 percent, based on the total amount of ingredients.

Table II Example 3: Preparation of a Clarithromycin Composition.

Clarithromycin, lactose, starch, and Ac-Di-Sol were mixed in a high-shear VG5 Glatt 2.5-liter granulator for 5 minutes, with a propeller set at 400 revolutions per minute, and without a chopper blade. Separately, polyvinyl pyrrolidone and poloxamer 188 were mixed with water at room temperature until dissolved. The solution of polyvinyl pyrrolidone and poloxamer 188 was added over a period of 15 minutes to the mixture containing clarithromycin, and mixed in the granulator at 62 milliliters / minute and in the above positions. The mixture in the granulator was continued for an additional 3 minutes in the above positions to form wet granules. The wet granules were unloaded and placed on a tray, which was placed in an oven at 55 ° C for 4 hours to form dry granules. The dried granules were sieved through US Standard Screen No. 30 mesh, 40, 50, and 80. The granules collected on the 30 mesh were milled using a Fitzpatrick mill equipped with a # 65 sieve to form microgranules. The microgranules were subjected to the sieving procedure as described above, and the particle size distribution was summarized in Table III. The yield of the remaining pellets on Sizes Nos. 40 to 80 was determined at 58.0 percent, based on the total amount of ingredients.

Table III Example 4: Preparation of a Clarithromycin Composition.

The cyarithromycin and Poloxamer 188 were mixed in a vessel mixer, with a rotation speed of 16 revolutions per minute for 5 minutes. The mixture was granulated using a Theisson extruder at a temperature of 70 ° C. The mass was collected, and cooled to room temperature. The cooled granules were sieved through a 0.5 mm sieve, using an oscillating Frewitt. The granules were sieved through a 200 micron sieve and harvested. The fine particles of < 200 microns could be used for a repeated extrusion process.

Example 5: Preparation of a Clarithromycin Composition.

Poloxamer 188 and polyvinyl-pyrrolidone K-30 were dissolved and mixed in a stainless steel vessel mixer with agitator, and clarithromycin was suspended in this solution. Then the solution was spray dried, and agglomerated to form granules in a Glatt GPCG 30-WSA Module as follows: Spray pressure of the spray guns: 2.5 bar. Nozzle size: 1.5 mm. Entry air temperature: 110 ° C-130 ° C. Exit air temperature: 65 ° C-75 ° C. The dried granules were sieved through a sieve of 500 microns. The remaining granules on the sieve could be redissolved.

Example 6: Preparation of the Internal Coating (Cellulose Polymer).

Hydroxy-propyl-methyl-cellulose, water, and yes ethylene were mixed.

Preparation of the External Coating (Enteric Coating Polymer). 1.5 grams of Polysorbate 80 were dissolved in 250 milliliters of water with heating at 70 ° C. 3.75 grams of glyceryl monostearate was added to the Polysorbate solution at 70 ° C, and mixed. The mixture was allowed to cool with stirring. 419.25 grams of Eudragit L30 D55, which is in the form of a 30 percent aqueous dispersion, was sieved through a US 40 mesh sieve, and the particles were collected on the 40 mesh mesh. 18.75 grams of triethyl citrate with 56.38 milliliters of water, to form a solution, which was combined with the Eudragit dispersion, and added to the mixture containing Polysorbate 80 and glyceryl monostearate, with stirring.

Example 8: Preparation of Coated Microgrosses. The microgranules prepared in Examples 1, 2, 3, 4, and 5, were first coated with a cellulose polymer coating composition prepared as in Example 6, using a Wuster Column in a Glatt Fluid Bed Granulator. The coated microgranules were further coated with an enteric coating composition prepared as in Example 7, using a Wuster Column in a Glatt Fluid Bed Granulator. The coated microgranules were subjected to the sieving procedure as described above, and the particle size distribution is summarized in Table IV.

Table IV Eiem pío 9 Preparation of Oral Suspension Products of Clarithromycin.

Poloxamer 188, Povidone K-30, and water, were mixed in a stainless steel vessel mixer with stirrer, and clarithromycin was suspended in this mixture. The mixture was spray dried, and pelleted to microgranules in a Glatt GPCG-30-WSA Module. The dried microgranules were screened through a 500m strainer. Separately, Pharmacoat 603, Macrogel 6000, and titanium dioxide were mixed to form an inner layer coating. Separately, Tween 80 was dissolved in 250 milliliters of water with heating at 70 ° C. Glyceryl monostearate was added to the Tween 80 solution at 70 ° C, and mixed. The mixture was allowed to cool with stirring. 419.25 grams of Eudragit L30D55, which is in the form of a 30 percent aqueous dispersion, was sieved through a US 40 mesh screen, and the particles were collected on the 40th mesh. Triethyl citrate was mixed with water to form a solution, which was combined with the Eudragit dispersion, and added to the mixture containing Tween 80 and glyceryl monostearate, with agitation, to form an enteric coating. The microgranules prepared above were first coated with the inner coating using a Wuster Column in a Glatt Fluid Bed Granulator. The coated microgranules were further coated with the enteric coating using a Wuster Column in a Glatt Fluid Bed Granulator. The coated microgranules were mixed with the additional excipients using a V-Mixer at 480 revolutions, to form a powder composition of clarithromycin. The powder composition of clarltromycin was placed in a bottle. Water was added to the bottle, and the bottle was shaken vigorously to form an oral suspension. The oral suspension is characterized by a lack of bitter taste.

