United States Patent [19]
`Curatolo et al.
`
`[54] METHOD OF ADMINISTERING
`AZITHROMYCIN
`
`[75]
`
`Inventors: William J, Curatolo, Niantic; George
`H. Foulds, Waterford, both of Conn.;
`Hylar L. Friedman, Brattleboro, Vt.
`
`[73] Assignee: Pfizer Inc., New York, N.Y.
`
`(21] Appl. No.: 235,009
`
`[22] Filed:
`
`Apr. 29, 1994
`
`[51]
`
`Int. Cl.6
`
`............................ A61K 31170; A61K 9114;
`A61K 9/20
`[52] U.S. Cl. ............................ 514/29; 514/960; 424/464;
`424/465; 424/474; 424/480; 424/481; 53617.2
`[58] Field of Search ...................... 514/29, 960; 53617.2;
`424/464,465,474, 480, 481
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5/1983 Sciavolino et al. ....................... 514/29
`4,382,085
`4,474,768 10/1984 Bright ....................................... 514/29
`4,517,359
`5/1985 Kobrehel et al. ........................ 536/7.4
`4,963,531 10/1990 Remington ................................ 514/29
`5,250,518 1011993 Kobrehel et al. ......................... 514/29
`5,350,839
`911994 Asaka et al .............................. 536/7.4
`
`FOREIGN PATENT DOCUMENTS
`
`0307128
`0582396
`
`3/1989 European Pat. Off ..
`211994 European Pat. Off ..
`
`OTHER PUBLICATIONS
`
`Curatolo et al. J. Pharm. Sci., vol. 77 (4), pp. 322-324,
`(1988).
`Welling et al. J. Pharm. Sci., vol. 67 (6), pp. 764--766,
`(1978).
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005605889A
`(Ill Patent Number:
`[451 Date of Patent:
`
`5,605,889
`Feb.25, 1997
`
`Welling et a!. J. Pharm. Sci., vol. 68 (2), pp. 150-155,
`(1979).
`Malmborg, A. Curr. Med. Res. Opin. vol. 5 (Suppl. 2), pp.
`15-18, (1978).
`
`Drew eta!., Pharmacotherapy, 12, 3, 161-173 (1992).
`Chu et al., J. Clin. Pharmacol., 32, 32-36 (1992).
`Hopkins, S., Am. J. Med., 91 (Suppl 3A), 405--455 (1991).
`
`Toothaker et al., Ann. Rev. Pharmacal. Toxicol. vol. 20,
`173-199, 1980.
`Russell et al., Pharmaceutical Research, vol. 10, No. 2,
`187-196, 1993.
`CA Abstracts: vol. 120:38194a; 1994.
`
`Zithromax (Trademark of Pfizer, Inc.) Capsules Package
`Insert for azithromycin capsule dosage form sold commer(cid:173)
`cially in U.S.
`
`Primary Examiner-John Kight
`Assistant Examiner-Howard C. Lee
`Attome)~ Agent, or Firm-Peter C. Richardson; Gregg C.
`Benson; James T. Jones
`
`[57]
`
`ABSTRACT
`
`An oral dosage form of azithromycin which does not exhibit
`an adverse food effect; Specific azithromycin oral dosage
`forms including tablets, powders for oral suspensions and
`unit dose packets; Methods of treating microbial infections
`with the dosage forms; And therapeutic packages containing
`the dosage forms.
`
`99 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1035
`Page 001
`
`

`

`5,605,889
`
`1
`METHOD OF ADMINISTERING
`AZITHROMYCIN
`
`This invention relates to a dosage form of azithromycin,
`and also to a method of treating a microbial infection which
`involves administering azithromycin in the fed state to a
`mammal, including a human patient, in need of such treat(cid:173)
`ment.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`2
`Welling, Ann. Rev. Pharmacal. Toxicol., 1980, 173-99,
`discuss various drugs whose absorption is delayed in the
`presence of food (cephalexin, cefaclor, metronidazole, aspi(cid:173)
`rin, alclofenac, indoprofen, digoxin, cimetidinc), whose
`5 absorption may be unaffected by food (ampicillin, erythro(cid:173)
`mycin estolate, spiramycin, propylthiouracil, oxazepam,
`bendroftumethiazide), and whose absorption is increased in
`the presence of food (erythromycin ethylsuccinate, nitro(cid:173)
`furantoin, 8-methoxsalen, propranolol, metoprolol, dicou-
`10 marol, diazepam, hydrochlorothiazide).
