WO2013173808A2

WO2013173808A2 - Methods for use of lower dose compositions of amoxicillin and clavulanate potassium and devices for use

Info

Publication number: WO2013173808A2
Application number: PCT/US2013/041725
Authority: WO
Inventors: Michael Spector
Original assignee: Michael Spector
Priority date: 2012-05-17
Filing date: 2013-05-17
Publication date: 2013-11-21
Also published as: WO2013173808A3

Abstract

The invention is directed to a method of treating bacterial infections by providing two or more dosages of a composition, over a period of about three to about fourteen consecutive days, containing amoxicillin and clavulanate potassium where the clavulanate potassium is present in an amount of about 0.1 mg/5 ML to about 32.5 mg/5 mL. The ratio of amoxicillin to clavulanate potassium is between about 28:1 to about 56:1. Further, the invention includes a dispensing system which dispenses two or more doses of a pharmaceutically active composition that is a mixture of at least two pharmaceutically active compounds. A device including one or more chambers containing two or more pharmaceutically active compounds is set for either constant doses or varying doses.

Description

METHODS FOR USE OF LOWER DOSE COMPOSITIONS OF AMOXICILLIN AND CLAVULANATE POTASSIUM AND DEVICES FOR USE

RELATED APPLICATIONS

[0001 ] This application claims priority from provisional application Serial No. 61/648,585 filed May 17, 2012.

FIELD OF THE INVENTION

[0002] The invention is for methods for use of lower dose compositions of amoxicillin and clavulanate potassium and dispensing system for use with various compositions.

BACKGROUND OF THE INVENTION

[0003] It is well known that patients have difficulty remembering how and when to take their medications or comply with various treatment regimens, especially given busy life styles and if an individual is taking multiple medications and under going concurrent treatments. Further, complex treatment regimens, age, physical or mental impairments, discipline problems and lack of pain all directly affect compliance, or lack thereof with prescribed therapies. Moreover, in hospitals, long-term care facilities and nursing homes, additional compliance problems are caused by dosage errors, accurate and timely distribution of medications, adherence to the particular regimen instructions, and more often with the aging population, busy care givers due to a shortage of nurses, doctors and other caregivers.

[0004] Additionally, it is commonly known and appreciated that many prescription drugs or health aids have specific ingestion requirements to ensure their effectiveness or minimize unnecessary side effects. These additional requirements have a further negative affect on compliance with the prescribed regiment. For instance, a treatment in which a medication must be taken over a period of time in varying dosages and/or frequency may not be followed properly given the multiple instructions. If a varying dose is prescribed of one medication, the patient must manually measure out the varying portions himself/herself. Even further confusing is if the treatment regimen includes multiple medications with doses that vary throughout the treatment.

[0005] Consequently, the need exists for a device which accommodates different dispensing needs, to assist in the administration of a given treatment regimen. Currently, containers do not have the capability to vary dosages of multiple medications at the same time. Thus, such containers do not include a reliable mechanism for monitoring compliance by the patient with a treatment regimen. Therefore, a device is needed which allows patients or care givers to access medications or other prescribed treatments in varying doses over the treatment regimen which includes one or more medications, vitamins or the like. Thus, the patient can successfully follow the treatment regimen.

[0006] Delivery systems for intake of prescription medicines and over the counter medicines are limited to generally liquids, suspensions, tablets, caplets, powders, inhalers and injections. As discussed, typically these medicines are in consistent and set doses for the time frame the individual is taking the medicine.

[0007] However, dosages may have certain side effects and there may be issues with consistency in the medicine delivery system. Thus, varying dosages or varying formulations must be metered out in separate and multiple dispensing systems.

[0008] Looking at specific medicines, amoxicillin is well known as a treatment for various bacterial infections and its use as an antibiotic, alone or in combination with other compositions and medications has been documented. For instance, amoxicillin is used to treat skin infections, dental infections, ear infections, respiratory tract infections, urinary tract infections, and gonorrhea. However, treatment of certain bacterial infections has been made more difficult by resistance. In particular, many gram negative bacteria produce an enzyme, β - lactamase, that attacks the β -lactam ring of β -lactam antibiotics and renders them ineffective. To counteract this effect, β-lactamase inhibitors have been developed that can bind to β-lactamase and prevent it from attacking the antibiotic. The antibiotic and the inhibitor are preferably administered together. For example the β-lactam antibiotic amoxicillin can be administered with the β- lactamase inhibitor ciavuianate potassium. This additional ciavuianate potassium is not needed in non-beta lactamase mediated resistance treatments.

[0009] To deal with resistant bacteria, the amount of amoxicillin has increased in dosage as certain bacteria have become resistant to the amoxicillin. For instance, Streptococcus pneumoniae have become resistant to amoxicillin such that the prescribed treatment dosage has increased from 400 mg/5 mL per day to over 600 mg/5 mL per day over the last decade. The amount of the ciavuianate potassium has similarly increased or remained constant, in ratio with the increase in amoxicillin. Further the actual combined taken dosage for the patient, of the combined amoxicillin and ciavuianate potassium has in fact doubled over the last few years.

[0010] A combination of amoxicillin and ciavuianate potassium is a treatment of choice for otitis media (middle ear infection), pharyngitis (sore throat), sinusitis (sinus infection), tonsillitis ^onsillopharyngitis, infections of the genital organs (vagina, uterus, fallopian tubes/ovaries) and the urinary tract (kidneys, ureters, bladder and urethra), cellulitis (infection of the dermis and subcutaneous tissue), erysipelas (superficial form of cellulitis), folliculitis

(inflammation of the hair follicles), furuncles, carbuncles, abscesses, impetigo (large vesicles or honey-crusted sores), infected ulcers and infected burns, tracheobronchitis, bronchitis, pneumoniae, gonorrhea, acute uncomplicated sexually transmitted diseases. The combination of amoxicillin and ciavuianate potassium is considered the gold standard for antibiotic treatment, against which most new products on the market are compared. Resistant bacteria is on the rise in the population, it is believed, due to resistant organisms.

[001 1] Concerns about the development of antimicrobial resistance have led to recommendations to withhold antibiotics from patients unless symptoms persist or worsen, which is sometimes referred to as a "watchful waiting strategy", which can prolong the symptoms for the patient.

[0012] Notably, due to vaccination there has been a selective reduction of treatable S. pneumoniae compared to resistant Haemophilus influenzae as causative agents. The resistance building up to amoxicillin has led to the increase of the dosage and/or dosage unit of amoxicillin in certain antibiotic compositions. Correspondingly, the other active pharmaceutical ingredients in such antibiotic compositions has also increased, typically based on ratios.

[0013] Certain current formulations of amoxicillin and clavulanate potassium have a high concentration of clavulanate potassium. However clavulanate potassium has the potential to cause rare serious side effects such as jaundice and hepatitis (see, for example, Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004). Other minor systemic reactions include headache, rash, mycosis, vaginitis, and agitation. The following infrequent and rare adverse reactions have been reported for ampicillin-class antibiotics: hepatitis; cholestatic jaundice; hemorrhagic/pseudomembranous colitis; angioedema; Stevens-Johnson syndrome; hypersensitivity vasculitis: tooth discoloration; and seizure. The most common side effect diarrhea.

Nausea, vomiting, and upset stomach are also common. In rare cases it can cause immediate and delayed allergic reactions - specifically, skin rashes, fever, and anaphylactic shock.

[0014] More frequently, patients taking clavulanate potassium may experience diarrhea (Reed, M. D. (1998) Clinical pharmacokinetics of amoxicillin and clavulanate potassium. Pediatric Infectious Disease Journal 17, 957-62), which can lead to dehydration and further sickness. Although advantageous from the standpoint of efficacy, use of amoxicillin and clavulanate potassium is also associated with a relatively high incidence of diarrhea. This diarrhea is infrequently severe enough to require discontinuing treatment, but it may occasion delays in a patient's returning to work if an adult or day care and school if a child. While not being bound by theory, it is possible that the occurrence of diarrhea is related to the clavulanate potassium component of the drug

combination. Formulations of amoxicillin-clavulanate potassium have used varying ratios of the two components; over time, the trend has been to increase the dosage of amoxicillin, mainly to achieve higher efficacy rates against S.

pneumoniae. [0015] Amoxicillin-ciavulanate potassium ratios have thus ranged from 4: 1 to 14:1. The currently available amoxicillin-ciavulanate potassium suspension for pediatric use contains 600 mg of amoxicillin and 42.9 mg of clavulanate potassium per 5 mL (a ratio of 14:1). The currently recommended adult dosage is 500 mg/250 mg through about 4,000 mg/250 mg per day with a common dose being about 1700 mg/250 mg per day, administered in two divided doses for 10 days. The currently recommended pediatric dosage, 90/6.4 mg/kg/day administered in two divided doses for 10 days, results in a dose of clavulanate potassium almost twice as high as the dose recommended for adults (6.4 mg/kg/day vs. 3.5 mg/kg/day).

