UA78793C2 - Oral dosage form of azitromycin with decreased side effects - Google Patents

Abstract

The invention relates to the oral dosage form containing Azitromycin and the effective amount of alkalization agent. Preferably, the said oral dosage form comprises the effective amount of alkalization agent and multiparticles of Azitromycin containing Azitromycin and the mixture of glycerylmonobechenate, glyceryldibechenate, glyceryltribechenate, and poloxamer. Also disclosed are the method for decreasing the gastrointestinal side effects and the method for treating bacterial or protozoal infection in the mammals using the said oral dosage form.

Description

Description of the invention

Azithromycin is an antibiotic taken orally or intravenously for the treatment of various 2 infectious diseases, especially infectious diseases of the urinary tract, bronchial tract, lungs, cavities and middle ear.

Oral dosing of azithromycin can lead to adverse gastrointestinal (GI) side effects, such as nausea, cramping, diarrhea, and vomiting, in a significant number of patients. Such gastrointestinal side effects are also observed in mammals such as dogs. In pooled 70 azithromycin clinical trials involving 3,995 patients (all dose levels pooled), 9,695 patients reported gastrointestinal side effects; the most frequent of these side effects were diarrhea (3.695), nausea (2.690), and abdominal pain (2.595) |(NorkKipv, 91. At. y). Honey. 405 (Zuirri ZA 1991)).

The frequency of these adverse effects increases with increasing dosage levels of azithromycin. When treating adults with single 1-gram doses taken orally in the form of a suspension, 12 cases of various gastrointestinal side effects were observed: diarrhea 795, nausea 595, abdominal pain 595, and vomiting 295 (0.5. RasKade Ipzegi yog 7yygotah 2 azithromycin for oral suspension However, the following gastrointestinal adverse effects were observed for single 2-gram doses taken orally as a suspension: diarrhea 1495, abdominal pain 790, and vomiting 795 (ibid.).

Similarly, in the treatment of children by oral administration of the suspension, which included 1Omg/kg on the first day and

BMI/kgg on days 2-5, various gastrointestinal side effects were observed: diarrhea 4905, abdominal pain 2905, and vomiting 295 (ibid.), while for a single dose of ZOmg/kg the following gastrointestinal side effects were observed effects: diarrhea 6.495, nausea 1.795, and vomiting 495 (ibid.).

Antacids, which are alkaline agents that in large doses raise the pH of the stomach from about 1-3 to about 4-7, can prevent diarrhea, cramping, and upset stomach in the patient. However, patients should be cautioned against concomitant administration of antacids, especially those containing aluminum or magnesium, with azithromycin, as antacids have been shown to decrease peak serum azithromycin concentrations.

Stakh on 2495 (ibid.). In addition, to avoid the effect of antacid on azithromycin, patients were also advised to separate the administration of azithromycin and antacid by at least two hours.

Currently, commercially available dosage forms of azithromycin add small amounts, approximately 132 mg o or less, of the alkaline agent tribasic sodium phosphate anhydrous to mask the bitter taste of c) azithromycin, and to reduce the solubility of azithromycin before ingestion. In addition, in the treatment of uncomplicated gonococcal infectious diseases, packages with two single doses of azithromycin, each of which contains - 8 mg of anhydrous tribasic sodium phosphate, are simultaneously used as a single dose by a patient who needs it. 3o Previously, controlled-release dosage forms of azithromycin were prepared as described in (US Pat.

Mob,068,859) that reduced gastrointestinal side effects resulting from a dose of azithromycin compared to an equivalent dose of commercially available azithromycin immediate-release capsules. However, it was later found that the bioavailability of many controlled release dosage forms, particularly 4 exemplified herein, was less than their immediate release equivalents. C 50 Therefore, there is a need for a dosage form of azithromycin that has similar bioavailability and less gastrointestinal side effects than an equivalent dose of immediate-release azithromycin.

This invention relates to an oral dosage form of azithromycin containing azithromycin and an effective amount of an alkaline agent. Preferably, such an oral dosage form includes an effective amount of an alkaline agent and multiparticles of azithromycin, said multiparticles containing azithromycin, a mixture of mono-, di- and tribehenates of glycerol and poloxamer. 7 The presented invention further relates to a suspension for oral administration, which contains

Ge | azithromycin, an effective amount of alkalizing agent and carrier. Preferably, azithromycin is in multiparticulate form. More preferably, multiparticles include azithromycin, a mixture of mono-, di- and tribehenates of glycerol and poloxamer. (Te) 20 Even more preferably, the oral dosage form of azithromycin and the oral suspension additionally contain from 300 to 400 mg of tribasic sodium phosphate, from 200 to 300 mg of magnesium hydroxide, and multiparticulates, where c» said multiparticulates include (His) azithromycin, (ii) a mixture of glycerol monobehenate, glycerol dibehenate and glycerol tribehenate, (iii) poloxamer 407, wherein said dosage form contains approximately 1.5d9A to 4dA of azithromycin. 25 In addition, this invention also relates to a method of reducing gastrointestinal side effects associated

HF) with the effect of azithromycin on mammals, which consists in administering to said mammal azithromycin together with an effective amount of an alkaline agent, while the frequency of gastrointestinal side effects is lower compared to cases of taking an equivalent dose of azithromycin without an alkaline agent. In this method, it is preferred that the multiparticles include (i) azithromycin, (ii) a mixture of glyceryl monobehenate, glyceryl dibehenate 60 and glyceryltribehenate, and (ii) poloxamer.

The invention further relates to a method of treating bacterial or protozoan infections in a mammal in need thereof, comprising co-administering to said mammal an oral dosage form, wherein said oral dosage form comprises azithromycin together with an effective amount of an alkaline agent. Preferably, according to this method, a person is prescribed from 250mMmgA to 7gA of azithromycin. More preferably, a person is prescribed azithromycin from 1.5 GhA to ZHA, even more preferably - in a single dose. Also, more preferably, for children weighing ZOkg or less, azithromycin is prescribed in the range from 45 mgA/kg to 75 mgA/kg, even more preferably - in a single dose.

The present invention further relates to azithromycin multiparticulates comprising azithromycin, a surfactant and a pharmaceutically acceptable carrier.

Figure 1, discussed further in Example 1, shows the effects on pH of titrating various basifying agents with increasing volumes of 0.1M CARRIER.

Figure 2, discussed further in Examples 1 and 8, shows the calculated pH of various basifying agents when they are titrated with 0.1M HCl after some time. 70 Fig. 3, further discussed in Example 8, shows the calculated pH of various basifying agents when they are titrated with 0.1M NCIII after some time.

As used herein, the term "about" means a specific value of -1095 from a specific value.

As used herein, the term "a" or "ap" means one or more. For example, the term "alkalizing agent" means one or more alkalizing agents, the term "carrier" means one or more carriers, and the term "dissolution enhancer" means one or more dissolution enhancers.

The term "alkalizing agent" in this context means a pharmaceutically acceptable excipient that will increase the pH level in the formulated suspension or stomach of the patient after oral administration of the medication by said patient.

The term "pharmaceutically acceptable" in this context means a component that, in combination with other components of the composition, is not harmful to the recipient.

The term "formulated suspension" means that the powder has been mixed with a carrier to form an "oral suspension".

In this oral suspension, the azithromycin particles and excipients may be (a) completely suspended in the carrier or (b) partially suspended in the carrier and partially dissolved therein. Oral suspensions of this invention include carriers that contain azithromycin suspended in the carrier or azithromycin temporarily suspended in the carrier after shaking, shaking, or mixing. at

The solvent of the present invention includes unflavored water, flavored water, or a natural or artificial fruit filler, or other flavored aqueous beverage type solution.

In the presented invention, the alkalizing agent, excipients and carrier are pharmaceutically acceptable. co

The term "effective amount of alkalizing agent" in this context means the amount of one or more alkalizing agents which, when administered in combination with azithromycin, provide a relative degree of improvement in tolerance in a certain percentage of recipients who are tolerant to the administration of azithromycin without gastrointestinal side effects, relative to a control dosage form containing the same amount of active azithromycin. co

The term "relative degree of improvement in tolerance" is defined as the ratio of (1) the percentage of adverse effects resulting from the administration of the immediate-release control dosage form to (2) the percentage of adverse effects resulting from the administration of the multiparticulate controlled-release dosage form according to the present invention, where the control immediate-release dosage form and the multiparticulate controlled-release dosage form contain the same amount of azithromycin. The controlled-release dosage form can be any conventional immediate-release dosage form, such as 7ipgotach F tablets, capsules, or unit-dose sachets for oral and suspension. For example, if the immediate release controlled dosage form provides a percentage of adverse effects resulting from the use of the drug - 2095, while the multiparticulate dosage form of the present invention provides a percentage of adverse effects resulting from oral administration of the drug, - 10965, then the relative degree of tolerability improvement is equal to 2090-1090 or 2. -I The term "oral dosage form" includes many means that together deliver orally the necessary amount of azithromycin to achieve the required dose of azithromycin. Typically, the oral dosage form is a powder for oral suspension, a unit-dose packet or sachet, a tablet, or a capsule.

The term "administration" generally refers to the introduction of a dosage form into the environment of use either by introducing the dosage form into a dissolution medium or by ingestion by an animal to introduce the dosage form into the conditions of the gastrointestinal tract.

In this context, the term "use medium" can be either the medium of the gastrointestinal tract of an animal, such as a mammal and, in particular, a human, or the medium with a pH of 6.0 Mag»HPO, a buffered test medium, as described in Example 5.

The term "mammal" means an individual animal that is a member of the taxonomic class of mammals. The class Mammalia includes,

F, for example, humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice and rats. ko In this invention, a human is most often understood as a mammal. The dosage forms of this invention provide better tolerance to azithromycin by increasing the pH level in the stomach to a level sufficient to significantly reduce the rate of release, or the rate of dissolution of azithromycin in the stomach and thus reduce the concentration of dissolved azithromycin in the stomach and duodenum. Such a decrease in the concentration of dissolved azithromycin in the stomach, and mainly in the duodenum, leads to a decrease in the incidence and frequency of gastrointestinal side effects when taking azithromycin. In particular, for dosage forms of the present invention comprising azithromycin and an effective amount of an alkalizing agent, 65 the release rate of azithromycin or the dissolution rate for a dose of 1.5 gA to 7 gA i.p. in a medium with a pH of 6.0 Mag»HPO, the buffer test medium of Example 5 , should be (i) from 15 to 55 wag.9o of azithromycin in the indicated dosage form in 0.25 hours, but not more than 1.1 gA; (her) from 30 to 75g.9o of azithromycin in the mentioned dosage form in 0.5 hours, but not more than 1.5 gA, and preferably not more than 1.3 gA; and (iii) more than 5Owag.9o of azithromycin in the mentioned dosage 1 hour after introduction into the buffered test medium. For doses lower than 1.5HgA, such as pediatric doses, the dose should be increased to 2HA and then evaluated using it in ip migo trials.

The term "gA" refers to grams of active azithromycin, meaning a non-salt, non-hydrated azithromycin macrolide molecule having a molecular weight of 749g/mol.

Presented dosage forms provide a relative degree of improvement in the tolerability of oral azithromycin of at least 1.1 compared to an equivalent immediate release dosage form. Preferably, the relative degree of improvement in tolerability is at least about 1.25. More preferably, the relative improvement in tolerability is at least about 1.5. Even more preferably, the relative improvement in tolerability is at least about 2.0. Most preferably, the relative tolerability improvement is at least about 3.0.

In a preferred embodiment, the presented dosage forms also maintain a suitable level of bioavailability by slightly reducing the rate of release of azithromycin and/or the rate of dissolution of azithromycin used in the duodenum or in the distal segment of the duodenum. Typically, the presented dosage forms provide bioavailability at a level of at least 6095, more preferably at least 7095, even more preferably at least 8095, and most preferably at least 9095 relative to the control

Compositions.

The alkalizing agents of this invention increase the pH level of acidic aqueous solutions and include, for example, antacids as well as other pharmaceutically acceptable (1) organic and inorganic bases, (2) salts of strong organic and inorganic acids, (3) salts of weak organic and inorganic acids, and (4) buffers.

Examples of such alkalizing agents include, but are not limited to, aluminum salts such as aluminum magnesium silicate; magnesium salts, such as magnesium carbonate, magnesium trisilicate, aluminum-magnesium silicate, magnesium stearate; calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium bicarbonate; i) phosphates, such as monobasic calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate (T5R), dibasic potassium phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide, sodium hydroxide and magnesium hydroxide; metal oxides, such as magnesium oxide; c zo M-methylglucamine; arginine and their salts; amines such as monoethanolamine, diethanolamine, triethanolamine, and tri(hydroxymethyl)aminomethane (TC); and their combinations. Me

Preferably, the alkalizing agent is TKI5, magnesium hydroxide, magnesium oxide, dibasic sodium phosphate, M

TOR, dibasic potassium phosphate, tribasic potassium phosphate, or a combination thereof. More preferably, the alkalizing agent is a combination of T5P and magnesium hydroxide. co

When the alkalizing agent includes TP, it is preferred that the TP is anhydrous. The minimum amount of alkalizing agent corresponding to an "effective amount" is such an amount that provides a relative degree of tolerability improvement of at least 1.1.

This suitable amount of alkalizing agent can be easily determined by carrying out a multi-step study of the rate of dissolution of azithromycin by titrating a solution of a fixed dose of azithromycin with 0.1 M "40. NOI and increasing the amount of alkalizing agent or combinations of alkalizing agents as described in Example 1. For dosage forms containing multiparticles of azithromycin, an effective amount of alkalizing agent agent, there is such an amount that, when titrated using a titration test, it could be compared to 0.1 M

A NOI that simulates postprandial gastric fluid as described in Example 1 maintains a pH of about 5 or more for at least about 10 minutes, and more preferably a pH of about b or more for about 10 minutes. Even more preferably, the alkalizing agent should maintain a pH of about 6 or more for about 20 minutes or more. For immediate-release dosage forms of azithromycin, the effective amount of alkalizing agent is that amount which, when titrated using the ip mygo titration test against 0.1 M CARRIER as described in Example 1, maintains a pH of about 6.4 or greater for at least about 10 minutes, and more preferably for at least about 30 minutes. 4) Alternatively, an effective amount of alkalizing agent can be determined in a subsequent IP study. First, a sample of 0.1 M CARRIER, with a volume of 20 ml, is placed in the appropriate container. Then, an alkalizing agent is added to bOmol of water. Then, the solution of the alkalizing agent formed in this way is added to the sample in two 20 ml volumes, and the pH of the resulting solution is monitored for some time. When the azithromycin is in the form of multiparticulates with delayed release, the effective amount of alkalizing agent (F) is such that the pH of the solution is at least 5, preferably at least 6, and more preferably at least 7. When the azithromycin is in the form of a composition rapid release, an effective amount of alkalizing agent is such that the pH of the solution is at least 6.4, preferably at least 7.5, and more preferably at least 8. 60 The alkalizing agent of the present invention is administered at the same time as the dose of azithromycin. In this context, the term "together" means that the alkalinizing agent is taken before, simultaneously, or after the azithromycin for a time sufficient to slow the rate of release of azithromycin in the stomach and reduce the concentration of released azithromycin in the duodenum. For example, when using azithromycin in multiparticulate form, the alkalizing agent should be taken between approximately 20 minutes before and 65 approximately 10 minutes after the use of azithromycin. For the immediate-release dosage form of azithromycin, the alkalizing agent should be taken at the same time as the azithromycin or approximately 20 minutes before taking the azithromycin.

Preferably, the alkalizing agent is taken at the same time as azithromycin.

The alkalizing agent can be mixed with the dosage form of azithromycin as an integral part of a tablet, capsule, or preferably in a powder mixture, if the form of controlled release is a powder for oral administration.

The alkalizing agent may be in the same dosage form as the azithromycin, the alkalizing agent may be contained in the nome used to administer the azithromycin, and/or the alkalizing agent may be taken separately from the azithromycin. 70 Wherein the azithromycin dosage form contains at least a portion of the alkalizing agent, the dosage form of azithromycin can be any oral dosage form, such as a suspension, tablet, capsule or sachet.

Where the alkalizing agent is at least partially contained in the carrier, the dosage form of azithromycin may be a sachet, powder for oral suspension, tablet or capsule.

In addition, the alkalizing agent is at least partially administered separately from the azithromycin, the alkalizing agent may be in any oral dosage form such as a liquid, suspension, tablet, capsule, or sachet.

In this context, "azithromycin" means all amorphous and crystalline forms of azithromycin, including all polymorphs, isomorphs, clathrates, salts, solvates and hydrates of azithromycin, as well as anhydrous azithromycin.

Preferably, the azithromycin of this invention is azithromycin dihydrate, which is disclosed in (US patent 20 Meb,268,489 B1).