`As a further example, there appears to be no clear or
`definitive support for the proposition that tablets might
`exhibit fewer food effects than capsules, or vice-versa.
`Toothaker and Welling review studies which demonstrate
`food related reduced absorption for tablet dosage forms of
`erythromycin stearate, aspirin, nafcillin, and sotalol.
`In the case of azithromycin, at least one (unpublished)
`study has shown that the absorption of azithromycin can be
`adversely affected if the patient is in a fed state, and it has
`20 heretofore been conventional wisdom that azithromycin
`capsule dosage forms exhibit a so-called adverse "food
`effect". Accordingly, in countries where azithromycin is
`currently available for use in the treatment of human
`patients, the product is sold with the specific direction that
`it be administered only in the fasted state, i.e. at least one
`hour before or two hours following a meal.
`It would accordingly be useful if azithromycin could be
`administered to patients that have eaten recently and also if
`a dosage form for azithromycin were available which could
`be administered to patients that have eaten, as well as
`patients in a fasted state.
`
`25
`
`30
`
`SUMMARY OF THE INVENTION
`
`Azithromycin is the U.S.A.N. (generic name) for 9a-aza-
`9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spec(cid:173)
`trum antimicrobial compound ~erived from erythromycin A.
`Azithromycin was independently discovered by Bright, U.S.
`Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No.
`4,517,359. These patents disclose that azithromycin and
`certain derivatives thereof possess antibacterial properties
`and are accordingly useful as antibiotics.
`In general, it is known that the absorption and bioavail(cid:173)
`ability of any particular therapeutic agent can be affected by
`numerous factors when dosed orally. Such factors include
`the presence of food in the gastrointestinal (GI) tract
`because, in general, the gastric residence time of a drug is
`usually significantly longer in the presence of food than in
`the fasted state. If the bioavailability of a drug is affected
`beyond a certain point due to the presence of food in the GI
`tract, the drug is said to exhibit a "food effect". Food effects
`are important inasmuch as, when a drug exhibits an adverse
`food effect, there is risk associated with administering it to
`a patient who has eaten recently. The risk derives from the
`potential that absorption into the bloodstream may be
`adversely affected to the point that the patient risks insuf(cid:173)
`ficient absorption to remediate the condition for which the
`drug was administered.
`Other factors can also be involved in drug bioavailability,
`the following being a non-comprehensive listing:
`(1) The particular dosage form can affect bioavailability.
`For example, the gastric residence time of a tablet or capsule
`can be significantly longer than that of a suspension, and the 40
`difference may vary depending on whether the subject has
`eaten or is fasted.
`(2) The pH of the stomach varies, between the fed and
`fasted state, with the amount of food therein, and drugs
`which are decomposition-sensitive to pH can be affected 45
`accordingly.
`(3) The capacity of the liver to metabolize an absorbed
`drug (so-called "first pass" metabolism) may vary with the
`type of meal eaten. For example some vegetables (such as
`brussels sprouts) can stimulate first pass metabolism of some
`drugs, but not others. Grapefruit juice, on the other hand,
`may inhibit first pass metabolism of some drugs.
`(4) Bile, which is released from the gallbladder into the
`small intestine when a meal is ingested, has the ability to
`solubilize poorly soluble drugs and thus increase bioavail(cid:173)
`ability.
