Tetracycline antibiotic product, use and formulation thereof

This invention relates to an antibiotic product, as well as the use and formulation thereof. The invention further relates to a tetracycline antibiotic product and in particular doxycycline and its derivatives, salts, hydrates, esters, metabolites, etc.

A wide variety of antibiotics have been used, and will be used, in order to combat bacterial infection. In general, such antibiotics can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at higher administered doses. The present invention is directed to providing for an improved antibiotic product.

In accordance with one aspect of the present invention, there is provided an antibiotic pharmaceutical product which is comprised of at least two, preferably at least three, antibiotic dosage forms. Such dosage forms are formulated so that each of the dosage forms has a different release profile.

In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which has a different release profile and the release profile of each of the dosage forms is such that the dosage forms each start release of the antibiotic contained therein at different times after administration of the antibiotic product.

Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antibiotic product that has contained therein at least two, preferably at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of such dosage forms is released at different times.

In accordance with a further aspect of the invention, the antibiotic product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product.

The antibiotic product generally does not include more than five dosage forms with different release times.

In accordance with a preferred embodiment, the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration of the total antibiotic released from the antibiotic product is achieved no earlier than four hours after administration.

In accordance with one preferred embodiment of the inventions there are at least three dosage forms. One of the at least three dosage forms is an immediate release dosage form whereby initiation of release of the antibiotic therefrom is not substantially delayed after administration of the antibiotic product. The second and third of the at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic product), whereby the antibiotic released therefrom is delayed until after initiation of release of the antibiotic from the immediate release dosage form. More particularly, the antibiotic release from the second of the at least two dosage forms achieves a C

max

(maximum serum concentration in the serum) at a time after the antibiotic released from the first of the at least three dosage forms achieves a C

max

in the serum, and the antibiotic released from the third dosage form achieves a C

max

in the serum after the C

max

of antibiotic released from the second dosage form.

In one embodiment, the second of the at least two dosage forms initiates release of the antibiotic contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.

In general, the immediate release dosage form produces a C

max

for the antibiotic released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a C

max

for the antibiotic released therefrom in no more than about four hours. In general, the C

max

for such second dosage form is achieved no earlier than two hours after administration of the antibiotic product; however, it is possible within the scope of the invention to achieve C

max

in a shorter period of time.

As hereinabove indicated, the antibiotic product may contain at least three or at least four or more different dosage forms. For example, if the antibiotic product includes a third dosage form, the antibiotic released therefrom reaches a C

max

at a time later than the C

max

is achieved for the antibiotic released from each of the first and second dosage forms. In a preferred embodiment, release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form. In one embodiment, C

max

for antibiotic release from the third dosage form is achieved within eight hours.

In another embodiment, the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the antibiotic release from each of the at least four different dosage forms achieves a C

max

at a different time.

As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic contains at least two or at least three or at least four different dosage forms each with a different release profile, C

max

for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.

In a preferred embodiment, the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antibiotic product with the antibiotic being released in a manner such that overall antibiotic release is effected with different release profiles in a manner such that the overall C

max

a for the antibiotic product is reached in less than twelve hours. The term single administration means that the total antibiotic administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.

Applicant has found that a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile is an improvement over a single dosage antibiotic product comprised of an antibiotic dosage form having a single release profile. Each of the dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics and each of the dosage forms may have the same antibiotic or different antibiotics.

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

If at least four dosage forms are used, the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though C

max

of the fourth dosage form of the at least four dosage forms is reached after the C

max

of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.

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

For example, in formulating the antibiotic product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an antibiotic, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be 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 dosage form, and oil dispersed in the water containing a third delayed release dosage form.

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

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

Furthermore, the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.

As a further embodiment, the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.

In a preferred embodiment, the antibiotic product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.

Alternatively, in formulating an oral delivery system, each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product. Thus, for example, antibiotic products may include a first dosage form 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 of the antibiotic, as hereinabove described, whereby the C

max

of the antibiotic released from each of the tablets is reached at different times, with the C

max

of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.

The formulation of an antibiotic product including at least three dosage forms 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 the concentration of antibiotics in the coating and/or the thickness of the coating.

