Oral extended-release composition

[0001] The invention relates to sustained release formulations comprising drugs that are considered to be poorly soluble to insoluble, and which are suitable for administration to a patient in need who is in need of such treatment.

BACKGROUND OF THE INVENTION [0002] It is known in the pharmaceutical art to provide controlled release of pharmacologically active substances contained in compositions after oral administration to humans or animals. Such slow release compositions may be used to delay drug absorption until certain parts of the GI tract are reached. Such sustained release of the drug in the gastrointestinal tract then maintains the desired concentration of the drug in the bloodstream for a longer period of time than would otherwise be the case for the administration of conventional fast release dosage forms. It is contemplated that such controlled release dosage forms improve patient therapy.

[0003] For example, standard dosage regimens for a class of antibiotics called macrolide antibiotics are two, three or four times a day. These dosage regimens have been shown to be detrimental to macrolide antibiotics as well as to other drugs due to lack of convenience, and most importantly due to non-compliance. Therefore, many techniques are used to provide controlled and sustained release of pharmaceutical dosage forms to maintain therapeutic drug levels in serum and to minimize the effects of missed doses of medications due to patient failure to follow the instructions.

[0004] Typically, the goal of all sustained release formulations is to provide a longer period of pharmacological response after administration of the dosage form than would normally be experienced after the administration of the rapid release dosage form. However, it is often not easy to predict whether a specific sustained release formulation will provide the desired sustained release relatively poorly soluble to insoluble drug and it has generally been found that significant amounts of experiments are needed to obtain a formulation of such sustained release drugs that has the desired bioavailability after ingestion. .

[0005] It is generally known that the absorption and bioavailability of any particular therapeutic agent together with the sustained release formulations containing therapeutic agents can be influenced by a number of factors when taken orally. Such factors generally include, but are not limited to, the presence of food in the gastrointestinal tract. The presence of food in the gastrointestinal tract usually causes that the time spent in the stomach is much longer than if it is administered on an empty stomach. If the bioavailability of the drug is modified over a certain point from

- the presence of food in the gastrointestinal tract, then for the given drug there is a "food effect".

[0006] When the food adversely affects the food then there is a risk associated with administering it to a patient who has recently consumed the meal, potentially including but not limited to the fact that absorption into the bloodstream may be adversely affected to such a level that the patient risks absorption, which is insufficient to treat the condition for which the drug is administered. In addition, drugs that are sensitive to disintegration under the influence of pH can affect the change in stomach pH between the state after a meal and fasting state depending on the amount of food contained in it. Many other factors may also affect the absorption and bioavailability of a particular drug and currently there is no way to predict whether there will be a food effect for a particular drug in the absence of testing. At Toothaker and Welling, Ann. Rev. Pharmacol. Toxicol., 1980,

[0007] In the prior art, it is generally known that sustained-release formulations have a "food effect". Often, to avoid this effect, enteric coating is used that allows the drug to pass through the full stomach (after a meal) and absorption in the intestine. These formulations do not release significant amounts of active ingredients until the dosage form is in an environment with a higher pH of the small intestine. However, certain active ingredients may have reduced solubility at a higher pH and thus may be poorly absorbed in the intestine.

[0008] In view of the above, there is a need in the art for sustained-release formulations for drugs that are poorly soluble to insoluble. In addition, there is an additional need to provide a sustained release formulation for drugs that are sparingly soluble to insoluble, which do not show significant food effects. The invention provides a new, controlled release formulation comprising a drug that has a solubility of less than about 1 part of the drug per 30 parts of water, which provides gradual release of the drug without substantial or significant food effects, and methods for its preparation.

[0009] US 5,009,895 discloses a sustained release ibuprofen formulation using two different HMPC polymers.

[0010] US2003 / 0444668 discloses techniques and compounds of the induction of a "feeding regime" in a patient. The inducer of the feeding mode can be included in the sustained drug delivery system.

SUBJECT AND SUMMARY OF THE INVENTION

[0011] It is an object of certain embodiments of the invention to provide a sustained release oral composition comprising clarithromycin and its method of preparation.

[0012] It is an object of certain embodiments to provide a sustained release form of a macrolide antibiotic that does not have a significant effect on the food and its method of preparation.

