Patent Grant
8062672
This invention relates to an antibiotic product, as well as the use and formulation thereof.
A wide variety of antibiotics have been used, and will be used, in order to combat bacterial infection. In general, such antibiotics can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at higher administered doses. The present invention is directed to providing for an improved antibiotic product.
In accordance with one aspect of the present invention, there is provided an antibiotic pharmaceutical product which is comprised of at least two, preferably at least three, antibiotic dosage forms. Such dosage forms are formulated so that each of the dosage forms has a different release profile.
In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which has a different release profile and the release profile of each of the dosage forms is such that the first and second dosage forms each start release of the antibiotic contained therein at about the same time, and the third dosage form starts release of the antibiotic contained therein at a time after the second dosage form starts release of antibiotic contained therein.
In another particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which has a different release profile and the release profile of each of the dosage forms is such that the dosage forms each start release of the antibiotic contained therein at different times after administration of the antibiotic product.
Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antibiotic product that has contained therein at least two, preferably at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in at least two of such dosage forms is released at different times.
In general neither of the second or third dosage forms starts release of antibiotic contained therein before the first dosage form starts release of antibiotic contained therein.
More particularly, in one aspect, the antibiotic product contains at least three dosage forms, the first of which is a delayed release dosage form, the second of which is a delayed release sustained release dosage form, and the third of which is a delayed release sustained release dosage form, with the second dosage form initiating release at about the same time as the first dosage form or at a time after the first dosage form (the initiation of sustained release is delayed for a period of time after initiation of release from the first dosage form), with the third dosage form initiating release after release is initiated from both the first and second dosage forms.
In accordance with a further aspect of the invention, the antibiotic product may be comprised of at least four different dosage forms, at least three of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product.
The antibiotic product generally does not include more than five dosage forms with different release times.
In accordance with a preferred embodiment, the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours after initiation of release of antibioitic from the first dosage form. In an embodiment, the maximum serum concentration of the total antibiotic released from the antibiotic product is achieved no earlier than four hours after initiation of release of antibioitic from the first dosage form.
In accordance with one preferred embodiment of the invention, there are at least three dosage forms. The first of the at least three dosage forms is a delayed release dosage form whereby initiation of release of the antibiotic therefrom is delayed after administration of the antibiotic product. The second and third of the at least three dosage forms are each delayed sustained release dosage forms. Additionally, initiation of release of the antibiotic from the third sustained release dosage form is delayed until after initiation of release from the second, however, when release is initiated the second and third dosage forms release antibioitc as sustained release dosage forms. The delay of initiation of release of each of the sustained release dosage forms, may be accomplished for example by using a pH sensitive or a non-pH sensitive enteric coating, depending on the type of antibiotic product, whereby the sustained release of the antibiotic from the second and third dosage form is delayed with the second dosage form initiating release at about the same time or at a time after initiation of release of antibiotic from the first dosage form. More particularly, the antibiotic released from the second of the at least two dosage forms achieves a Cmax (maximum serum concentration in the serum) at a time after the antibiotic released from the first of the at least three dosage forms achieves a Cmax in the serum, and the antibiotic released from the third dosage form achieves a Cmax in the serum after the Cmax of antibiotic released from the second dosage form.
In one embodiment the first and second of the at least two dosage forms initiate their respective delayed and delayed sustained releases of antibiotic at about the same time.
In one embodiment the initiation of the sustained release of antibiotic from the second of the at least two dosage forms is delayed until after the initiation of release of antibiotic from the first dosage form.
In all embodiments comprising three or more dosage forms, the initiation of the sustained release of antibiotic from the third dosage form is delayed until after the sustained release of antibiotic is initiated from the second dosage form.
In one embodiment, the second of the at least two dosage forms initiates release of the antibiotic contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.
In general, the first dosage form produces a Cmax for the antibiotic released therefrom within from about 0.5 to about 2 hours after initiation of release of antibioitic, with the second dosage form of the at least three dosage forms producing a Cmax for the antibiotic released therefrom in no more than about four hours after initiation of release of antibiotic from the first dosage form. In general, the Cmax for such second dosage form is achieved no earlier than two hours after initiation of release of antibiotic from the first dosage form; however, it is possible within the scope of the invention to achieve Cmax in a shorter period of time.
As hereinabove indicated, the antibiotic product may contain at least three or at least four or more different dosage forms. For example, if the antibiotic product includes a third dosage form, the antibiotic released therefrom reaches a Cmax at a time later than the Cmax is achieved for the antibiotic released from each of the first and second dosage forms. In a preferred embodiment, release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form. In one embodiment, Cmax for antibiotic release from the third dosage form is achieved within eight hours after initiation of release of antibiotic from the first dosage form.
In another embodiment, the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the antibiotic released from each of the at least four different dosage forms achieves a Cmax at a different time.
As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic contains at least two or at least three or at least four different dosage forms each with a different release profile, Cmax for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours after initiation of release of antibiotic from the first is initiated.
In a preferred embodiment, the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antibiotic product with the antibiotic being released in a manner such that overall antibiotic release is effected with different release profiles in a manner such that the overall Cmax for the antibiotic product is reached in less than about twelve hours after initiation of release of antibiotic. The term single administration means that the total antibiotic administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.