In formulating an antibiotic product in accordance with the invention, in one embodiment, the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic to be delivered by the product, with such immediate release dosage forms generally providing at least 25% of the total dosage of the antibiotic to be delivered by the product. In many cases, the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% of the total dosage of antibiotic to be delivered by the product.

The remaining dosage forms deliver the remainder of the antibiotic. If more than one delayed release dosage form is used, in one embodiment, each of the delayed release dosage forms may provide about equal amounts of antibiotic; however, they may also be formulated so as to provide different amounts.

In accordance with the present invention, each of the dosage forms contains the same antibiotic; however, each of the dosage forms may contain more than one antibiotic.

In one embodiment, where the composition contains one immediate release component and two delayed release components, the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of the total antibiotic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total antibiotic; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, of the total antibiotic.

With respect to the delayed release components, where there are two delayed release components, the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total antibiotic provided by the two delayed release components with the second delayed release component providing the remainder of the antibiotic.

Where there are three delayed release components, the earliest released component provides 20% to 35% by weight of the total antibiotic provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the antibiotic provided by the three delayed release components and the last in time providing the remainder of the antibiotic provided by the three delayed release components.

When there are four delayed release components, the earliest delayed release component provides from 15% to 30%, by weight, the next in time delayed release component provides from 15% to 30%, the next in time delayed release component provides from 20% to 35%, by weight, and the last in time delayed release component provides from 20% to 35%, by weight, in each case of the total antibiotic provided by the four delayed release components.

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 antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.

The materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.

It may be useful to have these materials present in the range of 1.0 to 60% (W/W).

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 monostearate, 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.

These materials may be present in the rate of 0.05-15% (W/W).

The non-pH Sensitive Delayed Release Component

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

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 0.5-25% (W/W) 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.

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

These materials can be present in concentrations from 4-20% (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 the pellet or granule.

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

These materials can be present in concentrations from 4-20% (W/W).

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

The antibiotic composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally. The composition includes a therapeutically effective amount of the antibiotic, which amount will vary with the antibiotic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day. The composition is administered to a host in an amount effective for treating a bacterial infection.

This system will be especially useful in extending the practial therapeutic activity for antibiotics with elimination half lives of less than 20 hours and more particularly with elimination half-lives of less than 12 hours, and will be particularly useful for those drugs with half-lives of 2-10 hours. The following are examples of some antibiotics with half-lives of about 1 to 12 hours: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef, imipenem, erythromycin (and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliin salts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co-triamoxazole, pentamidine, and trimetrexate.

The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight.

EXAMPLES

Immediate Release Component

Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.

Ingredient

Conc. (% W/W)

Example 1:

Amoxicillin

65%

(W/W)

Microcrystalline cellulose

20

Povidone

10

Croscarmellose sodium

5

Example 2:

Amoxicillin

55%

(W/W)

Microcrystalline cellulose

25

Povidone

10

Croscarmellose sodium

10

Example 3:

Amoxicillin

65%

(W/W)

Microcrystalline cellulose

20

Hydroxypropylcellulose

10

Croscarmellose sodium

5

Example 4:

Amoxicillin

75%

(W/W)

Polyethylene glycol 4000

10

Polyethylene glycol 2000

10

Hydroxypropylcellulose

5

Example 5:

Amoxicillin

75%

(W/W)

Polyethylene glycol 8000

20

Polyvinylpyrrolidone

5

Example 6:

Clarithromycin

65%

(W/W)

Microcrystalline cellulose

20

Hydroxypropylcellulose

10

Croscarmellose sodium

5

Example 7:

Clarithromycin

75%

(W/W)

Microcrystalline cellulose

15

Hydroxypropylcellulose

5

Croscarmellose sodium

5

Example 8:

Clarithromycin

75%

(W/W)

Polyethylene glycol 4000

10

Polyethylene glycol 2000

10

Hydroxypropylcellulose

5

Example 9:

Clarithromycin

75%

(W/W)

Polyethylene glycol 8000

20

Polyvinylpyrrolidone

5

Example 10:

Ciprofloxacin

65%

(W/W)

Microcrystalline cellulose

20

Hydroxypropylcellulose

10

Croscarmellose sodium

5

Example 11:

Ciprofloxacin

75%

(W/W)

Microcrystalline cellulose

15

Hydroxypropylcellulose

5

Croscarmellose sodium

5

Example 12:

Ciprofloxacin

75%

(W/W)

Polyethylene glycol 4000

10

Polyethylene glycol 2000

10

Hydroxypropylcellulose

5

Example 13:

Ciprofloxacin

75%

(W/W)

Polyethylene glycol 8000

20

Polyvinylpyrrolidone

5

Example 14:

Ceftibuten

75%

(W/W)

Polyethylene glycol 4000

10

Polyethylene glycol 2000

10

Hydroxypropylcellulose

5

Example 15:

Ceftibuten

75%

(W/W)

Polyethylene Glycol 4000

20

Polyvinylpyrrolidone

5

non-pH Sensitive Delayed Release Component

Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.

Ingredient

Conc. (% W/W)

Example 16:

Amoxicillin

65%

(W/W)

Microcrystalline cellulose

20

Polyox

10

Croscarmellose sodium

5

Example 17:

Amoxicillin

55%

(W/W)

Microcrystalline cellulose

25

Polyox

10

Glyceryl monooleate

10

Example 18:

Amoxicillin

65%

(W/W)

Polyox

20

Hydroxypropylcellulose

10

Croscarmellose sodium

5

Example 19:

Clarithromycin

70%

(W/W)

Polyox

20

Hydroxypropylcellulose

5

Croscarmellose sodium

5

Enteric Release Component

Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.

Ingredient

Conc. (% W/W)

Example 20:

Amoxicillin

65%

(W/W)

Microcrystalline cellulose

20

Cellulose Acetate Pthalate

15

Example 21:

Amoxicillin

55%

(W/W)

Microcrystalline cellulose

25

Cellulose Acetate Pthalate

10

Hydroxypropylmethylcellulose

10

Example 22:

Amoxicillin

65%

(W/W)

Polyox

20

Hydroxypropylcellulose pthalate

10

Eudragit L30D

5

Example 23:

Amoxicillin

40%

(W/W)

Microcrystalline Cellulose

40

Cellulose Acetate Pthalate

10

Example 24:

Clarithromycin

70%

(W/W)

Hydroxypropylcellulose pthalate

15

Croscarmellose sodium

10

Example 25:

Clarithromycin

75%

(W/W)

Polyethylene glycol 2000

10

Eudragit E 30D

15

Example 26:

Clarithromycin

40%

(W/W)

Lactose

50

Eudgragit L 30D

10

Example 27:

Ciprofloxacin

65%

(W/W)

Microcrystalline Cellulose

20

Eudragit L 30D

10

Example 28:

Ciprofloxacin

75%

(W/W)

Microcrystalline Cellulose

15

Hydroxypropylcellulose pthalate

10

Example 29:

Ciprofloxacin

80%

(W/W)

Lactose

10

Eudgragit L 30D

10

Example 30:

Ciprofloxacin

70%

(W/W)

Polyethylene glycol 4000

20

Cellulose acetate pthalate

10

Example 31:

Ceftibuten

60%

(W/W)

Polyethylene glycol 2000

10

Lactose

20

Eudragit L 30D

10

Example 32:

Ceftibuten

70%

(W/W)

Microcrystalline cellulose

20

Cellulose acetate pthalate

10

Sustained Release Component

Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.

Ingredient

Conc. (% W/W)

Example 33:

Amoxicillin

65%

(W/W)

Ethylcellulose

20

Polyox

10

Hydroxypropylmethylcellulose

5

Example 34:

Amoxicillin

55%

(W/W)

Lactose

25

Polyox

10

Glyceryl monooleate

10

Example 35:

Amoxicillin

70%

(W/W)

Polyox

20

Hydroxypropylcellulose

10

Example 36:

Clarithromycin

75%

(W/W)

Lactose

15

Hydroxypropylcellulosee

5

Ethylcellulose

5

Example 37:

Clarithromycin

75%

(W/W)

Polyethylene glycol 4000

10

Lactose

10

Eudragit RL 30D

5

Example 38:

Clarithromycin

80%

(W/W)