[0013] The invention provides a sustained release dosage form comprising:

a) clarithromycin,

b) a first polymer having a viscosity of less than 50 cps, wherein the first polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose, and wherein the first polymer is present in an amount greater than 50% based on the weight of the dosage form; and

c) a second polymer having a viscosity greater than 200 cps, wherein the second polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose;

said dosage form is suitable for administration to human or other mammals twice or once per day.

[0014] In this invention, the drug is a macrolide antibiotic, 6-O-methylerythromycin A (clarithromycin), which is particularly beneficial for the treatment of common pediatric infections of the middle ear and upper respiratory tract. Other uses of clarithromycin are given in the 54th edition of Pysicians' Desk Reference 2000, pp. 409-417, which is incorporated herein by reference.

[0015] In certain preferred embodiments of the invention, the controlled release oral dosage form does not substantially show any significant effect of food when administered with food to a human patient or other mammal.

[0016] In certain embodiments of the invention, the controlled release oral dosage form ensures that the maximum active drug concentration in the blood plasma (Cmax) is less than 50% higher or lower than the Cmax of this fasted dosage form. Preferably, the maximum concentration of the active drug in the blood plasma (Cmax) is less than 40% higher or lower than Cmax of this fasted dosage form.

[0017] In certain embodiments of this invention, the controlled release dosage form ensures that the after-meal area-based bioavailability (AUC) is less than 20% higher or lower than the AUC of this fasted dosage form when fed. Preferably, the bioavailability based on area under the curve (AUC) when administered under fasted conditions is less than 10% higher or lower than the AUC of a given fasting dosage form.

[0018] As used herein, the term "dosage form" means a dose contained in at least one unit of the dosage form of this invention (e.g., a daily dose).

4-claritromycin may be included in two units of the dosage form of this invention for single administration once daily).

[0019] The terms "sustained release" and "controlled release" are used interchangeably in this application and are defined for purposes of this invention as releasing a drug from a dosage form at such a rate that when a dose of the drug is administered twice a day or once a day in the form with sustained release or controlled release, then drug concentrations (levels) in the blood (e.g., plasma) are maintained in the therapeutic range, but below toxic levels in the period from about 12 to about 24 hours.

[0020] The term "Cmax" is the highest drug concentration in the plasma obtained in the dosing interval, e.g. about 24 hours.

[0021] The term "Tmax" is the time that passes from the administration of the dosage form until the plasma drug concentration reaches the highest drug concentration in the plasma obtained in the dosing interval, e.g. about 24 hours.

[0022] As used herein, the term "AUC0-48" means the area under the plasma concentration-time curve, calculated by the trapezoidal method over the entire 48-hour interval.

[0023] The term "single dose" means that the human patient received a single dose of the drug formulation and the plasma drug concentration did not reach steady state.

[0024] The term "multiple dose" means that a human patient has received at least two doses of a drug formulation according to a dosage interval for that formulation (e.g., once a day). Patients who have received multiple doses of the controlled release formulation of the invention may or may not maintain constant drug levels in plasma, as defined in the term multiple dose.

[0025] The term "means" introduced before the pharmacokinetic value (e.g., Tmax), unless otherwise stated, refers to the arithmetic mean value of the pharmacokinetic value obtained for the patient population.

[0026] The term "feeding effect" or "food effect" in this invention means that at least one of the following occurs when the dosage form is administered after a meal:

a. there is a greater than about 20% increase or decrease in the area under the curve (ie AUC) relative to that when the dosage form is administered on an empty stomach.

b. there is a greater than 50% increase or decrease in the maximum plasma active drug levels (i.e., Cmax) relative to that when the dosage form is administered under fasting conditions; and / or

c. there is a greater than 40% increase or decrease in time to reach the maximum concentration of active drug in the blood plasma (i.e., Tmax) relative to that when the dosage form is administered on an empty stomach.

[0027] References herein and in the claims to a mammal (including a human) which is "after a meal" means that a mammal has ate a food (e.g., a high fat meal defined by the US Food and Drug Administration) within one hour prior to administration and or up to two hours after administration.

[0028] The term "bioavailable" is defined for the purposes of this invention as the rate and extent of drug uptake into circulation from a drug product at the site of administration and which becomes available at the site of action of the drug. Bioavailability is usually measured by the area under the curve (time to plasma drug concentration (AUC).