In alternative embodiments of the present invention, azithromycin includes undehydrated azithromycin, a mixture of undehydrated azithromycin, or a mixture of azithromycin dihydrate and undehydrated azithromycin.

Examples of suitable non-hydrated azithromycin include, but are not limited to, alternative crystal forms B, O, E, B, b, H, 2), MM, 0, P, Si Kk. with

Azithromycin Form B, which is a hygroscopic hydrate of azithromycin, is disclosed in (US Pat. No. 4,474,7681.

Forms of azithromycin O, E, ER, b, H, u), M., M, O, R, O Her K are disclosed in the application for (US patent Mo (OBBM) 0 10/152,106, published on August 28, 2003) , as well as in the published (US patent application Mo20030162730

ALI.

Forms B, E, 0, H, U, M., M, O, and P belong to the family | azithromycin and belong to the monoclinic P24 c zo space group with cell sizes a-16.3-0.3E, B-16.2--0.3 A, c-18.4-0.3 A and beta-109- 2.

The GE form of azithromycin is azithromycin ethanol solvate of the formula Сз8Н.2М2О42.Н»О.0.5С2НьОН in the structure of a single crystal, especially, azithromycin monohydrate hemi-ethanolsolvate. Form E is further characterized as containing 2-595 water and 1-495 ethanol by weight in powder samples. The single crystal of form E crystallizes in the monoclinic space group, P2i, with an asymmetric unit containing two molecules of azithromycin, two so molecules of water and one molecule of ethanol, in the form of monohydrate/hemi-ethanolate. It is isomorphic to the entire h-family | azithromycin in crystalline forms. The theoretical content of water and ethanol is 2.3 and 2.9 wt.9, respectively.

Form b of azithromycin has the formula СзвН72М2О012.1,5Н2О in a single crystal structure, which is "azithromycin sequihydrate." Form C is further characterized as containing 2.5 mg of water and 9 mg of organic solvent(s) in powder samples. The structure of the o-shaped single crystal consists of two molecules - azithromycin and three water molecules in an asymmetric unit. This corresponds to a sequihydrate with a theoretical water content of 3.5 wt.95. The water content in powder samples of the o form ranges from approximately 2.5 to approximately , "bvag.uo. The total residual amount of organic solvent is less than 1wg.9o of the corresponding solvent used for crystallization.

Form H of azithromycin has the formula СзвН7У2М2012.Н»О0.0.5С3НаеО», which is azithromycin monohydrate and hemi-1,2 propanediol solvate. Form H is a monohydrate/hemi-propylene glycol solvate of azithromycin in its free base form.

Form 4 of azithromycin has the formula СзвН.2М2012.Н»2О.0.5С5Н7ОН in a single crystal structure, which is azithromycin monohydrate hemi-n-propanolsolvate. Form. further characterized as containing so 50 2-5 wt. of water and 1-5 wt. of n-propanol in powder samples. The calculated content of the solvent is approximately 3.9% by weight of n-propanol and approximately 2.9% by weight of water. c» Form M of azithromycin is an isopropanol solvate of azithromycin with the formula

СзвН/2М2042.Н»О.0.505Н7ОН, in particular, monohydrate hemi-isopropanol solvate of azithromycin. Form M is further characterized as containing 2-5 wt.9o of water and 1-4 wt.96o of 2-propanol in powder samples. 595 The single crystal structure of form M would be monohydrate/hemi-isopropanolate.

GF) Form M of azithromycin is a mixture of isomorphs of the ! family. The mixture may contain variable percentages of isomorphs E, b, H, y, M, and others, and variable amounts of water and organic solvents, such as ethanol, isopropanol, di-n-propanol, propylene glycol, acetone, acetonitrile, butanol, pentanol, etc. The amount of water can be from 1 to 5,Zwag.9o and the total amount of organic solvents can be 2-5wag.9o with each solvent making 60 from 0.5 to 4wag.95.

The OO form of azithromycin has the formula Сз8Н./2М20О425.0.5Н20.0.5С,НоОН, which is / hemihydrate of hemi-n-butanolsolvate of azithromycin in the form of a free base with a single crystal structure.

Form P of azithromycin has the formula /C38H72M20425.H2O0.0.5C5H420, which is the monohydrate of hemi-n-pentanolsolvate of azithromycin. because Form (e) of azithromycin has the formula /С38вН7»М»2О12.Н2О.0.5С;НаБО, which is the monohydrate of azithromycin hemi-tetrahydrofuransolvate. It contains approximately 4.95 g of water and approximately 4.5 g.90 THF.

Forms 0, E and K belong to the II family of azithromycin and belong to the orthorhombic P242424 space group with cell size a-8.9--0.4A, 0-12.3-40.5A and C-45.8-0.5A . Form C is different from families | and II.

Form 0 of azithromycin has the formula СзвН.72М2О12-.Н»О.СеНио in a single crystal structure, which is monohydrate of monocyclohexanesolvate of azithromycin. Form O is further characterized as containing 2 wt.bo of water and 3-12 wt.bo of cyclohexane in powder samples. Based on the characteristics of the single crystal form, the calculated content of water and cyclohexane form O is 2.1 and 9.9 wt.9o, respectively.

Form E of azithromycin has the formula СзвНИ2 М2012.Н2О.С) НБО, which is monohydrate 70 monotetrahydrofuransolvate of azithromycin. Form E is a monohydrate and a mono-THF solvate according to single crystal analysis.

Form Kk of azithromycin has the formula, СзвНИ»М2042-Н2О.С5НИ20, which is the monohydrate of monomethyl-tert-butyl ether solvate of azithromycin. Form K has a theoretical water content of 2.1 wt.9o and a theoretical methyl tert-butyl ether content of 10 wt.9b.

Both family 1 and family 2 isomorphs are hydrates and/or solvates of azithromycin. Solvent molecules in voids tend to exchange with water molecules under certain conditions. Therefore, the solvent/water content of the isomorphs may vary to some extent.

Other examples of azithromycin non-dihydrates include, but are not limited to, azithromycin ethanol solvate or azithromycin isopropyl solvate. Examples of such ethanol and isopropyl solvates of azithromycin are disclosed in U.S. Patent Mob. 365,574, Zipdeg et al., entitled "Azithromycin Ethanolate, Method of Preparation and Pharmaceutical Compositions", U.S. Patent Mob. 365,574, Kagitiap et al., entitled "Isopropanol Clathrate Monohydrate azithromycin and methods of its preparation" or in the US patent application Mo10/152,1061.

Additional examples of azithromycin non-dihydrates include, but are not limited to, azithromycin monohydrate disclosed in US patent applications No. 20010047089, issued Nov. 29, 2001, and Ge

Mo20020111318 published on August 15, 2002, as well as in international patent applications with publication numbers MO 01/00640, MO 01/49697, MO 02/10181 and MO 02/42315).

Further examples of azithromycin non-dihydrates include, but are not limited to, anhydrous azithromycin as disclosed in application (US patent No. Mo20030139583, issued July 24, 2003 and patent

USA Mob,528,4921. co

Examples of suitable azithromycin salts include, but are not limited to, azithromycin salts as described in (US Pat. No. 4,474,768).

Preferably, at least 7% of the azithromycin in the multiparticulates is crystalline. More preferably, at least one half of azithromycin is crystalline. Even more preferably, at least 30% of the azithromycin is crystalline. co

Most preferably, at least 50% of azithromycin is crystalline. Crystalline azithromycin is preferred because it is more chemically and physically stable than amorphous or soluble azithromycin. -

The crystallinity of azithromycin can be determined using X-ray diffraction (XRD) powder analysis. As a sample of RKKO, the analysis can be carried out on the Vgykeg AH 08 improved diffractometer. In this assay, samples weighing approximately 5000 mg are packed into I isie beakers and the surface of the sample is smoothed with a glass slide to ensure a smooth surface of the sample flush with the surface of the beaker. The samples are rotated in the p plane at a speed of 30 revolutions per minute in order to minimize the effects of crystal orientation. The X-ray source (5/V KSio, X-1.54A) operates at a voltage of 45KV and a current of 40mA. Data "" for each sample is collected over a time period of approximately 20 to 60 minutes in continuous " detector scanning mode at a scan rate of about 1.8 seconds/step to about 12 seconds/step and a step size of about 0.022/step. Diffractograms. are obtained in the 28 range from approximately 42 to 302.

The crystalline state of the sample is determined by comparison with two or more calibration standards consisting of physical mixtures of crystalline azithromycin and the carrier. Each physical mixture is mixed together

Go) about 15 minutes on Tigrshia mixer. Using the instrument software, the area under the curve of the diffractogram is integrated over a range of 20 using a linear basis. This integration range 7 includes as many specific peaks associated with the medicinal substance as possible, despite (Te) 20 that the peaks associated with the carrier are excluded. The linear calibration curve of the dependence of the percentage of the crystalline medicinal substance on the area under the diffractogram curve is built on the basis of calibrated standards. Then c» the crystallinity of the sample is determined using these calibration results and the area under the curve for the test sample. Results are reported as the average percent crystallinity of azithromycin (by crystal mass). 29 Azithromycin as used herein includes particles of azithromycin contained in a dosage form which, according to

GF) in the absence of an alkalizing agent of this invention, is either a rapid release dosage form or a sustained release dosage form. As defined herein, the term "azithromycin particles" means that the azithromycin may be in the form of a powder or granules that have been preformed from the azithromycin powder and, optionally, with at least one pharmaceutically acceptable inert excipient. 60 Immediate-release dosage forms are forms in which at least 7595 azithromycin is released or dissolved within half an hour after administration. Such immediate release dosage forms include tablets, capsules, multiparticulates, powders for oral suspension, and sachets of azithromycin. Examples of immediate release dosage forms include, but are not limited to, commercially available 7mg F tablets, capsules, suspensions, or unit dose sachets for oral suspension (Rigieg Ips., Mem/-Mogk, MU) or a multiparticulate controlled release dosage form, which is described here in Example 2.

Sustained-release dosage forms are those forms that release azithromycin more slowly than quick-release dosage forms. Such sustained release dosage forms include, but are not limited to, tablets, capsules, multiparticulates, suspension powders, and azithromycin sachets.

Examples of sustained-release dosage forms of azithromycin suitable for use in the present invention include, but are not limited to, the sustained-release dosage forms described in (US Patent Mob,068,859).

Preferably, the azithromycin used in the present invention is contained in the form of multiparticulates comprising azithromycin and a pharmaceutically acceptable carrier. 70 Multiparticulates are well-known dosage forms that include many particles containing a drug substance, the aggregate of which represents an intended therapeutically useful dose of the drug substance. When taken orally, multiparticles generally disperse freely in the gastrointestinal tract, leave the stomach relatively quickly and reproducibly, and maximize absorption. See, for example,

Miyiragisatsiae Oh! JuOgid OeiYimegu (Magse! Oekkkeg, 1994), and RpNnaptaseciisai ReiPeigaiop ThesppoYodu 7/5 "(Magse! Oekkeg, 1989)).

Multiparticles are often used to provide sustained release of a medicinal substance.

The problem in creating a formulation for sustained release of multiparticles is to determine the rate of release of the medicinal substance. The rate of drug release depends on a variety of factors, including the carriers used in the formation of the multiparticles and the amount of drug in the multiparticles. It is desirable to provide such carriers for multiparticulates that allow control of the drug release rate from the multiparticulates over a wide range of release rates, so that the same matrix materials in different proportions can be used, if desired, to provide slow or rapid drug release. To achieve this result, the rate of drug release must vary significantly in response to relatively small changes in the proportions of the corresponding carriers in the multiparticulates.

The term "multiparticles" is intended to encompass a dosage form comprising multiple particles, i) the total of which represents an intended therapeutically useful dose of azithromycin. The term broadly applies to small particles regardless of their composition or the manner in which they are formed. The particles are small enough that they travel with the gastrointestinal fluids to be dispersed throughout the gastrointestinal tract immediately after ingestion. The particles generally have an average diameter of from about 40 to about 300 µm, preferably from about 50 to about 100 µm, and most preferably from about 100 to about 300 µm. Preferably, the azithromycin comprises from about 5% by weight to about 9% by weight of the total weight of the multiparticle. More preferably, the azithromycin comprises from about 10 wt.95 to about 8 wt.90 multiparticulates, and even more preferably, at least from about 30 wt.90 to about 60 wt.90 multiparticulates. uh-

While multiparticles can have any shape and texture, spherical ones with a smooth surface texture are preferred. Such physical characteristics provide improved palatability, ease of swallowing, and ease of coating, if desired.

Such multiparticles of azithromycin are especially suitable for taking in single doses of drugs, since relatively

A large amount of medicinal substance can be released at a controlled rate for a long period of time. Multiparticulates suitable for use in the present invention are disclosed in (US Pat. Mob,068,859), including multiparticulates obtained by extrusion/spheronization, wax granulation, spray drying, and spray coating.

The multiparticulate carrier includes at least one pharmaceutically acceptable inert filler that

Functions as a matrix for the multiparticle or controls the rate of release of azithromycin from the -I multiparticle, or performs both functions.

All references to the term "acid and/or ester substituents" herein mean carboxylic acid, sulfonic acid, and phosphoric acid substituents or carboxylic acid ester, sulfonyl ester, or phosphoric acid -I ester substituents, respectively. As described in detail below, azithromycin can react with acid substituents or ester substituents on the excipient to form azithromycin esters. Azithromycin can potentially react with carriers and optional excipients having acid groups 4) or ester groups to form azithromycin esters. Carriers and excipients can be characterized as having "low reactivity", "medium reactivity" and "high reactivity" for the formation of azithromycin esters.

Examples of carriers with low reactivity and optional excipients with low reactivity include long-chain alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol;

F) poloxamers (block copolymers of ethylene oxide and propylene oxide, such as poloxamer 188, poloxamer 237, ka poloxamer 338 and poloxamer 407); ethers, such as polyoxyethylene alkyl ethers; ether-substituted celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and ethyl cellulose; sugars such as glucose, sucrose, xylitol, sorbitol and mannitol; and salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate.

Carriers of moderate reactivity and optional excipients often contain acid or ester substituents, but relatively few compared to the molecular weight of the carrier or optional excipient. 65 Examples include long-chain fatty acid esters such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils,

glyceryl dibehenate, and mixtures of mono-, di- and trialkylglycerides; esters of glycols and fatty acids, such as polyethylene glycol stearate and polyethylene glycol distearate; polysorbates; and waxes such as carnauba wax and white and yellow beeswax. Glyceryl behenate, as defined herein, includes glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, or a mixture of any two or all three of said glyceryl mono-, di-, and tribehenate.

Carriers with high reactivity and optional excipients usually have few acid or ester substituents, or low molecular weights. Examples include carboxylic acids such as stearic acid, benzoic acid, citric acid, fumaric acid, lactic acid and maleic acid; 7/0 short to medium chain fatty acid esters such as isopropyl palmitate, isopropyl myristate, triethyl citrate, lecithin, triacetin, and dibutyl sebacinate; ester-substituted celluloses, such as cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimethylate, and hydroxypropylmethylcellulose acetate succinate; and polymethacrylates and polyacrylates with acid and ester functional groups. In general, the concentration of acid and ester functional groups on highly reactive carriers and optional excipients is so high that, if such carriers and optional excipients come into direct contact with azithromycin in the composition, an unacceptably high concentration of azithromycin esters is created in the preparation process processing or storage of the composition. Thus, such highly reactive carriers and optional excipients are preferably used only in combination with a carrier or optional excipient of lower reactivity such that the total number of acid and ester groups on the carrier and optional excipient used in the multiparticles is low

To produce multiparticulates with an acceptable amount of azithromycin esters (ie, less than approx

Ivag.9o), there is an alternative relationship between the concentration of acid and ester substituents on the carrier and the crystallinity of azithromycin in the multiparticle. The greater the crystallinity of azithromycin in the multiparticle, the greater the degree of substitution of the carrier by acid/ester groups can be obtained in the multiparticle with acceptable amounts of azithromycin esters. This ratio can be quantified by the following i) mathematical equation:

IA1«0.04/1-5) (I) s y y sho ' s. where IA) means the total concentration of acid/(ester substituents on the carrier and optional excipients /F) in meq./g of azithromycin and is less than or equal to 2 meq./7, and x means the weight fraction of azithromycin in the composition, which is crystalline. When the carrier and optional excipients include more than one excipient, the value of CIAI| refers to the total concentration of acid/ester substituents on all excipients, which (ee) make up carriers and optional excipients, in units of meq./g of azithromycin.