Polyethylene glycol 8000

10

Hydroxypropylmethylcellulose

5

Eudgragit RS 30D

5

Example 39:

Ciprofloxacin

75%

(W/W)

Hydroxyethylcellulose

10

Polyethylene glycol 4000

10

Hydroxypropylcellulose

5

Example 40:

Ciprofloxacin

75%

(W/W)

Lactose

10

Povidone (PVP)

10

Polyethylene glycol 2000

5

Example 41:

Ceftibuten

75%

(W/W)

Polyethylene glycol 4000

10

Povidone (PVP)

10

Hydroxypropylcellulose

5

Example 42:

Ceftibuten

75%

(W/W)

Lactose

15

Polyethylene glycol 4000

5

Polyvinylpyrrolidone

5

Three Pulses

Example 43

1. Metronidazole Matrix Pellet Formulation and Preparation Procedure (Immediate Release)

A. Pellet Formulation

The composition of the metronidazole matrix pellets provided in Table 1.

TABLE 1

Composition of Metronidazole Pellets

Component

Percentage (%)

Metronidazole

50

Avicel PH 101

20

Lactose

20

PVP K29/32*

10

Purified Water

Total

100

*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

B. Preparation Procedure for Metronidazole Matrix Pellets

1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.

1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

1.2.5 Dry the spheronized pellets at 50° C. overnight.

1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

A. Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 2.

TABLE 2

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

55.0

Triethyl Citrate

1.6

Talc

8.0

Purified Water

37.4

Solids Content

25.5

Polymer Content

15.9

B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

1.3.1 Suspend triethyl citrate and talc in deionized water.

1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.

1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

A. Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 3.

TABLE 3

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

12.0

1 N Ammonium Hydroxide

6.1

Triethyl Citrate

6.0

Purified Water

65.9

Part B

Talc

2.0

Purified Water

8.0

Solid Content

20.0

Polymer Content

12.0

B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part I:

(i) Dispense Eudragit® S 100 powder in deionized water with stirring.

(ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

(iii) Allow the partially neutralized dispersion to stir for 60 minutes.

(iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.

Part II:

(i) Disperse talc in the required amount of water

(ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.

(iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

1.5 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S100 aqueous film coating.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.8 Bar

Pump Rate

2 gram per minute

(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

(ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.

1.6 Encapsulation of the Metronidazole Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%:30%:40%: Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100 coated pellets respectively.

The capsule is filled with the three different pellets to achieve a total dose of 375 mg/capsule.

Three Pulses

Example 44

Amoxicillin Pellet Formulation and Preparation Procedure

44.1 Pellet Formulations for subsequent coating

The composition of the Amoxicillin trihydrate matrix pellets provided in Table 4.

TABLE 4

Composition of Amoxicillin Matrix Pellets

Component

Percentage (%)

Amoxicillin Trihydrate powder

92

Avicel PH 101

7.0

Hydroxypropyl methylcellulose, NF*

1.0

Total

100

*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

44.2 Preparation Procedure for Amoxicillin Matrix Pellets

44.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

44.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

44.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.

44.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.

44.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

44.2.6 Pellets between 20 and 40 Mesh were collected for further processing.

44.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

44.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 5.

TABLE 5

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

41.6

Triethyl Citrate

2.5

Talc

5.0

Purified Water

50.9

Solids Content

20.0

Polymer Content

12.5

44.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

44.4.1 Suspend triethyl citrate and talc in deionized water.

44.4.2 The TEC/talc suspension is mixed using laboratory mixer.

44.4.3 Add the TEC/taic suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

44.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

44.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

44.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 6.

TABLE 6

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

10.0

1 N Ammonium Hydroxide

5.1

Triethyl Citrate

5.0

Water

64.9

Part B

Talc

5.0

Water

10.0

Solid Content

25.0

Polymer Content

10.0

44.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

44.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

44.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

44.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

44.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.

Part B:

44.6.5 Disperse talc in the required amount of water

44.6.6 Stir the dispersion using an overhead laboratory mixer.

44.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

44.7 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.

Coating Equipment

STREA 1 ™ Table Top Laboratory

Fluid Bed Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.8 Bar

Pump Rate

2-6 gram per minute

44.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

44.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.