[0016] Clavulanate potassium may also cause vomiting, diarrhea, diaper rash in children, and oral moniliasis, which while not as serious as the other side effects, are debilitating to the patient and his/her caregivers. Adult or geriatric patients may be affected by vomiting and diarrhea resulting in lost work days. The pediatric patient with diarrhea and/or vomiting cannot return to school or day care until typically twenty-four (24) hours after the last episode of diarrhea or vomiting. Such constraints affect the parents and care giver of the pediatric patient in that they typically must use vacation days to stay home with the vomiting child, or work from home with a reduced productive outcome. Given the data that approximately twenty percent (20%) of all pediatric patients taking the current dosage of amoxicillin and clavulanate potassium experience some diarrhea and/or vomiting, this translates to twenty percent (20%) of children not able to return to school or day care and consequently twenty percent (20%) of parents or care givers staying home with the affected pediatric patient.

[0017] Indeed, the guidelines for treatment of acute otitis media by the

American Academy of Pediatrics recently discussed the side effects of

clavulanate potassium as including diarrhea, diaper dermitis, rashes and allergic reactions. In "The Diagnosis and Management of Acute Otitis Media" by Allan S. Lieberthal, et al. (published online February 25, 2013 in Pediatrics, the official journal of the American Academy of Pediatrics), the recommendations to primary care clinicians for the management of children from 6 months through 12 years of age with uncomplicated acute otitis media (AOM) remains amoxicillin alone, though the article states "Amoxicillin-clavulanate has a broader spectrum than amoxicillin and may be a better initial antibiotic. However, because of cost and adverse effects, the subcommittee has chosen amoxicillin as first-line AOM treatment." Thus, the side effects of the clavulanate potassium seem to affect the treatment recommendations. It is thus discovered and sought in the present invention to minimize the amount of clavulanate potassium necessary for treatment of antibiotics to be very useful.

[0018] While not wishing to be bound by theory, it is possible that clavulanate potassium has the property of binding irreversibly to β-lactamase. (Reed, M. D. (1998). Clinical pharmacokinetics of amoxicillin and clavulanate potassium. Pediatric Infectious Disease Journal 17, 957-62), thus enhancing the effectiveness of amoxicillin. If so, then this might explain the rapidly declining need for clavulanate potassium in the course of a combined treatment with amoxicillin and clavulanate potassium. After an initial loading dose of clavulanate potassium is provided, it is contemplated in the invention that either the same amount or much less may be needed. Continuing to administer the same composition of amoxicillin and clavulanate potassium over the treatment regimen period, as the currently prescribed method, may result in too much clavulanate potassium being taken in subsequent doses.

[0019] Clearly for the working population it is particularly important to use the minimal, yet effective, amount of clavulanate potassium so as to reduce the risk of diarrhea and vomiting. We have discovered that overall less clavulanate potassium is required for the entire treatment regimen, which can either be (a) a lower dose through the regimen, (b) high dose of clavulanate potassium at the beginning of treatment to bind to β-lactamase and then less throughout the regimen, or (c) a combination thereof and varying dosages throughout the treatment regimen. Thus, either the same smaller amount, or less, clavulanate potassium may be required as treatment progresses. However in current treatments amoxicillin and clavulanate potassium are administered in a set combined dosage form administered at the same level at a ratio of about 4:1- 14:1 over a period of days (typically ten (10) days). Although various amoxicillin and clavulanate potassium regimens are available, the need for minimizing clavulanate potassium has not been adequately addressed. Until recently, the thrust behind reformulations of amoxicillin-clavulanate potassium has been adequate coverage of S. pneumoniae. Currently, focus has shifted to adequate coverage of H. influenzae. However, minimizing adverse events and side effects has not been given precedence over the efficacy of the dosage formulation to address S. pneumoniae, H. influenzae and other bacteria.

[0020] For instance, in a study published in the New England Journal of Medicine in January 201 1 , the table below (Table 1) shows the higher rates of diarrhea, vomiting and diaper dermatitis in children taking amoxicillin-clavulanate potassium versus those taking a placebo.

Ml) Ml)

)5 )^1

Ml)

J

I

[0021] Thus, a need exists for a dispensing device including an

amoxicillin-clavulanate potassium composition, and treatment method, which reduces the side effects of diarrhea and vomiting while still maintaining the high efficacy of the antibiotic combination. One of the objectives of the invention is to maintain high efficacy while improving safety profile, namely reducing the common and disruptive side effects of diarrhea and vomiting in working, pediatric and geriatric patients.

[0022] Various formulations and dosing modalities currently exist for the combination of amoxicillin-clavulanate potassium. Tablets and suspensions are also available. Delayed release tablet formulations have been developed (see for example U.S. Pat. Nos. 5,910,322; 6,299,903; 6,544,558; 6,756,057;

6,783,773; 6,977,086;7, 122,204; 7,534,781 , and publications 2006/0121 106, 2008/0300569, and 201 1/0020408). However, these systems provide

combination doses of amoxicillin- clavulanate potassium that do not address the need for a reduced set amount of clavulanate potassium (whether constant throughout the treatment or in a reduced set amount when compared to current conventional and known amounts) throughout the treatment regimen, including reducing the amount as treatment progresses. There is a need for a dosage, and a method that provides a means of reducing the overall amount of

clavulanate potassium for the treatment regimen, when compared to current conventional and known dosage amounts.

[0023] Thus, a need exists for a dispensing system including a

composition having amoxicillin and clavulanate potassium without elevating the possibility of the severe side affects of jaundice and hepatitis and the more common and disruptive side effects of diarrhea and vomiting.

[0024] Various formulations and dosing modalities exist for

amoxicillin/clavulanate. Tablets and suspensions are also available. Delayed release tablet formulations have been developed (see for example U.S. Pat. Nos. 5,910,322, 6,299,903, 6,544,558, 6,756,057,6,783,773, 6,977,086,7, 122,204, 7,534,781 , and publications 2006,0121 106, 2008/0300569, and 201 /0020408).

[0025] However, these systems provide combination doses of amoxicillin and clavulanate that do not address the reduced need for clavulanate as treatment progresses. There is a need for a dosage dispensing systems that provides a means of reducing the amount of clavulanate over the course of treatment. [0026] If the individual doses themselves could be administered to provide an initial high dose of clavulanate followed by a subsequent reduced dose, this could be accomplished. However this would require for each dose different amounts of clavulanate combined with the amoxicillin. Compliance with such a regimen would be awkward and prone to error in execution. End users could not be expected to consistently measure mix their own combined doses. Providing each unit dose in a separate container would not only waste materials and space, but could cause confusion in dose sequence.

[0027] A dosage dispensing system designed to provide premixed, discrete doses of amoxicillin/clavulanate packaged sequentially such that the first unit dose has a higher ratio of amoxicillin to clavulanate than the subsequent doses would solve the problem.

[0028] In such a system it is important to avoid any confusion as to the order in which doses should be taken no matter what form the dosages take (suspension, tablet, aerosol, and so on). This is important to ensure that antibiotic dosing is complied with to complete treatment and reduce resistance. It is also important to minimize the possibility of side effects and fulfill the aim of the system.

[0029] Accordingly, a dispensing system which dispenses separate, discrete, and premeasured doses of a combination of medicines, for example of amoxicillin and clavulanate, where the amount of clavulanate decreases with each dose subsequent to the first, would have the advantages of reduced side effects and easy use and compliance with the dosage regimen.

[0030] Such a system could not only be used for amoxicillin/clavulanate, but for other combination dosages as well, whether prescription or over the counter.

[0031] Thus, a need exists for a device in which one or more compositions may be dispensed in varying doses throughout a treatment regimen. Further, a need exists for a device in which one or more compositions may be dispensed in a set dosage throughout a treatment regimen and one or more compositions may be dispensed in varying doses throughout a treatment regimen. A need exists for a dispensing system which may dispense a set dosage of amoxicillin and a varying, or subsequently reduced, dosage of clavulanate. Further, a need exists for a device in which to monitor compliance with prescribed treatment regimens and to minimize or alleviate side effects from certain medications and treatment regimens.

