Azithromycin dosage forms with reduced side effects

ES 2 312 929 T3

DESCRIPTION

Azithromycin dosage forms with reduced side effects.

Background of the invention

Azithromycin is an antibiotic that is administered orally or intravenously, to treat various infections, particularly infections of the urinary tract, bronchial tract, lungs, sinuses, and middle ear.

Oral dosing of azithromycin can lead to adverse gastrointestinal (GI) side effects such as nausea, spasms, diarrhea, and vomiting in a significant number of patients. Such GI side effects can also occur in non-human mammals, for example dogs. In combined azithromycin clinical studies involving 3,995 human patients (all dose levels combined), 9.6% of patients reported GI side effects; the most frequent side effects of these were diarrhea (3.6%), nausea (2.6%) and abdominal pain (2.5%) Hopkins, 91 Am. J. Med.40S (Suppl 3A, 1991).

The frequency of these adverse side effects increases with higher dose levels of azithromycin. When treating adult humans, with a single 1 gram dose, administered as an oral suspension, the incidence of the various GI side effects reported was 7% diarrhea / loose stools, 5% nausea, 5% pain abdominal pain and 2% vomiting (Azithromycin Zithromax^® for oral suspension). However, with a single 2-gram dose, administered as an oral suspension, the incidence of the various GI side effects reported was 14% diarrhea / loose stools, 7% abdominal pain, and 7% vomiting (reference previous).

Similarly, in the treatment of pediatric humans, administering an oral suspension containing 10 mg / kg on Day 1 and 5 mg / kg on days 2-5, the incidence of the various Gi side effects reported was 4 % diarrhea / loose stools, 2% abdominal pain and 2% vomiting (reference above), whereas with a single dose of 30 mg / kg, administered as an oral suspension, the incidence of the various GI side effects reported was 6.4% diarrhea / loose stools, 1.7% nausea, and 4% vomiting (previous reference).

Antacids, which are alkalizing agents that are provided in large doses to raise stomach pH from about 1-3 to about 4-7, can provide relief to a patient from diarrhea, spasms, and gastric discomfort. However, patients have been discouraged from taking an antacid, particularly those containing aluminum or magnesium, with azithromycin simultaneously, as antacids have been shown to reduce the maximum serum C concentration._max of azithromycin by 24% (previous reference). In addition, to avoid interference with azithromycin absorption caused by antacids, patients have also been advised to space the administration of azithromycin and antacid at least two hours apart.

Currently, small amounts, about 132 mg or less, of the anhydrous tribasic sodium phosphate alkalizing agent are used in commercial azithromycin dosage forms to mask the bitter taste of azithromycin by reducing the solubility of azithromycin before swallowing. In addition, in the treatment of uncomplicated gonococcal infections, two single dose containers of azithromycin, each containing 88 mg of anhydrous tribasic sodium phosphate, are administered concurrently to a patient in need of it.

EP 0679400 A1 describes a rapidly disintegrating oral dosage form of azithromycin.

US 5,633,006 describes a pharmaceutical composition composed of a bitter pharmaceutical agent (such as azithromycin), a taste masking component, and a pharmaceutically acceptable carrier.

More recently, controlled release dosage forms of azithromycin have been prepared, as described in US Patent No. 6,068,859, that reduce gastrointestinal side effects, which occur from an administered dose of azithromycin, compared with an equivalent dose of commercial immediate-release azithromycin capsules. However, it was subsequently found that the bioavailability of many of the controlled release dosage forms, which are specifically exemplified therein, was lower than that of their immediate release equivalents.

Therefore, what is needed is an azithromycin dosage form that has similar bioavailability and lower gastrointestinal side effects than an immediate release azithromycin equivalent dose.

Summary of the invention

The present invention relates to an oral dosage form of azithromycin comprising an effective amount of an alkalizing agent and multiparticulates of azithromycin, said multiparticles comprising azithromycin, a mixture of glyceryl mono-, di- and tribehenates and a poloxamer.

The present invention further relates to an oral suspension comprising azithromycin, an effective amount of an alkalizing agent, and a carrier. Preferably the azithromycin is in multiparticulate form and the multiparticles comprise azithromycin, a mixture of glyceryl mono-, di- and tribehenates and a poloxamer.

ES 2 312 929 T3

Even more preferably, the azithromycin oral dosage form and the oral suspension further comprise 300 mg to 400 mg of tribasic sodium phosphate, 200 mg to 300 mg of magnesium hydroxide and multiparticulates, said multiparticles comprising (i) azithromycin, (ii ) a mixture of glyceryl mono-, di- and tribehenates, and (iii) poloxamer 407, and said dosage form containing from about 1.5 gA to about 4 gA of azithromycin.

Furthermore, the present invention also relates to the uses defined in claims 12 and 13 below.

Preferably, between 250 mgA and 7 gA of azithromycin is administered to a human. More preferably, 1.5 gA to 3 gA of azithromycin is administered to a human, even more preferably in a single dose. Also more preferably, for a pediatric human weighing 30 kg or less, said child is administered between 45 mgA / kg and 75 mgA / kg of azithromycin, even more preferably in a single dose.

Brief description of the drawings

Fig. 1, which is described in more detail in Example 1, shows the effects on pH of titration of different alkalinizing agents with increasing volumes of 0.1N HCl.

Fig. 2, which is described in more detail in Examples 1 and 8, shows the calculated pH of different alkalinizing agents when titrated with 0.1N HCl as a function of time.

Fig. 3, which is described in more detail in Example 8, shows the calculated pH of different alkalinizing agents when titrated with 0.1N HCl as a function of time.

Detailed description of the invention

As used in the present invention, the term "about" means the specified value + 10% of the specified value.

As used in the present invention, the terms "a" or "one" mean one or more. For example, the term "an alkalizing agent" means one or more alkalizing agents, the term "a vehicle" means one or more vehicles, and the term "a dissolution enhancer" means one or more dissolution enhancers. .

The term "alkalizing agent", as used herein, means a pharmaceutically acceptable excipient that will increase the pH of a suspension made up or in the stomach of a patient after being administered orally to said patient.

The term "pharmaceutically acceptable", as used herein, means that it is compatible with other ingredients of the composition and not deleterious to the recipient thereof.

The term "constituted suspension" means that the powder has been mixed with a vehicle and forms an "oral suspension." In this oral suspension, the azithromycin and excipients can (a) be completely suspended in the vehicle or (b) partially suspended in the vehicle and partially in solution in the vehicle. Oral suspensions of the present invention include vehicles containing azithromycin that are suspended in the vehicle, or in which the azithromycin is temporarily suspended, in the vehicle after shaking, stirring or mixing.

A vehicle of the present invention comprises non-flavored water, flavored water, or an aqueous solution with a natural or artificial fruit flavor, or with other flavors such as a beverage.

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

An "effective amount of an alkalizing agent", as used herein, means an amount of one or more alkalizing agents which, when administered in combination with azithromycin, provides a relative degree of tolerance improvement in terms of the Percentage of patients tolerating azithromycin administration, without GI side effects, compared to a control dosage form containing the same amount of active azithromycin.

A "relative degree of improved tolerance" is defined as the ratio of (1) the percentage of adverse events that appear from administration of an immediate release control dosage form and (2) the percentage of adverse events that appear by the administration of a controlled release multiparticulate dosage form of the present invention, wherein the immediate release control dosage form and the controlled release multiparticulate dosage form contain the same amount of azithromycin. The immediate release control dosage form can be any conventional immediate release dosage form, such as tablets, capsules, or single dose oral suspension containers of Zithromax.^®. For example, if an immediate release control dosage form provides a 20% percentage of adverse events appearing on administration, whereas the dosage form in

ES 2 312 929 T3 multiparticulate of the present invention provides a percentage of adverse events that appear by the administration of 10%, then the relative degree of improvement of tolerance is 20% © 10% or 2.

The term "oral dosage form" includes a plurality of devices that collectively deliver, by oral ingestion, the desired amount of azithromycin, to achieve a desired dose of azithromycin. Typically, the oral dosage form is a powder for oral suspension, a unit dose pack or sachet, a tablet or a capsule.

"Administration" refers generally to introducing the dosage form into an environment of use, either by placing the dosage form in a dissolution medium in vitro or by ingestion by an animal so as to penetrate the in vivo environment of the tract. GI.

As defined herein, the term "environment of use" can be either the in vivo environment of the GI tract of an animal, such as a mammal and in particular a human, or the in vitro environment of a medium. Na buffer experimentation₂HPO₄ at pH 6.0 as described in Example 5.

The term "mammal" is an individual animal that is a member of the taxonomic class Mammals. The class Mammals includes, for example, humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice, and rats.

In the present invention, the preferred mammal is a human.

The dosage forms of the present invention provide better tolerance of administered azithromycin, raising stomach pH to a level sufficient to substantially reduce the release rate, or rate of dissolution, of azithromycin in the stomach and thus reduce the concentration of azithromycin. dissolved in the stomach and duodenum. This reduction in the concentration of dissolved azithromycin in the stomach, and preferably in the duodenum, causes a decrease in the incidence, or frequency of GI side effects when azithromycin is administered. Specifically, for a dosage form of the present invention, comprising azithromycin and an effective amount of an alkalinizing agent, the release rate or dissolution rate of azithromycin for a dose of 1.5 gA to 7 gA, in the environment in vitro of the experiment medium with Na buffer₂HPO₄ at pH 6.0 of Example 5, it should be (i) 15 to 55% by weight of said azithromycin dosage form at 0.25 hours but not more than 1.1 gA; (ii) 30 to 75% by weight of said azithromycin dosage form at 0.5 hours but not more than 1.5 gA, and preferably not more than 1.3 gA; and (iii) greater than 50% by weight of said azithromycin dosage form 1 hour after administration to the buffer testing medium. For doses less than 1.5 gA, such as pediatric doses, the dose should be scaled up to 2 gA and then evaluated using this in vitro experiment.

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

The present dosage forms provide a relative degree of improvement in tolerance of administered azithromycin of at least 1.1 compared to an equivalent immediate release form. Preferably, the relative degree of tolerance improvement is at least about 1.25. More preferably, the relative degree of tolerance improvement is at least about 1.5. Even more preferably, the relative degree of tolerance improvement is at least about 2.0. Most preferably, the relative degree of tolerance improvement is at least about 3.0. In a preferred embodiment, the present dosage forms also maintain an appropriate level of bioavailability by not significantly reducing the release rate of azithromycin and / or the rate of dissolution of azithromycin delivered in the duodenum or distal to the duodenum. Typically, the present dosage forms provide a bioavailability of at least 60%, more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% compared to the control composition. .

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

Examples of such alkalizing agents include, but are not limited to, aluminum salts such as magnesium and aluminum silicate; magnesium salts such as magnesium carbonate, magnesium trisilicate, magnesium aluminum silicate, magnesium stearate; calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide, sodium hydroxide, and magnesium hydroxide; metal oxides such as magnesium oxide; N-methylglucamine; arginine and its salts; amines such as monoethanolamine, diethanolamine, triethanolamine, and tris (hydroxymethyl) aminomethane (TRIS); and their combinations.

Preferably, the alkalizing agent is TRIS, magnesium hydroxide, magnesium oxide, dibasic sodium phosphate, TSP, dibasic potassium phosphate, tribasic potassium phosphate, or a combination thereof. Most preferably, the alkalizing agent is a combination of TSP and magnesium hydroxide.

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When the alkalizing agent comprises TSP, it is preferred that the TSP is anhydrous.

The minimum amount of alkalizing agent suitable to constitute an "effective amount" is the amount that would provide a relative degree of tolerance improvement of at least 1.1.

This adequate amount of alkalizing agent can be readily determined by conducting a scaled in vitro study of dissolution rates of azithromycin by titrating a solution of a fixed dose of azithromycin with 0.1 N HCl and increasing amounts of an alkalizing agent or combinations of alkalizing agents such as as described in Example 1.

For dosage forms containing multiparticulate azithromycin, an effective amount of an alkalinizing agent is the amount that, when titrated using an in vitro titration experiment against 0.1 N HCl, simulates gastric fluid in the fed state. , 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 6, or more, for a period of approximately 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, an effective amount of an alkalinizing agent is the amount that, when titrated using an in vitro titration experiment against 0.1 N HCl, as described in Example 1, maintains a pH of about 6.4, or more, for at least about 10 minutes, and more preferably for at least about 30 minutes.

Alternatively, an effective amount of an alkalizing agent can be determined in the following in vitro experiment. First, a 20 ml sample of 0.1 N HCl is placed in an appropriate container. Second, the candidate alkalizing agent is added to 60 ml of water. The alkalizing agent solution thus formed is then added to the 20 ml 0.1N HCl sample and the pH of the resulting solution is monitored as a function of time. When azithromycin is in sustained release multiparticulate form, an effective amount of alkalinizing agent is such that the pH of the solution is at least 5, preferably at least 6, and more preferably at least 7. When azithromycin is in a formulation For immediate 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.

An alkalizing agent of the present invention is administered contiguous with the administration of a dose of azithromycin. As used herein, the term "contiguously" means that the alkalinizing agent is administered before, concurrently, or after azithromycin in a period of time sufficient to slow the rate of azithromycin release into the body. stomach and reduce the concentration of dissolved azithromycin in the duodenum. For example, when azithromycin is administered in multiparticulate form, the alkalizing agent should be administered, between about 20 minutes before and about 10 minutes after the administration of azithromycin. For an immediate release dosage form of azithromycin, the alkalinizing agent should be administered concurrently with azithromycin or up to approximately 20 minutes prior to administration of azithromycin.

Preferably, the alkalizing agent is administered concurrently with the administration of azithromycin.

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

The alkalizing agent can be in the same dosage form as azithromycin, the alkalizing agent can be contained in a vehicle used to administer the azithromycin, and / or the alkalizing agent can be administered separately from the azithromycin.

When the azithromycin dosage form contains at least a portion of the alkalizing agent, the azithromycin dosage form can be in any oral dosage form such as a suspension, tablet, capsule, or sachet.

When the alkalizing agent is at least partially contained in the vehicle, the azithromycin dosage form can be a sachet, powder for oral suspension, tablet, or capsule.

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

As used herein, "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 the present invention is azithromycin dihydrate which is described in US Patent 6,268,489 B1.

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In alternative embodiments of the present invention, the azithromycin comprises a non-dihydrated azithromycin, a mixture of non-dihydrated azithromycin, or a mixture of azithromycin dihydrate and non-dihydrated azithromycin. Examples of suitable nondihydrated azithromycins include, but are not limited to, alternative crystal forms B, D, E, F, G, H, J, M, N, O, P, Q, and R.

Azithromycin in form B which is a hygroscopic hydrate of azithromycin is described in US Patent No. 4,474,768.

Azithromycin in forms D, E, F, G, H, J, M, N, O, P, Q, and R is described in US Patent Application Serial Number (USSN) 10 / 152,106, which is published August 28, 2003 as United States Patent Application Publication No. 20030162730 A1.

Forms B, F, G, H, J, M, N, O and P belong to Family I of azithromycin and belong to a monoclinic space group P2₁ with cell dimensions of a = 16.3 + 0.3 A, b = 16.2 + 0.3 A, c = 18.4 + 0.3 A and beta = 109 + 2 °.

Azithromycin in form F is azithromycin ethanol solvate of formula C_i8Il72N_;OR_1;4I_;OO, 5C-415OH in the single crystal structure which is specifically a hemiethanol solvate of azithromycin monohydrate. Form F is further characterized in that it contains 2-5% water and 1-4% ethanol by weight in the powdered samples. The single crystal form F crystallizes into a monoclinic space group, P2i, with the asymmetric unit containing two azithromycins, two waters, and an ethanol in the monohydrate / hemiethanolate form. It is isomorphic to all crystalline forms of azithromycin of Family I. The theoretical contents in water and ethanol are 2.3 and 2.9% by weight, respectively.

