KR20000050265A - Package for treatment comprising oral dosage forms of azithromycin - Google Patents

Abstract

PURPOSE: A package for the treatment comprising an oral dosage forms of azithromycin is provided which does not exhibit an adverse food effect and which is administrable to a subject including a mammal that has eaten. CONSTITUTION: A package for the treatment comprises: the oral dosage forms of azithromycin having not less than 0.80 of area ratio under the curve of blood concentration of a drug-time £(AUCfed)/(AUCfst)| in eating or non-eating and 0.75 or higher of lower 90 % confidence limit, a container and an undefined printed matter described whether it is able to take the oral dosage forms with foods or not.

Description

Therapeutic Packages Containing Azithromycin Oral Dosage Forms

The present invention relates to a therapeutic package comprising an azithromycin dosage form, and also to a microbial infection comprising administering azithromycin in the presence of food to a mammal, including a person in need thereof. To a method of treatment.

Azithromycin is the U.S.A.N name (general name) of 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antimicrobial compound derived from erythromycin A. Azithromycin was separately found by Bright and Cobrihel et al. (US Patent Nos. 4,474,768 (Bright) and 4,517,359 (Kobrehel et al.)). These patent documents disclose that azithromycin and certain derivatives thereof have antimicrobial properties and thus can be usefully used as antibiotics.

In general, the absorption and bioavailability of certain therapeutic agents are known to be affected by various factors upon oral administration. In general, the intestinal residence time of the drug is much longer in the presence of food than in the fasting state, the presence of food in the gastrointestinal GI (GI), etc. may be a factor. If the drug's bioavailability exceeds certain limits due to the presence of food in the gastrointestinal tract, the drug is said to have a "food effect." If the drug has an adverse food effect, the food effect is important because the drug presents a risk when administered to a patient who has just taken the food. The risk stems from the possibility that absorption into the blood may be undesirable to the extent that the patient faces an insufficient risk of absorption to treat the disease.

Other factors may also be related to the bioavailability of the drug and listed non-inclusively as follows:

(1) Certain dosage forms may affect bioavailability. For example, the intragastric residence time of a tablet or capsule may be much longer than the residence time of the suspension and the difference may depend on whether the subject has been fed.

(2) The pH in the stomach depends on the amount of food in the stomach in the state of eating and fasting, so that the drug sensitive to pH sensitivity is affected.

(3) The liver's ability to metabolize absorbed drugs (the so-called "first route" metabolism) depends on the type of food consumed. For example, some vegetables (such as sprout cabbage) may promote the first pathway metabolism of some drugs but do not promote the metabolism of other drugs. Grapefruit juice, on the other hand, inhibits the first pathway metabolism of some drugs.

(4) Bile secreted from the gallbladder into the small intestine when food is digested has the ability to dissolve weakly soluble drugs, thus increasing bioavailability.

Other factors may also be related to the absorption and bioavailability of a particular drug and the absorbency can be increased as well as decreased. For example, these additional factors include pH-dependent solubility, site-specific intestinal permeability, instability of intestinal enzymes, sensitivity to first pathway metabolism and instability of colonic bacteria. Given the many factors that can affect bioavailability, it is almost impossible to predict whether a drug will have a food effect without actually being tested. See, eg, Toothaker & Welling, Ann. Rev. Pharmacol. Toxicol., 1980, 173-99], various drugs that delay absorption in the presence of food (cephalexin, cefacller, metronidazole, aspirin, alkopenac, indoprofen, digoxin, cimetidine), and absorption affect food. Drugs that do not receive (ampicillin, erythromycin estoleate, spiramycin, propylthiouracil, oxazepamine, bendroflumethiazide) and drugs that increase absorption in the presence of food (erythromycin ethylsuccinate, nitrofurandoin , 8-methoxalene, propranolol, metoprolol, dicomarol, diazepam, hydrochlorothiazide) and the like.

As another example, there is no clear or conclusive evidence supporting the fact that tablets may have a lower food effect than capsules or vice versa. The results of the above-mentioned reference [Toothaker & Welling] reveal that the food-related absorbency is low for the purification of erythromycin stearate, aspirin, naphclean and sotarol.

In the case of azithromycin, the absorption of azithromycin is negatively affected when the patient is ingested with food, and thus the azithromycin capsule formulation is generally considered to exhibit the so-called "food effect". Therefore, in countries where azithromycin is recently used in human treatment, this product is marketed under special prescription for fasting, i.e., at least 1 hour before or 2 hours after meals.

Thus, it would be very useful if azithromycin could be administered to a patient who had just eaten, or the azithromycin formulation could be administered to a patient who has eaten as well as to a fasting patient.

The present invention relates to azithromycin oral dosage forms which can be administered to a mammal ingesting food (including humans) and that do not substantially exhibit negative food effects (except formulations containing significant amounts of alkaline earth metal oxides or hydroxides). to provide. Dosage formulations exhibit an average “(AUC _fed ) / (AUC _fst )” of at least 0.80 with a lower 90% confidence limit of at least 0.75. "(AUC _fed ) / (AUC _fst )" and "90% confidence limits" are described in detail below.

The present invention provides certain oral azithromycin formulations that do not exhibit negative dietary effects. This formulation comprises azithromycin and a pharmaceutically acceptable carrier, as described in detail below. This formulation may be in the form of tablets (including both swallowed and chewed), in the form of unit dose packets (sometimes referred to in the art as "chassists"), in the form of suspensions made from unit dose packets, in powder form for oral suspensions, and Oral suspension itself. It is recognized that the suspension form is mainly preferred when reconstituted according to the instructions, although the solution-to-suspension range depends on many factors such as pH when constructing unit dosage packets. The term "suspension" is used herein to encompass partly a suspension and partly a solution and a liquid containing azithromycin in the solution as a whole.

In another aspect, the invention includes administering an antimicrobially effective amount of azithromycin in an oral dosage form that exhibits substantially no negative food effects when ingested in a mammal in need thereof. Provided are methods for treating microbial infections in animals. Dosage formulations used represent an average "(AUC _fed ) / (AUC _fst )" of at least 0.80 with a lower 90% confidence limit of at least 0.75.

As used in the claims and the specification, "food ingested mammals (including humans)" means that the mammal consumes any kind of food within 1 hour before drug administration and within 2 hours after drug administration.

In another aspect, the present invention relates to a container, an oral dosage form of azithromycin that does not exhibit a negative food effect contained within the container, and a non-referenced formulation to which the dosage form can be taken depending on the presence or absence of food in combination with the container. Provided is a therapeutic package suitable for commercial use, including limited print.

It will of course be appreciated that unit dosage packets and powders for oral suspensions are not directly absorbed and digested by the patient but reconstituted in the appropriate vehicle. Nevertheless, these concepts are considered to be within the meaning of the "dosage formulation" of the present invention.

Capsules as dosage forms do not form part of the invention.

For the purposes of the present invention, azithromycin may be administered alone or in combination with other therapeutic agents.

