JP2005523309A - Antibiotic products, their usage and formulation - Google Patents

Abstract

An antibiotic consists of at least 3 dosage forms, each with a different release profile, and the C _max for that antibiotic is reached within about 12 hours. In one embodiment, there are immediate release dosage forms, as well as two or more delayed release dosage forms, each dosage form having a different release profile, where each dosage form reaches C _max at different times. To do.

Description

  This application is a U.S. application serial number 10 / 027,366 filed on December 20, 2001, a U.S. application serial number 10 / 027,866 filed on December 20, 2001, and filed on December 20, 2001. United States application serial number 10 / 028,590, US application serial number 10 / 028,595 filed December 20, 2001, US application serial number 10 / 027,837 filed December 20, 2001, and Claim the benefit of US Application Serial No. 10 / 027,609, filed December 20, 2001. Each of the foregoing is a continuation application of US application serial number 09 / 792,092 filed on February 22, 2000, which is also a continuation application of US application serial number 09 / 687,229 filed October 13, 2000. And also claims the priority of US Provisional Application Serial No. 60 / 184,546, filed February 24, 2000.

  The present invention relates to antibiotic products, as well as their uses and formulations.

  The invention further relates to levofloxacin antibiotic products and derivatives thereof such as salts, esters, metabolites and the like.

  The invention further relates to metronidazole antibiotic products and derivatives thereof such as salts, esters, metabolites and the like.

  The invention further relates to tetracycline antibiotic products, especially doxycycline and its derivatives, salts, hydrates, esters, metabolites and the like.

  The invention further relates to erythromycin antibiotic products, especially erythromycin derivatives, or macrolides or ketrites (including derivatives such as salts, esters, etc.), especially clarithromycin.

  The present invention further relates to fluroquinilone antibiotic products, and more particularly to ciprofloxacin and its derivatives such as salts, esters, bases, metabolites and the like.

  The invention further relates to betalactam antibiotic products, and more particularly to products comprising cephalosporin, such as cefuroxime and or cefpodoxime, or penicillin, such as amoxicillin or dicloxacillin, as well as its derivatives, metabolites and any active isomers.

  A wide variety of antibiotics have been and will be used to combat bacterial infections. In general, such antibiotics can be administered by repeated dosing in an immediate release dosage form, but they are not seriously adhered to, or they begin to work slowly over a period of time at higher doses (sustained release) ). The present invention is directed to improved antibiotic products.

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

  In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each having a different release profile, and the release profile of each dosage form is such that each dosage form is for administration of an antibiotic product. Later, the dosage form starts releasing the antibiotic contained therein at different times.

  Thus, according to one aspect of the present invention, there are at least two, preferably at least three antibiotic dosage forms therein, each having a different release profile, whereby the antibiotics contained in each dosage form are: Single or integral antibiotic products are provided that are released at different times.

  In accordance with a further aspect of the invention, the antibiotic product can consist of at least four different dosage forms, each of which contains antibiotics contained therein at different times after administration of the antibiotic product. Start releasing.

  Antibiotic products generally do not contain more than 5 doses with different release times.

  According to a preferred embodiment, the antibiotic product has a total release profile such that when administered, the maximum serum concentration of all antibiotics released from the product is reached within 12 hours, preferably within 11 hours. In certain examples, the maximum serum concentration of total antibiotic released from the antibiotic product is not achieved within 4 hours after administration.

In accordance with a preferred embodiment of the present invention, there are at least three dosage forms. One of the at least three dosage forms is an immediate release dosage form so that the onset of antibiotic release therefrom is not substantially delayed after administration. The second and third of the at least three dosage forms are delayed dosage forms (though they are pH sensitive or non-pH sensitive delayed dosage forms depending on the type of antibiotic product) and are thereby released therefrom. The antibiotic is extended until after the onset of antibiotic release from the immediate release dosage form. More specifically, the antibiotic released from the second of the at least two dosage forms is the same as the antibiotic released from the first of the at least three dosage forms is C _max ( At a later time to achieve the maximum serum concentration in the serum), the C _max is achieved and the antibiotic released from the third dosage form is after the C _max of the antibiotic released from the second dosage form. To achieve C _max in serum.

  In one embodiment, the second of the at least two dosage forms initiates the release of the antibiotic contained therein at least 1 hour after the first dosage form, and the onset of release therefrom generally Occurrence of antibiotic release from the first dosage form of at least 3 dosage forms occurs in as little as 6 hours.

In general, immediate release dosage forms yield C _max due to constituents released therefrom within about 0.5 to about 2 hours, and at least three dosage forms of the second dosage form require only about 4 hours. The C _max is produced by the antibiotics released there. In general, such second dosage form C _max is achieved no later than 2 hours after administration of the antibiotic product. However, it is possible within the scope of the invention to achieve C _max in a shorter time.

As indicated previously, the antibiotic product comprises at least 3, or at least 4 or more different dosage forms. For example, if the antibiotic product includes a third dosage form, the antibiotic released therefrom will be C C after achieving the C _max with the antibiotic released from each of the first and second dosage forms. _max is reached. In a preferred embodiment, the release of antibiotic from the third dosage form is initiated after the start of antibiotic release from both the first and second dosage forms. In one example, the C _max for antibiotic release from the third dosage form is achieved within 8 hours.

In another embodiment, the antibiotic comprises at least 4 dosage forms, each of the at least 4 dosage forms having a different release profile, thereby providing an antibiotic from each of the at least 4 different dosage forms. Release achieves C _max at different times.

As indicated previously, in preferred embodiments, the antibiotic is released from the antibiotic product regardless of whether it contains at least 2, or at least 3, or at least 4 different dosage forms each having a different release profile. The C _max for all antibiotics is achieved within 12 hours, and even more typically less than 11 hours.

In a preferred embodiment, the antibiotic product is a once-daily product, so that no further product is administered throughout the day after administration of the antibiotic product. That is, the preferred dosing method is to administer the product only once over a 24 hour period. Thus, according to the present invention, there is a single administration of antibiotics with antibiotics, and the release of all antibiotics is achieved with different release profiles in such a way that the total C _max to the antibiotic is reached in 12 hours or less Is done. The term single dose refers to a single tablet, or capsule or two or more, provided that all antibiotics administered over a 24 hour period are administered at essentially the same time. Mean that they may be administered at the same time.

  A single-dose antibiotic product containing at least three antibiotic dosage forms each with a different release profile is an improvement over a single-dose antibiotic product containing an antibiotic dosage form with a single release profile. Applicant discovered that there is. Within the pharmacologically acceptable carrier, each antibiotic form can have one or more antibiotics, and each dosage form can have the same or different antibiotics.

  When it is disclosed herein that a dosage form begins to release after one dosage form, such terminology is designed and intended to produce that later initiated release. It must be understood to mean. However, despite such a design and intention, it is also known in the prior art that some “leakage” of antibiotics can occur. Such “leakage” is not “release” as used herein.

If at least 4 dosage forms are used, the fourth of the at least 4 dosage forms is a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even if the C _max of the fourth dosage form of at least four dosage forms is reached after reaching the C _max of each of the other dosage forms Antibiotic release from such a fourth dosage form may be initiated before or after release from the second and third dosage forms.

  As described previously, the antibiotic products of the invention are formulated for administration by various routes of administration. For example, antibiotic products are formulated for administration by various routes of administration. For example, the antibiotic product is formulated by methods such as topical administration, ocular or otic administration, rectal or vaginal administration, nasal drops, inhalation, injectable, or oral administration. In a preferred embodiment, the antibiotic product is formulated in a manner suitable for oral administration.

For example, in formulating topical antibiotic products by application to the skin, at least two different dosage forms, each containing one antibiotic, may be oil-in-water or water-in-oil emulsion dosage forms, etc. Is formulated for topical administration. In such formulations, the immediate release dosage form is in the continuous phase and the delayed release dosage form is in the discontinuous phase. The formulation is produced in a manner of delivery in the three dosage forms described further above. For example, an oil-in-water emulsion is provided, wherein the oil is a continuous phase containing an immediate release component, the water dispersed in the oil contains a first delayed release dosage form, and the oil dispersed in the water is a third delayed release. Includes release dose form.

  Providing the antibiotic product in the form of a patch is also within the scope of the present invention, including antibiotic dosage forms with different release profiles as previously described.

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

  In addition, antibiotic products having at least three different dosage forms with different release profiles are formulated for rectal or vaginal administration known in the prior art. This takes the form of a cream or emulsion, or other dissolvable dosage form similar to that used for topical administration.

  As a further example, the antibiotic product is 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 dosage form is used as a pellet or particle, which is then embedded in, for example, a capsule or tablet, or suspended in a liquid for oral administration to form an integral drug product. Formed.

As an option, when formulating an oral delivery system, each of the product dosage forms is formulated as a tablet, and each of the tablets is encapsulated to produce an integral antibiotic product. Thus, for example, the antibiotic product includes a first dosage form in the form of a tablet that is an immediate release tablet, and further includes two or more additional tablets, each of which has a delayed release of the antibiotic described above. Provided, whereby the C _{max of the} antibiotic released from each tablet is reached at different times, and the C _{max of} all antibiotics released from the antibiotic product is achieved within 12 hours.

  Formulations of constituent products comprising at least three dosage forms with different release profiles for different routes of administration are considered herein within the scope of the prior art from the teachings. As is known in the art, for delayed release, the time of release can be controlled by the concentration of antibiotic within the skin and / or the thickness of the skin.

  In formulating an antibiotic product according to the present invention, in one embodiment, the immediate release dosage form of the product generally provides about 20% to about 50% of the total antibiotic dose delivered by the product. And such immediate release dosage forms generally provide at least 25% of the total dose of antibiotic delivered by the product. Often, immediate release dosage forms provide about 20-30% of the total dose of antibiotic delivered by the product. In some cases, however, it may be desirable to have an immediate release dosage form that provides from about 45% to about 50% of the total dose of antibiotic delivered by the product.

  The remaining dosage form delivers the remainder of the antibiotic. When one or more delayed release dosage forms are used in one embodiment, each delayed release dosage form provides approximately the same amount of antibiotic. However, they can also be formulated to provide different amounts.

  In accordance with the present invention, each dosage form contains the same antibiotic. However, each dosage form can contain one or more antibiotics.

  In one embodiment, if the composition comprises one immediate release component and two delayed release components, the immediate release component is 20 to 35% (preferably 20% to 30%) by weight of the total antibiotic. provide. Also, if there are four delayed release components, the immediate release component provides 10% to 25% by weight of the total antibiotic.

  In the context of a delayed release component, if there are two delayed release components, the first delayed release component (one that is released earlier in time) is the total antibiotic supplied by the two delayed release components The second delayed release component provides the remaining antibiotic.