Azithromycin in form G is of formula C₃₈H₇₂N₂OR₁₂-1.5 H₂Or with a simple crystal structure, which is azithromycin sesquihydrate. Form G is further characterized in that it contains 2.5-6% by weight of water and <1% by weight of organic solvent (s) by weight in the powdered samples. The single crystal structure of Form G consists of two azithromycin molecules and three water molecules per asymmetric unit. This corresponds to a sesquihydrate with a theoretical water content of 3.5% by weight. The water content of Form G powder samples ranges from about 2.5 to about 6% by weight. The total residual organic solvent is less than 1% by weight of the corresponding solvent that is used for crystallization.

Azithromycin in form H is of formula C₃₈H₇₂N₂OR₁₂-H₂O-0.5C₃H₈OR₂ which is azithromycin monohydrate hemi-1,2-propanediol solvate. Form H is a hemipropylene glycol monohydrate / solvate of the azithromycin free base.

Azithromycin in J form is of formula C₃₈H₇₂N₂OR₁₂-H₂O-0.5C₃H₇OH with the single crystal structure, which is hemi-n-propanol solvate of azithromycin monohydrate. Form J is further characterized in that it contains 2-5% by weight of water and 1-5% by weight of n-propanol in the powdered samples. The calculated solvent content is about 3.8% by weight of n-propanol and about 2.3% by weight of water.

Azithromycin in form M is an isopropanol solvate of azithromycin of the formula C₃₈H₇₂N₂OR₁₂-H₂O-0.5C₃H₇OH which is specifically azithromycin monohydrate hemi-isopropanol solvate. Form M is further characterized in that it contains 2-5% by weight of water and 1-4% by weight of 2-propanol by weight in the powdered samples. The single crystal structure of Form M would be a monohydrate / hemi-isopropanolate.

Azithromycin in N form is a mixture of Family I isomorphs. The mixture may contain varying percentages of F, G, H, J, M and other isomorphs and varying amounts of water and organic solvents, such as ethanol, isopropanol , n-propanol, propylene glycol, acetone, acetonitrile, butanol, pentanol etc. The percentage by weight of water can vary in the range of 1-5.3% by weight and the percentage by total weight of organic solvents can be 2-5% by weight, each solvent contributing from 0.5 to 4% by weight. .

Azithromycin in form O is of formula C₃₈H₇₂N₂OR₁₂-0.5H₂O-0.5C₄H₉OH, which is azithromycin free base hemi-n-butanol hemihydrate solvate based on single crystal structure data.

Azithromycin in form P is of formula C₃₈H₇₂N₂OR₁₂-H₂O-0.5C₅H₁₂Or that it is azithromycin monohydrate hemi-n-pentanol solvate.

Azithromycin in form Q is of formula C₃₈H₇₂N₂OR₁₂-H₂O-0.5C₄H₈Or that it is azithromycin monohydrate hemitetrahydrofuran solvate. It contains approximately 4% by weight of water and approximately 4.5% by weight of THF.

Forms D, E, and R belong to Family II of azithromycin and belong to an orthorhombic space group P21 2₁2₁ with cell dimensions of a = 8.9 + 0.4 A, b = 12.3 + 0.5 A, c = 45.8 + 0.5 A. The Q shape is different from Families I and II.

Azithromycin in form D is of formula C₃₈H₇₂N₂OR₁₂-H₂OC₆H₁₂ in its single crystal structure, which is azithromycin monohydrate monocyclohexane solvate. Form D is further characterized by containing 2-6%

ES 2 312 929 T3 by weight of water and 3-12% by weight of cyclohexane by weight in the powdered samples. From the single crystal data, the calculated water and cyclohexane content of form D is 2.1 and 9.9% by weight respectively.

Azithromycin in form E is of formula C₃₈H₇₂N₂OR₁₂-H₂OC₄H₈Or, which is azithromycin monohydrate monotetrahydrofuran solvate. Form E is a monohydrate and mono-THF solvate based on single crystal analysis.

Azithromycin in R form is of formula C₃₈H₇₂N₂OR₁₂-H₂OC₅H₁₂Or, which is azithromycin monohydrate mono-methyl-tert-butyl ether solvate. Form R has a theoretical water content of 2.1% by weight and a theoretical methyl-tert-butyl ether content of 10.3% by weight.

Both Family I and Family II isomorphs are hydrates and / or solvates of azithromycin. The solvent molecules in the cavities have a tendency to exchange between solvent and water under specific conditions. Therefore, the solvent / water content of the isomorphs can vary somewhat.

Other examples of nondihydrated azithromycin include, but are not limited to, an ethanol solvate of azithromycin or an isopropanol solvate of azithromycin. Examples of such azithromycin ethanol and isopropanol solvates are disclosed in US Patent No. 6,365,574 to Singer et al., Which is entitled "Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereol", US Pat. United States No. 6,245,903, by Karimian et al., Entitled "Azithromycin monohydrate isopropanol clatharate and methods for the manufacture thereof" or in USSN 10 / 152,106.

Other examples of non-dihydrated azithromycin include, but are not limited to, azithromycin monohydrate, as described in US patent application publication numbers 20010047089 which was published on November 29, 2001 and 20020111318 which was published on August 15 of 2002, as well as international patent application publication numbers WO 01/00640, WO 01/49697, WO 02/10181 and WO 02/42315.

Other examples of non-dihydrated azithromycin include, but are not limited to, anhydrous azithromycin as described in US Patent Application Publication No. 20030139583 which was published on July 24, 2003 and US Patent No. 6,528,492 .

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

Preferably, at least 70% by weight of the azithromycin in the multiparticles is crystalline. More preferably, at least 80% by weight of the azithromycin is crystalline. Even more preferably, at least 90% by weight of the azithromycin is crystalline. Most preferably, at least 95% by weight of the azithromycin is crystalline. Crystalline azithromycin is preferred as it is more physically and chemically stable than the amorphous form or dissolved azithromycin.

The crystallinity of azithromycin can be determined using powder X-ray diffraction (PXRD) analysis. In an example procedure, PXRD analysis can be performed on a Bruker AXS D8 Advance diffractometer. In this analysis, samples of approximately 500 mg are loaded into Lucite sample cuvettes and the sample surface is matched using a microscope glass slide to provide a consistently matched sample surface that is level with the top of the sample cuvette. The samples are centrifuged in the φ plane at a speed of 30 rpm to minimize the effects of orientation of the crystals. The X-ray source (S / B KCu_to, λ = 1.54 A) is operated with a voltage of 45 kV and with a current of 40 mA. Data for each sample is collected over a period of approximately 20 to approximately 60 minutes in continuous detection scan mode and with a scan speed of approximately 1.8 seconds / increment to approximately 12 seconds / increment and an increment of 0, 02 ° / increment. The diffractograms are collected in the 2Θ range of about 4 ° to 30 °.

The crystallinity of the test sample is determined by comparing it with two or more calibration standards consisting of physical mixtures of crystalline azithromycin and vehicle. Each physical mix is ​​mixed for approximately 15 minutes in a Turbula mixer. Using the program of the apparatus, the area under the curve of the diffractogram in the interval of 2Θ is integrated using a linear baseline. This integration range includes as many drug-specific peaks that are possible excluding vehicle-related peaks. A linear calibration curve of percent crystalline drug versus area under the diffractogram curve is generated from the calibration standards. The crystallinity of the test sample is then determined using these calibration results and the area under the curve for the test sample. Results are expressed as a mean percentage of azithromycin crystallinity (by crystal mass).

The azithromycin used herein comprises azithromycin particles that are contained in a dosage form which, when the alkalizing agent of the present invention is absent, is an immediate release or sustained release dosage form. As defined herein, the term "azithromycin particles" means that azithromycin may be in the form of a powder or granules that were previously formed from azithromycin powder and, optionally, at least one pharmaceutically excipient. acceptable.

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Immediate release dosage forms are the forms in which at least 75% of your azithromycin is released or dissolved within about half an hour after administration. Such immediate release dosage forms include azithromycin tablets, capsules, multiparticulates, powders for oral suspension, and sachets. Examples of immediate release dosage forms include, but are not limited to, Zithromax tablets, capsules, oral suspensions, or single-dose oral suspension containers.^® commercially available (Pfizer Inc., New York, NY) or the multiparticulate control dosage form described herein in Example 2.

Sustained-release dosage forms are forms that release azithromycin more slowly than immediate-release dosage forms. Such sustained release dosage forms include, but are not limited to, tablets, capsules, multiparticles, powders for oral suspension, and sachets of azithromycin.

Examples of sustained release dosage forms of azithromycin that are suitable for use in the present invention include, but are not limited to, the sustained release dosage forms that are described in US Patent No. 6,068,859.

Preferably, the azithromycin used in the present invention is contained in multiparticles comprising azithromycin and a pharmaceutically acceptable carrier.

Multiparticles are prominent dosage forms that comprise a multiplicity of drug-containing particles all of which represent the intended therapeutically useful dose of a drug. When taken orally, the multiparticles generally disperse freely in the gastrointestinal tract, exiting the stomach relatively quickly and reproducibly, and maximizing absorption. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989).

Multiparticles are often used to provide sustained release of a drug. One problem in formulating sustained release multiparticles is adjusting the rate of drug release. The rate of drug release depends on a variety of factors, including the vehicles used to form the multiparticles and the amount of drug in the multiparticles. It is desirable to provide carriers for multiparticles that allow the rate of drug release from the multiparticles to be controlled over a wide range of release rates, so that the same matrix materials can be used, in different ratios, to provide slow or slow release. rapid drug as desired. To achieve this result, the drug release rate should change significantly in response to relatively small changes in the proportions of the respective carriers in the multiparticles.

The term "multiparticles" is intended to include a dosage form that comprises a multiplicity of particles all of which represent the intended therapeutically useful dose of azithromycin. The term is intended broadly to refer to small particles regardless of their composition or the way they are formed. The particles are small enough for the particles to travel with the GI fluids to disperse through the GI tract shortly after ingestion. The particles generally are of a mean diameter from about 40 to about 3000 µm, preferably from about 50 to about 1000 µm, and most preferably from about 100 to about 300 µm. Preferably, azithromycin represents from about 5% by weight to about 90% by weight of the total weight of the multiparticles. More preferably, azithromycin represents from about 10% by weight to about 80% by weight of the multiparticles, and even more preferably, at least about 30% by weight to about 60% by weight of the multiparticles.

Although the multiparticles can be of any shape and texture, it is preferred that they be spherical, with a smooth surface texture. These physical characteristics lead to excellent flow properties, improved "mouthfeel", ease of swallowing, and ease of uniform coating, if necessary.

Such azithromycin multiparticles are particularly suitable for the administration of single doses of the drug as long as a relatively large amount of the drug can be delivered at a controlled rate over a relatively long period of time. Suitable multiparticles for use in the present invention are described in US Patent No. 6,068,859, including multiparticles formed by extrusion / spheronization, wax granulation, spray drying, and spray coating.

The multiparticle carrier comprises at least one pharmaceutically acceptable excipient that functions as a matrix for the multiparticles or to control the release rate of azithromycin from the multiparticles or both.

All references to "acid and / or ester substituents" herein are intended to mean carboxylic acid, sulfonic acid, and phosphoric acid substituents or carboxylic acid ester, sulfonyl ester, or phosphate ester substituents, respectively. As described in detail below, azithromycin can react with acid or ester substituents on an excipient to form azithromycin esters.

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Azithromycin can potentially react with carriers, and optional excipients, that have acid or ester groups to form azithromycin esters. Carriers and excipients can be characterized as having "low reactivity", "medium reactivity" and "high reactivity" to form azithromycin esters.

Examples of optional low-reactivity carriers and excipients include long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; poloxamers (block copolymers of ethylene oxide and propylene oxide, such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407); ethers, such as polyoxyethylene alkyl ethers; ether substituted cellulosics, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and ethyl cellulose; sugars such as glucose, sucrose, xylitol, sorbitol, and maltitol; 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.

Optional vehicles and excipients of moderate reactivity often contain acid or ester substituents, but relatively few compared to the molecular weight of the optional vehicle or excipient. 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; glycolized fatty acid esters, 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, comprises glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, or a mixture of any two or all three of said glyceryl mono-, di- and tribehenates.

Optional high reactivity carriers and excipients usually have various low molecular weight acid or ester substituents. Examples include carboxylic acids such as stearic acid, benzoic acid, citric acid, fumaric acid, lactic acid, and maleic acid; short to medium chain fatty acid esters, such as isopropyl palmitate, isopropyl myristate, triethyl citrate, lecithin, triacetin, and dibutyl sebacate; ester substituted cellulosics such as cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, and hydroxypropylmethylcellulose acetate succinate; and polymethacrylates and polyacrylates with acid or ester functions. Generally, the acid / ester concentration in highly reactive carriers and optional excipients is so high that if these optional carriers and excipients come into direct contact with the azithromycin in the formulation, azithromycin esters are formed at unacceptably high concentrations during processing or storage of the composition. Thus, such high-reactivity optional carriers and excipients only are preferably used in combination with a lower-reactivity carrier or optional excipient so that the total amount of acid and ester groups in the carrier and in the optional excipients used in the multiparticles. it is low.

To obtain multiparticles with an acceptable amount of azithromycin esters (i.e., less than about 1% by weight), there is a trade-off between the concentration of the acid and ester substituents in the vehicle and the crystallinity of azithromycin in the multiparticles. . The higher the crystallinity of azithromycin in the multiparticles, the greater the degree of acid / ester substitution in the vehicle can be to obtain multiparticles with acceptable amounts of azithromycin esters. This relationship can be quantified by the following mathematical expression:

[A] <0.04 / (1-x) (I) where [A] is the total concentration of the acid / ester substitution in the vehicle and optional excipients in meq / g of azithromycin and is less or equal to 2 meq / g and x is the weight fraction of the azithromycin in the composition that is crystalline. When the vehicle and optional excipients comprise more than one excipient, the value of [A] refers to the total concentration of the acid / ester substitution in all excipients that make up the vehicle and optional excipients, in units of meq / g of azithromycin.

For more preferable multiparticles having less than about 0.5% by weight of azithromycin esters, the azithromycin, the carrier, and the optional excipients will meet the following expression:

[A] <0.02 / (1-x) (II)

For the most preferable multiparticles having less than about 0.2% by weight of azithromycin esters, the azithromycin, the carrier, and the optional excipients will meet the following expression:

[A] <0.008 / (1-x) (III)

For the most preferred multiparticles having less than about 0.1% by weight of azithromycin esters, the azithromycin, the carrier, and the optional excipients will meet the following expression:

[A] <0.004 / (1-x) (IV)

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From the above mathematical expressions (I) - (IV) the trade-off between the degree of acid / ester substitution of the carrier and optional excipients and the crystallinity of azithromycin in the composition can be determined.

The carriers that are used in the multiparticles of the present invention will generally constitute from about 10% by weight to about 95% by weight of the multiparticles, preferably about 20% by weight to about 90% by weight, and most preferably from about 40%. by weight to about 70% by weight, based on the total mass of the multiparticles.

To minimize the possibility of changes in the physical characteristics of the multiparticles as a function of time, especially when stored at elevated temperatures, it is preferred that the carrier is solid at a temperature of at least about 40 ° C. More preferably, the carrier should be solid at a temperature of at least about 50 ° C and even more preferably at least about 60 ° C.

In one embodiment, the vehicle forms a solid solution with one or more optional excipients, which means that the vehicle 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 can 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 that are used and the relative amount of carrier that is included in the composition.

In another embodiment, the vehicle and one or more optional excipients do not form a solid solution, which means that the vehicle and one or more optional excipients form two or more thermodynamically stable phases. In such cases, the carrier / excipient mixture may melt entirely at the processing temperatures that are used to form multiparticles or one material may be solid while the other (s) melt, resulting in a suspension of a material in the molten mixture.

When the vehicle and one or more optional excipients do not form a solid solution but a solid solution is desired, for example, to obtain a specific controlled release profile, an additional excipient can be included in the composition to produce a solid solution comprising the vehicle. , the optional excipient or excipients and the additional excipient. For example, it may be desirable to use a carrier comprising microcrystalline wax and a poloxamer to obtain multiparticles with the desired release profile. In such cases, a solid solution does not form, in part due to the hydrophobic nature of the microcrystalline wax and the hydrophilic nature of the poloxamer. By including a small amount of a third excipient, such as stearyl alcohol, in the formulation, a solid solution can be obtained, resulting in multiparticles with the desired release profile.