44.8 Preparation of Amoxicillin Granulation (Immediate Release Component) for tabletting

TABLE 7

Composition of Amoxicillin Granulation

Component

Percentage (%)

Amoxicillin Trihydrate powder

92

Avicel PH 101

7.0

Hydroxypropyl methylcellulose, NF*

1.0

Total

100

*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

44.8.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

44.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

44.8.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

44.8.4 Granules between 20 and 40 Mesh are collected for further processing.

44.9 Tabletting of the Amoxicillin Pellets

TABLE 8

Composition of Amoxicillin Tablets

Component

Percentage (%)

Amoxicillin granules

32.5

Avicel PH 200

5.0

Amoxicillin L30D-55 coated pellets

30

Amoxicillin S100 coated pellets

30

Colloidal silicon dioxide

1.5

Magnesium stearate

1.0

Total

100

44.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

44.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.

44.9.3 Compress the blend on a rotary tablet press.

44.9.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Three Pulses

Example 45

Clarithromycin Pellet Formulation and Preparation Procedure

45.1 Pellet Formulation

The composition of the clarithromycin matrix pellets provided in Table 1.

TABLE 9

Composition of Clarithromycin Pellets

Component

Percentage (%)

Clarithromycin

50.6

Lactose monohydrate, spray dried

32.1

Silicified microcrystalline cellulose

14.6

Polyoxyl 35 Castor Oil*

1.7

Hydroxypropyl methylcellulose*

1.0

Total

100

*Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

45.2 Preparation Procedure for Clarithromycin Matrix Pellets

45.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

45.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.

45.2.3 Add binder solution slowly into the powder blend under continuous mixing.

45.2.4 Granulate the powders in the high shear granulator with the binder solution.

45.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.2 mm.

45.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

45.2.7 Dry the spheronized pellets at 50° C. overnight.

45.2.8 Pellets between 18 and 30 Mesh were collected for further processing.

45.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

45.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 10.

TABLE 10

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

40.4

Triethyl Citrate

1.8

Talc

6.1

Water

51.7

Solids Content

20.0

Polymer Content

12.1

45.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

45.4.1 Suspend triethyl citrate and talc in deionized water.

45.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

45.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

45.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

45.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

45.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 11.

TABLE 11

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

10.0

1 N Ammonium Hydroxide

5.1

Triethyl Citrate

5.0

Water

64.9

Part B

Talc

5.0

Water

10.0

Solid Content

25.0

Polymer Content

10.0

45.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

45.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

45.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

45.6.3 Allow the partially neutralized dispersion to stir for 60 minutes

45.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B.

Part B:

45.6.5 Disperse talc in the required amount of water

45.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

45.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

45.7 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used for coating the matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid

Bed Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.6 Bar

Pump Rate

2 gram per minute

45.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

45.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.

4. Capsules were filled with the uncoated pellets, the L30D-55 coated pellets and S100 coated pellets in weight percentages of 30%:30%:40%, respectively to provide 250 mg. capsules.

Four Pulses

Example 46

1 Metronidazole Matrix Pellet Formulation and Preparation Procedure

46.1 Pellet Formulation

The composition of the metronidazole matrix pellets provided in Table 12.

TABLE 12

Composition of Metronidazole Pellets

Component

Percentage (%)

Metronidazole

50

Avicel PH 101

20

Lactose

20

PVP K29/32*

10

Purified Water

Total

100

*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

46.2 Preparation Procedure for Metronidazole Matrix Pellets

46.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

46.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.

46.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

46.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

46.2.5 Dry the spheronized pellets at 50° C. overnight.

46.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

46.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

46.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 13.

TABLE 13

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

55.0

Triethyl Citrate

1.6

Talc

8.0

Purified Water

37.4

Solids Content

25.5

Polymer Content

15.9

46.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

46.4.1 Suspend triethyl citrate and talc in deionized water.

46.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

46.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

46.4.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.

46.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

46.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 14.

TABLE 14

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

12.0

1 N Ammonium Hydroxide

6.1

Triethyl Citrate

6.0

Purified Water

65.9

Part B

Talc

2.0

Purified Water

8.0

Solid Content

20.0

Polymer Content

12.0

46.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

46.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

46.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

46.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

46.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.