For more preferred multiparticulates having less than about 0.5 wt.90 azithromycin esters, he azithromycin, carrier and optional excipients will satisfy the following equation:

IA1kO,021-5) (I) "

For more preferred multiparticulates having less than about 0.2 wt.90 azithromycin esters, the azithromycin, carrier, and optional excipients will satisfy the following equation: is" IAT" 0.008/(1st). (PI)

For more preferred multiparticulates having less than about 0.1 wt.90 of azithromycin esters, the azithromycin, carrier, and optional excipients will satisfy the following equation: (IM) -I

The relationship between the degree of acid/ester substitution of carriers and optional excipients and the crystallinity of azithromycin in the composition can be determined from the previous mathematical equations (1I)-IM). 4) The carriers used in the multiparticulates of the present invention will generally be from about 1 wt.95 to about 95 wt.95 by weight of the multiparticle, preferably from about 2 wt.95 to about 00 wt.9b, and more preferably from about 4 wt.95 to about 7 wt. .90o, from the total mass of the multiparticle.

To minimize the possibility of changes in the physical properties of the multiparticles over time, especially when stored at elevated temperatures, the carrier should preferably be solid at a temperature of at least 40°C. More preferably, the carrier should be solid at a temperature of at least 502C and even more preferably at least where 602C.

In one embodiment, the carrier forms a solid solution with one or more optional excipients, meaning that the carrier and one or more optional excipients form a single thermodynamically stable phase. In such cases, excipients that are not solid at a temperature of at least 40°C may be used provided that the carrier/excipient mixture is solid at a temperature of at least 40°C. This will depend on the melting point of the excipients used and the relative amount of carrier included in the composition. for In another embodiment, the carrier and one or more optional excipients do not form a solid solution,

that is, the carrier and one or more optional excipients form two or more thermodynamically stable phases. In such cases, the carrier/excipient mixture may be completely molten at the processing temperatures used to form the multiparticulates, or one material may be solid while the other is molten, resulting in a suspension of one substance in the molten mixture

When the carrier and one or more optional excipients do not form a solid solution, but a solid solution is desired, for example to achieve a particular controlled release profile, an additional excipient may be included in the composition to provide a solid solution that includes the carrier, one or more optional excipients and an additional excipient. For example, it may be desirable to use a 70 carrier that contains microcrystalline wax and poloxamer to produce a multiparticulate with a desired release profile. In such cases, a solid solution does not form, partly due to the hydrophobicity of the microcrystalline wax and the hydrophilic nature of the poloxamer. By including a small amount of a third excipient, such as stearyl alcohol, a solid solution can be obtained, resulting in multiparticles with the desired release profile.

Examples of carriers suitable for use in the multiparticles of this invention include waxes such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax and beeswax; glycerides such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated derivatives of castor oil, hydrogenated vegetable oils, glyceryl behenates, glyceryl tristearate, glyceryl tripalmitate; long chain alcohols such as stearyl alcohol, cetyl alcohol and polyethylene glycol; and their mixtures.

Preferably, the carrier includes a glyceride having at least one alkylate substituent with 16 or more carbon atoms. More preferably, the carrier includes glyceryl behenate. In an alternative embodiment, the multiparticles are in the form of a non-disintegrated matrix. The term "non-disintegrated matrix" is understood to mean that at least part of the carrier does not dissolve or disintegrate after the introduction of multiparticles into the aqueous environment of use. In such cases, azithromycin and optionally a part of one or more carriers, for example, a solvent booster, are removed from the multiparticles by dissolution. At least a portion of the carrier does not dissolve or disintegrate and is released when the medium is used, or remains i) suspended in the test solution when the medium is used. In this aspect, it is preferred that at least part of the carrier has low solubility in the aqueous medium of use. Preferably, the solubility of at least a portion of the carrier in an aqueous medium is less than about mg/ml, more preferably less than about 0.1 mg/ml, and most preferably less than about 0.01 mg/ml. Examples of suitable carriers with low solubility include waxes such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax and beeswax; glycerides such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenates, glyceryl tristearate, glyceryl tripalmitate; and their mixtures. co

In a preferred embodiment of the present invention, the azithromycin multiparticles of the present invention (M) include azithromycin, a carrier, and a dissolution enhancer. The carrier and dissolution enhancer act as a matrix for the multiparticle or control the release rate of azithromycin from the multiparticle, or both. The term "dissolution enhancer" means an excipient , which, when included in the composition of the multiparticle, provides a higher rate of azithromycin release than that provided by the control multiparticle, which contains the same amount of azithromycin without a dissolution enhancer. In general, the rate of release of azithromycin from the multiparticle increases with the increase in the amount of the dissolution enhancer. Such agents are generally highly soluble in water and are often surfactants or wetting agents that can enhance the solubilization of other excipients in the formulation. Typically, the weight percent dissolution of the enhancer present in the multiparticle is less than the weight percent of the carrier present in the multiparticle.

The multiparticles of the present invention include from about 20 to about 75 wt.90 of azithromycin, and from about 25 to about 80 wt.95 of a carrier and from about 0.1 to about 30 wt.90 of a dissolution enhancer, based on the total weight of the multiparticle. In a preferred embodiment, the multiparticle contains from 35 to 55 grams of azithromycin, from 40 to 5 grams of carrier and from 1 to 15 grams of dissolution enhancer. -I Examples of suitable dissolution enhancers include, but are not limited to, alcohols such as stearyl alcohol, cetyl alcohol and polyethylene glycol; surfactants, such as poloxamers and (polyoxyethylene polyoxypropylene copolymers, including poloxamer 188, poloxamer 237, poloxamer 338 4) and poloxamer 407), docusate salts, alkyl ethers of polyoxyethylene, polyoxyethylene derivatives of castor oil, polyoxyethylene sorbitan esters of fatty acids, sorbitan esters, alkyl sulfates (such as sodium lauryl sulfate), polysorbates and alkyl esters of polyoxyethylene; ether-substituted celluloses, such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; sugars such as glucose, sucrose, xylitol, sorbitol and maltitol; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium,

F) potassium sulfate, sodium carbonate, magnesium sulfate and potassium phosphate; amino acids such as alanine and glycine; and their mixtures. Preferably, the dissolution enhancer contains a surfactant.

More preferably, the dissolution enhancer contains a poloxamer. Poloxamers are a series of closely linked block copolymers of ethylene oxide and propylene oxide that do not have acid or ester substituents. In this case, large amounts of poloxamers, such as

ZOwg.95, and still achieves a target value of less than about 0.1 ZmEq./h of azithromycin. Even more preferably, the poloxamer is poloxamer 407, as described herein in the examples.

In this embodiment, when the multiparticulates additionally contain a dissolution enhancer, preference is given to 65 NOoSis selected from the group consisting of waxes such as synthetic wax, microcrystalline wax, paraffin, carnauba wax and beeswax; glycerides such as glyceryl monooleate,

glyceryl monostearate, glyceryl palmitostearate, polyethoxylated derivatives of castor oil, hydrogenated vegetable oils, glyceryl mono-, di- or tribehenates, glyceryl tristearates, glyceryl tripalmitates and their mixtures.

Azithromycin present in multiparticulates has been found to be particularly chemically active towards dissolution enhancers. As a result, the concentration of acid and ester substituents on the dissolution enhancer must be kept low so that the formation of azithromycin esters remains at acceptably low levels.

From the point of view of reactivity for the formation of azithromycin esters, dissolution enhancers preferably 7/0 have a concentration of acid/ester substituents less than about 0.1 ZmEq./g of azithromycin present in the composition. Preferably, the dissolution enhancer has a concentration of acid/ester substituents less than about 0.1 Meq/g of azithromycin, more preferably less than about 0.02 meq/g of azithromycin, even more preferably less than about 00.01 meq/g. g, and most preferably, less than about 0.002 meq./g.

In addition to a low concentration of acid/ester substituents, solubilizers should generally be hydrophilic so that the rate of release of azithromycin from the multiparticle increases with increasing concentration of the solubilizer in the multiparticle.

Further description of suitable dissolution enhancers and the selection of appropriate excipients for azithromycin multiparticulates is disclosed in (US Patent Mobo/527,319 ("Controlled Release of Multiparticulates Prepared with Dissolution Enhancers", Patent Attorney MORS25016), filed concurrently).

In a more preferred embodiment, multiparticles according to this invention include (a) azithromycin; (B) a glyceride carrier having at least one alkylate substituent with 16 or more carbon atoms; and (c) a poloxamer dissolution enhancer. The choice of these particular carriers allows precise control of the release rate of azithromycin over a wide range of release rates. Small changes in the relative amounts of the glyceride carrier and poloxamer lead to significant changes in the rate of drug release. This method allows you to precisely control the rate of release of the medicinal substance from the multiparticle by choosing the appropriate ratio of the medicinal substance, glyceride carrier and poloxamer. These substances have a further i) advantage in releasing almost all medicinal substances from the multiparticle. Such multiparticulates are disclosed in more detail in the application for (US patent Mob6b60/527,329 ("Multiparticulate Crystalline Compositions of Medicinal Substance with Controlled Release", patent attorney MORS25020), filed concurrently herewith). Additional optional excipients may also be included in multiparticles of azithromycin. For example, agents that inhibit or delay the release of azithromycin from Me multiparticles can also be included in the carrier. Such dissolution inhibiting agents are generally hydrophobic. Examples of M dissolution inhibiting agents include hydrocarbon waxes such as: microcrystalline and paraffin waxes.

Another useful class of excipients are substances used to adjust the viscosity of the molten sorghum used for the formation of multiparticles, for example, through a melt-freeze process. Such viscosity-adjusting excipients will generally comprise from 0 to 25 wt.90 of the multiparticle, relative to the total weight of the multiparticle. The viscosity of the molten raw material is a key variable in the production of multiparticles with a narrow particle size distribution. For example, when using a rotating disc atomizer, the viscosity of the molten mixture should preferably be at least "about 1 centipoise (sp) and less than about 10,000sp, more preferably at least 5Osp and less than pt") with about 1,000sp. If the molten mixture has a viscosity outside these preferred limits, may be added. a viscosity adjustment agent to obtain a molten mixture within the preferred viscosity range. and?" Examples of viscosity-reducing excipients include stearyl alcohol, cetyl alcohol, low molecular weight polyethylene glycol (eg, less than about 1000 daltons), isopropyl alcohol, and

water Examples of viscosity-increasing excipients include microcrystalline wax, paraffin wax, synthetic -I wax, high molecular weight polyethylene glycols (eg, greater than about 5,000 daltons), ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, silicon dioxide, microcrystalline so cellulose, magnesium silicate, sugar and salt. -And to reduce the static charge in multiparticles, other excipients can be added; examples of such antistatic agents include talc and silicon dioxide. Flavorings, colorings and other excipients may also be added in their usual amounts for their usual purposes. In addition to multiparticles and an alkaline agent, the dosage form of azithromycin of this invention may additionally contain one or more additional excipients.

For example, surfactants may be included in dosage forms. Examples of suitable surfactants include fatty acid and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (NHMAME (F 1622, from Iopla, Ips., Raypump, NJ);

Ф) dioctyl sodium sulfosuccinate (POSIOBATE BOBIOMtmM, from MayijipsKkgodi Zresiaiu SpetisI5, 5. I1otsiv, co Missouri); polyoxyethylene sorbitan esters of fatty acids (TUMUEEMF), from ISI Ategisaz Ips., UMitipdAyup,

OeiIazhshage; PROBOMKVOYA R-20, from Girospet Ips., Ratseggop New Jersey; SARMYOGYA ROBE-0O, from Abies Sogr., because chapevmiye, MuUizsopzip); and natural surfactants such as natritaurocholic acid, 1-palmitoyl-2-oleyl-zp-glycero-3-phosphocholine, lecithin and other phospholipids and mono- and diglycerides. Such substances can preferably be used to increase the speed with which multiparticles disperse when they enter the environment of use.

Conventional matrix materials, fillers, diluents, lubricants, preservatives, thickeners, anti-caking agents, disintegrants or binders may also be included in the dosage form.

Examples of matrix materials, fillers or diluents include lactose, mannitol, xylitol,

microcrystalline cellulose, dibasic calcium phosphate and starch.

Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, croscarmellose sodium, and cross-linked forms of polyvinylpyrrolidone, also known as crospovidone.

Examples of binders include methylcellulose, microcrystalline cellulose, starch and resins such as guar gum, and tragacanth.

Examples of lubricants include magnesium stearate, calcium stearate and stearic acid.

Examples of preservatives include sulfites (antioxidants), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol, and sodium benzoate. 70 Examples of suspending agents or thickeners include xanthan gum, starch, guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica gel, aluminum silicate, magnesium silicate, and titanium dioxide.

Examples of anti-caking agents or fillers include colloidal silicon oxide and lactose.

Other conventional excipients may be used in the compositions of this invention, including those known in the art. In general, excipients such as dyes, lubricants, flavorings, etc. can be used for generally accepted purposes and in normal quantities without adversely affecting the properties of the compositions.

In one embodiment, the dosage form is in the form of a tablet. The term "tablet" is intended to cover compressed tablets, coated tablets, and other forms known in the art. | See example,

Ketipdiopye Rpagtaseciisa! Zsiepsez (18th ed. 1990)). When entering the environment of use, the tablet quickly disintegrates, allowing the multiparticles to disperse in the environment of use.

In one embodiment, the tablet includes multiparticulates that are mixed with binders, disintegrants, or other excipients known in the art, and then formed into tablets using compression force. Examples of binders include microcrystalline cellulose, starch, gelatin, polyvinylpyrrolidone, polyethylene glycol, and sugars such as sucrose, glucose, dextrose, and lactose. Examples of (8) disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone and sodium carboxymethyl cellulose. The tablet may also include an effervescent agent (acid-base combinations) that produces carbon dioxide when consumed. The carbon dioxide produced helps the tablet disintegrate. Other sezo excipients, such as those mentioned above, may also be included in the tablet.

Multiparticles, binders and other excipients used in the tablet may be first formed into granules prior to tablet formation. Wet or dry granulation processes well known in the art can be used as long as the granulation process does not alter the multiparticulate release profile.

Alternatively, the materials can be formed into a tablet by direct compression. co

The compression force used to form tablets should be high enough to provide a high strength tablet, but not too high to damage the multiparticulates contained in the tablet. In general, a compression force applied to the tablets of from about 3 to about 10 kPa is desirable.

Alternatively, tablets such as multi-coated and osmotic coated tablets may also be "

Made using a non-compression process. In one of the embodiments, the tablet is formed by the method of lyophilization. In this process, multiparticles are mixed with an aqueous solution or a paste of water-soluble excipients and placed in a mold. Then the water is removed by lyophilization, which leads to obtaining porous, ;" quickly soluble tablets containing multiparticles. Examples of water-soluble excipients used in such tablets include gelatin, dextran, dextrin, polyvinylpyrrolidone, polyvinyl alcohol, trexalose, xylitol, sorbitol, and mannitol. -I In another embodiment, the dosage form is in the form of a capsule, well known in the art. | See Ketipdiop'z

Rpagtaseciisa! Zsiepsez (183rd edition 1990). The term "capsule" covers solid dosage forms in which the multiparticulates and optional excipients are contained in either a hard or soft dissolvable container or shell. When entering the environment of use, the shell dissolves or disintegrates, releasing the contents of the capsule into the environment of use. A hard gelatin capsule, usually made of gelatin, consists of two parts, one of which is placed on top of the other. Capsules are made by first mixing 4) multiparticles and optional excipients, such as those mentioned above. The ingredients can be formed into granules using a wet or dry granulation method to improve the movement of substances filling the capsule. Capsules are filled by injecting substances into the longer end or body of the capsule and then closing with a cap. For soft gelatin capsules, the filler may first be suspended in an oil or liquid before filling the capsule.

F) The dosage form can also be in the form of pills. The term "pill" covers small, round solid dosage forms that include multiparticulates mixed with a binder and other excipients as described above. Once in the environment of use, the pill disintegrates rapidly, allowing the boron multiparticles to disperse in the environment of use.

In another embodiment, the multiparticulate dosage form is in the form of a powder or granules comprising the multiparticulates and other excipients as described above, which are then suspended in a liquid carrier, including an aqueous solvent, prior to dosing. Such dosage forms can be obtained in several ways. In one method, the powder is placed in a container to which a certain amount of liquid, such as 65 Water, is added. The container is then mixed, stirred, or shaken to dissolve the dosage form in the water. In another method, the multiparticulates and metered carrier excipients are divided into two or more separate packets.

Dosed carrier excipients are first dissolved or suspended in a liquid, such as water, and then the multiparticles are added to the liquid carrier solution. Alternatively, metered carrier excipients and multiparticulates in two or more individual packets may be added to the container first, then added

Water and the contents of the containers are mixed or stirred to form a suspension.

Water is an example of a liquid that can be used to form a dosage form according to the invention.

Other liquids may also be used and are within the scope of the invention. Examples of suitable liquids include beverages such as coffee, tea, milk and various juices. They also include water mixed with other excipients that help to form finished forms, including surfactants, thickeners, suspending agents, etc.

The multiparticulate dosage form may also be in the form of a straw or other device that allows the patient to sip water or other liquid through a device designed to mix the liquid with the powder or granular dosage form contained in the device.

