Ciprofoxacin-metronidazole antibiotic composition

[0002] This invention relates to antibiotic compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more antibiotics, and the use thereof.

[0003] In many cases, it is desirable to employ two different antibiotics in the treatment of a bacterial infection, in that such antibiotics may have complementary mechanisms of action that facilitate treatment of the bacterial infection.

[0004] The present invention is directed to a new and improved composition that delivers two or more antibiotics, and the use thereof, with the two antibiotics being Ciprofoxacin and Metronidazole.

[0005] In accordance with an aspect of the present invention, there is provided an antibiotic product for delivering at least two different antibiotics that is comprised of at least three dosage forms each comprised of at least one antibiotic and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two antibiotics and at least one dosage form including at least a second antibiotic of the at least two antibiotics, wherein one of the antibiotics is Ciprofoxacin and the other antibiotic is Metronidazole.

[0006] Thus, for example, each of the dosage forms may include two or more antibiotics, or one or two of the dosage forms may include only one of the two or more antibiotics and each of the remaining dosage forms may include only one or more of the different antibiotics or two or more of the antibiotics. Thus, in accordance with this aspect of the invention, there is an antibiotic product for delivering at least two different antibiotics wherein the product includes at least three dosage forms wherein each of the at least two antibiotics is present in at least one of the three dosage forms. In each case, one of the antibiotics is Ciprofoxacin and the other of the antibiotics is Metronidazole.

[0007] In a preferred embodiment each of the dosage forms has a different release profile, with one of the dosage forms being an immediate release dosage form.

[0008] In another aspect, the present invention is directed to treating a bacterial infection by administering to a host in need thereof an antibiotic product as hereinabove and hereinafter described.

[0009] 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 three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of the at least three dosage forms is released at different times, and wherein at least one of the dosage forms includes at least Ciprofoxacin and at least one of the dosage forms includes at least Metronidazole. One or more of the dosage forms may include both Ciprofoxacin and Metronidazole.

[0010] 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.

[0011] The antibiotic product generally does not include more than five dosage forms with different release times.

[0012] 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.

[0013] In accordance with one preferred embodiment of the invention, one of the at least three dosage forms is an immediate release dosage form whereby initiation of release of 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 antibiotic released therefrom is delayed until after initiation of release of antibiotic from the immediate release dosage form. More particularly, antibiotic release from the second of the at least two dosage forms achieves a Cmax (maximum serum concentration in the serum) at a time after antibiotic released from the first of the at least three dosage forms achieves a Cmax in the serum, and antibiotic released from the third dosage form achieves a Cmax in the serum after the Cmax of antibiotic released from the second dosage form.

[0014] In one embodiment, the second of the at least two dosage forms initiates release of 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.

[0015] In general, the immediate release dosage form produces a Cmax for 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 Cmax for antibiotic released therefrom in no more than about four hours. In general, the Cmax 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 Cmax in a shorter period of time.

[0016] As hereinabove indicated, the antibiotic product may contain at least three or at least four or more different dosage forms. For example, the antibiotic released from the third dosage form reaches a Cmax at a time later than the Cmax is achieved for 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, Cmax for antibiotic release from the third dosage form is achieved within eight hours.

[0017] 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 antibiotic released from each of the at least four different dosage forms achieves a Cmax at a different time.

[0018] As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic contains at least three or at least four different dosage forms each with a different release profile, Cmax 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.

[0019] 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 Cmax 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.

[0020] Thus in accordance with an aspect of the invention, there is provided a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile with each of the dosage forms including at least one of Ciprofoxacin or Metronidazole and at least one of the three dosage forms including at least Ciprofoxacin and at least one of the dosage forms including at least Metronidazole. Each of the dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics.

[0021] 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.

[0022] 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 Cmax of the fourth dosage form of the at least four dosage forms is reached after the Cmax 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.

[0023] In accordance with an aspect of the present invention, there is provided an antibiotic composition that is a mixture of antibiotic compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first antibiotic and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first antibiotic and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second antibiotic different from the first antibiotic and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second antibiotic and a pharmaceutically acceptable carrier; wherein the second and third compositions each have a release profile that provides a maximum serum concentration of the first antibiotic released from the second composition and a maximum serum concentration for the second antibiotic released from the third composition at a time after the first antibiotic released from the first composition reaches a maximum serum concentration, and wherein the fourth composition has a release profile that provides for a maximum serum concentration of the second antibiotic released from the fourth composition at a time after the antibiotics released from the second and third compositions reach a maximum serum concentration. The first antibiotic is one of Ciprofoxacin or Metronidazole and the second antibiotic is the other of Ciprofoxacin or Metronidazole.

[0024] In one embodiment, the release profiles of the second and third composition are such that the maximum serum concentration of the first antibiotic released from the second composition, and the maximum serum concentration of the second antibiotic released from the third composition are reached at approximately the same time, or where the first antibiotic reaches a maximum serum concentration before or after the second antibiotic reaches a maximum serum concentration.

[0025] In effect, in accordance with a preferred embodiment of the present invention, there is provided a first pulse in which a first antibiotic reaches a maximum serum concentration, a second pulse wherein a further dosage of the first antibiotic, and an initial dosage of the second antibiotic reach a maximum serum concentration at a time after the first pulse of the first antibiotic reaches a maximum serum concentration, and a third pulse wherein an additional dosage of the second antibiotic reaches a maximum serum concentration at a time after the maximum serum concentration is reached for each of the first and second antibiotic dosages provided in the second pulse.