[0032] These and other needs are met by the present invention including a dispensing system, a device, and a method for treating bacterial infections. Other advantages of the present invention will become apparent from the following description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is one embodiment of a device of the present invention.

[0034] Figure 2 is a further embodiment of a device of the present invention.

[0035] Figure 3 is a further multi-chamber embodiment of a device of the present invention.

[0036] Figure 4 is further embodiment of a dispensing system of the present invention.

[0037] Figure 5 is further embodiment of a multi-chamber dispensing system of the present invention.

[0038] Figure 6 is further embodiment of a dispensing system of the present invention.

[0039] Figure 7 is further embodiment of a multi-chamber dispensing system of the present invention.

[0040] Figure 8 is further embodiment of a dispensing system of the present invention.

[0041] Figure 9 is further embodiment of a dispensing system of the present invention.

SUMMARY OF THE INVENTION [0042] This invention provides a method for two or more doses of a composition. More particularly, the exemplary non-limiting illustrative

embodiments disclosed herein relate to a method including a mixture of clavulanate and amoxicillin including an amount of amoxicillin and an amount of about 1 mg/5 mL to about 125 mg/5 ml_ of clavulanate potassium, preferably from about 1 mg/5 mL to about 65 mg/5 mL, more preferably from about 20 mg/5 mL to about 45 mg/5 mL, and most preferably in an amount not greater than about 21.5 mg/5 mL to about 32.5 mg/5 mL of clavulanate potassium.

[0043] The method may include a set dosage throughout the treatment regimen of the composition and the second, third, etc. composition may have a varied dosage throughout the treatment regimen. Further, if two compositions are dispensed in the method then both may have a varied dosage throughout the treatment regimen. Moreover, if more than three compositions are dispensed, any combination of compositions may have a set and consistent dosage throughout the treatment regimen and any combination of the compositions may have a varied dosage throughout the treatment regimen. In one embodiment of the invention a dispensing system is included such as a device which dispenses a set dosage of amoxicillin and a varying dosage of clavulanate, such as dispensing one dosage of clavulanate than the device dispenses thereafter. The system provides an easily used means of ensuring administration of an effective but not excessive unit dose of clavulanate. In this embodiment, the first unit dose may contain more or the same amount of clavulanate in the subsequent doses.

[0044] A further embodiment of this invention is a method of use including a composition including an amount of amoxicillin and an amount no greater than about 21.5 mg/5 mL to about 32,5 mg/5 mL of clavulanate potassium, where the composition is administered over a period of days. The period of days of treatment may be between about one (1 ) day to about fourteen (14) days, preferably between about five (5) days to about ten (10) days. The dosage of clavulanate potassium may be constant, tapered downward, or tapered in a combination of upward and downward over the treatment period. The dosage of c!avulanate potassium may be modified such that the last or near last dosages have no clavulanate potassium to amoxicillin.

[0045] A further embodiment of this invention is a method of use including a composition including an amount of amoxicillin and an amount of clavulanate potassium in at a ratio of at least about 28:1 , preferably in a range of about 28:1 through about 56: 1 , where the composition is administered over a period of days. The period of days of treatment may be between about one (1) day to about fourteen (14) days, preferably between about five (5) days to about ten (10) days.

[0046] Various dosage forms and corresponding dispensing modes can achieve the purposes of this invention. Suspensions which can be taken orally or inhaled, powders, granules, tablets, and injections are part of this invention.

These dosage forms are delivered in an organized manner in order of constant or decreasing concentration of clavulanate.

[0047] This system may also be used to deliver combined doses of other medications. For example a cold medication containing an antihistamine and a decongestant could also be packaged in an organized array where each dose has a different amount of antihistamine and/or decongestant depending on the stage of treatment or any other factor.

[0048] Accordingly, part of this invention is a dispensing system containing compositions with a first pharmaceutically active compound and a second pharmaceutically active compound (further pharmaceutically active compounds may be added). The compositions contain different amounts of the second pharmaceutically active compound. There may be two or more such

compositions, and the compositions are arranged in order so that (i) each contains either progressively more or less of the first pharmaceutically active compound, or (ii) each contains either progressively more or less of the second pharmaceutically active compound, or (iii) each contains either progressively more or less of both the first and second pharmaceutically active compound. There may be a constant amount of the first pharmaceutically active compound in each composition or different amounts. However there is preferably a concentration gradient of the second pharmaceutically active compound from composition to composition, either more or less. There may also be a functional gradient developed by using different forms of the first or second

pharmaceutically active compound rather than different amounts, which for example may be metabolized at different rates. Although two pharmaceutically active compounds are preferred and amoxicillin and clavulanate are particularly preferred, the dispensing systems of this invention may be designed to contain and dispense more than two pharmaceutically active compounds as

compositions containing differing amounts of these compounds.

[0049] The dispensing system of this invention may include a dispenser for dispensing the compositions in the form of dosages (which may include one or more than one unit dose - i.e. the same composition may be dispensed just once or may be dispensed several time, providing multiple unit doses). The first dosage dispensed may contain more of the second pharmaceutically active compound than the subsequent dosages dispensed. The compositions in the dispenser are preferably arranged in order by decreasing amount (concentration) of the second pharmaceutically active compound.

[0050] The dispenser may dispense a series of unit doses of the

compositions, in order of decreasing amount of the second pharmaceutically active compound. Or, as discussed above, each of the two or more

compositions may be dispensed multiple times but in order of concentration - preferably by decreasing amount of the second pharmaceutically active compound.

[0051] Also part of this invention is a dispensing system which includes compositions having a first pharmaceutically active compound and a second pharmaceutically active compound. The compositions can contain different amounts of both, but preferably of the second pharmaceutically active

compound. In one embodiment the dispensing system constitutes a chambered dispenser where first chamber contains the first pharmaceutically active compound and the second chamber contains the second pharmaceutically active compound and the dispenser provides unit doses by combining the first pharmaceutically active compound with the second pharmaceutically active compound in variable ratios. In another embodiment the dispensing system has three or more chambers and a third or more pharmaceutically active compound may be added to the doses.

[0052] Also part of this invention is a dispensing system including a composition including an amount of amoxicillin and an amount of clavulanate potassium in at a ratio of at least about 28:1 , preferably in a range of about 28:1 through about 56:1.

DETAILED DESCRIPTION OF THE INVENTION

[0053] This invention provides a method for two or more doses of a composition including a mixture of clavulanate and amoxicillin including an amount of amoxicillin and an amount of about 21 .5-25.0 mg/5 ml_ of clavulanate potassium. The method may include a set dosage throughout the treatment regimen of the composition and the second, third, etc. composition may have a varied dosage throughout the treatment regimen. Further, if two compositions are dispensed in the method then both may have a varied dosage throughout the treatment regimen. Moreover, if more than three compositions are dispensed, any combination of compositions may have a set and consistent dosage throughout the treatment regimen and any combination of the compositions may have a varied dosage throughout the treatment regimen. In one embodiment of the invention a dispensing system is included such as a device which dispenses a set dosage of amoxicillin and a varying dosage of clavulanate, such as dispensing one dosage of clavulanate than the device dispenses thereafter. The system provides an easily used means of ensuring administration of an effective but not excessive unit dose of clavulanate. In this embodiment, the first unit dose may contain more or the same amount of clavulanate in the subsequent doses.

[0054] A further embodiment of this invention is a method of use including a composition including an amount of amoxicillin and an amount no greater than about 21.5 mg/5 ml_ of clavulanate potassium, where the composition is administered over a period of days. Also disclosed is a method of use of including a composition including an amount of amoxicillin and an amount of clavulanate potassium in at a ratio of at least about 28: 1 , preferably in a range of about 28: 1 through about 56:1 , where the composition is administered over a period of days. The period of days of treatment may be between about one (1) day to about fourteen (14) days, preferably between about five (5) days to about ten (10) days.

[0055] The dispensing systems of the present invention deliver

compositions designed to deliver set or varying doses of a medication over a treatment regimen. More particularly, the exemplary non-limiting illustrative embodiments disclosed herein relate to a dispensing system including a combined dosage medication such as amoxicillin and clavulanate in a sequential manner with the amount of clavulanate per dose remaining constant or declining relative to the amount of amoxicillin. In order to ensure compliance with this antibiotic regimen the doses are provided in dispensers that can provide an array of sequential, graded doses. In one embodiment of the invention, as the treatment regimen progresses the amount of amoxicillin should preferably be held constant while the amount of clavulanate decreases, however the amount of amoxicillin may also vary if desired. In another embodiment of the invention, the dispensing system includes a composition comprised of amoxicillin and clavulanate potassium where the amount of clavulanate potassium is less than about 21.5 mg/5 ml_. A multiple day dosage method is included.