Examples of suitable carriers for use in the multiparticles of the present 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 castor oil derivatives, hydrogenated vegetable oils, a glyceryl behenate, glyceryl tristearate, glyceryl tripalmitate; long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and their mixtures.

Preferably, the carrier comprises a glyceride having at least one alkylate substituent of 16 or more carbon atoms. More preferably, the carrier comprises a glyceryl behenate.

In an alternative embodiment, the multiparticles are in the form of a matrix that does not disintegrate. By "non-disintegrating matrix" is meant that at least a portion of the carrier does not dissolve or disintegrate after introduction of the multiparticles into an aqueous environment of use. In such cases, azithromycin and optionally a portion of one or more of the carriers, eg, a dissolution enhancer, are removed from the multiparticles by dissolution. At least a portion of the vehicle does not dissolve or disintegrate and is excreted when the environment of use is in vivo, or remains suspended in a test solution when the environment of use is in vitro. In this regard, it is preferred that at least a portion of the carrier has low solubility in the aqueous environment of use. Preferably, the solubility of at least a portion of the carrier in the aqueous environment of use is less than about 1 mg / ml, more preferably less than about 0.1 mg / ml, and most preferably, less than about 0.01 mg / ml. ml. Examples of suitable low solubility vehicles 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.

In a preferred embodiment of the present invention, the azithromycin multiparticles of the present invention comprise azithromycin, a carrier, and a dissolution enhancer. The vehicle and the dissolution enhancer function as a matrix for the multiparticles or to control the release rate of azithromycin from the multiparticles or both. The term "dissolution enhancer" means an excipient that, when included in the multiparticles, results in a higher rate of azithromycin release than that provided by control multiparticles containing the same amount of azithromycin without the dissolution enhancer. . Generally, the release rate of azithromycin from multiparticles increases with increasing amount of enhancers in solution. Agents of this type generally have high solubility in water and are often surfactants or wetting agents that can promote the solubilization of other excipients in the composition.

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Typically, the weight percent dissolution enhancer present in the multiparticles is less than the weight percent vehicle present in the multiparticles.

The multiparticles of the present invention comprise from about 20 to about 75% by weight of azithromycin, from about 25 to about 80% by weight of a carrier, and from about 0.1 to about 30% by weight of a dissolution enhancer based on in the total mass of the multiparticles. In a preferred embodiment, the multiparticles comprise from 35 to 55% by weight of azithromycin, from 40 to 65% by weight of a carrier, and from 1 to 15% by weight of solution enhancer.

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 (polyoxyethylene and polyoxypropylene copolymers, including poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), docusate salts, polyoxyethylene alkyl ethers, polyoxyethylene derivatives of castor oil, esters of polyoxyethylene esters of polyethylene esters sorbitan, alkyl sulfates (such as sodium lauryl sulfate), polysorbates, and polyoxyethylene alkylesters; ether substituted cellulosics, 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 sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate; amino acids such as alanine and glycine; and their mixtures. Preferably, the dissolution enhancer comprises a surfactant.

More preferably, the dissolution enhancer comprises a poloxamer. Poloxamers are a series of closely related ethylene oxide and propylene oxide block copolymers that have no acid or ester substituents. When this is the case, large amounts of poloxamers can be used, up to 30% by weight in a multiparticulate formulation and still achieve the target value of less than about 0.13 meq / g of azithromycin. Even more preferably, the poloxamer is poloxamer 407 which is described in the examples herein.

In this embodiment, where the multiparticles further comprise a dissolution enhancer, it is further preferred that the vehicle is selected from the group consisting of waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax and beeswax. ; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono-, di- or tribehenates, glyceryl tristearate, glyceryl tripalmitate; and their mixtures.

Azithromycin present in multiparticles has been found to be particularly reactive with dissolution enhancers. As a result, the concentration of acid and ester substituents in the dissolution enhancer must be kept low to keep the formation of azithromycin esters at acceptably low levels.

From the viewpoint of reactivity to form azithromycin esters, the dissolution enhancers preferably have a concentration of acid / ester substituents of less than about 0.13 meq / g of azithromycin present in the composition. Preferably, the dissolution enhancer has an acid / ester substituent concentration of less than about 0.10 meq / g of azithromycin, more preferably less than about 0.02 meq / g of azithromycin, even more preferably less than about 0.01 meq / g and most preferably less than about 0.002 meq / g.

In addition to having low concentrations of acid and ester substituents, the dissolution enhancer should generally be hydrophilic, such that the release rate of azithromycin from the multiparticles increases with increasing concentration of the dissolution enhancer in the multiparticles.

In US Patent Application Serial No. 60 / 527,319 ("Controlled Release Multiparticulates Formed with Dissolution Enhancers" File No. PC25016), filed herewith, dissolution enhancers and a selection of suitable excipients for azithromycin multiparticles.

In a more preferred embodiment, the multiparticles of the present invention comprise (a) azithromycin; (b) a glyceride carrier having at least one alkylate substituent of 16 or more carbon atoms; and (c) a poloxamer dissolution enhancer. The choice of these particular excipients as vehicles 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 produce large changes in the rate of drug release. This allows the rate of drug release from the multiparticles to be precisely controlled by selecting the appropriate ratio of drug, glyceride carrier, and poloxamer. These materials have the additional advantage that they release virtually all of the drug from the multiparticles. Such multiparticles are described in more detail in US Patent Application No. 60 / 527,329 ("Multiparticulate Crystalline Drug Compositions Having Controlled Release Profiles", docket No. PC25020), filed herewith.

Additional optional excipients can also be included in the azithromycin multiparticles. For example, agents that inhibit or delay the release of azithromycin from multigens can also be included in the vehicle.

ES 2 312 929 T3 particles. Dissolution inhibitors of this type are generally hydrophobic. Examples of dissolution inhibiting agents include hydrocarbon waxes, such as microcrystalline wax and paraffin wax.

Another useful class of excipients are materials that are used to adjust the viscosity of the molten mixture used to form the multiparticles, for example, by a melt-coagulation process. Such viscosity adjusting excipients will generally constitute 0 to 25% by weight of the multiparticles, based on the total mass of multiparticles. The viscosity of the molten mixture is a key variable in obtaining multiparticles with a narrow particle size distribution. For example, when using a rotating disk atomizer, it is preferred that the viscosity of the molten mixture is at least about 1 centipoise (cp) (1 mPa-s) and less than about 10,000 cp (10,000 mPa-s), more preferably at least 50 cp (50 mPa-s) and less than about 1000 cp (1000 mPa-s). If the melt mix has a viscosity outside of these preferred ranges, a viscosity adjusting vehicle can be added to obtain a melt mix in the preferred viscosity range. Examples of excipients that reduce viscosity include stearyl alcohol, cetyl alcohol, low molecular weight (eg, below about 1000 dalton) polyethylene glycol, isopropyl alcohol, and water. Examples of excipients that increase viscosity include microcrystalline wax, paraffin wax, synthetic wax, high molecular weight polyethylene glycols (eg, greater than about 5000 daltons), ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, silicon dioxide, microcrystalline cellultoose, magnesium, sugars and salts.

Other excipients can be added to reduce the static charge of the multiparticles; examples of such antistatic agents include talc and silicon dioxide. Flavorings, colorants and other excipients can also be added in their usual amounts for their usual purposes.

In addition to multiparticles and an alkalizing agent, the azithromycin dosage form of the present invention may further comprise one or more additional excipients.

For example, surfactants can be included in the dosage form. Examples of suitable surfactants include fatty acids and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (HYAMINE^®1622, available from Lonza, Inc., Fairlawn, NJ); dioctyl sodium sulfosuccinate (DOCUSATE SODIUM ™, available from Mallinckrodt Specialty Chemicals, St. Louis, Missouri); fatty acid esters of polyoxyethylene sorbitan (TWEEN^®, available from ICI Americas Inc., Wilmington, Delaware; LIPOSORB^® P-20, available from Lipochem Inc., Patterson, NJ; CAPMUL^® POE-0, available from Abitec Corp., Janesville, Wisconsin); and natural surfactants, such as sodium taurocholic acid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin and other phospholipids and mono- and diglycerides. Such materials can be used to advantage to increase the rate at which multiparticles disperse when delivered to 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 glycollate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, croscarmellose sodium, and cross-linked forms of polyvinylpyrrolidone, also known as crospovidone.

Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth.

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

Examples of preservatives include sulfites (an antioxidant), benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcohol, and sodium benzoate.

Examples of suspending or thickening agents include xanthan gum, starch, guar gum, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, 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, including excipients well known in the art, may be employed in the compositions of this invention. Generally, excipients such as pigments, lubricants, flavors and the like can be used for customary purposes and in typical amounts 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 include compression formed tablets, coated tablets, and other shapes that are known in the art. See for example, Remington's Pharmaceutical Sciences (Issue 18^to, 1990). When administered to the environment of use, the tablet rapidly disintegrates, allowing the multiparticulates to disperse in the environment of use.

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In one embodiment, the tablet comprises multiparticles that have been mixed with a binder, disintegrators, or other excipients that are known in the art and then shaped into a tablet using compression forces. Examples of binders include microcrystalline cellulose, starch, gelatin, polyvinylpyrrolidone, polyethylene glycol, and sugars such as sucrose, glucose, dextrose, and lactose. Examples of disintegrators include sodium starch glycollate, croscarmellose sodium, crospovidone, and sodium carboxymethyl cellulose. The tablet may also include an effervescent agent (acid-base combinations) that generates carbon dioxide when introduced into the environment of use. The carbon dioxide that is generated helps the disintegration of the tablet. Other excipients, such as those described above, may also be included in the tablet.

The multiparticles, binder and other excipients that are used in the tablet can be granulated prior to forming the tablet. Wet or dry granulation processes, well known in the art, can be used, provided that the granulation process does not change the release profile of the multiparticles. Alternatively, the materials can be compressed into a tablet by direct compression.

The compressive forces used to shape the tablet should be high enough to provide a high strength tablet, but not so high as to damage the multiparticles contained in the tablet. Generally, compression forces that provide tablets with a hardness of from about 3 to about 10 kp are desirable.

Alternatively, tablets, such as multilayer and osmotic coated tablets, may also be prepared using non-compression methods. In one embodiment, the tablet is formed by a lyophilization process. In this procedure, the multiparticles are mixed with an aqueous solution or paste of water-soluble excipients and placed in a mold. The water is then removed by lyophilization, resulting in a highly porous, rapidly dissolving tablet containing the multiparticles. Examples of water soluble excipients that are used in such tablets include gelatin, dextran, dextrin, polyvinylpyrrolidone, polyvinyl alcohol, trehalose, xylitol, sorbitol, and mannitol.

In another embodiment, the dosage form is in the form of a capsule, well known in the art. See Remington's Pharmaceutical Sciences (Edition 18^to, 1990). The term "capsule" is intended to include solid dosage forms in which the multiparticles and optional excipients are included in a hard or soft soluble capsule or container. When administered to the environment of use, the capsule dissolves or disintegrates, releasing the contents of the capsule to the environment of use. The hard gelatin capsule, typically formed from gelatin, consists of two sections, which slide over each other. Capsules are prepared by first mixing the multiparticles and optional excipients, such as those mentioned above. The ingredients can be granulated using wet or dry granulation techniques to improve the flow of the filler material. Capsules are filled by inserting the filling material into the longer end or body of the capsule and then sliding the cover over it. For soft gelatin capsules, the filler can first be suspended in an oil or liquid prior to filling the capsule.

The dosage form can also be in the form of pills. The term "pill" is intended to include small, round solid dosage forms comprising the multiparticles mixed with a binder and other excipients as described above. When administered to the environment of use, the pill disintegrates rapidly, allowing the multiparticles to disperse therein.

In another embodiment, the multiparticulate dosage form is in the form of a powder or granules comprising the multiparticles and other excipients as described above, which are then suspended in a liquid delivery vehicle, including an aqueous delivery vehicle, prior to of the administration. Such dosage forms can be prepared by various procedures. In one method, the powder is placed in a container and an amount of a liquid, such as water, is added to the container. The container is then mixed, stirred, or shaken to suspend the dosage form in the water. In another method, the multiparticles and excipients of the delivery vehicle are provided in two or more different packages. The excipients of the delivery vehicle are first dissolved or suspended in a liquid such as water and then the multiparticles are added to the liquid vehicle solution. Alternatively, the delivery vehicle excipients and multiparticles, in two or more individual packages, can be added to the container first, water added to the container, and the container mixed or stirred to form a suspension.

Water is an example of a liquid that can be used to form the dosage form of the invention. Other liquids can also be used and are intended to be within the scope of the invention. Examples of suitable liquids include beverages, such as coffee, tea, milk, and various juices. Water in admixture with other excipients is also included to help form the dosage form, including surfactants, thickeners, suspending agents, and the like.

The multiparticulate dosage form may also be in the form of an administration straw or other similar device that allows the patient to sip water or other liquid through the device, the device being designed to mix the liquid with the powdered pharmaceutical dosage form. or granulated that is contained in the device.

The multiparticulate dosage form can also be in the form of a paste, thick solution, or suspension.

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In one embodiment, the multiparticulate dosage form comprises multiparticulates of azithromycin, an alkalizing agent, and one or more optional excipients selected from a sweetener, an anti-caking agent, a viscosity-enhancing agent, and a flavoring agent. Preferably, the multiparticulate dosage form further comprises a sweetener, an anti-caking agent, a viscosity-enhancing agent, and a flavoring agent.

In an even more preferred embodiment of the present invention, the azithromycin multiparticles are administered with the alkalizing agent TSP. The amount of TSP is preferably at least about 200 mg. More preferably the amount of TSP ranges from about 300 mg to about 400 mg. In another embodiment of the present invention, TSP and magnesium hydroxide are used as the alkalizing agent. The amount of magnesium hydroxide that is used is at least about 100 mg and preferably about 200 mg to about 300 mg.

In yet another preferred embodiment, the azithromycin dosage form comprises multiparticles of azithromycin, comprising from about 45 to about 55% by weight of azithromycin, from about 43 to about 50% by weight of glyceryl behenate and from about 2 to about 5% by weight of poloxamer and an alkalinizing agent comprising from about 300 to about 400 mg of TSP and from about 200 to about 300 mg of hydroxide magnesium.

In a still more preferred embodiment, the azithromycin dosage form comprises multiparticles of azithromycin, comprising about 50% by weight of azithromycin dihydrate, about 46 to about 48% by weight Compritol® 888 ATO and about 2 to about 4% by weight Poloxamer 407 and an alkalizing agent comprising from about 300 to about 400 mg of TSP and from about 200 to about 300 mg of magnesium hydroxide. More preferably, said dosage form comprises between about 47% by weight Compritol^® 888 ATO and approximately 3% by weight of poloxamer 407. Compritol^® 888 ATO and poloxamer 407 are further described in the Examples below.

The multiparticles of the present invention can be prepared by any known method that provides particles, containing azithromycin and a carrier, with the size and release rate characteristics desired for azithromycin. Preferred processes for forming such multiparticles include thermally based processes, such as melt- and spray-coagulation; 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.

Multiparticles generally have a mean diameter of less than about 5000 pm, preferably less than 3000 pm, and most preferably less than about 1000 pm. In a preferred embodiment, the mean diameter of the multiparticles ranges from about 40 to about 3000 pm, preferably from about 50 to about 1000 pm, and most preferably from about 100 to about 300 pm. Note that the diameter of the multiparticles can be used to adjust the release rate of azithromycin from the multiparticles. Generally, the smaller the diameter of the multiparticles, the faster the release rate of azithromycin from a particular multiparticle formulation. This is because the total surface in contact with the dissolution medium increases as the size of the multiparticles decreases. Thus, adjustments to the mean diameter of the multiparticles can be used to adjust the azithromycin release profile.

Multiparticles can be prepared by a melt-coagulation process comprising the steps of (a) forming a molten mixture comprising azithromycin and a pharmaceutically acceptable carrier; (b) administering the molten mixture from step (a) to an atomization medium to form droplets of the molten mixture; and (c) coagulating the droplets of step (b) to form multiparticles.