BRIEF DESCRIPTION OF THE DRAWINGS [0029] The following examples are illustrative embodiments of the present invention and are not intended to limit the scope of the invention.

FIG. 1 is a graph of profiles of the mean concentration in vivo versus time for Examples 1, 2 and the reference standard after one dose of 500 mg of clarithromycin prolonged-release fasting tablets.

FIG. 2 is a graph of the profiles of the mean concentration in vivo versus time for Examples 1, 2 and the reference standard after one dose of 500 mg of clarithromycin prolonged-release or non-fasting tablet.

FIG. 3 is a block diagram showing a method for producing clarithromycin prolonged release tablets with 500 mg of clarithromycin.

FIG. 4 is an in vitro dissolution data graph that shows the dissolution profiles of the formulations of Examples 1, 2 separately ER1 granules and ER2 granules in 0.1 M acetate at pH 5.0 in a USP XXII Type II dissolution apparatus at 50 revs / min.

DETAILED DESCRIPTION OF THE INVENTION [0030] The invention provides for controlled release of clarithromycin to a patient who needs such therapy e.g. when administered once a day. In particular, the invention provides a sustained release pharmaceutical composition comprising controlled release polymers for drug delivery over a prolonged period of time. Preferably, the composition of this invention is in the form of a tablet or capsule.

[0031] In certain preferred embodiments, the sustained release oral dosage form of this invention comprises from about 50 to about 1000 mg of clarithromycin and more preferably from about 250 to about 500 mg of clarithromycin.

[0032] In certain embodiments of this invention, the pharmaceutical composition may include other drugs in combination with macrolide clarithromycin. They can be formulated in conjunction with preparations for standard therapy of gastritis, ulcers or gastroesophageal reflux disease (GERD) such as preparations containing antiulcer drugs or against catarrh of the stomach; e.g. omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine or

- diisatidine or antacids such as magnesium hydroxide, aluminum hydroxide, sodium carbonate, sodium bicarbonate, simethicone or aluminum-magnesium hydroxide or their hydrates (e.g., the monohydrate known as magaldrat). In addition to the clarithromycin, the pharmaceutical composition of this invention may be administered in combination with a formulation containing bismuth salts such as basic bismuth citrate, bismuth basic salicylate, bismuth basic bicalutate, basic bismuth nitrate or basic bismuth gallate.

[0033] The amount of drug and drugs in the pharmaceutical composition can range from about 1 to 99% of the dosage form.

The amount may suitably range from 25% up to about 75% by weight of the dosage form, preferably from about 30 to about 60% by weight of the dosage form.

[0035] In the invention, the dosage form comprises at least one low viscosity polymer having a viscosity of less than 50 cps; and at least one high viscosity polymer with a viscosity greater than 200 cps, wherein the rate of drug release from the dosage form can be modified by adjusting the ratio of low and high viscosity polymers. The medicaments may be granulated (e.g., wet granulation) to give single granules or they may be dry blended prior to incorporation into the dosage form.

[0036] The polymers are present in mass percentages that provide sustained release of the drug in a dosage form.

[0037] The dosage form comprises at least one low viscosity polymer with a total amount greater than 50% w / w of this dosage form. In other embodiments, at least one high viscosity polymer is present in a total amount of less than 5% w / w of this dosage form.

[0038] The low-viscosity polymers of this invention preferably have a viscosity of less than 50 cps, e.g. less than about 25 cps, less than about 15 cps, less than about 10 cps, or less than about 5 cps. A polymer with a viscosity of less than 50 cps is hydroxypropylcellulose or hydroxypropylmethylcellulose.

[0039] The high viscosity polymers of this invention have a viscosity of greater than 200 cps, e.g. 1000 cps or more, 10,000 cps or more, or 100,000 cps or more.

[0040] A polymer with a viscosity of less than 50 cps is hydroxypropylcellulose or hydroxypropylmethylcellulose.

[0041] In certain embodiments of this invention, when the dosage form is administered after a meal, there is less than about 20% increase or decrease, preferably less than about 10% increase or decrease in area under the curve (ie AUC) relative to dosage form administered on an empty stomach.