`Additional factors can also be involved in the absorption
`and bioavailability of a particular drug, and absorption can
`actually be increased as well as decreased. These additional
`factors include, for example, pH-dependent solubility, site(cid:173)
`specific intestinal permeation rate, instability to intestinal
`enzymes, susceptibility to first pass metabolism, and insta(cid:173)
`bility to colonic bacteria. Given the plethoraoffactors which
`can influence bioavailability, there usually is no way to
`predict, in the absence of actual testing, whether a particular
`drug will exhibit a food effect. For example, Toothaker and
`
`35
`
`This invention provides an oral dosage form of azithro(cid:173)
`mycin which can be administered to a mammal (including
`humans) that has eaten and which exhibits substantially no
`adverse food effect, excluding any dosage form which
`contains a significant amount of an alkaline earth oxide or
`hydroxide. The dosage form exhibits a mean (AUC1~d)/
`(AUC1.,) of at least 0.80 with a lower 90% confidence limit
`of at least 0.75, the terms "(AUC1ed)I(AUC1,,)'' and "90%
`confidence limit" being fully defined below.
`In a further aspect, this invention provides a specific oral
`azithromycin dosage form which does not exhibit an adverse
`food effect. The dosage form comprises azithromycin and a
`pharmaceutically acceptable carrier, as hereinafter further
`detailed and described. The dosage form is in the form of a
`tablet (including both swallowable-only and chewable
`forms), in the form of a unit dose packet (sometimes referred
`to in the art as a "sachet"), in the form of a suspension made
`from a unit dose packet, in the form of a powder for oral
`suspension, and in the form of an oral suspension per se. It
`is noted that when a unit dose packet is constituted, it is
`probably mainly in the form of a suspension if reconstituted
`according to directions, although the extent of suspension
`versus solution depends on a number of factors such as pH.
`The use of the term "suspension" herein is intended to
`60 embrace liquids containing azithromycin partially in sus(cid:173)
`pension and partially in solution, and also totally in solution.
`In a further aspect, this invention provides a method for
`treating a microbial infection in a mammal which comprises
`administering, to a mammal that has eaten in need of such
`treatment, an antimicrobially effective amount of azithro(cid:173)
`mycin in an oral dosage form which exhibits substantially no
`adverse food effect. The dosage form employed exhibits a
`
`50
`
`55
`
`65
`
`Par Pharm., Inc.
`Exhibit 1035
`Page 002
`
`

`

`5,605,889
`
`3
`mean (AUCJ"ed)/(AUC;:rr) of at least 0.80 with a lower 90%
`confidence limit of at least 0.75.
`Reference herein and in the claims to a mammal (includ(cid:173)
`ing humans) that has "eaten" means that the mammal has
`eaten food of any sort within one hour prior to dosing up to 5
`two hours after dosing.
`Jn a further aspect, this invention provides a therapeutic
`package suitable for commercial sale, comprising a con(cid:173)
`tainer, an oral dosage form of azithrornycin which does not
`exhibit an adverse food effect contained therein, and, asso(cid:173)
`ciated with said container, written matter non-limited as to
`whether the dosage form can be taken with or without food.
`It is noted that powders for oral suspension and unit dose
`packets, of course, are not ingested directly by patients;
`rather, they are reconstituted in a suitable vehicle. These
`terms are nonetheless considered to be within the penumbra
`of the term "dosage form" for purposes of this invention.
`Capsules as a dosage form do not form a part of the
`invention.
`For purposes of this invention azithromycin may be
`administered alone or in combination with other therapeutic 20
`agents.
`A food effect can be detected and quantified as described,
`for example in Toothaker and Welling, supra, by determin(cid:173)
`ing the area under a curve (AUC) which plots the serum
`concentration (e.g., in Jlg/rnL) of azithromycin along the
`ordinate (Y-axis) against time along the abscissa (X-axis).
`Generally, the values for AUC represent a number of values
`taken from all the subjects in a patient test population and
`are, therefore, mean values averaged over the entire test
`population. By measuring the area under the curve for a fed
`population of subjects (AUC1.d) and comparing it with the
`area for the same population of fasted subjects (AUC15,), it
`can be determined whether a given drug exhibits an adverse
`food effect or not.