The multiparticulate dosage form may also be in the form of a paste, slurry or suspension.

In one embodiment, the multiparticulate dosage form includes azithromycin multiparticulates, an alkalizing agent, and one or more optional excipients selected from sweeteners, anti-caking agents, viscosity-increasing agents, and flavors. Preferably, the multiparticulate dosage form additionally includes a sweetener, an anti-caking agent, a viscosity-increasing agent, and a flavoring agent.

In a more preferred embodiment of the present invention, multiparticles of azithromycin are used with an alkaline agent

ZR. The amount of T5P is preferably at least about 200 Ωg. More preferably, the range of the amount of TOR ranges from about ZOOmg to about 400mg. In another embodiment of this invention, TOR and magnesium hydroxide are used as alkaline agents. The amount of magnesium hydroxide used is at least about 100mg and preferably from about 200mg to about 300mg.

In a further preferred embodiment, the dosage form of azithromycin contains multiparticulate azithromycin in amounts of from about 45 to about 55 wt.90 of azithromycin, from about 43 to about 5 wt.90 of glyceryl behenate, and from about 2 to about 5 wt.90 of poloxamer, as well as an alkaline agent that contains from i) about 300 to about 40Omg of T5P and from about 200 to about ZbOmg of magnesium hydroxide.

In an even more preferred embodiment, the dosage form of azithromycin comprises azithromycin multiparticulates containing about 5% to about 46% to about 48% of azithromycin dihydrate. 888 ATO, with from about 2 to about 4 wt.90 of Poloxamer 407, and include an alkalizing agent from about 300 to about 400 mg of T5R and from about 200 to about 30 mg of magnesium hydroxide. More preferably, said Me) dosage form includes approximately 47 wt.o Sotrgyokyu 888 ATO and approximately 95 wt.o Poloxamer 407. h-

Sotrpyo|ee 888 ATO and Poloxamer 407 are further described below in illustrative examples

The multiparticles of the present invention can be prepared by any known method, which leads to the formation of particles containing azithromycin and a carrier, with the desired size and characteristics of the rate of release of azithromycin. The most common methods of forming such multiparticles include thermal processes, such as solidification of the melt and sprayed particles; liquid-based processes such as extrusion spheronization, wet granulation, spray coating, and spray drying; and other granulation processes, such as dry granulation and melt granulation. "

The multiparticles generally have an average diameter of less than about 50000 µm, preferably less than 500 µm, and most preferably less than about 10000 µm. In a preferred embodiment, the average diameter of the multiparticles is from about 40 to about 300 Ωm, preferably from about 50 to about 1000 Ωm, and most preferably from about 100 to about 30 Ωm. It should be noted that the diameter of the multiparticles can be used to adjust the rate of release of azithromycin from the multiparticles. In general, the smaller the diameter of the multiparticles, the greater will be the rate of release of -I azithromycin from a specific multiparticle composition. This is due to the fact that the total surface area in contact with the dissolution medium increases as the diameter of the multiparticles decreases. Thus, adjusting the mean diameter of the multiparticles can be used to adjust the release profile of azithromycin.

Multiparticles can be obtained by the process of solidification from the melt, which includes the following steps (a) the formation of a molten mixture containing azithromycin and a pharmaceutically acceptable carrier; (5) supplying the molten mixture 4) from step (a) to the spraying means for the formation of droplets from the molten mixture; and (c) opening of droplets from step (p) to form multiparticles.

When using thermal processes, such as melt solidification, to form multiparticles according to the present invention, heat transfer to azithromycin is minimized to prevent thermal degradation of azithromycin during the process. It is also desirable that the carrier has a melting point lower than the temperature

F, melting of azithromycin. For example, azithromycin dihydrate has a melting point of 113°C to 11596°C. Thus, when azithromycin dihydrate is used in the multiparticulates of the present invention, it is preferred that the carrier has a melting point of less than 11320°C. In this context, the term "melting point of the carrier" is 60 or " mp"" means the temperature at which the carrier containing the drug substance and any optional excipients present in the multiparticle changes from a crystalline to a liquid state. When the carrier is not crystalline, "melting point of the carrier" means the temperature in which the carrier becomes a liquid in that it will flow to some extent when subjected to one or more forces, such as pressure, shear, and centrifugal force, similar to a crystalline material in a liquid state.65 Azithromycin in a molten mixture may dissolve in the molten mixture, may be in the form of a suspension of crystalline azithromycin distributed in the molten mixture, or any combination of these states or rome states. Preferably, the molten mixture comprises a homogeneous suspension of crystalline azithromycin in a molten carrier, wherein the fraction of azithromycin that melts or dissolves in the molten carrier is kept relatively low. Preferably, less than about 30% by weight of the total amount of azithromycin melts or dissolves in the molten carrier. Azithromycin is preferably in the form of crystalline dihydrate.

Thus, the term "molten mixture" is understood to mean that the mixture of azithromycin and the carrier is heated to a temperature sufficient for the mixture to become sufficiently liquid that droplets or powders can be formed from the mixture. Spraying of the molten mixture can be accomplished using any of the 7/0 spray methods described below. In general, the mixture is meltable in the sense that it will flow when subjected to one or more forces, such as pressure, shear, and a wicking force, such as that produced in a wicking atomizer or rotating disk atomizer. Thus, the azithromycin/carrier mixture can be considered "melted" when any part of the carrier and azithromycin becomes liquid, provided that the mixture as a whole is sufficiently liquid to be sprayed. In general, the mixture is sufficiently liquid for spraying when the viscosity of the molten mixture is less than about 2000Osp, preferably less than about 15000Osp, more preferably less than about 1000Osp. Often, the mixture becomes molten when it is heated above the melting point of one or more components of the carrier in cases where the carrier is sufficiently crystalline to have a relatively distinct melting point; or, when the carrier components are amorphous, above the softening temperature of one or more carrier components. Thus, the 2o molten mixture is often a suspension of solid particles in a liquid matrix. In one preferred embodiment, the molten mixture comprises a mixture of substantially crystalline azithromycin particles suspended in a substantially liquid carrier. In such cases, part of the azithromycin may be dissolved in the liquid carrier, while part of the carrier may remain solid.

Although the term "melt" refers to the transformation of a crystalline material from its crystalline to its liquid state, which occurs at its melting point, and the term "molten" refers to a crystalline material in its liquid state, the terms used herein refer to broader concepts, with respect to the term i) "melt", which refers to the heating of any material or mixture of materials to the point where it becomes a liquid, i.e. it can be pumped or sprayed in a manner similar to a crystalline material in its liquid state. Similarly, "molten" refers to any material or mixture of materials that is in such a liquid state.

In fact, any process can be used to produce the molten mixture. One of the Me methods involves melting the carrier in a tank, adding azithromycin to the molten carrier, and then mixing M the mixture to ensure even distribution of the azithromycin in it. Alternatively, both the azithromycin and the carrier can be added to the reservoir and then the mixture heated and mixed to form a molten mixture. co

When the carrier contains more than one substance, the molten mixture can be prepared using two (M tanks), melting the first carrier in one tank and the second in the other. Azithromycin is added to one of these tanks and mixed as described above. In the other The method may employ a continuously stirred tank where the azithromycin and carrier are continuously added to a heated tank equipped with means for continuous mixing while the molten mixture is continuously removed from the tank. The molten mixture may also be formed using a continuous mill. , type Oupob

And MI. Azithromycin and the carrier are usually supplied in solid form to a continuous grinder, directly to the i? crushing chamber containing grinding media such as glass balls with a diameter of 0.25 to Bbmm.

The crushing chamber is equipped with a casing so that the heating or cooling liquid can circulate around it

Cameras to regulate its temperature. The molten mixture is formed in the crushing chamber and exits compartment -I through the separator to separate the grinding media.

A particularly preferred method of forming the molten mixture is the method using an extruder. The term "extruder" means a device or several devices that form a molten extrudate -I by heating and/or shear force, and/or form a uniformly mixed extrudate from solid and/or liquid (for example, molten) raw materials. Such devices include , but are not limited to single-screw extruders, twin-screw extruders, including those in which the screws rotate in the same direction, in the opposite direction, interchangeable extruders and non-interchangeable extruders, multi-screw extruders, plunger extruders, consisting of a heated cylinder and piston to extrude the molten mixture; gear pump extruders consisting of a heated gear pump, usually with two revolution counters, which simultaneously heats and pumps the molten feedstock; and conveyor extruders. Conveyor extruders include conveyor means for transporting the solid and/or powder raw materials, such as

F) screw conveyors or pneumatic conveyors and pumps. At least part of the conveyor means is heated to a sufficiently high temperature to obtain a molten mixture. The molten mixture can be directed arbitrarily into the storage tank, before it is directed to the pump, which directs the molten mixture to the nozzle. Optionally, a combi mixer may be used before or after the pump to ensure homogeneity of the molten mixture. In each of these extruders, the molten mixture is stirred to form a uniformly mixed extrudate. Such mixing can be accomplished by a variety of mechanical and technological means, including mixing elements, stirring elements, and countercurrent shear mixing. Thus, in such devices, the composition is fed to the extruder, which 65 forms a molten mixture, which is directed to the nozzle.

As soon as the mixture melts, it is directed to a nozzle that sprays the molten mixture into small droplets. Virtually any method can be used to direct the molten mixture to the nozzle, including the use of pumps and various types of pneumatic devices such as sealed vessels or piston tanks. When an extruder is used to form a molten mixture, the extruder itself

Can be used to deliver the molten mixture to the nozzle. As a rule, the molten mixture in the process of delivery to the nozzle is maintained at an elevated temperature in order to prevent solidification of the mixture and maintain the flow of the molten mixture.

In general, spraying occurs in one or more ways, including (1) a "pressure" or single-stream nozzle; (2) two-flow nozzle; (3) venter or disk nozzles; (4) 7/0 with ultrasonic nozzles; and (5) mechanical vibrating nozzles. Detailed descriptions of atomization processes, including the use of disc nozzles to produce particles of specific sizes, can be found in

And etermge, Aiotigayop apa Zrhauz (1989) or in Regtuz Spetis! Epdipeegv' Naparsok (7th issue 1997).

Once the molten mixture is sprayed, the droplets solidify, usually in contact with a gas or liquid at a temperature below the solidification temperature of the droplets. Generally, it is desirable that the droplets solidify in /5 Time less than about 60 seconds, preferably less than about 10 seconds, more preferably less than about 1 second. Often, solidification at ambient temperature results in sufficiently rapid solidification of the droplets to avoid excessive formation of azithromycin esters. However, the solidification process often takes place in a confined space to facilitate assembly of multiparticles. In such cases, the temperature of the solidification medium (either gas or liquid) will increase after some time, 2o as the droplets are introduced into the confined space, leading to the possible formation of azithromycin esters.

Thus, to maintain the solidification temperature, a cooling gas or liquid is often circulated in the enclosed space. If the carrier used is highly reactive with the azithromycin and the time during which the azithromycin is exposed to the molten carrier must be limited, the cooling gas or liquid may be cooled to a temperature below ambient temperature, thus c

Ensuring the formation of azithromycin esters within acceptable limits.

Suitable thermal processes are disclosed in detail in the application for (US patent (Patent Attorney's case and)

MoRS25015) entitled "Improved multiparticulate dosage forms of azithromycin formed by the melting-solidification method" and in the US patent application (the patent attorney's case MORS25122, entitled "Extrusion method of forming chemically stable multiparticulates", filed simultaneously with this application). c zo Multiparticles can also be obtained on the basis of liquid processes, which include the following steps (a) forming a mixture that contains azithromycin, a pharmaceutically acceptable carrier and a liquid; (5) formation of Me particles from the mixture of stage (a); and (c) removing a substantial portion of the liquid from the particles of stage (B) for M multiparticle formation. Preferably, stage (B) is a method selected from (ii) spraying the mixture, (iii) coating the main core with the mixture, (ii) wet granulation of the mixture and (m) extruding the mixture into a solid mass with subsequent spheronization or grinding of the mass. uh-

Preferably, the liquid has a boiling point less than about 1509C. Examples of liquids suitable for the formation of multiparticles used in liquid processes include water; alcohols such as methanol, ethanol, various isomers of propanol and various isomers of butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, octane and mineral oils; ethers such as methyl tert-butyl ether, ethyl ether and ethylene glycol monoethyl ether; with chlorinated hydrocarbons, such as chloroform, methylene dichloride and ethylene chloride; tetrahydrofuran; c dimethyl sulfoxide; M-methylpyrrolidinone; M,M-dimethylacetamide; acetonitrile; and their mixtures. "» In one embodiment, the particles are formed by spraying the mixture, using a suitable nozzle to form small droplets of the mixture, which are sprayed into a drying chamber, where the liquid is evaporated to form solid, mostly spherical particles. The evaporation of the liquid is generally ensured by -I maintaining the partial pressure of the liquid in the drying chamber well below the vapor pressure of the liquid at the particle temperature This is achieved by (1) maintaining the drying chamber pressure at a partial vacuum (e.g., 0.01 to 0.0 barm), or (2) mixing the droplets with the warm drying by gas; or (3) both (1) and (2). Spray-drying processes and spray-drying equipment are described generally in

Naparsok, pages 20-54 to 20-57 (second issue 1984)). In another embodiment, the particles are formed by applying a liquid mixture to the nuclei. The cores can be made from any suitable material such as starch, microcrystalline cellulose, sugars or waxes by any known method such as melt cooling or spray solidification, extrusion/spheronization, granulation, spray drying, etc. .p.

The liquid mixture can be sprayed onto such cores using coating equipment known in the pharmaceutical art, such as lubrication coaters (e.g. Ni-Soayeg from

F, Egeshpi Sogr. Tokyo, Japan, Asseia-Soya of Mapeziu Liverpool, UK), fluidized bed coaters (e.g. UUigwieg coaters or spray coaters from Sai Aig Tesppoiodiez, Ips., Katzeu, New Jersey and from Migo Rpapt Zuzvietv, 6bo Vibrepaop, Switzerland) and rotary granulators (for example, CE-Granulator, from Egeip Sogr.).

In another embodiment, the liquid mixture can be subjected to wet granulation to form particles. Granulation is the process by which relatively small particles are converted into large granular particles, often with the aid of a carrier, also known as a binder in the pharmaceutical industry. In wet granulation, the liquid is used to enhance the intermolecular forces between the particles, which leads to increased granule integrity, 65 referred to as granule "strength". Often, the strength of a granule is determined by the amount of liquid present in the interstitial spaces between the particles during the granulation process. In this case, it is important that the liquid wets the particles, ideally with a wetting angle equal to zero. Since a large percentage of the granular particles make up the very hydrophilic azithromycin crystals, the liquid must be sufficiently hydrophilic to meet this criterion. Thus, effective wet granulation fluids tend to be hydrophilic as well. Examples of liquids that have been found to be effective liquids for wet granulation include water, ethyl alcohol, isopropyl alcohol, and acetone. Preferably, the liquid for wet granulation is water with a pH of 7 or higher.

Several types of wet granulation processes can be used to form azithromycin-containing multiparticulates. Examples include fluidized bed granulation, rotary granulation, and 7/0 High Shear mixers. In the granulation process, air is used in the fluidized bed to mix or "pseudo-liquefy" the particles of azithromycin or the carrier in the fluidization chamber. The liquid is then sprayed into this fluidized bed, forming granules. In rotary granulation, horizontal disks rotate at high speed, forming a rotating "rope" of azithromycin and/or carrier particles on the walls of the granulation tank.

The liquid is sprayed into this rope, forming granules. High shear mixers contain an agitator or /5 Impeller to mix the azithromycin particles and/or carrier. The liquid is sprayed into a layer of moving particles, forming granules. In these processes, all or part of the carrier can be dissolved in a liquid before spraying the liquid onto the particles. Thus, in these processes, the stage of formation of a liquid mixture and the formation of particles from a liquid mixture occur simultaneously.

In another embodiment, the particles are formed by extruding a liquid mixture into a solid mass followed by spheronization or grinding of the mass. In this process, a liquid mixture in the form of a pasty plastic suspension is extruded through a perforated plate or die to form a solid mass, often in the form of elongated, solid rods. This solid mass is then crushed to form multiparticles. In one embodiment, the solid mass is placed, with or without the intervention of a drying step, to a rotating disc having protrusions that break the material into spheres, spheroids, or rounded rods of multiparticles. The multiparticles formed in this way are then dried to remove the residual liquid. This process is sometimes referred to. in the pharmaceutical industry as an extrusion/spheronization process. and)

Once the particles are formed, some of the liquid is removed, usually during the drying step, thus forming multiparticles. Preferably, at least 8095 liquid is removed from the particles, more preferably at least 9090, and most preferably at least 9595 liquid is removed from the particle during the drying step. Suitable liquid-based processes are more fully disclosed in the application for (US patent Mob00/527,405, patent attorney's office RS25018, entitled "Improved Multiparticulate Dosage Forms of Azithromycin, Me Prepared by Liquid-Based Processes", filed concurrently herewith). M

Multiparticles can also be obtained by a granulation process, which includes the steps of: (a) forming a solid mixture including azithromycin and a pharmaceutically acceptable carrier; and (b) granulation of the solid mixture with the formation of so

Зз5 Multiparticles. Examples of such granulation processes include dry granulation and melt granulation, both of which are known in the art. (See Keptipdiop'z Rpagtaseciisa!| Zsiepsez (18th edition, 1990)|).