[0042] In certain embodiments of the invention, there is less than about 50% increase or decrease and preferably less than about 40% increase or decrease in the maximum levels of active drug in blood plasma (i.e., Cmax) relative to the condition when the dosage form is administered on an empty stomach. .

[0043] In certain example embodiments of this invention, there is less than about

40% increase or decrease, preferably less than about 20% increase or decrease and most preferably less than about 10% increase over time to the maximum concentration of the active drug in the blood plasma (i.e., Tmax) relative to the condition when the dosage form is administered on an empty stomach.

[0044] In certain embodiments of the invention after oral administration, the composition induces a lower mean fluctuation rate in the plasma than the immediate release drug composition while maintaining a substantially equivalent bioavailability to that of the immediate drug release composition (e.g., erythromycin derivative).

[0045] In certain embodiments, the peak drug concentrations (e.g., erythromycin derivative) are lower than those obtained from the immediate release pharmaceutical composition and the area under the concentration-time curve and the minimum plasma concentration are substantially equal to those of the immediate-release pharmaceutical composition. .

In certain embodiments, a controlled release dosage form is obtained by granulating a clarithromycin (drug) with at least one polymer having a viscosity of less than 50 cps and together with at least one polymer having a viscosity greater than 200 cps; and compressing the granules into a tablet / tablet or caplet / caplet, or placing granules inside the capsule / capsule . A sustained release dosage form is alternatively obtained by granulating a portion of the drug with at least one polymer having a viscosity of less than 50 cps and granulating the remainder of the drug with at least one polymer with a viscosity greater than 200 cps, combining the two granulates to form a mixture and compressing the mixture into tablets / tablets or caplets / caplets or placing the mixture inside the capsule.

[0047] In certain embodiments, the controlled release dosage form is obtained by granulating the drug from a poorly soluble to insoluble at least one polymer with a viscosity of less than 50 cps and combining the granules with at least one polymer having a viscosity of greater than 200 cps to form a mixture; and compressing the mixture into a tablet / tablet or caplet / caplet, or placing the mixture inside the capsule / capsules. The controlled release dosage form is alternatively obtained by granulating the drug with at least one polymer having a viscosity greater than 200 cps and combining the granules with at least one polymer having a viscosity of less than 50 cps to form a mixture; and compressing the mixture into a tablet / tablet or caplet / caplet, or placing the mixture inside the capsule / capsules.

[0048] Pharmaceutically acceptable polymers useful in this invention include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, vinyl acetate / crotonic acid copolymers, copolymers of maleic anhydride / methyl vinyl ether, poly (alkylene oxide) including but not limited to oxide (polyethylene), (polymethylene) oxide, polybutylene oxide;

-8poli (hydroksyalkilometakrylan); poly (vinyl alcohol) having a small amount of acetal residues which is cross-linked with glyoxal, formaldehyde or glutamic aldehyde and with a degree of polymerization of from 200 to 30,000; a mixture of methylcellulose, crosslinked agar and carboxymethylcellulose; a hydrogel forming copolymer obtained by forming a dispersion of a particulate maleic anhydride polymer with styrene, ethylene, propylene, butylene or crosslinked isobutylene with from 0.001 to 0.5 moles of a saturated crosslinking agent per mole of maleic anhydride in the copolymer; Carbopol® acid carboxylic polymers with a molecular weight from 450,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linked water-swellable indene-maleic anhydride polymers; Goodrite® polyacrylic acid with molecular weight 80,000 to 200,000; grafted starch copolymers; Aqua-Keeps® acrylate polysaccharide polymers composed of condensed glucose units, such as cross-linked diester polyglycans and the like. Other polymers that form hydrogels are described in US 3,865,108; US 4,002,173 and US 4,207,893 all of which are incorporated into this document by reference. Mixtures of the above pharmaceutically acceptable polymers may also be used.

[0049] The polymers with given viscosities are hydroxypropylmethylcellulose or hydroxypropylcellulose. The dosage forms may contain the same polymers with different viscosities and / or different molecular weights. For example, at least one pharmaceutically acceptable polymer may contain two hydroxypropylmethylcellulose polymers such as, for example, Methocel K3 LV (having a viscosity of about 3 cps) and Methocel K100M CR (having a viscosity of about 100,000 cps). The polymer may further comprise two hydroxypropylcellulose forms such as Klucel LF and Klucel EF. In addition, the at least one polymer may comprise a mixture of Klucel and Methocel.

