EP1969134A1

EP1969134A1 - Modified release amoxicillin products

Info

Publication number: EP1969134A1
Application number: EP06847542A
Authority: EP
Inventors: Donald Treacy; Alan R. Potts; Henry H. Flanner; Beth A. Burnside; Sanna Tolle-Sander; Susan P. Clausen
Original assignee: Advancis Pharmaceutical Corp
Current assignee: Shionogi Inc
Priority date: 2005-12-08
Filing date: 2006-12-08
Publication date: 2008-09-17
Also published as: EP1969134A4; WO2008069806A8; WO2008069806A1; AU2006351475A1; AU2006351475B2

Abstract

Disclosed are amoxicillin products comprising at least one modified release component(s), wherein the at least one modified release component(s) comprises at least amoxicillin and a pharmaceutically acceptable carrier. In some embodiments, when administered to a patient or subject in the fed state the amoxicillin products exhibit a pharmacokinetic profile for amoxicillin in the plasma characterized as follows: (1) the ratio of the portion of the AUC as measured from 2 hours post-administration to 5 hours post-administration to the portion of the AUC as measured from administration to 2 hours post- administration is at least 2.0: 1 : and (2) the ratio of the portion of the AUC as measured from 5 hours post-administration to 12 hours post-administration to the portion of the AUC as measured from administration to 2 hours post-administration is at least 1.1:1. In additional embodiments the amoxicillin products exhibit a mean in-vitro dissolution profile within a defined range characterized as follows: 1) the percent dissolved at 0.25 hours is between 25 and 55 percent; 2) the percent dissolved at 0.5 hours is between 30 and 60 percent; 3) the percent dissolved at 1 hour is between 50 and 85 percent; 4) the percent dissolved at 1.5 hours is between 70 and 95 percent; and 5) the percent dissolved at 2 hours is at least 85 percent. In preferred embodiments the amoxicillin products exhibit both of these characteristics.

Description

MODIFIED RELEASE AMOXICILLIN PRODUCTS

This invention is directed to amoxicillin products, and to methods of use thereof.

y (b.i.d.), whereby the composition is administered every 12 hours; three times daily (ti.d.), whereby the composition is administered every 8 hours; four times daily (q.i.d.), whereby the composition is administered every 6 hours; or such dosing regimens may even conceive of dosing the composition in excess of four administrations per day.

Amoxicillin is also available in a modified release formulation, e.g., as sold under the trademark AUGMENTIN XR.

The present invention is directed to an amoxicillin product and use thereof in which all or a portion of the amoxicillin is present as a modified release component.

In one embodiment, the amoxicillin product is formulated in a manner such that (x) the amoxicillin product has a mean AUC such that the ratio of (i) the portion of the mean AUC for the amoxicillin of the product during the period from 2 hours after administration to 5 hours after administration to (ii) the portion of the mean AUC of the amoxicillin of the product during the period extending from administration to 2 hours after administration is at least 2.0:1 and (y) the ratio of (iii) the portion of the mean AUC for the amoxicillin of the product during the period extending from 5 hours after administration to 12 hours after administration to (ii) the portion of the mean AUC of the amoxicillin of the product during the period extending from administration to 2 hours after administration is at least 1.1:1.

An AUC (area under the curve) for a specified period is referred to as a "partial AUC" for the period.

As used in the Specification and Claims AUQo-₂) means the portion of the amoxicillin AUC that is determined substantially in accordance with the procedure of Example 1 from time 0 to 2 hours after the administration of the amoxicillin product. AUC(2-5) means the portion of the amoxicillin AUC that is determined substantially in accordance with the procedure of Example 1 from time 2 to 5 hours after the administration of the amoxicillin product.

AUC(5.i2) means the portion of the amoxicillin AUC that is determined substantially in accordance with the procedure of Example 1 from time 5 to 12 hours after the administration of the amoxicillin product.

In one embodiment, the amoxicillin product has an AUC p-s) to AUC (o-2) ratio that is at least 2.2:1 and in another at least 2.4:1.

In another embodiment, the AUC (s.i2> to AUC (o-₂> ratio is at least 1.2:1 or at least 1.3:1.

In general, the AUC (2-₅) to AUC (0.2) ratio does not exceed 10:1, or in some cases 8:1 or in other cases 6:1.

In general, the AUC (₅.₁₂) to AUC (o-₂) ratio does not exceed 10:1, or in some cases 8:1 or in other cases 6:1.

For Ihe purposes of the specification and claims, an amoxicillin product may be tested substantially in accordance with Example 1 by use of either the high fat or low fat Fed State Regimen of Example 1, and such amoxicillin product is deemed to fall within a specified range of partial AUC ratios if it falls within such range by testing substantially in accordance with either one of such Fed State Regimens.

As used herein the term "amoxicillin" shall be broadly interpreted to include not only that active ingredient, but also all, polymorphs, salts, and/or hydrates thereof.

As known in the art an AUC (area under the curve) for amoxicillin in human plasma is a pharmacokinetic profile of the amoxicillin of the product in human plasma after administration of the amoxicillin product to a human, where AUC is the area under the curve resulting from a plot of the amoxicillin concentration in human plasma as a function of time after administration such that the Y axis is the concentration of amoxicillin in human plasma after administration of the amoxicillin product and the X axis is time after administration.

The hereinabove ratios are determined substantially in accordance with the procedure set forth in Example 1 wherein the pharmacokinetic profile is determined from administration of a single dose of amoxicillin product in the fed state substantially in accordance with Example 1, human plasma samples are obtained and analyzed substantially in accordance with Example 1 and the AUC ratios are determined substantially in accordance with Example 1.