  If three delayed release components are present, the earliest released component provides 20% to 35% by weight of the total antibiotic provided by the three delayed release components and is delayed in time. The next component released in time provides 20% to 40% by weight of the antibiotic provided by the three delayed release components, the last in time provided by the three delayed release components Provide the rest of the antibiotic.

If there are four delayed release components, the earliest delayed release component provides 15% to 30% by weight for each of the total antibiotics provided with the four delayed release components, and the time The next delayed release component provides 15% to 30% by weight, the next delayed release component provides 20% to 35% by weight, and the last delayed release component 20% to 35% by time. %I will provide a.

Immediate Release Components The immediate release portion of the system can be a mixture of components that degrade rapidly after administration to release the constituents. This can take the form of either two pellets or granules that are mixed or compressed with the other three components.

  Substances added to the antibiotic as an immediate release component are not necessarily limited thereto, but include microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, carboxymethyl sodium starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, Hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylated chitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glycose, reprose, sucrose, polyvinylpyrrolidone (PVP ), Acrylic acid derivatives (carbopol, Eudragit, etc.), polyethylene glycol, such as low molecular weight PEG (PEG2000-10000) and high molecular weight PEGs (Polyox) a molecular weight of 20,000 daltons or more, and the like.

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

  In addition, it is useful to have other components in the system to aid in the degradation of the drug, or the components after ingestion or administration. These ingredients are surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, surfactants One of the nonionic surfactants such as pluronics, or any other substance having surface activity, or some blend of the foregoing.

  These materials can be present in a 0.05-15% (W / W) ratio.

Non-pH Sensitive Delayed Release Ingredients The components of the composition are the same immediate release unit, but incorporate additional polymer into the composition or added as a coating on the surface of the pellets or granules.

  Materials that can be used to obtain a release delay suitable for this component of the present invention are not necessarily limited thereto, but include polyethylene glycol (PEG) having a molecular weight greater than 4,000 daltons (carbowax, polyox), Waxes such as white wax or beeswax, paraffin, acrylic acid derivatives (eudragit), polypropylene glycol, and ethyl cellulose can be used.

  Typically, these materials can be in the range of 0.5-25% (W / W) of the component.

pH Sensitive (Enteric) Release Ingredients The ingredients of the composition are the same as the immediate release ingredients, but with an additional polymer incorporated into the composition or as a shell over the pellets or granules.

  The types of materials useful for this purpose are not necessarily limited thereto, but can be phthalate acetate, cellulose acetate, Eudragit L, and other phthalates of cellulose derivatives.

These materials can be present at a concentration of 4-20% (W / W).

Sustained Release Ingredients The components of the composition are the same as the immediate release ingredients but with an additional polymer incorporated into the composition or as a shell over the pellets or granules.

  The types of materials useful for this purpose are not necessarily limited thereto, but include ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or It can be a polyethylene glycol with a molecular weight above 8,000 daltons.

  These materials can be present at a concentration of 4-20% (W / W).

  As previously described, the unit comprising the antibiotic composition of the present invention may be in the form of separate pellets or particles contained within a capsule, or particles embedded in a tablet or suspended in a liquid suspension. Can be.

  The antibiotic composition of the present invention is administered, for example, by any of the following administration routes: sublingual, transmucosal, transdermal, parenteral, etc., and desirably administered orally. The composition includes a therapeutically effective amount of an antibiotic, which amount will vary depending on the antibiotic used, the disease or infection being treated, the number of times the composition is delivered per day, and the like. The composition is administered to the host in an amount effective to treat the bacterial infection.

  The system is particularly useful for extending the substantial therapeutic activity of antibiotics with an elimination half-life of 20 hours or less, especially an elimination half-life of 12 hours or less, and has a half-life of 2-10 hours. It is particularly useful for drugs. The following are examples of some antibiotics with a half-life of about 1-12 hours. Cefadroxyl, cefazoline, cephalexin, cephalothin, cephapyrine, cefacelol, cefaprodil, cephadrine, cefamandole, cefoniside, cefolanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftifitem, ceftifitem Cefoxitin, lauracarbef, imipenem, erythromycin (and erythromycin salts such as estrate, ethyl succinate, glucoceptate, lactobionate, stearic acid, etc.), azithromycin, clarithromycin, dirithromycin, tolorenomycin, penicillin V, penicillin salts and complexes, methicillin, nafushi Oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, bacampicillin, carpenicillin indanyl sodium (and other salts of carbenicillin), mezlocillin, piperacillin, piperacillin and taxobacilum, ticarcillin calciline, Potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, etabitol hydrochloride and other salts, etiominad, and isoniazid, ciprofloxacin, levofloxacin, lomefloxysan, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin , Sulfacitin, sulfamerazine, sulfamethazine, sulfame Xol, sulfasalazine, sulfisoxazole, sulfapyridine, sulfadiazine, sulfamethoxazole, sulfapyridine (original), metronidazole, mesenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, cotriamoxazole, pentamidine , And trimetrexate.

The invention will be further described in connection with the following examples. However, the scope of the present invention is not limited thereby. All percentages herein are by weight unless otherwise specified.

Examples Immediate release ingredients The ingredients are dried in a suitable drug stirrer or granulator, such as a planetary stirrer, high shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or dry. Mix in blend to formulate composition. If water or other solvent is used, the mixture is dried in a suitable drug dryer such as a vacuum dryer or forced air oven. The product is sieved or granulated and compressed using a suitable tablet press, for example a rotary tablet press.

Component concentration (% 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
Hydroxypropyl cellulose 10
Croscarmellose sodium 5
Example 4
Amoxicillin 75% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropyl cellulose 5
Example 5
Amoxicillin 75% (W / W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 6
Clarithromycin 65% (W / W)
Microcrystalline cellulose 20
Hydroxypropyl cellulose 10
Croscarmellose sodium 5
Example 7
Clarithromycin 75% (W / W)
Microcrystalline cellulose 15
Hydroxypropyl cellulose 5
Croscarmellose sodium 5
Example 8
Clarithromycin 75% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropyl cellulose 5
Example 9
Clarithromycin 75% (W / W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 10
Ciprofloxacin 65% (W / W)
Microcrystalline cellulose 20
Hydroxypropyl cellulose 10
Croscarmellose sodium 5
Example 11
Ciprofloxacin 75% (W / W)
Microcrystalline cellulose 15
Hydroxypropyl cellulose 5
Croscarmellose sodium 5
Example 12
Ciprofloxacin 75% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropyl cellulose 5
Example 13
Ciprofloxacin 75% (W / W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 14
Ceftibbuten 75% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropyl cellulose 5
Example 15
Ceftibbuten 75% (W / W)
Polyethylene glycol 4000 20
Polyvinylpyrrolidone 5

Non-pH sensitive delayed release component The component is removed in a suitable drug stirrer or granulator, such as a planetary stirrer, high shear granulator, fluid bed granulator or extruder, in the presence of water or other solvent, or hot melt Mix the composition to formulate the composition. If water or other solvent is used, the mixture is dried in a suitable drug dryer such as a vacuum dryer or forced air oven. The product is cooled, the product is sieved or granulated and compressed using a suitable tablet press such as a rotary tablet press.

Component concentration (% 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
Hydroxypropyl cellulose 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
Ethyl cellulose 5
Example 21
Clarithromycin 70% (W / W)
Polyox 20
Hydroxypropyl cellulose 5
Croscarmellose sodium 5
Example 22
Clarithromycin 75% (W / W)
Polyox 15
Hydroxypropyl cellulose 5
Ethyl cellulose 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
Eudragit R 30D 5
Example 25
Ciprofloxacin 65% (W / W)
Polyethylene glycol 4000 20
Hydroxypropyl cellulose 10
Eudragit RL 30D 5
Example 26
Ciprofloxacin 75% (W / W)
Microcrystalline cellulose 15
Hydroxypropyl cellulose 5
Ethyl cellulose 5
Example 27
Ciprofloxacin 80% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 5
Eudragit RL 30D 5
Example 28
Ciprofloxacin 75% (W / W)
Polyethylene glycol 8000 20
Ethyl cellulose 5
Example 29
Ceftibbuten 75% (W / W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Eudragit RL 30D 5
Example 30
Ceftibbuten 75% (W / W)
Polyethylene glycol 8000 20
Ethyl cellulose 5

Enteric-release ingredients The ingredients are placed in a suitable drug stirrer or granulator, such as a planetary stirrer, high shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or hot melt process To prepare a composition. If water or other solvent is used, the mixture is dried in a suitable drug dryer such as a vacuum dryer or forced air oven. The product is cooled, the product is sieved or granulated and compressed using a suitable tablet press such as a rotary tablet press.

Component concentration (% W / W)
Example 31
Amoxicillin 65% (W / W)
Microcrystalline cellulose 20
Cellulose acetate phthalate 15
Example 32
Amoxicillin 55% (W / W)
Microcrystalline cellulose 25
Cellulose acetate phthalate 10
Hydroxypropyl cellulose 10
Example 33
Amoxicillin 65% (W / W)
Polyox 20
Hydroxypropylcellulose phthalate 10
Eudragit L 30D 5
Example 34
Amoxicillin 75% (W / W)
Polyethylene glycol 2000 10
Eudragit L 30D 10
Eudragit RL 30D 5
Example 35
Amoxicillin 40% (W / W)
Microcrystalline cellulose 49
Cellulose acetate phthalate 10
Polyvinylpyrrolidone 1
Example 36
Clarithromycin 70% (W / W)
Hydroxypropylcellulose phthalate 15
Crosscarulose sodium 10
Microcrystalline cellulose 5
Example 37
Clarithromycin 70% (W / W)
Eudragit E 30D 15
Hydroxypropyl cellulose 10
Ethyl cellulose 5
Example 38
Clarithromycin 75% (W / W)
Polyethylene glycol 2000 10
Eudragit E 30D 15
Example 39
Clarithromycin 40% (W / W)
Lactose 50
Eudragit L 30D 10
Example 40
Ciprofloxacin 65% (W / W)
Microcrystalline cellulose 20
Eudragit L 30D 10
Akji Sole 5
Example 41
Ciprofloxacin 75% (W / W)
Microcrystalline cellulose 15
Hydroxypropylcellulose phthalate 10
Example 42
Ciprofloxacin 80% (W / W)
Lactose 10
Eudragit L 30D 10
Example 43
Ciprofloxacin 70% (W / W)
Polyethylene glycol 4000 20
Cellulose acetate phthalate 10
Example 44
Ceftibden 60% (W / W)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 30D 10
Example 45
Ceftibden 70% (W / W)
Microcrystalline cellulose 20
Cellulose acetate phthalate 10

Sustained release ingredients The ingredients are placed in a suitable drug stirrer or granulator, such as a planetary stirrer, high shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process Mix to formulate the composition. If water or other solvent is used, the mixture is dried in a suitable drug dryer such as a vacuum dryer or forced air oven. Product dry cooling. The product is cooled, the product is sieved or granulated and compressed using a suitable tablet press such as a rotary tablet press.