[0050] The polymer preferably forms a viscous gel in a water or other solvent system at a concentration sufficient to control the release of the drug.

[0051] In certain embodiments, a lubricant, e.g. glycerol monostearate, may be added prior to mixing of the two granules.

[0052] In the preparation of granulates, a binder may be used in an amount sufficient to form granules in combination with a suitable solvent (e.g., water) that may be compressed to the tablet core. Examples of binders include gum arabic, cellulose derivatives (such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose), gelatine, glucose, dextrose, xylitol, polymethacrylates, poly (vinylpyrrolidone), starch paste, sucrose, sorbitol, pre-gelatinized starch, gum tragacanth , alginic acids and their salts, such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites and the like.

Prior to extruding the granules into the granulation mixture, standard solid pharmaceutical diluents such as microcrystalline cellulose, lactose, dextrose and the like may be added.

-Similar in amounts from about 0 to 60% by weight based on the weight of the compressed, uncoated tablets.

[0054] In the preparation of the tablets of the invention, various solvents may be used to obtain granules. In addition to the optimization of the formulations according to the invention, various other diluents, excipients, lubricants, dyes, pigments, flavors, colorants, dispersants, emulsifiers, lubricants, plasticizers etc. can be used. The amounts of these additional materials will be adequate to provide the desired desired result. formulation. Particular examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated herein by reference.

[0055] Examples of lubricants are magnesium stearate, glycerol monostearate, glycerol monostearate, stearic acid, glycerol behenate, polyethylene glycol, ethylene oxide polymers (for example, available under the registered trademark Carbowax from Union Carbide, Inc., Danbury, Conn.), Sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, fumarate, DL-leucine, colloidal silica and others known in the art. The lubricant will be in the range of 0 to about 4 percent and preferably 0 to about 2.5 percent of the mass compacted uncoated tablet.

Examples of some of the disintegrants used in the invention are croscarmellose sodium, crospovidone, alginic acid, sodium alginate, DVB methacrylic acid, crosslinked PVP, microcrystalline cellulose, potassium polacrilin, sodium starch glycollate, starch, pregelatinized starch and the like. Some of the preferred disintegrants are crosslinked poly (vinylpyrrolidone) (e.g., Kollidon CL), cross-linked sodium carboxymethylcellulose (e.g., Ac-Di-Sol), starch or starch derivatives such as sodium starch glycollate (e.g. Explotab®) or combinations with starch (e.g. Primojel), swellable ion exchange resins such as Amberlite IRP 88, formaldehyde casein (e.g., Esma Spreng). Most preferably, the disintegrant is sodium starch glycolate. The disintegrant may contain approximately 0 to about 20% of the total weight of the tablet.

Aromas introduced into the composition may be selected from synthetic flavor oils and flavor flavors and / or natural oils, extracts from leaves, flowers, fruits and the like, and combinations thereof. These may include cinnamon oil, creeping gutting oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil and essential oil. strączyńca. Useful aromas are also vanilla, citrus oil, including lemon, orange, grape, lime, grapefruit and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like . The amount of aroma can depend on many factors including the desired organoleptic effect. In general, the aroma will be

- occurred in an amount of 0 to about 2% by mass based on the total weight of the tablet when the aroma is used.

[0058] Coloring agents may include titanium dioxide and / or food-appropriate dyes such as those known as F, D, and C, dyes and natural coloring agents such as grape skin extract, powdered red beetroot, beta carotene, annatto, carmine , turmeric, peppers and the like.

[0059] More specifically, the first protective layer can be applied at a level ranging from about 0 to about 10% by mass, which can be applied by a coating system such as Opadry Clear sold by Colorcon Corporation. In an especially preferred embodiment, the Opadry Clear is about 2.83% by mass and is combined with an osmotic agent in the range of about 0 to about 10% by weight. While the osmotic agent may be salt, low molecular weight molecules or water-soluble polymers, the preferred agent is sodium chloride. The osmotic agent is added to the coating system when the coating system is dispersed in purified water. The scattering system that contains the osmotic agent can then be sprayed onto the tablets to give a protective coating layer.