[0026] In a preferred embodiment of the present invention, the first dosage of the first antibiotic achieves a maximum serum concentration within four hours after administration of the antibiotic composition; the second dosage of the first antibiotic and the first dosage of the second antibiotic each reach a maximum serum concentration within four to eight hours after administration of the antibiotic composition; and the second dosage of the second antibiotic reaches a maximum serum concentration within twelve hours after administration of the antibiotic composition.

[0027] Thus, in accordance with an aspect of the present invention, there is provided an antibiotic composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first antibiotic, the second dosage form providing a further dosage of the first antibiotic; the third dosage form providing an initial dosage of a second antibiotic; and the fourth dosage form providing an additional dosage of the second antibiotic, wherein the antibiotics released from the second and third dosage forms reach a maximum serum concentration at a time after the antibiotic released from the first dosage form reaches a maximum serum concentration, and the antibiotic released from the fourth dosage form reaching a maximum serum concentration at a time after the times at which the antibiotics released from each of the first, second, and third dosage forms reach a maximum serum concentration.

[0028] In one embodiment of the invention, the first dosage form provides for immediate release, the second and third dosage forms provide for a delayed release (pH or non pH dependent, with the second dosage form preferably being a pH dependent release), and the fourth dosage form provides for pH dependent or non pH dependent release preferably non pH dependent release.

[0029] In formulating the antibiotic composition of the present invention, which contains four different dosage forms, as hereinabove described, the first dosage form generally contains from about 30 percent to about 80 percent of the first antibiotic; the second dosage form contains from about 30 percent to about 80 percent of the first antibiotic; the third dosage form contains from about 30 percent to about 80 percent of the second antibiotic, and the fourth antibiotic dosage form contains from about 30 percent to about 80 percent of the second antibiotic. In formulating a composition comprised of such four dosage forms or units, each unit or dosage form is present in an amount of at least 20 percent by weight, with each dosage form or unit being present in the overall composition in an amount that generally does not exceed 60 percent by weight.

[0030] Each of the first and second dosage forms include from 20% to 80% of the total dosage of the first antibiotic to be provided by the composition, and each of the first and second dosage forms may include the same or different dosages of the first antibiotic.

[0031] Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second antibiotic to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of the antibiotic.

[0032] 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 form 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] The overall composition includes each of the antibiotics in a therapeutically effective amount. The specific amount(s) is dependant on the antibiotic used, the disease or infection to be treated, and the number of times of day that the composition is to be administered.

[0039] The antibiotic composition of the present invention may be administered for example, by any one of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, oral, preferably by oral administration.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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 Cmax of the antibiotic released from each of the tablets is reached at different times, with the Cmax of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.

[0048] 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.

[0049] As hereabove indicated, the first and second antibiotics employed in the antibiotic composition may be a wide variety of products. In one embodiment, the combination of first and second antibiotics that are used in the composition may be, for example, a penicillin and an aminoglycoside, such as gentamycin, tobramicin, amikacin or vancomycin. Another antibiotic composition that may be employed is a combination of a sulfonamide, such as sulfamethoxasol, which would be combined with trimethoporim. In a preferred embodiment, the first and second, antibiotics are different antibiotics and each is from a different class of antibiotic.

[0050] The Immediate Release Component

[0051] 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.

[0052] 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, ydroxypropylmethylcellulose, 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.

[0053] It may be useful to have these materials present in the range of 1.0 to 60% (W/W).

[0054] 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.

[0055] These materials may be present in the rate of 0.05-15% (W/W).

[0056] The Delayed Release Component

[0057] 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.

[0058] 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.

[0059] Typically these materials can be present in the range of 0.5-25% (W/W) of this component.

[0060] The Enteric Release Component

[0061] 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.

[0062] 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.

[0063] These materials can be present in concentrations from 4-20% (W/W).

[0064] The invention will be further described with respect to the following examples; however the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified.

EXAMPLES

[0065]

1

Ingredient
Conc. (% W/W)

Immediate Release Component

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:
Ciprofoxacin
65% (W/W)

Microcrystalline cellulose
20

Hydroxypropylcellulose
10

Croscarmellose sodium
5

Example 11:
Ciprofoxacin
75% (W/W)

Microcrystalline cellulose
15

Hydroxypropylcellulose
5

Croscarmellose sodium
5

Example 12:
Ciprofoxacin
75% (W/W)

Polyethylene glycol 4000
10

Polytheylene glycol 2000
10

Hydroxypropylcellulose
5

Example 13:
Cirpofoxacin
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

Delayed Release Component (non-pH dependant)

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:
Amoxicillin
75% (W/W)

Polyethylene glycol 4000
10

Polyethylene glycol 2000
10

Eudragit RL 30D
5

Example 20:
Amoxicillin
75% (W/W)

Polyethylene glycol 8000
20

Ethylcellulose
5

Example 21:
Clarithromycin
70% (W/W)

Polyox
20

Hydroxypropylcellulose
5

Croscarmellose sodium
5

Example 22:
Clarithromycin
75% (W/W)

Polyox
15

Hydroxypropylcellulose
5

Ethylcellulose
5

Example 23:
Clarithromycin
75% (W/W)

Polyethylene glycol 4000
10

Polyethylene glycol 2000
10

Eudragit RL 30D
5

Example 24:
Clarithromycin
80% (W/W)

Polyethylene glycol 8000
10

Polyvinylpyrrolidone
5

Eudgragit R 30D
5

Example 25:
Ciprofoxacin
65% (W/W)