Applicant has found that a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile is an improvement over a single dosage antibiotic product comprised of an antibiotic dosage form having a single release profile. Each of the dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics and each of the dosage forms may have the same antibiotic or different antibiotics.
It is to be understood that when it is disclosed herein that a dosage form initiates release after another dosage form, such terminology means that the dosage form is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, some “leakage” of antibiotic may occur. Such “leakage” is not “release” as used herein.
If at least four dosage forms are used, the fourth of the at least four dosage forms may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though Cmax of the fourth dosage form of the at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
The antibiotic product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the antibiotic product is formulated in a manner such that it is suitable for oral administration.
For example, in formulating the antibiotic product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an antibiotic, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the delayed release dosage form is in the continuous phase, and the delayed sustained release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the delayed release component, water dispersed in the oil containing a first delayed sustained release dosage form, and oil dispersed in the water containing a third sustained release dosage form.
It is also within the scope of the invention to provide an antibiotic product in the form of a patch, which includes antibiotic dosage forms having different release profiles, as hereinabove described.
In addition, the antibiotic product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase of the emulsion.
Furthermore, the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.
As a further embodiment, the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
In a preferred embodiment, the antibiotic product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
Alternatively, in formulating an oral delivery system, each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product. Thus, for example, antibiotic products may include a first dosage form in the form of a tablet that is a delayed release tablet, and may also include two or more additional tablets, each of which provides for a delayed sustained release of the antibiotic, as hereinabove described, whereby the Cmax of the antibiotic released from each of the tablets is reached at different times, with the Cmax of the total antibiotic released from the antibiotic product being achieved in less than twelve hours after initial release of antibiotic.
The formulation of an antibiotic product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill of the art from the teachings herein. As known in the art, with respect to sustained release, the time of release can be controlled by the concentration of antibiotics in the coating and/or the thickness of the coating.
In accordance with the present invention, each of the dosage forms contains the same antibiotic; however, each of the dosage forms may contain more than one antibiotic.
Immediate Release Component
An immediate release component may be initially produced and then coated to produce the delayed release dosage forms used in the present invention.
An immediate release component is used in formulating the delayed release dosage form and can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
The materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such as low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
It may be useful to have these materials present in the range of 1.0 to 60% (W/W). More preferably these materials are present in the range of 3-40%. Most preferably these materials are present in the range of 5-20% so that the drug loading may be kept high and the overall dosage form size is minimized.
In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monostearate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, caprylocaproyl macrogol-8-glycerides, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above. The material may also be a disentegrant or superdisentegrant known to those in the art such as coscarmellose sodium, cross linked PVP, and others.
These materials may be present in the rate of 0.05-15% (W/W).
The Non-pH Sensitive Delayed Release Component
The components in this composition are the same as the immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule. Several methods to affect a delayed release with non pH dependent polymers are known to those skilled in the art. These include soluble or erodible barrier systems, enzymatically degraded barrier systems, rupturable coating systems, and plugged capsule systems among others. These systems have been thoroughly described in the literature (see “A Review of Pulsatile Drug Delivery” by Bussemer and Bodmeier in the Winter 2001 issue of American Pharmaceutical Review) and formulations and methods for their manufacture are hereby incorporated by reference.
Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit RS) cellulose acetate, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this component. Preferably the materials are present in an amount just enough to provide the desired in vivo lag time and Tmax.
The pH Sensitive (Enteric) Release Component
The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, Eudragit S, Eudragit FS, and other pthalate salts of cellulose derivatives.
These materials can be present in concentrations from 4-20% (W/W) or more. Preferably the materials are present in an amount just enough to provide the desired in vivo lag time and Tmax.
Sustained Release Component
The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to, ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit RS, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons.
These materials can be present in concentrations from 4-20% (W/W). Preferably the amounts are just enough to provide the desired in vivo release profile.
When it is desired to delay inititiation of release of the sustained release dosage form, an appropriate coating may be used to delay inititiation of the sustained release, such as a pH sensitive or a non-pH sensitive coating.
The Non-pH Sensitive Coating for Sustained Release Dosage Form
Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit RS), cellulose acetate, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this component. Preferably the materials are present in an amount just enough to provide the desired in vivo lag time and Tmax.
The pH Sensitive Coating for Sustained Release Dosage Form
The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, Eudragit S, Eudragit FS, and other pthalate salts of cellulose derivatives.
These materials can be present in concentrations from 4-20% (W/W) or more. Preferably the materials are present in an amount just enough to provide the desired in vivo lag time and Tmax.
As hereinabove indicated, the units comprising the antibiotic composition of the present invention can be in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.
The antibiotic composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally. The composition includes a therapeutically effective amount of the antibiotic, which amount will vary with the antibiotic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day. The composition is administered to a host in an amount effective for treating a bacterial infection.
This system will be especially useful in extending the practial therapeutic activity for antibiotics with elimination half lives of less than 20 hours and more particularly with elimination half-lives of less than 12 hours, and will be particularly useful for those drugs with half-lives of 2-10 hours. The following are examples of some antibiotics with half-lives of about 1 to 12 hours: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef, imipenem, erytliromycin (and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliin salts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfinethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co-triamoxazole, pentamidine, and trimetrexate.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight.