[0060] An optional inner or outer coating may also be applied, which comprises a pH-sensitive polymer that functions as an enteric polymer, i.e. it will not start to dissolve until it reaches a wide scale to enter gastric pH conditions. In general, pH-sensitive materials do not dissolve and start to release the active drug above pH 3.0 and preferably above 5.5. Materials such as Eudragit L (copolymer of poly (methacrylic acid, methylmethacrylate), 1: 1 ratio, average molecular weight of US $ 135000 Type A) or Eudragit S (poly (methacrylic acid, methyl methacrylate) copolymer, 1: 2 ratio) Average molecular weight can be used. 135000 - USP Type B) hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate and the like in the range of 0 to about 30% by mass,

[0061] The following examples illustrate various aspects of the invention. They should not be construed as limiting reservations in any way.

Example 1 [0062] A controlled release dual-granulated tablet containing 500 mg of clarithromycin was prepared, with the following composition. The first granules (ER1) were obtained using Clarithromycin, USP and one of the hydroxypropylmethylcellulose forms (Methocel K3LV), which were weighed and wet granulated using isopropyl alcohol / water (9: 1) in a vertical granulator. The first granulation formulation is shown in Table 1 below:

-11 Table 1

<td>COMPONENTS</td><td>%</td><td>^kg</td>

<td>Clarithromycin pellets (ER 1)</td><td></td><td></td>

<td>Clarithromycin, USP</td><td>44,00</td><td>0,440</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K3 LV)</td><td>56,00</td><td>0.560</td>

<td>Isopropyl alcohol, USP</td><td></td><td>0.540</td>

<td>Water</td><td></td><td>0,060</td>

<td>Together:</td><td>100.00</td><td>1,000</td>

[0063] A second granulate (ER2) was prepared using Clarithromycin, USP and two hydroxypropylmethylcellulose forms (Methocel K3LV and Methocel K100M CR) which were weighed and wet granulated using isopropyl alcohol / water (9: 1) in a vertical granulator. The second granulate formulation is shown in Table 2 below:

Table 2

<td>Clarithromycin pellets (ER 2):</td><td></td><td></td>

<td>Clarithromycin, USP</td><td>44,00</td><td>0,440</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K3 LV)</td><td>52.00</td><td>0,520</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K100M CR)</td><td>4.00</td><td>0,040</td>

<td>Isopropyl alcohol, USP</td><td>*</td><td>0.540</td>

<td>Water</td><td>*</td><td>0,060</td>

<td>Together:</td><td>100.00</td><td>1,000</td>

[0064] The two granules were weighed separately and mixed in specific amounts together with glyceryl monostearate to form a two-granular formulation, which was then compressed into a tablet using a tablet press as shown in Table 3 below:

Table 3

<td>Clarithromycin tablets with Extended Release, 500 mg</td><td></td><td></td>

<td>Clarithromycin pellets (ER 1)</td><td>23,64</td><td>.1655</td>

<td>Clarithromycin pellets (ER 2)</td><td>74.86</td><td>.5240</td>

<td>Glycerol monostearate, NF (Eastman 600P)</td><td>1.50</td><td>0.0105</td>

<td>TOGETHER</td><td>100.00</td><td>0,700</td>

Example 2 [0065] As in Example 1, a controlled release dual-granulated tablet containing 500 mg of clarithromycin was prepared and characterized as follows and is shown in the following Table 4:

Table 4

<td>COMPONENTS</td><td>%</td><td>^kg</td>

<td>Clarithromycin pellets (ER 1)</td><td></td><td></td>

<td>Clarithromycin, USP</td><td>44,00</td><td>0,440</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K3 LV)</td><td>56,00</td><td>0.560</td>

<td>Isopropyl alcohol, USP</td><td>*</td><td>0.540</td>

<td>Water</td><td>*</td><td>0,060</td>

<td>Together:</td><td>100.00</td><td>1,000</td>

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

<td>Clarithromycin pellets (ER 2):</td><td></td><td></td>

<td>Clarithromycin, USP</td><td>44,00</td><td>0,440</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K3 LV)</td><td>52.00</td><td>0,520</td>