The dietary effect is defined by the curve of the serum concentration of azithromycin in ordinate (Y-axis) versus time in abscissa (X-axis) (e.g. in μg / ml), as described, for example, in Toothaker & Welling. It can be quantified and analyzed by measuring the area under AUC). In general, the value of AUC represents a number of values taken from all subjects in the patient test crowd, and therefore averaged over the entire test group. Determine whether a particular drug exhibits a negative food effect by measuring the area under the curve (AUC _fed ) for the subjects who consumed food and comparing it to the area (AUC _fst ) for the same subjects who did not eat. do.

For the limited purpose of the invention and in particular with respect to the azithromycin dosing formulation, the average (AUC _fed ) / (AUC _fst ) is below 0.80 and / or after administration to the test group once ingested and once ingested. Dosage formulations of azithromycin exhibit a negative dietary effect when the lower 90% confidence limit for the ratio is 0.75 or less.

Conversely, a dosage form of azithromycin that did not exhibit a negative dietary effect showed an (AUC _fed ) / (AUC _fst ) value of at least 0.80 and a lower 90% confidence limit of at least 0.75 for this value when tested in the test group. Formulation. The values for the average (AUC _fed ) / (AUC _fst ) have values above 0.80 and are still within the scope of the present invention, although it is desirable to have an upper limit (average) of 1.25 and an upper 90% confidence limit of 1.40 or less. Included.

For the purpose of defining and measuring AUC _fed , the “food intake” subject group consumed (ie, swallowed) a test dosage form immediately after eating a Food and Drug Administration (FDA) -recommended standard high fat meal within 20 minutes. It is made up of a target. For example, a standard high fat meal consists of two eggs fried in one table spoon of butter, two strips of bacon, six ounces of hash brown potatoes, two pieces of toast containing two tablespoons of butter and two chunks of jelly and eight ounces of whole milk. This standard high fat diet was calculated by the method described in the article "Nutritive Value of Foods", US Department of Agriculture Home and Garden Bulletin Number 72, which calculated about 964 calories of 54% fat (58 g) and 12% protein. It contains. Also within 20 minutes, other foods are consumed and subjects are grouped into the "food intake" group. For the purposes of defining and measuring AUC _fst , “ _subsisted subjects” means subjects who have not eaten at least 8 hours, typically overnight, before taking the dosage form.

In the case of subjects with or without food, the 90% confidence limits for AUC _fed / AUC _fst for a particular test group are calculated as described below using Schurman's two one-sided test procedure. And can be calculated.

Log-converted AUC is analyzed through analysis of variables suitable for 2-period, 2-treatment crossover design. Analyzes are performed using Statistical Analysis System software (SAS), SAS Institute, Cary, North Carolina. The SAS process, referred to as PROC GLM in SAS software, is used to determine the sequence, the objects within the sequence, the duration, and the treatment (food intake / no ingestion) effects. Ordinal effects are tested using mean squares (objects in the sequence) from the ANOVA analysis as error items. All other effects are tested for residual error (error mean square) from ANOVA. Use the LSMEANS specification from SAS to calculate the minimum square mean and their standard error and co-deviation. These are used to obtain an estimate of the adjustment difference between the process mean and the standard error associated with the other difference (log-converted).

The 90% confidence interval for the two-way crossover design is based on these estimates, with the 95th percentile of the t-distribution with the standard error of the difference + (or-) difference x degrees of freedom (sample size 2-2). Configure. Take the inverse of the logarithm to the limit plot to obtain the corresponding reliability for this ratio.

The fact that the dosage form according to the invention does not exhibit a negative dietary effect is surprising in view of the fact that azithromycin is unstable at low pH (acid) at the level of acidity encountered at the pH of gastric acid. The inventors have found that azithromycin decomposes upon exposure to gastric juice which essentially represents the pH of the acid. Thus, it is surprising that rapid disintegration in the gastrointestinal tract gives considerable importance to the present invention, even if it is not linked to a working metabolic mechanism.

U.S. Patent Application No. 07 / 922,262 (filed July 30, 1992, assigned to the same person as the present application, pending) discloses a basic compound selected from the group consisting of alkaline earth metal oxides and alkaline earth metal hydroxides. Disclosed is a taste-masking composition of a bitter drug such as an azalide antibiotic containing as a taste-masking component. The composition of the present invention contains less than the taste-covering amount of the taste-masking component when it contains alkaline earth metal oxide or hydroxide. Therefore, the compositions of the present invention preferably contain up to about 1% alkaline earth metal oxides or hydroxides and may be entirely free of such taste-masking components.

Azithromycin is generally present in the formulations of the present invention in an amount of about 25 mg to about 3 g, preferably 250 mg to 2 g, for the treatment of humans. When the formulation is used in the animal / veterinary art, the amount can of course be adjusted beyond these limits depending on the size of the animal to be treated (eg horse). "Azithromycin" includes pharmaceutically acceptable salts, and anhydrides thereof, as well as hydrated forms. Azithromycin is preferably present as a dihydrate as disclosed, for example, in European Patent Application Publication No. 0 298 650 A2.

The most reliable method for testing whether a particular azithromycin dosage formulation exhibits a negative dietary effect is to test the dosage formulation in vivo in a food intake and non-ingestion subject group and measure serum (or plasma) azithromycin levels over time. As described above, draw a curve for the concentration of serum (or plasma) azithromycin over time in each subject (food intake and non-ingestion) and determine the area under each curve (usually simply integral). The method determines whether the average ratio (AUC _fed ) / (AUC _fst ) exceeds 0.80 and the lower 90% confidence limit is 0.75 or above.

Most of the azithromycin dosage forms of the present invention are ready to be eluted from the gastrointestinal tract immediately after administration (suspension) or disintegrate rapidly after administration to prepare the azithromycin to elute (tablet). It does not have a food effect. Although not relevant to the theory, azithromycin dosage forms allow azithromycin to be eluted immediately after ingestion in the gastrointestinal tract, or at least if azithromycin does not substantially produce a negative food effect if it is eluted within a certain amount of time. It is thought to be absorbed into the bloodstream. It is believed that the dosage form should provide azithromycin at a rate such that at least about 90% of azithromycin is eluted within 30 minutes, preferably about 15 minutes after dosing, to achieve an appropriate rate of absorption. Non-capsule dosage forms containing azithromycin are considered to be included in the appended claims if they meet the in vitro dissolution test conditions enumerated herein. The azithromycin dosage form according to the present invention is about 30 when the amount of the dosage form corresponding to 200 mg of azithromycin is tested as set forth in USP test <711> in a USP-2 elution device under strict conditions as follows. Elution of at least about 90% of azithromycin in minutes, preferably 15 minutes: 900 mL of about 0.1 M dibasic sodium phosphate buffer, pH 6.0, 37 ° C. with stirring vane rotation at 100 rpm. This test is described in US Pharmacopaea XXII, pp. 1578-1579. Dosage formulations that pass this test under more stringent conditions (lower buffer volume, higher dosage formulations, lower temperature, higher pH, lower stirring blade speed) are also included as defined above. Variations of this test are also described below. The time required for dissolution of certain azithromycin dosage forms in such an in vitro test is believed to represent the time required for dissolution of the dosage form in the gastrointestinal tract environment. This is described below.