Part B:

46.6.5 Disperse talc in the required amount of water

46.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

46.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

46.7 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment

STREA 1 ™ Table Top Laboratory

Fluid Bed Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.8 Bar

Pump Rate

2 gram per minute

46.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

46.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.

46.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.

46.8 Encapsulation of the Metronidazole Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%:30%:20%:30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 375 mg/capsule.

Four Pulses

Example 47

Amoxicillin Pellet Formulation and Preparation Procedure

47.1 Pellet Formulations

The composition of the Amoxicillin trihydrate matrix pellets provided in Table 15.

TABLE 15

Composition of Amoxicillin Matrix Pellets

Component

Percentage (%)

Amoxicillin Trihydrate powder

92

Avicel PH 101

7.0

Hydroxypropyl methylcellulose, NF*

1.0

Total

100

*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

47.2 Preparation Procedure for Amoxicillin Matrix Pellets

47.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

47.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

47.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.

47.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.

47.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

47.2.6 Pellets between 20 and 40 Mesh were collected for further processing.

47.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

47.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 16.

TABLE 16

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

41.6

Triethyl Citrate

2.5

Talc

5.0

Purified Water

50.9

Solids Content

20.0

Polymer Content

12.5

47.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

47.4.1 Suspend triethyl citrate and talc in deionized water.

47.4.2 The TEC/talc suspension is mixed using laboratory mixer.

47.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

47.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

47.5 Preparation of an Eudragit® claim

11

, wherein S 100 Aqueous Coating Dispersion

47.6 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 17.

TABLE 17

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

10.0

1 N Ammonium Hydroxide

5.1

Triethyl Citrate

5.0

Water

64.9

Part B

Talc

2.0

Water

10.0

Solid Content

25.0

Polymer Content

10.0

47.7 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

47.7.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

47.7.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

47.7.3 Allow the partially neutralized dispersion to stir for 60 minutes.

47.7.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.

Part B:

47.7.5 Disperse talc in the required amount of water

47.7.6 Stir the dispersion using an overhead laboratory mixer.

47.7.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

47.8 Preparation of Aquacoat Coating Dispersion

47.8.1 Dispersion Formulation

The composition of the aqueous Aquacoat dispersion applied to Amoxicillin L30 D-55 coated pellets is provided below in Table 18.

TABLE 18

Component

Percentage (%)

Aquacoat ECD

79.3

Hydroxypropyl methylcellulose

15.9

Dibutyl Sebacate

4.8

Purified Water (300 g)

47.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15) solution by dispersing in water with continuous stirring.

47.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and continue to stir overnight.

47.9 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment

STREA 1 ™ Table Top Laboratory

Fluid Bed Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.8 Bar

Pump Rate

2-6 gram per minute

47.9.1 Coat Amoxicillin matrix pellet s with L30 D-55 dispersim to achieve a 20% coat weight gain.

47.9.2 Coat another batch of Amoxicillin matrix pellets with L30 D-55 dispersion to achieve a 20% weight gain. Coat the L30 D-55 pellets with the Aquacoat Dispersion to achieve a 10% coat weight gain.

47.9.3 Coat Amoxicillin matrix pellets with S100 dispersion to achieve a 37% coat weight gain.

47.10 Preparation of Amoxicillin Granulation for Tabletting

TABLE 19

Composition of Amoxicillin Granulation (Immediate Release)

Component

Percentage (%)

Amoxicillin Trihydrate powder

92

Avicel PH 101

7.0

Hydroxypropyl methylcellulose, NF*

1.0

Total

100

*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

47.10.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

47.10.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

47.10.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

47.10.4 Granules between 20 and 40 Mesh are collected for further processing.

47.11 Tabletting of the Amoxicillin Pellets

TABLE 20

Composition of Amoxicillin Tablets

Component

Percentage (%)

Amoxicillin granules

32.5

Avicel PH 200

5.0

Amoxicillin L30D-55 coated pellets

20

Amoxicillin Aquacoated pellets

20

Amoxicillin S100 coated pellets

20

Colloidal silicon dioxide

1.5

Magnesium stearate

1.0

Total

100

47.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

47.11.2 Add the magnesium stearate to the blender, and blend for 5 minutes.

47.11.3 Compress the blend on a rotary tablet press.

47.11.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Four Pulses

Example 48

Clarithromycin Pellet Formulation and Preparation Procedure

48.1 Pellet Formulation

The composition of the clarithromycin matrix pellets provided in Table 21.