I. Immediate Release Component
Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press, or filled into a capsule or sachet with a suitable filler.
II. Non-pH Sensitive Delayed Release Component
Any of the methods described in “A Review of Pulsatile Drug Delivery” by Bussemer and Bodmeier in the Winter 2001 issue of American Pharmaceutical Review may be utilized to make the pH independent delayed release component described. Examples 16 and 17 utilize an organic acid layer underneath a layer of Eudragit RS to result in a rapid increase in the permeability of the Eudragit film after a set amount of time depending on the permeability and thickness of the film thus allowing the inner core to release through the Eudragit membrane. Example 18 utilizes a core with a highly swellable polymer that ruptures the insoluble coating membrane after a certain amount of time determined by the permeability, plasticity and thickness of the external cellulose acetate membrane. The coatings are applied to the core via methods such as wurster column coating in a fluid bed processor as known to those skilled in the art.
Additionally, this component may be formed as in example 19. In this example the component is prepared by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven.
After the component is allowed to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press, or filled into a capsule with a suitable encapsulator.
III. Enteric Delayed Release Component
Examples 20-27 utilize film coating techniques commonly known to those skilled in the art to create the enteric release component by layering of such enteric polymers onto an active core. In general the steps involve first making a coating dispersion or solution in organic or aqueous solvent. Second, the coating is applied at the proper conditions to produce an acceptably uniform film. This is done in a suitable coating apparatus such as a pan coater or a fluid bed wurster column coater. Optionally the product may be further cured if necessary.
To create a matrix type enteric component, formulate the ingredients of examples 28-32 by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool.
The product produced by either manner may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press, or filled into capsules using a suitable capsule filler such as a MG2 Futura.
IV. Sustained Release Component
Examples 33-38 utilize film coating techniques commonly known to those skilled in the art to create the sustained release component by layering of such sustained release polymers onto an active core. In general the steps involve first making a coating dispersion or solution in organic or aqueous solvent. Second, the coating is applied at the proper conditions to produce an acceptably uniform film. This is done in a suitable coating apparatus such as a pan coater or a fluid bed wurster column coater. Optionally the product may be further cured if necessary. Curing studies are recommended with sustained release membranes.
To create a matrix type sustained release component, formulate the ingredients of example 39-42 by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool.
The product produced by either manner may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press, or filled into capsules using a suitable capsule filler such as a MG2 Futura.
V. Sustained Release Dosage Form With Coating to Delay Initiation of Sustained Release:
Delaying the initiation of the sustained release of antibiotic in the present invention is achieved by either coating the immediate release component bead with a sustained release coating and then subsequently applying an enteric coating or non-pH sensitive delayed release coating to that coated bead, or alternatively the sustained release matrix component bead may be coated with an enteric coating or non-pH sensitive delayed release coating.
Coatings can be applied to either the sustained release coated beads or the sustained release matrix beads to form a product which pulses the therapeutical agent in a desired environment or location of the GI tract.
V A. The following examples describe the detailed preparation of the sustained-release coating materials to be applied to the immediate release beads from section I of the examples, resulting in a sustained release component of the invention.
Step 1. Mix surelease and water for 30 minutes before spraying.
Directions for application of the sustained release coating to the beads:
Charge a wurster column equipped fluid bed with the beads to be coated. Spray the coating onto the beads at a rate and temperature known to those skilled in the art of bead coating so as to efficiently coat the beads to give a weight gain of between 4 and 20%. Dry the beads to the specified level of coating solvent for optimum handling and stability. Cure the beads for additional congealing of the sustained release film if required.
V B. The following are examples of the pH sensitive, or enteric release, coating that can be used to optionally delay the onset of action of any or all of the second, third, or additional dosage forms.
The composition of the aqueous Eudragit L30D-55 dispersion to be applied to the immediate release components that have been treated with the above-described sustained release coatings, or to the sustained-matrix pellets is provided below in Example 45.
Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit® S 100 dispersion applied to the matrix pellets is provided below:
Eudragit® S 100 Aqueous Coating Dispersion
Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
Part I:
Part II:
Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
V. C. The following examples describe the detailed preparation of the non pH sensitive coating materials to be used to optionally delay the onset of action of any or all of the second, third, or additional dosage forms.
Directions for application of the sustained release coating to the beads:
Charge a wurster column equipped fluid bed with the beads to be coated. The beads must contain a component which will swell rapidly upon exposure to moisture. Beads containing croscarmellose sodium in Section I are good candidates as are beads with swellable hydrophilic polymers from Section IV. Spray the coating onto the beads at a rate and temperature known to those skilled in the art of bead coating so as to efficiently coat the beads to give a weight gain of between 4 and 20%. Dry the beads to the specified level of coating solvent for optimum handling and stability.
Coating Conditions for the Application of the Rupturable Film Coating.
The following coating parameters were used to coat matrix mini tablets from example 39 with the rupturable film coating. A 2.5% weight gain provided the desired lag time.
The enteric coatings and non-pH sensitive coatings as described above can be applied to either a sustained release matrix bead as in examples 33-42, or to the immediate release component beads that have been previously treated with a sustained release coating, to thereby provide a sustained release bead with a delayed onset of action. In addition, the enteric coating or non-pH sensitive coating can be applied to the immediate release component bead directly to provide delayed onset of action.