[0056] For purposes of this invention, the following terms have the meanings given below unless otherwise indicated.

[0057] "Unit Dose" means a discrete dose of a composition of this invention given once, in a single administration.

[0058] "Dose" or "dosage" may mean either a single administration of a composition or can mean several administrations of the same composition depending on context. For example if the composition is given twice a day, a dose could be taken to mean two administrations of the same composition, in suitably measured amounts. Thus the same "dose" may be given two or three times (or more if necessary) in the treatment regimen before progressing to the subsequent dose, which would be of a composition having a different given amount of medication. However as defined above a unit dose means a single dose given a single time, i.e. in one administration.

[0059] "Dosage form" is the type of formulation in which the compositions of this invention are administered, such as but not limited to amoxici!lin- clavulanate potassium. A dosage form may be a discrete unit such as a tablet or may be a liquid form or a suspension, from which unit dosages are measured.

[0060] "Dispensing system" describes compositions of this invention arranged for administration. The compositions may be formulated to be taken as unit doses, or may be formulated for measuring out in a suitable container or by a suitable dispenser. The dispensing system may include the compositions and a dispenser for holding and dispensing the compositions in suitable unit or measurable doses.

[0061] "Patient" may be any living thing treated with a composition of this invention. The patient is preferably a human child or adult, but could also be a non-human such as an animal.

[0062] "About" when used in connection with an amount shall mean a scientifically reasonable variance above and below that amount keeping in mind artifacts of measurement and other variables. For example, a ratio of about 1 :15 may encompass ± 5% of the unit of measure used. A concentration of 1 mg/mL may encompass a range of about ± 0.05 mg, while a concentration of 1000 mg/mL may encompass a range of ± 50 mg.

[0063] "Amoxicillin" and "clavulanate potassium" or "clavulanic acid" refer to any existing acid and salt forms, whether alkali, alkaline, or acid salts, polymorphs, hydrates, solvates, racemates and mixtures. Examples are amoxicillin trihydrate or sodium, and potassium clavulanate. The weights of amoxicillin and clavulanate potassium refer to weight in equivalents of

corresponding free acids unless otherwise indicated. The weights used in a formulation may also be adjusted by known methods depending on potency.

[0064] Standard abbreviations may be used. All publications cited herein, including but not limited to patents and patent applications, are incorporated by reference in their entirety as if individually specified as incorporated by reference, unless otherwise indicated.

[0065] Accordingly this invention provides a method for two or more doses of a composition including amoxicillin and clavulanate potassium. The dose may be set and consistent throughout a treatment regimen or it may varying, either increasing or decreasing, throughout a treatment regimen.

[0066] The preferred active ingredients in the inventive method are amoxicillin and clavulanate used together in a constant or tapering treatment modality described, however other active ingredients may be used in the same type of dispensing system to provide compositions of this invention.

[0067] Clavulanate potassium includes clavulanic acid, which is the generic name for (2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1- azabicyclo[3.2.0]heptane-2 -carboxylic acid, which is a known compound of the following formula:

[0068] The inventive method and composition also includes amoxicillin, which is an analog of ampicillin, derived from the basic penicillin nucleus 6- aminopenicillanic acid. Chemically, a=Amoxicillin is (2S,5R,6R)-6-[l-(-)-2-amino- 2-(p-hydroxyphenyl)acetamido]-3,3-dimet— 7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid.

[0069] The method includes one or more doses of a composition comprised of about 25 mg/5 ml to about 1200 mg/5 ml of amoxicillin and from about 1 mg/5 ml to about 125 mg/5 ml of clavulanate. Preferably the method includes one or more doses of a composition comprised of about 125 mg/5 ml to about 1200 mg/5 ml of amoxicillin and from about 1 mg/5 ml to about 70 mg/5 ml of clavulanate. More preferably the method includes one or more doses of a composition comprised of about 125 mg/5 ml to about 600 mg/5 ml of amoxicillin and from about 10 mg/5 ml to about 43 mg/5 ml clavulanate. Most preferably the method includes one or more doses of a composition comprised of about 125 mg/5 ml to about 600 mg/5 ml amoxicillin and from about 1 to about 33 mg/5 ml of clavulanate. Within the ranges provided, the clavulanate may be constant over the dosage treatment or taper down, up, or a combination of tapering over the days of treatment. On one embodiment of the method the composition of may contain no more than about 28.5 mg/5 mL of clavulanate potassium.

[0070] A particularly preferred mode of administration of the inventive method is orally via an aqueous suspension. For preparing such suspensions amoxicillin and clavulanate potassium can be combined with buffers, emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. These active compounds can be directly mixed with liquid ingredients to provide a suspension, or can be formed into granules or powders which are then made into a suspension, by known methods and using known ingredients examples of which are provided below. The resulting suspension can be stored in the presence of water, especially if refrigerated, for an appropriate period. However, a preferred method is to store the mixture as a dry powder until its use is required, at which time it is mixed with an appropriate diluent, e.g., water.

[0071] The prescribing physician will ultimately determine the appropriate dose for a given human subject, and this can be expected to vary according to the age, weight, and response of the individual patient as well as the nature and severity of the patient's symptoms. The patient may be pediatric, an adult or a geriatric human.

[0072] Dosage forms contemplated for the compositions of this invention containing amoxicillin and clavulanate potassium, include any known liquids for pharmaceutical use, preferably oral suspensions as the typical patient will be a human child or adult. The most common formulation is a powder for suspension to be mixed with water at the time of use. [0073] The inventive method, composition and/or dispensing device may also include a composition containing excipients, vehicles, and solvents include sterile water, saline, Ringer's solution, polyalkylene glycols, natural and synthetic fatty acids, mono, di, and triglycerides and oils, and hydrogenated naphthalenes. Carriers may be included such as but not limited to lactose, saccharose, sorbitol, mannitoi, starch, amylopectin, cellulose derivatives, and gelatin.

[0074] D is integrants may be included such as but not limited to starch such as pregelatinized and sodium starch glycolate, cellulose such as

microcrystalline, sodium carboxymethyl, hydroxypropyl, croscarmellose sodium, crosspovidone, and crosslinked polyvinyl pyrrolidone. Fillers may be included such as but not limited to cellulose, dibasic calcium phosphate, lactose, sucrose, glucose, mannitoi, sorbitol, calcium carbonate, and fats and oils for capsules.

[0075] Antifriction agents may be included such as but not limited to magnesium and calcium stea rates, and polyethylene glycol waxes. Glidants may be included such as but not limited to colloidal silicon dioxide and talc.

Lubricants may be included such as but not limited to talc, silica, colloidal silicon dioxide, and fats such as zinc or magnesium stearate or stearic acid.

Preservatives may be included such as but not limited to e m-cresol, p-cresol, o- cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (hexahydrate), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosal,

antioxidants (vitamins A, C, E, retinyl palmitate), selenium, cysteine, methionine, citric acid, sodium citrate, and lower alkylparabens. Mucoadhesives may be included such as but not limited to methyl, hydroxypropyl, and sodium

carboxymethyl cellulose, chitosan, polyvinyl pyrrolidone, and hydrogels.

[0076] Binders may be included such as but not limited to

polyvinylpyrrolidone, pregelatinized starch, methacrylic acid polymers, gelatin, and hydroxypropylcellulose. pH modifiers may be included such as but not limited to various organic and inorganic acids, bases, and their salts such as orthophosphoric acid, hydrochloric acid, nitric acid, sulphuric acid, sulfamic acid, hydrofluoric acid, oxoacids, sodium and potassium dihydrogen phosphates, citric acid, ascorbic acid, tartaric acid, maiic acid, maionic acid, succinic acid, fumaric acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, polyacrylic acid, sodium carbonate, sodium bicarbonate, magnesium carbonate, magnesium oxide, calcium carbonate, calcium oxide, aluminium hydroxide, magnesium hydroxide, and sodium hydroxide.