Example I is provided as an analytical tool for determining whether or not an amoxicillin product has the hereinabove described partial AUC ratios. Such analytical tool of the Example does not limit the invention to administering to a human the amoxicillin product only in the fed state; and does not limit the invention to treating a patient in accordance with the protocol of Example 1.

As a result, as used in the Specification and Claims a partial AUC ratio is one determined in the fed state substantially in accordance with Example 1, even though the amoxicillin product is used or administered in a manner different from Example 1, and even if in any regulatory filing for an amoxicillin product, the AUC and/or partial AUC is determined in a manner different from Example 1.

In another embodiment, the present invention is directed to an amoxicillin product that includes at least one modified release component which has a mean in-vitro dissolution profile when tested according to the method of Example 8, wherein at the following specified times, the percent dissolution of the total amoxicillin in the product is at least the specified minimum and does not exceed the specified maximum percent dissolution as follows:

In one embodiment, the amoxicillin product has a mean in-vitro dissolution profile that falls within the following range of percent dissolution at the specified times:

In another embodiment, the amoxicillin product has a mean in-vitro dissolution profile that falls within the following range of percent dissolution at the specified times:

The mean in-vitro dissolution profile is determined in accordance with the dissolution method of Example 8. The mean results generated using the dissolution method of Example 8 would generally exhibit a % RSD (relative standard deviation) of less than 10%.

As a result, when the Specification and Claims, refer to a mean in-vitro dissolution profile of an amoxicillin product, the dissolution method of Example 8 is used to determine whether or not the amoxicillin product has lhe mean in-vitro dissolution profile that at the specified times fells within the specified minimum and maximum dissolution percentages.

It is to be understood that the in vivo dissolution profile of the amoxicillin product may or may not fall within the hereinabove described mean in- vitro dissolution profile ranges.

Although the Specification and Claims are not intended to be limited thereby, an amoxicillin product is formulated to have the herein described mean in- vitro dissolution profiles to extend the T_n^ of the amoxicillin product in-vivo and to thereby extend time over the minimum inhibitory concentration (MIC) in the plasma, while maintaining an acceptable area under the curve (AUC).

In an embodiment of the invention, there is provided an amoxicillin product that includes at least one modified release component wherein such product when administered in the fasted state has an equivalent extent of absorption to that of such product when administered in the fed state.

As used herein an "equivalent extent of absorption" means that the absorption in the fasted state is within 80% to 125% of the absorption in the fed state with a 90% confidence interval, as set forth in FDA Guidance for Industry - Food-Effect Bioavailability and Fed Bioequivalence Studies, December 2002.

In accordance with such guidelines, a protocol for determining extent of absorption in the 'fasted state" means that following an overnight fast of at least 10 hours, subjects should be administered the drug product with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study. In accordance with such guidelines a protocol for determining extent of absorption in the "fed state" means that following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to administration of the drug product. Study subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after start of the meal. The drug product should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study. The "Recommended Meal" means: A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA (bioavailability) and fed BE (bioequivalence) studies. This test meal should derive approximately 150, 250, and 500- 600 calories from protein, carbohydrate, and fat, respectively. The procedure of Example 1 complies with such guidelines tor fasted wd fed states.

Extent of absorption is generally determined by area under the curve (AUC). Two types of AUC are typically reported and are typically referred to as AUCo._b where the AUC is calculated over the range from time zero until the last plasma sample was taken, time t, and AUCo-mf often denoted AUQn_f where the AUCt-ύr_f is calculated and added to AUCo-t. AUC_t-i_nf is extrapolated from time t until the infinity point, which is the time point where the active ingredient concentration reaches 0 determined by extrapolation from the last measured concentration based on the elimination rate determined from the individual subject data.

An amoxicillin product that includes at least a modified release component that is formulated to have the partial AUC ratios and/or the in vitro dissolution profiles as hereinabove described may be produced in a wide variety of forms and dosages of amoxicillin and may be administered in accordance with a variety of different protocols; for example, once-a-day, twice-a-day, three times a day.

In one embodiment, the product includes an immediate release component and a delayed release component.

In another embodiment, the product includes an immediate release component and two or more delayed release components.

In another embodiment, the product includes one, two or three or more delayed release components and is free of an immediate release component.

In another embodiment, the product includes one, two or more extended (sustained) release components and is free of an immediate release component.

In a further embodiment, the product includes an immediate release component and one, two or more extended release components.

In yet another embodiment, the product includes an immediate release component and a combination of one or more delayed release components and one or more extended release components.

As used herein and as known in the art, an immediate release component is one in which the initiation of release, and / or the rate of release, of active ingredient is not substantially delayed, and / or slowed, and / or sustained, after administration of the product. As used herein and as known in the art, a modified release component is other than an immediate release component. Non-limiting examples of such modified release components include: delayed release components) which is one where after the delay the release is not sustained over a period of time, and a sustained (or extended) release component, which is one where release of active ingredient is sustained over a period of time and/or combinations of the foregoing. Immediate release, delayed released and sustained (extended) release components are components and terminology well known in the art and the formulation thereof is well within the skill of the art. The use of various combinations of the aforementioned components will be apparent to those of ordinary skill in the art in view of the disclosures herein, further guided by the disclosures of U.S. Patent Application Serial Numbers 10/894,787; 10/894,786; 10/894,994; 10/917,059; 10/922,412; and 10/940,265; and by the disclosures of U.S. Patents 6,544,555; 6,623,757; and 6,669,948; all of which are hereby incorporated by this reference in their entireties. In accordance with an embodiment of the invention, irrespective of the various components used in the amoxicillin product that includes at least one modified release, such components are formulated such that the amoxicillin product has the partial AUC ratios hereinabove described.