VI. Final Composition
After all of the individual components are manufactured the final dosage form is assembled and may take the shape of a tablet, capsule or sachet. Preferably the final dosage form takes the shape of a capsule or tablet. Most preferably the final dosage form is a tablet.
The various dosage forms will be combined in the final dosage form in a ratio such that the Cmax is achieved in less than twelve hours after initiation of release of antibiotic and the product provides once a day coverage of anti-infective agent. Preferably the first, second, and third dosage forms provides 20-70%, 10-70%, and 10-70% of the total dosage form, respectively. More preferably the ratio of first, second and third dosage forms are in the range of 25-66%, 15-60%, and 15-60% of the total dosage form respectively. Most preferably the ratio of the first, second and third dosage forms are in the range of 33-60%, 25-50%, and 25-50%, respectively.
The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration of the antibiotic.
Numerous modifications and variations of the present invention are possible in light of the above teachings, and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described.
This application claims the priority of U.S. Provisional Application Ser. No. 60/494,454 filed on Aug. 12, 2003, the disclosures of which are hereby incorporated by reference in their entireties.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3108046 | Harbit | Oct 1963 | A |
| 3870790 | Lowey et al. | Mar 1975 | A |
| 4007174 | Laundon | Feb 1977 | A |
| 4008246 | Ochiai et al. | Feb 1977 | A |
| 4018918 | Ayer et al. | Apr 1977 | A |
| 4048306 | Maier et al. | Sep 1977 | A |
| 4131672 | Huffman | Dec 1978 | A |
| 4175125 | Huffman | Nov 1979 | A |
| 4226849 | Schor | Oct 1980 | A |
| 4236211 | Arvesen | Nov 1980 | A |
| 4250166 | Maekawa et al. | Feb 1981 | A |
| 4331803 | Watanabe et al. | May 1982 | A |
| 4362731 | Hill | Dec 1982 | A |
| 4369172 | Schor et al. | Jan 1983 | A |
| 4399151 | Sjoerdsma et al. | Aug 1983 | A |
| 4430495 | Patt et al. | Feb 1984 | A |
| 4435173 | Siposs et al. | Mar 1984 | A |
| 4474768 | Bright | Oct 1984 | A |
| 4517359 | Kobrehel et al. | May 1985 | A |
| 4525352 | Cole et al. | Jun 1985 | A |
| 4529720 | Cole et al. | Jul 1985 | A |
| 4560552 | Cole et al. | Dec 1985 | A |
| 4568741 | Livingston | Feb 1986 | A |
| 4598045 | Masover et al. | Jul 1986 | A |
| 4616008 | Hirai et al. | Oct 1986 | A |
| 4634697 | Hamashima | Jan 1987 | A |
| 4644031 | Lehmann et al. | Feb 1987 | A |
| 4670549 | Morimoto et al. | Jun 1987 | A |
| 4672109 | Watanabe et al. | Jun 1987 | A |
| 4680386 | Morimoto et al. | Jul 1987 | A |
| 4710565 | Livingston et al. | Dec 1987 | A |
| 4723958 | Pope et al. | Feb 1988 | A |
| 4728512 | Mehta et al. | Mar 1988 | A |
| 4749568 | Reusser et al. | Jun 1988 | A |
| 4755385 | Etienne et al. | Jul 1988 | A |
| 4775751 | McShane | Oct 1988 | A |
| 4794001 | Mehta et al. | Dec 1988 | A |
| 4808411 | Lu et al. | Feb 1989 | A |
| 4812561 | Hamashima et al. | Mar 1989 | A |
| 4828836 | Elger et al. | May 1989 | A |
| 4831025 | Godtfredsen et al. | May 1989 | A |
| 4835140 | Smith et al. | May 1989 | A |
| 4842866 | Horder et al. | Jun 1989 | A |
| 4849515 | Matier et al. | Jul 1989 | A |
| 4879135 | Greco et al. | Nov 1989 | A |
| 4894119 | Baron, Jr. et al. | Jan 1990 | A |
| 4895934 | Matier et al. | Jan 1990 | A |
| 4904476 | Mehta et al. | Feb 1990 | A |
| 4915953 | Jordan et al. | Apr 1990 | A |