When thermal-based processes, such as the melt-coagulation process, are used to prepare the multiparticles of the present invention, heat transfer to azithromycin is minimized to avoid significant thermal degradation of azithromycin during the process. It is also preferred that the carrier has a melting point that is lower than the melting point of azithromycin. For example, azithromycin dihydrate has a melting point of 113 ° C to 115 ° C. Thus, when azithromycin dihydrate is used in the multiparticles of the present invention, it is preferred that the carrier has a melting point that is less than about 113 ° C. As used herein, the term "vehicle melting point" or "T_m"Refers to the temperature at which the vehicle, when it contains the drug and any optional excipients present in the multiparticles, transitions from its crystalline state to its liquid state. When the vehicle is not crystalline, "vehicle melting point" refers to the temperature at which the vehicle becomes fluid in the sense that it will flow when subjected to one or more forces such as pressure, shear, and centrifugal force. shape similar to that of a crystalline material in liquid state.

The azithromycin in the molten mixture can be dissolved in the molten mixture, it can be a suspension of crystalline azithromycin distributed in the molten mixture, or any combination of such states or the states in between. Preferably, the molten mixture comprises a homogeneous suspension of crystalline azithromycin in the molten vehicle in which the fraction of azithromycin that melts or dissolves in the molten vehicle

ES 2 312 929 T3 remains relatively low. Preferably, less than about 30% by weight of the total azithromycin melts or dissolves in the molten carrier. It is preferred that azithromycin is present as the crystalline dihydrate.

Thus, "molten mixture" refers to the mixture of azithromycin and vehicle being heated sufficiently for the mixture to become fluid enough that the mixture can be droplet or atomized. The atomization of the molten mixture can be carried out using any of the atomization procedures described below. Generally, the mixture melts in the sense that it will flow when subjected to one or more forces such as pressure, shear, and centrifugal force, such as exerted by a spinning disc or centrifugal atomizer. Therefore, the azithromycin / vehicle mixture can be considered "molten" when any portion of the vehicle and azithromycin are rendered fluid such that the mixture as a whole is fluid enough that it can be atomized. In general, a mixture is fluid enough to atomize when the viscosity of the molten mixture is less than about 20,000 mPa-s, preferably less than about 15,000 mPa-s, more preferably less than about 10,000 mPa-s. Often the mixture melts when the mixture is heated above the melting point of one or more of the vehicle components, in cases where the vehicle is crystalline enough to have a relatively sharp melting point; or, when the vehicle components are amorphous, above the softening point of one or more of the vehicle components. Thus, the molten mixture is often a suspension of solid particles in a fluid matrix. In a preferred embodiment, the molten mixture comprises a mixture of substantially crystalline azithromycin particles suspended in a carrier that is substantially fluid. In such cases, a portion of the azithromycin may dissolve in the fluid carrier and a portion of the carrier may remain solid.

Although the term "melt" refers specifically to the transition of a crystalline material from its crystalline state to its liquid state, which occurs at its melting point, and the term "molten" refers to such a crystalline material in its liquid state, as used herein, the terms are used in a broader sense, referring in the case of "melting" to the heating of any material or mixture of materials sufficiently so that it becomes fluid in the sense that it can be pumped or atomized similarly to a crystalline material in a liquid state. Similarly "molten" refers to any material or mixture of materials that is in such a fluid state.

Virtually any procedure can be used to form the molten mixture. One procedure involves melting the vehicle in a tank, adding the azithromycin to the molten vehicle, and then mixing the mixture to ensure that the azithromycin is evenly distributed throughout. Alternatively, both the azithromycin and the carrier can be added to the reservoir and the mixture heated and mixed to form the molten mixture. When the carrier comprises more than one material, the molten mixture can be prepared using two tanks, melting a first carrier in one tank and a second in another. Azithromycin is added to one of these reservoirs and mixed as described above. In another procedure, a continuously stirred tank system can be used, in which the azithromycin and vehicle are added continuously to a heated tank equipped with means for continued mixing, while the molten mixture is continuously withdrawn from the tank.

The molten mixture can also be formed using a continuous mill, such as a Dyno® mill. Azithromycin and vehicle are typically fed to the continuous mill in solid form, entering a milling chamber containing media for milling, such as beads 0.25 to 5mm in diameter. The grinding chamber is typically covered with a jacket so that heating or cooling fluid can be circulated around the chamber to control its temperature. The molten mixture is formed in the grinding chamber and exits the chamber through a separator to remove the grinding media.

An especially preferred method of forming the molten mixture is by means of an extruder. "Extruder" refers to a device or set of devices that creates a molten extrudate by heat and / or shear forces and / or produces a uniformly mixed extrudate from a solid and / or liquid mixture (eg molten) . Devices of that type include, but are not limited to, single screw extruders; twin screw extruders, including co-rotating, counter-rotating, criss-cross, and non-criss-cross extruders; multi-screw extruders; piston extruders, consisting of a heated cylinder and a piston to extrude the molten mixture; gear pump extruders, consisting of a heated gear pump, generally counter-rotating, that simultaneously heats and pumps the molten mixture; and conveyor extruders. Conveyor extruders comprise a conveyor means for conveying solid and / or powder mixtures, such as a screw conveyor or pneumatic conveyor and a pump. At least a part of the carrier medium is heated to a temperature high enough to produce the molten mixture. The molten mixture can optionally be directed to an accumulation tank, before being directed to a pump, which directs the molten mixture to an atomizer. Optionally, an in-line mixer can be used before or after the pump to ensure that the molten mixture is substantially homogeneous. In each of these extruders the molten mixture is mixed to form a uniformly mixed extrudate. Such mixing can be accomplished by a variety of mechanical and processing means, including mixing elements, kneading elements, and countercurrent shear mixing. Therefore, in such devices, the composition is fed into the extruder, which produces a molten mixture that can be directed to the atomizer.

Once the molten mixture has formed, it is taken to an atomizer that breaks up the molten mixture into small drops. Virtually any method can be used to bring the molten mixture to the atomizer, including the use of pumps and various types of pneumatic devices such as pressurized vessels or piston cups.

ES 2 312 929 T3

When an extruder is used to form the molten mixture, the extruder itself can be used to bring the molten mixture to the atomizer. Typically, the molten mixture is kept at an elevated temperature while the mixture is brought into the atomizer to prevent solidification of the mixture and to keep the molten mixture fluid.

Generally, atomization occurs in one of several ways, including (1) by "pressure" or single fluid nozzles; (2) by means of two-fluid nozzles; (3) by centrifugal or rotating disk atomizers; (4) by ultrasonic nozzles; and (5) by mechanical vibrating nozzles. Detailed descriptions of atomization procedures, including the use of spinning disc atomizers to obtain specific particle sizes, can be found in Lefebvre, Atomization and Sprays (1989) or in Perry's Chemical Engineers' Handbook (7^to Ed. 1997).

After the molten mixture has been atomized, the droplets are coagulated, typically by contacting them with a gas or liquid at a temperature below the solidification temperature of the droplets. Typically, it is desirable that the droplets coagulate in less than about 60 seconds, preferably in less than about 10 seconds, more preferably in less than about 1 second. Often coagulation at room temperature causes the droplets to solidify fast enough to avoid excessive azithromycin ester formation. However, the coagulation step is often performed in a closed space to simplify the collection of the multiparticles. In such cases, the temperature of the coagulation medium (either gas or liquid) will increase over time as the droplets are introduced into the closed space, causing the possible formation of azithromycin esters. Thus, a refrigerant gas or liquid is often circulated through the enclosed space to maintain a constant coagulation temperature. When the vehicle being used is highly reactive with azithromycin and the time that azithromycin is exposed to the molten vehicle must be limited, the refrigerant gas or liquid can be cooled below room temperature to promote rapid coagulation, thus maintaining formation. of azithromycin esters at acceptable levels.

Suitable heat-based procedures are described in detail in US Patent Application File No. PC25015, entitled "Improved Azithromycin Multiparticulate Dosage Forms by Melt-Congeal Processes" and in US Patent Application No. File No. PC25122, entitled "Extrusion Process for Forming Chemically Stable Multiparticulates," filed together with this document.

Multiparticles can also be prepared by a liquid-based process comprising the steps of (a) forming a mixture comprising azithromycin, a pharmaceutically acceptable carrier, and a liquid; (b) forming particles from the mixture of step (a); and (c) removing a substantial portion of the liquid from the particles of step (b) to form multiparticles. Preferably, step (b) is a process that is selected from (i) atomization of the mixture, (ii) coating of germ nuclei with the mixture, (iii) wet granulation of the mixture and (iv) extrusion of the mixture into a solid mass followed by spheronization or milling of the mass.

Preferably, the liquid has a boiling point of less than about 150 ° C. Examples of suitable liquids for multiparticle formation using liquid-based 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 oil; ethers, such as methyl tert-butyl ether, ethyl ether, and ethylene glycol monoethyl ether; chlorocarbons, such as chloroform, methylene dichloride, and ethylene dichloride; tetrahydrofuran; dimethylsulfoxide; N-methylpyrrolidinone; N, N-dimethylacetamide; acetonitrile; and their mixtures.

In one embodiment, the particles are formed by atomizing the mixture using an appropriate nozzle to form small droplets of the mixture, which are sprayed into a drying chamber in which there is a powerful force driving the evaporation of the liquid, to produce particles. generally spherical solid. The powerful force driving the evaporation of the liquid is generally provided by maintaining the partial pressure of the liquid well below the vapor pressure of the liquid at the temperature of the particles in the drying chamber. This is accomplished by (1) maintaining the drying chamber pressure under partial vacuum (eg, 0.01 (1.01 KPa) to 0.5 atm (50.66 KPa)); or (2) mixing the droplets with a hot drying gas; or (3) both (1) and (2). Spray-drying procedures and spray-drying equipment are generally described in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (6th Ed. 1984).

In another embodiment, the particles are formed by coating the liquid mixture on the germ nuclei. The germ cores can be prepared from any suitable material such as starch, microcrystalline cellulose, sugar or wax and by any known process, such as melt- or spray-coagulation, extrusion / spheronization, granulation, spray-drying and the like.

The liquid mixture can be sprayed onto such germ cores using coating equipment that is known in the pharmaceutical art, such as pan coaters (e.g. Hi-Coater available from Freund Corp. of Tokyo, Japan, Accela-Cota available from Manesty of Liverpool, UK), fluid bed coaters (e.g. Würster coaters or top spray coaters, available from Glatt Air Technologies, Inc. from Ramsey, NJ and from Niro Pharma Systems of Bubendorf, Switzerland) and rotary granulators (eg CF-Granulator, available from Freund Corp).

ES 2 312 929 T3

In another embodiment, the liquid mixture can be wet granulated to form the particles. Granulation is a process whereby relatively small particles are developed to provide larger granular particles, often with the aid of a carrier, which is also known as a binder in the pharmaceutical art. In wet granulation, a liquid is used to increase the intermolecular forces between the particles, which results in an enhancement of granular integrity, which is called "strength" of the granule. Often the strength of the granule is determined by the amount of liquid that is present in the interstitial spaces between the particles during the granulation process. When this is the case, it is important that the liquid dampens the particles, ideally with a contact angle of zero. Since a high percentage of the particles being granulated are highly hydrophilic azithromycin crystals, the liquid has to be quite hydrophilic to meet this criterion. Thus, liquids effective for wet granulation tend to be hydrophilic as well. Examples of liquids that have been found to be effective liquids for wet granulation include water, ethanol, isopropyl alcohol, and acetone. Preferably, the wet granulate liquid is water at pH 7 or higher.

Various types of wet granulation processes can be used to form azithromycin-containing multiparticles. Examples include fluid bed granulation, rotary granulation, and high shear mixers. In fluid bed granulation air is used to agitate or "fluidize" the azithromycin particles and / or carrier in a fluidization chamber. The liquid is then sprayed into this fluid bed, forming granules. In rotary granulation, the horizontal discs rotate at high speed, forming a rotating "string" of azithromycin and / or carrier particles on the walls of the granulate container. The liquid is sprayed into this string, forming the granules. High shear mixers contain an agitator or impeller to mix the azithromycin particles and / or carrier. The liquid is sprayed onto the bed of moving particles, forming granules. In these procedures, all or part of the carrier can be dissolved in the liquid before spraying the liquid onto the particles. Thus, in these processes, the steps of formation of the liquid mixture and the formation of particles from the liquid mixture occur simultaneously.

In another embodiment, the particles are formed by extruding the liquid mixture into a solid mass followed by spheronization or milling of the mass. In this process, the liquid mixture, which is in the form of a paste-like 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 ground to form the multiparticles. In one embodiment, the solid mass is placed, with or without a drying step in between, on a rotating disk having protrusions that break the material down into multiparticulate rounded spheres, spheroids or rods. The multiparticles thus formed are then dried to remove any residual liquid. This process is sometimes referred to as an extrusion / spheronization process in the pharmaceutical arts.

Once the particles have been formed, a part of the liquid is removed, typically in a drying step, thus forming the multiparticles. Preferably, at least 80% of the liquid is removed from the particles, more preferably at least 90% and most preferably at least 95% of the liquid is removed from the particle during the drying step.

Suitable liquid-based procedures are more fully described in US Patent Application Serial No. 60 / 527,405, File No. PC25018, which is entitled "Improved Azithromycin Multiparticulate Dosage Forms by Liquid-Based Processes," filed in conjunction with the present.

Multiparticles can also be prepared by a granulation process comprising the steps of (a) forming a solid mixture comprising azithromycin and a pharmaceutically acceptable carrier; and (b) granulating the solid mixture to form multiparticles. Examples of such granulation processes include dry granulation and melt granulation, both well known in the art. See Remington's Pharmaceutical Sciences (Edition 18^to, 1990).

An example of a dry granulation process is roller compaction. In roll compaction procedures, the solid mixture is compressed between rolls. The rollers can be designed such that the resulting compressed material is in the form of small beads or granules of the desired diameter. Alternatively, the compressed material is in the form of a ribbon that can be milled into multiparticles using procedures well known in the art. See, for example, Remington's Pharmaceutical Sciences (18th Edition, 1990).

In melt granulation processes, the solid mixture is fed to a granulator that has the ability to heat or melt the vehicle. Suitable equipment for use in this process includes high shear granulators and single or multiple screw extruders, such as those described above for melt-coagulation processes. In melt granulation processes, the solid mixture is placed in the granulator and heated until the solid mixture forms an agglomerate. The solid mixture is then kneaded or mixed until the desired particle size is obtained. The granules thus formed are then cooled, removed from the granulator and sieved to the desired size fraction, thus forming the multiparticles.

Although the azithromycin in the multiparticles may be amorphous or crystalline, it is preferred that a substantial portion of the azithromycin is crystalline, preferably the crystalline dihydrate. "Substantial portion" means that at least 80% of the azithromycin is crystalline. The crystalline form is preferred because it tends to produce multiparticles with

ES 2 312 929 T3 improved chemical and physical stability. The crystallinity of azithromycin in the multiparticles is determined using X-ray powder diffraction analysis (PXRD). In an example procedure, PXRD analysis can be performed on a Bruker AXS D8 Advance diffractometer. In this analysis, approximately 500 mg samples are loaded into Lucite sample cuvettes and the sample surface is matched using a microscope glass slide to provide a consistently matched sample surface that is level with the top of the sample cuvette. The samples are centrifuged in the φ plane at a speed of 30 rpm to minimize the effects of orientation of the crystals. The X-ray source (S / B KCu_to, λ = 1.54 A) is operated with a voltage of 45 kV and with a current of 40 mA. Data for each sample is collected over a period of about 20 to about 60 minutes in continuous detection scan mode and at a scan speed of about 12 seconds / increment and 0.02 ° increment / increment. The diffractograms are collected in the range of 2Θ from 10 ° to 16 °.