Component concentration (% W / W)
Example 46
Amoxicillin 65% (W / W)
Ethylcellulose 20
Polyox 10
Hydroxypropyl methylcellulose 5
Example 47
Amoxicillin 55% (W / W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 48
Amoxicillin 70% (W / W)
Polyox 20
Hydroxypropyl cellulose 10
Example 49
Clarithromycin 75% (W / W)
Lactose 15
Hydroxypropyl cellulose 5
Ethyl cellulose 5
Example 50
Clarithromycin 75% (W / W)
Polyethylene glycol 4000 10
Lactose 10
Eudragit RL 30D 5
Example 51
Clarithromycin 75% (W / W)
Polyethylene glycol 8000 10
Hydroxypropyl methylcellulose 5
Eudragit RS 30D 5
Example 52
Ciprofloxacin 75% (W / W)
Hydroxyethyl cellulose 10
Polyethylene glycol 4000 10
Hydroxypropyl cellulose 5
Example 53
Ciprofloxacin 75% (W / W)
Lactose 10
Povidone (PVP) 10
Polyethylene glycol 2000 5
Example 54
Ceftibbuten 75% (W / W)
Polyethylene glycol 4000 10
Povidone (PVP) 10
Hydroxypropyl cellulose 5
Example 55
Ceftibbuten 75% (W / W)
Lactose 15
Polyethylene glycol 4000 5
Polyvinylpyrrolidone 5

Three pulses Example 56

1. Metronidazole matrix pellet formulation and preparation procedure (immediate release)
A. Pellet Formulation The composition of metronidazole matrix pellets is provided at 1.

B. Procedure for preparing metronidazole matrix pellets 1.2.1 Metronidabourg and Avicel® pH 101 are mixed using a robotic coupe high shear granulator.
1.2.2 Slowly add 20% povidone K29 / 32 binder solution to the powder mixture under continuous mixing.
1.2.3 Extrude the wet mass using an LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
1.2.4 The extrudate is spheronized using a model SPH20 curry bass ferronizer.
1.2.5 Dry spherical pellets at 50 ° C. overnight.
1.2.6 16-30 mesh pellets were collected for further processing.

1.3 Preparation of Eudragit® L30D-55 aqueous coating dispersion Dispersion Formulation The composition of the aqueous Eudrazide L30D-55 dispersion applied to metronidazole matrix pellets is provided in Table 2 as follows.

B. Preparation of Eudragit® L30D-55 aqueous dispersion 1.3.1 Suspend triethyl citrate and talc in deionized water.
1.3.2 The TEC / talc suspension is then homogenized in a PowerGen 700 high shear mixer.
1.3.3 Add TEC / talc suspension slowly to Eudragit® L30D-55 latex dispersion with stirring.
1.3.4 Stir coating dispersion for 1 hour before application to metronidazole matrix pellets.

1.4 Preparation of Eudragit® S100 aqueous coating dispersion Dispersion Formulation The composition of an aqueous Eudragit® S100 dispersion applied to metronidazole matrix pellets is provided in Table 3 as follows.

B. Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part I:
(I) Disperse Eudragit® S100 powder with deionized water with stirring.
(ii) Ammonium hydroxide solution is added to the dispersion in the form of water droplets with stirring.
(Iii) Stir the partially neutralized dispersion for 60 minutes.
(Iv) Triethyl citrate is added to the dispersion in the form of water droplets with stirring. Stir for about 2 hours before adding Part B.

Part II:
(I) Disperse the talc with the required amount of water.
(Ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
(Iii) Part B is then slowly added to the Part A polymer dispersion with light agitation.

1.5 Coating Conditions for Applying Aqueous Coating Dispersion The following coating parameters are used to coat matrix pellets with Eudragit® L30D-55 and Eudragit® S100 aqueous film coating, respectively. It was done.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

(I) Coat the matrix pellets with L30D-55 dispersion to give the pellets a 12% increase in coating amount.
(Ii) Coat the matrix pellets with S100 dispersion to give the pellets a 20% increase in coating amount.

1.6 Capsule formation of metronidazole pellets The pellets are filled in size 00 hard gelatin capsules in a ratio of 30%: 30%: 40% respectively with uncoated immediate release matrix pellets, L-30D-55 coated pellets and S100 coated pellets Is done.

Capsules are filled with three different pellets to achieve a total dose of 375 mg / capsule.

Three pulses Example 57

Amoxicillin Pellet Formulation and Preparation Procedure 57.1 Pellet Formulation for Subsequent Coating Amoxicillin trihydrate matrix pellet composition is provided in Table 4.

57.2 Preparation Procedure for Amoxicillin Matrix Pellet 57.2.1 Mix Amoxicillin and Avicel® PH101 using a low shear mixer.
57.2.2 Hydroxypropyl methylcellulose is slowly mixed into the powder mixture with continuous mixing of the binder solution.
57.2.3 Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator is 0.8 mm.
57.2.4 Spheronize the extrudate using a QJ-230 spheronizer with a small cross-section plate.
57.2.5 The spheroidized pellets are dried at 60 ° C. in a fluid bed dryer until the discharge temperature reaches 40 ° C.
57.2.6 20-40 mesh pellets were collected for further processing.

57.3 Preparation of Eudragit (R) L30D-55 Aqueous Coating Dispersion 57.3.1 Dispersion Formulation The composition of the aqueous Eudragit (R) L30D-55 dispersion applied to the amoxicillin matrix is shown in Table 5. Is provided as follows.

57.4 Procedure for Preparation of Eudragit® L30D-55 Aqueous Dispersion 57.4.1 Suspend triethyl citrate and talc in deionized water.
57.4.2 The TEC / talc suspension is mixed using a laboratory mixer.
57.4.3 The TEC / talc suspension is slowly added to the Eudragit® L30D-55 dispersion with stirring.
57.4.4 Stir the coating dispersion for 1 hour before use on amoxicillin matrix pellets.

57.5 Preparation to Eudragit® S100 aqueous coating dispersion 57.5.1 Dispersion formulation The composition of the aqueous Eudragit® S100 dispersion used for amoxicillin matrix pellets is as follows in Table 6 Provided as follows.

57.6 Preparation of Eudragit® S100 aqueous dispersion Part A:
57.6.1 Disperse Eudragit® S100 powder with deionized water with stirring.
57.6.2 Ammonium hydroxide solution is added to the dispersion in the form of water drops with stirring.
57.6.3 The partially neutralized dispersion is stirred for 60 minutes.
57.6.4 Triethyl citrate is added to the dispersion in the form of water drops with stirring and stirred overnight before Part B addition.
Part B
57.6.5 Disperse the talc with the required amount of water.
57.6.6 Stir the dispersion using an overhead laboratory mixer.
57.6.7 Part B is then slowly added to the Part A polymer dispersion with gentle agitation.

Coating Conditions for Application of 57.7 Aqueous Coating Dispersion The following coating parameters were used in both Eudragit® L30D-55 and Eudragit® S100 aqueous film coating processes.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2-6g / min

57.7.1 Coat the matrix pellets with L30D-55 dispersion to give the pellets a 20% increase in coating weight.
57.7.2 Coat the matrix pellets with S100 dispersion to give the pellets a 37% increase in coating amount.

  57.8 Preparation of Amoxilysin Granulation (Immediate Release Component) for Tablet Formation

57.8.1 Amoxicillin and Avicel® PH101 are mixed using a low shear mixer.
57.8.2 Hydroxypropyl methylcellulose binder solution is slowly added to the powder mixture under continuous mixing.
57.8.3 The granulation is dried at 60 ° C. using a fluid bed dryer until the discharge temperature reaches 40 ° C.
57.8.4 20-40 mesh granules were collected for further processing.

  57.9 Tablet formation of amoxicillin pellets

57.9.1 Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide are mixed in a tumble blender for 15 minutes.
57.9.2 Add magnesium stearate to blender and mix for 5 minutes.
57.9.3 Compress the mixture in a rotary tablet press.
57.9.4 The fill should be adjusted to be a 500 mg dose tablet.

Three pulses Example 58

Clarithromycin Pellet Formulation and Preparation Procedure 58.1 Pellet Formulation The composition of the clarithromycin matrix pellet was provided in Table 9.

58.2 Preparation Procedure for Clarithromycin Matrix Pellet 58.2.1 Clarithromycin, silicified microcrystalline cellulose and lactose monohydrate are mixed in a robotic coupe high shear granulator.
58.2.2 Prepare a binder solution by adding polyoxyl to purified water with stirring. After it has been mixed, hydroxypropylmethylcellulose is slowly added and continuously stirred until the solution is complete.
58.2.3 Add the binder solution to the powder mixture with continuous mixing.
58.2.4 Granulate the powder with a high shear granulator to which the binder solution has been added.
58.2.5 Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.2 mm.
58.2.6 Spheronize the extrudate using a model SPH20 curry bass ferronizer.
58.2.7 Dry spherical pellets at 50 ° C. overnight.
58.2.8 18-30 mesh pellets were collected for further processing.

58.3 Eudragit® L30D-55 aqueous coating dispersion 58.3.1 Dispersion formulation The composition of the aqueous Eudragit L30D-55 dispersion used in the clarithromycin matrix pellet is Provided on the street.

58.4 Procedure for Preparation of Eudragit® L30D-55 Aqueous Dispersion 58.4.1 Suspend triethyl citrate and talc in deionized water.
The 58.4.2 TEC / talc suspension is then homogenized using a PowerGen 700 high shear mixer.
58.4.3 Slowly add the suspension from 4.2.2 to Eudragit® L30D-55 latex dispersion with stirring.
58.4.4 Stir the coating dispersion for about 1 hour before using the clarithromycin matrix pellets.

58.5 Preparation of Eudragit® S100 aqueous coating dispersion 58.5.1 Dispersion formulation The composition of the aqueous Eudragit® S100 dispersion used for clarithromycin matrix pellets is shown in Table 11. Provided as follows.

58.6 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
58.6.1 Disperse Eudragit® S100 powder with deionized water with stirring.
58.6.2 Ammonium hydroxide solution is added dropwise to the dispersion with stirring.
58.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
58.6.4 Triethyl citrate is added to the dispersion in the form of water droplets and stirred for 60 minutes before adding Part B.
Part B:
58.6.5 Disperse the talc with the required amount of water.
58.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
58.6.7 Part B is then slowly added to the Part A polymer dispersion with light agitation.

58.7 Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters are for matrix pellet coating with each of Eudragit® L30-55 and Eudragit® S100 aqueous film coating. Used.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.6 bar Pump rate 2g / min

58.7.1 Coat the matrix pellets with L30D-55 dispersion to give the pellets a 20% increase in coating weight.
58.7.2 Coat the matrix pellets with S100 dispersion to give the pellets a 37% increase in coating amount.