Polyethylene glycol 4000
20

Hydroxypropylcellulose
10

Eudragit RL 30D
5

Example 26:
Ciprofoxacin
75% (W/W)

Microcrystalline cellulose
15

Hydroxypropylcellulose
5

Ethylcellulose
5

Example 27:
Ciprofoxacin
80% (W/W)

Polyethylene glycol 4000
10

Polyethylene glycol 2000
5

Eudgragit RL 30D
5

Example 28:
Ciprofoxacin
75% (W/W)

Polyethylene glycol 8000
20

Ethylcellulose
5

Example 29:
Ceftibuten
75% (W/W)

Polyethylene glycol 4000
10

Polyethylene glycol 2000
10

Eudragit RL 30D
5

Example 30:
Ceftibuten
75% (W/W)

Polyethylene glycol 8000
20

Ethylcellulose
5

Example 31:
Gentamicin
20% (W/W)

Sodium lauryl sulfate
2

Sodium monoglycerides
10

Sodium diglycerides
20

Diethyleneglycolmethylether
5

Microcrystalline cellulose
43

Example 32:
Gentamicin
10% (W/W)

Glyvceryl behanate
30

Pluronic
10

Carbopol 94P
30

Microcrystalline cellulose
20

Example 33:
Gentamicin
25% (W/W)

Carbopol 94P
35

Microcrystalline cellulose
20

Vitamin E TPGS
15

Sodium monoglycerate
5

Example 34:
Amikacin
25% (W/W)

Carbopol 94P
10

Sodium monoglycerate
15

Sodium diglycerate
15

Pluronic
10

Lactose
25

Example 35:
Gentamicin
30% (W/W)

Triacetin
15

Capryol 90
5

Poloxamer Synperonic PE/F66
10

Cab-O-Sil
5

Microcrystalline cellulose
35

Enteric Release Component

Example 36:
Clarithromycin
70% (W/W)

Hydroxypropylcellulose
15

pthalate
10

Croscarmellose sodium

Example 37:
Clarithromycin
70% (W/W)

Eudragit E30D
15

Hydroxypropylcellulose
10

Ethylcellulose
5

Example 38:
Clarithromycin
75% (W/W)

Polyethylene glycol 2000
10

Eudragit E 30D
15

Example 39:
Clarithromycin
40% (W/W)

Lactose
50

Eudgragit E 30D
10

Example 40:
Ciprofoxacin
65% (W/W)

Microcrystalline Cellulose
20

Eudragit E 30D
10

Example 41:
Ciprofoxacin
75% (W/W)

Microcrystalline Cellulose
15

Hydroxypropylcellulose
10

pthalate

Example 42:
Ciprofoxacin
80% (W/W)

Lactose
10

Eudragit E 30D
10

Example 43:
Ciprofoxacin
70% (W/W)

Polyethylene glycol 4000
20

Cellulose acetate pthalate
10

Example 44:
Ceftibuten
60% (W/W)

Polyethylene glycol 2000
10

Lactose
20

Eudragit E 30D
10

Example 45:
Ceftibuten
70% (W/W)

Microcrystalline cellulose
20

Cellulose acetate pthalate
10

Example 46:
Amoxicillin
65% (W/W)

Microcrystalline cellulose
20

Cellulose Acetate Pthalate
15

Example 47:
Amoxicillin
55% (W/W)

Microcrystalline cellulose
25

Cellulose Acetate Pthalate
10

Hydroxypropylmethylcellulose
10

Example 48:
Amoxicillin
65% (W/W)

Polyox
20

Hydroxypropylcellulose
10

pthalate
5

Eudragit E30D

Example 49:
Amoxicillin
75% (W/W)

Polyethylene glycol 2000
10

Eudragit E30D
10

Eudragit RL 30D
5

Example 50:
Amoxicillin
40% (W/W)

Microcrystalline Cellulose
40

Cellulose Acetate Pthalate
10

Example 51:
Ceftibuten
75% (W/W)

Polyethylene glycol 8000
20

Ethylcellulose
5

Example 52:
Gentamicin
20% (W/W)

Sodium lauryl sulfate
2

Sodium monoglycerides
10

Sodium diglycerides
20

Diethyleneglycolmethylether
5

Microcrystalline cellulose
30

Cellulose acetate pthalate
13

Example 53:
Gentamicin
10% (W/W)

Glyceryl behanate
30

Pluronic
10

Carbopol 94P
10

Microcrystalline cellulose
20

Eudragit E30D
20

Example 54:
Gentamicin
25% (W/W)

Carbopol 94P
15

Microcrystalline cellulose
20

Vitamin E TPGS
15

Sodium Monoglycerate
5

Eudragit E30D
20

Example 55:
Amikacin
25% (W/W)

Carbopol 94P
10

Sodium monoglycerate
15

Sodium diglycerate
15

Pluronic
10

Lactose
15

Cellulose acetate pthalate
10

Example 56:
Gentamicin
30% (W/W)

Triacetin
15

Capryol 90
5

Poloxamer SynperonicPE/F66
10

Cab-O-Sil
5

Microcrystalline cellulose
25

Eudragit E30D
10

[0066] Three Pulses

Example 57.

[0067] 1. Antibiotic Matrix Pellet Formulation and Preparation Procedure (Immediate Release)

[0068] A. Pellet Formulation

[0069] The composition of the antibiotic matrix pellets provided in Table 1.