In accordance with one embodiment of the invention, there are at least two components (at least one of which is a modified release component). One of the at least two components is an immediate release component, whereby initiation of release of the amoxicillin therefrom is not substantially delayed after administration of the amoxicillin composition, or is a delayed release component, whereby initiation of release of the amoxicillin therefrom is substantially delayed after administration of the amoxicillin composition. The second of the at least two components is a delayed release component (each delayed release component may be a pH sensitive or a non-pH sensitive delayed release component, depending on the type of amoxicillin composition), whereby the amoxicillin released therefrom is delayed until after initiation of release of the amoxicillin from the immediate release or first delayed release component. More particularly, the amoxicillin released from the second of the at least two components achieves a C_018x (maximum concentration in the plasma) at a time after the amoxicillin released from the first of the at least two components achieves a Q_πax in the plasma.

In accordance with one embodiment of the invention, there are at least three components (at least one of which is a modified release component). One of the at least three components is an immediate release component whereby initiation of release of the amoxicillin therefrom is not substantially delayed after administration of the amoxicillin composition. The second and third of the at least three components are delayed release components (each of which may be a pH sensitive or a non-pH sensitive delayed release component, depending on the type of amoxicillin composition), whereby the amoxicillin released therefrom is delayed until after initiation of release of the amoxicillin from the immediate release component. More particularly, the amoxicillin released from the second of the at least three components achieves a C_max (maximum concentration in the plasma) at a time after the amoxicillin released from the first of the at least three components achieves a Cmax in the plasma, and the amoxicillin released from the third component achieves a Cmax in the plasma after the C_max of amoxicillin released from the second component.

In one embodiment, the second of the at least three components initiates release of the amoxicillin contained therein at least one hour after the first component, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of amoxicillin from the first component of the at least three components.

As hereinabove indicated, some embodiments of the amoxicillin composition may contain two, three, four, or more different components (provided that at least one is a modified release component).

In one three-component embodiment, the amoxicillin released from the third component reaches a C_m4x at a time later than the C₀₁₁₁X is achieved for the amoxicillin released from each of the first and second components. In a preferred embodiment, release of amoxicillin from the third component is started after initiation of release of amoxicillin from both the first component and the second component. In one embodiment, C_013x for amoxicillin released from the third component is achieved within eight hours.

In another three-component embodiment the release of amoxicillin from the second component may be contemporaneous with initiation of release of amoxicillin from the first component.

In another three-component embodiment the release of amoxicillin from the third component may be contemporaneous with initiation of release of amoxicillin from the second component.

In another embodiment, the amoxicillin composition may contain four components (at least one of which is a modified release component), with each of the four components having different release profiles, whereby the amoxicillin released from each of the four different components achieves a Qua_* at a different time.

Ih one preferred embodiment, the amoxicillin product contains at least two or at least three or at least four different components each with a different release profile, Cm_3x for all the amoxicillin released from the amoxicillin product in those is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.

In one embodiment, the amoxicillin product is a once-a-day composition, whereby after administration of the amoxicillin product, no further composition is administered during the day; i.e., the regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with this embodiment, there is a single administration of an amoxicillin product with the amoxicillin being released in a manner such that overall amoxicillin release is effected with different release profiles in a manner such that the overall Cmax for the amoxicillin composition is reached in less than twelve hours. The term single administration means that the total amoxicillin administered over a twenty-four hour period is administered at the same time, which can be a single dosage unit (tablet, capsule or sprinkle/sachet) or two or more thereof, provided that they are administered at essentially the same time.

In one embodiment, such once-a-day product is comprised of an immediate release component and two delayed release components wherein the first delayed release component initiates release of amoxicillin after release of amoxicillin from the immediate release component and the second delayed release component initiates release of amoxicillin after release of amoxicillin from the first delayed release component.

In a once-a-day amoxicillin product, such product has partial AUC ratios and/or the in vitro dissolution profiles as hereinabove described.

In one embodiment, the amoxicillin product is a twice-a-day product, whereby after an initial administration of the amoxicillin product, there is a further administration of the amoxicillin product at another time during the day; i.e., the regimen is that the composition is administered only twice over a twenty-four hour period.

hi one embodiment, the twice-a-day amoxicillin product includes two or more components with one of such two components being an immediate release component and the other of the two components being a modified release component.

In another embodiment the twice-a-day amoxicillin product contains one immediate release component and two or more modified release components, with a particular embodiment including two modified release components.

hi a twice-a-day amoxicillin product, such product has partial AUC ratios and/or the in vitro dissolution profiles as hereinabove described.

Thus, in accordance with one embodiment, there is a b.i.d. administration of an amoxicillin product with the amoxicillin being released in a manner such that overall amoxicillin release is effected with different release profiles in a manner such that the overall C₁B_3x for each of the two administrations of the product is reached in less than twelve hours after each administration. The dose administered at each of the two administrations can be a single amoxicillin product or a plurality of amoxicillin products.

hi one embodiment, the hereinabove described amoxicillin products having the hereinabove described partial AUC ratios and/or the in vitro dissolution profiles have an extent of absorption (AUCo-_mf) that is at least 75% and in a preferred embodiment at least 80% of the extent of absorption (AUCo-inf) of an amoxicillin product that provides for only immediate release of amoxicillin. In general, the extent of absorption (AUCo_j_nf) of an amoxicillin product of the invention does not exceed the extent of absorption (AUCo-inf) of an amoxicillin product that provides for only immediate release of amoxicillin. In comparing the products to determine extent of absorption, the AUC₀-Uf is determined in either the fed state or the fasted state in accordance with the hereinabove referred to FDA Guidance for Industry and each of the products has the same amount of amoxicillin.

When administering the amoxicillin product orally to a human, such product may be taken in the fed state or fasted state, preferably in the fed state.