4). The capsules were filled to provide 250 mg / capsule, with the uncoated pellets L30D-55 coated pellets and S100 coated pellets being 30%: 30%: 40% by weight, respectively.

Four pulses Example 59

1. Metronidazole Matrix Pellet Formulation and Preparation Procedure 59.1 Pellet Formulation The composition of metronidazole matrix pellets is provided in Table 12.

59.2 Procedure for preparing metronidazole matrix pellets 59.2.1 Mix metronidazole and Avicel® PH101 using a robotic coupe high shear granulator.
59.2.2 Slowly add 20% povidone K29 / 32 binder solution to the powder mixture under continuous mixing.
59.2.3 Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
59.2.4 Spheronize the extrudate using a model SPH20 curry bass ferronizer.
59.2.5 Spherical pellets dried at 50 ° C. overnight.
59.2.6 16-30 mesh pellets were collected for further processing.

59.3 Preparation of Eudrazide® L30D-55 aqueous coating dispersion 59.3.1 Dispersion formulation The composition of aqueous Eudragit L30D-55 used in metronidazole matrix pellets is provided in Table 13 as follows: Is done.

59.4 Procedure for Preparation of Eudragit® L30D-55 Aqueous Dispersion 59.4.1 Suspend triethyl citrate and talc in deionized water.
59.4.2 The TEC / talc suspension is then homogenized using a PowerGen 700 high shear mixer.
59.4.3 Slowly add the TEC / talc suspension to the Eudragit® L30D-55 latex dispersion with stirring.
59.4.4 Stir the coating dispersion for 1 hour prior to application to metronidazole matrix pellets.

59.5 Preparation of Eudrazide® S100 Coating Dispersion 59.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S100 dispersion applied to metronidazole matrix pellets is shown in Table 14 below. Provided on the street.

59.6 Procedure for Preparation of Eudragit® S100 Aqueous Dispersion Part A:
59.6.1 Disperse Eudragit® S100 powder with deionized water with stirring.
59.6.2 Ammonium hydroxide solution is added in drops to the dispersion with stirring.
59.6.3 Stir the partially neutralized dispersion for 60 minutes.
59.6.4 Triethyl citrate is added to the dispersion while stirring in drops. Stir for about 2 hours before adding Part B.
Part B:
59.6.5 Disperse the talc with the required amount of water.
59.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
59.6.7 Part B is then slowly added to the Part A polymer dispersion with light agitation.

59.7 Coating Conditions for Use of Aqueous Coating Dispersion The following coating parameters were used for each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

59.7.1 Coat the matrix pellets with the L30D-55 dispersion to give the pellets a 12% increase in coating amount.
59.7.2 Coat the matrix pellets with the L30D-55 dispersion to give the pellets a 30% increase in coating weight.
59.7.3 Coat the matrix pellets with S100 dispersion to give the pellets a 20% increase in coating amount.
59.8 Capsule formation of metronidazole pellets

The pellets were respectively immediate release matrix pellets (uncoated), L30-D55 coated pellets 12% weight increase, L30D-55 coated pellets 30% weight increase, and S100 coated pellets 20%: 30%: 20%: 30% Filled in size 00 hard gelatin capsules in proportion. Capsules are filled to achieve a total dose of 375 mg / capsule with 4 pellets.

Four pulses Example 60

Amoxicillin Pellet Formulation and Preparation Procedure 60.1 Pellet Formulation The composition of the amoxicillin trihydrate matrix was provided in Table 15.

60.2 Procedure for Amoxicillin Matrix Pellets 60.2.1 Mix Amoxicillin and Avicel® PH101 using a low shear mixer.
60.2.2 Slowly add the hydroxypropyl methylcellulose binder solution to the powder mixture under continuous mixing.
60.2.3 Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator is 0.8 mm.
60.2.4 Spheronize the extrudate using a QJ-230 spheronizer with a small cross-section plate.
60.2.5 Dry the spherical pellets at 60 ° C. using a fluid bed dryer until the discharge temperature reaches 40 ° C.
60.2.6 20-40 mesh pellets were collected for further processing.

60.3 Preparation of Eudragit® L30D-55 aqueous coating dispersion 60.3.1 Dispersion formulation The composition of aqueous Eudragit L30D-55 used in amoxicillin matrix pellets is provided in Table 16 as follows: Is done.

60.4 Preparation Procedure of Eudragit® L30D-55 Aqueous Dispersion 60.4.1. Suspend triethyl citrate and talc in deionized water.
60.4.2 The TEC / talc suspension is mixed using a laboratory mixer.
60.4.3 Add TEC / talc suspension slowly to Eudragit® L30D-55 latex dispersion with stirring.
60.4.4 Stir the coating dispersion for 1 hour before use on amoxicillin matrix pellets.

60.5 Preparation of Eudragit® S100 aqueous coating dispersion 60.6 Dispersion formulation The composition of Eudragit® S100 dispersion used for amoxicillin matrix pellets is provided in Table 17 as follows: The

60.7 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
60.7.1 Disperse Eudragit® S100 powder with deionized water with stirring.
60.7.2 Ammonium hydroxide is added to the dispersion with stirring in drops.
60.7.3 Stir the partially neutralized dispersion for 60 minutes.
60.7.4 Triethyl citrate is added to the dispersion in water drop form with stirring and stirred overnight before adding Part B.
Part B:
60.7.5 Disperse the talc with the required amount of water.
60.7.6 Stir using an overhead laboratory mixer.
60.7.7 Part B is then slowly added to the Part A polymer dispersion with light agitation.

60.8 Preparation of Aqua Coat Coating Dispersion 60.8.1 Dispersion Formulation The composition of the aqueous aqua coat dispersion used for Amoxicillin L30D-55 coated pellets is provided in Table 18 as follows.

60.8.1.1 A hydroxypropyl methylcellulose (Methocel E15) solution is prepared by dispersing in water with continuous stirring.
60.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and stir overnight.

60.9 Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for coating with each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coating. .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2-6g / min

60.9.1 Coat Amoxicillin matrix pellets with L30D-55 dispersion to achieve 20% coating weight gain.
60.9.2 One batch of amoxicillin matrix pellets is coated with L30D-55 dispersion to achieve a 20% weight gain. To achieve a 10% increase in coating weight, L30D-55 pellets are coated with an aquacoat dispersion.
60.9.3 Coat with Amoxicillin matrix pellet S100 dispersion to achieve 37% coating weight gain.

  60.10 Formulation of amoxicillin granules for tablet formation

60.10.1 Amoxicillin and Avicel® PH101 are mixed using a low shear mixer.
60.10.2 Hydroxypropyl methylcellulose binder solution is slowly added to the powder mixture under continuous mixing.
A 60.10.20-40 mesh granulation is collected for further processing.

  60.11 Tablet formation of amoxicillin pellets

60.11.1 Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide are mixed in a tumble blender for 15 minutes.
60.11.2 Magnesium stearate is added to the blender and mixed for 5 minutes.
60.11.3 The mixture is compressed in a rotary tablet press.
The filling amount must be adjusted to achieve a 60.11.4 500 mg dose tablet.

Four pulses Example 61

Clarithromycin Pellet Formulation and Preparation Procedure 61.1 Pellet Formulation The composition of the clarithromycin matrix pellet was provided in Table 21.

61.2 Preparation Procedure for Clarithromycin Matrix Pellet 61.2.1 Clarithromycin, silicified microcrystalline cellulose and lactose hydrate are mixed in a robotic coupe high shear granulator.
61.2.2 Add polyoxyl to purified water with stirring to prepare a binder solution. After this is mixed, hydroxypropylmethylcellulose is added slowly and stirring is continued until a solution is formed.
61.2.3 Add the binder solution slowly to the powder mixture under continuous mixing.
61.2.4 The powder is granulated with a binder solution in a high shear granulator.
61.2.5 Extrude wet mass using LCI bench top granulator.
61.2.6 Spheronize the extrudate using a model SPH20 curry bass ferronizer.
61.2.7 Dry spherical pellets at 50 ° C. overnight.
61.2.8 18-30 mesh pellets were collected for further processing.

61.3 Preparation of Eudragit® L30D-55 Aqueous Coating Dispersion 61.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the Clarislo machine matrix pellets is shown in Table 22. Provided as follows.

61.4 Preparation Procedure for Eudragit® L30D-55 Aqueous Dispersion 61.4.1 Suspend triethyl citrate and talc in deionized water.
61.4.2 The TEC / talc suspension is homogenized using a PowerGen 700 high shear mixer.
61.4.3 Add the suspension from 4.2.2 slowly to Eudragit® L30D-55 with stirring.
61.4.4 Stir the coating dispersion for 1 hour before application to clarithromycin matrix pellets.

61.5 Preparation of Eudragit® S100 aqueous coating dispersion 61.5.1 Dispersion formulation The composition of the aqueous Eudragit® S100 dispersion applied to clarithromycin matrix pellets is shown in Table 23 Provided as follows.

61.6 Procedure for preparing Eudragit® S100 aqueous dispersion Part A:
61.6.1 Disperse Eudragit® S100 powder with deionized water with stirring.
61.6.2 Ammonium hydroxide solution is added to the dispersion while stirring in drops.
61.6.3 Stir the partially neutralized dispersion for 60 minutes.
61.4.4 Add triethyl citrate to the dispersion in water droplets and stir for 60 minutes before adding Part B.
Part B:
61.6.5 Disperse the talc with the required amount of water.
61.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
61.6.7 Part B is then slowly added to the Part A polymer dispersion with light agitation.

61.7 Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coating, respectively.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.6 bar Pump rate 2g / min

61.7.1 Coat the matrix pellets with L30D-55 dispersion to give the pellets a 12% increase in coating weight.
61.7.2 Coat the matrix pellets with L30D-55 dispersion to give the pellets a 30% increase in coating weight.
61.7.3 Coat the matrix pellets with S100 dispersion to give the pellets a 37% increase in coating weight.

61.8 Encapsulation of clarithromycin pellets Pellets were immediate release matrix pellets (uncoated), L30D-55 coated pellets 12% weight increase, L30D-55 coated pellets 30% weight increase, and S100 coated pellets, 20 Filled into size 00 hard gelatin capsules in a ratio of%: 30%: 20%: 30%. Capsules are filled to achieve a total dose of 250 mg / capsule with 4 different pellets.

Four pulses Example 62

Levofloxacin pellet formulation and preparation procedure Pellet formulation The composition of levofloxacin pellets is provided in Table 1.

Preparation Procedure for Levofloxacin Pellet • Mix levofloxacin, Avicel® PH101, and methocel using a robotic coupe high shear granulator.
• Slowly add purified water to the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
-Spheronize the extrudate using a model SHP20 curry bass ferronizer.
Dry spherical pellets at 50 ° C. until moisture content <3%.
• 16-30 mesh pellets were collected for further processing.