2TABLE 1Composition of Antibiotic PelletsComponentPercentage (%)Antibiotic50Avicel PH 10120Lactose20PVP K29/32*10Purified WaterTotal100*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

[0070] B. Preparation Procedure for antibiotic Matrix Pellets

[0071] 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

[0072] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.

[0073] 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.

[0074] 1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0075] 1.2.5 Dry the spheronized pellets at 50° C. overnight.

[0076] 1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

[0077] The above procedure is used to make pellets of a first antibiotic and pellets of a second different antibiotic.

[0078] 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

[0079] A. Dispersion Formulation

[0080] The composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 2.

3TABLE 2Eudragit ® L 30 D-55 Aqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30 D-5555.0Triethyl Citrate1.6Talc8.0Purified Water37.4Solids Content25.5Polymer Content15.9

[0081] B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

[0082] 1.3.1 Suspend triethyl citrate and talc in deionized water.

[0083] 1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

[0084] 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

[0085] 1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.

[0086] 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0087] A. Dispersion Formulation

[0088] The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 3.

4TABLE 3Eudragit ® S 100 Aqueous Coating DispersionComponentPercentage (%)Part AEudragit ® S 10012.01 N Ammonium Hydroxide6.1Triethyl Citrate6.0Purified Water65.9Part BTalc2.0Purified Water8.0Solid Content20.0Polymer Content12.0

[0089] B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

[0090] Part i:

[0091] (i) Dispense Eudragit® S 100 powder in deionized water with stirring.

[0092] (ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

[0093] (iii) Allow the partially neutralized dispersion to stir for 60 minutes.

[0094] (iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.

[0095] Part II:

[0096] (i) Disperse talc in the required amount of water

[0097] (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.

[0098] (iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

[0099] 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.

5Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature40 to 45° C.Outlet Air Temperature30 to 33° C.Atomization Air Pressure1.8 BarPump Rate2 gram per minute

[0100] (i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

[0101] (ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.

[0102] 1.6 Encapsulation of the Antibiotic Pellets

[0103] 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.

[0104] The capsule is filled with the three different pellets to achieve a the desire dosage.

[0105] The immediate release matrix pellets include the first antibiotic, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antibiotic and the S100 coated pellets are made by coating matrix pellets that contain the first antibiotic.

[0106] Three Pulses

Example 58

[0107] Antibiotic Pellet Formulation and Preparation Procedure

[0108] 58.1 Pellet Formulations for Subsequent Coating

[0109] The composition of the Antibiotictrihydrate matrix pellets provided in Table 4.

6TABLE 4Composition of AntibioticMatrix PelletsComponentPercentage (%)AntibioticTrihydrate powder92Avicel PH 1017.0Hydroxypropyl methylcellulose, NF*1.0Total100

[0110] *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

[0111] 58.2 Preparation Procedure for AntibioticMatrix Pellets

[0112] 58.2.1 Blend Antibioticand Avicel® PH 101 using a low shear blender.

[0113] 58.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

[0114] 58.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0115] 58.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.

[0116] 58.2.5Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

[0117] 58.2.6 Pellets between 20 and 40 Mesh were collected for further processing.

[0118] 58.2.7 The above procedure is used to produce pellets that contain a first antibiotic and pellets that contain a second and different antibiotic.

[0119] 58.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

[0120] 58.3.1 Dispersion Formulation

[0121] The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antibioticmatrix pellets is provided below in Table 5.

7TABLE 5Eudragit ® L 30 D-55 Aqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30 D-5541.6Triethyl Citrate2.5Talc5.0Purified Water50.9Solids Content20.0Polymer Content12.5

[0122] 58.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

[0123] 58.4.1 Suspend triethyl citrate and talc in deionized water.

[0124] 58.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0125] 58.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

[0126] 58.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antibioticmatrix pellets.

[0127] 58.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0128] 58.5.1 Dispersion Formulation

[0129] The composition of the aqueous Eudragit® S 100 dispersion applied to the Antibioticmatrix pellets is provided below in Table 6.

8TABLE 6Eudragit ® S 100 Aqueous Coating DispersionComponentPercentage (%)Part AEudragit ® S 10010.01 N Ammonium Hydroxide5.1Triethyl Citrate5.0Water64.9Part BTalc5.0Water10.0Solid Content25.0Polymer Content10.0

[0130] 58.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

[0131] Part A:

[0132] 58.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

[0133] 58.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

[0134] 58.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

[0135] 58.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.

[0136] Part B:

[0137] 58.6.5 Disperse talc in the required amount of water

[0138] 58.6.6 Stir the dispersion using an overhead laboratory mixer.

[0139] 58.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

[0140] 58.7 Coating Conditions for the Application of Aqueous Coating Dispersions

[0141] The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.

9Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature40 to 45° C.Outlet Air Temperature30 to 33° C.Atomization Air Pressure1.8 BarPump Rate2-6 gram per minute

[0142] 58.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

[0143] 58.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.

[0144] 58.8 Preparation of AntibioticGranulation (Immediate Release Component) for tabletting

10TABLE 7Composition of AntibioticGranulationComponentPercentage (%)AntibioticTrihydrate powder92Avicel PH 1017.0Hydroxypropyl methylcellulose, NF*1.0Total100*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

[0145] 58.8.1 Blend Antibioticand Avicel® PH 101 using a low shear blender.

[0146] 58.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

[0147] 58.8.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

[0148] 58.8.4 Granules between 20 and 40 Mesh are collected for further processing.