`For definitional purposes of this invention, and specifi(cid:173)
`cally with respect to azithrornycin dosage forms only, a
`dosage form of azithrornycin exhibits an adverse food effect
`if, after dosing a population, once fasted and once fed, the
`mean (AUC1.d)I(AUC151) is below the value 0.80 and/or the
`lower 90% confidence limit for this ratio is below 0.75.
`Conversely, a dosage form of azithrornycin which does
`not exhibit an adverse food effect is one which, when tested
`on a test population, exhibits a value for (AUCf.ed)I(AUCfs.t)
`of at least 0.80 and a lower 90% confidence limit for this
`value of at least 0.75. The value for mean (AUC.f•d)/(AUC15,)
`can have any value above 0.80 and still be within the scope
`of this invention, though it is preferred that it have an upper
`(mean) limit of 1.25, with an upper 90% confidence limit of
`1.40 or below.
`A population of "fed" subjects, for purposes of definition
`and for measuring AUCfed• is one made up of subjects each 50
`of whom has eaten a Food and Drug Administration (FDA)(cid:173)
`recornrnended standard high fat breakfast within a period of
`twenty minutes, and then ingested (i.e., swallowed) the test
`dosage form essentially immediately thereafter. A standard
`high-fat breakfast consists of, for example, two eggs fried in 55
`one tablespoon of butter, two strips of bacon, six ounces of
`hash brown potatoes, two pieces of toast with two teaspoons
`of butter and two pats of jelly, and eight ounces of whole
`milk. This standard high-fat breakfast contains approxi(cid:173)
`mately 964 calories, 54% supplied as fat (58 gm) and 12%
`supplied as protein, calculated using the monograph "Nutri- 60
`tive Value of Foods", U.S. Department of Agriculture Horne
`and Garden Bulletin Number 72. Additional food can also be
`consumed within the twenty minute period and the subject
`still qualifies as "fed". A "fasted subject" for purposes of
`definition and for measuring AVC1s, is one who has not eaten 65
`for at least eight hours, typically overnight, prior to ingestion
`of the dosage form.
`
`45
`
`4
`The 90% confidence limits on AUC1.JAUC151 for a par(cid:173)
`ticular population, in this case either a fed or a fasted
`population, can be (and were) calculated as described fol(cid:173)
`lowing using Schuirman's two one-sided test procedure.
`The log-transformed AUCs were analyzed by means of an
`analysis of variance appropriate for a two-period, two(cid:173)
`treatment crossover design. Analysis was carried out using
`Statistical Analysis System (SAS) software from SAS Insti(cid:173)
`tute, Cary, N.C. SAS procedure referred to in the SAS
`10 software as PROC GLM was used to determine sequence,
`subject within sequence, period and treatment (Fed/Fasted)
`effects. The sequence effect was tested using the [subject
`within sequence] mean square from the analysis of variance
`(ANOVA) as an error term. All other effects were tested
`against residual error (error mean square) from the ANOVA.
`15 The LSMEANS statement of SAS was used to calculate the
`least square means and their standard errors and co variances.
`These were used to obtain estimates for adjusted differences
`between treatment means and standard errors associated
`with these differences (log transformed).
`The 90% confidence interval for two-way crossover
`design was constructed, based on these estimates, as the
`difference plus (or minus) the standard error of the difference
`times the 95th percentile of the t-distribution with (twice the
`sample size-2) degrees of freedom. The anti-log was taken
`25 on the limits to obtain the corresponding confidence for the
`ratio.
`That a dosage form according to the invention does not
`exhibit an adverse food effect is surprising in view of the fact
`that azithrornycin is unstable at low (acid) pH, on the order
`30 of the acidity encountered at the pH of stomach acid. The
`inventors have demonstrated that azithrornycin breaks down
`if exposed to stomach juices which inherently exhibit acid
`pH. Thus, without being bound to any mechanism of action,
`it is surprising that rapid disintegration in the GI tract
`35 appears to be of importance to the invention.
`Commonly assigned co-pending application Ser. No.