The crystallinity of the test sample is determined by comparing with calibration standards as follows. Calibration standards consist of physical mixtures of 20% by weight / 80% by weight of azithromycin / vehicle and 80% by weight / 20% by weight of azithromycin / vehicle. Each physical mix is ​​mixed together for 15 minutes in a Turbula mixer. Using the program of the apparatus, the area under the curve of the diffractogram in the range of 2Θ from 10 ° to 16 ° is integrated using a linear baseline. This integration range includes as many drug-specific peaks as possible excluding vehicle-related peaks. Furthermore, the large specific azithromycin peak is omitted at approximately 2Θ of 10 ° due to the large scan-to-scan variability in this integrated area. A linear calibration curve of the percentage of crystalline azithromycin versus the area under the diffractogram curve is generated from the calibration standards. The crystallinity of the test sample is then determined using these calibration results and the area under the curve for the test sample. Results are expressed as a mean percentage of azithromycin crystallinity (by crystal mass).

A key to maintaining the crystalline form of azithromycin during multiparticulate formation by thermal-based and liquid-based processes is to maintain high activity of the water and any solvate solvents in the vehicle, atmosphere, or gas with which the composition comes in contact. The activity of the water or solvent should be equivalent to or greater than that of 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 a loss of water from the hydrate or solvent from the solvate. For example, if the process for the formation of the multiparticles requires that crystalline azithromycin, the crystalline dihydrate for example, be exposed to elevated temperatures (for example, during a melt- or spray-coagulation process), High humidity should be maintained in the atmosphere surrounding azithromycin to limit loss of hydrate water from azithromycin crystals and thereby a change in the crystalline form of azithromycin.

The level of humidity required is equal to or greater than the activity of water in the crystalline state. This can be determined experimentally, for example, using a dynamic vapor absorption apparatus. In this experiment, a sample of crystalline azithromycin is placed in a chamber and equilibrated at a constant temperature and relative humidity. The weight of the sample is then recorded. The weight of the sample is then controlled while the relative humidity of the atmosphere in the chamber decreases. When the relative humidity in the chamber falls below the level equivalent to the activity of water in the crystalline state, the sample will begin to lose weight as it loses water of hydration. Thus, to maintain the crystalline state of azithromycin, the humidity level should be maintained at or above the relative humidity at which azithromycin begins to lose weight. A similar experiment can be used to determine the appropriate amount of solvent vapor needed to maintain a crystalline solvate form of azithromycin.

When crystalline azithromycin, such as the dihydrate form, is added to a molten vehicle, a small amount of water, on the order of 30 to 100% by weight of the solubility of water in the molten vehicle at processing temperature, can be added to the vehicle. , to ensure that there is sufficient water to prevent loss of the crystalline form of azithromycin dihydrate.

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

Procedures for maintaining the crystalline form of azithromycin while multiparticulates are formed are described in more detail in US Patent Application Serial No. 60 / 527,316 ("Method for Making Pharmaceutical Multiparticulates", File No. PC25021), filed along with the present.

The multiparticles of the present invention can be post-treated to improve drug crystallinity and / or the stability of the multiparticles. In one embodiment, the multiparticles comprise azithromycin and a carrier, wherein the carrier, when in the multiparticles and contains the azithromycin and optional excipients, has a melting point of T_m in ° C; The multiparticles are treated after formation with at least one of (i) heating the multiparticles to a temperature of at least 35 ° C but lower than (T_m ° C -10 ° C) and (ii)

ES 2 312 929 T3 exposing multiparticles to a mobility enhancing agent. Such a post-treatment step results in an increase in the crystallinity of the drug in the multiparticles and typically an improvement of at least one in chemical stability, physical stability and dissolution stability of the multiparticles. Post-treatment procedures are more fully described in co-filed United States Patent Application Serial No. 60 / 527,245 ("Multiparticulate Compositions with Improved Stability", File No. PC11900).

Preferably, when the azithromycin dosage form comprises multiparticles of azithromycin, comprising from about 45 to about 55% by weight of azithromycin, from about 43 to about 50% by weight of glyceryl behenate, and from about 2 to about 5% by weight of weight of poloxamer and an alkalizing agent comprising from about 300 to about 400 mg of TSP, Azithromycin multiparticles are post-treated by maintaining them at a temperature of approximately 40 ° C and a relative humidity of approximately 75%, or they are sealed with water in a container that is kept at 40 ° C, for 2 days or more. It is more preferred that this dosage form further comprise about 200 to about 300 mg of magnesium hydroxide.

More preferably, when the azithromycin dosage form comprises azithromycin multiparticles, comprising about 50% by weight of azithromycin dihydrate, about 46 to about 48% by weight of Compritol® 888 ATO, and from about 2 to about 4% by weight Lutrol® F127 NF; and an alkalizing agent comprising from about 300 to about 400 mg of TSP, the azithromycin multiparticles are post-treated by holding them at a temperature of about 40 ° C at a relative humidity of about 75%, or they are sealed with water in a container that is kept at 40 ° C, from approximately 5 days to approximately 3 weeks. It is more preferred that this dosage form further comprise about 200 to about 300 mg of magnesium hydroxide.

More preferably, when the azithromycin dosage form comprises azithromycin multiparticles, comprising about 50% by weight of azithromycin dihydrate, about 47% by weight of Compritol® 888 ATO, and about 3% by weight of Lutrol® F127 NF, the multiparticulates of azithromycin are subjected to post-treatment keeping them at a temperature of about 40 ° C at a relative humidity of about 75%, or they are sealed with water in a container that is kept at 40 ° C, for approximately 10 days or more.

Preferably, the concentration of azithromycin esters in the multiparticles is less than about 1% by weight, based on the total amount of azithromycin present in the multiparticles, more preferably less than about 0.5% by weight, more preferably less than about 0 2% by weight, and most preferably less than about 0.1% by weight.

Azithromycin esters can be formed during the multiparticulate formation process, during other processing steps that are required for the manufacture of the finished dosage form, or during storage after manufacture but prior to administration. Because azithromycin dosage forms can be stored for up to two years or even longer prior to administration, it is preferred that the amount of azithromycin esters in the stored dosage form not exceed the above values ​​prior to administration.

Procedures for reducing ester formation are described in more detail in commonly assigned U.S. Patent Applications Serial No. 60 / 527,244 ("Improved Azithromycin Multiparticulate Dosage Forms by Melt-Congeal Processes", File No. PC25015); 60 / 527.319 ("Controlled Release Multiparticulates Formed with Dissolution Enhancers" File No. PC25016) and 60 / 527.405, ("Improved Azithromycin Multiparticulate Dosage Forms by Liquid-Based Processes", File No. PC25018) filed together with this document.

The term "effective amount of azithromycin" refers to the amount of azithromycin which, when administered, in accordance with the present invention, prevents the onset of, or alleviates symptoms, or stops the progress, or eliminates a bacterial or protozoal infection in a mammal.

In a preferred embodiment, the dosage forms of the present invention are used to treat bacterial or protozoal infection (s). When it comes to bacterial or protozoal infections, the term "treat" means to treat or prevent bacterial or protozoal infection (s), which includes curing, reducing symptoms, or slowing the progress of such infection (s). ) infection (s).

As used herein, unless otherwise indicated, the term "bacterial or protozoal infection (s)" includes bacterial infections and protozoal infections that occur in mammals, as well as related disorders. with bacterial infections and protozoal infections that can be treated or prevented by administering antibiotics such as the compound of the present invention. Bacterial infections and protozoal infections cited and disorders related to such infections include, but are not limited to, the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp .; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Streptococcal Groups C and G, Clostridium diptheriae, or Actinobacillus haemolyticum; rela respiratory tract infections

ES 2 312 929 T3 infected with infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses, and osteomyelitis and puerperal fever related to infection with Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal Groups CF (microscopic colony streptococci), Viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp .; urethritis and cervical infection; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neisseria gonorroeae; toxin diseases related to S. aureus (food poisoning and toxic shock syndrome), or Group A, B, and C streptococci; ulcers related to Helicobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp .; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp .; odontogenic infection related to infection by Viridans streptococci; persistent cough related to Bordetella pertussis infection; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp .; and atherosclerosis related to Helicobacter pylori or Chlamydia pneumoniae infection. Bacterial infections and protozoal infections and such infection-related disorders that can be treated or prevented in animals include, but are not limited to, the following: bovine respiratory disease related to infection with P. haem., P multocida, Mycoplasma bovis, or Bordetella spp .; enteric cow disease related to infection by E. coli or protozoa (ie, coccidia, cryptosporidia, etc.); Dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp .; Pig respiratory disease related to infection by A. pleuro, P. multocida, or Mycoplasma spp .; pig enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; Glossopeda of the cow related to infection by Fusobacterium spp .; metritis of the cow related to infection by E. coli; hairy warts of the cow related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow's pink eye related to Moraxella bovis infection; premature abortion of the cow related to protozoal infection (ie, neosporium); urinary tract infections in dogs and cats related to E. coli infection; Skin and soft tissue infections in dogs and cats related to Staph infection. epidermidis, Staph. intermedius, Staph. negative for coagulase or P. multocida; and dental or oral infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other conditions that can be treated by the compounds and preparations of the present invention include malaria and atherosclerosis. Other bacterial infections and protozoal infections and such infection-related disorders that can be treated or prevented according to the method and compositions of the present invention are mentioned in JP Sandford et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition , (Antimicrobial Therapy, Inc., 1996).

The amount of azithromycin to be administered will necessarily vary in accordance with principles well known in the art, taking into account such factors as the severity of the disease or condition being treated and the size and age of the patient. In general, the drug should be administered so that an effective dose is received, the effective dose being determined from known safe and effective administration ranges for azithromycin.

For adult humans and for pediatric humans weighing more than 30 kg, the amount of azithromycin that is administered in one dose typically ranges from about 250 mgA to about 7 gA. Preferably, for adult humans and for pediatric humans over 30 kg in weight, the dosage form contains from about 1.5 to about 4 gA, more preferably from about 1.5 to about 3 gA and most preferably about 1.8 to about 2.2 gA. For pediatric humans weighing 30 kg or less, the dose of azithromycin is proportionally adjusted according to the weight of the patient and contains from about 30 to about 90 mgA / kg of the patient's body weight, preferably from about 45 to about 75 mgA / kg and more preferably about 60 mgA / kg.

The present invention is particularly useful for administering relatively large amounts of azithromycin to a patient, with reduced GI side effects, with a single dose therapy in which the total dose administered in therapy comprises from about 1.5 gA to about 4, 0 gA azithromycin. Even more preferably, this single dose comprises from about 1.5 gA to about 3.0 gA of azithromycin and most preferably 1.8 to 2.2 gA of azithromycin.

For animal / veterinary applications, the amount can of course be adjusted outside of these limits depending for example on the size of the animal subject being treated.

In the use of the present invention, azithromycin can be administered using single dose therapy or multiple dose therapy (eg, administering more than one dose in a single day or administering one or more doses over the course of 2-5 days or more). A daily dose can be administered 1 to 4 times a day in equal doses. Preferably, a daily dose of azithromycin is administered.

ES 2 312 929 T3

Most preferably, in the use of the present invention, azithromycin is administered using a single dose therapy on a single day.

"Single dose" as used herein, means administering only one dose of azithromycin over the entire course of therapy.

Examples

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 experiments have been used:

Specifying an amount in percent (%) means percent by weight based on total weight, unless otherwise indicated.

Lutrol® F127 NF (hereinafter referred to as “Lutrol®”) and Pluronic® F127 (hereinafter referred to as “Pluronic^®") Which are also known as poloxamer 407 NF, are block copolymers of polyoxypropylenepolyoxyethylene that have a molecular weight, calculated on the OH value of 9,840 to 14,600 g / mol and that have a general structure of

<img file="ES2312929T3_D0001.tif" />

wherein a is about 101 and b is about 56, which is obtained from BASF Corporation, Mount Olive, NJ. Lutrol^® is the pharmaceutical equivalent of Pluronic^®.

Compritol^® 888 ATO (hereinafter referred to as “Compritol^®”), Which is composed of a mixture of glyceryl mono-, di- and tribehenates, the diester fraction being predominant, is synthesized by esterification of glycerol by behenic acid (C22 fatty acids) and then atomized by spraying-cooling , was obtained from GATTEFOSSÉ Corporation, Saint Priest, Cedex, France.

"GA" is an abbreviation for "grams of active azithromycin." For example "2 gA" means 2 grams of active azithromycin.

Example 1

Effect of various alkalizing agents on stomach pH

A clinical study was conducted to monitor stomach pH (using a pH probe) after administering six different formulations containing alkalizing agents. Before conducting the clinical study, a titration study was performed with the alkalizing agent formulation to determine the change in pH that resulted from adding 0.1 N HCl (pH 1.2) to the alkalizing agent.

The formulations tested included the following alkalizing agents:

<td>Formulation 1</td><td>- 176 mg anhydrous TSP</td>

<td>Formulation 2</td><td>- 352 mg anhydrous TSP</td>

<td>Formulation 3</td><td>- 352 mg of anhydrous TSP and 500 mg of calcium carbonate</td>

<td>Formulation 4</td><td>- 352 mg of anhydrous TSP and 250 mg of magnesium hydroxide</td>

<td>Formulation 5</td><td>- 352 mg of anhydrous TSP and 500 mg of Tromethamine (TRIS)</td>

<td>Formulation 6</td><td>- 352 mg of anhydrous TSP and 1000 mg of Tromethamine (TRIS)</td>

In addition, each formulation was prepared by mixing the specified 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 titanium dioxide.

ES 2 312 929 T3

Stage a

In vitro assessment of alkalizing agents

In vitro titration curves were developed for each of the six formulations. A volume of 60 ml of water was used to make up the suspensions of each formulation and of the placebo. The in vitro titration curves were then determined for each suspension, titrating the suspension in increments of 0.2 ml to 5 ml of 0.1 N HCl where the size of the subsequent increase depended on the change in pH associated with the previous increase. Titration curves for suspensions containing magnesium hydroxide or calcium carbonate were allowed to equilibrate for approximately 5 minutes after each acid addition before reading the pH values. The results of the in vitro experiment for each of the formulations are provided in Fig. 1.

The data in Fig. 1 are used in the procedure to estimate the change in stomach pH as a function of time after ingestion of an alkalizing agent. To calculate it, one must assume the amount of acid present in the stomach and also the rate of acid production. From the bibliography (C. Lentner. Basle, CIBA-GEIGY, Units of measurement, Body Fluids, Composition of the Body, Nutrition, Geigy Scientific Tables (1981) 1: 123-133; Yamada, Tadataka (ed.), “Textbook of Gastroenterology”, Volume 1, Lippincott Williams &amp; Wilkens, 1999, pages 284-285), the fasting basal stomach acid volume is 40 ml of 0.04 M HCl, or 0.96 mEq of H + or 9.6 ml of 0.1 N HCl (0.1 mmol / ml). The basal rate of acid secretion is 3 mEq / h (or 3/60 = 0.05 mEq / min). For H +, the number of milliequivalents (mEq) equals the number of mmol. The calculation procedure further assumes that equilibrium conditions are applied (ie, good mixing) and that the stomach is not emptied of the formulation or gastric acid. Those skilled in the art of acid-base equilibria will recognize that with the assumptions described above, The theoretical estimate of the change in stomach pH as a function of time after ingestion of an alkalizing agent is mathematically identical to the estimate of the pH of the alkalizing agent formulation as a function of time after (1) adding the full basal amount of acid ( 0.96 mmol) to the formulation in time zero and (2) simultaneously adding acid at a rate of 0.05 mmol / min to the formulation in a time greater than 0. At any given time t, the volume of 0.1 N HCl, V, corresponding to these conditions is calculated as follows:

V = 0.96 mmol / (0.1 mmol / ml) + (0.05 mmol / ml) / (0.1 mmol / ml) xt (min)

[Note: 0.1 mmol / ml is the definition of 0.1 N HCl]

Therefore, t = (V - 9.6) / 0.5

Where t is the time in minutes and V is the volume of 0.1 N HCl in Fig. 1.

For the different formulations of alkalizing agents, graphs of pH versus time (theoretically calculated) are shown in Fig. 2.

Stage B

Clinical study

The study was an open-label, randomized, placebo-controlled study of gastric pH of healthy adult volunteers, specifically, eighteen (18) healthy adult volunteers (6 subjects per group) between 18 and 55 years of age and with a weight range of 15% to 30% of the recommended based on gender, height and body structure.