| 4945080 | Lindstrom et al. | Jul 1990 | A |
| 4945405 | Hirota | Jul 1990 | A |
| 4971805 | Kitanishi et al. | Nov 1990 | A |
| 4990602 | Morimoto et al. | Feb 1991 | A |
| 5011692 | Fujioka et al. | Apr 1991 | A |
| 5045533 | Philippe et al. | Sep 1991 | A |
| 5051262 | Panoz et al. | Sep 1991 | A |
| 5110597 | Wong et al. | May 1992 | A |
| 5110598 | Kwan et al. | May 1992 | A |
| 5143661 | Lawter et al. | Sep 1992 | A |
| 5158777 | Abramowitz et al. | Oct 1992 | A |
| 5178874 | Kwan et al. | Jan 1993 | A |
| 5182374 | Tobkes et al. | Jan 1993 | A |
| 5200193 | Radebaugh et al. | Apr 1993 | A |
| 5204055 | Sachs et al. | Apr 1993 | A |
| 5213808 | Bar-Shalom et al. | May 1993 | A |
| 5229131 | Amidon et al. | Jul 1993 | A |
| 5230703 | Alon | Jul 1993 | A |
| 5274085 | Amano et al. | Dec 1993 | A |
| 5288503 | Wood et al. | Feb 1994 | A |
| 5334590 | DiNinno et al. | Aug 1994 | A |
| 5340656 | Sachs et al. | Aug 1994 | A |
| 5358713 | Shimamura | Oct 1994 | A |
| 5387380 | Cima et al. | Feb 1995 | A |
| 5393765 | Infeld et al. | Feb 1995 | A |
| 5395626 | Kotwal et al. | Mar 1995 | A |
| 5395628 | Noda et al. | Mar 1995 | A |
| 5399723 | Iinuma et al. | Mar 1995 | A |
| 5401512 | Rhodes et al. | Mar 1995 | A |
| 5413777 | Sheth et al. | May 1995 | A |
| 5414014 | Schneider et al. | May 1995 | A |
| 5422343 | Yamamoto et al. | Jun 1995 | A |
| 5430021 | Rudnic et al. | Jul 1995 | A |
| 5445829 | Paradissis et al. | Aug 1995 | A |
| 5457187 | Gmeiner et al. | Oct 1995 | A |
| 5462747 | Radebaugh et al. | Oct 1995 | A |
| 5466446 | Stiefel et al. | Nov 1995 | A |
| 5472708 | Chen | Dec 1995 | A |
| 5476854 | Young | Dec 1995 | A |
| 5490962 | Cima et al. | Feb 1996 | A |
| 5508040 | Chen | Apr 1996 | A |
| 5518680 | Cima et al. | May 1996 | A |
| 5538954 | Koch et al. | Jul 1996 | A |
| 5543417 | Waldstreicher | Aug 1996 | A |
| 5556839 | Greene et al. | Sep 1996 | A |
| 5567441 | Chen | Oct 1996 | A |
| 5576022 | Yang et al. | Nov 1996 | A |
| 5578713 | McGill, III | Nov 1996 | A |
| 5599557 | Johnson et al. | Feb 1997 | A |
| 5607685 | Cimbollek et al. | Mar 1997 | A |
| 5633006 | Catania et al. | May 1997 | A |
| 5672359 | Digenis et al. | Sep 1997 | A |
| 5688516 | Raad et al. | Nov 1997 | A |
| 5702895 | Matsunaga et al. | Dec 1997 | A |
| 5705190 | Broad et al. | Jan 1998 | A |
| 5707646 | Yajima et al. | Jan 1998 | A |
| 5719132 | Lin et al. | Feb 1998 | A |
| 5719272 | Yang et al. | Feb 1998 | A |
| 5725553 | Moenning | Mar 1998 | A |
| 5733886 | Baroody et al. | Mar 1998 | A |
| 5756473 | Liu et al. | May 1998 | A |
| 5780446 | Ramu | Jul 1998 | A |
| 5789584 | Christensen et al. | Aug 1998 | A |
| 5808017 | Chang | Sep 1998 | A |
| 5817321 | Alakhov et al. | Oct 1998 | A |
| 5827531 | Morrison et al. | Oct 1998 | A |
| 5837284 | Mehta et al. | Nov 1998 | A |
| 5837829 | Ku | Nov 1998 | A |
| 5840329 | Bai | Nov 1998 | A |
| 5840760 | Carraher, Jr. et al. | Nov 1998 | A |
| 5844105 | Liu et al. | Dec 1998 | A |
| 5849776 | Czernielewski et al. | Dec 1998 | A |
| 5852180 | Patel | Dec 1998 | A |
| 5858986 | Liu et al. | Jan 1999 | A |
| 5864023 | Ku et al. | Jan 1999 | A |
| 5869170 | Cima et al. | Feb 1999 | A |
| 5872104 | Vermeulen et al. | Feb 1999 | A |
| 5872229 | Liu et al. | Feb 1999 | A |
| 5877243 | Sarangapani | Mar 1999 | A |
| 5883079 | Zopf et al. | Mar 1999 | A |
| 5892008 | Ku et al. | Apr 1999 | A |
| 5910322 | Rivett et al. | Jun 1999 | A |
| 5919219 | Knowlton | Jul 1999 | A |
| 5919489 | Saleki-Gerhardt et al. | Jul 1999 | A |