`07/922,262 filed Jul. 30, 1992 discloses taste masking corn(cid:173)
`positions of bitter pharmaceutical agents, such as azalide
`antibiotics, containing, as a taste-masking component, a
`40 basic compound selected from the group consisting of
`alkaline earth oxides and alkaline earth hydroxides. A corn(cid:173)
`position of this invention, if it contains an alkaline earth
`oxide or hydroxide at all, contains less than a taste-masking
`amount of the taste-masking component. A composition of
`this invention therefore preferably contains less than about
`1% of an alkaline earth oxide or hydroxide, and may be free
`of such taste-masking component entirely.
`
`DETAILED DESCRIPTION
`
`Azithrornycin is typically present in formulations accord(cid:173)
`ing to the invention in an amount of from about 25 rng to
`about three grams, preferably 250 rng to two grams, for
`treatment of a human. If dosage forms are to be used for
`animal/veterinary applications, the amount can, of course,
`be adjusted to be outside these limits depending, for
`example, on the size of the animal subject being treated (e.g.,
`a horse). The term "azithrornycin" includes the pharmaceu(cid:173)
`tically acceptable salts thereof, and also anhydrous as well
`as hydrated forms. The azithrornycin is preferably present as
`the dihydrate, disclosed, for example, in published European
`Patent Application 0 298 650 A2.
`In order to test whether a particular azithrornycin dosage
`form exhibits an adverse food effect, the most reliable
`method is actually to test the dosage form in vivo on a
`subject population, once fed and once fasted, determine the
`level of serum (or plasma) azithrornycin with time, plot
`curves for the concentration of serum (or plasma) azithro-
`
`Par Pharm., Inc.
`Exhibit 1035
`Page 003
`
`

`

`5,605,889
`
`5
`mycin with time in each subject (fed and fasted) as described
`above, determine the area under each curve (conventionally,
`for example by simple integration) and finally determine
`whetherthe mean ratio (AUCJed)/(AUC1,) exceeds 0.80, and
`whether the lower 90% confidence limit equals or exceeds
`0.75.
`It is believed that the azithromycin dosage forms of the
`invention do not exhibit a food effect in large part because
`they either provide azithromycin ready for dissolution in the
`Gl tract essentially immediately following ingestion (sus(cid:173)
`pensions), or they disintegrate rapidly following ingestion
`(tablets) and thereby provide azithromycin rapidly for dis(cid:173)
`solution. While not wishing to be bound by theory, it is
`believed that if an azithromycin dosage form provides
`azithromycin immediately following ingestion for dissolu(cid:173)
`tion in the GI tract, or at least provides azithromycin for
`dissolution within a certain time period following ingestion,
`the azithromycin will be absorbed into the bloodstream at a
`rate which results in substantially no adverse food effect. In
`order for an adequate rate of absorption to occur, it is
`believed that the dosage form should provide azithromycin
`at a rate such that at least about 90% of the azithromycin
`dissolves within about 30 minutes following ingestion,
`preferably within about 15 minutes following ingestion. A
`non-capsule dosage form comprising azithromycin is also
`considered to fall within the scope of the appended claims if 25
`it satisfies the in vitro dissolution testing requirements
`enumerated herein. An azithromycin dosage form according
`to the invention exhibits at least about 90% dissolution of
`azithromycin within about 30 minutes, preferably within 15
`minutes, when an amount of the dosage form equivalent to
`200 mg of azithromycin is tested as set forth in USP test
`<711> in a USP-2 dissolution apparatus under conditions at
`least as stringent as the following: 900 m1 approx. O.lM
`dibasic sodium phosphate buffer, pH 6.0, 37° C. with
`paddles turning at 1 00 rpm. This test is described in US
`Pharmacopaea XXII, pp. 1578-1579. Dosage forms which 35
`pass this test under more stringent conditions (lower volume
`of buffer, greater amount of dosage form, lower temperature,
`higher pH, lower paddle speed) are also included under the
`above definition. Any modifications to this test are also
`described herein. The time required for dissolution of a 40
`particular azithromycin dosage form in this in vitro test is
`believed to be an indicator of the time required for disso(cid:173)
`lution of the dosage form in the GI environment. The
`following discussion is believed pertinent in this regard.