Levofloxysan enteric-release pellet formulation and preparation procedure Preparation of Eudragit® L30D-55 aqueous coating dispersion

Dispersion Formulation The composition of the aqueous Eudragit L30D-55 coating dispersion applied to levofloxacin pellets is provided in Table 2 as follows.

Preparation procedure for Eudragit® L30D-55 aqueous dispersion Triethyl citrate and talc are suspended in deionized water.
The TEC / talc suspension is then homogenized using a PowerGen 700 high shear mixer.
Slowly add the TEC / talc suspension to the Eudragit® L30D-55 latex dispersion with stirring.
The coating dispersion is stirred for 1 hour before application to levofloxacin pellets.

Coating conditions for application of Eudragit L30D-55 aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

Coat the levofloxacin pellets with Eudragit L30D-55 film coating dispersion to give the pellets a 12% coating weight increase.

Levofloxacin Delayed Enteric Release Pellet Formulation and Preparation Procedures Preparation of Opadry Clear Coating Solution Dispersant Formulation The composition of the aqueous opadri solution applied to levofloxacin pellets is provided in Table 3 as follows.

Preparation Procedure for Opadry Clear Aqueous Solution • Put purified water in a container.
• Add Opadryclear YS-1-7006 slowly to water under continuous mixing.

Preparation of AQOAT AS-HF / Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of the aqueous AQOAT AS-HF / Eudragit FS30D coating dispersion applied to the Opadori Coat levofloxacin pellets is as follows in Table 4 Provided as follows.

Preparation procedure of AQOAT AS-HF / Eudragit FS30D aqueous dispersion-Disperse triethyl citrate in purified water with stirring.
• Slowly add sodium lauryl sulfate to the triethyl citrate dispersion with stirring.
Add AQOAT AS-HF powder slowly to the dispersion and stir for a minimum of 30 minutes.
• Slowly add Eudragit FS30D dispersion to AQOAT AS-HF dispersion and continue stirring for a minimum of 1 hour.
Slowly add talc to the coating dispersion and continue stirring for at least 2 hours.
-Sift the dispersion with a 60 mesh sieve.
• Continue stirring the sieve dispersion through the coating process.

Coating Conditions for Application of Opadry and AQOAT AS-HF / Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for coating with the Opadry Film Coating Dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 350g
Inlet air temperature 60 ℃
Outlet air temperature 40 ℃
Atomizing air pressure 1.6 bar

      -Coat the levofloxacin pellets with the Opadry coating solution to give the pellets a 3% coating weight increase.

  The following coating parameters were used for coating with the AQOAT AS-HF / Eudragit FS30D aqueous coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 50 ℃
Outlet air temperature 30 ℃
Atomizing air pressure 1.6 bar

-Coat opadricoat levofloxacin pellets with AQOAT AS-HF / Eudragit FS30D aqueous coating dispersion to give the pellets a 30% increase in coating weight. The coated pellets are dried in a fluid bed for 20 minutes at 50 ° C.

Preparation of levofloxysan colon release pellet formulation and preparation procedure Eudragit® S100 aqueous coating / dispersion preparation Dispersion formulation The composition of Eudragit® S100 dispersion applied to levofloxacin pellets is as follows in Table 5 Provided.

Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
Disperse Eudragit® S100 powder with stirring in deionized water.
Add ammonium hydroxide solution to the dispersion in the form of water droplets with stirring.
• Stir the partially neutralized dispersion for 60 minutes.
-Add triethyl citrate in water droplets to the dispersion with stirring. Stir for about 2 hours before adding Part B.
Part B:
・ Disperse the talc with the required amount of water.
-Homogenize the dispersion using PowerGen and 700D high shear mixer.
• Part B is then slowly added to the Part A polymer dispersion with light agitation.

Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for coating Eudragit® S100 aqueous film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

-Coat the pellets with S100 dispersion to give the pellets a 20% increase in coating amount.

Encapsulation of levofloxacin pellets Each pellet is an immediate release pellet (uncoated), Eudragit L30D-55 coated pellet 12% weight increase, APOAT AS-HF Eudragit FS30D coated pellet 30% weight increase, Eudragit S100 coated pellet, 25 Hard gelatin capsules are filled in the ratio of%: 25%: 25%: 25%.

Capsules are filled to achieve a total dose of 250 mg / capsule with 4 different pellets.

Tablet formation of levofloxacin pellets Levofloxysan tablet composition

Preparation Procedure for Levofloxacin Tablets • Mix all ingredients except magnesium stearate together for 10 minutes using a tumble blender.
Add magnesium stearate to the mixture and mix for an additional 3 minutes.
• Mix the mixture on a rotary tablet press to achieve a dose of 250 mg.

Four pulses Example 62

Metronidazole Pellet Formulation and Preparation Procedure Pellet Formulation The composition of metronidazole pellets is provided in Table 1.

Procedure for preparing metronidazole pellets • Mix metronidazole, Avicel® PH101 and Methocel in a robotic coupe high shear granulator.
• Slowly add purified water to the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
-Spheroidize the extrudate with a model SPH20 curry bass ferronizer.
Dry the spherical pellets at 50 ° C. until moisture content <3%.
• 10-30 mesh pellets were collected for further processing.

Metronidazole and Enteric Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® L30D-55 Aqueous Coating Dispersion The composition of the aqueous Eudragit L30D-55 coating dispersion applied to Metronidazole pellets is as follows in Table 2. Provided.

Procedure for preparation of Eudragit® L30D-55 aqueous dispersion Triethyl citrate and talc are suspended in deionized water.

The TEC / talc suspension is then homogenized using a PowerGen 700 high shear mixer.
Slowly add the TEC / talc suspension to the Eudragit® L30D-55 latex dispersion with stirring.
Stir the coating dispersion for 1 hour before applying the metronidazole pellets.

Coating conditions for application of Eudragit L30D-55 aqueous coating dispersion The following coating parameters were used for coating Eudragit L30D-55 film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

Coat Metronidazole pellets with Eudragit L30D-55 film coating dispersion to add 12% coat weight increase to the pellets.

Metronidazole Delayed Enteric Release Pellet Formulation and Preparation Procedures Formulation of Opadoclear Clear Coating Solution Dispersion Formulation The composition of the aqueous opadri solution applied to metronidazole pellets is provided in Table 3 as follows.

Procedure for preparing Opadry clear aqueous solution ・ Purify purified water into a container.
• Slowly add Opadry Clear YS-1-7006 to the water with continuous mixing.

Preparation of AQOAT AS-HF / Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of the aqueous AQOAT AS-HF / Eudragit FS30D coating dispersion applied to Opadry coated metronidazole pellets is as follows in Table 4 Provided as follows.

Preparation procedure of AQOAT AS-HF / Eudragit FS30D aqueous dispersion-Disperse triethyl citrate with purified water with stirring.
• Slowly add sodium lauryl sulfate to the triethyl citrate dispersion with stirring.
-Slowly add AQOAT AS-HF powder to the above dispersion and stir for a minimum of 30 minutes.
Slowly add Eudragit FS30D dispersion to AQOAT AS / HF dispersion and continue stirring for a minimum of 1 hour.
Slowly add talc to the coating dispersion and continue stirring for at least 2 hours.
-Sift the dispersion with a 60 mesh sieve.
• Continue stirring the sieve dispersion through the coating process.

Coating Conditions for Application of Opadry and AQOAT / Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for coating with an Opadry film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 60 ℃
Outlet air temperature 403 ° C
Atomizing air pressure 1.6 bar

      Coat the metronidazole pellets with the opadri coating solution to add a 3% coating weight increase to the pellets.

  The following coating parameters were used for coating with the AQOAT AS-HF / Eudragit FS30D film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 50 ℃
Outlet air temperature 30 ℃
Atomizing air pressure 1.6 bar

-Coat the opadodri coated metronidazole pellets with AQOAT AS-HF / Eudragit FS30D coating dispersion to give the pellets a 30% increase in coating amount.

Metronidazole Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® S100 Aqueous Coating Dispersion Dispersion Formulation The composition of the aqueous Eudragit® S100 dispersion applied to Metronidazole pellets is as follows in Table 5 Provided.

Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
Disperse Eudragit® S100 powder with deionized water with stirring.
Add ammonium hydroxide solution in the form of water droplets to the dispersion with stirring.
• Stir the partially neutralized dispersion for 60 minutes.
-Add triethyl citrate in water droplets to the dispersion with stirring. Stir for about 2 hours before adding Part B.
Part B:
・ Disperse the talc with the required amount of water.
-Homogenize the dispersion using PowerGen and 700D high shear mixer.
Part B is then slowly added to the Part A polymer dispersion with light agitation.

Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for coating Eudragit® S100 aqueous film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 40 to 45 ° C
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump rate 2g / min

-Coat the pellets with S100 dispersion to give the pellets a 20% increase in coating amount.

Capsule formation of metronidazole pellets Pellets were immediate release (uncoated), Eudragit L30D-55 coated pellets 12% weight increase, AQOAT AS-HF / Eudragit F30D coated pellets 30% weight increase and Eudragit S100 coated pellets 20 Filled into size 00 hard gelatin capsules in a ratio of%: 30%: 20%: 30%.

Capsules are filled to achieve a total dose of 375 mg / capsule with 4 different pellets.

Metronidazole Pellet Tablet Formulation Metronidazole Tablet Formulation

Procedure for preparing metronidazole tablets • Mix all ingredients except magnesium stearate together using a tumble blender for 10 minutes.
Add magnesium stearate to the mixture and mix for an additional 3 minutes.
Compress the mixture in a rotary tablet press to achieve a dose of 375 mg.

Four pulses Example 62

Doxycycline hydrate pellet formulation and preparation procedure Pellet formulation The composition of doxycycline hydrate pellets was prepared in Table 1.

Procedure for preparing doxycycline hycrate pellets • Mix doxycycline hycrate, Avicel® PH101, and Methocel in a robotic coupe high shear granulator.
• Slowly add purified water to the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
-Spheronize the extrudate using a model SPH20 curry bass ferronizer.
Dry the spherical pellets at 50 ° C. until the moisture content is <3%.
• 16-30 mesh pellets were collected for further processing.

Doxycycline Hycrate Enteric Release Pellets and Preparation Procedure Eudragit® L30D-55 / Eudragit NE30D Aqueous Coating Dispersion Dispersion Formulation Aqueous Eudragit L30D-55 / Eudragit NE30D Aqueous Coating Applied to Doxycycline Hycrate Pellets The composition of the dispersion is provided in Table 2 as follows.

Procedure for preparing Eudragit® L30D55 / Eudragit NE30D aqueous dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for a minimum of 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for a minimum of 10 minutes.
-Sift the dispersion with a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

  Doxycycline hydrate pellets are coated with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% weight gain.

Doxycycline Hycrate Delayed Enteric Release Pellet Formulation and Preparation Procedures Preparation of Opadry Clear Coating Solution Dispersant Formulation The composition of the aqueous opadri solution applied to doxycycline hydrate paste is provided in Table 3 as follows.