| 5919916 | Gracey et al. | Jul 1999 | A |
| 5929219 | Hill | Jul 1999 | A |
| 5932710 | Liu et al. | Aug 1999 | A |
| 5945124 | Sachs et al. | Aug 1999 | A |
| 5945405 | Spanton et al. | Aug 1999 | A |
| 5972373 | Yajima et al. | Oct 1999 | A |
| 5980942 | Katzhendler et al. | Nov 1999 | A |
| 5985643 | Tomasz et al. | Nov 1999 | A |
| 5998194 | Summers, Jr. et al. | Dec 1999 | A |
| 6008195 | Selsted | Dec 1999 | A |
| 6010718 | Al-Razzak et al. | Jan 2000 | A |
| 6013507 | Tomasz et al. | Jan 2000 | A |
| 6027748 | Conte et al. | Feb 2000 | A |
| 6031093 | Cole et al. | Feb 2000 | A |
| 6048977 | Cole et al. | Apr 2000 | A |
| 6051255 | Conley et al. | Apr 2000 | A |
| 6051703 | Cole et al. | Apr 2000 | A |
| 6057291 | Hancock et al. | May 2000 | A |
| 6059816 | Moenning | May 2000 | A |
| 6063613 | De Lencastre et al. | May 2000 | A |
| 6063917 | Ascher et al. | May 2000 | A |
| 6068859 | Curatolo et al. | May 2000 | A |
| 6110925 | Williams et al. | Aug 2000 | A |
| 6117843 | Baroody et al. | Sep 2000 | A |
| 6120803 | Wong et al. | Sep 2000 | A |
| 6127349 | Chasalow | Oct 2000 | A |
| 6132768 | Sachs et al. | Oct 2000 | A |
| 6132771 | Depui et al. | Oct 2000 | A |
| 6136587 | Tomasz et al. | Oct 2000 | A |
| 6156507 | Hiramatsu et al. | Dec 2000 | A |
| 6159491 | Durrani | Dec 2000 | A |
| 6162925 | Williams et al. | Dec 2000 | A |
| 6183778 | Conte et al. | Feb 2001 | B1 |
| 6187768 | Welle et al. | Feb 2001 | B1 |
| 6214359 | Bax | Apr 2001 | B1 |
| 6218380 | Cole et al. | Apr 2001 | B1 |
| 6228398 | Devane et al. | May 2001 | B1 |
| 6231875 | Sun et al. | May 2001 | B1 |
| 6248363 | Patel et al. | Jun 2001 | B1 |
| 6251647 | De Lencastre et al. | Jun 2001 | B1 |
| 6265394 | Sterzycki et al. | Jul 2001 | B1 |
| 6270805 | Chen et al. | Aug 2001 | B1 |
| 6280771 | Monkhouse et al. | Aug 2001 | B1 |
| 6294199 | Conley et al. | Sep 2001 | B1 |
| 6294526 | Higuchi et al. | Sep 2001 | B1 |
| 6296873 | Katzhendler et al. | Oct 2001 | B1 |
| 6297215 | Hancock et al. | Oct 2001 | B1 |
| 6299903 | Rivett et al. | Oct 2001 | B1 |
| 6306436 | Chungi et al. | Oct 2001 | B1 |
| 6309663 | Patel et al. | Oct 2001 | B1 |
| 6322819 | Burnside et al. | Nov 2001 | B1 |
| 6333050 | Wong et al. | Dec 2001 | B2 |
| 6340475 | Shell et al. | Jan 2002 | B2 |
| 6352720 | Martin et al. | Mar 2002 | B1 |
| 6358525 | Guo et al. | Mar 2002 | B1 |
| 6358528 | Grimmett et al. | Mar 2002 | B1 |
| 6383471 | Chen et al. | May 2002 | B1 |
| 6384081 | Berman | May 2002 | B2 |
| 6391614 | Tomasz et al. | May 2002 | B1 |
| 6399086 | Katzhendler et al. | Jun 2002 | B1 |
| 6403569 | Achterrath | Jun 2002 | B1 |
| 6406717 | Cherukuri | Jun 2002 | B2 |
| 6406880 | Thomton | Jun 2002 | B1 |
| 6440462 | Raneburger et al. | Aug 2002 | B1 |
| 6444796 | Suh et al. | Sep 2002 | B1 |
| 6468964 | Rowe | Oct 2002 | B1 |
| 6479496 | Wolff | Nov 2002 | B1 |
| 6495157 | Pena et al. | Dec 2002 | B1 |
| 6497901 | Royer | Dec 2002 | B1 |
| 6503709 | Bekkaoui et al. | Jan 2003 | B1 |
| 6506886 | Lee et al. | Jan 2003 | B1 |
| 6514518 | Monkhouse et al. | Feb 2003 | B2 |
| 6515010 | Franchini et al. | Feb 2003 | B1 |
| 6515116 | Suh et al. | Feb 2003 | B2 |
| 6530958 | Cima et al. | Mar 2003 | B1 |
| 6541014 | Rudnic et al. | Apr 2003 | B2 |
| 6544555 | Rudnic et al. | Apr 2003 | B2 |
| 6548084 | Leonard et al. | Apr 2003 | B2 |
| 6550955 | D'Silva | Apr 2003 | B2 |
| 6551584 | Bandyopadhyay et al. | Apr 2003 | B2 |
| 6551616 | Notario et al. | Apr 2003 | B1 |
| 6558699 | Venkatesh | May 2003 | B2 |