As known in the art, oral administration of such a product to a human in a. fed or fasted state has a meaning different from the FDA requirements for testing extent of absorption, hi terms of administering a product to a human for use of a product, fed state means in conjunction with food (immediately prior to, with or immediately after intake of food). The fasted or non-fed state means other than in conjunction with the intake of food.

It is to be understood that when it is disclosed herein that a component initiates release after another component, such terminology means that the component is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, that some "leakage" of antibiotic may occur. Such "leakage" is not "release" as used herein.

The amoxicillin product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the amoxicillin composition may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as a nasal preparation; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the amoxicillin composition is formulated in a manner such that it is suitable for oral administration.

For example, in formulating the amoxicillin product for topical administration, such as by application to the skin, the components, each of which contains amoxicillin, may be formulated for topical administration by including such components in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, an immediate release component may be in the continuous phase, and a delayed release component may be in a discontinuous phase. The formulation may also be produced in a manner for delivery of three components as hereinabove described. For example, there maybe provided an oil-in- water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release component, and oil dispersed in the water containing a third delayed release component

It is also within the scope of the invention to provide an amoxicillin product in the form of a patch, which includes amoxicillin components having different release profiles, as hereinabove described.

In addition, the amoxicillin product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the component may be coated with a hydrophobic polymer whereby a component is in the oil phase of the emulsion, and a component may be coated with hydrophilic polymer, whereby a component is in the water phase of the emulsion.

Furthermore, the amoxicillin product having at least one modified release component (whether or not combined with additional components to provide a plurality of different release profiles) may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream, an emulsion, a suppository, or other dissolvable component similar to those used for topical administration. The amoxicillin product may include an amount of amoxicillin from about 200 mg to about 2500 nag, depending on the form of the product. As non-limiting examples, the amoxicillin product may contain 475 mg or 775 mg or 1250 mg or 1550 mg or 2325 mg of amoxicillin.

In a preferred embodiment, the amoxicillin product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the components may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical composition, for example, in. a capsule, or embedded in a tablet, as a sprinkle, or suspended in a liquid for oral administration. In one non- limiting embodiment, the tablet may be a rapidly disintegrating tablet, whereby the various components of the product are released upon ingestion for further transport into the intestine in the form of pellets or granules.

Alternatively, in formulating an oral delivery system, each of the components of the composition- may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary amoxicillin product. Thus, as a non-limiting example, a three component amoxicillin product may include a first component in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release or a sustained release of the amoxicillin, as hereinabove described.

The amoxicillin product may be in the form of a sprinkle product; for example by placing the various components of the product in particulate form (for example as pellets) in a sachet, capsule or other form that can be used for administering the components in particulate form at the same time.

The formulation of an amoxicillin product including at least three components with different release profiles for different routes of administration is deemed to be within the skill of the art from the teachings herein. As known in the art, with respect to delayed release, the time of release can be controlled by a variety of mechanisms such as pH trigger point, coating thickness, choice of polymer, choice of plasticizer, osmotic pressure, physical swelling pressure and combinations of the foregoing. In formulating an amoxicillin product in accordance with one embodiment of the invention, an immediate release component generally comprises about 45% of the total amoxicillin dose in the product, a first delayed release component generally comprises about 30% of the total amoxicillin dose in the product, and a second delayed release component generally comprises about 25% of the total amoxicillin dose in the product (all by weight). This embodiment is non-limiting, and when the disclosures herein are considered along with the entirety of the further knowledge that necessarily informs the level of ordinary skill in the art, the person of ordinary skill in the art will readily appreciate component percentages differing from those noted in the non-limiting embodiment, which percentages when combined to form an amoxicillin product has the hereinabove described partial AUC ratios and/or the in vitro dissolution profiles.

In accordance with an embodiment of the present invention, each of the components contains amoxicillin; however, each of the components may contain another antibiotic or other type of active ingredient.

In the embodiments hereinabove described, the amoxicillin product has the partial AUC ratios as hereinabove described and/or the hereinabove described in vitro dissolution profiles. In one preferred embodiment, the amoxicillin product has both partial AUC ratios, as hereinabove described and and in vitro dissolution profile as hereinabove described.

The Immediate Release Component

The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the amoxicillin. This can take the form of either a discrete tablet, pellet or granule that is mixed in with, or compressed with, the other components in the product.

In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl tnonostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above.

The non-pH Sensitive Delayed Release Component

The components in this composition are the same as the immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.

Several methods to affect a delayed release with non-pH dependent polymers are known to those skilled in the art. These include soluble or erodible barrier systems, enzyrnatically degraded barrier systems, rupturable coating systems, and plugged capsule systems among others. These systems have been thoroughly described in the literature (see "A Review of Pulsatile Drug Delivery" by Bussemer and Bodmeier in the Winter 2001 issue of American Pharmaceutical Review) and formulations and methods for their manufacture are hereby incorporated by reference.

Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.

Typically these materials can be present in the range of 0.5-40% (WAV) of this component.

The pH Sensitive (Enteric) Release Component

The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule to delay release. The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, Eudragit S, Eudragit FS, and other pthalate salts of cellulose derivatives.

These materials can be present in concentrations from 4-30% (W/W).

Sustained Release Component

The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over a tablet, pellet or granule to provide a sustained release of the pharmaceutical.

The kind of materials useful for this purpose can be, but are not limited to, ethylcellulose; hydroxypropylmethylcellulose; hydroxypropylcellulose; hydroxyethylcellulose; carboxymethylcellulose; methylcellulose; nitrocellulose; Eudragit R; Eudragit RS; and Eudragit RL; Carbopol; or polyethylene glycols with molecular weights in excess of 8,000 daltons.