The subjects were assigned to three different groups. Each group received two experimental formulations and one placebo treatment in a 3-way crossover design:

Group 1: Formulation 1, Formulation 2 and placebo

Group 2: Formulation 3, Formulation 4 and placebo

Group 3: Formulation 5, Formulation 6 and placebo

Subjects were randomly assigned treatment sequences in each group. The test formulation was administered as an oral solution in a single dose. Water was used as a placebo. Each subject received only one treatment (formulation) per day. There was at least 1 day of washout period between treatment days.

ES 2 312 929 T3

Before administration, the following procedures were performed:

Each subject was intubated with the Synectics Digitrapper pH probe (Synectics Medical Ltd, Middlesex, UK) approximately 30 minutes prior to administration of the alkalizing agent formulation or placebo to obtain an initial pH. Continuous pH recording was made from 30 minutes prior to dosing while in a sitting position. If a baseline pH &lt;2.0 had not been demonstrated for a subject, that subject would have been excluded from the study. However, no subject was excluded.

Afterwards, the experimental dose of a Formulation (1,2, 3,4, 5 or 6) or placebo, depending on the group and assigned treatment sequence, was administered orally. The dose was easily swallowed around the Digitrapper. To normalize conditions, all subjects were required to refrain from lying down and eating and drinking beverages (including water) for the first 2 hours after administration. A continuous pH recording was made up to 2 hours after administration in a sitting position.

Considering some variability between subjects for all formulations, the following conclusions were drawn.

Formulations containing TRIS, in general, exhibited the longest duration of pH rise of all formulations.

The subject response to the formulation containing calcium carbonate was equal to or greater than that of the formulation containing magnesium hydroxide. Except for Formulation 1, all other formulations, on average, raised the pH to 6, or higher, for at least 20 minutes.

Example 2

Comparison of in vitro release rates for dosage forms with different amounts of the same alkalizing agent

In vitro azithromycin release rates were determined for various sustained release dosage forms of azithromycin, each containing 2 gA of the same multiparticulate azithromycin (MP1) and varying amounts of TSP as an alkalinizing agent, compared to one form of azithromycin dosage containing multiparticulate MP1 and without TSP and with an immediate release dosage form of azithromycin that did contain TSP. The sustained release dosage forms were prepared as described in Step A, below, while the in vitro release rate study and its results are described in Step B below.

Stage a

Preparation of Azithromycin Sustained Release Dosage Forms

Five sustained release dosage forms of azithromycin (hereinafter referred to as "SR1", "SR2", "SR3", "SR4", "SR5") were prepared by mixing 2000 mgA of azithromycin MP1 multiparticles, prepared as described then with one of six excipient mixtures, as described below in this example:

SR1 included 38.7 g of sucrose and 50 mg of TSP,

SR2 included 38.7 g of sucrose and 100 mg of TSP,

SR3 included 38.7 g of sucrose and 264 mg of TSP,

SR4 included 38.7 g of sucrose and 356 mg of TSP, and

SR5 included 38.7 g of sucrose and 500 mg of TSP,

In addition, a Control multiparticulate dosage form was prepared by mixing 2000 mgA of azithromycin multiparticles, which are described in this example, and 38.7 g of sucrose.

Azithromycin multiparticulates "MP1"

Azithromycin MP1 multiparticles were prepared comprising 50 wt% azithromycin dihydrate, 46 wt% Compritol® and 4 wt% Lutrol®. Specifically, Azithromycin dihydrate (5000g), Compritol® (4600g), and Lutrol® (400g) were mixed in a double layer mixer (Blend Master C419145 purchased from Patterson Kelly, East Stroudsberg, PA) for 20 minutes. Lumps were then removed from this mixture using a FitzMill® Comminutor L1A mill (The Fitzpatrick Company, Elmhurst, IL) at 3000 rpm, with the blades in direct position using a 0.065 inch (0.165 cm) screen. The mixture was homogenized again in a double layer mixer for 20 minutes, forming a premix. The premix was delivered to a 19mm B&amp;P twin screw extruder (MP19-TC with an L / D ratio of 25 purchased from B&amp;P Process Equipment and Systems, LLC, Saginaw, MI)

ES 2 312 929 T3 with a speed of 120 g / minute, to form the molten mixture at a temperature of about 90 ° C. No water was added to the extruder. The extruder produced a molten mixture consisting of a suspension of azithromycin dihydrate in Compritol® / Lutrol®. The molten mixture was then fed into the center of a rotating disk atomizer to form azithromycin multiparticles.

The spinning disc atomizer, which was custom made, consisted of a gut-shaped stainless steel disc 4 inches in diameter. The surface of the disc is heated to approximately 90 ° C with a thin film heater below the disc. That disk is mounted on a motor that drives the disk up to approximately 10,000 rpm. The complete assembly is contained in a plastic bag approximately 8 feet (243.84 cm) in diameter to allow coagulation and to capture the multiparticles formed by the atomizer. Air is introduced from an outlet below the disk to provide cooling of the multiparticles as they coagulate and to inflate the bag to its unfolded size and shape.

A suitable commercial equivalent to this spinning disc atomizer is the FX1 100mm spinning atomizer manufactured by Niro A / S (Soeborg, Denmark).

The surface of the rotating disk atomizer was held at 90 ° C and the disk was rotated at 5500 rpm, while the multiparticulates of azithromycin were formed. The average residence time of the azithromycin dihydrate in the extruder was approximately 60 seconds and the total time the azithromycin remained in the molten suspension was less than approximately 3 minutes. The particles formed by the rotating disk atomizer coagulated in ambient air and collected. The azithromycin multiparticles prepared by this procedure had a diameter of approximately 200 µm.

The properties of the melt-coagulated multiparticles such as particle size can be controlled by the viscosity of the melt mixture and the processing conditions. Given the combination of the materials of the preferred embodiments of the present invention, the viscosity of the molten mixture does not change as long as the temperature of the heating system is maintained at 90 ° C. The size of the azithromycin multiparticles can be controlled by the feed rate (the amount of molten materials that are loaded into the rotating disk atomizer) and the speed of the disk (diameter of 4 inches (10.16 cm)). For example, 200 pm particles can be formed by a combination of 1) 8.4 kg / h feed rate and 5500 rpm disc speed or 2) 20 kg / h feed rate and 5800 rpm disc speed, or 3) 25kg / h feed speed and 7100rpm disc speed.

Subsequently, the azithromycin multiparticles were subjected to post-treatment by placing them in a shallow tray, at a depth of approximately 2 cm and then placing the tray in an oven at 40 ° C, maintaining a relative humidity of 75%, for 5 days.

Each azithromycin multiparticulate dosage form was prepared using 4.2 grams of azithromycin multiparticles to provide an equivalent of 2 gA of azithromycin.

Stage B

In vitro azithromycin release rate study

Azithromycin release rates were determined in vitro, in 0.01 N HCl that simulates stomach fluid when in a fed state and was used instead of 0.1 N HCl to avoid acid degradation of azithromycin, for forms sustained-release dosage cups (2 gA each) SR1, SR2, SR3, SR5, and SR5 containing varying amounts of TSP as an alkalizing agent. The in vitro release rate of the multiparticles (2 gA), which did not contain TSP, was also determined. In addition, the in vitro release rate of the immediate release (IR) control of two commercially available single dose containers of azithromycin dihydrate for oral suspension (Zithromax®, Pfizer Inc., New York, NY) was determined. . Each single-dose container contained 1048 mg of azithromycin dihydrate (1 gA), 88 mg of TSP, and other excipients.

The data in Table 1, shown below, demonstrate that the release rate of azithromycin from these multiparticles is increasingly slowed when administered with increasing amounts of TSP.

This in vitro azithromycin release rate study, which is reflected in Table 1, was conducted as follows. The sustained release dosage forms, each containing approximately 2 gA of multiparticulate azithromycin and the multiparticulate control and immediate release control, were placed in individual 125 ml bottles. Then 60 ml of purified water was added and the flask was shaken for 30 seconds. The contents were added to a USP Type 2 dissoette flask equipped with Teflon coated paddles rotating at 50 rpm. The flask contained a 750 ml volume of 0.01 N HCl which was kept at 37.0 ± 0.5 ° C. The bottle was rinsed twice with 20 ml of HCl from the flask and the rinse was returned to the flask to make a final volume of 750 ml. A 3 ml sample of the fluid was then collected from the flask 15, 30, 60, 120 and 180 minutes after the addition of the multiparticles to the flask. Samples were filtered using a 0.45 pm syringe filter before analysis by high performance liquid chromatography (Hewlett Packard 1100, Waters Symmetry C column₈, acetonitrile buffer: methanol: KH₂PO₄ 25 mM 45:30:25 at 1.0 ml / minute, absorbance measured at 210 nm with a diode array spectrophotometer).

ES 2 312 929 T3

TABLE 1

<td>Formulation</td><td>Time (h)</td><td>Total azithromycin released (mg)</td><td>Azithromycin released (%)</td>

<td rowspan="6">SR1 (50 mg TSP)</td><td> 0,08</td><td> 350</td><td> 17</td>

<td> 0,25</td><td> 760</td><td> 38</td>

<td> 0,5</td><td> 1130</td><td> 57</td>

<td> 1</td><td> 1440</td><td> 72</td>

<td> 2</td><td> 1610</td><td> 81</td>

<td> 3</td><td> 1680</td><td> 84</td>

<td rowspan="6">SR2 (100 mg TSP)</td><td> 0,08</td><td> 340</td><td> 17</td>

<td> 0,25</td><td> 740</td><td> 37</td>

<td> 0,5</td><td> 1020</td><td> 51</td>

<td> 1</td><td> 1260</td><td> 63</td>

<td> 2</td><td> 1420</td><td> 71</td>

<td> 3</td><td> 1520</td><td> 76</td>

<td rowspan="6">SR3 (264 mg TSP)</td><td> 0,08</td><td> 300</td><td> 15</td>

<td> 0,25</td><td> 630</td><td> 31</td>

<td> 0,5</td><td> 880</td><td> 44</td>

<td> 1</td><td> 1160</td><td> 58</td>

<td> 2</td><td> 1400</td><td> 70</td>

<td> 3</td><td> 1480</td><td> 74</td>

<td rowspan="6">SR4 (356 mg TSP)</td><td> 0,08</td><td> 250</td><td> 12</td>

<td> 0,25</td><td> 490</td><td> 24</td>

<td> 0,5</td><td> 710</td><td> 35</td>

<td> 1</td><td> 920</td><td> 46</td>

<td> 2</td><td> 1120</td><td> 56</td>

<td> 3</td><td> 1240</td><td> 62</td>

<td rowspan="6">SR5 (500 mg TSP)</td><td> 0,08</td><td> 160</td><td> 8</td>

<td> 0,25</td><td> 340</td><td> 17</td>

<td> 0,5</td><td> 480</td><td> 24</td>

<td> 1</td><td> 640</td><td> 32</td>

<td> 2</td><td> 850</td><td> 42</td>

<td> 3</td><td> 1010</td><td> 50</td>

<td rowspan="6">Multiparticulate control (without TSP)</td><td> 0,08</td><td> 420</td><td> 21</td>

<td></td><td> 860</td><td> 43</td>

<td> 0,5</td><td> 1160</td><td> 58</td>

<td> 1</td><td> 1460</td><td> 73</td>

<td> 2</td><td> 1660</td><td> 83</td>

<td> 3</td><td> 1720</td><td> 86</td>

<td rowspan="6">IR control (176 mg TSP)</td><td> 0.08</td><td> 1050</td><td> 79</td>

<td> 0.25</td><td> 1180</td><td> 88</td>

<td> 0.5</td><td> 1230</td><td> 92</td>

<td> 1</td><td> 1270</td><td> 95</td>

<td> 2</td><td> 1950</td><td> 97</td>

<td> 3</td><td> 1960</td><td> 98</td>

Example 3

Comparison of in vitro release rates for dosage forms having different alkalinizing agents

Azithromycin release rates were determined in vitro, in 0.01 N HCl for various sustained release dosage forms of azithromycin, each containing 2 gA of the azithromycin MP1 multiparticles that were prepared with one of three excipient mixtures. , as described below:

"SR6" included 38.7 g of sucrose and 100 mg of the weak base sodium carbonate, "SR7" included 38.7 g of sucrose and 50 mg of magnesium hydroxide, and

ES 2 312 929 T3 ^"SR8" included 38.7 g of sucrose and 1.0 g of Liquid Maalox^® (soft cherry, medium strength, from Novartis) containing 37.1 mg of aluminum hydroxide, 37.1 mg of magnesium hydroxide and 3.7 mg of simethicone.

Azithromycin release rates from these sustained release dosage forms were measured in vitro as described in Example 2. The results of these dissolution experiments, which are provided in Table 2, below, demonstrated that the addition of various alkalizing agents slowed the release of azithromycin from the MP1 multiparticles compared to the release of these multiparticles without an alkalizing agent that is shown in Table 1.

TABLE 2

<td>Formulation</td><td>Time (h)</td>

<td rowspan="6">SR6</td><td> 0,08</td>

<td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="6">SR7</td><td> 0,08</td>

<td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="6">SR8</td><td> 0,08</td>

<td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td>Azithromycin released (mg)</td><td>Azithromycin released (%)</td>

<td> 130</td><td> 10</td>

<td> 270</td><td> 20</td>

<td> 430</td><td> 32</td>

<td> 590</td><td> 45</td>

<td> 1170</td><td> 59</td>

<td> 1360</td><td> 68</td>

<td> 210</td><td> 16</td>

<td> 470</td><td> 35</td>

<td> 670</td><td> 50</td>

<td> 830</td><td> 62</td>

<td> 1460</td><td> 73</td>

<td> 1580</td><td> 79</td>

<td> 220</td><td> 17</td>

<td> 490</td><td> 36</td>

<td> 650</td><td> 49</td>

<td> 830</td><td> 62</td>

<td> 1440</td><td> 72</td>

<td> 1520</td><td> 76</td>

Example 4

In vitro evaluation of the effect of the addition of alkalizing agent on the release rates of immediate release dosage forms

The comparative effect of the addition of an alkalizing agent on the in vitro release rates in 0.01 N HCl was determined for the immediate release dosage form of azithromycin tablets Zithromax®. Zithromax® tablets contain azithromycin dihydrate equivalent to 250 mgA of azithromycin, dibasic calcium phosphate (138.84 mg), which is an alkalizing agent, and various other excipients.

Azithromycin release rates from Zithromax® tablets, whether or not an additional alkalinizing agent was added, specifically 176 mg of TSP, were measured in vitro as described in Example 2. The results of these dissolution experiments are provided in Table 3, below.

ES 2 312 929 T3

TABLE 3

<td>Control dosage form</td><td>Time (h)</td>

<td rowspan="7">8 tablets without TSP</td><td> 0</td>

<td> 0,08</td>

<td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="7">8 tablets 176 mg TSP</td><td> 0</td>

<td> 0,08</td>

<td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td>Azithromycin released (mg)</td><td>Azithromycin released (%)</td>

<td> 0</td><td> 0</td>

<td> 1100</td><td> 55</td>

<td> 1480</td><td> 74</td>

<td> 1600</td><td> 80</td>

<td> 1700</td><td> 85</td>

<td> 1720</td><td> 86</td>

<td> 1700</td><td> 85</td>

<td> 0</td><td> 0</td>

<td> 1040</td><td> 52</td>

<td> 1380</td><td> 69</td>

<td> 1500</td><td> 75</td>

<td> 1580</td><td> 79</td>

<td> 1600</td><td> 80</td>

<td> 1620</td><td> 81</td>

These results confirm that, when combined with an alkalizing agent, the release rate of an immediate release azithromycin dosage form is slowed.

Example 5

Comparison of in vitro release rates in dosage forms having different azithromycin multiparticles

The in vitro release rates of azithromycin were determined, in Na₂HPO₄ 0.1 M, for various sustained release dosage forms of azithromycin, each containing 2 gA of different multiparticulates of azithromycin and the same amount of a common alkalizing agent. The sustained release dosage forms were prepared as described in Step A below, while the in vitro release rate study and its results are described in Step B below.