| 6565873 | Shefer et al. | May 2003 | B1 |
| 6565882 | Rudnic | May 2003 | B2 |
| 6569463 | Patel et al. | May 2003 | B2 |
| 6585997 | Moro et al. | Jul 2003 | B2 |
| 6599884 | Avrutov et al. | Jul 2003 | B2 |
| 6605069 | Albers et al. | Aug 2003 | B1 |
| 6605300 | Burnside et al. | Aug 2003 | B1 |
| 6605609 | Barbachyn et al. | Aug 2003 | B2 |
| 6605751 | Gibbins et al. | Aug 2003 | B1 |
| 6610323 | Lundberg et al. | Aug 2003 | B1 |
| 6610328 | Rudnic et al. | Aug 2003 | B2 |
| 6617436 | Avrutov et al. | Sep 2003 | B2 |
| 6623757 | Rudnic et al. | Sep 2003 | B2 |
| 6623758 | Rudnic et al. | Sep 2003 | B2 |
| 6624292 | Lifshitz et al. | Sep 2003 | B2 |
| 6627222 | Rudnic et al. | Sep 2003 | B2 |
| 6627743 | Liu et al. | Sep 2003 | B1 |
| 6630498 | Gudipati et al. | Oct 2003 | B2 |
| 6632453 | Wassink et al. | Oct 2003 | B2 |
| 6635280 | Shell et al. | Oct 2003 | B2 |
| 6638532 | Rudnic et al. | Oct 2003 | B2 |
| 6642276 | Wadhwa | Nov 2003 | B2 |
| 6663890 | Rudnic et al. | Dec 2003 | B2 |
| 6663891 | Rudnic et al. | Dec 2003 | B2 |
| 6667042 | Rudnic et al. | Dec 2003 | B2 |
| 6667057 | Rudnic et al. | Dec 2003 | B2 |
| 6669948 | Rudnic et al. | Dec 2003 | B2 |
| 6669955 | Chungi et al. | Dec 2003 | B2 |
| 6673369 | Rampal et al. | Jan 2004 | B2 |
| 6682759 | Lim et al. | Jan 2004 | B2 |
| 6696426 | Singh et al. | Feb 2004 | B2 |
| 6702803 | Kupperblatt et al. | Mar 2004 | B2 |
| 6706273 | Roessler | Mar 2004 | B1 |
| 6723340 | Gusler et al. | Apr 2004 | B2 |
| 6723341 | Rudnic et al. | Apr 2004 | B2 |
| 6730320 | Rudnic et al. | May 2004 | B2 |
| 6730325 | Devane et al. | May 2004 | B2 |
| 6735470 | Henley et al. | May 2004 | B2 |
| 6740664 | Cagle et al. | May 2004 | B2 |
| 6746692 | Conley et al. | Jun 2004 | B2 |
| 6756057 | Storm et al. | Jun 2004 | B2 |
| 6767899 | Kay et al. | Jul 2004 | B1 |
| 6777420 | Zhi et al. | Aug 2004 | B2 |
| 6783773 | Storm et al. | Aug 2004 | B1 |
| 6818407 | Hancock et al. | Nov 2004 | B2 |
| 6824792 | Foreman et al. | Nov 2004 | B2 |
| 6872407 | Notario et al. | Mar 2005 | B2 |
| 6878387 | Petereit et al. | Apr 2005 | B1 |
| 6906035 | Hancock et al. | Jun 2005 | B2 |
| 6929804 | Rudnic et al. | Aug 2005 | B2 |
| 6946458 | Turos | Sep 2005 | B2 |
| 6984401 | Rudnic et al. | Jan 2006 | B2 |
| 6991807 | Rudnic et al. | Jan 2006 | B2 |
| 7008633 | Yang et al. | Mar 2006 | B2 |
| 7025989 | Rudnic et al. | Apr 2006 | B2 |
| 20010046984 | Rudnic | Nov 2001 | A1 |
| 20010048944 | Rudnic et al. | Dec 2001 | A1 |
| 20020004070 | Rudnic et al. | Jan 2002 | A1 |
| 20020004499 | Rudnic et al. | Jan 2002 | A1 |
| 20020015728 | Payumo et al. | Feb 2002 | A1 |
| 20020028920 | Lifshitz et al. | Mar 2002 | A1 |
| 20020042394 | Hogenkamp et al. | Apr 2002 | A1 |
| 20020068078 | Rudnic et al. | Jun 2002 | A1 |
| 20020068085 | Rudnic et al. | Jun 2002 | A1 |
| 20020081332 | Rampal et al. | Jun 2002 | A1 |
| 20020103261 | Ninkov | Aug 2002 | A1 |
| 20020106412 | Rowe et al. | Aug 2002 | A1 |
| 20020115624 | Behar et al. | Aug 2002 | A1 |
| 20020119168 | Rudnic et al. | Aug 2002 | A1 |
| 20020136764 | Rudnic et al. | Sep 2002 | A1 |
| 20020136765 | Rudnic et al. | Sep 2002 | A1 |
| 20020136766 | Rudnic et al. | Sep 2002 | A1 |
| 20020150619 | Rudnic et al. | Oct 2002 | A1 |
| 20020197314 | Rudnic et al. | Dec 2002 | A1 |
| 20030012814 | Rudnic et al. | Jan 2003 | A1 |
| 20030018295 | Henley et al. | Jan 2003 | A1 |
| 20030049311 | McAllister et al. | Mar 2003 | A1 |
| 20030064100 | Rudnic et al. | Apr 2003 | A1 |
| 20030073647 | Chao et al. | Apr 2003 | A1 |