These materials can be present in concentrations from 4-40% (WAV).

When it is desired to delay initiation of release of the sustained release component, an appropriate coating may be used to delay initiation of the sustained release, such as a pH sensitive or a non-pH sensitive coating.

The non-pH Sensitive Coating for Sustained Release Component

Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit RS), cellulose acetate, and ethylcellulose.

Typically these materials can be present in the range of 0.5-25% (W/W) of this component. Preferably the materials are present in an amount just enough to provide the desired in vivo lag time and T_ma_x-

The pH Sensitive Coating for Sustained Release Component

The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, Eudragit S, Eudragit FS, and other pthalate salts of cellulose derivatives.

These materials can be present in concentrations from 4-30% (W/W) or more. Preferably the materials are present in an amount just enough to provide the desired in vivo

As hereinabove indicated, the units comprising the amoxicillin composition of the present invention can be in the form of discrete pellets or particles contained in a capsule, or particles embedded in a tablet or suspended in a liquid suspension.

The amoxicillin products of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably are administered orally. The product includes a therapeutically effective amount of the amoxicillin, which amount will vary with the disease or infection to be treated, and the number of times that the product is to be delivered in a day. The product is administered to a patient or subject (i.e., a human or an animal) in an amount effective for treating a bacterial infection.

In accordance with one embodiment, the amoxicillin product has an overall release profile such that when administered to a human the maximum plasma concentration of the total amoxicillin released from the product is reached in less than twelve hours, preferably in less than eleven hours.

In a further aspect, the present invention provides a method of treating various infections in a human, caused by bacterial pathogens, which treating comprises administering to the patient, or to the subject, the herein described amoxicillin product. As non-limiting examples of the indications for which the amoxicillin product may be used to treat a patient there may be mentioned: pharyngitis, tonsillitis, sinusitis, bronchitis, pneumoniae, ear infection (otitis media), uncomplicated skin and skin structure infections, and uncomplicated urinary infections.

As non-limiting examples of the infectious bacterial pathogens against which the amoxicillin products may be used, there may be mentioned Gram-Positive Aerobes such as Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus saprophytics, Streptococcus pneumoniae. Streptococcus pyogenes, and viridans group Streptococcus; Gram-Negative Aerobes such as Enterobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella species, Moraxella catarrhalis, Eikenella corrodens, Neisseria gonorrhoeae, and Proteus mirabilis; Anaerobic Bacteria such as Bacteroides species, including Bacteroides fi-agilis, Fusobacterium species, and Peptostreptococcus species.

In one embodiment the amoxicillin product is formulated to specifically target tonsillopharyngitis secondary to Streptococcus pyogenes.

It will be appreciated by those of ordinary skill in the art that the methods and formulations described for the amoxicillin products are also applicable to amoxicillin in combination with clavulanatc, or in combination with other beta-lactamase inhibitors, particularly for treating infections where beta-lactamase producing pathogens are implicated as the primary infection or as a co-infection.

In treating a bacterial infection, the amoxicillin product is formulated to provide a concentration of amoxicillin in the plasma that is above the MIC of the bacterial pathogen for a period of time each day that is effective for treating the bacterial infection. The amoxicillin product is administered for a number of days that provides a concentration of MIC in the plasma for a total time over MIC (daily time over MIC multiplied by the number of days of treatment) that is effective for treating the bacterial infection.

The invention will be further described with respect to the following Examples; however, the scope of the invention is not limited by such Examples. Unless otherwise specified parts and percentages are by weight.

IS EXAMPLE l

A single dose pharmacokinetic study in human subjects is utilized to characterize the performance of the amoxicillin modified release product.

(a) Fed State Regimen

High Fat Regimen: While administering the experimental study medication, under high fat meal conditions, all subjects will be required to fast for at least 10 hours until 30 minutes prior to their scheduled dosing times, when they will be given a high-fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) breakfast which will be entirely consumed within 30 minutes. The breakfast will consist of 2 slices of buttered toast, 2 fried eggs, 2 strips of bacon, 1 serving of hash brown potatoes, and 240 mL of whole milk. The study medication will be administered with 240 mL of water. Water will be allowed ad lib during the study, except for 1 hour pre-dose through 1 hour post-dose. All subjects will continue to fast through at least 4 hours following drug administration.

Low Fat Regimen: While administering the experimental study medication under standardized meal conditions, all subjects will be required to fast for at least 10 hours until 30 minutes prior to their scheduled dosing times, when they will be given a standardized breakfast (approximately 25-30% of total caloric content of meal from fat and a total of approximately 470 calories), which will be entirely consumed within 30 minutes. The breakfast will consist of 2 slices of toast with 1 tablespoon of butter, 1 ounce of cornflake cereal in 120 mL of whole milk, 150 mL of orange juice. The study medication will be administered with 240 mL of water. Water will be allowed ad lib during the study, except for 1 hour pre-dose through 1 hour post-dose. All subjects will continue to fast through at least 4 hours following drug administration.

(b) Fasted Regimen: While administering the experimental study medication under fasting conditions, all subjects will be required to fast for at least 10 hours prior to dosing. Water will be allowed during the study, except for 1 hour pre-dose through 1 hour post-dose. AU subjects will continue to fast through at least 4 hours following drug administration.

(c) Drug Administration Protocol

While under fed conditions, each subject will receive an oral amoxicillin product administered with 240 mL of tap water in the morning at Hour 0, 30 minutes after administration of a high-fat/high-calorie breakfast or a low fat/standardized breakfast as per study randomization.

Typical clinical study site meals will be provided 4 and 9-hours after dosing, and at appropriate times thereafter. The same menu and meal schedule is to be administered uniformly for all subjects.