[0149] 58.9 Tabletting of the AntibioticPellets

11TABLE 8Composition of AntibioticTabletsComponentPercentage (%)First antibioticgranules32.5Avicel PH 2005.0Second antibioticL30D-55 coated pellets30First antibioticS100 coated pellets30Colloidal silicon dioxide1.5Magnesium stearate1.0Total100

[0150]

58
.9.1 Blend the Antibioticgranules, Avicel PH-200, Antibioticpellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

[0151] 58.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.

[0152] 58.9.3 Compress the blend on a rotary tablet press.

[0153] 58.9.4 The fill weight should be adjusted to achieve the desired dosage.

[0154] Four Pulses

Example 59

[0155] 1 Antibiotic Matrix Pellet Formulation and Preparation Procedure

[0156] 59.1 Pellet Formulation

[0157] The composition of the antibiotic matrix pellets provided in Table 9.

12TABLE 9Composition of Antibiotic PelletsComponentPercentage (%)Antibiotic50Avicel PH 10120Lactose20PVP K29/32*10Purified WaterTotal100*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

[0158] 59.2 Preparation Procedure for Antibiotic Matrix Pellets

[0159] 59.2.1 Blend antibiotic and Avicel® PH 101 using a Robot Coupe high shear granulator.

[0160] 59.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.

[0161] 59.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0162] 59.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0163] 59.2.5 Dry the spheronized pellets at 50° C. overnight.

[0164] 59.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

[0165] 59.2.7 The above procedure is used to prepare pellets that contain a first antibiotic and pellets that contain a second antibiotic.

[0166] 59.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

[0167] 59.3.1 Dispersion Formulation

[0168] The composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 10.

13TABLE 10Eudragit ® L 30 D-55 Aqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30 D-5555.0Triethyl Citrate1.6Talc8.0Purified Water37.4Solids Content25.5Polymer Content15.9

[0169]

59
.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

[0170] 59.4.1 Suspend triethyl citrate and talc in deionized water.

[0171] 59.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

[0172] 59.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

[0173] 59.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.

[0174] 59.5 Preparation of an Eudragit S 100 Aqueous Coating Dispersion

[0175] 59.5.1 Dispersion Formulation

[0176] The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 11.

14TABLE 11Eudragit ® S 100 Aqueous Coating DispersionComponentPercentage (%)Part AEudragit ® S 10012.01 N Ammonium Hydroxide6.1Triethyl Citrate6.0Purified Water65.9Part BTalc2.0Purified Water8.0Solid Content20.0Polymer Content12.0

[0177]

59
.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

[0178] Part A:

[0179] 59.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

[0180] 59.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

[0181] 59.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

[0182] 59.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.

[0183] Part B:

[0184] 59.6.5 Disperse talc in the required amount of water

[0185] 59.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

[0186] 59.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 59.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

15Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature40 to 45° C.Outlet Air Temperature30 to 33° C.Atomization Air Pressure1.8 BarPump Rate2 gram per minute

[0187] 59.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

[0188] 59.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.

[0189] 59.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.

[0190] 59.8 Encapsulation of the Antibiotic Pellets

[0191] 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 the desired dosage.

[0192] The immediate release pellets contain the first antibiotic; the L30 D-55 12% weight gain coated pellets containe the second antibiotic; the L30 D-55 30% weight gain coated pellets contain the first antibiotic and the S100 coated pellets contain the second antibiotic.

Example 60.

[0193] Metronidazole Pellet Formulation and Preparation Procedure

[0194] Pellet Formulation

[0195] The composition of the metronidazole pellets provided in Table 12.

16TABLE 12Composition of Metronidazole PelletsComponentPercentage (%)Metronidazole93Avicel PH 1013Methocel E5P LV4Purified Water*Total100*Removed during processing

[0196] Preparation Procedure for Metronidazole Pellets

[0197] Blend metronidazole, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.

[0198] Add the purified water slowly into the powder blend under continuous mixing.

[0199] Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0200] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0201] Dry the spheronized pellets at 50° C. until moisture level is <3%.

[0202] Pellets between 16 and 30 Mesh were collected for further processing.

[0203] Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure

[0204] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion Dispersion Formulation

[0205] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 13.

17TABLE 13Eudragit ® L 30 D-55/Eudragit NE 30D Aqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30D-5544.4Eudragit NE 30D14.8Triethyl Citrate1.3Imwitor 9000.9Purified Water*38.6Solid Content20.6Polymer Content16.4*Removed during processing

[0206] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion

[0207] 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.

[0208] The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35° C.

[0209] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.

[0210] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.

[0211] Screen the dispersion through a No. 60 mesh sieve prior to coating.

[0212] Continue to stir the dispersion until the coating process is complete.

[0213] Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0214] The following coating parameters were used for coating of the Eudragit® L 30 D-55/Eudragit NE30D film coating dispersion.

18Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature45° C.Outlet Air Temperature32 to 35° C.Atomization Air Pressure1.6 BarPump Rate3-4 gram per minute

[0215] Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.

[0216] Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation Procedure

[0217] Preparation of an Opadry Clear Coating Solution Dispersion Formulation

[0218] The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 14.

19TABLE 14Opadry Clear Aqueous Coating SolutionComponentPercentage (%)Opadry Clear YS-1-70067.0Purified Water*93.0Solid Content %7.0Polymer Content %7.0*Removed during processing

[0219] Preparation Procedure for Opadry Clear Aqueous Solution

[0220] Charge the purified water into a container

[0221] Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.

[0222] Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation

[0223] The composition of the aqueous AQOAT AS-HF/Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 15.