Procedure for preparing Opadry clear aqueous solution ・ Purify purified water into a container.
• Slowly add Opadry Clear YS-1-7006 to the water with continuous mixing.

Eudragit FS30D / Eudragit L30D-55 Aqueous Coating Dispersion Formulation The composition of the aqueous Eudragit FS30D / Eudragit L30D-55 coating dispersion applied to Opadry Coated Doxycycline Hycrate Pellet is provided in Table 4 as follows: The

Preparation procedure of Eudragit FS30D / Eudragit L30D-55 aqueous dispersion-Disperse triethyl citrate in water with stirring.
• Slowly add the talc to the triethyl citrate dispersion with stirring.
• Slowly add Eudragit L30D-55 to the dispersion and stir for a minimum of 10 minutes.
Slowly add Eudragit FS30D to the Eudragit L30D-55 dispersion and continue stirring for a minimum of 1 hour.
-Sift the dispersion with a 60 mesh sieve.
• Continue stirring the sieve dispersion through the coating process.

Coating Conditions for Application of Opadry and Eudragit FS30D / Eudragit L30D-55 Aqueous Coating Dispersion The following coating parameters were used for coating with an Opadry film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 350g
Inlet air temperature 60 ℃
Outlet air temperature 40 ℃
Atomizing air pressure 1.6 bar

      -Coat the doxycycline hydrate pellets with the Opadry coating solution to add 3% coating to the pellets.

  The following coating parameters were used for coating with Eudragit FS30D / Eudragit L30D-55 film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 50 ℃
Outlet air temperature 30 ℃
Atomizing air pressure 1.6 bar

• Coat the opadodri coated doxycycline hycrate pellets with Eudragit FS30D / Eudragit L30D-55 coating dispersion to add 20% coating weight to the pellets.

Doxycycline Hycrate Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of Eudragit® FS30D dispersion applied to doxycycline hydrate pellets is given in Provided as follows.

Preparation Procedure of Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) with purified water.
Add talc to the triethyl citrate dispersion.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.
Continue stirring the coating dispersion until the coating process is complete.

Coating Conditions for Application of Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for each coating with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

The pellets are coated with Eudragit FS30D coating dispersion to give the pellets a 30% coating weight increase.

Encapsulation of doxycycline hycrate pellets Pellets were immediately released pellets (uncoated), Eudragit L30D-55 / Eudragit NE30D coated pellets increased by 20%, Eudragit FS30D Eudragit L30D-55 coated pellets increased by 20%, and Eudora, respectively. Filled hard gelatin capsules with JIT FS30D coated pellets in a ratio of 25%: 25%: 25%: 25%.

Capsules are filled with 4 different pellets to achieve a total volume of 100 mg / capsule or 200 mg / capsule.

Four pulses Example 62

Clarithromycin Pellet Formulation and Preparation Procedure Pellet Formulation The composition of clarithromycin pellets is provided in Table 1.

Preparation procedure of clarithromycin ・ Add polyoxyl to purified water with stirring to prepare a binder solution. After it has been mixed, hydroxypropylmethylcellulose is slowly added and continuously stirred until the solution is complete.
• Mix clarithromycin, lactose monohydrate, and croscarmellose sodium using a robotic coupe high shear granulator.
• Slowly add the binder solution to the powder mixture under continuous mixing.
-Granulate the powder with a binder solution in a high shear granulator.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
• Spheroidize the extrudate using a model SPH20 curry bass ferronizer.
Dry spherical pellets at 50 ° C. until moisture content> 3%.
• 16-30 mesh pellets were collected for further processing.

Clarithromycin Enteric Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® L30D-55 / Eudragit NE30D Aqueous Coating Dispersion Dispersion Formulation Aqueous Eudragit L30D-55 / Eudragit applied to clarithromycin pellets The composition of the NE30D aqueous coating dispersion is provided in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 / Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for a minimum of 10 minutes.
-Sift the dispersion with a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat clarithromycin pellets with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to provide a 20% increase in coating weight on the pellets.

Clarithromycin Delayed Enteric Release Pellet Formulation and Preparation Procedure Preparation of AQOAT AS-HF Coating Dispersion Dispersion Formulation The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the clarithromycin pellets is shown in Table 3 below. Provided on the street.

Procedure for preparing AQOAT AS-HF aqueous dispersion: Add triethyl citrate (TEC) to purified water with stirring.
• Slowly add sodium lauryl sulfate (SLS) to the TEC dispersion with stirring until completely dissolved.
Add AQOAT to the TEC / SLS dispersion and stir for at least 30 minutes.
Add the talc to the AQOAT dispersion until thoroughly mixed and with stirring for at least 30 minutes.
Sift the dispersion through a # 60 mesh before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of AQOAT AS-HF aqueous coating dispersion

  The following coating parameters were used for coating with the AQOAT AS-HF film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 48 ℃
Outlet air temperature 27 ℃
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat clarithromycin pellets with AQOAT AS-HF film coating dispersion to give the pellets a 30-35% coat coverage increase.

Clarithromycin Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of Eudragit® FS30D dispersion applied to clarithromycin pellets is shown in Table 4. Provided as follows.

Preparation Procedure of Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) with purified water with stirring.
Add talc to the triethyl citrate dispersion.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.
Continue stirring the coating dispersion until the coating process is complete.

Coating Conditions for Application of Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for each coating with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

  The pellets are coated with Eudragit FS30D coating dispersion to give the pellets a 30% coat weight increase.

Capsule formation of clarithromycin pellets The pellets were respectively immediate release matrix pellets (uncoated), L30-D55 / Eudragit NE30D coated pellets 20% weight increase, AQOAT AS-HF coated pellets 30-35% weight increase and Eudragit FS30D Hard gelatin capsules are filled at a ratio of 25%: 25%: 25%: 25% with coated pellets.

Capsules are filled with 4 different pellets to achieve a total dose of 250 mg / capsule.

Clarithromycin pellet tablet formation Clarithromycin tablet formulation

Preparation Procedure for Clarithromycin Tablets • All ingredients except coated pellets and magnesium stearate are mixed together using a granulator for 10 minutes.
-Granulate the mixture with purified water.
• Sift the granulated material through a 16 mesh sieve.
Dry the sieved granules in a fluid bed dryer at 50-60 ° C. until the moisture content is 3% or less.
Add dry granule coated pellets to tumble blender and mix for 10 minutes.
Add magnesium stearate to the mixture and mix in an additional 3 minutes.
Compress the mixture in a rotary tablet press to achieve a dose of 500 mg.

Four pulses Example 62

Ciprofloxacin pellet formulation and preparation procedure Pellet formulation The composition of ciprofloxacin pellets is provided in Table 1.

Preparation Procedure for Ciprofloxacin Pellet • Ciprofloxacin, Avicel® PH101 and methocel are mixed in a robotic coupe high shear granulator.
• Slowly add purified water to the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top mixer. The screen diameter of the bench top granulator was 1.0 mm.
• Spheroidize the extrudate using a model SPH20 curry bass ferronizer.
Dry spherical pellets at 50 ° C. until moisture content <3%.
• 16-30 mesh pellets were collected for further processing.

Ciprofloxacin Enteric Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® L30D-55 / Eudragit NE30D Aqueous Coating Dispersion Dispersion Formulation

  The composition of the aqueous Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion applied to the ciprofloxacin pellets is prepared in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 / Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for a minimum of 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for a minimum of 10 minutes.
Sift the dispersion through a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat ciprofloxacin pellets with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% coat weight increase.

Ciprofloxysan Delayed Enteric Release Pellet Formulation and Preparation Procedures Preparation of Opadry Clear Coating Solution Dispersion Formulation The composition of the aqueous opadri solution applied to the ciprofloxysan pellet is provided in Table 3 as follows.

Procedure for preparing Opadry clear aqueous solution ・ Purify purified water into a container.
-Slowly add Opadry Clear YS-1-7006 to the water with continuous mixing.

Preparation of Eudragit® FS30D / Eudragit L30D-55 aqueous coating dispersion formulation Dispersion formulation Composition of aqueous Eudragit FS30D / Eudragit L30D-55 coating dispersion applied to opadricoat ciprofloxacin pellets Are provided in Table 4 as follows.

Preparation procedure of Eudragit FS30D / Eudragit L30D-55 aqueous dispersion-Disperse triethyl citrate in purified water with stirring.
• Slowly add talc to the triethyl citrate dispersion with stirring.
• Slowly add Eudragit L30D-55 to the dispersion and stir for a minimum of 10 minutes.
• Slowly add Eudragit FS30D dispersion to Eudragit L30D-55 dispersion and continue stirring for a minimum of 1 hour.
• Sift the dispersion through a # 60 mesh sieve.
• Continue stirring the sieve dispersion through the coating process.

Coating Conditions for Application of Opadry and Eudragit FS30D / Eudragit L30D-55 Aqueous Coating Dispersion The following coating parameters were used for coating with an Opadry solution film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 350g
Inlet air temperature 60 ℃
Outlet air temperature 40 ℃
Atomizing air pressure 1.6 bar

      Coat ciprofloxacin pellets with an opadoli coating solution to give the pellets a 3% coat weight gain.

  The following coating parameters were used for coating with Eudragit FS30D / Eudragit L30D-55 film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 50 ℃
Outlet air temperature 30 ℃
Atomizing air pressure 1.6 bar

-Coat Opadry coated ciprofloxacin pellets with Eudragit FS30D / Eudragit L30D-55 coating dispersion to give 20% coat weight to the pellets.

Ciprofloxacin colon release pellet formulation and preparation procedure Preparation of Eudragit® FS30D aqueous coating dispersion Dispersion formulation The composition of the aqueous Eudragit® FS30D dispersion applied to the ciprofloxacin pellet is: Table 4 provides as follows.

Preparation Procedure of Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) in purified water with stirring.
Add the talc to the triethyl citrate dispersion with stirring.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D to the talc / TEC dispersion with stirring.
Continue stirring the coating dispersion until the coating process is complete.

Coating Conditions for Application of Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for each coating with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

The pellets are coated with Eudragit FS30D coating dispersion to give the pellets a 30% coat weight increase.

Encapsulation of ciprofloxacin pellets The pellets were respectively an immediate release pellet (uncoated), Eudragit L30D-55 / Eudragit NE30D coated pellet 20% increased, Eudragit FS30D Eudragit L30D-55 coated pellet 20% expanded, and Hard gelatin capsules are filled with Eudragit FS30D coated pellets in a ratio of 25%: 25%: 25%: 25%.

Capsules are filled with 4 different pellets to achieve a total volume of 250 mg / capsule.

Ciprofloxacin pellet tablet formation Ciprofloxacin tablet formulation

Preparation Procedure for Ciprofloxacin Tablets • Mix all ingredients except magnesium stearate together using a tumble blender for 10 minutes.
Add magnesium stearate to the mixture and mix for an additional 3 minutes.
Compress the mixture in a rotary tablet press to achieve a dose of 500 mg or 750 mg.