In general, it has been observed and assumed that the in vitro dissolution rate of the dosage form exhibits a rank order correlation with in vivo dissolution, particularly for single dosage forms, such as tablets, which vary throughout the composition. Thus, in vitro dissolution evaluation plays an important role in controlling the quality of the prepared dosage form. In vitro dissolution rate is not necessarily the same as in vivo dissolution rate. This is not surprising because the artificial conditions of the in vitro dissolution test (eg, container structure, stirring rate, stirring method, etc.) are not the same as the conditions under which the dosage form disintegrates and elutes in the gastrointestinal tract.

When comparing different types of dosage forms, such as capsules and tablets, the in vitro dissolution rate should be roughly related to the in vivo dissolution rate. In capsules, at least partial dissolution of the gelatin shell should precede the complete dissolution of the closed drug. The capsule shell also generally elutes first at the capsule end and later at the capsule center. Tablets, on the other hand, disintegrate uniformly. Thus, when comparing capsules and tablets, there are subtle differences in in vitro / in vivo dissolution correlations. For example, capsules and tablets that appear similar in in vitro dissolution rates may exhibit subtle differences in in vivo dissolution rates. Such subtle differences have no therapeutically significant effect on the systemic bioavailability of orally administered drugs, but there are situations where noteworthy effects may occur. For example, if a drug has the potential to exhibit a negative dietary effect, drug-containing tablets and capsules that appear similar to in vitro dissolution rates may actually differ in terms of whether they exhibit a negative dietary effect upon oral administration of the formulation. Indeed, this was observed in azithromycin as illustrated in the examples below.

In the in vitro dissolution studies described herein, azithromycin is a hydrocarbonaceous spherical particle chromatography column based on 5 micron alumina (15 cm × 0.4 cm) and a hydrocarbonaceous spherical particle precolumn (5 cm × 0.4 cm). HPLC was performed. A mobile phase consisting of an electrochemical detector (eg Bioanalytical Systems, West Lafa yette, IN, LC-4B current detector with dual series glass carbon electrodes) and 71% phosphate / 29% acetonitrile (pH 11) was used.

To study the effects of food in vivo, serum azithromycin was assayed by an electrochemical current detector in R.M. Shepard et al., (1991) J. Chromatog. Biomed. Appl. 565, 321-337]. Alternatively, an assay that produces similar results, such as, for example, a bioassay can be used.

Tablets according to the invention contain azithromycin and disintegrants as essential ingredients. Examples of tablet disintegrants include starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, crosslinked carboxymethylcellulose sodium (crosscamelose; crosslinked starch: Ac-Di-Sol, FMC Corp. , Philadelphia, PA), clays (e.g., magnesium aluminum silicate), microcrystalline cellulose (Avicel, FMC Corp .; Emcocel, Mendell Corp., Carmel, NY), alginates, gums, surfactants, effervescent mixtures, hydrated aluminum Silicates, crosslinked polyvinylpyrrolidone (PVP-XL, International Specialty Products, Inc.) and other known materials. Preferred disintegrants for azithromycin tablets are croscarmellose sodium (Ac-Di-Sol), starch glycolate sodium (Primojel, Avebe, Union, NJ; or Generichem, Little Falls, NJ; Explotab, Mendell Corp.), Microcrystalline cellulose (Avicel) and crosslinked polyvinylpyrrolidone (PVP-XL). The azithromycin tablets of the present invention contain 1 to 25%, preferably 3 to 15% of disintegrants based on the azithromycin and the total tablet weight. For example, a 463.5 mg tablet (250 mg active azithromycin) may contain 9 mg of croscarmellose sodium and 27 mg of pregelatinized starch.

In addition to the active ingredients azithromycin and disintegrants, tablets according to the present invention, depending on the complete formulation, may contain various conventional excipients such as binders, flavors, buffers, diluents, colorants, lubricants, sweeteners, profound agents and glidants and the like. It may be optionally contained and formulated. Some excipients, such as binders and disintegrants, may play a plurality of roles.

Examples of binders include acacia, cellulose derivatives (eg, methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol, polymethacrylate , Polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, tragacanta gum, alginic acid and salts thereof, such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonite and the like. Can be. Preferred binders for azithromycin tablets are pregelatinized starch (eg, Starch 1500, Colorcon, Inc., West Point, PA).

Flavors incorporated into the compositions can be selected from synthetic flavor oils, flavoring aromas and / or natural oils, extracts from plant leaves, flowers, fruits, and combinations thereof. These include cinnamon, camellia, peppermint, clove, laurel, anise, eucalyptus, thyme oil, cedar leaf oil, nutmeg tree oil, sage oil, bitter almond oil and Chinese cinnamon oil. Also useful as citrus oils are citrus oils such as vanilla, lemon, orange, grape, lime and grapefruit, and fruit extracts such as apples, bananas, pears, peaches, strawberries, raspberries, cherries, plums, pineapples and apricots. The amount of flavourant can depend on many factors, such as the desired orgogenic effect. Flavoring agents are generally present in amounts of from 0.5 to about 3.0 weight percent, based on the total tablet weight when used.

Various materials can be used as fillers or diluents. Examples include spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg starch 1500), cellulose (eg microcrystalline cellulose; Avicel), dihydrated or anhydrous dibasic calcium phosphate (Emcompress). Or Mendell; or A-Tab and Di-Tab, Rhone-Poulenc, Inc., Monmouth Junction, NJ), calcium carbonate, calcium sulfate, and other known materials.

Lubricants may also be used in the manufacture of certain formulations herein, and lubricants are generally used when making tablets. Examples of lubricants include magnesium stearate, stearic acid, glyceryl begotate, polyethylene glycol, ethylene oxide polymers (e.g. Carbowax, Union Carbide, Inc., Danbury, CT), sodium lauryl sulfate, lauryl sulfate magnesium, sodium oleate And sodium stearyl fumarate, DL-leucine, colloidal silica, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.5 to 7.0% of the total tablet weight.

Other excipients such as glidants and colorants may also be added to the azithromycin tablets. Colorants include pigments suitable for foodstuffs such as FD & C. dyes and / or natural colorants such as titanium dioxide, grape husk extract, beet powder, beta carotene, anato, carmine, turmeric, paprika and the like. have. Colorants are optional ingredients in the compositions of the present invention and, when used, are generally present at about 3.5% or less based on the total tablet weight.

As is known in the art, tablet blends may be dry-granulated or wet-granulated before tableting. On the other hand, the tablet blend can be compressed directly. The choice of treatment method depends on the nature of the drug and the excipients selected, such as particle size, blending miscibility, density and flowability and the like. Granulation is preferred for azithromycin tablets and wet granulation is most preferred. Azithromycin can be wet-granulated and then other wetting agents can be added extragranularly. On the other hand, azithromycin and one or more excipients may be wet-granulated. The tablets may also be coated with a coating that does not interfere or hardly affect the dissolution of the tablets in order to improve swallowing or appearance.