20TABLE 15AQOAT AS-HF/Eudragit FS 30D Coating DispersionComponentPercentage (%)AQOAT AS-HF5.25Eudagit FS30D5.83Triethyl Citrate1.96Sodium Lauryl Sulfate0.21Talc2.10Purified Water*84.65Solid Content11.27Polymer Content7.0*Removed during processing

[0224] Preparation Procedure for AQOAT AS-HF/Eudragit FS30D Aqueous Dispersion

[0225] Disperse triethyl citrate in purified water with stirring.

[0226] Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.

[0227] Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.

[0228] Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.

[0229] Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.

[0230] Screen the dispersion through a No. 60 mesh sieve.

[0231] Continue to stir the screened coating dispersion throughout the coating process.

[0232] Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D Aqueous Coating Dispersions

[0233] The following coating parameters were used for coating with the Opadry solution film coating.

21Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge350 gramInlet Air Temperature60° C.Outlet Air Temperature40° C.Atomization Air Pressure1.6 Bar

[0234] Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.

[0235] The following coating parameters were used for coating with the AQOATAS-HF/Eudragit FS30D film coating dispersion.

22Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature50° C.Outlet Air Temperature30° C.Atomization Air Pressure1.6 Bar

[0236] Coat Opadry coated metronidazole pellets with the AQOATAS-HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50° C.

[0237] Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure

[0238] Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion

[0239] Dispersion Formulation

[0240] The composition of the aqueous Eudragit® FS 30D dispersion applied to the Metronidazole pellets is provided below in Table 16.

23TABLE 16Eudragit ® FS 30D Aqueous Coating DispersionComponentPercentage (%)Eudragit ® FS 30D54.8Triethyl Citrate0.9Talc3.3Purified Water*41.0Solid Content20.6Polymer Content16.4*Removed during processing

[0241] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0242] Disperse triethyl citrate (TEC) in the purified water.

[0243] Add the talc in the triethyl citrate dispersion.

[0244] Homogenize the dispersion using a homogenizer.

[0245] Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.

[0246] Continue to stir the coating dispersion until the coating process is complete.

[0247] Coating Conditions for the Application of Eudragit FS30D Aqueous Coating Dispersion

[0248] The following coating parameters were used for coating with each of the Eudragit® FS 30 D aqueous film coating.

24Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.2 mmMaterial Charge300 gramInlet Air Temperature38° C.Outlet Air Temperature22° C.Atomization Air Pressure1.6 BarPump Rate6 gram per minute

[0249] Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.

[0250] Ciprofloxacin Pellet Formulation and Preparation Procedure

[0251] Pellet Formulation

[0252] The composition of the Ciprofloxacin pellets provided in Table 17.

25TABLE 17Composition of Ciprofloxacin PelletsComponentPercentage (%)Ciprofloxacin93Avicel PH 1013Methocel E5P LV4Purified Water*Total100*Removed during processing

[0253] Preparation Procedure for Ciprofloxacin Pellets

[0254] Blend Ciprofloxacin, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.

[0255] Add the purified water slowly into the powder blend under continuous mixing.

[0256] Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0257] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0258] Dry the spheronized pellets at 50° C. until moisture level is <3%.

[0259] Pellets between 16 and 30 Mesh were collected for further processing.

[0260] Ciprofloxacin Enteric-Release Pellet Formulation and Preparation Procedure

[0261] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion Dispersion Formulation

[0262] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Ciprofloxacin pellets is provided below in Table 18.

26TABLE 18Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30D-5544.4Eudragit NE 30D14.8Triethyl Citrate1.3Imwitor 9000.9Purified Water*38.6Solid Content20.6Polymer Content16.4*Removed during processing

[0263] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion

[0264] 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.

[0265] The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35° C.

[0266] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.

[0267] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.

[0268] Screen the dispersion through a No. 60 mesh sieve prior to coating.

[0269] Continue to stir the dispersion until the coating process is complete.

[0270] Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0271] The following coating parameters were used for coating of the Eudragit® L 30 D-55/Eudragit NE30D film coating dispersion.

27Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature45° C.Outlet Air Temperature32 to 35° C.Atomization Air Pressure1.6 BarPump Rate3-4 gram per minute

[0272] Coat Ciprofloxacin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.

[0273] Ciprofloxacin Delayed Enteric-Release Pellet Formulation and Preparation Procedure

[0274] Preparation of an Opadry Clear Coating Solution

[0275] Dispersion Formulation

[0276] The composition of the aqueous Opadry solution applied to the Ciprofloxacin pellets is provided below in Table 19.

28TABLE 19Opadry Clear Aqueous Coating SolutionComponentPercentage (%)Opadry Clear7.0YS-1-7006Purified Water*93.0Solid Content %7.0Polymer Content %7.0*Removed during processing

[0277] Preparation Procedure for Opadry Clear Aqueous Solution

[0278] Charge the purified water into a container

[0279] Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.

[0280] Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Aqueous Coating Dispersion Dispersion Formulation

[0281] The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Ciprofloxacin pellets is provided below in Table 20.

29TABLE 20Eudragit FS 30D/Eudragit L 30D-55 Coating DispersionComponentPercentage (%)Eudragit L 30D-555.8Eudagit FS 30D17.5Triethyl Citrate1.3Talc1.4Purified Water*74.0Solid Content9.7Polymer Content7.0*Removed during processing

[0282] Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aqueous Dispersion

[0283] Disperse triethyl citrate in purified water with stirring.