[0077] Buffers may be included such as but not limited to acetic acid, citric acid, boric acid, and phosphoric acid. Isotonicity agents may be included such as but not limited to glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes, Emulsifiers may be included such as but not limited to soy lecithin, calcium steamy I dilactate, various esters of polyglycerol and sorbitan, and monoglycerides. Suspending agents may be included such as but not limited to natural and synthetic polysaccharides such as gums (acacia, tragacanth, guar, and xanthan), celluloses (sodium carboxymethyl, methyl, hydroxyethyl, hydroxypropyl, and microcrystalline), cargeenan, sodium alginate, carbomer, colloidal silicon dioxide, and clays (aluminum magnesium silicate, bentonite, hectorite).

[0078] Further components such as solubilizers may be added including but not limited to Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) and non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, polyols, other block copolymers, and chelators such as EDTA and EGTA.

[0079] Flavorants may be included such as but not limited to sodium saccharin, sugar, and other natural and artificial compounds which mask or enhance flavor. Colorants may be included such as but not limited to natural dyes such as caramel coloring, annatto, cochineal, betanin, turmeric, saffron, paprika, elderberry, pandan, and butterfly pea, and artificial dyes such as FD&C Blue Nos. 1 and 2, Green No. 3, Yellow Nos. 5 and 6, and Red Nos. 3 and 40. Thickening agents may be included such as but not limited to alginic acid and salts (such as sodium, potassium, ammonium, calcium), agar, carrageenan, locust bean gum, gelatin, and pectin. Stabilizing agents may be included such as but not limited to fatty acid salts, sulfates, sulfate esters and phosphate esters (for example polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitan monoofeate, polysorbate 80 and polysorbate 20). Surfactants may be included such as but not limited to sorbitan trioleate, soya lecithin, and oleic acid.

[0080] The sweetener included in the method and composition, used without or without the dispensing device or system, may be any natural or synthetic compound, or combination of compounds, which provides adequate sweetening to overcome the bitterness of the inventive composition. Natural sweeteners include carbohydrates such as sucrose, dextrose, fructose, invert sugar, mannitol, sorbitol, and the like. Synthetic sweeteners include saccharin, aspartame, cyclamates, and other so-called artificial sweeteners familiar to those of skill in the art. The flavoring of the composition may be any natural or synthetic compound, or combination of compounds, which provides acceptable taste to overcome the b!andness of the base composition. Such flavorings include bubble gum, grape, cherry, berry, citrus, other fruits, peppermint, spearmint, other mints, vanilla, chocolate, and the like, familiar to those of skill in the art.

[0081] In more detail, the method and composition, used without or without the dispensing device or system, of the present invention may be liquid

formulations for oral use. Such formulations may include a suitable selection of appropriate known ingredients such as those provided above alone or in combination. The liquid formulations may be formulated as syrups, solutions or emulsion, elixir, suspensions or other known types of liquid suitable for oral administration. The liquid formulations may be aqueous or nonaqueous and include for example buffers with any pharmaceutically acceptable salts, preservatives, emulsifiers, humidifiers, isotonicity agents, solubilizers, buffers, thickening and suspending agents, dyes, and flavorants.

[0082] Specific ingredients may include water, saline, polyalkylene glycols, oils, hydrogenated naphthalenes, sugar, ethanol, glycerol, propylene glycol, dyes, flavorants, and thickening agents. The liquid formulations may be prepared by known methods using the compositions of this invention. The active compounds of the amoxicillin and clavulanate potassium may be obtained from existing powders, granules, or tablets for liquid formulations.

[0083] The liquid formulations which may be used in the inventive method and composition, used without or without the dispensing device or system, of the present invention may be provided for oral administration. For example the formulations may be taken in measured doses using a cup, straw, spoon, syringe, or other device. The formulations may be provided in liquid form, or may be provided in dry form (for example granule or powder) to which an

appropriately formulated water or liquid solvent is added to provide a liquid formulation of a composition of this invention. Ingredients suitable for liquid formulations are known and such a formulation may be made by methods known in the art.

[0084] A liquid formulation (for example solution, suspension, emulsion) can be made by combining the amoxicillin and clavulanate potassium with suitable aqueous and or nonaqueous diluents, water, buffers, and preservatives as discussed above and mixing with known methods under suitable known conditions. The specific ingredients and concentrations will depend on the type of formulation desired, for example oral suspension as known in the art.

However, as an example, a oral suspension may also include a vehicle such as water, saline, Ringer's solution, dextrose, serum albumin, sodium chloride, mannitoi, buffers, and preservatives. The formulation may be sterilized by known techniques.

[0085] Dosage forms contemplated for the method and composition, used without or without the dispensing device or system, include any known liquid, aerosolized, or solid formulations whether formulated for enteral (for example oral, nasal, buccal, sublingual, or rectal), parenteral or injectable (for example intravenous, intradermal, intraosseous, intramuscular, intraperitoneal, and subcutaneous), topical, inhaled, recta! or vaginal, via mucous surfaces (such as corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, stomachic, intestinal, and rectal) or any other route of administration. Examples are capsules, powders, sachets, pills, tablets, hard or soft gelatin capsules, colloids, granules, lozenges, crystals, douches, pessaries, suppositories, injectable solutions, syrups, suspensions, pastes, elixirs, films, emulsions, ointments, lotions, gels, liniments, balms, creams, eye or ear drops, skin patches, and aerosols, inhalants, nebulized forms, vaporized forms, liposomes, microspheres, and any other known formulations.

[0086] The dosage forms of the method and composition, used without or without the dispensing device or system, of the present invention may be formulated for any convenient release profile such as immediate, sustained, or delayed by well known methods.

[0087] The method and composition, used without or without the dispensing device or system, of the present invention may be in the form of a tablet, capsule, powder or any other known dosage delivery. The composition may include carriers such as but not limited to lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, and gelatin. A tablet or capsule form may include coatings and enteric coatings such as but not limited to talc, cellulose, shellac, corn protein, zein, sugar, gum arabic, titanium dioxide, gelatin, or other polymers such as polysaccharides.

[0088] Disintegrants may be included such as but not limited to starch such as pregelatinized and sodium starch glycolate, cellulose such as

microcrystalline, sodium carboxymethyl, hydroxypropyl, croscarmellose sodium, crosspovidone, and crosslinked polyvinyl pyrrolidone. Fillers may be included such as but not limited to cellulose, dibasic calcium phosphate, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and fats and oils for capsules.

[0089] Antifriction agents may be included such as but not limited to magnesium and calcium stea rates, and polyethylene glycol waxes. Glidants may be included such as but not limited to colloidal silicon dioxide and talc.

Preservatives may be included such as but not limited to m-cresol, p-cresol, o- cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (hexahydrate), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosa!,

antioxidants (vitamins A, C, E, retinyl pa Imitate), selenium, cysteine, methionine, citric acid, sodium citrate, and lower alkylparabens. Mucoadhesives may be included such as but not limited to methyl, hydroxypropyl, and sodium

carboxymethyl cellulose, chitosan, polyvinyl pyrrolidone, and hydrogels. The tablets and capsules may also include binders, buffers, flavorants, colorants, thickening agents, stabilizing agents, surfactants, and other additives.

[0090] In more detail, the method and composition, used without or without the dispensing device or system, of the present invention, which contain a first and second pharmaceutically active compound, preferably

amoxicil!in/clavulanate, may be liquid formulations for oral use. Such

formulations may include a suitable selection of appropriate known ingredients such as those provided above alone or in combination. The liquid formulations may be formulated as syrups, solutions or emulsion, elixir, suspensions or other known types of liquid suitable for oral administration. The liquid formulations may be aqueous or nonaqueous and include for example buffers with any

pharmaceutically acceptable salts, preservatives, emulsifiers, humidifiers, isotonicity agents, solubilizers, buffers, thickening and suspending agents, dyes, and flavorants.

[0091] Specific ingredients may include water, saline, polyalkylene glycols, oils, hydrogenated naphthalenes, sugar, ethanol, glycerol, propylene glycol, dyes, flavorants, and thickening agents. The liquid formulations may be prepared by known methods using the compositions within the dispensing device or system of the present invention. The active compounds such as amoxicillin and clavuianate may be obtained from existing powders, granules, or tablets for liquid formulations.

[0092] The liquid formulations of the method and composition, used without or without the dispensing device or system, of the present invention may be provided for oral administration. For example the formulations may be taken in measured doses using a cup, straw, spoon, syringe, or other device. The formulations may be provided in liquid form, or may be provided in dry form (for example granule or powder) to which an appropriately formulated liquid solvent is added to provide a liquid formulation of a composition of this invention.

Ingredients suitable for liquid formulations are known and such a formulation may be made by methods known in the art.