In a preferred embodiment, the tablets of the present invention are film-coated in order to be swallowable or to look good. Many polymeric film-coating materials are known. Preferred film-coating material is hydroxypropylmethylcellulose (HPMC). HPMC is commercially available under the trade name Opadry, Colorcon Corp., in a coating formulation comprising excipients which serve as a coating aid. Opadry formulations may contain lactose, polydextrose, triacetin, polyethyleneglycol, polysorbate 80, titanium dioxide and one or more dyes or lakes. Other suitable film-forming polymers such as hydroxypropylcellulose and acrylate-methylacrylate copolymers can also be used in the present invention.

The purification process itself is a standard process and is readily accomplished by using conventional tablet presses to form tablets of the appropriate form from the desired blend or mixture of ingredients. Tablet compositions and existing purification techniques are described, for example, in Pharmaceutical Dosage Forms: Tablets; EDIT: Lieberman, Lachman, & Schwartz, Published by Marcel Dekker, Inc., 2 ed., Copyright 1989].

The azithromycin dosage forms of the invention also include powders for preparing oral suspensions and the oral suspensions themselves. Generally, the powder is a non-cake, free-flowing powder that is sold directly to a pharmacy or other wholesaler and then made into an actual suspension by a pharmacist. Thus oral suspensions are actual dosage forms that are absorbed by the patient. Typical shelf life for suspensions is about 5 days since azithromycin therapy is generally about 5 days.

Azithromycin suspensions according to the present invention are 0.1 to 2% total amount of one or more symptoms, and 0.1 to 2.5% amount of buffer or pH-adjusting agent, as a percentage based on the dry powder formulation weight as a necessary ingredient other than azithromycin. It contains. Dispersants may also be used in amounts of 0.05 to 2%. Preservatives may also be used in amounts of 0.1 to 2%.

Suitable symptom agents include hydrocolloid gums that serve as suspending agents and are known for such uses, such as xanthan gum, guar gum, soya bean gum, tragacanth gum and the like. On the other hand, synthetic suspending agents such as carboxymethylcellulose sodium, polyvinylpyrrolidone, hydroxypropylcellulose and the like can also be used.

Dispersants include colloidal silicon dioxide (trade name, Cab-O-Sil; Cabot Corporation, Boston, Mass.).

To prepare powder formulations for oral suspensions, the bitter taste of azithromycin can be neutralized by the inclusion of a basic buffer or pH adjuster which provides a pH of about 10 in the composed suspension. Maintaining the pH at about 10 minimizes the amount of azithromycin in the solution and thus neutralizes the bitter taste of the drug. Many flavor combinations or flavoring systems can be used to neutralize the bitter taste of azithromycin. The flavoring agent is preferably a formulation that provides a constant flavor for about 5 days at high pH of the formulation after drug composition. Preferred flavor systems consist of spray dried cherry # 11929, artificial krem de vanilla # 11489 and spray dried artificial banana # 15223 (Bush Boake Allen, Inc., Chicago, IL). Artificial sweeteners may also be used.

Powders used to prepare suspensions in the present invention include, for example, wetting agents such as (1) sorbitan monolaurate, polysorbate 80 and lauryl sulfate sodium, (2) antifoam agents and (3) fillers such as glucose, and the like. It may contain any of the existing ingredients. The powder may also contain a buffer to maintain high pH upon reconstitution as described above. Suitable buffers and pH-adjusting agents include anhydrous tribasic sodium phosphate, anhydrous sodium carbonate, glycine and the like. Suitable preservatives such as sodium benzoate and the like are known. After swallowing, azithromycin from the suspension elutes rapidly.

In the preparation of azithromycin powder for oral suspension formulations, all ingredients are blended together and ground according to known methods. Preferably the azithromycin and flavoring agents are blended and the other ingredients are blended separately. Finally these two blends are mixed and ground.

The oral suspension is preferably resuspended in an aqueous medium after construction and preferably does not form a cake upon storage after construction. Preferred suspensions contain sucrose NF when sucrose is used and anhydrous excipients, if available, to ensure a smooth suspension in construction. Drug-containing powders are generally reconstituted with water.

The suspension of the present invention exhibits about 90% dissolution rate of azithromycin in about 15 minutes in vitro. The test can be summarized as follows:

The azithromycin-containing vessel is shaken to loosen the powder, and the sample is constructed as instructed by the label as described, for example, in Example 12, to form a 40 mg / ml azithromycin suspension. Shake the container vigorously for 2 minutes and let stand for 30 minutes. Shake vigorously for another 15 seconds. Recover 5 ml (typically equivalent to 200 mg of azithromycin) from the vessel and carefully remove air bubbles. A 5 ml aliquot of azithromycin suspension is carefully dispersed to approximately 10 cm above the surface of the eluate (0.10 M sodium phosphate buffer, pH 6.0) in USP Apparatus 2 with a stirring vane at 2.5 cm from the bottom of the vessel. After the oral suspension sample has settled to the bottom of the vessel, begin rotating the stirring vanes at 25 rpm. About 10 mL is removed from the elution vessel at each sampling, filtered and the filtrate is analyzed for azithromycin using the HPLC analysis described above.

Azithromycin unit packet dosage formulations (also referred to herein as "chassists") consist of unit packets designed to be reconstituted with aqueous vehicles such as, for example, water or natural or artificial juices. The packet is reconstructed containing a blend of azithromycin and excipients. The packet contains, as a necessary component, a dispersant that allows good flow of the chasset powder, such as colloidal silicon dioxide (Cab-O-Sil, Cabot) and azithromycin. Dispersants are generally present in amounts of about 0.2 to 2.0% by weight, based on the weight of the dry chassiset to be commercially available. Dispersants also act as glidants. This formulation also includes (1) a filler or sweetener (eg, glucose); (2) buffers (eg, sodium phosphate); And (3) humectants, such as surfactants such as sodium lauryl sulfate, and flavoring agents such as those listed above. The powder in the packet flows freely and disperses quickly upon stirring when reconstituted. Azithromycin unit packet dosage formulations can be prepared by blending and grinding as is known in the art. Preferably the filler (e.g. sucrose), buffer (e.g. anhydrous tribasic sodium phosphate) and glidant (e.g. colloidal silicon dioxide) are blended and pulverized, then blended with azithromycin and flavoring and then pulverized do. Azithromycin in the packet is rapidly eluted when evaluated as follows. The contents of the packet are added to a 250 ml beaker containing 60 ml of water treated with the Milli-Q Plus system (Millipore Corp.,> 18 megohm resistance). The beaker inner melt is stirred with a spoon until a homogeneous suspension is obtained (1-2 minutes). The stirring vane is mounted and the suspension is poured into the center of the elution vessel of the USP-2 elution apparatus containing 900 ml of 0.1 M sodium phosphate buffer (pH 6.0). The stir blade is then lowered into the vessel and rotated at 50 rpm. At each time point a 10 ml aliquot is removed and filtered and the filtrate is analyzed for azithromycin in solution using HPLC analysis as described above. Using this method, it is observed that 1 g of azithromycin packet elutes at least 90% within 5 minutes or less. Thus, the packet does not exhibit negative food effects.