<td>Hydroxypropylmethylcellulose, USP (Methocel K100M CR)</td><td>4.00</td><td>0,040</td>

<td>Isopropyl alcohol, USP</td><td>*</td><td>0.540</td>

<td>Water</td><td>*</td><td>0,060</td>

<td>Together:</td><td>100.00</td><td>1,000</td>

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

<td>Clarithromycin prolonged tablets</td><td rowspan="2"></td><td rowspan="2"></td>

<td>Release, 500mg</td>

<td>Clarithromycin pellets (ER 1)</td><td>88.65</td><td>.6206</td>

<td>Clarithromycin pellets (ER 2)</td><td>9.85</td><td>.0690</td>

<td>Glycerol Monostearate, NF (Eastman 600P)</td><td>1.50</td><td>0.0105</td>

<td>TOGETHER</td><td>100.00</td><td>0,700</td>

[0066] To check whether a particular dosage form of the erythromycin derivative has a significant food effect, the most reliable way to test the in vivo dosage form on the study population is to administer the dose under fasting and fed conditions, determining the drug level in serum (or plasma) versus time, delineating the curves drug concentration in serum (or plasma) versus time (fasting and after meals) as described above and determining the area under each curve.

[0067] Table 5 shows the mean plasma pharmacokinetic values ​​based on fasting and non-fasting doses with Examples 1 and 2 and the equivalent dose of the reference standard (Biaxin XL).

Table 5

<td colspan="4">Comparison of Data [Regarding] the Bioavailability of Examples 1 and 2 and Reference Standard (Biaxin XL) on an empty stomach and not on an empty stomach.</td>

<td>formulation</td><td>Cmax (ug / mL)</td><td>Tmax (h)</td><td>AUC0-48 (Gg.h / ml)</td>

<td>On an empty stomach</td><td></td><td></td><td></td>

<td>Example 1</td><td>1.17 ± 0.46</td><td>5.6 ± 2.1</td><td>13.7 ± 5.1</td>

<td>Example 2</td><td>1.14 ± 0.32</td><td>4.3 ± 1.6</td><td>14.7 ± 4.8</td>

<td>Standard Reference (Biaxin XL)</td><td>0.62 ± 0.15</td><td>6.9 ± 2.7</td><td>10.0 ± 3.3</td>

<td>Not fasting</td><td></td><td></td><td></td>

<td>Example 1</td><td>1.61 ± 0.45</td><td>5.3 ± 3.5</td><td>12.8 ± 4.8</td>

<td>Example 2</td><td>1.85 ± 0.34</td><td>4.4 ± 1.9</td><td>13.8 ± 3.8</td>

<td>Standard Reference (Biaxin XL)</td><td>1.3 ± 0.34</td><td>3.8 ± 1.5</td><td>12.8 ± 3.5</td>

[0068] The data in Table 5 show that there is only a small difference in the maximum plasma concentration of clarithromycin or when administered to a fasting patient or patient not

Non-fasting with Example 1 or 2. Furthermore, a time difference of only 0.3 and 0.1 hours is needed respectively to obtain maximum serum calridotricin concentration using Example 1 and Example 2 of this invention.

[0069] However, when clarithromycin is administered using a tablet formulation according to the prior art (reference standard (Biaxin XL)), the difference in peak plasma concentration is observed when administered to a non-fasted patient relative to a fasted patient. In this case, there is a significant difference in the time required for the dose of clarithromycin non-fasting to achieve maximum serum concentration compared to the fasted dose. This difference in the "food effect" between the prior art tablet formulation (Biaxin XL) for clarithromycin is surprising and appears to be the result of the formulation.

[0070] The dosage form may further comprise any of the above binders, diluents, excipients, lubricants, dyes, pigments, flavors, coloring agents, dispersing agents, disintegrants and emulsifiers.

[0071] In certain embodiments, a dosage form can optionally be obtained by mixing the ingredients dry or using the concept of one granulate.

[0072] Preferably, the dosage form provides an average time to obtain a maximum plasma drug concentration (Tmax) of about 1 hour to about 12 hours after administration, preferably about 2 to about 10 hours after administration and most preferably from about 2 hours to about 8 hours after administration.