Beverages containing alcohol, caffeine, xanthine and/or grapefruit will be restricted during the confinement period of the study.

A compliance check of the hand and mouth will be performed to ensure ingestion of each dose.

Subjects will remain ambulatory or seated upright for the first 4 hours after drug administration. However, should adverse events occur at any time, subjects may be placed in an appropriate position or will be permitted to lie down on their right side. Subjects will not engage in strenuous activity at any time during the confinement period.

(d) Blood Sampling Protocol

Blood samples (3 mL) will be drawn in lavender top/EDTA vacutainer tubes at the following times: Pre-dose (Hour 0) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours post-dose. Intravenous catheters may be used as an alternative for straight needle sticks.

There will be 21 blood samples collected during each period for a total of 63 blood samples per subject. As a result, the subjects will have 189 mL of blood collected during the study for drug analysis and 60 mL of blood (15 mL at screening and 15 mL at end of each period or upon early termination) for clinical laboratory evaluation. An additional 20 mL (5 tήL at screening and 5 mL at each check-in) will be collected from females for serum pregnancy testing.

Blood samples will be stored on ice prior to processing and storing (fluorescent lighting acceptable). Plasma samples will be separated by centrifugation (approximately 2500 rpm. x IS minutes at 4⁰C) as soon as possible (within 30 minutes). The plasma from each sample should be aliquotted in approximately equal volume into duplicate tubes (minimum of 0.5 mL per tube). Within approximately 90 minutes of collection, samples will be stored in clearly labeled containers (polypropylene) in a freezer set at or below - 80⁰C, until shipped for assay. The sample storage containers will be labeled with clinical study site standard bar-code labels.

At the end of the period, samples will be shipped on dry ice via overnight courier to the bioanalytical laboratory for analysis.

(e) Bio-analytical Method for Plasma Analysis

Plasma samples are analyzed using a bioanalytical method suitable for amoxicillin that is validated over the range of 0.05 μg/mL - 25 μg/mL in accordance with the FDA Guidance for Industry- Bioanalytical Method Validation, May, 2001.

(f) Method for Calculating Partial AuCs

For partial AUC calculations the standard linear trapezoidal summation over each time interval is used. The partial AUCs are calculated from the mean pharmacokinetic profile, e.g. a single mean PK profile is calculated as the average amoxicillin plasma concentration of all subjects at each timepoint. For time 0 to 2 hours the partial AUC is AUC{<j.2) and for time 2 to 5 hours the partial AUC is AUCp_-5) and for time 5-12 hours the partial AUC is AUC(j.i2) where each partial AUC is calculated according to standard pharmaceutical industry pharmacokinetic calculation methodologies as given by:

AUC(o-₂) Area under the drug concentration-time curve calculated using linear trapezoidal summation from time zero to time 2 hours. AUC<2-5) Area under the drug concentration-time curve calculated using linear trapezoidal summation from time 2 hours to time 5 hours.

AUC(s-i₂) Area under the drug concentration-time curve calculated using linear trapezoidal summation from time 5 hours to time 12 hours.

The ratios are then calculated by dividing each of the AUQ2-5) value and the AUQ5.12) value by the AUQ0.2) value.

EXAMPLE 2 FORMULATION

An amoxicillin tablet (Applicants' MP) is made that incorporates an immediate release component (Pulse 1); a first delayed release component (Pulse 2) and a second delayed release component (Pulse 3). The tablet rapidly disintegrates upon ingestion.

1. Product Description

The Applicants' MP Tablet, 775 mg, is a three-pulse dosage form. The tablet is manufactured by combining the immediate-release granulation (Pulse 1, 45%) with two functionally coated deiayed-release pellets (Pulse 2, 30% and Pulse 3, 25%). A non- functional, protective film is then applied to the tablet.

The qualitative composition, the pharmaceutical grade and the function of the individual components comprising each dosage form are listed in Table l-i. Table 1-1 Qualitative Composition of Applicants' MP Tablet, 775 mg

2. Quantitative Composition of Applicants' MP Tablet, 775 mg The quantitative composition for Applicants¹ MP Tablet, 775 mg, amoxicillin granules, amoxicillin core pellets, and pulsatile pellets are located in Tables 2-1 through 2- 5.

2.1 Applicants' MP Tablet, 775 mg

A batch of 144.9 kg of Applicants' MP Tablet, 775 mg, containing 891.2 mg of amoxicillin trihydrate, equivalent to 775 mg amoxicillin is manufactured. The total tablet weight is approximately 1.5 grams. The quantitative composition for Applicants' MP Tablet, 775 mg is listed below in Table 2-1.

Table 2-1 Quantitative Composition of Applicants' MP Tablet, 775 mg

^♦Weight percent of solids content

2.2 Amoxicillin Trihydrate (97%) Granules

A batch of 20 kg of Amoxicillin Trihydrate (97%) Granules is manufactured. The Amoxicillin granules serve as Pulse 1 of the final formulation. The granules are compressed with Pulse 2 and 3 pellets and other inactive components to form the tablet core.

A standard wet granulation process known to one skilled in the art is used for preparation of the Amoxicillin Granules. The wet granules are discharged and fed into a Dome Extrusion Granulator. The wet extruded granules are then dried for a fixed period of time or until the LOD (loss on drying) of the granules is suitable for the formulation, typically less than 15%. The dried granules are then sized in a Rotating Impeller Screening Mill. The milled material is collected into drums. The quantitative composition for Amoxicillin Trihydrate (97%) Granules is listed below in Table 2-2.

Table 2-2 Quantitative Composition of Amoxicillin Trihydrate (97%) Granules (Used for Pulse 1 in compression blend)

23 Amoxicillin Trihydrate (92%) Core Pellets

A batch of 20 kg Amoxicillin Trihydrate (92%) Core Pellets is manufactured. The Amoxicillin core pellets are coated with functional film coating to produce Pulse 2 and 3 pellets.