As noted above, the oral azithromycin dosage forms disclosed and described above may be administered to a mammal, including a person in need thereof, ingesting food, regardless of the amount, nature, and amount of time the food has been eaten. Can be. With this object and other features of the present invention, the present invention relates to a container, whether or not azithromycin oral dosage form which does not exhibit the negative food effect contained in the container, and whether the dosage form can be taken depending on the intake of the food bound to the package. Provided are commercial therapeutic packages that include non-limiting printed material. Prints are in a form that contains information and / or instructions for a doctor, pharmacist or patient. The imprint is non-limiting as to whether the dosage form can be taken with or without food in terms of not mentioning whether the food can be taken with or without food, ie not referring to the food effect. On the other hand, the printout may include one or more indications (optionally “food,” assuring the user that the oral dosage form can be administered or taken to the patient regardless of whether the patient has eaten or drank food). May be non-limiting by including a " The printed matter may not include a definitive sentence regarding food, such as, for example, "this dosage form may not be taken with food" or "this dosage form may be taken only by a patient after fasting".

The containers consist of paper or cardboard boxes, glass or plastic containers or bottles, re-sealable bags (e.g., refilling tablets for transport to other containers), or bubble packs that release individual formulations out of the pack according to a treatment plan. It may be a known form or shape. The container used depends on the dosage form, for example conventional cardboard boxes are not used in suspension formulation. More than one container may be used together in a single package to market a single dosage form. For example, the tablet may again be contained in a container that is contained in a box.

The print or other printed material is bound to a package in which the azithromycin dosage form is commercially available. By “coupled” is meant to include all manner in which printed matter, such as instructions or informational content, can be attached to a drug, for example, as is known in the art. Thus, the printed matter may be printed, for example, on a label (eg, a prescription label or separate label) adhered to and attached to a container containing azithromycin suspension; Contained within a box containing unit dose packets; Applied directly to a container such as printed on a box; Alternatively, it may be attached to the container, such as tied or taped in the form of a card fixed to the container bottle via a string, string or other string, lace or rope device. The printed matter may be printed directly on a unit dose pack or bubble pack or bubble card. If the printed matter does not include a non-limiting statement definitely, the printed matter may also include other information. For example, the definitive non-limiting statement can illustrate the following:

"This product does not have a negative food effect and can therefore be taken with or without food, regardless of the amount or type of food." Or similarly

"You can take it with or without food".

The invention is illustrated below by way of non-limiting examples. In general, Examples include: (1) azithromycin capsules with negative dietary effects and slower eluting capsules with higher dietary effects; and (2) rapid eluting azithromycin tablets, powders for oral suspension, and unit dose packet administration. It is found that the formulation does not exhibit a negative food effect.

Example 1

This example is a comparative example and shows the effect of a high fat diet on azithromycin included in the capsule formulation having a moderate dissolution rate.

Capsules containing 250 mg of active azithromycin were prepared. The composition of these capsules is shown in Table 1 below. Elution of these capsules was evaluated by the above method using a stirring blade rotating at 100 rpm in 900 ml of pH 6.0 phosphate buffer at 37 ° C. The mean azithromycin% eluted at 15 minutes was 25% and 76% at 30 minutes.

The effect of food intake on azithromycin bioavailability was determined as follows. Eleven healthy adult male volunteers were orally administered 500 mg (2 × 250 mg capsule) of azithromycin in each case in two cases. In one case it was administered after fasting overnight for 12 hours. It was taken with 150 ml of water and drank an additional 150 ml of water 1 hour after administration. In other cases a meal consisting of whole milk, bread and butter, bacon, two fried eggs and coffee was served. Thirty minutes after a meal, it was taken with 150 ml of water. Blood samples were taken before and after 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. The area under the drug serum concentration versus time curve (AUC) for each subject under each dosing condition was measured for each diet condition. The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability. The mean AUC _fed / AUC _fasted was 0.22, and the lower and upper 90% confidence levels were 0.06 and 0.84, respectively.

Table 1.

Composition of 250 mg azithromycin capsules. Manufactured in # 0 White Opaque Locked Capsules

ingredient mg / capsules Azithromycin ^* 263.72 Lactose, anhydride 149.88 Corn Starch, Carb 47.0 Magnesium Stearate / Lauryl Sulfate 9.40 Sodium (90/10) gun 470.0 * Based on 94.8% volume capacity; Non-stoichiometric Hydrate

Example 2

This example is a comparative example and shows the effect of a high fat diet on azithromycin administered in a capsule formulation that elutes faster than the capsule of Example 1.

Azithromycin capsules (250 mg strength) were prepared according to the compositions in Table 2 below. Elution of azithromycin from these capsules was evaluated as in Example I. After 15 minutes, 97% of the encapsulated azithromycin eluted.

The effect of food on azithromycin bioavailability from this dosage form was evaluated as follows. Twelve healthy adult male volunteers were orally administered 500 mg (2 × 250 mg capsule) of azithromycin in each case in two cases. In one case, the drug was administered after overnight fasting, in the other case two eggs fried in one spoon of butter, two strips of bacon, two ounces of ham, two teaspoons of butter and two chunks of jelly and jelly whole milk The drug was taken after a meal consisting of 8 ounces. The drug was taken orally with 250 ml of water. Blood samples were taken before dosing, 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72 and 96 hours after dosing. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. The mean AUC _fed / AUC _fasted was 0.80 and the lower and upper 90% confidence levels were 0.67 and 0.96, respectively.

Table 2.

Composition of Azithromycin Capsules. This formulation is made from dry granules and prepared as # 0 opaque locked capsule.

ingredient mg / capsules Azithromycin Dihydrate ^* 262.05 Lactose, anhydride 151.55 Corn Starch, Carb 47.00 Magnesium Stearate / Lauryl Sulfate salt 94.0 gun 470.00 * Corresponds to 250mg azithromycin, based on 95.4% volume capacity

Example 3

This example is a comparative example and shows the effect of a simple meal on azithromycin administered in a rapidly eluting capsule formulation.

Azithromycin capsules (250 mg strength) were prepared according to the composition of Table 2 above. Elution of azithromycin from these capsules was evaluated as in Example I. After 15 minutes, 99% of the encapsulated azithromycin eluted.

The effect of a simple continental diet on azithromycin bioavailability from this dosage form was evaluated as follows. Twelve healthy adult male volunteers were orally administered 1000 mg (4 × 250 mg capsule) of azithromycin in each case in two cases. In one case the drug was administered after overnight fasting and in another case 2 rolls of bread containing butter and butter, coffee or tea with whole milk Ca. The drug was taken after a simple meal consisting of 300 ml. The drug was taken orally with 240 ml of water. Blood samples were taken before dosing, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, and 46.5 hours post dose. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. The mean AUC _fed / AUC _fasted was 0.71 and the lower and upper 90% confidence levels were 0.53 and 0.95, respectively.

Example 4

This example shows the effect of a high fat diet on azithromycin administered in a rapidly eluting tablet formulation.

Azithromycin tablets were prepared according to the compositions in Table 3 below. Dissolution evaluation was performed as in Example 1. After 30 minutes, 100% of azithromycin eluted.