Claims (17)

1. An antibiotic composition comprising coated microgranules, and optionally one or more excipients, wherein said coated microgranules comprise: (i) a core comprising at least one antibiotic; (ii) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (iii) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns.

2. The composition according to claim 1, wherein the coated microgranules have an average particle size of about 200 microns to about 500 microns.

3. The composition according to claim 1, wherein at least about 90 percent of the coated microgranules have a particle size of about 100 microns to about 650 microns.

4. The composition according to claim 1, wherein the cellulose polymer is selected from the group consisting of hydroxy-propyl-methyl-cellulose, hydroxy-propyl-cellulose, methyl-cellulose, ethyl-cellulose, carboxy- methyl ethyl cellulose, carboxy methyl cellulose sodium, ethyl carboxy ethyl cellulose, and combinations thereof.

The composition according to claim 1, wherein the internal coating additionally comprises at least one plasticizer.

6. The composition according to claim 5, wherein the plasticizer is selected from the group consisting of acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triethyl citrate, glycerol diacetate, triacetate glycerol, acetylated monoglycerides, castor oil, dibutyl phthalate, diamyl phthalate, diethyl phthalate, dimethyl phthalate, dipropyl phthalate, di- (2-methoxy- or 2-ethoxy-ethyl) phthalate, ethyl glycolate -phthalide, butyl-phthalyl-butyl glycolate, butyl glycolate, propylene glycol, polyethylene glycol, diethyl adipate, di- (2-methoxy- or 2-ethoxy-ethyl) adipate, benzophenone, diethyl and dibutyl sebacate, succinate of dibutyl, dibutyl tartrate, diethylene glycol dipropionate, ethylene glycol dlacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate, tributyl phosphate, tributyl tin, polyethylene glycol sorbitan mono-oleate, sorbitan mono-oleate, and combinations of the same.

The composition according to claim 6, wherein the plasticizer is polyethylene glycol.

The composition according to claim 1, wherein the enteric coating polymer is selected from the group consisting of crosslinked polyvinyl pyrrolidone; non-crosslinked polyvinyl pyrrolidone; hydroxy-propyl-methyl-cellulose phthalate, hydroxy-propyl-methyl-cellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxy-propyl-methyl-cellulose acetate succinate, cellulose acetate trimellitate, hydroxy-propyl-methyl-cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; starch acetate phthalate; poly-vinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate; methyl cellulose succinate; methyl cellulose phthalate succinate; methyl-cellulose italic acid half-ester; ethyl cellulose succinate; carboxymethyl amide; potassium methacrylate / divinylbenzene copolymer; polyvinyl alcohols; poly oxyethylene glycols; polyethylene glycol; sodium alginate; galacto-manona; carboxy-polymethyl; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with at least one monomer selected from the group consisting of methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, Phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, and octadecyl acrylate; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; gluten; ethyl acrylate-maleic acid anhydride copolymer; maleic acid anhydride / vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl acrylate-maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutamine only / glutamic acid ester copolymer; glycerol-carboxy-methyl-et i i-cellulose mono-octanoate; polyarginine; polyethylene); Polypropylene); poly (ethylene oxide); poly (ethylene terephthalate); p or I i (v i n i 1 -isobutyl ether); poIi (vinyl chloride); polyurethane, and combinations thereof.

The composition according to claim 8, wherein the enteric coating polymer is selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate.

10. The composition according to claim 1, wherein the outer coating additionally comprises at least one plasticizer.

The composition according to claim 10, wherein the plasticizer is triethyl citrate and glycerol monostearate.

12. The composition according to claim 1, wherein the antibiotic is clarithromycin.

13. An oral suspension, which comprises: (a) an antibiotic composition comprising coated microgranules, and optionally one or more excipients, (b) additional excipients, and (c) a solvent, wherein said coated microgranules comprise: (i) ) a core comprising at least one antibiotic; (ii) an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (iii) an outer coating comprising at least one enteric coating polymer, wherein the coated microgranules have an average particle size of about 100 microns to about 650 microns.

14. The oral suspension according to claim 13, wherein the solvent is an aqueous solvent.

15. A method for preparing an antibiotic composition comprising coated microgranules and optionally one or more excipients, said method comprising: (A) mixing at least one antibiotic, and optionally one or more excipients, to form a premix; (B) adding a solvent, and optionally one or more excipients, to the premix formed in Step (A), and granulating in the presence of a propeller set at at least 50 revolutions per minute, to form a wet granulation; (C) drying the wet granulation, and optionally grinding and sieving the dried granules to form microgranules; and (D) coating the microgranules with an internal coating comprising at least one cellulose polymer that is not an enteric coating polymer; and (E) coating the microgranules of Step (D) with an outer coating comprising at least one enteric coating polymer to form coated microgranules, wherein these coated microgranules have an average particle size of about 100 microns to about 650 microns.

16. The method according to claim 15, wherein the granulation is further conducted in the presence of a chopper.

17. The method according to claim 16, wherein the chopper is set at at least 1,000 revolutions per minute.