An example of a dry granulation process is roller compaction. In roller compaction processes, the solid mixture is compressed between the rollers. The rollers can be designed so that the compressed material is in the form of small balls or granules of the desired diameter. Alternatively, the compressed material is in the form of a "ribbon" that can be ground into multiparticles by methods known in the art. |See, for example, pe) s Ketipdiopye Rnagtaseciisa! Zsiepsez (18th ed. 1990)). . In melt granulation processes, the solid mixture is fed to the granulator, which has the ability to heat or melt the carrier. Equipment suitable for use in this process includes high shear granulators and single or multi-screw extruders of the type mentioned above for melt-solidification processes. In the processes of granulation from the melt, the solid mixture is placed in a granulator and heated until the formation of solid -I agglomerates. The solid mixture is then ground or mixed until the desired particle size is reached. The granules formed in this way are then cooled, removed from the granulator and sieved to obtain fractions of the desired size, thereby forming multiparticles. -I While the azithromycin in the multiparticulates may be amorphous or crystalline, it is preferred that a substantial portion of the azithromycin be crystalline, preferably a crystalline dihydrate. By "substantial portion" it is understood that at least 8095% of the azithromycin is crystalline. The crystalline form is desirable because it has 4) a tendency to improve the chemical and physical stability of multiparticles. The crystalline state of azithromycin is determined using powder X-ray diffraction analysis (XRD). In one of the examples of such a method, the РЧКО analysis can be carried out on an advanced VgyKeg AHZ 08 diffractometer. In this analysis, samples of approximately 50 Ω are packed in I isige glasses and the surface of the sample is leveled using a microscope slide to ensure a smooth surface of the sample at the level of the glass surface. . Samples

F) rotate in the f plane at a speed of 30 revolutions per minute in order to minimize the effects of crystal orientation. co X-ray source (5/V KSiod, 5-1.54A) operates at a voltage of 45KV and a current of 40mA. Data for each sample is collected over a period of approximately 20 to 60 minutes in a continuous scan mode with a scan rate of approximately 12 seconds/step and a step size of 0.02g/step. The diffractograms are collected in the range 28 from approximately 102 to 1659.

The crystalline state of the sample is determined by comparison with two or more calibration standards as follows. Calibration standards consist of physical mixtures of 2Owag.95/8Owag.9o azithromycin/carrier, and 8Owag.96b/20wag.9o azithromycin/carrier. Each physical mixture is mixed together for approximately 15 to 5 minutes on a Tiger mixer. Using the instrument software, the area under the curve of the diffractogram is integrated over a range of 26 using a linear basis. This integration range includes as many specific azithromycin peaks as possible while excluding carrier peaks. In addition, the large specific peak of azithromycin at about 1092 26 is not taken into account due to the large instability in its integrated region. A linear calibration curve of the dependence of the percentage of crystalline azithromycin on the area under the diffractogram curve is built on the basis of calibrated standards. The crystallinity of the sample is then determined using these calibrated results and the area under the curve for the test sample. Results are reported as the average percent crystallinity of azithromycin (by crystalline mass).

The key point in maintaining the crystalline form of azithromycin during the formation of multiparticles through thermal and liquid processes is maintaining the high activity of water and any solvated solvents in the carrier, atmosphere or gas with which the composition comes into contact. The activity of water or solvent must be equivalent to or greater than in the crystalline state. This will ensure that the water or solvent present in the crystalline form of azithromycin remains in equilibrium with the atmosphere, thus preventing loss of hydrated water or solvated solvent. For example, if the multiparticulate formation process requires crystalline azithromycin, crystalline dihydrate, for example, to be exposed to high temperatures 75 (e.g., during melting or in a spray-solidification process), the atmosphere around the azithromycin should be maintained at high humidity to prevent loss of hydrated water from crystals of azithromycin, and thus a change in the crystalline form of azithromycin.

The required humidity level is a level equivalent to or greater than the activity of water in the crystalline state. This can be determined experimentally, for example, using a dynamic vapor sorption apparatus.

In this experiment, a sample of crystalline azithromycin is placed in a chamber and equilibrated at constant temperature and relative humidity. Then the weight of the sample is recorded. The weight of the sample is then checked as the relative humidity of the atmosphere in the compartment decreases. When the relative humidity in the compartment decreases to a level below the equivalent activity of water in the crystalline state, the sample will begin to decrease in weight as hydration waters are lost. Thus, to maintain the crystalline state of azithromycin, the moisture level of the SU must be maintained at or above the relative humidity at which azithromycin begins to lose weight. at

A similar experiment can be used to determine the appropriate amount of solvent vapor required to support the crystalline form of azithromycin solvate.

When crystalline azithromycin, e.g., in dihydrate form, is added to the molten carrier, a small amount of water may be added to the carrier, from 30 to 100g.9o of water solubility in the molten carrier at the process temperature to provide sufficient water to prevent loss of the crystalline dihydrate form. azithromycin. F

Similarly, if a liquid-based process is used to form the composition, the liquid should contain sufficient water (eg, 30 to 100% water solubility in the liquid) to prevent loss of water from the hydrated crystalline azithromycin. In addition, the atmosphere around the azithromycin 09 during any liquid removal step must be sufficiently humidified to prevent water loss and thus maintain the crystalline form of the dihydrate. In general, the higher the processing temperature, the higher the required concentration of water vapor or solvent in the carrier, atmosphere, or gas to which the azithromycin is exposed to maintain the hydrated or solvated form of the azithromycin. "

Processing, with the support of the crystalline form of azithromycin, in the formation of multiparticles is more fully disclosed in the application for (US patent Mob0/527,316 ("Method of obtaining pharmaceutical multiparticles", right - from the patent attorney MORS25021), filed simultaneously with this one). The multiparticles of this invention can be processed after production to improve the crystallinity of the drug substance and/or the stability of the multiparticles. In one embodiment, multiparticles include azithromycin and a carrier, wherein the carrier in the multiparticle containing azithromycin and optional excipients have a melting temperature of Tpl. in "C; multiparticles are processed after formation by at least one of the following methods: (i) heating the multiparticle to a temperature of at least 352C, but less than (Tpl.eC - 10232), and (ii) subjecting the multiparticle to the action of an agent for increasing mobility. Such a post-treatment step leads to an increase in the crystallinity of the medicinal substance in the multiparticles, and usually improves at least one of the indicators of chemical stability, physical stability and dissolution stability of the multiparticles. The post-treatment processes are more fully disclosed in the application for (US Patent Mob00/527,245 ("Multiparticle Compositions with Improved Stability", patent attorney MORS11900), filed concurrently herewith). c» Preferably, when the dosage form of azithromycin comprises azithromycin multiparticulates containing from about 45 to about 55 wt.95 of azithromycin, from about 43 to about 50 wt.90 of glyceryl behenate and from about 2 to about 5 wt.90 of poloxamer, and an alkalizing agent containing from about 300 to about 400 mg TR, the azithromycin multiparticles are treated after formation by holding them at a temperature of about 40°C and a relative humidity of about 7595, or placing them in a sealed container with water maintained at a temperature of 40°C for a period of 2 days or where more It is more desirable that such a dosage form further contains from about 200 to about

ZbOmg of magnesium hydroxide. More preferably, the azithromycin dosage form comprises azithromycin multiparticulates comprising about B5Owag.9o of azithromycin dihydrate, from about 46 to about 48w.o Sotrgyo(yayu 888 ATO, and from about 2 to about 4w.9o | shigoku 127 IU; and alkalizing agent containing from about 300 to about 400 ug T5P, the azithromycin multiparticulates are treated after formation by holding them at a temperature of about 40°C and a relative humidity of about 7595, or placing them in a sealed container of water maintained at a temperature of 40°C for a period of for from 5 days to about 3 weeks.It is more preferred that such dosage form further contains from about 200 to about

ZbOmg of magnesium hydroxide.

Most preferably, the dosage form of azithromycin comprises azithromycin multiparticulates containing about 5wg.9o of azithromycin dihydrate, about 47wg.9o of Sotrgyo!F 888 ATO and about Zwag.9o of I shock

E127 IU, azithromycin multiparticulates are treated after formation by holding them at a temperature of about 40°C at a relative humidity of about 7595 or placing them in a sealed container of water maintained at a temperature of 40°C for about 10 days or more.

Preferably, the concentration of azithromycin esters in the multiparticle is less than about 1 wt.95, relative to 70 of the total amount of azithromycin in the multiparticle, more preferably less than about 0.5 wt.95, more preferably less than about 0.2 wt.90, and most preferably, less than about 0.1 wt.9o.

Esters of azithromycin may be formed during the multiparticulate formation process, during other processing steps necessary to produce the final dosage form, or during storage after manufacture but prior to use. Since dosage forms of azithromycin can be stored for up to two years or even longer 75 before use, it is desirable that the amount of esters of azithromycin in the dosage form stored does not exceed the above values before use.

The processes of reducing the formation of esters are described in more detail in the applications for |(US patent Mob0/527,244 ("Improved multiparticulate dosage forms of azithromycin obtained by the process of melt-solidification", the case of the patent attorney MoRS25015), 60/527,319 ("Multiparticulate controlled release formed with boosters dissolution", the case of the patent attorney MoRS25016), and 60/527,405 ("Improved multiparticulate dosage forms of azithromycin obtained by the process of melting - solidification", the case of the patent attorney MORS25018), filed simultaneously with this one).

The invention also relates to a method of treating a disease or condition treatable with azithromycin, which consists in administering to a mammal, preferably a human in need of such treatment, a therapeutically effective amount of azithromycin and an effective amount of an alkalizing agent. It is also desirable that azithromycin is in the form of multiparticulates. and)

The term "effective amount of azithromycin" means an amount of azithromycin which, when administered in accordance with the invention, prevents the onset of, alleviates the symptoms of, halts the progression of, or eliminates a bacterial or protozoan infection in a mammal. co

In a preferred embodiment, the pharmaceutical dosage forms of the present invention are used to treat bacterial or protozoan infections. With respect to bacterial or protozoal infections, the term "treatment" means the treatment or prevention of bacterial or protozoal infections, including curing, reducing symptoms, or slowing the progression of said infection.

As used herein, unless otherwise indicated, the term "bacterial or protozoan infection" includes co-bacterial and protozoan infections occurring in mammals, as well as disorders caused by non-bacterial and protozoan infections that can be treated or prevented by the administration of antibiotics , such as the compounds of this invention. Such bacterial and protozoan infections and disorders caused by such infections include, but are not limited to: pneumonia, otitis, sinusitis, bronchitis, tonsillitis, and "mastoiditis caused by Zigeriosossis rpeshtopiaye, Naetorpiyiz ipPcepgae, Mogaheiia sayagtnaiiv5, eharpuiosossiv aitsgeiv or Reriovigeriosossiv ovzrr.; pharyngitis, rheumatic fever, and glomerulonephritis caused by Zygeriosossivs ruodepez, groups C and b streptococci, Siovigidisht aiiripegiae, or Asiiporasii5 Jaaepto|puiisit; respiratory tract infections caused by Musoriazta rpeshtopiae, I ediopeia rpeshtopiae, Zigeriosossiv "» rpeshtopiae, Naetorpiyiz ipiYacepgae, or Spiatuaia rpeshtopiae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, postpartum fever caused by Ziarpuiosossis ashcyokogeiz5, coagulase-positive that is, Z. eridegtidiv, 5. Petoiuisiv, etc.), Zgeriosossis ruodepevz, Bigerirsossiv -I adaiasivae, groups C-E streptococci, migidape vigeriosossi, Soguperasiegisht tipshiivvitit, Siovigidisht zgrr., or VagpopeMya Ppepzeiae, uncomplicated acute infections of the urinary tract, caused by Ziarpuiosossiv

Me zargorpuiisiz or Epiegosossivz srr.; urethritis and cervicitis; and sexually transmitted diseases, -And caused by Spiatuadia (Igaspotiasis, Naetorphysis dysgeui, Tgeropeta raiiidytis, Ogeariazta igeausut, or

Toxic diseases caused by 5.acgetz (food poisoning and toxic shock syndrome), or by groups A, B, and C streptococci; ulcers caused by Neiijsorasieg ruiogi; systemic febrile syndromes caused by Vogteiia hesyggepiiv; Iute disease caused by Voiteiia bBygoddopegi; conjunctivitis, keratitis, and dacryocystitis caused by SPiatuaia igaspotais, Meiizzegia dopogpoeae, 5. atsgei5, Z. rpeptopiae, 5. ruodepev,

N. ipipeplgaye, or | iziyegia zrr.; disseminated Musobrasiegicht amisht complex (MAS), caused by Musobasiegicht amisht or Musorasiegicht ipigaseiIshShiage; gastroenteritis caused by Satruiorasieg |e)ipi; intestinal protozoan infection caused by Sturiozrogidisht v8zrr.; odontogenic infection caused by Mygidapz zigeriosossi; o persistent cough caused by Vogaeyeia regizzis; gas gangrene caused by Siovigidisht rephipdepz ko or Vasiegoiidesz srr.; and atherosclerosis caused by Neiissobrasieg ruiogi or Spiatudia rpeshtopiae. Bacterial and protozoan infections and disorders caused by such infectious agents that can be treated or prevented in animals include, but are not limited to: Bovine respiratory disease caused by R. Naet., R. tiiMosida, Musoriazta romiz or Vogaeia spp.; enteritis in cows caused by E. soii or protozoa (ie, Sossidia, Sguriozogidia, etc.); mastitis in cows caused by Ziary. A!tsgeiz, Sieger, Shibregiz, Sieger, adaiasiaye,

Seeger, duhraiasiiae, Kierziea zvzrr., Soguperasiegitst or Epiegosossiz zrr.; respiratory disease in pigs caused by A. rieigo., R. tiyMosida, or Musoriazta spp.; swine enteritis caused by E. soi, 65 Gamvopia ipigaseiIschmiagiz, salmonella or Zegriyipa Puosauizipiegiae; purulent lesion of the legs in cows, caused

Eizorasiegicht Co., Ltd.; metritis in cows caused by E. soii; warts in cows caused by Rizorasiegitst peshorpogyt or Vasiegoides sudoziv; acute epidemic conjunctivitis in cows caused by Mogaheiia bBomiv; abortion in cows caused by a protozoan infection (i.e. pyohornitis); urinary tract infection in cats and dogs caused by E. soy; skin and soft tissue infections in dogs and cats caused by Ziara. Eridegtiaiv, e(arr.

Ipiegteadiiv, soadsztzaze ped. Get it together. or R. that Mosida; and infections of the oral cavity and teeth in cats and dogs caused by Aisidepez vzrr. Vasiegoidez vrr., Siovigidisht v8vrr., Epiegorasieg vzrr., Eibasiegisht,

Reriozygeriosossiv, Rogrpugotopaz or RgemoieMya. Other conditions that can be treated with the compounds and drugs of this invention include malaria and atherosclerosis. Other bacterial and protozoan infections and disorders caused by such infections that can be treated or prevented according to the method and compositions of this invention are mentioned in |U. R. Zaptoga and others, " Te bZapioga Scide To Apiiptisgoriai Tregaru," 26th edition, (Apiitisgobia!| TNegaru, Ips., 1996).

The amount of azithromycin prescribed will necessarily vary according to principles known in the art, taking into account factors such as the severity of the disease or condition, weight and age of the patient.

In general, the drug should be prescribed so that an effective dose is obtained, which is due to the safety and effectiveness of the dosage ranges already known for azithromycin.

For adults and children weighing more than 200 kg, the amount of azithromycin is prescribed in a dose from about 250 mg to about 7 HgA. Preferably, for adults and children weighing more than 30 kg, the dosage form contains between about 1.5 to about 4 gA, more preferably from 1.5 to about ZHA, and most preferably from about 1.8 to about 2.2 gA of active compound. For children weighing 30 kg or less, the dose of azithromycin is typically calculated according to the patient's weight and is from about 30 to about 9 ΩmA/kg, preferably from about 45 to about 75 mg/kg, and more preferably from about 10 Ωg/kg.