The effect of food on azithromycin bioavailability from these tablets was evaluated as follows. Twelve healthy adult male volunteers were orally administered 500 mg (2 × 250 mg tablets) of azithromycin in each case in two cases. In one case, the drug was administered after overnight fasting, and in the other case, two eggs fried in one tablespoon butter, one strip of bacon, two teaspoons of butter and two pieces of toast, eight ounces of whole milk, and After eating a meal of 6 ounces of hash-brown potatoes, they were digested for 20 minutes before taking the medication. The drug was taken orally with 240 ml of water. Blood samples were taken before dosing, 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72 and 96 hours after dosing. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. The average AUC _fed / AUC _fasted was 0.97 and the lower and upper 90% confidence levels were 0.82 and 1.13, respectively.

Table 3.

Composition of Azithromycin Film-Coated Tablets. The formulation is compressed to form a 0.262 "x 0.5312" modified capsuler, top "Pfizer", bottom scaled tablets and coated with "Pink Opadry".

ingredient Weight (mg / unit) Azithromycin Dihydrate ^* 262.05 Pregelatinized Starch ^** 27.00 Dibasic Calcium Phosphate, Anhydride 138.84 Croscarmellose sodium ^*** 9.00 Magnesium Stearate / Lauryl Sulfate Sodium (90/10) 13.11 Pink Opadry II 18.00 * Corresponds to 250 mg azithromycin on a 95.4% volumetric capacity. ** Starch 1500 *** Ac-Di-Sol ## lactose, hydroxypropyl methylcellulose, titanium dioxide, triacetin and D & C Red No. Contains 30 aluminum rakes.

Example 5

This example shows the effect of a Japanese meal on azithromycin administered as a rapidly eluting tablet.

Tablet dosage forms of azithromycin were prepared according to the compositions described in Table 4 below. Elution of these dosage forms was evaluated as in Example I. After 15 minutes, 100% of azithromycin eluted.

The food effect on azithromycin bioavailability from this tablet was evaluated as follows. Eight healthy adult male volunteers were orally administered 500 mg (4 × 250 mg capsule) of azithromycin in each case in two cases. In one case, the drug was administered after 12 hours of fasting, and in another case, the drug was taken 30 minutes after a Japanese meal consisting of rice, miso soup, fried eggs, seaweed, spinach and pickles containing butter and butter. The drug was taken orally with 240 ml of water. Blood samples were taken before dosing, at 0.5, 1, 2, 3, 4, 6, 9, 12, 24, 48, 96, 120, 144, and 168 hours post dose. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. The average AUC _fed / AUC _fasted was 1.00 and the lower and upper 90% confidence levels were 0.87 and 1.15, respectively.

Table 4.

Composition of Azithromycin Film-Coated Tablets. The capsuleer pale white film-coated tablets (0.262 "x 0.5312") were compressed and then coated with "White Opadry" and "Clear Opadry".

ingredient Weight (mg / unit) Azithromycin Dihydrate ^* 262.05 Pregelatinized Starch ^** 27.00 Dibasic Calcium Phosphate, Anhydride 138.84 Croscarmellose sodium ^*** 9.00 White Opadry 12.825 Clear Opadry 0.675 Magnesium Stearate / Lauryl Sulfate Sodium (90/10) 13.11 * Corresponds to 250 mg azithromycin based on 95.4% volume capacity. ** Starch 1500 *** Contains Ac-Di-Sol ## lactose, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80. ### Contains hydroxypropyl methylcellulose and polyethylene glycol.

Example 6

This example compares the effects of high fat and low fat meals on azithromycin administered in a "powder for oral suspension" dosage form.

Azithromycin powder “for oral suspension” was prepared according to the compositions described in Table 5 below. This formulation was designed to wet and disperse quickly when reconstituted with an aqueous vehicle. Elution of this suspension was evaluated as described in "Detailed Invention". After 15 minutes 97% of the azithromycin formulation was eluted, and after 30 minutes 99.6% of the azithromycin formulation was eluted.

The food effect of high fat and low fat diet on azithromycin bioavailability from this suspension dosage formulation was evaluated as follows. Six healthy adult male volunteers were orally administered 500 mg (40 mg / ml oral suspension 12.5 ml) of azithromycin in each case divided into three cases. In one case, the drug was administered after fasting for 10 to 12 hours, and in another case, 2 eggs fried in 1 tablespoon butter, 2 strips of bacon, 2 slices of toast with 2 chunks of butter, 8 ounces of whole milk, and hash brown potatoes The drug was taken 20 minutes after a 6-ounce high fat meal. In another case, the drug was taken after a low-fat meal consisting of 1 ounce of Cerios, General Mills Inc. cereal and 8 ounces of whole milk. The drug was taken orally with 240 ml of water (two oral washes with 60 ml of water and 120 ml of water). Blood samples were taken before dosing, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post dose. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. For high fat meals, the average AUC _fed / AUC _fasted was 1.01 and the lower and upper 90% confidence levels were 0.79 and 1.28, respectively. For low fat meals, the average AUC _fed / AUC _fasted was 1.04 and the lower and upper 90% confidence levels were 0.82 and 1.33, respectively.

Table 5.

Azithromycin powder composition for oral suspension. To reconstitute this composition, 0.52 ml of water per gram of dry formulation was added.

ingredient Weight (mg / unit) Azithromycin Dihydrate ^* 838.57 Sucrose 15487.74 Tribasic Sodium Phosphate, Anhydride 70.01 Hydroxypropylcellulose (Klucel-EF) 26.62 Khanthan Sword (Keltrol) 26.62 FD & C Red # 40 0.67 Spraying dried cherries # 11929 59.94 Art. Creme de Vanilla # 11489 133.28 S.D. Art. Banana # 15223 99.96 sum 16743.41 * Based on 95.4% volume capacity

Example 7

This example shows the effect of a high fat meal on azithromycin administered in a "single dose packet" (chassit) formulation.

A "single dose packet" (chassit) formulation of azithromycin was prepared according to the composition described in Table 6 below. Elution of this dosage form was assessed as described in "Detailed Description" above. After 15 minutes 99% of azithromycin was eluted.

The food effect on azithromycin bioavailability from this chasette formulation was evaluated as follows. Twelve healthy adult male volunteers were orally administered 1000 mg (1 g chassis) for azithromycin in each case in two cases. In one case, the drug was administered after at least 12 hours of fasting overnight, and in another case, two tablespoons of fried eggs in one tablespoon butter, two strips of bacon, two teaspoons of butter and two chunks of jelly, whole milk whole 8 The drug was taken after a high-fat meal consisting of ounces and 6 ounces of hash brown potatoes. The drug was taken orally with 240 ml of water (two oral washes with 60 ml of water and 120 ml of water). Blood samples were taken before dosing, 0.25, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, 24, 48, 72, 96, and 120 hours post-dose. Serum azithromycin concentrations were determined by high performance liquid chromatography analysis. For each subject under each dose condition, the area under the drug serum concentration versus time curve (AUC) was measured for each diet condition.