[0284] Slowly add talc into the triethyl citrate dispersion with stirring.

[0285] Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.

[0286] Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.

[0287] Screen the dispersion through a No. 60 mesh sieve.

[0288] Continue to stir the screened coating dispersion throughout the coating process.

[0289] Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit L 30D-55 Aqueous Coating Dispersions

[0290] The following coating parameters were used for coating with the Opadry solution film coating.

30Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge350 gramInlet Air Temperature60° C.Outlet Air Temperature40° C.Atomization Air Pressure1.6 Bar

[0291] Coat Ciprofloxacin pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.

[0292] The following coating parameters were used for coating with the Eudragit FS 30D/Eudragit L30D-55 film coating dispersion.

31Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature50° C.Outlet Air Temperature30° C.Atomization Air Pressure1.6 Bar

[0293] Coat Opadry coated Ciprofloxacin pellets with the Eudragit FS30D/Eudragit L 30D-55 coating dispersion such that you apply 32% coat weight gain to the pellets.

[0294] Ciprofloxacin Colonic-Release Pellet Formulation and Preparation Procedure

[0295] Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion

[0296] Dispersion Formulation

[0297] The composition of the aqueous Eudragit® FS 30D dispersion applied to the Ciprofloxacin pellets is provided below in Table 21.

32TABLE 21Eudragit ® FS 30D Aqueous Coating DispersionComponentPercentage (%)Eudragit ® FS 30D54.8Triethyl Citrate0.9Talc3.3Purified Water*41.0Solid Content20.6Polymer Content16.4*Removed during processing

[0298] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0299] Disperse triethyl citrate (TEC) in the purified water.

[0300] Add the talc in the triethyl citrate dispersion.

[0301] Homogenize the dispersion using a homogenizer.

[0302] Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.

[0303] Continue to stir the coating dispersion until the coating process is complete.

[0304] Coating Conditions for the Application of Eudragit FS30D Aqueous Coating Dispersion

[0305] The following coating parameters were used for coating with each of the Eudragit® FS 30 D aqueous film coating.

33Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.2 mmMaterial Charge300 gramInlet Air Temperature38° C.Outlet Air Temperature22° C.Atomization Air Pressure1.6 BarPump Rate6 gram per minute

[0306] Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.

[0307] Metronidazole and Ciprofloxacin Tablets

[0308] Preparation of Metronidazole and Ciprofloxacin Granulation for Tableting

34TABLE 22Composition of Metronidazole and Ciprofloxacin Granulation(Immediate Release)ComponentPercentage (%)Metronidazole Trihydrate powder13.3Ciprofloxacin9.0Lactose monohydrate, spray dried56.7Avicel PH 10120.0Hydroxypropyl methylcellulose, NF*1.0Total100*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

[0309] Blend Metronidazole, Ciprofloxacin, lactose, and Avicel® PH 101 using a high shear mixer.

[0310] Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

[0311] Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 400C.

[0312] Granules between 20 and 40 Mesh are collected for further processing.

[0313] Tableting of the Metronidazole and Ciprofloxacin

35TABLE 23Composition of Metronidazole and Ciprofloxacin TabletsComponentPercentage (%)Metronidazole/Ciprofloxacin granules49.0Avicel PH 2003.5Eudragit L30D-55/NE 30D coated Metronidazole8.4PelletsEudragit L30D-55/NE 30D coated Ciprofloxacin5.6PelletsAQOAT/Eudragit FS 30D coated Metronidazole9.5PelletsEudragit FS 30D/L30D coated Ciprofloxacin Pellets6.3Eudragit FS 30D coated Metronidazole Pellets9.1Eudragit FS 30D coated Ciprofloxacin Pellets6.1Colloidal silicon dioxide1.5Magnesium stearate1.0Total100

[0314] Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200, Metronidazole coated pellets, Ciprofloxacin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

[0315] Add the magnesium stearate to the blender, and blend for 5 minutes.

[0316] Compress the blend on a rotary tablet press.

[0317] The fill weight should be adjusted to achieve a 625 mg total dose tablet.

Example 61

[0318] Metronidazole Pellet Formulation and Preparation Procedure

[0319] Pellet Formulation

[0320] The composition of the metronidazole pellets provided in Table 24.

36TABLE 24Composition of Metronidazole PelletsComponentPercentage (%)Metronidazole93Avicel PH 1013Methocel E5P LV4Purified Water*Total100*Removed during processing

[0321] Preparation Procedure for Metronidazole Pellets

[0322] Blend metronidazole, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.

[0323] Add the purified water slowly into the powder blend under continuous mixing.

[0324] Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0325] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0326] Dry the spheronized pellets at 50° C. until moisture level is <3%.

[0327] Pellets between 16 and 30 Mesh were collected for further processing.

[0328] Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure

[0329] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion

[0330] Dispersion Formulation

[0331] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 25.

37TABLE 25Eudragit ® L 30 D-55/Eudragit NE 30DAqueous Coating DispersionComponentPercentage (%)Eudragit ® L 30D-5544.4Eudragit NE 30D14.8Triethyl Citrate1.3Imwitor 9000.9Purified Water*38.6Solid Content20.6Polymer Content16.4*Removed during processing

[0332] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion

[0333] 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.

[0334] The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35° C.

[0335] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.

[0336] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.

[0337] Screen the dispersion through a No. 60 mesh sieve prior to coating.

[0338] Continue to stir the dispersion until the coating process is complete.

[0339] Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0340] The following coating parameters were used for coating of the Eudragit® L 30 D-55/Eudragit NE30D film coating dispersion.