`It is generally assumed and observed that the in vitro 45
`dissolution rate of dosage forms exhibits a rank order
`correlation with in vivo dissolution, particularly for a single
`dosage form type, e.g. tablets, which vary systematically in
`composition. Thus in vitro dissolution evaluation serves an
`important role in control of the quality of manufactured 50
`dosage forms. It is not necessarily true that the in vitro
`dissolution rate is exactly the same as the in vivo dissolution
`rate. This is not surprising, since the artificial conditions of
`an in vitro dissolution test (e.g. vessel geometry, stirring rate,
`stirring method, and so forth) are not identical to the
`conditions under which a dosage form disintegrates and 55
`dissolves in the GI tract.
`When comparing dosage forms of different type, e.g.
`capsules and tablets, in vitro dissolution rate should corre(cid:173)
`late roughly with in vivo dissolution rate. However, subtle
`differences exist between the disintegration mechanisms of 60
`capsules and tablets. For capsules, at least partial dissolution
`of the gelatin shell must precede complete dissolution of the
`enclosed drug. Furthermore, capsule shells generally dis(cid:173)
`solve first at the capsule ends, and later at the capsule center.
`Tablets, on the other hand, disintegrate homogeneously. 65
`Thus subtle differences may exist in the in vitro/in vivo
`dissolution correlation when comparing capsules and tab-
`
`6
`lets. For example, capsules and tablets which exhibit similar
`in vitro dissolution rates may exhibit subtle differences in in
`vivo dissolution rate. While such subtle differences may
`have no therapeutically significant effect on systemic bio(cid:173)
`availability of an orally dosed drug, there are situations in
`which a significant effect may occur. For example, if a drug
`has the potential to exhibit an adverse food effect, drug(cid:173)
`containing capsules and tablets which exhibit similar in vitro
`dissolution rates may actually differ with respect to whether
`an adverse food effect is observed when the dosage forms
`10 are orally dosed. In fact, this has been observed for azithro(cid:173)
`mycin, as exemplified in the Examples herein.
`For the in vitro dissolution studies disclosed herein,
`azithromycin was assayed by HPLC, utilizing a 5 micron
`alumina based hydrocarbonaceous spherical particle chro-
`15 matographic column (15 cmx0.4 em), and a 5 micron
`alumina based hydrocarbonaceous spherical particle precol(cid:173)
`urnn (5 cmx0.4 em) (both available from ES Industries,
`Marlton, N.J.). A mobile phase consisting of 71% phosphate
`buffer/29% acetonitrile (pH 11) was used, with electro-
`20 chemical detection (e.g. Bioanalytical Systems, West Lafay(cid:173)
`ette, Ind., LC-48 amperometric detector with dual series
`glassy carbon electrodes).
`For in vivo food effect studies, serum azithromycin is
`assayed using an HPLC assay described by R. M. Shepard
`eta!. (1991) J. Chromatog. Biomed. Appl. 565, 321-337,
`with amperometric electochemical detection. Alternatively,
`any assay method that produces equivalent results, for
`example, bioassay, can be used.
`Tablets according to the invention contain, as necessary
`ingredients, azithromycin and a disintegrant. Examples of
`tablet disintegrants are starch, pregelatinized starch, sodium
`starch
`glycolate,
`sodium
`carboxymethylcellulose,
`crosslinked sodium carboxymethylcellulose (sodium cros(cid:173)
`carmellose; crosslinked starch available under the registered
`trademark Ac-Di-Sol from FMC Corp., Philadelphia, Pa.),
`clays (e.g. magnesium aluminum silicate), microcrystalline
`cellulose (of the type available under the registered trade-
`mark Avice) from FMC Corp. or the registered trademark
`Emcocel from Mendell Corp., Carmel, N.Y.), alginates,
`gums, surfactants, effervescent mixtures, hydrous aluminum
`silicate, cross-linked polyvinylpyrrolidone (available com(cid:173)
`mercially under the registered trademark PVP-XL from
`International Specialty Products, Inc.), and others as known
`in the art. Preferred disintegrants for azithromycin tablets are
`sodium croscarmellose (Ac-Di-Sol), sodium starch glyco(cid:173)
`late (available commercially under the registered trademarks
`Primojel from Avebe (Union, N.J.) or Generichem, (Little
`Falls, N.J.) and Explotab from Mendell Corp.), microcrys(cid:173)
`talline cellulose (Avice!), and cross-linked polyvinylpyrroli(cid:173)
`done (PVP-XL). Azithromycin tablets of this invention
`comprise azithromycin and 1-25% disintegrant, preferably
`3-15% disintegrant based on total tablet weight. For
`example, a 463.5 mg tablet (250 mg activity azithromycin)
`may contain 9 mg sodium croscarmellose and 27 mg prege(cid:173)
`latinized starch.