The AUC _fed / AUC _fasted ratio was used as a measure of the effect of food on oral bioavailability of azithromycin. The average AUC _fed / AUC _fasted was 1.12, and the lower and upper 90% confidence levels were 0.99 and 1.27, respectively.

Table 6.

Azithromycin "Unit Dosage Packet" Dosage Form. This blend was prepared and filled in a 3.25 "x 4" white paper / aluminum / polyethylene thin layer chassis. In order to reconstitute the formulation, the contents of the chasset were added to 60 ml of water and stirred well.

ingredient Weight (g / unit) Azithromycin Dihydrate ^* 1.048 Sucrose 9.707 Tribasic Sodium Phosphate, Anhydride 0.088 Colloidal silicon dioxide 0.055 Spraying Dried Artificial Cherry # 11929 0.038 Spraying Dried Artificial Banana # 15223 0.064 sum 11.000 * Corresponds to 1 g azithromycin based on 95.4% volume capacity for azithromycin dihydrate

Example 8

Azithromycin tablets of the invention were prepared at 150, 200, 250, 300, 500 and 600 mg dose strengths. Purified cores were prepared by wet granulation of all purified core components (except magnesium stearate / sodium lauryl sulfate). The dried granules were blended with the lubricant mixture magnesium stearate / sodium lauryl sulfate and then compressed on a tablet press. The tablets were coated with an aqueous film containing colored and / or transparent Opadry. These tablet formulations do not exhibit a negative food effect. The tablet composition is as described in Table 7 below.

TABLE 7

Examples of azithromycin tablet formulations that do not exhibit negative food effects

Weight (mg / tablet) ingredient 150 mg strength 200 mg strength 250 mg strength 300 mg strength 500 mg strength 600 mg strength Azithromycin Dihydrate ^* 157.23 209.613 262.05 314.46 524.10 628.93 Pregelatinized Starch ^** 16.20 21.60 27.00 32.40 54.00 64.80 Dibasic Calcium Phosphate Anhydride 83.305 111.01 138.84 166.61 277.68 333.21 Croscarmellose Sodium 5.400 7.200 9.00 10.80 18.00 21.60 Magnesium Stearate / Sodium Lauryl Sulfate (90/10) 7.865 10.486 13.11 15.73 26.22 31.46 Opadry @ 8.1 10.8 13.5 16.2 27.0 32.4 sum 278.1 370.8 463.5 556.2 927.0 1,112.4 * Based on theoretical strength of 95.4% ** starch 1500 # such as Ac-Di-Sol @ hydroxypropylmethylcellulose and suitable plasticizers, film-coating aids, milking agents and lakes

Example 9

Another tablet formulation of azithromycin (250 mg) was prepared that did not exhibit a negative dietary effect, as described in Table 8 below. Diluents (dibasic calcium phosphate, anhydride) in these formulations were replaced with dibasic calcium phosphate dihydrate, microcrystalline cellulose, lactose NF / BP / EP / JP or other suitable diluent. The lubricants in these tablets (magnesium stearate / sodium lauryl sulfate, 90/10) can be replaced with magnesium stearate and / or colloidal silica or sodium stearyl fumarate. Magnesium stearate and sodium stearyl fumarate are generally used in amounts of 0.5-7% of the total tablet weight. Colloidal silica is generally used in amounts of 0.1 to 1% of the total tablet weight. While a significant free range of relative excipient ratios is possible, the ratio of calcium phosphate / pregelatinized starch should be about 2: 1 or greater. Opadry film coating is not necessary to achieve food-independent drug effects, but it is easy to swallow, improves the appearance of tablets, and acts to differentiate strength. Opadry coatings account for 2-6% of the total tablet weight. Tablets of different strengths can be obtained by maintaining a suitable azithromycin / excipient ratio as described in Table 8 below and reducing or increasing the total tablet weight.

Table 8

Example of azithromycin tablet formulation (250 mg) that does not exhibit negative food effects

Weight (mg / tablet) ingredient Formulation 1 Formulation 2 Formulation 3 Azithromycin Dihydrate 262.05 262.05 262.05 Pregelatinized starch 50.0 13.9 50.0 Dibasic Calcium Phosphate Anhydride 115.84 140.94 104.84 Croscarmellose sodium 9.0 20.0 20.0 Magnesium Stearate / Sodium Lauryl Sulfate 13.11 13.11 13.11 Opadry @ 13.50 13.50 13.50 sum 463.5 463.5 463.5 Hydroxypropylmethylcellulose and suitable plasticizers, film-coating aids, milk whites and lakes

Example 10

Azithromycin tablet formulations (250 mg) were prepared that did not exhibit negative dietary effects, as described in Tables 9 and X below. In these formulations corn starch, sodium starch glycolate and crosslinked polyvinylpyrrolidone act as disintegrants. Dibasic calcium phosphate, lactose NF / BP / EP and microcrystalline cellulose serve as diluents.

Magnesium stearate / sodium lauryl sulfate acts as a lubricant. Magnesium stearate / sodium lauryl sulfate may be replaced with magnesium stearate and / or colloidal silica or sodium stearyl fumarate. Magnesium stearate and sodium stearyl fumarate are generally used in amounts of 0.5-7% of the total tablet weight. Colloidal silica is generally used in amounts of 0.1 to 1% of the total tablet weight. While a significant free range of relative excipient ratios is possible, the diluent / disintegrant ratio should be about 2: 1 or greater. Opadry film coating is not necessary to achieve food-independent drug effects, but it is easy to swallow and serves to improve the appearance of tablets. Opadry coatings account for 2-6% of the total tablet weight. Tablets of different strengths can be obtained by maintaining a suitable azithromycin / excipient ratio as described in Tables 9 and X below and reducing or increasing the total tablet weight. These compositions are exemplary and substitution of other disintegrants, diluents and lubricants is possible as is known in the art.

Table 9

Azithromycin tablet formulation that does not exhibit negative food effects

Weight (mg / tablet) ingredient Formulation 4 Formulation 5 Formulation 6 Azithromycin Dihydrate ^$ 262.05 262.05 262.05 Corn Starch ^* 13.9 27.0 50.0 Dibasic Calcium Phosphate ^** or Lactose NF / BP / EP / JP or Microcrystalline Cellulose 151.94 138.84 115.84 Starch sodium glycolate # or crosslinked polyvinylpyrrolidone ## 9.0 9.0 9.0 Magnesium Stearate / Sodium Lauryl Sulfate 13.11 13.11 13.11 Opadry @ 13.5 13.5 13.5 sum 463.5 463.5 463.5 $ Equivalent to azithromycin 250 mg * Also referred to as starch NF or corn starch ** Anhydride or Dihydrate # such as Explotab or Primojel ## such as International Specialty Products Inc. @ Hydroxypropylmethylcellulose and suitable plasticizers, film-coating aids, whitening agents and lakes

Table 10

Azithromycin tablet formulation example that does not exhibit negative food effect

ingredient Formulation 7 Formulation 8 Formulation 9 Azithromycin Dihydrate ^$ 262.05 262.05 262.05 Corn Starch ^* 13.9 27.0 27.0 Dibasic Calcium Phosphate ^** or Lactose NF / BP / EP / JP or Microcrystalline Cellulose 140.94 127.84 Starch sodium glycolate # or crosslinked polyvinylpyrrolidone ## 20.0 3.0 20.0 Magnesium Stearate / Sodium Lauryl Sulfate 13.11 13.11 13.11 Opadry @ 13.5 13.5 13.5 sum 463.5 463.5 463.5 $ Equivalent to azithromycin 250 mg * Also referred to as starch NF or corn starch ** Anhydride or Dihydrate # such as Explotab or Primojel ## such as International Specialty Products Inc. @ Hydroxypropylmethylcellulose and suitable plasticizers, film-coating aids, whitening agents and lakes

Example 11

The "powders for oral suspension" described in Table 11 were prepared. This formulation does not exhibit a negative dietary effect.