The present invention is particularly useful for administering relatively large amounts of azithromycin to a patient with reduced gastrointestinal side effects in a single dose therapy, wherein the total dose used in the therapy comprises from about 1.5g to about 4.0gA of azithromycin. Even more preferably, this single dose contains from about 1.5g to about 3.00gA of azithromycin and, most preferably, from 1.8 to 2.2HA of azithromycin. (8)

For veterinary use, the amount may, of course, be adjusted to be outside these limits, for example, depending on the size of the animal being treated.

In the method of the present invention, azithromycin can be administered using a single-dose therapy or multiple-dose therapy (eg, administering more than one dose once a day or administering one or more doses over a course of 2-5 days or more). Daily dosing can be from 1 to 4 times Me per day in equal doses. Preferably, azithromycin is prescribed once.

Most preferably, in the method of the present invention, azithromycin is administered using a single dose, once daily therapy. "Single dose" as used herein means administration of only one dose of azithromycin for a full course of therapy.

The present invention will be further illustrated by the following examples. It should be understood, however, that the invention is not intended to be limited to the details described therein.

In the following examples, the following definitions and tests were used. "

A percentage quantity specification (95) means a percentage by weight based on the total weight, unless otherwise specified.

І shgoIF 127 ME (hereinafter referred to as "I shigo! F") and Ridgopis? E127 (hereinafter referred to as "RishgopisF"), that ;» also known as Poloxamer 407 ME, are polyoxypropylene-polyoxyethylene block copolymers, having a molecular weight, calculated by the OH value, from 9,840 to 14,600 g/mol and represented by the general formula а 7 бы и, и их их и , ЦИ! " yah z zl z .- ry m M we i y -- Yu - - . - a -

Me yak chu Xiang pon inten inkov peaks ini inst niy univ kozh NN S 5 UA and Bin S in sei m Zh 45; -I z y -Y-y yah a y: ZY ' so 50 where a is about 101 and B about 56, obtained from VABE Sogrogayop, Moipi Oiime, MU. And Sho is the pharmaceutical equivalent of Rishigopise). syu SotrgpyoIe! 888 ATO (hereinafter referred to as "Sotrgyo! 2"), consisting of a mixture of glycerol Mopo-, di- and tri-behenates, the diester fraction is predominant, is synthesized by esterification of glycerol with behenic acid (C22 fatty acid) and is sprayed with cold small drops, was received from ZSZATTEROZ5ZE Sogrogayop,

Zayipi Rgievi, Sedeh, Egapse. "GA" is an abbreviation for "grams of active azithromycin." For example, "2gA" means 2 grams of active azithromycin. name) Example 1

Effect of Different Alkalinizing Agents on Gastric pH 60 A clinical study was conducted to monitor gastric pH (using a pH probe) after administration of six different compositions containing alkaline agents. Prior to performing the clinical study, a titration study was performed with the alkalizing agent composition to determine the pH changes that occur upon addition of 0.1M NOI (pH 1.2) to the alkalizing agent.

Compositions including the following alkaline agents were tested: 65 Composition 1 - 17bmg anhydrous TOR

Composition 2 - 352 mg of anhydrous TOR

Composition C - 352 mg of anhydrous T5R and calcium carbonate - 5X00 mg

Composition 4 - 352 mg of anhydrous T5R and 250 mg of magnesium hydroxide

Composition 5 - 352 mg of anhydrous T5R and 500 mg of tromethamine (TKIZ)

Composition 6 - 352 mg of anhydrous T5R and 1000 mg of tromethamine (TKIB)

Next, each composition was prepared by mixing the indicated alkalizing agent with 19.36 g of sucrose, 0.067 g of hydroxypropyl cellulose, 0.067 g of xanthan gum, 0.2 g of colloidal silicon dioxide, 0.14 g of artificial cherry flavor, 0.23 g of artificial banana flavor, and 0.4 g of carbon dioxide. titanium

Stage A - Titration of Baseline Agents 70 Baseline titration curves were constructed for each of these six compositions. A volume of water in bOml was used to form suspensions of each composition and placebo. Then the titration curves were determined for each suspension by titrating the suspensions with increments from 0.2-bml of 0.1M HCl, where the value of the next increment depended on the change in pH associated with the previous increment. Titration curves for suspensions containing magnesium hydroxide or calcium carbonate were equilibrated for approximately 5 minutes after each addition of acid /5 before determination of pH. The results of IP migo tests for each of the compositions are shown in Fig. 1.

The data in Fig.1 are used in the method of evaluating pH changes in the stomach later after absorption of the alkalizing agent. To calculate, you need to take the amount of acid in the stomach and also the rate of acid production. From literature |S. Iepipeg. Wavie, SIVA-SBEISU, Opiiv oi Teazigetepi, Vodu Ritsiavs,

Sotrovzyiop oi (She Vodu, Mygiiop, SZzeiidu Zsiepiyys Tarieev (1981) 1:123-133; Matada, Tadagaka (ed.), 2o "TehirookK oi (zazigoepiegoiyudu, vol. 1, Prripsoi UMiPatze and UMiKepv, 1999, pp. 284-285 ), the basal volume of gastric acid on an empty stomach is 40 ml of 0.04 M MEDIA or 0.96 mEq. H "zh or 9.bml of 0.1 M MEDIA (0.Tmmol/ml). The rate of basal secretion is 3 mEq/h (or from 3 /60 - 0.05 mEq/min).The calculation procedure further assumes that equilibrium conditions apply (ie, good mixing) and that there is no evacuation of the composition from the stomach, nor of acid. It will be recognized by those skilled in the art that acid- basic equilibrium, according to the assumptions discussed above, the theoretical estimation of the pH change in the stomach subsequently after absorption of the alkalizing agent is mathematically identical to the estimation of the pH of the alkalizing agent compositions subsequently after (1) i) addition of the full basic amount of acid (0.9 mmol) to the compositions at time-0O, and (2) acid is simultaneously added at a rate of O.O05mmol/min to the comp position at time is greater than 0. At any given time, the volume is 0.1 M

NOI, M, corresponding to these conditions, was calculated in the following way: c zo U-0.9bmmol/(0.mmol/ml)k(0.O05mmol/min)(0.mmol/min)Xi (min.)

Note: O.1 mmol/ml - definition of 0.1 NOSI) Me

Therefore, M eEB (M-9.6U/0.5,

Where r is the time in minutes, and M is the volume of O0.1M NSI in Fig. 1. co

For different compositions of alkaline agents, the curve of pH versus time (theoretically calculated) is shown in Fig.2. uh-

Stage B - Clinical studies

The gastric pH study was an open-label, randomized, placebo-controlled study in healthy adult volunteers, including eighteen (18) healthy adult volunteers (b subjects per group), 18-55 years of age within the recommended weight range of 1595-3095, depending on sex, height and constitution. "

Subjects were divided into three different groups. Each group received two test compositions and a placebo in a triple crossover design:

Group 1: Composition 1, Composition 2 and placebo;" Group 2: Composition 3, Composition 4 and placebo

Group 3: Composition 5, Composition 6 and placebo

Subjects were randomized to sequential treatment within each group. Test composition -I was prescribed as a single dose of an oral solution. Water was used as a placebo. Each subject received only one type of treatment (composition) per day. The washout period between days of treatment is at least 1 day. Before the appointment, the following procedures were performed: -Each subject was intubated with a Zupesiisz Bidgarreg pH probe (Zupesiisz Meadisa!tsa, Midwayzech, OK) approximately 30 minutes before administration of the alkalinizing agent composition or placebo to determine baseline pH. Continuous pH monitoring was performed 30 minutes before the dose was administered. If a baseline pH of 2.0 was not 4) demonstrative for the subject, the subject was excluded from the study. However, none of the subjects was excluded.

The dose of the test composition (1, 2, 3, 4, 5 or 6) or placebo, depending on the group and sequence of treatment, was administered orally. In order to standardize the conditions, all subjects were required to refrain from lying down and from eating and drinking (including water) for the first 2 hours after dosing.

Continuous pH monitoring was carried out up to 2 hours after the dose in a sitting position.

F) Compositions containing TKIZ, in general, demonstrate the longest duration of pH increase. ka The response of the subjects to the calcium carbonate contained in the composition was equivalent or greater than to the composition with magnesium hydroxide. With the exception of Composition 1, all other compositions, on average, raised the pH to 5 or higher for at least 20 minutes.

Example 2

Comparison of the release rate of the alkalizing agent ip migo from dosage forms with different amounts of alkalizing agent

The rate of release of azithromycin ip was determined for various azithromycin 65 sustained-release dosage forms, each containing 2 gHA of the same multiparticulate azithromycin (MP) and varying amounts of TR as an alkalizing agent, compared to a dosage form of azithromycin containing the MP1 multiparticulate and not TR, and the dosage form of azithromycin rapid release, containing TR.

Sustained release dosage forms were prepared as described in stage A, below, while the study of the release rate of ip miigo and its results are described in stage B below.

Stage A - production of dosage forms of sustained-release azithromycin

Five dosage forms of azithromycin sustained release (hereafter "ZK1", "5K2", "BU", "Ka", "BKB") were prepared by mixing 2000 mgA of azithromycin MR multiparticulates prepared as described below with one or six excipient mixtures as described below in this example:

ZK1 includes C8.7g of sucrose and 5Omg TR, 70 ZK2 includes C38.7g of sucrose and 100MgT5R,

ZKZ includes 38.7 g of sucrose and 264 mg of TR,

ZK4 includes Z38.7g of sucrose and Z5bmg TOR, and

ZK5 includes 38.7 g of sucrose and 500 mg of TR.

In addition, a multiparticulate dosage form of the control was prepared by mixing 200Omg 7/5 Multiparticulates of azithromycin described in this example and 38.7g of sucrose.

Multiparticles of Azithromycin "MP1"

Multiparticles of azithromycin MR were prepared and included 5095 azithromycin dihydrate, 4695 SotrgyoF and 490 "I sho". In particular, azithromycin dihydrate (5000g), SotriyokU (4600g) and I shoyu (400g) were mixed in a blender (Viepa Mawieg C419145 from Ratseggop Keiu, Eavi Zygotzarego, RA) for 20 minutes. This mixture was concentrated using a RIMI Sopttipig (LA mill (Rigranisk Sotrapu, EItigwi, I) at 3,000 rpm with the advancing blades, using a 0.065-inch screen. The mixture was again blended in a twin-hull blender for 20 minutes to form a premixed raw materials

The pre-mixed raw materials were fed into the VR of a 19-millimeter twin-screw extruder (MP19-TS with a 25/0 ratio, from V UR Rgosezz Edyirtepi apa Zuzietv, GII S, Zadipamu, MI) at a speed of 120 Og/min. until the formation of a molten mixture at a temperature of approximately 9022. Water was not added to the extruder. The extruder formed a molten mixture consisting of a suspension of azithromycin dihydrate in SotrioF/I shgo/!F. at

The molten mixture was then fed into the center of a nebulizer with a rotating disk to form multiparticles of azithromycin.

The custom-made disc atomizer consists of a 10.1 cm (4 inch) diameter stainless steel barrel-shaped disc. The surface of the disk is heated by a thin film heater below the disk to about 9022. The disk is mounted on a motor that drives the disk to about 10,000 revolutions per minute. The complete design is enclosed in a plastic bag approximately 8 feet in diameter to allow h-curing and fixation of the multiparticles generated by the sprayer. Air is introduced through a channel below the disc to provide cooling of the multiparticles during solidification and to fill the tank to its expanded size and shape. M

An acceptable commercial equivalent of this disc atomizer is the EX1 100 mm rotary atomizer manufactured by Migo A/5 (Zoebrogo, Denmark).

The surface of the disk atomizer was maintained at 902 and the disk rotated at 5500 rpm during the formation of multiparticles of azithromycin. The average residence time of azithromycin dihydrate in the 70 extruder was approximately 60 seconds and the total time of azithromycin in the molten suspension was less than - s to approximately 3 minutes. The formed particles solidified in ambient air and were collected. Multiparticles of azithromycin produced by this method had a diameter of approximately 200 µm. "» Properties of molten solidified multiparticles, such as particle size, can be controlled by melt viscosity and processing conditions. In view of the combination of materials in a preferred embodiment of the present invention, the melt viscosity is constant as long as the temperature of the heating system is maintained at 90 2C. Size -and azithromycin multiparticulates can be controlled by feed rate (the amount of molten material fed into the disc atomizer) and disc speed (4" diameter). For example, 200µm particles can be formed by combining: 1) a feed rate of 8.4kg/h and a disc speed of 5500 rpm per minute - and either 2) a feed speed of 20 kg/h and a disc speed of 5800 revolutions per minute or 3) a feed speed of 25 kg/h and a 50 disc speed of 7100 revolutions per minute.

The azithromycin multiparticles were subsequently treated by placing them in a shallow trough at a depth of

I) approximately 2cm, and then placing the trough in a thermostat at 402C, maintaining a relative humidity of 7595 for 5 days.

Each azithromycin multiparticulate dosage form was manufactured using 4.2g of azithromycin multiparticulates to provide the equivalent of 2HA of azithromycin.

Gee! Stage B - Investigation of the rate of release of azithromycin

The rate of release of i.p. migo azithromycin in 0.01 M NSI, which simulates gastric fluid, was determined in the state of digestion and is used instead of 0.1 M NS to avoid acid degradation of azithromycin for dosage forms of prolonged release (2 gHA each) ZK1, 5K2, 5KZ, ZK4, and 5K5 which contain variable amounts of TOR, as 60 alkalizing agent. The release rate of ip migo multiparticles (2HA) containing no TOR was also determined. Next, the release rate of a control immediate-release (IC) formulation of two commercially available single-dose packets of azithromycin dihydrate oral suspension (Apgotachoe, Riigeg Ips) was determined. Each single-dose package contained 1048 mg of azithromycin dihydrate (1 gA), 8 mg of T5R and other excipients. 65 The results in Table 1 below demonstrate that the release rate of azithromycin from these multiparticulates is further slowed when administered with increased amounts of T5P.

This ip myo azithromycin release rate study, shown in Table 1, was performed as follows. The sustained release dosage forms, each containing approximately 2 gA of azithromycin in multiparticulates, and the multiparticulate control form and the immediate release control form were placed in separate 125ml vials. Then bOml of purified water was added and the bottle was shaken for 30 seconds. The contents were added to a ZR type 2 flask equipped with Teflon blades rotating at 50 rpm. The flask contained a volume of 7500 ml of 0.01 M NSI, maintained at 372C. The flask was rinsed twice with 20 ml of NS from the bottle and the wash was returned to the flask to a final volume of 750 ml. Zml of the liquid sample in the flask was collected at 15, 30, 60, 120 and 180 minutes after adding the multiparticles to the flask. Samples were filtered using a 0.45-μm 7/0 syringe filter before analysis by high-performance liquid chromatography (Nemek Raskaga 1100, Umai (egv bZButteiu Sv, column 45:30:25 acetonitrile:methanol" 25 mM KNoRO buffer, at 1.Oml/min ., absorption was measured at 210 pt by a diode spectrophotometer).

Ovimg ter) Fo zo

F

M so zv (zve tv) M « o zke same | 17700108 With s (boome tag) with 5 - And so (without ter) -

FO c" in

Quick release control

Ptvme ter) o o v lev v Example Z

Comparison of the rate of release of ip migo dosage forms with different alkalizing agents

The release rates of azithromycin ip mygo in 0.01 M NSI were determined for various dosage forms of azithromycin sustained release, each of which contains 2 gHA of azithromycin MR multiparticles prepared with one of three excipient mixtures, as described below: in 5 "zn includes 38.7 g of sucrose and 1 bomg of weakly basic sodium carbonate,

ZK7" includes 38.7g of sucrose and 5mg magnesium hydroxide, i

"58K8" includes 38.7g of sucrose and 1.0g of liquid Maaioch (K) (mild cherry, regular strength, from Momagi), which contains 37.1mg of aluminum hydroxide, 37.1mg of magnesium hydroxide and 3.7mg of simethicone.

The release rates of azithromycin from these sustained release dosage forms were measured i.p. as described in Example 2. The results of these solubility tests, provided in Table 2, below, indicated that the addition of various basifying agents slowed the release of azithromycin from MP1 multiparticulates compared to release from these multiparticles without the alkalizing agent listed in Table 1.

Example 4

Evaluation of the effect of the addition of an alkalizing agent on the release rate of rapid-release dosage forms

The comparative effect of adding an alkalizing agent on the release rate of ip migo in 0.01 M NOSI was determined for 7-week azithromycin tablets? quick release The 7-pack tablets contain 500 mg of azithromycin dihydrate, equivalent to 250 mg of azithromycin, dibasic calcium phosphate (138.84 mg), which is an alkaline agent, and several other excipients.