`In addition to the active ingredient azithromycin and a
`disintegrant, tablets according to this invention may be
`formulated to optionally include a variety of conventional
`excipients, depending on the exact formulation, such as
`binders, flavorings, buffers, diluents, colors, lubricants,
`sweetening agents, thickening agents, and glidants. Some
`excipients can serve multiple functions, for example as both
`binder and disintegrant.
`Examples of binders are acacia, cellulose derivatives
`(such as methylcellulose and carboxymethylcellulose,
`hydroxypropylmethylcellulose,
`hydroxypropylcellulose,
`hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol,
`polymethacrylates, polyvinylpyrrolidone,
`starch paste,
`sucrose, sorbitol, pregelatinized starch, gum tragacanth,
`
`30
`
`Par Pharm., Inc.
`Exhibit 1035
`Page 004
`
`

`

`5,605,889
`
`20
`
`25
`
`7
`alginic acids and salts thereof such as sodium alginate,
`magnesium aluminum silicate, polyethylene glycol, guar
`gum, bentonites, and the like. A preferred binder for azithro(cid:173)
`rnycin
`tablets
`is pregelatinized starch (available, for
`example, under the registered trademark Starch 1500, from
`Colorcon, Inc., West Point, Pa.).
`Flavors incorporated in the composition may be chosen
`from synthetic flavor oils and flavoring aromatics and/or
`natural oils, extracts from plants leaves, flowers, fruits, and
`so forth and combinations thereof. These may include cin(cid:173)
`namon oil, oil of wintergreen, peppermint oils, clove oil, bay
`oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of
`nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Also
`useful as flavors are vanilla, citrus oil, including lemon,
`orange, grape, lime and grapefruit, and fruit essences,
`including apple, banana, pear, peach, strawberry, raspberry,
`cherry, plum, pineapple, apricot, and so forth. The amount of
`flavoring may depend on a number of factors including the
`organoleptic effect desired. Generally the flavoring will be
`present in an amount of from 0.5 to about 3.0 percent by
`weight based on the total tablet weight, when a flavor is
`used.
`A variety of materials may be used as fillers or diluents.
`Examples are spray-dried or anhydrous lactose, sucrose,
`dextrose, mannitol, sorbitol, starch (e.g. starch 1500), cel(cid:173)
`lulose (e.g. microcrystalline cellulose; Avice!), dihydrated or
`anhydrous dibasic calcium phosphate (available commer(cid:173)
`cially under the registered trademark Emcornpress from
`Mendell or A-Tab and Di-Tab from Rhone-Poulenc, Inc.,
`Monmouth Junction, N.J.), calcium carbonate, calcium sul(cid:173)
`fate, and others as known in the art.
`Lubricants can also be employed herein in the manufac(cid:173)
`ture of certain dosage forms, and will usually be employed
`when producing tablets. Examples of lubricants are magne(cid:173)
`sium stearate, stearic acid, glycerylbehaptate, polyethylene
`glycol, ethylene oxide polymers (for example, available
`under the registered trademark Carbowax from Union Car(cid:173)
`bide, Inc., Danbury, Conn.), sodium Iaury! sulfate, magne(cid:173)
`sium Iaury! sulfate, sodium oleate, sodium stearyl fumarate,
`DL-leucine, colloidal silica, and others as known in the art.