[0093] The liquid formulations method and composition, used without or without the dispensing device or system, of the present invention can also be provided for inhalation in the form of an aerosol by known methods as described further below. A liquid formulation as described above is useful also as an aerosol. Ingredients suitable for aerosol liquid formulations are known and such a formulation may be made by methods known in the art. Various types of spraying devices are known in the art. A suitable formulation may include known excipients, buffers, isotonicity agents, preservatives, surfactants, and zinc.

Stabilizing agents may be included.

[0094] A liquid formulation (for example solution, suspension, emulsion) can be made by combining a first and second pharmaceutically active compound of this invention, preferably amoxicillin and clavulanate with suitable aqueous and or nonaqueous diluents, water, buffers, and preservatives as discussed above and mixing with known methods under suitable known conditions. The specific ingredients and concentrations will depend on the type of formulation desired, for example oral or parenteral as known in the art. For example, a parenteral formulation may include a vehicle such as water, saline, Ringer's solution, dextrose, serum albumin, sodium chloride, mannitol, buffers, and preservatives. The formulation may be sterilized by known techniques.

[0095] Formulations for use as liquid aerosols may be aqueous and include suitable excipients, buffers, isotonicity agents, preservatives, surfactants, and possibly zinc. Bulk proteins may be used for stabilizing, such as albumin or protamine. Carbohydrates such as sucrose, mannitol, lactose, trehalose, and glucose may be used. A surfactant may also be included, such as po!yoxyethy!ene fatty acid esters and alcohols or polyoxyethylene sorbital fatty acid ester.

[0096] Formulations of the method and composition, used without or without the dispensing device or system, of the present invention for use with metered dose inhalers may take the form of finely divided powders.

Compositions of this invention can be made by combining the amoxicillin and clavulanate in a nonaqueous suspension such as in a propeilant. The propeilant can be a conventional propeliant such as a fluorocarbon (chloro, hydrochloro, hydro, dichloro, trichloro) or other halogenated hydrocarbons such as

dichlorotetrafluoroethanol, 1 ,1 ,1 ,2-tetrafluoroethane, hydrofIuoroalkane- 34a, and hydrofluoroalkan227. A surfactant such as sorbitan trioleate, soya lecithin, and oleic acid may be used.

[0097] Compositions used within the method, without or without the dispensing device or system, of the present invention can be provided in the form of powders or granules or lyophilized preparations using suitable ingredients provided above by methods known in the art. Such granules and powders may be used to make liquid formulations by addition of a suitable solvent by known methods, or may be provided for inhalation as an aerosol by known methods, or be used in capsules. An example of a powder formulation is provided by the packet insert for Augmentin. The powder contains colloidal silicon dioxide, xanthan gum, and flavorings, aspartame and/or hypromellose and/or mannitol and/or silica gel and/or silicon dioxide and/or sodium saccharin.

[0098] The compositions used within the method, used without or without the dispensing device or system, of the present invention may be provided in tablet form. The amoxicillin and clavulanate may be mixed with a suitable solid carrier as described above (for example lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, and an antifriction agent such as magnesium stearate, calcium stearate, or polyethylene glycol waxes. Once pressed, the resulting tablets can be coated with coating solution of ingredients provided above such as sugar, gum arabic, gelatin, talc, or titanium dioxide. Various dyes may be added if desired, for example to indicate different amounts of clavulanate.

[0099] Tablets may be designed for delayed release within the dispensing device or system of the present invention. Ingredients suitable for delayed or immediate release are combined with the granules, to provide immediate or delayed release amoxicillin and clavulanate forms. Bilayer tablets may also be used, made by known methods. Such tablets may contain a layer of amoxicillin on a layer of clavulanate, two such layers separated by a barrier layer, and may or may not have a coating layer over all or some of the tablet. Either or both of the layers may be formulated for immediate or sustained release by known methods. More than two layers are possible. In the alternative, a tablet with a core and surrounding component separated by barriers may also be made by known methods, having delayed or immediate release properties if desired. An example of chewable tablets is provided by the packet insert for Augmentin (Augmentin prescribing information, September 2009 GlaxoSmithKline). The tablets contain colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, and 1 or more of aspartame, D&C Yellow No. 10, FD&C Red No. 40, glycine, sodium saccharin and succinic acid.

[0100] The compositions used within method, used without or without the dispensing device or system, of the present invention may be provided in the form of soft or hard gelatin capsules. Soft gelatin capsules may include vegetable oil or polyethylene glycol. Hard gelatin capsules may contain powder or granules of compositions of this invention made with carriers, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. Suppositories may be prepared from the compositions of this invention as gelatin capsules or a formulation in a base of polyalkyleneglycols and/or neutral fats such as Vaseline, or cocoa butter.

[0101] Compositions used within the method, used without or without the dispensing device or system, of the present invention may be formulated for absorption through mucosal surfaces, for example in the form of an emulsion made up of active particles and mucoadhesive in an aqueous phase. ucoadhesion of the emulsion permits absorption of the active ingredients through mucosal surfaces. Intranasal formulations can be aqueous or nonaqueous, or can be solid with excipients such as lactose. Buccal

formulations may include excipients such as sugars, calcium or magnesium stearate, and pregelatinized starch.

[0102] Compositions used within the method, used without or without the dispensing device or system, of the present invention may be formulated for transdermal administration. Delivery devices known in the art, such as

liposomes, nanoparticles, microparticles, microcapsules, or microspheres may be used. These may be produced from various synthetic polymers such as polyhydroxy acids, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides. [0103] Liquid formulations of the method and composition, used without or without the dispensing device or system, of the present invention of this invention can be prepared by mixing the pharmaceutically active compounds preferably amoxicillin and clavulanate with a preservative and any desired buffers in an aqueous diluent using conventional procedures for mixing and dissolution. Liquid formulations can be made by reconstituting powders or granules or lyophilized preparations.

[0104] Suspensions of the method and composition, used without or without the dispensing device or system, of the present invention may be provided at any concentration providing acceptable stability for the

pharmaceutically active compounds (for example the length of the desired treatment period, optionally with refrigeration) and within the range that would provide a composition having suitable flow parameters for dispensing the inventive composition. Reconstituting oral suspensions from an

amoxicillin/clavulanate powder composition may be done as follows from a powder prepared for oral suspension (provided above). The suspension may be prepared from freely flowing powder in a suitable container. A little over half of the solvent such as water needed should be added and the container shaken vigorously to suspend. Then the rest of the solvent should be added and the container shaken vigorously.

[0105] Granules prepared for the method or the compositions, whether with or without the dispensing device or system, of the present invention can be provided by known methods, either wet or dry. For example, a binding agent is suspended in a solvent while solid ingredients may be ground to a desired particle size. The first and second pharmaceutically active compounds, preferably amoxicillin and clavulanate, are mixed with the binding agent in solution to form a suspension. The mixture is sieved and dried for a

predetermined length of time. The granules may be sieved again and other ingredients added. Other ingredients such as disintegrating agents, antiadhesive agents, and antifriction agents may be added. Amoxicillin, clavulanate, and the various carrier ingredients discussed above are all available from known suppliers, or may be made by known methods.

[0106] Tablets may be prepared from the granules by use of punches and dies in the appropriate pressing machine. Modified release tablets may be prepared by known methods using immediate release granules, inert barrier granules, and slow release granules formed into layers.

[0107] This invention is directed to a method of treatment by providing two or more doses of a first pharmaceutically active compound and a second pharmaceutically active compound, where the first dose or doses taken contain more of the second pharmaceutically active compound than the second dose or doses and any subsequent dose or doses. Preferably the first compound is amoxicillin and the second is clavulanate. A preferable condition to be treated is a bacterial infection, most preferably otitis media.