| 20030073648 | Chao et al. | Apr 2003 | A1 |
| 20030073826 | Chao et al. | Apr 2003 | A1 |
| 20030077323 | Rudnic et al. | Apr 2003 | A1 |
| 20030086969 | Rudnic et al. | May 2003 | A1 |
| 20030091627 | Sharma | May 2003 | A1 |
| 20030096006 | Rudnic et al. | May 2003 | A1 |
| 20030096007 | Rudnic et al. | May 2003 | A1 |
| 20030096008 | Rudnic et al. | May 2003 | A1 |
| 20030099706 | Rudnic et al. | May 2003 | A1 |
| 20030099707 | Rudnic et al. | May 2003 | A1 |
| 20030104054 | Rudnic et al. | Jun 2003 | A1 |
| 20030104055 | Rudnic et al. | Jun 2003 | A1 |
| 20030104058 | Rudnic et al. | Jun 2003 | A1 |
| 20030124196 | Weinbach et al. | Jul 2003 | A1 |
| 20030129236 | Heimlich et al. | Jul 2003 | A1 |
| 20030143268 | Pryce Lewis et al. | Jul 2003 | A1 |
| 20030147953 | Rudnic et al. | Aug 2003 | A1 |
| 20030190360 | Baichwal et al. | Oct 2003 | A1 |
| 20030198677 | Pryce Lewis et al. | Oct 2003 | A1 |
| 20030199808 | Henley et al. | Oct 2003 | A1 |
| 20030203023 | Rudnic et al. | Oct 2003 | A1 |
| 20030206951 | Rudnic et al. | Nov 2003 | A1 |
| 20030216555 | Lifshitz et al. | Nov 2003 | A1 |
| 20030216556 | Avrutov et al. | Nov 2003 | A1 |
| 20030232082 | Li et al. | Dec 2003 | A1 |
| 20030232089 | Singh et al. | Dec 2003 | A1 |
| 20030235615 | Rudnic | Dec 2003 | A1 |
| 20040018234 | Rudnic et al. | Jan 2004 | A1 |
| 20040033262 | Kshirsagar et al. | Feb 2004 | A1 |
| 20040043073 | Chen et al. | Mar 2004 | A1 |
| 20040047906 | Percel et al. | Mar 2004 | A1 |
| 20040048814 | Vanderbist et al. | Mar 2004 | A1 |
| 20040052842 | Rudnic et al. | Mar 2004 | A1 |
| 20040058879 | Avrutov et al. | Mar 2004 | A1 |
| 20040091528 | Rogers et al. | May 2004 | A1 |
| 20040126427 | Venkatesh et al. | Jul 2004 | A1 |
| 20040176737 | Henley et al. | Sep 2004 | A1 |
| 20040219223 | Kunz | Nov 2004 | A1 |
| 20040253249 | Rudnic et al. | Dec 2004 | A1 |
| 20040265379 | Conley et al. | Dec 2004 | A1 |
| 20050053658 | Venkatesh et al. | Mar 2005 | A1 |
| 20050064033 | Notario et al. | Mar 2005 | A1 |
| 20050064034 | Li et al. | Mar 2005 | A1 |
| 20050163857 | Rampal et al. | Jul 2005 | A1 |
| 20050203076 | Li et al. | Sep 2005 | A1 |
| 20050203085 | Li et al. | Sep 2005 | A1 |
| 20050209210 | Ding et al. | Sep 2005 | A1 |
| 20050238714 | Rudnic et al. | Oct 2005 | A1 |
| 20050256096 | Combrink et al. | Nov 2005 | A1 |
| 20050261262 | Ma et al. | Nov 2005 | A1 |
| 20050277633 | Ma et al. | Dec 2005 | A1 |
| 20060019985 | Ma et al. | Jan 2006 | A1 |
| 20060019986 | Ding et al. | Jan 2006 | A1 |
| 20060111302 | Romesberg et al. | May 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| 0052075 | Nov 1981 | EP |
| 0293885 | Dec 1988 | EP |
| 0436370 | Jul 1991 | EP |
| 0652008 | May 1995 | EP |
| 2585948 | Feb 1982 | FR |
| 2087235 | May 1982 | GB |
| WO 9008537 | Aug 1990 | WO |
| WO 9427557 | Dec 1994 | WO |
| WO 9520946 | Aug 1995 | WO |
| WO 9530422 | Nov 1995 | WO |
| WO 9604908 | Feb 1996 | WO |
| WO 9722335 | Jun 1997 | WO |
| WO 9743277 | Nov 1997 | WO |
| WO 9822091 | May 1998 | WO |
| WO 9846239 | Oct 1998 | WO |
| WO 9903453 | Jan 1999 | WO |
| WO 9940097 | Aug 1999 | WO |
| WO 0048607 | Aug 2000 | WO |
| WO 0061116 | Oct 2000 | WO |
| WO 0126663 | Apr 2001 | WO |
| WO0162229 | Aug 2001 | WO |
| WO 0238577 | May 2002 | WO |
| WO 03029439 | Apr 2003 | WO |
| WO 2005056754 | Jun 2005 | WO |
| WO 2005070941 | Aug 2005 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050037076 A1 | Feb 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60494454 | Aug 2003 | US |