`Preferred lubricants are magnesium stearate, and mixtures of
`magnesium stearate with sodium Iaury! sulfate. Lubricants 40
`generally comprise 0.5 to 7.0% of the total tablet weight.
`Other excipients such as glidants and coloring agents may
`also be added to azithrornycin tablets. Coloring agents may
`include titanium dioxide and/or dyes suitable for food such
`as those known as F. D. & C, dyes and natural coloring 45
`agents such as grape skin extract, beet red powder, beta
`carotene, annato, carmine, turmeric, paprika, and so forth. A
`coloring agent is an optional ingredient in the compositions
`of this invention, but when used will generally be present in
`an amount up to about 3.5 percent based on the total tablet
`~~
`As known in the art, tablet blends may be dry-granulated
`or wet granulated before tableting. Alternatively, tablet
`blends may be directly compressed. The choice of process(cid:173)
`ing approach depends upon the properties of the drug and
`chosen excipients, for example particle size, blending corn- 55
`patibility, density and flowability. For azithromycin tablets,
`granulation is preferred, with wet granulation being most
`preferred. Azithrornycin may be wet-granulated, and then
`other excipients may be added extragranularly. Alterna(cid:173)
`tively, azithrornycin and one or more excipients may be 60
`wet-granulated. In addition, tablets may also be coated, with
`a coating that exhibits little or no effect on or interference
`with tablet dissolution, to assure ease of swallowing or to
`provide an elegant appearance.
`In a preferred embodiment, tablets of this invention are 65
`film-coated to provide ease of swallowing and an elegant
`appearance. Many polymeric film-coating materials are
`
`8
`known in the art. A preferred film-coating material is
`hydroxypropylrnethylcellulose (HPMC). HPMC may be
`obtained commercially, for example from Colorcon Corp.,
`in coating formulations containing excipients which serve as
`5 coating aids, under the registered trademark Opadry. Opadry
`formulations may contain lactose, polydextrose, triacetin,
`polyethyleneglycol, polysorbate 80, titanium dioxide, and
`one or more dyes or lakes. Other suitable film-forming
`polymers also may be used herein, including, hydroxypro-
`10 pylcellulose, and acrylate-methacrylate copolymers.
`The tableting process itself is otherwise standard and
`readily practiced by forming a tablet from a desired blend or
`mixture of ingredients into the appropriate shape using a
`conventional tablet press. Tablet formulation and conven(cid:173)
`tional processing techniques have been widely described, for
`15 Example in Phannaceutical Dosage Forms: Tablets; Edited
`By Lieberman, Lachman, and Schwartz; Published by Mar(cid:173)
`cel Dekker, Inc., 2d Edition, Copyright 1989, the text of
`which is herein incorporated by reference.
`The azithrornycin dosage forms of this invention also
`include powders to make oral suspensions, and also the oral
`suspensions themselves. Generally the powder is a non(cid:173)
`caking, free flowing powder which is sold direct to phar(cid:173)
`macies or other retail outlets and then made up into the
`actual suspension by a pharmacist. The oral suspension is
`thus the actual dosage form ingested by patients. The typical
`shelf life for a suspension is about five days because
`azithrornycin therapy is generally of five days duration.
`Azithromycin suspensions according to the invention
`contain, as necessary ingredients in addition to azithromy-
`30 cin, one or more thickening agents in a total amount of 0.1
`to 2%, and a buffer or pH-altering agent in an amount of 0.1
`to 2.5%, with percentages being based on the weight of the
`dry powder formulation. Dispersing agents may also be used
`in an amount of from 0.05 to 2%. Preservatives may also be
`35 used in an amount from 0.1 to 2%.
`Suitable thickening agents function as suspending agents
`and include, for example, hydrocolloid gums known for
`such purpose, examples of which include xanthan gum, guar
`gum, locust bean gum, gum tragacanth, and the like. Alter(cid:173)
`natively, synthetic suspending agents may