Four pulses Example 62

Amoxicillin Pellet Formulation and Preparation Procedure Pellet Formulation The composition of amoxicillin trihydrate pellets is provided in Table 1.

Procedure for preparing Amoxicillin pellets • Mix Amoxicillin and Adcel® PH101 using a low shear mixer.
• Slowly mix the hydroxypropyl methylcellulose and polyoxyl 35 castor oil binder solution into the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator is 0.8 mm.
• Spheronize the extrudate using a QJ-230 spheronizer using a small cross-section plate.
• 20-40 mesh pellets were collected for further processing.

Amoxicillin Enteric Release Pellet Formulation and Preparation Procedure Eudragit® L30D-55 / Eudragit NE30D Aqueous Coating Dispersion Dispersion Formulation The composition is provided in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for at least 10 minutes.
-Sift the dispersion with a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters are used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion It was.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

The amoxicillin pellets are coated with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% coat weight increase.

Amoxacillin Delayed Enteric Release Pellet Formulation and Preparation Procedures Preparation of AQOAT AS-HF Coating Dispersion Dispersion Formulation The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to amoxicillin pellets is provided in Table 3 as follows: .

Preparation Procedure for AQOAT AS-HF Aqueous Dispersion Add triethyl citrate (TEC) to purified water with stirring.
• Slowly add sodium lauryl sulfate (SLS) to the TEC dispersion with stirring until completely dissolved.
Add AQOAT to the TEC / SLS dispersion and stir for at least 30 minutes.
Add talc to the AQOAT dispersion and stir for at least 30 minutes until thoroughly mixed.
Sift the dispersion through a # 60 mesh before coating.
• Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of AQOAT AS-HF aqueous coating dispersions The following coating parameters were used for coating with AQOAT AS-HF film coating dispersions.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 48 ℃
Outlet air temperature 27 ℃
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat the amoxicillin pellets with the AQOAT AS-HF coating dispersion to give the pellets a 30-35% coat weight increase.

Amoxicillin Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of Eudragit® FS30D dispersion applied to amoxicillin pellets is provided in Table 4 as follows: Is done.

Preparation Procedure for Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) in purified water with stirring.
Add the talc to the triethyl citrate dispersion with stirring.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.
The coating dispersion is continuously stirred until the coating process is complete.

Coating Conditions for Application of Eudragit Aqueous Coating Dispersion The following coating parameters were used for coating each with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

  The pellet is coated with Eudragit FS30D coating dispersion to give the pellet a 30% coat weight increase.

Coat the pellets with Eudragit FS30D coating dispersion to give the pellets a 30% coating weight increase.

Amoxicillin Tablets Amoxicillin Granulation Formulation for Tablet Formation

Mix Amoxicillin and Avicel® PH101 using a low shear mixer.
• Slowly add the hydroxypropyl methylcellulose binder solution to the powder mixture under continuous mixing.
Dry the formed granulation using a fluid bed dryer at 60 ° C. until the exhaust temperature reaches 40 ° C.
• Formed granulation of 20-40 mesh was collected for further processing.

  Tablet formation of amoxicillin pellets

Mix Amoxicillin granulation, Avicel PH-200, Amoxicillin coated pellets and colloidal silicon dioxide for 15 minutes with a tumble blender for 15 minutes.
Add magnesium stearate to blender and mix for 5 minutes.
Compress the mixture with a rotary tablet press.
• The fill must be adjusted to achieve a 500 mg dose tablet.

Amoxicillin tablet capsule formation pellets are immediate release pellet (uncoated), L30D-55 / Eudragit NE30D coated pellet 20% increased coating amount, AQOAT AS-HF coated pellet 30% weight increased, Eudragit FS30D coated pellet, Hard gelatin capsules are filled at a ratio of 30%: 30%: 20%: 20%. Capsules are filled with 4 different pellets to achieve a total dose of 250 mg / capsule.

  In particular, the present invention provides a single antibiotic product, which provides an improvement over a twice-daily antibiotic and provides an improvement over a once-daily antibiotic. It is advantageous.

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

Four pulses Example 63

Cefuroxime axetil pellet formulation and preparation procedure Pellet formulation The composition of cefuroxime axetyl pellets is provided in Table 1.

Preparation procedure of cefuroxime axetyl pellet ・ Add polyoxyl to purified water while stirring to prepare a binder solution. After mixing this, hydroxypropylmethylcellulose is added slowly and stirring is continued until dissolution is achieved.
Mix cefuroxime axetil, lactose hydrate, and croscarmellose sodium using a robotic coupe high shear granulator.
• Slowly add the binder solution to the powder mixture under continuous mixing.
-Granulate high shear granulator powder with other binder liquids.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
• Spheroidize the extrudate using a model SPH20 curry bass ferronizer.
Dry the spherical pellet at 50 ° C. until the moisture content is> 3%.
• 16-30 mesh pellets were collected for further processing.

Cefuroxime axetil enteric-release pellet formulation and preparation procedure Preparation of Eudragit® L30D-55 / Eudragit NE30D aqueous coating dispersion Dispersion formulation

The composition of the aqueous Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion applied to the cefuroxime axetil pellets is provided in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 / Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for at least 10 minutes.
-Sift the dispersion with a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters are used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion It was.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat cefuroxime axetyl pellets with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% coat weight increase.

Cefuroxime axetil delayed enteric release pellet formulation and preparation procedure AQOAT AS-HF aqueous coating dispersion Dispersion formulation The composition of aqueous AQOAT AS-HF aqueous coating dispersion applied to cefuroxime axetil pellets is as follows in Table 3 Provided as follows.

AQOAT AS-HF aqueous dispersion preparation procedure-Add triethyl citrate (TEC) to purified water with stirring.
• Slowly add sodium lauryl sulfate (SLS) to the TEC dispersion with stirring until completely dissolved.
Add AQOAT to TEC / SLS and stir for at least 30 minutes.
Add talc to the AQOAT dispersion and stir again for at least 30 minutes until thoroughly mixed.
Sift the dispersion through a # 60 mesh before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of AQOAT AS-HF coating dispersion The following coating parameters were used for coating with AQOAT AS-HF film coating dispersion.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 48 ℃
Outlet air temperature 27 ℃
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Coat cefuroxime axetyl pellets with AQOAT AS-HF coating dispersion to give the pellets a 30-35% coat weight increase.

Cefuroxime Axetil Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation The composition of Eudragit® FS30D dispersion applied to cefuroxime axetyl pellets is 4 is provided as follows.

Preparation Procedure for Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) in purified water with stirring.
Add the talc to the triethyl citrate dispersion with stirring.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.
Continue stirring the coating dispersion until the coating process is complete.

Coating Conditions for Application of Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for each coating with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

Coat the pellets with Eudragit FS30D coating dispersion to give the pellets a 30% coat weight increase.

Cefuroxime axetil capsule formation Pellets are respectively immediate release pellets (uncoated), Eudragit L30D-55 / Eudragit NE30D coated pellets 20% increase, AQOAT AS-HF coated pellets 30-35% weight increase, and Eudragit Hard gelatin capsules are filled at a ratio of 25%: 25%: 25%: 25% with FS30D coated pellets.

Capsules are filled with 4 different pellets to achieve a total dose of 250 mg / capsule.

Tablet formation of cefuroxime axetil pellets Cefuroxime axetil tablet formulation

Preparation Procedure for Cefuroxime Axetil Tablet • Mix all ingredients except coated pellets and magnesium stearate together for 10 minutes using a granulator.
-Granulate the mixture with purified water.
-Sift the granulated material through a 16 mesh screen.
-The sieved granulation is dried at 50-60 ° C in a fluid bed dryer until the moisture content is 3% or less.
Add dry granule coated pellets to tumble blender and mix for 10 minutes.
Add magnesium stearate to the mixture and mix for an additional 3 minutes.
Compress the mixture in a rotary tablet press to achieve a dose of 500 mg.

  In particular, the present invention provides a single antibiotic product, which provides an improvement over a twice-daily antibiotic and provides an improvement over a once-daily antibiotic. It is advantageous.

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

Four pulses Example 64

Cefpodoxime Proxetyl Pellet Formulation and Preparation Procedure Pellet Formulation The composition of cefpodoxime proxetyl pellets is provided in Table 1.

Procedure for preparing cefpodoxime proxetyl pellets-Prepare a binder solution by adding polyoxyl to purified water with stirring. After it has been mixed, hydroxypropylmethylcellulose is slowly added and continuously stirred until the solution is complete.
Cefpodoxime proxetil, lactose monohydrate, and croscarmellose sodium are mixed using a robotic coupe high shear granulator.
• Slowly add the binder solution to the powder mixture under continuous mixing.
-Granulate the powder with a high shear granulator using the binder solution.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 1.0 mm.
• Spheroidize the extrudate using a model SPH20 curry bass ferronizer.
Dry spherical pellets at 50 ° C. until moisture content> 3%.

• 16-30 mesh pellets were collected for further processing.

Cefpodoxime Proxetil Enteric Release Pellets Formulation and Preparation Procedure Preparation of Eudragit® L30D-55 / Eudragit NE30D Aqueous Coating Dispersion Dispersion Formulation Aqueous Eudragit Applied to Cefpodoxime Proxetyl Pellets The composition of the L30D-55 / Eudragit NE30D aqueous coating dispersion is provided in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 / Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for at least 10 minutes.
Sift the dispersion through a # 60 mesh before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30D aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Cefpodoxime proxetyl pellets are coated with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% coat weight increase.

Cefpodoxime Proxetil Delayed Enteric Release Pellet Formulation and Preparation Procedure AQOAT AS-HF Coating Dispersion Preparation Dispersion Formulation The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to cefpodoxime proxetyl pellets is: , Provided in Table 3 as follows.

Procedure for preparing AQOAT AS-HF aqueous dispersion: Add triethyl citrate (TEC) to purified water with stirring.
• Slowly add sodium lauryl sulfate (SLS) to the TEC dispersion with stirring until completely dissolved.
Add AQOAT to the TEC / SLS dispersion and stir for at least 30 minutes.
Add talc to the AQOAT dispersion and stir for at least 30 minutes until thoroughly mixed.
Sift the dispersion through a # 60 mesh before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of AQOAT AS-HF aqueous coating dispersions The following coating parameters were used for coating with AQOAT AS-HF film coating dispersions.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 48 ℃
Outlet air temperature 27 ℃
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

Cefpodoxime proxetyl pellets are coated with AQOAT AS-HF film coating dispersion to give the pellets a 30-35% coat weight increase.

Cefpodoxime Proxetil Colon Release Pellet Formulation and Preparation Procedure Preparation of Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation Aqueous Eudragit® FS30D Dispersion Applied to Cefpodoxime Proxetil Pellets The composition of is provided in Table 4 as follows.