TABLE 21

Composition of Clarithromycin Pellets

Component

Percentage (%)

Clarithromycin

50.6

Lactose monohydrate, spray dried

32.1

Silicified microcrystalline cellulose

14.6

Polyoxyl 35 Castor Oil*

1.7

Hydroxypropyl methylcellulose*

1.0

Total

100

*Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

48.2 Preparation Procedure for Clarithromycin Matrix Pellets

48.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

48.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.

48.2.3 Add binder solution slowly into the powder blend under continuous mixing.

48.2.4 Granulate the powders in the high shear granulator with the binder solution.

48.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.2 mm.

48.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

48.2.7 Dry the spheronized pellets at 50° C. overnight.

48.2.8 Pellets between 18 and 30 Mesh were collected for further processing.

48.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

48.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 22.

TABLE 22

Eudragit ® L 30 D-55 Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30 D-55

40.4

Triethyl Citrate

1.8

Talc

6.1

Water

51.7

Solids Content

20.0

Polymer Content

12.1

48.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

48.4.1 Suspend triethyl citrate and talc in deionized water.

48.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

48.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

48.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

48.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

48.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 23.

TABLE 23

Eudragit ® S 100 Aqueous Coating Dispersion

Component

Percentage (%)

Part A

Eudragit ® S 100

10.0

1 N Ammonium Hydroxide

5.1

Triethyl Citrate

5.0

Water

64.9

Part B

Talc

5.0

Water

10.0

Solid Content

25.0

Polymer Content

10.0

48.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

48.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

48.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

48.6.3 Allow the partially neutralized dispersion to stir for 60 minutes

48.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B.

Part B:

48.6.5 Disperse talc in the required amount of water

48.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

48.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

48.7 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters were used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment

STREA l ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

40 to 45° C.

Outlet Air Temperature

30 to 33° C.

Atomization Air Pressure

1.6 Bar

Pump Rate

2 gram per minute

48.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

48.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.

48.7.3 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.

48.8 Encapsulation of the Clarithromycin Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%:30%:20%:30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 250 mg/capsule.

Four Pulses

Example 49

Doxycycline Hyclate Pellet Formulation and Preparation Procedure

Pellet Formulation

The composition of the Doxycycline hyclate pellets provided in Table 24.

TABLE 24

Composition of Doxycycline hyclate Pellets

Component

Percentage (%)

Doxycycline hyclate

93

Avicel PH 101

3

Methocel E5P LV

4

Purified Water

*

Total

100

*Removed during processing

Preparation Procedure for Doxycycline Hyclate Pellets

Blend Doxycycline hyclate, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.

Add the purified water slowly into the powder blend under continuous mixing.

Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

Dry the spheronized pellets at 50° C. until moisture level is <3%.

Pellets between 16 and 30 Mesh were collected for further processing.

Doxycycline Hyclate Enteric-Release Pellet Formulation and Preparation Procedure

Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the doxycycline hyclate pellets is provided below in Table 25.

TABLE 25

Eudragit ® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® L 30D-55

44.4

Eudragit NE 30D

14.8

Triethyl Citrate

1.3

Imwitor 900

0.9

Purified Water*

38.6

Solid Content

20.6

Polymer Content

16.4

*Removed during processing

Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion

Heat purified water to 75-80° C. and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55° C.

The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35° C.

Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.

Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.

Screen the dispersion through a No. 60 mesh sieve prior to coating.

Continue to stir the dispersion until the coating process is complete.

Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE 30D Agueous Coating Dispersion

The following coating parameters were used for coating of the Eudragit® L 30 D-55/Eudragit NE30D film coating dispersion.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

45° C.

Outlet Air Temperature

32 to 35° C.

Atomization Air Pressure

1.6 Bar

Pump Rate

3-4 gram per minute

Coat doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.