Table 11

Azithromycin Powder for Oral Suspensions

ingredient Weight (mg / g) Azithromycin Dihydrate 47.97 Sucrose NF 579.71 Sorbitol, Crystals, Powders, NF / FCC 289.86 Sodium Carbonate Anhydride, NF 18.84 Sodium benzoate, NF / FCC 4.35 Tragacanth Gum Powder, NF 14.49 Titanium Dioxide, USP 14.49 Colloidal Silicon Dioxide, NF 1.45 Amino Acetic Acid (Glycine) USP 5.80 Spray-dried Art. Strawberry 15.26 Tropical apple punts # 26508 7.63 Spraying-dried peppermint pieces # 15634 0.15 sum 1000.00

Example 12

"Azithromycin powder for oral suspension" was prepared as shown in Table 12 and XIII. The unit strength of these formulations is 600 mg azithromycin / container and the strength of use after reconstitution with water is 40 mg / ml. 0.52 ml of water per gram of blend was added to make up. 9 ml of water and 16.74 g of the blend form about 20 ml of the suspension. These formulations contain 200 mg azithromycin when the container is fully filled. The “flavoring system” listed can be freely substituted with other flavoring agents that are stable at pH 10 and provide a sweet taste over the storage period of the configured suspension (about 5 days). The dye can also be freely substituted. The formulation of this example is illustrative and not limiting. These formulations do not exhibit a negative dietary effect.

Table 12

Formulation Example of "Azithromycin Powder for Oral Suspensions"

Weight (mg / container) ingredient Formulation 1 Formulation 2 Formulation 3 Azithromycin Dihydrate 838.57 838.57 838.57 Sucrose NF 15487.74 15370.54 15487.74 Tribasic Sodium Phosphate Anhydride 70.01 70.01 70.01 Hydroxypropyl cellulose 26.62 26.62 0 Xanthan gum 26.62 26.62 0 Carboxymethylcellulose Sodium 0 0 53.24 Colloidal silicon dioxide 0 16.74 0 Glycine 0 100.46 0 Spraying-Dried Cherries # 11929 59.94 59.94 59.94 Artificial Vanilla Cream # 11489 133.28 133.28 133.28 Spray-dried Artificial Banana $ 15223 99.96 99.96 99.96 FD & C Red # 40 0.67 0.67 0.67 sum 16743.41 16743.41 16743.41

Table 13

Formulation Example of "Azithromycin Powder for Oral Suspensions"

Weight (mg / container) ingredient Formulation 4 Formulation 5 Formulation 6 Azithromycin Dihydrate 838.57 838.57 838.57 Sorbitol 15138.55 7743.87 7656.37 Sucrose NF 0 7743.87 7656.37 Sodium Carbonate Anhydride, NF 302.00 0 150.00 Tribasic Sodium Phosphate Anhydride 0 70.01 35.00 Hydroxypropyl cellulose 0 26.62 17.75 Kshantan Sword 0 26.62 17.75 Carboxymethylcellulose Sodium 53.24 0 17.75 Colloidal silicon dioxide 16.74 0 10.00 Glycine 100.46 0 50.00 Spraying-Dried Cherries # 11929 59.94 59.94 59.94 Artificial Vanilla Cream # 11489 133.28 133.28 133.28 Spray-dried Artificial Banana $ 15223 99.96 99.96 99.96 FD & C Red # 40 0.67 0.67 0.67 sum 16743.41 16743.41 16743.41

Example 13

Non-limiting, exemplary, azithromycin unit dose packet formulations of the invention were prepared (Tables 14 and 15). The flavor system for these dosage forms can be freely substituted with a flavor system that provides a flavor when reconstituting the contents of the packet in water or an aqueous liquid. When reconstituted in water or aqueous liquid, these dosage forms do not exhibit a negative dietary effect.

Table 14

Example of Unit Dose Packet Formulation

Furtherance Formulation 1 Formulation 2 Formulation 3 Azithromycin Dihydrate 1.048 1.048 1.048 Sucrose 9.707 9.707 5.0 Sorbitol 0 0 0 Tribasic Sodium Phosphate Anhydride 0.04 0.2 0.088 Sodium carbonate anhydride 0 0 0 Glycine 0 0 0 Colloidal silicon dioxide 0.022 0.22 0.055 Spraying-Dried Artificial Cherry # 11929 0.038 0.038 0.038 Spraying-Dried Artificial Banana # 15223 0.064 0.064 0.064

Table 15

Example of Unit Dose Packet Formulation

Furtherance Formulation 1 Formulation 2 Formulation 3 Azithromycin Dihydrate 1.048 1.048 1.048 Sucrose 0 4.85 4.85 Sorbitol 9.707 4.85 4.85 Tribasic Sodium Phosphate Anhydride 0.088 0.088 0.044 Sodium carbonate anhydride 0 0 0.022 Glycine 0 0 0.022 Colloidal silicon dioxide 0.055 0.055 0.055 Spraying-Dried Artificial Cherry # 11929 0.038 0.038 0.038 Spraying-Dried Artificial Banana # 15223 0.064 0.064 0.064

As described above, according to the present invention, when the intake and non-intake of blood drug concentration-time curve area ratio, (AUC _fed ) / (AUC _fst ) is 0.80 or more and the lower limit 90% confidence limit of 0.75 or more A therapeutic package containing an oral dosage form of mycin does not exhibit negative food effects because the absorption rate of the drug is not lowered even when the patient takes ingested food. Therefore, the therapeutic package of the present invention has the advantage that can be taken irrespective of the intake of food.

Claims (6)

Oral dosage form of azithromycin with serum drug concentration-time curve under food intake and non-ingestion, (AUC _fed ) / (AUC _fst ) of at least 0.80 and a lower limit of 90% confidence limit of at least 0.75, the container and A therapeutic package containing non-limiting printed matter as to whether or not it can be taken with food. The method of claim 1, The therapeutic package of the dosage form is a tablet. The method of claim 1, The dosage form is a therapeutic package in the form of a powder for oral suspension. The method of claim 3, wherein The dosage form is a therapeutic package in the form of a suspension prepared from the powder. The method of claim 1, The therapeutic package is in the form of a unit dosage packet. The method of claim 5, The therapeutic package is in the form of a suspension prepared from the unit dose packet.