The core pellets are prepared using the unit operations of wet granulating, extruding, spheronizing, fluid bed drying and sizing. The quantitative composition for Amoxicillin Trihydrate (92%) Core Pellets is listed below in Table 2-3.

Table 2-3 Quantitative Composition of Amoxicillin Trihydrate (92%) Core Pellets (Used for Amoxicillin Pulse 2 and 3 Pellets)

2.4 Amoxicillin Trihydrate (76.7%) Pulse 2 Pellets

A 16.8 kg batch of Amoxicillin Trihydrate (76.7%) Pulse 2 Pellets is manufactured by applying a 20 % total solids weight gain of Eudragit L30D-55 to 14.0 kg of the Amoxicillin Trihydrate (92%) Core Pellets.

The Pulse 2 Pellets are prepared by coating the previously prepared Core Pellets with a functional film coat of methacrylic acid copolymer dispersion, 20% w/w. Prior to the coating process, a dispersion of the methacrylic acid copolymer is made according to the manufacturer's instructions. The dispersion is applied to the Amoxicillin Core pellets using a Fluid Bed Bottom Spray Coater, equipped with appropriate spray nozzles and a fixed column gap distance.

The pellets are then appropriately sized. The Amoxicillin Pulse 2 Pellets may be held in ambient warehouse conditions until further processing. The quantitative composition for Amoxicillin Trihydrate (76.7%) Pulse 2 Pellets is listed below in Table 2-4.

Table 2-4 Quantitative Composition of Amoxicillin Trihydrate (76.7%) Pulse 2 Pellets

e g t percent o so s content

2.5 Amoxicillin Trihydrate (76.0%) Pulse 3 Pellets

A 12.5 kg batch of Amoxicillin Trihydrate (73.6%) Pulse 3 Pellets is manufactured by applying a 5% total solids wt gain sub-coat of Eudragit L3OD-55 and an over-coat of 20% total solids weight gain of AQOAT AS-HF to 10.0 kg of the Amoxicillin Trihydrate (92%) Core Pellet.

Prior to the subcoating process, a dispersion of the methacrylic acid copolymer is made according to the manufacturer's instructions. The second coating material is prepared according to the manufacturer's instructions. The subcoat layer is then applied to the Amoxicillin Core Pellets using the same Fluid Bed Bottom Spray Coater as used for preparation of the Pulse 2 Pellets.

The second coating dispersion is then immediately applied to the sub-coated pellets still in the Fluid Bed Bottom Spray Coater. The atomization air used for the second coating process is set at the same pressure as used for the sub coating process. The coating process is complete when all of the dispersion has been applied. Following a drying period the final coated pellets are cooled. The quantitative composition for Amoxicillin Trihydrate (73.6%) Pulse 3 Pellets is listed below in Table 2-5. Table 2-5 Quantitative Composition of Amoxicillin Trihydrate (73.6%) Pulse 3 Pellets

• eight percent o so s content

For example, the above product may be used to treat streptococcus pyogenes in adults by administering such product to a human once-a-day for 10 days.

EXAMPLE 3

The core pellets of Part 2.3 of Example 2 are coated with a non-functional immediate release film coating to produce Pulse 1 pellets. The Pulse 1 pellets as well as Pulse 2 and Pulse 3 pellets of Example 2 are used as a sprinkle product by placing the Pulse 1, Pulse 2 and Pulse 3 pellets in a sachet, capsule or other form that can be used for simultaneous delivery of the three pulses in a particulate form. In one embodiment, Pulse 1, Pulse 2 and Pulse 3 are combined to provide 45%, 30% and 25% of Pulse 1, Pulse 2, and Pulse 3, respectively.

Such combination of Pulses 1, 2 and 3 may be formulated into a sprinkle product; e.g., a twice-a-day product that contains 475 mg or 775 mg of amoxicillin. In another embodiment, Pulse 1, 2 and 3 may be combined into a once-a-day sprinkle product that contains 775 mg or 1250 mg or 1550 mg of amoxicillin. The sprinkle product may be sprinkled over applesauce, yogurt, or other soft food for administration. The product should not be chewed or crushed. EXAMPLE 4

The amoxicillin product of Example 2 was tested using the procedure of Example 1 and the low fat Fed State Regimen of Example 1. The following partial AUC ratios were determined for such amoxicillin product in this study.

In addition, the product of Example 2 was tested using the procedure of Example 1 and in the low fat Fed State Regimen of Example 1, but in a multidose fashion. The product was administered once daily for seven days and blood draws were taken and analyzed on the first and seventh day. There was no accumulation evident at the time zero point on day seven, therefore this multidose data can be viewed as two single dose studies. Thus the partial AUC ratios were determined at both day 1 and day 7 of administration of the amoxicillin product and are provided in the table below.

EXAMPLE 5

The amoxicillin product of Example 2 was tested using the procedure of Example 1 with the high fat Fed State Regimen.

The following partial AUC ratios were as follows:

EXAMPLE 6 The amoxicillin product of Example 2 was tested using the procedure of Example 1 in the fasted, low fat Fed State, and high fat Fed State. The AUCo-inf for each of the fasted, low fat fed and high fat fed tests was about 31.5 μg*hour/raL.