[0108] Certain known dosing combinations of amoxicillin and clavulanate potassium are listed in Table 2 below. In these conventional dosing

combinations the amount of clavulanate potassium is between about 28.5 mg/5 mL to about 62.5 mg/5 mL. The previous known and used ratios of amoxicillin to clavulanate potassium are between 4:1 to 14:1. TABLE 2

Amoxicillin Clavulanate potassium Ratio

1 125 mg/5 mL 31.25 4:1

2 200 mg/5 mL 28.5 7:1

3 250 mg/5 mL 62.5 4:1

4 400 mg/5 mL 57 7:1

5 600 mg/5 mL 42.9 14:1

[0109] The method of the present invention instead may include a treatment dosage including amoxicillin and clavulanate potassium wherein the amount of clavulanate potassium is from about 1 mg/5 mL to about 80 mg/5 mL, preferably from about 1 mg/5 mL to about 65 mg/5 mL, more preferably from about 20 mg/5 mL to about 45 mg/5 mL, and most preferably in an amount not greater than about 21.5 mg/5 mL to about 32.5 mg/5 mL of clavulanate

potassium. In one embodiment of the method the dosage of the composition includes clavulanate potassium in an amount which does not exceed about 28.5 mg/5 mL and in another embodiment the dosage of the composition includes clavulanate potassium in an amount which does not exceed about 21.5 mg/5 mL. Further, another embodiment of the inventive composition contains amoxicillin and clavulanate potassium in a ratio of at least 28:1 and preferably between 28:1 and 56:1 . Most such embodiments of the invention result in a reduced amount of clavulanate potassium compared to current known compositions. While not being bound by theory, the reduced amount of clavulanate potassium may be especially good for geriatric and pediatric patients as it may lead to reduced chance of diarrhea, nausea, and vomiting, as well as for pediatric patients experiencing diaper rash. The reduced amount of clavulanate potassium does not affect the treatment efficacy of the amoxicillin to treat acute otitis media or other illnesses such as respiratory illnesses.

[0 10] The method of the invention is to patients with a dosing regimen of about one to about fourteen days, using a composition of amoxicillin and clavulanate potassium wherein the clavulanate potassium is present in an amount of about 20 mg/5 mL to about 33 mg/5 mL, preferably in an amount not to exceed about 21.5 mg/5 m to about 28.5 mg/5 mL. In one embodiment of the method of the present invention the amount of clavulanate potassium remains constant, with the amount being less than about 28,5 mg/5 mL, more preferably not less than about 21.5 mg/5 mL.

[01 11] In another embodiment of the method of the present invention using the dispensing device or system of the present invention it is preferred that the first dose contains more of clavulanate potassium, than the second, or any subsequent dosage. For example, in a multiple day method spanning ten (10) days, the dosage of clavulanate potassium on days 1 and 2 may be in an amount of about 20 mg/5 mL to about 35 mg/5 mL (preferably in an amount about 21 .5 mg/5 mL), followed by dosage in an amount of about 15 mg/5 mL on days 3-10.

[01 12] A further embodiment of the method of the present invention within the dispensing device or system of the present invention includes a dosage for the first two days of the treatment containing about 20 mg/5 mL to about 35 mg/5 mL (preferably in an amount no more than about 21.5 mg/5 mL of clavulanate potassium) and then the subsequent dosages contain a less amount of clavulanate potassium. In yet another embodiment of the method of the present invention the first dose contains more of the clavulanate potassium than the second dose, and the subsequent dosages contain decreasing amounts of clavulanate potassium. The less amount of clavulanate potassium may be constant or can continue to decrease over the treatment days. For example, in a multiple day method spanning ten (10) days, the dosage of clavulanate potassium on days 1 and 2 may be in an amount of about 20 mg/5 mL to about 35 mg/5 mL (preferably in an amount about 21.5 mg/5 mL), then an amount of about 15 mg/5 mL to about 20 mg/5 mL on days 3-6, and an amount of about 5 mg/5 mL to about 10 mg/5 mL on days 7-10. In all the embodiments of the inventive method the amounts used should be effective for the treatment contemplated, as can be determined by a person skilled in the art.

[01 13] In another embodiment of the inventive method, whether within or without the dispensing device or system, of the present invention the method of the invention is to treat patients with a dosing regimen of one to about fourteen days, using a composition of amoxicillin and clavulanate potassium in a ratio of at least about 28:1. In another embodiment of the method of the present invention it is preferred that the first dose contains more of clavulanate potassium, than the second, and any subsequent dosages contain decreasing amounts of

clavulanate potassium, so that the ratio increases over the dosage treatment regimen. The amounts used should be effective for the treatment contemplated, as can be determined by a person skilled in the art.

[01 14] The amounts of the amoxicillin in either embodiment of the inventive method, will preferably remain the same during the treatment regimen, but may also decrease, or may even increase for any treatment that would require increasing amounts, or even be a combination of decreased followed by increased followed by decreased amount. The amounts of the clavulanate potassium may decrease with each dosage or may remain constant over several doses, or even increase if the treatment requires. But it is most preferable that the amount of the clavulanate potassium decreases with successive dosages. The dosages may be formulated to contain more than one unit dose and thus be administered more than once. Thus it is possible that two or more successive dosages as administered may contain the same amount of the clavulanate potassium, while the next subsequent dosage contains less. The dosages may also be provided as a unit dose, in which case each is only provided once. Any combination of dosages and unit doses may be used. One embodiment of the method is for a multiple day dosage wherein the clavulanate potassium is a constant amount over the treatment days, with the days being anywhere from about two days to about fourteen days or more. Another embodiment of the method is for a multiple day dosage wherein the clavulanate potassium is reduced over the dosage period. The dosage period may also be about two days or increased up to about fourteen days or more, with either constant or reduced clavulanate potassium over the dosing period.

[01 15] For instance, the amount or concentration of the clavulanate potassium can remain constant in the ratio of at least about 28:1 to the

amoxicillin, or could taper down in succeeding dosages of the method. In the reducing embodiment, thus each composition will contain less of the clavulanate potassium and the ratio will increase. The final dosing composition may optionally contain none of the clavulanate potassium.

[01 6] In general the compositions within the dispensing device or system of the present invention contain effective amounts for the treatment contemplated of the amoxicillin and clavulanate potassium. These amounts may be

determined by a skilled person with routine experimentation.

[01 17] However preferred amounts of amoxicillin and clavulanate potassium are provided as follows. In any liquid formulations of the compositions of this invention described above, preferably suspensions, each composition may contain from about 100 to about 1200 mg/5 mL (or about 20 to about 140 mg/mL) of amoxicillin and about 0.1 to about 80 mg/5 mL of clavulanate potassium. The compositions preferably contain from about 125 mg/6 mL to about 600 mg/5 mL of amoxicillin. Preferably the amount of clavulanate potassium is from about 0.1 mg/5 mL to about 35 mg/5 mL of liquid formulation. For purposes of dosing 5 mL is equal to one teaspoon.

[01 18] For any given dispensing system of this invention, the amount of clavulanate potassium in the first composition should preferably determine the amount in the second (and succeeding) compositions in an embodiment wherein there will be the same or less clavulanate potassium in succeeding doses. For example, if the first composition contains 600 mg/5 mL of amoxicillin and about 21.5 mg/5 mL of clavulanate potassium, then the second dosing composition contains equal to or less than about 21.5 mg/5 mL clavulanate potassium.

[01 19] This invention is also directed to a liquid composition, either within or without a dispensing device or system, of the present invention of amoxicillin and clavulanate potassium which contains less than about 32.5 mg/5 mL and more than 0.1 mg/5 mL of clavulanate potassium. A preferred composition has from about 15 mg/5 mL to about 28.5 mg/5 mL. Another preferred composition has from about 10 mg/5 mL to less than about 21.5 mg/5 mL. Another preferred range is from about 2.5 mg to about 10 mg of clavulanate potassium. [0120] The concentrations of the dosage of the method are preferably expressed in mg as above. This invention also contemplates ratios to express the concentrations. For example the amoxicillin may be present in a ratio of about 28:1 to about 56:1 where 1 represents the amount of the clavulanate potassium. Preferably the amount of the amoxicillin is from about 30:1 to about 35:1. These ratios are preferably weight ratios. As discussed above, dosage of the method of this invention may start with any amount or concentration of the clavulanate potassium as long as the succeeding compositions contain the same or lower amounts or concentrations.

[0121] The amounts and concentrations of the pharmaceutically active compounds, preferably amoxicillin and clavulanate potassium, may also determined by known methods using desired serum concentrations at various points in the treatment regimen.

[0122] The compositions for use in the inventive method of the present invention can be prepared by known processes. Amoxicillin and clavulanate potassium, the preferred pharmaceutically active compounds can be obtained from suppliers or made by known methods. See for example U.S. Pat. Nos. 6,218,380 and 7,534,781.

[0123] The formulations discussed above can be made by methods known in the art using the various "inactive" formulation ingredients discussed with amoxicillin and clavulanate potassium. These known ingredients can be made by methods known in the art or obtained from chemical supply houses. The amounts and concentrations preferred for the amoxicillin and clavulanate potassium compositions of this invention are discussed above. The amounts of the other ingredients should be sufficient to provide the properties for which each of the ingredients are being used, for example, flavorant or other additives.