Stage a

Preparation of Azithromycin Sustained Release Dosage Forms

Six sustained release dosage forms of azithromycin, specifically SR9, SR10, SR11, Sr12, SR13, and SR14 were prepared by mixing azithromycin multiparticles, respectively, mP2, MP3, MP4, MP5, MP6, or MP7, each, with the same mixture. of two alkalizing agents (i.e. 352 mg of TSP and 250 mg of magnesium hydroxide) and excipients (i.e. 19.36 g of sucrose, 67 mg of hydroxypropyl cellulose, 67 mg of xanthan gum, 110 mg of colloidal silicon dioxide, 400 mg of titanium dioxide, 140 mg of cherry flavoring and 230 mg of banana flavoring).

Azithromycin multiparticles

Azithromycin multiparticles "MP2" were prepared comprising azithromycin dihydrate 50% by weight, Compritol^® 47% by weight and Lutrol^® at 3% by weight in the same way as the MP1 multiparticles in Example 2, except that the mixture was then fed through a 19mm B&amp;P twin screw extruder, with a

ES 2 312 929 T3 speed of 131 g / minute, to form the molten mixture. At the same time, water was added to the extruder with a speed that provided a water content in the molten mixture of 2% by weight and the multiparticles were post-treated for 21 days to form multiparticles of azithromycin with a mean diameter of about 188 microns .

"MP3" azithromycin multiparticles comprising 50 wt% azithromycin dihydrate, 47 wt% Compritol® and 3 wt% Lutrol® were prepared in the same manner as the MP2 multiparticles of this Example, except that the The disc rotated at 4800 rpm, to form azithromycin multiparticles with a mean diameter of approximately 204 microns.

Azithromycin multiparticles "MP4" were prepared comprising azithromycin dihydrate 50% by weight, Compritol^® 47% by weight and Lutrol^® at 3% by weight in the same way as the MP2 multiparticles of this Example, except that the disk rotated at 4100 rpm, to form azithromycin multiparticles with a mean diameter of about 227 microns.

Azithromycin multiparticles "MP5" comprising 50 wt% azithromycin dihydrate, 48 wt% Compritol® and 2 wt% Lutrol® were prepared in the same manner as the MP1 multiparticles in Example 1, except that The mixture was then fed through a 27mm Leistritz twin screw extruder, at a speed of 140g / minute, to form the molten mixture.

Azithromycin multiparticles "MP6" were prepared comprising azithromycin dihydrate 50% by weight, Compritol^® 47% by weight and Lutrol^® F127 at 3% by weight using the following procedure. First, 15 kg of azithromycin dihydrate, 14.1 kg of Compritol were weighed^® and 0.9 kg of Lutrol^® and they were passed through a Quadro 194S Comil mill in that order. The speed of the mill was 600 rpm. The mill was equipped with a # 2C-075-H050 / 60 (special stroke) screen, a # 2C1607-049 flat blade impeller, and a 0.225 inch (0.572 cm) spacer between the impeller and screen. The lump-free mix was mixed using a 100L Servo Lift stainless steel tumbler mixer rotating at 20 rpm, for a total of 500 rotations, forming a premix.

The premix was delivered to a Leistritz 50mm twin screw extruder (Model ZSE 50, American Leistritz Extruder Corporation, Somerville, NJ) at a rate of 25 kg / hr. The extruder was operated in consonant rotation mode at approximately 300 rpm and connected with a melt / spray-coag unit. The extruder had nine segmented drum zones and a total extruder length of 36 screw diameters (1.8 m). Water was injected into drum number 4 at a rate of 8.3 g / minute (2% by weight). The extrusion speed of the extruder was adjusted to produce a slurry of the molten mixture of the azithromycin dihydrate in the Compritol^®/ Pluronic^® at a temperature of about 90 ° C.

The suspension of the molten mixture was administered to a rotating disk atomizer rotating at 7600 rpm, the surface of which was kept at 90 ° C. The maximum total time that azithromycin dihydrate was exposed to the molten suspension was less than about 10 minutes. The particles formed by the rotating disk atomizer were cooled and coagulated in the presence of cooling air circulating through the product collection chamber. The mean particle size was determined to be 188 µm using a Horiba LA-910 particle size analyzer. Samples of the multiparticles were also evaluated by PXRD, which showed that approximately 99% of the azithromycin in the multiparticles was in the crystalline dihydrate form.

The multiparticles thus formed were subjected to post-treatment by placing the samples in sealed drums which were then placed in a controlled atmosphere chamber at 40 ° C for 3 weeks.

Azithromycin multiparticles "MP7" comprising azithromycin dihydrate 50% by weight, Compritol® 47% by weight and Lutrol® F127 3% were prepared as follows.

Azithromycin dihydrate (140 kg) was weighed and passed through a Quadro Comil 196S mill with a mill speed of 900 rpm. The mill was equipped with a # 2C-075-H050 / 60 screen (special path, 0.075 ”(0.191 cm)), an impeller # 2F-1607-254, and a 0.225 inch (0.572 cm) spacer between the impeller and strainer. Next, 8.4 kg of the Lutrol® and then 131.6 kg of the Compritol® were weighed and passed through a Quadro 194S Comil mill. The mill speed was set at 650 rpm. The mill was equipped with a # 2C-075-R03751 (0.075 "(0.191 cm)) screen, a # 2C-1601-001 impeller, and a 0.225 inch (0.572 cm) spacer between the impeller and screen. The ground mix was mixed using a Gallay 38 cu ft (1,076 m³) rotating at 10 rpm for 40 minutes, for a total of 400 rotations, forming a premix.

The premix was delivered to a Leistritz 50mm twin screw extruder at a rate of approximately 20 kg / hr. The extruder was operated in consonant rotation mode at approximately 100 rpm and connected with a melt / spray-coag unit. The extruder had five segmented drum zones and a total extruder length of 20 screw diameters (1.0 m). Water was injected into drum number 2 at a rate of 6.7 g / minute (2% by weight). The extrusion speed of the extruder was adjusted to produce a slurry of the molten mixture of the azithromycin dihydrate in the Compritol^®/ Lutrol^® at a temperature of about 90 ° C.

ES 2 312 929 T3

The slurry of the molten mixture was delivered to a 10.1 cm diameter rotating disc atomizer, described above in Example 2, rotating at 6400 rpm and maintaining a disc surface temperature of 90 ° C. The maximum total time that azithromycin was exposed to the molten suspension was less than 10 minutes. The particles formed by the rotating disk atomizer were cooled and coagulated in the presence of cooling air circulating through the product collection chamber. The mean particle size was determined to be approximately 200 µm using a Malvern particle size analyzer.

The multiparticles thus formed were subjected to post-treatment by placing a sample in a sealed drum which was then placed in a controlled atmosphere chamber at 40 ° C for 10 days. The samples of the post-treated multiparticles were evaluated by PXRD, which showed that approximately 99% of the azithromycin in the multiparticles was in the crystalline dihydrate form.

Stage B

Study of the release rate of azithromycin in vitro

In vitro azithromycin release rates were determined for sustained release dosage forms (2 gA each) SR9, SR10, SR11, SR12, SR13, and SR14 by the following dissolution experimentation procedure.

Water (60 ml) was added to the bottle containing the dosage form. The bottle was closed and then inverted several times to mix the suspension. Each sustained release dosage formulation, in suspension form, was tested by adding it to the dissolution buffer on a standard USP rotary paddle apparatus as described in United States Pharmacopoeia (USP 26), Dissolution Experiment, Chapter 711, Apparatus 2. The paddles were rotated at 50 rpm and the dissolution experiment was carried out in 840 ml of 0.1M sodium phosphate buffer, at pH 6.0 (+ 0.05) at 37 + 0.5 ° C. At the indicated times after the initiation of the experiment (i.e., introduction of the dosage form into the apparatus), filtered aliquots (typically 10 ml) of the experiment medium were analyzed for azithromycin by high performance liquid chromatography (HPLC ) in reverse phase and UV detection as follows. An aliquot of the test solution was filtered to remove particles. A fixed volume of 10 µl was injected into a column (15 cm length x 3.9 mm ID) kept at 35 + 3 ° C. The mobile phase consisted of volume ratios of 45% acetonitrile, 30% methanol, and 25% buffer. The buffer consisted of 25 mM KH2PO4, pH 6.5. The flow rate was adjusted to 1 ml / minute. In the dissolution experimentation medium, the actual quantification of azithromycin was determined by comparing the area of ​​the peaks of the sample chromatogram with the area of ​​the peaks of a conventional azithromycin chromatogram.

(Table goes to next page)

ES 2 312 929 T3

TABLE 4

<td>Formulation</td><td>Time (h)</td>

<td rowspan="5">SR9 (MP2)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="5">SR10 (MP3)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="5">SR11 (MP4)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="5">SR12 (MP5)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="5">SR13 (MP6)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td rowspan="5">SR14 (MP7)</td><td> 0,25</td>

<td> 0,5</td>

<td> 1</td>

<td> 2</td>

<td> 3</td>

<td>Azithromycin released (mgA)</td><td>Azithromycin released (%)</td>

<td> 560</td><td> 28</td>

<td> 920</td><td> 46</td>

<td> 1400</td><td> 70</td>

<td> 1800</td><td> 90</td>

<td> 1900</td><td> 95</td>

<td> 520</td><td> 26</td>

<td> 860</td><td> 43</td>

<td> 1320</td><td> 66</td>

<td> 1740</td><td> 87</td>

<td> 1860</td><td> 93</td>

<td> 500</td><td> 25</td>

<td> 800</td><td> 40</td>

<td> 1240</td><td> 62</td>

<td> 1680</td><td> 84</td>

<td> 1840</td><td> 92</td>

<td> 460</td><td> 23</td>

<td> 760</td><td> 38</td>

<td> 1180</td><td> 59</td>

<td> 1460</td><td> 73</td>

<td> 1640</td><td> 82</td>

<td> 600</td><td> 30</td>

<td> 1000</td><td> 50</td>

<td> 1540</td><td> 77</td>

<td> 1920</td><td> 96</td>

<td> 1980</td><td> 99</td>

<td> 730</td><td> 37</td>

<td> 1200</td><td> 60</td>

<td> 1700</td><td> 85</td>

<td> 1880</td><td> 94</td>

<td> 1920</td><td> 96</td>

The results of these dissolution experiments, which are provided above in Table 4, show that these various multiparticulate and alkalizing agent formulations meet the release rate criteria for the in vitro buffer experiment at pH 6.0 of (i ) from 15% to 55% by weight of said azithromycin in said dosage form at 0.25 hours; (ii) from 30% to 75% by weight of said azithromycin in said dosage form at 0.5 hour; and (iii) greater than 50% by weight of said azithromycin in said dosage form 1 hour after administration to the buffer experimentation medium.

ES 2 312 929 T3

Example 6

In Vivo Comparison of Azithromycin Sustained Release Dosage Forms and an Immediate Release Azithromycin Dosage Form

Two clinical studies were conducted to respectively evaluate the pharmacokinetics and gastrointestinal tolerance of three sustained-release dosage forms of azithromycin, of the present invention, each of which contained 352 mg of anhydrous TSP as an alkalizing agent and optionally contained 250 mg of hydroxide. magnesium, compared to an immediate release dosage form of azithromycin containing half the TSP (176 mg) at most and no magnesium hydroxide. The sustained release dosage forms were prepared as described in Step A below, while the pharmacokinetic and side effect clinical studies and their results are described, respectively, in Steps B and C below.

Stage a

Preparation of Azithromycin Sustained Release Dosage Forms

These sustained release dosage forms were prepared as follows. Two different sustained release dosage forms of azithromycin (hereinafter referred to as "SR15" and "SR16") were prepared by mixing 4.2 g (2 gA) of azithromycin multiparticles, prepared as described below, with different excipients. . Dosage form SR15 comprised a mixture of the azithromycin multiparticles and the mixture of excipients described below. Dosage form SR16 comprised a mixture of the azithromycin multiparticles, the same mixture of excipients and magnesium hydroxide. To prepare SR16, magnesium hydroxide was added to the bottle containing SR15. The contents were mixed by shaking the bottle.

SR12 was prepared as described in Example 5.

Azithromycin multiparticles

Azithromycin multiparticles "MP8" were prepared, comprising azithromycin dihydrate 50% by weight, Compritol^® 47% by weight and Lutrol^® at 3% by weight, in the same way as the MP1 multiparticles of Example 2, except that the mixture was then fed through a Leistritz 27 mm twin screw extruder (Model ZSE 27, American Leistritz Extruder Corporation, Somerville, NJ), at a rate of 140 g / minute to form the molten mixture.

Alkalizing agents and excipients

A mixture of excipients was prepared to be used in combination with the azithromycin multiparticles. The excipient mixture consisted of a mixture of 352 mg of anhydrous TSP as an alkalizing agent, 19.36 g of sucrose (NF), 67 mg of hydroxypropyl cellulose (NF), 67 mg of xanthan gum (NF), 200 mg of sodium dioxide. colloidal silicon (NF), 400 mg of titanium dioxide (USP), 140 mg of cherry flavoring and 230 mg of banana flavoring.

Separate bottles were also prepared, containing 250 mg of the optional alkalizing agent magnesium hydroxide (USP).

Stage B

Clinical study of pharmacokinetics

In vivo pharmacokinetics of azithromycin multiparticle dosage forms "SR15" and "SR16" were evaluated in 32 healthy fasting human subjects in a randomized, open-label, parallel, two-way crossover study. On Day 1, eight subjects received azithromycin SR15 multiparticulate dosage form and eight subjects received azithromycin SR16 multiparticulate dosage form. As controls, two groups (A and B) of eight subjects each received two single-dose containers of azithromycin dihydrate for oral suspension (Zithromax^®, Pfizer Inc., New York, NY) in which each dose contains 1048 mg of azithromycin dihydrate, which is equivalent to 1000 mgA of azithromycin, 88 mg of TSP and the inactive ingredients noted above.

Specifically, 2 gA of either azithromycin formulations (SR15 without magnesium hydroxide or SR16 with magnesium hydroxide) or commercially available azithromycin sachets were administered, based on computer-generated randomization for each of the two treatment groups. .

To administer formulations SR15 and SR16, 60 ml of water was added to the flask containing SR15 and shaken for 30 seconds. The entire contents of the vial were administered directly to the subject's mouth. An additional 60 ml of water was added to rinse the bottle and the rinse was administered to the subject's mouth. An additional 120 ml of water was administered using a measuring cup.

To administer two 1 g sachets of commercial azithromycin, the contents of a single dose 1 g Zithromax® container were emptied into a measuring cup containing 60 ml of water. The mixture was shaken and administered to the mouth of the

ES 2 312 929 T3 subject. An additional 60 ml of water was used to rinse the beaker and the rinse was administered. This procedure was repeated for the second container of single-dose Zithromax®.

All subjects received the dose orally after fasting overnight. All subjects were then asked to refrain from lying down and eating and drinking beverages other than water for the first 4 hours after administration.

Blood samples (5 ml each) were drawn from the veins of the subjects prior to administration and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours of administration. Serum azithromycin concentrations were determined using the high performance liquid chromatography assay described in Shepard et al., J Chromatography. 565: 321-337 (1991). Total systemic exposure to azithromycin was determined by measuring the area under the curve (AUC) for each subject in the group and then calculating a mean AUC for the group. Cmax is the maximum serum concentration of azithromycin that is achieved in a subject. Tmax is the time in which Cmax is reached. % CV is the coefficient of variance and DT is the standard deviation.

On Day 15, the procedure was repeated but the azithromycin multiparticulate dosage forms SR15 or SR16 were administered to the two groups of 8 subjects who received the control dosage forms on Day 1. Similarly, the azithromycin forms were administered control dosing to the two groups of 8 subjects who previously received the azithromycin multiparticulate dosage forms on Day 1.

The in vivo pharmakonia of azithromycin SR12 multiparticulate dosage form was also evaluated in sixteen healthy fasting human subjects in a randomized two-way crossover study. The control was two single-dose containers of azithromycin dihydrate for oral suspension (Zithromax®, Pfizer Inc., New York, NY) in which each dose contains 1048 mg of azithromycin dihydrate, which is equivalent to 1000 mgA of azithromycin , 88 mg of TSP and the inactive ingredients noted above.