Doxycycline hyclate Delayed Enteric-Release Pellet Formulation and Preparation Procedure

Preparation of an Opadry Clear Coating Solution

Dispersion Formulation

The composition of the aqueous Opadry solution applied to the Doxycycline hyclate pellets is provided below in Table 26.

TABLE 26

Opadry Clear Aqueous Coating Solution

Component

Percentage (%)

Opadry Clear YS-1-7006

7.0

Purified Water*

93.0

Solid Content %

7.0

Polymer Content %

7.0

*Removed during processing

Preparation Procedure for Opadry Clear Aqueous Solution

Charge the purified water into a container

Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.

Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Doxycycline hyclate pellets is provided below in Table 27.

TABLE 27

AQOAT AS-HF/Eudragit FS 30D Coating Dispersion

Component

Percentage (%)

Eudragit L 30D-55

5.8

Eudagit FS 30D

17.5

Triethyl Citrate

1.3

Talc

1.4

Purified Water*

74.0

Solid Content

9.7

Polymer Content

7.0

*Removed during processing

Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aqueous Dispersion

Disperse triethyl citrate in purified water with stirring.

Slowly add talc into the triethyl citrate dispersion with stirring.

Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.

Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.

Screen the dispersion through a No. 60 mesh sieve.

Continue to stir the screened coating dispersion throughout the coating process.

Coating Conditions for the Application of Opadry and Eudragit FS 30D/Eudragit L 30D-55 Aqueous Coating Dispersions

The following coating parameters were used for coating with the Opadry solution film coating.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.0 mm

Material Charge

350 gram

Inlet Air Temperature

60° C.

Outlet Air Temperature

40° C.

Atomization Air Pressure

1.6 Bar

Coat Doxycycline hyclate pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.

The following coating parameters were used for coating with the Eudragit FS 30D/Eudragit L30D-55 film coating dispersion.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.0 mm

Material Charge

300 gram

Inlet Air Temperature

50° C.

Outlet Air Temperature

30° C.

Atomization Air Pressure

1.6 Bar

Coat Opadry coated Doxycycline hyclate pellets with the Eudragit FS30D/Eudragit L 30D-55 coating dispersion such that you apply 20% coat weight gain to the pellets.

Doxycycline Hyclate Colonic-Release Pellet Formulation and Preparation Procedure

Preparation of an Eudragit® FS30D Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous Eudragit® FS 30D dispersion applied to the doxycycline hyclate pellets is provided below in Table 28.

TABLE 28

Eudragit ® FS 30D Aqueous Coating Dispersion

Component

Percentage (%)

Eudragit ® FS 30D

54.8

Triethyl Citrate

0.9

Talc

3.3

Purified Water*

41.0

Solid Content

20.6

Polymer Content

16.4

*Removed during processing

Preparation Procedure for an Eudragit® FS 30D Aqueous Disipersion

Disperse triethyl citrate (TEC) in the purified water.

Add the talc in the triethyl citrate dispersion.

Homogenize the dispersion using a homogenizer.

Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.

Continue to stir the coating dispersion until the coating process is complete.

Coating Conditions for the Application of Eudragit FS30D Aqueous Coating Dispersion

The following coating parameters were used for coating with each of the Eudragit® FS 30 D aqueous film coating.

Coating Equipment

STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter

1.2 mm

Material Charge

300 gram

Inlet Air Temperature

38° C.

Outlet Air Temperature

22° C.

Atomization Air Pressure

1.6 Bar

Pump Rate

6 gram per minute

Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.

Encapsulation of the Doxycycline Hyclate Pellets

Pellets are filled into hard gelatin capsules at a ratio of 25%:25%:25%:25% Immediate-Release Pellets (uncoated), Eudragit L30 D-55/Eudragit NE 30D coated pellets 20% weight gain, Eudragit FS 30D/Eudragit L 30 D-55 coated pellets 20% weight gain and Eudragit FS 30D coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 100 mg/capsule or 200 mg/capsule.

The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration of the antibiotic.

Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described.

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	Number	Date	Country
Parent	09/792092	Feb 2001	US
Child	10/028590		US
Parent	09/687229	Oct 2000	US
Child	09/792092		US

Tetracycline antibiotic product, use and formulation thereof

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