38Coating EquipmentSTREA 1 ™ Table Top LaboratoryFluid Bed CoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature45° C.Outlet Air Temperature32 to 35° C.Atomization Air Pressure1.6 BarPump Rate3-4 gram per minute

[0341] Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.

[0342] Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation Procedure

[0343] Preparation of an Opadry Clear Coating Solution

[0344] Dispersion Formulation

[0345] The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 26.

39TABLE 26Opadry Clear Aqueous Coating SolutionComponentPercentage (%)Opadry Clear7.0YS-1-7006Purified Water*93.0Solid Content %7.0Polymer Content %7.0*Removed during processing

[0346] Preparation Procedure for Opadry Clear Aqueous Solution

[0347] Charge the purified water into a container

[0348] Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.

[0349] Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion

[0350] Dispersion Formulation

[0351] The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 27.

40TABLE 27AQOAT AS-HF/Eudragit FS 30D Coating DispersionComponentPercentage (%)AQOAT AS-HF5.25Eudagit FS30D5.83Triethyl Citrate1.96Sodium Lauryl Sulfate0.21Talc2.10Purified Water*84.65Solid Content11.27Polymer Content7.0*Removed during processing

[0352] Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aqueous Dispersion

[0353] Disperse triethyl citrate in purified water with stirring.

[0354] Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.

[0355] Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.

[0356] Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour. Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.

[0357] Screen the dispersion through a No. 60 mesh sieve.

[0358] Continue to stir the screened coating dispersion throughout the coating process.

[0359] Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D Aqueous Coating Dispersions

[0360] The following coating parameters were used for coating with the Opadry solution film coating.

41Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge350 gramInlet Air Temperature60° C.Outlet Air Temperature40° C.Atomization Air Pressure1.6 Bar

[0361] Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.

[0362] The following coating parameters were used for coating with the AQOATAS-HF/Eudragit FS30D film coating dispersion.

42Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.0 mmMaterial Charge300 gramInlet Air Temperature50° C.Outlet Air Temperature30° C.Atomization Air Pressure1.6 Bar

[0363] Coat Opadry coated metronidazole pellets with the AQOATAS-HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50° C.

[0364] Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure

[0365] Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion

[0366] Dispersion Formulation

[0367] The composition of the aqueous Eudragit® FS 30D dispersion applied to the

[0368] Metronidazole pellets is provided below in Table 28.

43TABLE 28Eudragit ® FS 30D Aqueous Coating DispersionComponentPercentage (%)Eudragit ® FS 30D54.8Triethyl Citrate0.9Talc3.3Purified Water*41.0Solid Content20.6Polymer Content16.4*Removed during processing

[0369] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0370] Disperse triethyl citrate (TEC) in the purified water.

[0371] Add the talc in the triethyl citrate dispersion.

[0372] Homogenize the dispersion using a homogenizer.

[0373] Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.

[0374] Continue to stir the coating dispersion until the coating process is complete.

[0375] Coating Conditions for the Application of Eudragit FS30D Aqueous Coating Dispersion

[0376] The following coating parameters were used for coating with each of the Eudragit® FS 30 D aqueous film coating.

44Coating EquipmentSTREA 1 ™ Table Top Laboratory Fluid BedCoaterSpray nozzle diameter1.2 mmMaterial Charge300 gramInlet Air Temperature38° C.Outlet Air Temperature22° C.Atomization Air Pressure1.6 BarPump Rate6 gram per minute

[0377] Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.

[0378] Metronidazole and Ciprofloxacin Tablets

[0379] Preparation of Metronidazole and Ciprofloxacin Granulation for Tableting

45TABLE 29Composition of Metronidazole and Ciprofloxacin Granulation(Immediate Release)ComponentPercentage (%)Metronidazole22.5Ciprofloxacin59.0Lactose monohydrate, spray dried10.0Avicel PH 1017.5Hydroxypropyl methylcellulose, NF*1.0Total100*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

[0380] Blend Metronidazole, Ciprofloxacin, lactose, and Avicel® PH 101 using a high shear mixer.

[0381] Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

[0382] Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.

[0383] Granules between 20 and 40 Mesh are collected for further processing.

[0384] Tableting of the Metronidazole and Ciprofloxacin

46TABLE 30Composition of Metronidazole and Ciprofloxacin TabletsComponentPercentage (%)Metronidazole/Ciprofloxacin granules49.0Avicel PH 2003.5Eudragit L30D-55/NE 30D coated Metronidazole14.0PelletsAQOAT/Eudragit FS 30D coated Metronidazole15.8PelletsEudragit FS 30D coated Metronidazole Pellets15.2Colloidal silicon dioxide1.5Magnesium stearate1.0Total100

[0385] Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200, Metronidazole coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

[0386] Add the magnesium stearate to the blender, and blend for 5 minutes.

[0387] Compress the blend on a rotary tablet press.

[0388] The fill weight should be adjusted to achieve a 625 mg total dose tablet.

[0389] In one embodiment, Ciprofoxacin will be dosed in an alternate pulse to Metronidazole. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells.

[0390] In addition, even when Ciprofoxacin and Metronidazole are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection.

[0391] Numerous modifications and variations of the present invention are possible in light of the above teachings; therefore, within the scope of the appended claims, the invention may be practiced otherwise than as particularly described.

	Number	Date	Country
Parent	09791983	Feb 2001	US
Child	10092858	Mar 2002	US

Ciprofoxacin-metronidazole antibiotic composition

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