EXAMPLE 7

The product of Example 2 was tested in accordance with the procedure of Example 1 except the dosage of amoxicillin was 1550 mg in one regimen (2x) and 232S tng in a second regimen (3x)

Dose Fed State Regimen AUCWAUC _{β.« AUC _(S.₁₂₎/AUC _((M)

2x - 1550 mg High Fat 2.4 : 1 1.6 : 1

2x - 1550 mg Low Fat 5.0 : 1 2.5 : 1

3x - 2325 mg High Fat 2.8 : 1 1.6 : 1

EXAMPLE 8

Dissolution Method

The drug product dissolution rate is measured using USP Apparatus II (paddles) with a paddle speed of 75 rpm at 37⁰C. This procedure generally follows the procedure in USP General Chapter <711>- Dissolution. Additional parameters for execution of this test method are described below. The dissolution media used initially is 0.05 M phosphate buffer at a pH of approximately 2.0. After the dissolution has been run for 30 minutes at a pH of approximately 2.0, the pH of the media is adjusted to approximately 6.0 over approximately 5 minutes with a 5 M KOH solution. After the pH is stabilized at approximately 6.0, the pH of the media is linearly increased over a period of 2.5 hours to a pH endpoint of approximately 7.8 using a 0.5 M KOH solution. After reaching the pH endpoint for the dissolution, the paddles are allowed to run for an additional 30 minutes. Samples are pulled at 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 210 minutes. Samples are analyzed using a UV/VIS spectrophotometer using an external standard at a wavelength of 230 run.

EXAMPLE 9

The amoxicillin product of Example 2 was tested using the procedure of Example

8.

The dissolution profile was as follows:

Numerous modifications and variations of the present invention are possible in light of the above teachings; therefore, except as set forth in the claims the invention is not limited to described embodiments.

Claims

We claim:

1. An amoxicillin product comprising: at least one modified release components), wherein the at least one modified release component comprises at least amoxicillin and a pharmaceutically acceptable carrier; said product when administered as a single dose in the fed state having a ratio of AUQ2-5) to AUQ0-2) of at least 2.0:1 and a ratio of AUQ₅.12) to AUQ0.₂) of at least 1.1 :1, as determined in accordance with Example 1 herein.

2. The product of Claim 1 wherein the AUC(2-5> to AUQ0-2) ratio is at least 2.2: 1.

3. The product of Claim 1 wherein the AUQ₂-₅) to AUC(o-₂) ratio is at least 2.4:1.

4. The product of any preceding Claim wherein the AUQ5.₁₂) to AUQ0-2) ratio is at least 1.2:1.

5. The product of any preceding Claim wherein the AUC<s.i₂) to AUQ0.2) ratio is at least 1.3:1.

6. The product of any preceding Claim wherein the AUQ₂-₅) to AUC(ø-2) ratio does not exceed 10:1.

7. The product of any preceding Claim wherein the AUC(₂-s) to AUC(o-2) ratio does not exceed 8:1.

8. The product of any preceding Claim wherein the AUCp-s) to AUC(o-2) ratio does not exceed 6:1.

9. The product of any preceding Claim wherein the AUQ5-12) to AUQo-2) ratio does not exceed 10:1.

10. The product of any preceding Claim wherein the AUC(s-i2) to AUC(o-2) ratio does not exceed 8:1.

11. The product of any preceding Claim wherein the AUC(s_i2) to AUC(o-2) ratio does not exceed 6:1.

12. An amoxicillin product comprising: at least one modified release component(s) that includes amoxicillin, said product having a mean in-vitro dissolution profile as determined by the method of Example 8 herein wherein at the following times the percent dissolution of the total amoxicillin of the product is no less than the following minimum percent dissolution and no greater than the following maximum percent specified for such times:

13. The product of any preceding Claim having a mean in-vitro dissolution profile as determined by the method of Example δ herein wherein at the following times the percent dissolution of the total amoxicillin of the product is no less than the following minimum percent dissolution and no greater than the following maximum percent specified for such times:

14. The product of any preceding Claim having a mean in-vitro dissolution profile as determined by the method of Example 8 herein wherein at the following times the percent dissolution of the total amoxicillin of the product is no less than the following minimum percent dissolution and no greater than the following maximum percent specified for such times:

15. The product of any preceding Claim, wherein said product further comprises an immediate release component.

16. The product of any preceding Claim, wherein said modified release component is selected from the group consisting of: a delayed release component, sustained release component, and combinations of the foregoing.

17. The product of any preceding Claim, wherein said modified release component is a sustained release component.

18. The product of Claims 1-16, wherein said modified release component is a delayed release component.

19. The product of any preceding Claim wherein said product when administered as a single dose in either the/erf state or the fasted state has an AUCo-ω of at least 75% of the AUCo-_mf of an immediate release amoxicillin product, wherein the AUCo.jnf of said immediate release amoxicillin product is determined in either the fed state or the fasted state.

20. The product of any preceding Claim that includes a first delayed release component that includes amoxicillin and initiates release of amoxicillin after the immediate release component and a second delayed release component that includes amoxicillin and initiates release of amoxicillin after the first delayed release component

21. The product of any preceding Claim wherein the product is a twice-a-day product.

22. The product of any of Claims 1-20 wherein the product is a once-a-day product that includes the daily dosage of amoxicillin.

23. The product of any preceding Claim wherein the product contains about from about 200 mg to about 2500 mg of amoxicillin.

24. The product of any preceding Claim wherein the product contains about 775 mg of amoxicillin.

25. The product of any preceding Claim having an equivalent extent of absorption when administered in both the fed and fast state.

26. A process for treating a bacterial infection in a patient or a subject comprising: administering to a patient or a subject the product of any preceding claim.

27. The use of the product of any of claims 1-25 in the manufacture of a medicament for treating bacterial infection in a patient or a subject.

28. The product of any preceding Claim, further comprising clavulanate or other beta- lactamase inhibitor.

29. A process for treating a bacterial infection in a patient or a subject comprising: administering to a patient or a subject the product of Claim 28.