The release rates of azithromycin from 7LiGotahF tablets with and without the addition of an additional alkalizing agent, specifically 17bmg TR, were measured i.p.m. as described in Example 2. The results of these solubility tests are shown in Table C below. - с 4 - 51001 со 21т100006 - о же 0ю00001000000в6 211000 о име) These results confirm that, when combined with an alkaline agent, the release rate of the immediate release dosage form of azithromycin slows down. 60 Example 5

Comparison of ip migo release rates of dosage forms with different sizes of multiparticles of azithromycin

The release rates of azithromycin in 0.1 M NaOH were determined for various dosage forms of azithromycin sustained release, each of which contained 2 gA of different azithromycin multiparticulates and the same amounts of conventional alkalizing agent. Sustained release dosage forms were prepared as described in step A below, while the study of the release rate of ip myo and its results are described in step B below.

Stage A - Production of sustained-release dosage forms of azithromycin

Six sustained-release dosage forms of azithromycin, namely 5K9, ZK10, 5K11, 5K12, ZK13, and 5K14 were prepared by mixing azithromycin multiparticles of each MP2, MP3, MP4, MP5, MPb, or MP7, respectively.

With the same mixture of two alkalizing agents (ie, 352mg TOR and magnesium hydroxide - 25OmgH) and excipients (ie, 19.36g of sucrose, 6b7mg of hydroxypropylcellulose, b7mg of xanthan gum, 11Omg of colloidal silicon dioxide, 400mg of titanium dioxide, and 14O0mg of banana cherry flavor 23OmgH).

Azithromycin multiparticles

Azithromycin multiparticulates comprising "MP2" 5095 azithromycin dihydrate, 4795 SotriolKe, and 390 70 I shgo!F were prepared in the same manner as the MP1 multiparticulates in Example 2, except that the mixture was then fed through the B UR. 19-millimeter twin-screw extruder at a speed of 131g/min until the formation of a molten mixture. Simultaneously, water was added to the extruder at a rate to provide a melt water content of 295, and the multiparticles were post-treated for 21 days to form azithromycin multiparticles with an average diameter of approximately 188 microns.

Multiparticles of azithromycin "MRZ", containing 5095 azithromycin dihydrate, 4795 Sotrgpyo! is and C90 I shock were produced in the same manner as the MP2 multiparticles in this example, except that the disc was rotated at 4800 rpm to form azithromycin multiparticles with an average diameter of approximately 204 microns.

Multiparticles of azithromycin "MP4", including 5095 azithromycin dihydrate, 4796 SotrpyokKu and Z9o

, were prepared in the same manner as the MP2 multiparticles in this example, except that the disc was rotated at 4100 rpm to form azithromycin multiparticles with an average diameter of approximately 227 microns.

Multiparticles of azithromycin "MP5" were produced with the content of 5095 multiparticles of azithromycin, 4890

Sotrpyo!F), and 295 | shock in the same manner as MP1 in Example 1, except that the mixture was fed through a Cevipi twin-screw extruder 27 mm at a speed of 140 g/min until a molten mixture was formed.

Multiparticles of azithromycin "MRb" were prepared with the content of 5095 azithromycin dihydrate, 4796 SotrpjokU i) and Zbo I stock B127 using the following procedure. First, 15 kg of azithromycin dihydrate, 14 kg

SotrgyoMyu and O,Okg I shgoKYU were weighed and passed through Otsadgo 1945 Soti! the mill The grinding speed was set at 600 revolutions per minute. The mill was equipped with a MoS-075-NOBO/6O screen, and with a Mo2S-1607-049 flat blade agitator and a 0.225-inch spacer between the agitator and the screen.

The unconcentrated mixture was mixed using a Zegmo-100 stainless steel hopper mixer at a speed of 20 rpm for a total of 500 rotations until the premix was formed. M

The pre-mixed raw materials were fed to the Yeivigii 2 50mm twin-screw extruder (Modei! 25E 50,

Ategisaps and eivigii? Ehihideg Sogrogayop, Zothegmiye, MU) at a speed of 25 Bkg/h. The extruder was in the operating mode of rotation in one direction at approximately 300 revolutions per minute and was connected via an interface to the melt/spray-solidify unit. The extruder had nine segmented cylindrical zones and the full length of the extruder was 36 screw diameters (1.8m). Water was injected into cylinder 4 at a rate of 8.Zg/min (290 weights). The extrusion rate was adjusted to make a molten suspension of the raw material azithromycin dihydrate in the SotrpioIF/Rishopise at a temperature of about 9020.

The molten suspension was fed to a pulverizer with a disk rotating at 7600 rpm, the surface of which was maintained at 9023. The maximum total exposure time of azithromycin c dihydrate to the formation of a molten suspension was less than about 10 minutes. The particles generated by the "" disc pulverizer were cooled and frozen in the presence of cooling air circulating through the product collection compartment. The average particle size was determined to be 188 µm using a Nogira LA-910 particle size analyzer. which -I showed that approximately 9995 of the azithromycin in the multiparticulates was in the crystalline dihydrate form.

The multiparticles formed in this way were subjected to post-processing, introducing the samples into sealed cylinders, which

They were then placed in a controlled atmosphere chamber at 402C for 3 weeks. - I Multiparticles of azithromycin "MP7", including 5095 azithromycin dihydrate, 4795 SotriolKe, and Z9o with 50 shto 127 were produced in the following way.

Azithromycin dihydrate (14Okg) was weighed and passed through Otsaidga Sotii 1965 with a grinding speed of 900 rpm. The mill was equipped with a Mo2C-075-NOBO/6O sieve (special circle, 0.075"), a Mo2E-1607-254 impeller and a 0.225" spacer between the impeller and the sieve. Then, 8.4 kg of I of this CU and 131.6 bkg were weighed

Sotrpyoie and passed through the mill Otsaigo 1945 Sotii. The grinding speed was set at 650 revolutions per minute. The mill was equipped with a Mo2C-075-K03751 screen (0.075"), a Mo2 C-1601-001 impeller and a 0.225" spacer between the impeller and the screen. The ground mixture was mixed using a SaiIau 38 cubic stainless steel hopper mixer at a speed rotation at 10 rpm for 40 minutes, for a total of 400 rotations until the pre-mixed raw material was formed. 60 The pre-mixed raw material was fed to a 50 mm twin-screw extruder with a speed of approximately 20 kg/h. The extruder was set to rotate in one direction - approximately 100 rpm, and interfaced to the grinding/spraying/solidification assembly. The extruder had five segmented cylindrical zones and the full length of the extruder was 20 screw diameters (1.Ω). Water was fed into the Mo2 cylinder from at a rate of 6b.7g/min (295 wt). The extrusion rate was adjusted to form a 65% molten suspension of azithromycin dihydrate in SotrgioIF/I shgo!F p ry temperature of about 9020.

The slurry was fed to a 10.1 cm diameter disk pulverizer described in the above-mentioned Example 2, rotating at 6400 rpm, and the surface of the disk was heated at a temperature of 9020.

The maximum total exposure time of azithromycin to the formation of a molten suspension was less than 10 minutes. The particles formed by the disc pulverizer were subjected to cooling and solidification in the presence of cooling air circulating through the product collection chamber. The average particle size was determined to be approximately 200 μm using a Maimegp particle size analyzer.

The multiparticles thus formed were post-treated by placing the sample in a sealed cylinder, which was then placed in a controlled atmosphere chamber at 402 for 10 days. Samples of the multiparticles that were post-treated were evaluated by HPLC, which showed that approximately 9995% of the azithromycin in the 70 multiparticles was in the crystalline dihydrate form.

Stage B - Study of the rate of release of azithromycin ip mygo

The rate of release of azithromycin ip migo for dosage forms of prolonged release (2 g each) ZK,

ZK10, 5K11, 5K12, 5K13 and 5K14 were determined by the following solubility test.

Water (bOml) was added to the vial containing the dosage form. The vial was then inverted several times to mix the suspension. Each sustained release dosage form in suspension form was tested by adding it to the dissolution buffer in a standard О5R rotating paddle apparatus as disclosed in the United States Pharmacopoeia (SR 26), Solubility Test, Chapter 711, Apparatus 2. The paddles were rotated at 5O0o0b. /min., and the solubility test was carried out in 840 ml of 0.1 M sodium phosphate buffer, pH 6.0 (40.05) at 37--0.520. At specified times after the start of the study (i.e. dosage forms inserted into the apparatus), filtered aliquots (usually

LOml) from the studied environment were analyzed for azithromycin by high-performance liquid reverse-phase chromatography and determined in UV in the following way. The determined amount of the test solution was filtered to remove macro particles. A fixed volume of 1 μl was introduced into the column (15 cm length x internal diameter 3.9 mm) and maintained at 35-39. The mobile phase consisted of volume ratios: acetonitrile 4595, methanol 3095, and buffer 2595. The buffer consisted of 25 mM KH PO», pH 6.5. Flow rate - CM

M1ml/min. In the studied dissolving medium, the actual amount of azithromycin was determined by comparing the peak area of the sample against the area of the standard chromatographic peak of azithromycin. not from Tue (Mon)

Ф т 21015 that zv incl (mez) m 016 "from vky Me) i s iz" from vky (Me)

V. co

SHI

Ф выз(ме 02506001 со 21ю0011ж6 8 31018 вам ож 00000013 о 511185 ю в юлю11вв

The results of these solubility tests, shown in Table 4 above, show that these various multiparticulate and alkalizing agent compositions meet the release rate criterion for a pH 6.0 buffer in a study of 15 to 5595 ip mio(s) of said azithromycin in said dosage form of 0.25 hours; ve (i) from ZO to 7595 of the mentioned azithromycin in the mentioned dosage form in 0.5 hours; and (iii) more than 5095 of said azithromycin in said dosage form 1 hour after administration to the buffer medium.

Example 6

Comparison of ip mimo dosage forms of azithromycin sustained and rapid release

Two clinical studies were conducted to evaluate, respectively, the pharmacokinetics and gastrointestinal tolerance of three azithromycin sustained-release dosage forms of the present invention, each containing 352 mg of anhydrous TOR as an alkalizing agent and arbitrarily containing 25 mg magnesium hydroxide, in comparison with an immediate-release azithromycin dosage form. which contained half of TOR (17bmg) and without magnesium hydroxide. Sustained-release dosage forms were prepared as described in stage A, below, while pharmacokinetic and side-effect studies were described, respectively, in subsequent stages B and C.

Stage A - production of dosage forms of sustained-release azithromycin

These sustained-release dosage forms were prepared as follows: two different sustained-release azithromycin dosage forms (hereinafter "ZK15" and "VK16") were prepared by mixing 4.2 g (2HA) of azithromycin multiparticulates prepared as described below with different excipients. z"K15 dosage form included a mixture of 7/5 Multiparticles of azithromycin and the excipient mixture described below. ZK16 dosage form included a mixture of multiparticles of azithromycin, the same excipient mixture and magnesium hydroxide. To prepare ZK16, magnesium hydroxide was added to a vial containing 5K15. The contents were mixed by inverting the bottle.

ZK12 was produced as described in Example 5.

Azithromycin multiparticles

Multiparticles of azithromycin "MP8", including 5095 azithromycin dihydrate, 4796 Sotriyoke and 390 | rodU was produced in the same manner as MP1 multiparticles in Example 2, except that the mixture was fed through a 27 mm twin-screw extruder (Mode! 275E 27, I eivigii; Ehigodeg Sogrogayop, Zotegmiye, MU) at a speed of 140Og/min, to formation of a molten mixture.

Acidifying agents and excipients

An excipient mixture was produced for use in combination with multiparticles of azithromycin.

The excipient mixture consisted of a mixture of 352 mg of anhydrous TR as an alkalizing agent, 19.36 g of sucrose (ME), i) b7 mg of hydroxypropyl cellulose (ME), b/7 mg of xanthan gum (ME), 200 mg of colloidal silicon dioxide (ME), titanium dioxide - 400 mg ( OR), 140 mg of cherry flavoring and 230 mg of banana flavoring.

Separate vials containing 250 mg of optional magnesium hydroxide - an alkalizing agent (OR) were also prepared.

Stage B - Pharmacokinetic clinical study Me)

The pharmacokinetics of i.p. mimo "ZK15" and "VK16" multiparticulate dosage forms of azithromycin were evaluated in 32 M healthy human subjects under fasting conditions in a randomized, open-label, parallel, double-crossover study. On the first day, eight subjects received the multiparticulate dosage form of azithromycin ZK15, and eight subjects received the multiparticulate dosage form of azithromycin ZK16. As a control, two groups (A and B), each of eight subjects, received two single doses of an oral suspension of azithromycin dihydrate in sachets (2-packs, Riigeg Ips.), where each dose contained 1048 mg of azithromycin dihydrate, which is equivalent to 100OmgA of azithromycin, 88mg of T5R and previously mentioned inactive components.

In particular, 2 HgA of each composition of azithromycin (ZK15 without magnesium hydroxide or ZK16 with magnesium hydroxide), "or commercially available sachets of azithromycin were dosed based on computer randomization for each of the two c groups.

To the doses of ZK15 and ZK16 compositions, bOml of water was added to the bottle containing ZK15 and which was shaken for ;" 30 seconds. The entire contents of the vial were administered directly to the subject orally. Additionally, bOml of water was added to rinse the bottle and this water was given to the subject orally. The subject was given an additional 120 ml of water,

Using a dosing cup. -I To the dose of two one-gram packets of azithromycin, which is available for sale, the content of 1 g of a single dose of the packet is 7? added to a cup containing bOml of water. The mixture was stirred and given orally to the subject. co Additional bbml of water was used to rinse the cup and this water was given orally to the subject. This -I procedure was repeated for the second package 2Ipgotaho).

All subjects were dosed orally on an empty stomach. All subjects were restricted from lying down, eating and drinking (except water) for the first 4 hours after dosing. 4) Blood samples (ml each) were taken from subjects' veins before dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after dosage. The concentration of azithromycin in serum was determined using high-performance liquid chromatography, described in |ZPperaga et al., U, Spgotoiodharp. 565:321-337 (1991)). dv The total systemic exposure of azithromycin was determined by measuring the area under the pharmacokinetic curve (APC) for each subject in the group and then calculating the average AOC for the group. C groin "maximum

F) concentration of azithromycin in the subject's serum. T pah - the time at which C was reached. У0СМ is the coefficient of dispersion and 5О is the standard deviation.

On the 15th day, the procedure was repeated, except that two groups of 8 subjects, who received the control bo-dosed forms on the 1st day, then received azithromycin in the multiparticulate form of ZK15 or 5K16.

Similarly, two groups of 8 subjects previously received multiparticulate dosage forms of azithromycin on the 1st day, then - control dosage forms.

The pharmacokinetics of an i.p. mimo ZK12 multiparticulate dosage form of azithromycin was also evaluated in sixteen healthy subjects under fasted conditions in a randomized, double-crossover study. 65 The control was two single-dose packages of an oral suspension of azithromycin dihydrate (7IpgotakhFe, Riigeg Ips.

Mem ZhogK, MU), each dose of which contained 1048 mg of azithromycin dihydrate, which is equivalent to 1000 mgA of azithromycin, 88 mg of TR and previously indicated inactive components. The results of this study are given in

Tables 5. and

Composition

Bioavailability of 15-fold bioavailability Based on the results of Table 5, the bioavailability for ZK15, ZK1b and 5K12 was 7395, 8395 and 8990, respectively, relative to the rapid release control form. The data also showed that the ratio of the maximum concentration of azithromycin in the serum provided by the multiparticulate dosage form ZK15,

ZK16 and 5K12, to the maximum concentration of azithromycin provided by the control dosage form, were 0.44, 0.43 and 0.41, respectively. In addition, the time to reach the maximum concentration was longer for the multiparticulate forms of azithromycin than for the control immediate release dosage forms.

Stage C - study of gastrointestinal tolerance

The tolerability of ip mimo multiparticulate dosage forms of azithromycin 5K15 and 5K16 was evaluated in a randomized, parallel study. Specifically, 106 healthy subjects orally received azithromycin sustained-release multiparticulate formulation 5K15, 106 healthy human subjects with g5 orally received azithromycin sustained-release multiparticulate formulation ZK16, and 108 healthy human subjects received two single doses of 1gA azithromycin dihydrate in oral sachets about suspension. The entire contents of one sachet were mixed with about 20 ml of water in a cup and then drunk immediately.

Additionally, bOml of water was added to the cup, mixed and then drunk to ensure that the full dose was taken. These stages were repeated for the second package. Gastrointestinal side effects such as diarrhea, nausea, and vomiting were monitored for 48 hours after administration of each dosage form. Subjects were interviewed at least at the following approximate times: 1, 2, 4, 6, 8, 12 1 (2) 24 hours after dosing. uh-

The incidence of subject-reviewed gastrointestinal adverse events is shown in Table 6.