The results of this study are provided in Table 5.

TABLE 5

<td rowspan="2">Formulation</td><td colspan="2">Cmax (pg / ml)</td><td colspan="2">Tmax (h)</td><td colspan="2">AUC (pg-h / ml) O-Tult (96 h)</td>

<td>Geometric mean</td><td>% of CV</td><td>Arithmetic average</td><td>DT</td><td>Geometric mean</td><td>% of CV</td>

<td>SR15</td><td> 0,92</td><td> 36</td><td> 2,94</td><td> 1,7</td><td> 13,81</td><td> 35</td>

<td>SR16</td><td> 0,82</td><td> 26</td><td> 4,13</td><td> 1,6</td><td> 15,75</td><td> 40</td>

<td>Control for SR15</td><td> 2,09</td><td> 36</td><td> 1,13</td><td> 0,3</td><td> 18,98</td><td> 22</td>

<td>Control for SR16</td><td> 1,90</td><td> 49</td><td> 1,56</td><td> 0,7</td><td> 19,03</td><td> 24</td>

<td>SR12</td><td> 0,86</td><td> 26</td><td> 4,88</td><td> 1,86</td><td> 13,6</td><td> 25</td>

<td>Control for SR12</td><td> 2,10</td><td> 42</td><td> 1,25</td><td> 0,58</td><td> 15,3</td><td> 24</td>

Based on the results in Table 5, the bioavailability of SR15, SR16, and SR12 were 73%, 83%, and 89% respectively, compared to the immediate release control dosage form. The data also demonstrated that the ratios between the maximum serum concentration of azithromycin provided by the SR15, SR16 and SR12 multiparticulate dosage forms and the maximum serum concentration of azithromycin provided by the control dosage form were 0.44. 0.43 and 0.41, respectively. Furthermore, the time to achieve maximum serum concentration was longer for azithromycin multiparticulate dosage forms than for immediate release control dosage forms.

ES 2 312 929 T3

Stage C

Gastrointestinal tolerance clinical study

The tolerance of azithromycin multiparticulate dosage forms SR15 and SR16 was evaluated in vivo by a randomized and parallel group study. Specifically, the SR15 sustained-release azithromycin multiparticulate formulation was orally administered to 106 healthy human subjects, the SR16 sustained-release azithromycin multiparticle formulation was orally administered to 106 healthy human subjects and two single dose containers of azithromycin dihydrate of 1 gA for oral suspension was administered to each of 108 healthy human subjects by the following procedure. The entire contents of a container were mixed with approximately 60 ml of water in a glass and then immediately drank. An additional 60 ml of water was added to the glass, mixed and then drank to ensure full consumption of the dose. These steps were then repeated for the second package.

Adverse GI events, such as diarrhea, nausea, and vomiting, were monitored for 48 hours after administration of each dosage form. Subjects were verbally asked at least the following approximate times: 1, 2, 4, 6, 8, 12, and 24 hours after administration by asking neutral questions.

The incidence of gastrointestinal adverse events experienced by the analyzed subjects is provided in Table 6.

A similar in vivo tolerance study of the SR12 formulation was performed using a population of 16 healthy human subjects. The control used for this study was two 1 gA single dose containers of azithromycin dihydrate for oral suspension. The results of this study are also provided in Table 6.

TABLE 6

<td rowspan="2">Formulation</td><td colspan="3">Percentage of Subjects with Adverse Gl Events</td>

<td>Diarrhea</td><td>Sickness</td><td>Vomiting</td>

<td>SR15</td><td> 17,9</td><td> 17,0</td><td> 2,8</td>

<td>SR16</td><td> 23,6</td><td> 17,0</td><td> 3,8</td>

<td>Control</td><td> 27,8</td><td> 54,6</td><td> 25,9</td>

<td>SR12</td><td> 18,8</td><td> 18,8</td><td> 0</td>

<td>Control for SR12</td><td> 18,8</td><td> 50</td><td> 6</td>

The results in Table 5 and 6 show that both multiparticulate dosage forms of azithromycin, with or without magnesium hydroxide, in which the multiparticles included Lutrol^® at 2-3% by weight, provided lower immediate concentrations of azithromycin released from the forms compared to the immediate release control dosage form and substantially improved gastrointestinal tolerance compared to the immediate release control dosage form while maintaining the once a bioavailability substantially equivalent to that of the immediate release control. In addition, SR15 provided a relative degree of improvement, compared to control, of 1.6 for diarrhea, 3.2 for nausea, and 9.3 for vomiting, while SR16 provided a relative degree of improvement of 1.2 for diarrhea, 3.2 for nausea and 6.8 for vomiting. Similarly, SR12 provided no improvement in diarrhea compared to the control, a relative degree of improvement of 50, and no vomiting episodes compared to the 6 episodes that occurred with the control. Note that the results of SR12 cannot be exactly compared with those of SR15 and SR16 due to the small size of the study population of SR12.

Example 7

In vivo comparison of multiparticulate forms of azithromycin and an immediate release azithromycin dosage form

A clinical study was conducted to evaluate the pharmacokinetics and gastrointestinal tolerance of two multiparticulate dosage forms of azithromycin, which contained 2 gA or 3 gA of azithromycin, respectively and each contained 352 mg of anhydrous TSP as an alkalizing agent, compared with an immediate release dosage form of azithromycin containing half TSP (176 mg) at most and no magnesium hydroxide. The sustained release dosage form was prepared as described in Step A below, an in vitro release rate study of the 2 gA dosage form was performed as described in Step B, while the studies Clinical pharmacokinetics and side effects and their results are described, respectively, in Steps C and D below.

ES 2 312 929 T3

Stage a

Preparation of multiparticulate dosage forms of azithromycin

Azithromycin multiparticulate dosage forms (hereinafter "SR17" and "SR18") were prepared by mixing 4.2 g (2 gA) or 6.3 g (3 gA), respectively, of azithromycin MP9 multiparticles, prepared as described below, with excipients. The SR17 dosage form comprised a mixture of the azithromycin multiparticles (MP9) and the excipient mixture described below.

Azithromycin multiparticles

Azithromycin multiparticles "MP9" were prepared, comprising azithromycin dihydrate 50% by weight, Compritol^® 46% by weight and Lutrol^® at 4% by weight, in the same way as the MP9 multiparticles of Example 2, except that the mixture was fed through a Leistritz 27 mm twin screw extruder, at a rate of 140 g / minute to form the mixture fused. The rotating disk atomizer was rotated at 5500 rpm to form the multiparticles. The resulting multiparticles were exposed to 40 ° C and 75% relative humidity in a controlled environment chamber for 5 days.

Alkalizing agents and excipients

A mixture of excipients was prepared to be used in combination with the azithromycin multiparticles. The excipient mixture consisted of a mixture of 352 mg of anhydrous TSP as an alkalizing agent, 38.7 g of sucrose (NF), 67 mg of hydroxypropyl cellulose (NF), 67 mg of xanthan gum (NF), 200 mg of sodium dioxide. Colloidal Silicon (NF), 400mg Titanium Dioxide (USP), 140mg Cherry Flavor, 330mg Vanilla Flavor and 230mg Banana Flavor.

Stage B

In vitro study of azithromycin release rate

An in vitro release rate study of an SR17 multiparticulate dosage form was performed as described in Example 5.

TABLE 7

<td>Formulation</td><td>Time (h)</td><td>Azithromycin released (mgA)</td><td>Azithromycin released (%)</td>

<td rowspan="5">SR17 (MP9)</td><td> 0,25</td><td> 1080</td><td> 54</td>

<td> 0,5</td><td> 1540</td><td> 77</td>

<td> 1</td><td> 1880</td><td> 94</td>

<td> 2</td><td> 1920</td><td> 96</td>

<td> 3</td><td> 1920</td><td> 96</td>

Stage C

Clinical study of pharmacokinetics

The in vivo pharmacokinetics of azithromycin SR17 and SR18 multiparticulate dosage forms were evaluated in 300 healthy fasting human subjects (100 subjects per treatment group) in a randomized parallel group study. Subjects were randomly assigned to one of the following 3 treatment groups: SR17 (2 gA), SR18 (3 gA), and 8 x 250 mgA of Zithromax tablets.^® (control) which, combined, contain 2 gA of azithromycin, 1.1 g of dibasic sodium phosphate and other inactive ingredients.

For all doses, a total volume of 240 ml of water was consumed. To administer formulations SR17 and SR18, SR17 or SR18 was added to the bottle containing the excipient mixture. Water (60 ml) was added to this bottle containing SR17 or SR18 and the excipient mixture. The bottle was shaken for 30 seconds to mix the suspension. The entire contents of the bottle were administered directly to the subject's mouth. An additional 60 ml of water was added to rinse the bottle and the rinse was administered to the subject's mouth. An additional 120 ml of water was administered using a measuring cup.

ES 2 312 929 T3

To administer the eight Zithromax tablets^® 250 mg commercial, subjects were given 240 ml of water to orally administer eight tablets one at a time.

All subjects received the dose orally after fasting overnight. All subjects were then asked to refrain from lying down and eating and drinking beverages other than water for the first 4 hours after administration.

Sufficient blood was drawn from each subject to provide a minimum of 3 ml of serum to determine the pharmacokinetics of azithromycin. Blood was collected in tubes that had no preservative, anticoagulant, and serum separator at the following times: 0 (just before administration), 2 and 3 hours (around the projected Tmax) after drug administration. Serum azithromycin concentrations were determined using the high performance liquid chromatography assay described in Shepard et al., J Chromatography. 565: 321-337 (1991).

The results of this study are provided in Table 8.

TABLE 8

<td>Formulation</td><td>Serum azithromycin concentration (pg / ml) 2 hours after administration</td><td>Serum azithromycin concentration (pg / ml) 3 hours after administration</td>

<td>SR17</td><td>1.04 % CV 36</td><td>0.933 % CV 34</td>

<td>SR18</td><td>1.57 % CV 47</td><td>1.26 % CV 25</td>

<td>Tablets</td><td> 1,08</td><td> 0,962</td>

<td>(8 x 250 mg)</td><td>% CV 37</td><td>% CV 32</td>

Based on the results in Table 8, the serum azithromycin concentration for SR17 and SR18 at 2 and 3 hours after administration was not less than the serum concentrations of the 8 Zithromax® tablets. The data indicate that there was no delay in drug release from SR17 or SR18 given the amount of alkalinizing agent administered.

Stage D

Gastrointestinal tolerance clinical study

The azithromycin SR17 and SR18 multiparticulate dosage forms tested in Step B were assessed for tolerance. On day 1, subjects were verbally questioned for adverse events at least approximately the following times: 0, 2, 4, 8, 12 and 24 hours. The incidence of adverse gastrointestinal events experienced by the analyzed subjects is provided in Table 9.

TABLE 9

<td rowspan="2">Formulation</td><td colspan="3">Number of subjects with adverse GI side effects</td>

<td>Diarrhea</td><td>Sickness</td><td>Vomiting</td>

<td>SR17</td><td> 44</td><td> 28</td><td> 6</td>

<td>SR18</td><td> 59</td><td> 51</td><td> 9</td>

<td>Control (8 x 250 mg tablets)</td><td> 39</td><td> 30</td><td> 7</td>

ES 2 312 929 T3

The results in Tables 7 and 8 demonstrate that the 2 gA or 3 gA azithromycin multiparticulate dosage forms analyzed, in which the multiparticles included Lutrol^® at 4% by weight and the mixture of excipients having TSP in the amount of 352 mg, did not provide advantages in reducing serum concentration or improving GI tolerance compared to the immediate release tablet dosage form.

Thus, as the results in Tables 8 and 9 show, an effective amount of alkalizing agent was not used with these specific multiparticles to provide the desired GI release profiles and side effects.

Example 8

Procedure for Determining the Alkalizing Agent to Use with Immediate Release Azithromycin

The effective amount of alkalizing agent that would suppress dissolution of azithromycin in the stomach and therefore result in improved tolerance of the immediate release (IR) formulation was calculated as follows. The IR formulation, without alkalizing agent, releases approximately 92% of the drug in 30 minutes at pH 6.0 as described in Example 5, ie 3.07% per minute at pH 6.0. To improve tolerance, the dissolution rate of azithromycin should be reduced, preferably to a rate that will release only about 1.5 gA, or less, in the first 30 minutes or no more than 2.5% per minute. The dissolution rate of the drug from an IR formulation was assumed to be directly proportional to the solubility of azithromycin, which is pH dependent as shown in Table 10.

TABLE 10

<td>PH</td><td>Azithromycin Solubility (mg / ml)</td>

<td> 2,88</td><td> 440</td>

<td> 4,09</td><td> 430</td>

<td> 6,15</td><td> 380</td>

<td> 6,42</td><td> 310</td>

<td> 6,61</td><td> 250</td>

<td> 6,65</td><td> 140</td>

<td> 6,75</td><td> 120</td>

<td> 6,87</td><td> 36</td>

<td> 7,41</td><td> 5</td>

<td> 8,02</td><td> 0,5</td>

<td> 8,85</td><td> 0,02</td>

<td> 10,34</td><td> 0,005</td>

Since it was assumed that the release rate of azithromycin is directly proportional to its solubility, the solubility of azithromycin at pH 6.0, at a rate of 3.07% is 309 mg / ml, which was obtained by interpolation to from Table 10. The corresponding solubility that would provide improved tolerance is calculated as:

Solubility⁷ = (390 mg / ml) (2.5%) / (3.07%)

Solubility⁷ is defined as the solubility at which dissolution of azithromycin does not produce excessive adverse GI side effects. It was observed that the solubility⁷ of the equation was 318 mg / ml. Again, by interpolation from Table 10, the pH that corresponds to the solubility⁷ is 6.4.

Preferably, the amount of alkalizing agent that is formulated with IR azithromycin or dosed at the same time as IR azithromycin is that which, when administered, will raise the pH of the stomach to 6.63 for at least 30 minutes. To calculate this amount, it is assumed that the basal amount of stomach acid is about 0.96 mmol H + and that the average acid secretion rate is about 3 mmol per hour.

ES 2 312 929 T3

To calculate the amount of alkalizing agent (s) that should be included in the formulation, it is necessary to obtain titration data for various alkalizing agents and combinations of alkalizing agents. Thus, solutions of various alkalizing agents and combinations of alkalizing agents were prepared and titrated with 0.1 N HCl and the resulting pH values ​​were measured. From these data, it is possible to calculate a pH profile as a function of time as described in Step A of Example 1, assuming that the basal amount of acid in the stomach is about 0.96 mmol H + and that the average rate of acid secretion is approximately 3 mmol per hour. These data are presented in Figs. 2 and 3.

In Fig. 3, it is observed that formulations containing 176 mg of TSP or 176 mg of TSP plus 500 mg of CaCO3 are not expected to increase gastric pH to 6.8 during a period of 30 to 40 minutes while the Formulations containing (76 mg TSP and 500 mg TRIS, 176 mg TSP plus 1000 mg TRIS, or 176 mg TSP plus 250 mg Mg (OH) 2) are expected to provide increased pH for at least that weather. The 352 mg TSP formulation appears to provide a pH of 6.48 for just over 30 minutes and can therefore be considered to contain the minimum amount of alkalizing agent necessary to reduce GI side effects after administration of a high dose of IR formulation of azithromycin. Considering the inter-individual differences in gastric acid secretion rates and considering robust performance of a dosage form, a greater than minimal amount of alkalinizing agent is preferred.

Using a similar analysis of the data in Fig. 2, 352 mg TSP and 352 mg TSP + 500 mg calcium carbonate are predicted to barely provide the appropriate increased gastric pH for the desired time while the remainder of the combinations analyzed provide an adequate increase in gastric pH for the desired period of time. It should be appreciated that the above general procedure for determining the effective amount of alkalizing agent depends on the assumptions made about the basal acid conditions in the stomach and the rate of acid secretion. The values ​​that have been selected represent the means for generally healthy individuals and there may be significant variability between individuals and within individuals. The effective amount of alkalizing agent under a different set of assumptions can be calculated following the procedure described above.