Preparation Procedure of Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) with purified water with stirring.
Add the talc to the triethyl citrate dispersion with stirring.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.
Continue stirring the coating dispersion until the coating process is complete.

Coating Conditions for Application of Eudragit FS30D Aqueous Coating Dispersion The following coating parameters were used for coating each with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

Coat the pellets with Eudragit FS30D coating dispersion to give the pellets a 30% coat weight increase.

Cefpodoxime Proxetyl Pellet Capsule Formation Pellets are each an immediate release pellet (uncoated), Eudragit L30-D55 / Eudragit NE30D coated pellet 20% weight increase, AQOAT AS-HF coated pellet 30-35% weight increase And Eudragit FS30D coated pellets in hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%.

Capsules are filled with 4 different pellets to achieve a total dose of 200 mg / capsule.

Cefpodoxime Proxetyl Pellet Tablet Formation Cefpodoxime Proxetil Tablet Formulation

Preparation Procedure for Cefpodoxime Proxetil Tablets • Mix all ingredients except coated pellets and magnesium stearate for 10 minutes using a granulator.
-Granulate the mixture with purified water.
• Sift the granulated material through a 16 mesh sieve.
Dry the sieved granulation in a fluid bed dryer at 50-60 ° C. until the moisture content is 3% or less.
Add dry granule coated pellets to tumble blender and mix for 10 minutes.
Add magnesium stearate to the mixture and mix in an additional 3 minutes.
Compress the mixture with a rotary tablet press to achieve a dose of 400 mg.

  In particular, the present invention provides a single antibiotic product, which provides an improvement over a twice-daily antibiotic and provides an improvement over a once-daily antibiotic. It is advantageous.

Many modifications and variations of the present invention are possible in light of the above teachings, and therefore, the invention may be practiced otherwise than as specifically described within the scope of the claims appended hereto.

Four pulses Example 65

Dicloxacillin Pellet Formulation and Preparation Procedure Pellet Formulation The composition of dicloxacillin trihydrate pellets is provided in Table 1.

Preparation procedure of dicloxacillin pellets • Mix dicloxacillin and Avicel® PH101 using a low shear granulator.
• Slowly add hydroxypropyl methylcellulose and polyoxyl 35 castor oil binder solution to the powder mixture under continuous mixing.
Extrude wet mass using LCI bench top granulator. The screen diameter of the bench top granulator was 0.8 mm.
• Spheronize the extrudate using a QJ-230 spheronizer using a small cross-section plate.
Dry the spherical pellets at 60 ° C. using a fluid bed dryer until the exhaust temperature reaches 40 ° C.
• 20-40 mesh pellets were collected for further processing.

Dicloxacillin enteric-release pellet formulation and preparation procedure Preparation of Eudragit® L30D-55 / Eudragit NE30D aqueous coating dispersion Dispersion formulation Aqueous Eudragit L30D-55 / Eudragit NE30D aqueous applied to dicloxacillin pellets The composition of the coating dispersion is prepared in Table 2 as follows.

Preparation Procedure for Eudragit® L30D-55 / Eudragit NE30D Aqueous Dispersion • Heat purified water to 75-80 ° C., then add triethyl citrate (TEC) and Imviter 900. Homogenize the dispersion until the temperature is below 55 ° C.
The TEC / Imviter 900 dispersion is then stirred until the temperature is below 35 ° C.
Add TEC / Imviter 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE30D to the Eudragit L30D / TEC / Imviter 900 dispersion and stir for at least 10 minutes.
-Sieve the dispersion through a # 60 mesh sieve before coating.
Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of Eudragit L30D-55 / Eudragit NE30DA aqueous coating dispersion The following coating parameters were used for coating Eudragit® L30D-55 / Eudragit NE30D film coating dispersion .

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 45 ℃
Outlet air temperature 32 to 35 ° C
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

The dicloxacillin pellets are coated with Eudragit L30D-55 / Eudragit NE30D film coating dispersion to give the pellets a 20% coat weight increase.

Dicloxacillin Delayed Enteric Release Pellet Formulation and Preparation Procedure Dispersion Formulation The composition of the aqueous AQOAT AS-SH aqueous coating dispersion applied to dicloxacillin pellets is provided in Table 3 as follows.

Procedure for preparing AQOAT AS-HF aqueous dispersion: Add triethyl citrate (TEC) to purified water with stirring.
• Slowly add sodium lauryl sulfate (SLS) to the TEC dispersion with stirring until completely dissolved.
Add AQOAT to the TEC / SLS dispersion and stir for at least 30 minutes.
Add talc to the AQOAT dispersion and stir for at least 30 minutes until thoroughly mixed.
Sift the dispersion through a # 60 mesh before coating.
• Continue stirring the dispersion until the coating process is complete.

Coating conditions for application of AQOAT AS-HF aqueous coating dispersions The following coating parameters were used for coating with AQOAT AS-HF film coating dispersions.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.0mm
Material preparation 300g
Inlet air temperature 48 ℃
Outlet air temperature 27 ℃
Nebulization air pressure 1.6 bar Pump rate 3-4g / min

The dicloxacillin pellets are coated with AQOAT AS-HF film coating dispersion to give the pellets a 30-35% coat weight increase.

Dicloxacillin colon release pellet formulation and preparation procedure Preparation of Eudragit® FS30D aqueous coating dispersion Dispersion formulation The composition of Eudragit® FS30D dispersion applied to dicloxacillin pellets is shown in Table 4 below. Provided on the street.

Preparation Procedure of Eudragit® FS30D Aqueous Dispersion • Disperse triethyl citrate (TEC) with purified water with stirring.
Add the talc to the triethyl citrate dispersion with stirring.
-Homogenize the dispersion using a homogenizer.
• Slowly add Eudragit® FS30D dispersion to talc / TEC dispersion with stirring.

The coating dispersion is continuously stirred until the coating process is complete.

Coating conditions for Eudragit FS30D aqueous coating dispersion The following coating parameters were used for coating each with Eudragit® FS30D aqueous film coating.

Coating equipment STREA 1 ^TM Table top laboratory fluid bed coater Spray nozzle diameter 1.2mm
Material preparation 300g
Inlet air temperature 38 ℃
Outlet air temperature 22 ℃
Nebulization air pressure 1.6 bar Pump rate 6g / min

Coat the pellets with Eudragit FS30D coating dispersion to give the pellets a 30% coat weight increase.

Capsule formation of dicloxacillin pellets The pellets are respectively immediate release pellets (uncoated), L30-D55 / Eudragit NE30D coated pellets 20% weight increase, AQOAT AS-HF coated pellets 30% weight increase and Eudragit FS30D coated pellets Hard gelatin capsules are filled at a ratio of 25%: 25%: 25%: 25%.

Capsules are filled with 4 different pellets to achieve a total dose of 250 mg / capsule.

Dicloxacillin Tablets Dicloxacillin Granulation Formulation for Tablet Formation

Mix dicloxacillin and Avicel® PH101 using a low shear granulator.
• Slowly add the hydroxypropyl methylcellulose binder solution to the powder mixture under continuous mixing.
Dry the spherical pellets at 60 ° C. using a fluid bed dryer until the exhaust temperature reaches 40 ° C.
• 20-40 mesh granulation was collected for further processing.

  Tablet formation of dicloxacillin pellets

Mix dicloxacillin granulation, Adcel PH-200, dicloxacillin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender for 15 minutes.
Add magnesium stearate to blender and mix for 5 minutes.
Compress the mixture with a rotary tablet press.
• The fill must be adjusted to achieve a 500 mg dose tablet.

  In particular, the present invention provides a single antibiotic product, which provides an improvement over a twice-daily antibiotic and provides an improvement over a once-daily antibiotic. It is advantageous.

  Numerous modifications and variations of the present invention are possible in light of the above teachings, and thus the invention can be practiced otherwise than as specifically described within the scope of the claims appended hereto.

Claims (16)

An antibiotic product comprising a first antibiotic dosage form, a second antibiotic dosage form, and a third antibiotic dosage form, wherein each of the first, second and third antibiotic dosage forms is one The three dosage forms have different release profiles, the antibiotic product reaching C _max in about 12 hours or less, wherein the antibiotic is levofloxacin, The first dosage form is selected from the group consisting of metronidazole, tetracycline, doxycycline, erythromycin, clarithromycin, fluroquinilone, ciprofloxacin, betalactam antibiotic, cephalosporin, cefuroxime, cefpodoxime, penicillin, amoxicillin, and dicloxacillin. An immediate release dosage form, said second and Each of the third and third dosage forms is a delayed release dosage form, wherein the antibiotic released from the first dosage form reaches C _max in serum 0.5-2 hours after administration of the product, where The antibiotic released from the second dosage form reaches C _max in the serum within 4 hours after administration of the product and after the antibiotic from the first dosage form reaches C _max and The antibiotic released from the dosage form reaches C _max in the serum within 8 hours after administration of the product and after the antibiotic released from the second dosage form reaches C _max. Antibiotic products to do.   2. A product according to claim 1, wherein the second dosage form starts releasing antibiotics at least 1 hour after the first dosage form. 3. Product according to claim 2, characterized in that the second dosage form reaches C _max after 2 hours after administration of the product.   4. The product of claim 3, wherein the first dosage form contains from about 20 to about 50% by weight of the total antibiotic of the product, wherein the second dosage form is the second and third dosage forms. A product characterized in that it contains 30 to 60% by weight of the antibiotic contained therein.   A product according to claim 4, characterized in that the first dosage form contains 15 to 30% by weight of the total antibiotic present in the product.   The product of claim 1, wherein the product comprises a fourth delayed release antibiotic dosage form having a different release profile than the first, second and third dosage forms.   7. The product of claim 6, wherein the second dosage form contains 20-35% by weight of the total antibiotic present in the second, third and fourth dosage forms, A product characterized in that it contains 20-40% by weight of the total antibiotic present in the second, third and fourth dosage forms, with the remainder present in the fourth dosage form. 2. Product according to claim 1, characterized in that the C _max of the product is reached after 4 hours after administration.   A method of treating a bacterial infection in a host, comprising administering the antibiotic product of claim 1 to the host.   A method of treating a bacterial infection in a host, comprising administering the antibiotic product of claim 2 to the host.   A method of treating a bacterial infection in a host, comprising administering the antibiotic product of claim 3 to the host.   A method of treating a bacterial infection in a host, comprising administering the antibiotic product of claim 4 to the host.   A method of treating a bacterial infection in a host, comprising administering to the host an antibiotic product according to claim 5.   A method of treating a bacterial infection in a host comprising administering to the host an antibiotic product according to claim 6.   A method for treating a bacterial infection in a host, comprising administering to the host an antibiotic product according to claim 7.   A method of treating a bacterial infection in a host, comprising administering to the host an antibiotic product according to claim 8.