A similar study of the tolerance of ip mimo was carried out on the composition 5K12, using a population of 16 and 5 healthy human subjects. The control used in this study was two single doses of im-azithromycin dihydrate 1gHA in sachets for oral suspension. The results of this study are also given in

Tables 6. "and 7 IPercentages of individuals with lateral sphincter-valve erectors" 15 ERA PO UNYA PON RU UNN NO - Control for zd? 188516 (ee) The results in Tables 5 and 6 show that both multiparticulate dosage forms of azithromycin with or without -1 magnesium hydroxide in which the multiparticulates included 2-395 I Sho! Ф, provided lower concentrations of 50 azithromycin released from rapid release forms, compared to the control dosage form (Ce) of rapid release and significantly improved gastrointestinal tolerance compared to the control dosage form "c" of rapid release while simultaneously maintaining bioavailability substantially equivalent to the control rapid release liberation Further, ZK15 provided a relative degree of improvement compared to control: 1.6 for diarrhea, 3.2 for nausea, and 9.3 for vomiting, while ZK16 provided a relative degree of improvement of: 1.2 for diarrhea , 3.2 - for nausea, and 6.8 - for vomiting. Similarly, ZK12 provided no improvement in diarrhea over control, a relative degree of improvement of 50, and no cases of vomiting were observed in comparison

GF) with b cases that occurred in the control. - It should be noted that the results for ZK12 cannot be exact

The results are comparable to results for ZK15 and 5K16 due to the small population of the 5K12 study.

Example 7 in Comparison of multiparticulate forms of azithromycin and rapid release dosage forms of azithromycin

A clinical study was conducted to evaluate the pharmacokinetics and gastrointestinal tolerance of two multiparticulate dosage forms of azithromycin containing 2HA or ZhA of azithromycin, respectively, and each containing 352 mg of anhydrous TOR as an alkalizing agent, compared to an immediate-release dosage form of azithromycin containing half of TOR (17bmg) and without magnesium hydroxide. Sustained-release dosage form 65 was prepared as described in the following stage A, the above study of the rate of release of the ip myo dosage form 2gA was carried out as described in stage B, while the pharmacokinetics and side effects of the clinical studies and their results are described, respectively , in the next stages of the SIU.

Stage A - production of multiparticulate dosage forms of azithromycin

Multiparticulate dosage forms of azithromycin (hereinafter "ZK1T7" and "ZET18") were prepared by mixing 4.2 g (2HA) or 6.3 g (ZHA), respectively, of azithromycin MPO microparticles produced as described below with excipients. ZK17 dosage form included a mixture of multiparticles of azithromycin (MR) and a mixture of excipients, described below.

Azithromycin Multiparticles 70 Azithromycin Multiparticles "MRU" containing 50956 Azithromycin Dihydrate, 4695 Sotriyoke, and 490

Хо!Ф, were produced in the same manner as the MRO multiparticles in Example 2, except that the mixture was fed through a 27mm twin-screw extruder and a 27mm 140g/min until a molten mixture was formed. The atomizer disc was rotated at 5500 rpm to form the multiparticles.

The obtained multiparticles were kept at 402 and a relative humidity of 7595 in an acclimatization chamber for 75 DAYS.

Acidifying agents and excipients

An excipient mixture was prepared for use in combination with multiparticles of azithromycin.

The excipient mixture consisted of a mixture of 352 mg of anhydrous TOR as an alkalizing agent, 38.7 g of sucrose (ME), b7 mg of hydroxypropylcellulose (ME), b/7 mg of xanthan gum (ME), 200 mg of colloidal silicon dioxide (ME), 400 mg of titanium dioxide (OR), 140mg of cherry flavoring, 330mg of vanilla flavoring and banana flavoring - 23mg.

Stage B - Study of the rate of release of azithromycin

The study of the release rate of ip migo multiparticulate dosage form ZK 17 was performed as described in

Example 5. s y o vkyt (meo) not z 10011 Ф v leyu1vv i-

Stage C - Clinical study of the pharmacokinetics of co

The pharmacokinetics of IP mimo multiparticulate dosage forms of azithromycin 5K17 and ZK18 were evaluated in 300 healthy fasting subjects (100 subjects per group) in a randomized, parallel-group study.

Subjects were spontaneously assigned to one of the following 3 treatment groups: 5K17 (2gA), ZK18 (ZHgA) and 8 x250mgA tablets of 2ipgotaht? (control), which in combination, contain 2g of azithromycin, 1.1g of sodium diphosphate and other inactive components. "

A total volume of 240 ml of water was used for all doses. Doses of compositions ZK17 and 5K18, 5K17 or 5K18 -) were added to the vial containing the excipient mixture. Water (bOml) was added to the vial containing ZK17 or

ZK18 and excipient mixture. The vial was shaken for 30 seconds to mix the suspension. The entire contents of the vial were injected directly into the oral cavity. Additionally, bOml of water was added to rinse the vial and the subject's oral cavity. In addition, 120 ml of water was prescribed using a measuring cup.

For the dosage of eight tablets of 7ipgotah E 25Omg, the subjects were given 240 ml of water to orally administer -I eight tablets one after the other.

All subjects were dosed orally after an overnight fast. All subjects were required to limit lying down, food and drink, except water, during the first 4 hours after dosing. -I Blood samples were collected from each subject in an amount sufficient to provide a minimum of three milliliters of serum for azithromycin pharmacokinetics. Blood was collected in a container that did not contain preservatives or anticoagulants, or in a serum separator at the following times: 0 (before dosing), 2 and 3 hours (expected T roof) s" after the drug was prescribed. The concentration of azithromycin in serum was determined using high-performance liquid chromatography described by I (Zperaga et al., 3. Spgothaijodgarnu. 565:321-337(1991)).

The results of this study are shown in Table 8. o after dosing after dosing and

U5cM 36 U0CM ZA " 90CM AT 90CM 25 (Vx25Omg) 96CM 37 96CM 32 65 Based on the results of Table 8, the concentrations of azithromycin in the serum for ZK17 and ZK18 at 2 IZ hours after dosing were not less than the serum concentrations for 8 tablets 7(Igotah F. The data showed that there was no delay in the release of the active substance from zZK17 or 5K18 given the amount of alkalizing agent.

Stage O is a clinical study of gastrointestinal tolerance

At stage B, the tolerance of ZK17 and 5K18 multiparticulate dosage forms of azithromycin was evaluated. On the first day, subjects were interviewed for adverse events at least at the following approximate time intervals: 0, 2, 4, 8, 12, and 24 hours. The incidence of gastrointestinal side effects tested on subjects is shown in Table 9. and in 40111186 vysh 00000101198015018 and

The results in Tables 7 and 8 show that 2HgA or 3HA of the multiparticulate azithromycin dosage forms tested, where the multiparticulates include 4905 I ShgoMU and an excipient mixture containing 352 mg of TR, provide no advantage in reducing serum concentrations or improving gastrointestinal tolerance compared to the immediate release tablet dosage form.

Thus, as shown by the results in Tables 8 and 9, an effective amount of alkalizing agent was not used with these specific multiparticulates to provide the desired release profile and gastrointestinal side effects.

Example 8

Method for determining the amount of alkalizing agent for use with azithromycin rapid release

The effective amount of alkalizing agent that inhibits the disintegration of azithromycin in the stomach, and thus (o) thus, leads to an improvement in the tolerance of the rapid release composition, was calculated in the following way. The rapid release formulation without an alkalizing agent releases approximately 92,905 active substance within 30 minutes at pH 6.0 as described in Example 5, ie, 3.07956 per minute at pH 6.0. To improve tolerance, the rate of dissolution of azithromycin should be reduced, preferably to a rate at which only about 1.5 HgHA is released, or less in the first 30 minutes or no more than 2.595 (o) per minute. It was assumed that the dissolution rate of the rapid release composition is directly proportional to the pH-dependent solubility of azithromycin, as shown in Table 10.

Since it is accepted that the rate of release of azithromycin is directly proportional to the solubility of azithromycin, and) the solubility of azithromycin at pH 6.0 and at a rate of 3.079, - 39Omg/ml, obtained by interpolation of the data "from table 10. The corresponding solubility, which gives improved tolerance, is calculated as :

Solubility "-(39Omg/ml) (2.595)3.0796)

Solubility! defined as the solubility at which the dissolution of azithromycin does not lead to excessive side effects on the gastrointestinal tract. It was found that the solubility! from the equation is equal to

Gee! 318 mg/ml. Again, by interpolating the data of Table 10, it is obtained that the pH corresponding to the solubility of / is 6.4.

Preferably, the amount of alkalizing agent in the immediate release azithromycin composition or the amount dosed with the immediate release azithromycin composition is such that the pH of the stomach increases to 6.63 for at least 30 minutes. To calculate this amount, it is assumed that the basal amount of acid in the 60 stomach is about 0.9bmmol H", and that the average rate of acid secretion is about

Zmmol for an hour.

To calculate the amount of alkalizing agent or alkalizing agents to be included in the composition, it is necessary to obtain titration data for various alkalizing agents and combinations of alkalizing agents. Thus, solutions of several alkalizing agents and combinations of alkalizing agents were prepared and then titrated with 0.1M HCl and the final pH value was measured. From these data we can calculate the pH versus time profile as described in step A of Example 1, assuming that the basal amount of acid in the stomach is approximately 0.9 mmol H" and that the average rate of acid secretion is approximately 3 mmol per hour. These data are presented in Figures 2 and 3.

In Fig. 3, it can be seen that the compositions containing 17bmg TR or 17bmg TR plus 500mg Saso with, as expected, do not increase the gastric pH to 6.8 within 30 to 40 minutes, while the compositions containing ( 7bmg TR and 50Omg TKIZ, 17bmg TR plus 1000mg TKIZ, or 17bmg TR plus 250mg Ma(OH)" would be expected to provide an increase in pH of at least for the longer term. The formulation with 352mg TR was found to provide a pH of 6.48 for a little greater than 30 minutes and therefore may be considered to contain the minimum amount of 70 alkalizing agent necessary to reduce gastrointestinal adverse effects following administration of a high-dose immediate-release azithromycin formulation.When considering interindividual variation in the rate of gastric acid secretion and considering the potency of the dosage form, the amount of alkalizing agent is preferably higher than the minimum.

By similar analysis of the data in Figure 2, 352 mg TP and 352 mg TZRαABOOmMg calcium carbonate are predicted to provide only an adequate increase in gastric pH for the desired duration, while the other combinations tested are predicted to provide an adequate increase in gastric pH for the desired period of time. It should be noted that the above-mentioned general procedure for determining the effective amount of alkalizing agent depends on assumptions made about the basal acid state in the stomach and the rate of acid secretion. The selected values represent average numbers for generally healthy individuals and may vary significantly between individuals. The effective amount of alkalizing agent depending on the assumptions can be calculated by the procedure given above.

Claims (48)

The formula of the invention with I o 1. An oral dosage form containing: (a) an effective amount of an alkalizing agent; and (b) multiparticulates, wherein said multiparticulates include: (Y) from about 2095 to about 75905 of azithromycin; and so zo(ii) from about 2595 to about 8095 of a glyceride that contains glyceryl monobehenate, glyceryl dibehenate, and glyceryl tribehenate, or a mixture thereof; and b" (iii) poloxamer. h- 2. Oral dosage form according to claim 1, where the poloxamer includes poloxamer 407. 3. Oral dosage form according to claim 1, where the alkalizing agent includes bicarbonate, phosphate, metal hydroxide, metal oxide, or a combination thereof. M 4. Oral dosage form according to claim 3, where the alkalizing agent includes tribasic sodium phosphate and magnesium hydroxide. 5. The oral dosage form of claim 3, which contains from about 250 mgA to about 7 HA of azithromycin. 6. The oral dosage form of claim 5, which contains from about 1.5 HA to about 4 HA of azithromycin. " 7. Oral dosage form according to claim 5, which contains from 1.8 gA to 2.2 gA of azithromycin. shsh c 8. An oral dosage form of azithromycin comprising: (a) at least about 200 mg tribasic sodium phosphate; and "c" (b) multiparticles, where said multiparticles include: (I) azithromycin; (ii) a mixture of glyceryl monobehenate, glyceryl dibehenate and glyceryl tribehenate; i -i (ii) poloxamer 407; and wherein said dosage form contains from about 1.5 gA to about 4 gA of azithromycin. co 9. The oral dosage form of claim 8, which contains at least about 100 mg of magnesium oxide. -and 10. Oral dosage form according to claim 8, containing: (a) from 300 mg to 400 mg of tribasic sodium phosphate; ise) (6) from 200 mg to ZO00 mg of magnesium hydroxide; and c" (c) multiparticles, where said multiparticles include: (I) azithromycin; (iii) a mixture of glyceryl monobehenate, glyceryl dibehenate and glyceryl tribehenate; and (ii) poloxamer 407; and wherein said dosage form contains from about 1.5 gA to about 4 gA of azithromycin. F) 11. Oral dosage form according to claim 8, which contains from 1.8 HA to 2.2 HA of azithromycin. ka 12. The oral dosage form of claim 11, wherein said azithromycin is azithromycin dihydrate. 13. The oral dosage form of claim 1, wherein said azithromycin is azithromycin dihydrate. 60 14. The oral dosage form according to claim 3, wherein said azithromycin is at least 70 wt.9o crystalline. 15. The oral dosage form according to item C, wherein said oral dosage form is a powder for oral suspension, a single-dose sachet, an oral suspension, a tablet or a capsule. 16. A method of reducing the frequency of gastrointestinal side effects associated with the administration of azithromycin to a mammal, which consists in co-administering the oral dosage form according to claim 1 to said mammal, in which b5 the frequency of gastrointestinal side effects is reduced compared to the frequency when prescribed an equivalent dose of azithromycin without said alkalizing agent. 17. The method according to claim 16, wherein said mammal is a human. 18. The method of claim 17, which comprises administering from about 250 mgA to about 7 HA of azithromycin to said human. 19. The method according to claim 18, where azithromycin is administered in a single dose. 20. The method of claim 19, which includes administering from about 1.5 HA to about 4 HA of azithromycin. 21. The method of claim 19, which includes administering from about 1.5 HA to about 3 ha of azithromycin. 22. The method according to claim 19, which includes administering from 1.8 HA to 2.2 HA of azithromycin to said person in a single dose. 23. The method of claim 17, which comprises administering from 30 mgA/kg to 90 mgA/kg of azithromycin to a human, wherein said 7/0 human is a child weighing 30 kg or less. 24. The method according to claim 23, where azithromycin is administered in a single dose. 25. The method according to claim 24, which includes administering from 45 mgA/kg to 75 mgA/kg of azithromycin to a child weighing 30 kg or less. 26. The method of claim 24, which comprises administering approximately 60 mgA/kg of azithromycin to a child weighing 30 kg or less. 27. The method according to claim 16, where the alkalizing agent includes bicarbonate, phosphate, metal hydroxide, metal oxide, or a combination thereof. 28. The method according to claim 27, where the alkalizing agent includes tribasic sodium phosphate and magnesium hydroxide. 29. The method of claim 27, wherein said azithromycin comprises immediate release azithromycin. 30. The method of claim 27, wherein said azithromycin comprises azithromycin in a sustained release form. 31. The method according to claim 27, wherein said azithromycin includes multiparticles of azithromycin. 32. The method according to claim 31, where said multiparticles of azithromycin include: (a) azithromycin; and (b) a pharmaceutically acceptable carrier. 33. A method of treating a bacterial or protozoan infection in a mammal in need thereof, comprising administering to said mammal a unit dose of the oral dosage form of claim 1. 34. The method according to claim 33, wherein said mammal is a human. (8) 35. The method of claim 34, which comprises administering from about 250 mgA to about 7 gA of azithromycin to said human. 36. The method according to claim 35, where azithromycin is administered in a single dose. with zo 37. The method of claim 36, which comprises administering from about 1.5 HA to about 4 HA of azithromycin to said human. Me) 38. The method of claim 36, which includes administering from about 1.5 HA to about 3 HA of azithromycin to said human. 39. The method according to claim 36, which includes administering from 1.8 gA to 2.2 gA of azithromycin to said person. co 40. The method of claim 34, which includes administering from 30 mgA/kg to 90 mgA/kg of azithromycin to a human, wherein said human is a child weighing 30 kg or less. 41. The method according to claim 34, where azithromycin is administered in a single dose. 42. The method according to claim 41, which includes administering from 45 mgA/kg to 75 mgA/kg of azithromycin to a child weighing 30 kg or less. " 43. The method according to claim 41, which includes the administration of 60 mgA/kg of azithromycin to a child weighing 30 kg or less. from the village 44. The method according to claim 33, where the alkalizing agent includes bicarbonate, phosphate, metal hydroxide, metal oxide, or a combination thereof. ;" 45. The method according to claim 44, wherein the alkalizing agent includes tribasic sodium phosphate. 46. The method according to claim 45, where the alkalizing agent additionally includes magnesium hydroxide. 47. The method of claim 44, wherein said azithromycin comprises immediate release azithromycin. -AND 48. The method of claim 44, wherein said azithromycin comprises azithromycin in a sustained release form. (ee) -I o 50 Fe (F) ko bo b5