[0124] Liquid formulations of compositions for use within the inventive method, either within or without a dispensing device or system, of the present invention can be prepared by mixing the pharmaceutically active compounds preferably amoxicillin and clavulanate potassium with a preservative and any desired buffers in an aqueous diluent using conventional procedures for mixing, suspension or dissolution. Liquid formulations can be made by reconstituting powders or granules or lyophilized preparations.

[0125] Suspensions for use within the inventive method, either within or without a dispensing device or system, of the present invention may be provided at any concentration providing acceptable stability for the pharmaceutically active compounds (for example the length of the desired treatment period, optionally with refrigeration) and within the range that would provide a composition having suitable flow parameters for dispensing systems of this invention. Reconstituting oral suspensions from an amoxicillin and clavulanate potassium powder composition may be done as follows from a powder prepared for oral

suspension. The suspension may be prepared from freely flowing powder in a suitable container. A little over half of the solvent such as water needed should be added and the container shaken vigorously to suspend. Then the rest of the solvent should be added and the container shaken vigorously.

[0126] The preferred active ingredients of the present inventive method are amoxicillin and clavulanate potassium used together in the treatment regimen described, however other active ingredients may be used in the same type of composition of this invention. Further, the amoxicillin and clavulanate potassium may be present throughout the multiple day dosing method in a constant amount of about 21.5 mg/5 ml_ or less of clavulanate potassium to at least 600 mg/5 mL, or more of amoxicillin, in a ratio of at least about 28:1 .

[0127] Any pharmaceutically acceptable formulation of the compositions within the dispensing device or system of the present invention including the amoxicillin and clavulanate potassium at a ratio of at least 28:1 may be used in the dispensing systems of this invention. Such compositions may contain pharmaceutically acceptable ingredients whose nature and amounts will be known to a skilled practitioner depending on the dosage form and route of administration selected. Amoxicillin and clavulanate in any pharmaceutically acceptable form may be used in any combinations, including salts, complexes, prodrugs, hydrates, solvates, or polymorphs. Clavulanate potassium is preferred. Other pharmaceutically active ingredients may also be included in the

compositions of this invention.

[0128] This invention is directed to a method of treatment by providing two or more doses of a composition containing amoxicillin and clavuianate

potassium. A preferable condition to be treated is a bacterial infection, most preferably acute otitis media. Other conditions for treatment include respiratory bacteria illness such as sinusitis.

[0129] The patient or treatment subject may be a human such as a child, adult or elderly individual. Other patients may include non-humans such as animals. Therefore the method would include a veterinary method to treat infections and bacteria in mammals, fish, birds and animals.

[0130] The amount of the compounds of the dosage treatment of the invention are amounts effective to treat the condition. More specific amounts have been discussed in detail above. The dosage will depend on the age, weight, condition, and disease of the patient. In general the method of this invention includes dosages containing effective amounts for the treatment contemplated of the amoxicillin and clavuianate potassium. These amounts may be determined by a skilled person with routine experimentation.

[0131] The method of the claimed invention may include two or more doses of amoxicillin combined with clavuianate potassium, possibly within a dispensing device or system, where the dosing remains constant or the initial doses contain more or less clavuianate potassium than any subsequent doses. The clavuianate potassium amount may be constant throughout the dosage, with the amount being less than conventional dosages, such as less than about 21.5 mg/5 mL to about 35 mg/5 mL. In another embodiment, the initial dose may be a unit dose which contains more clavuianate potassium than the second dose which is a unit dose and any subsequent unit doses. The initial dosage may be more than one unit dose containing more clavuianate potassium than the second and subsequent unit dosages which also may include more than one unit dose. Similarly the first dose may be a unit dose and subsequent dosages include more than one unit dose. The first dosage may be more than one dose and second 41725

and/or subsequent doses may be unit doses. The distinction between the first and subsequent doses is an embodiment of this invention.

[0132] in a further embodiment of the inventive method, the treatment regimen may be over multiple days where the initial dosage amount of

clavulanate potassium is about or less than about 21.5 mg/5 ml_ to about 45 mg/5 ml_, the middle doses are a higher amount than the first while still being less than about 21 .5 mg/5 ml_ to about 45 mg/5 mL, and the next subsequent doses are in an amount lower than the middle doses. For example, in a multiple day method spanning ten (10) days, the dosage of clavulanate potassium on days 1 and 2 may be in an amount of about 10 mg/5 mL to about 19 mg/5 mL, then an amount of about 20 mg/5 mL to about 30 mg/5 mL on days 3-6, and an amount of about 5 mg/5 mL to about 10 mg/5 mL on days 7-10.

[0133] The compositions within the dispensing device or system of the present invention and the methods of this invention may be used to provide various treatment regimens to patients as methods of treatment of this invention. A method of treatment regimen of the present invention may be one day or multiple days, between about two days to about fourteen days, though it is preferred the dosing be for about three through about ten days. In one

embodiment of the present invention a dosage is given for seven (7) days with a constant amount of clavulanate potassium in an amount of about 20 mg/5 mL to about 35 mg/5 mL, preferably about 21.5 mg/5 mL to about 28.5 mg/5 mL. The dosage schedule below are given solely as examples, many others may readily be developed by a skilled practitioner based on known methods and information provided herein. In these examples "day" is a twelve hour period, meaning the patient would take 2 doses of the dosage per calendar day, preferably spaced out in 12 hour intervals.

[0134] For example a treatment period of about ten days providing amoxicillin and clavulanate potassium pot within the dispensing device or system of the present invention wherein the dosing remains constant of amoxicillin and clavulanate potassium where the clavulanate is in an amount of about 21 .5 mg/5 mL or less. [0135] Another example of a treatment period of ten days may include the following dosing as follows:

Days 1-4: 600 mg/kg amoxicillin and about 15 mg/kg to about 35 mg/kg clavulanate potassium; and

Days 5-10: 600 mg/kg amoxicillin and about 10.75mg/kg clavulanate potassium, should provide suitable dosages for a patient.

[0136] In another embodiment a treatment period of ten days providing amoxicillin and clavulanate potassium within the dispensing device or system of the present invention wherein the dosing remains constant of amoxicillin and clavulanate potassium where the clavulanate potassium is present in an amount of about 2 .5 mg/5 mL or less. In another embodiment a treatment period may be five (5) days, or even seven (7) days, wherein the dosing remains constant, or tapered downward, of amoxicillin and clavulanate potassium where the clavulanate potassium is present in an amount of about 21.5 mg/5 mL to about 32.5 mg/5 mL to or less. Further, the dosage of clavulanate potassium may be constant, tapered downward, or tapered in a combination of upward and downward over the treatment period. The dosage of clavulanate potassium may be modified such that the last or near last dosages have no clavulanate potassium, and as such only amoxicillin as an active ingredient (with any other fillers, flavorants, etc.) .

[0137] Another example of a treatment period of ten days may include the following dosing as follows:

Days 1-2: 600 mg/kg amoxicillin and about 21.5 mg/kg clavulanate potassium;

Days 3-5: 600 mg/kg amoxicillin and about 10.75mg/kg clavulanate potassium; and

Days 6-10: 600 mg/kg amoxicillin and about 5.5 mg/kg clavulanate potassium, should provide suitable dosages for a patient. [0138] As can be seen this exemplary regimen can be modified for different formulations, reduced or extended in length, and designed to provide further clavulanate potassium gradients if desired, by varying the amounts and concentrations of the compositions within the dispensing device or system of the present invention and selecting the appropriate dispensing system of this invention. Other examples will be apparent to a skilled practitioner and are part of this invention.

[0139] Preferably the amount of clavulanate potassium in subsequent dosages is from about 0.1 mg/5 mL of suspension to about 80 mg/5 ml_ of suspension, preferably from about 1 mg/5 mL to about 35 mg/5 mL of

suspension, more preferably from about 5 mg/5 mL of suspension to about 28.5 mg/5 mL of suspension, and most preferably from about 10 mg/5 mL of suspension to about 21.5 mg/5 mL of suspension.

[0140] In general, this invention provides methods of treatment as discussed above for infections in a patient, of any part of the body including specific cells, tissues, or organs. The infections may be acute or chronic and are primariiy bacterial such as meningitis, peritonitis, Chlamydia pneumoniae, S. pneumoniae, listeriosis, salmonellosis, toxic shock syndrome, tuberculosis, and other bacterial infections. Syndromes and conditions caused by bacterial infections may also be treated, such as hemolytic uremic syndrome and Lyme disease.

[0141] Bacterial infections for treatment with the compositions of this infection include but are not limited to acute otitis media and other infections such as those of the lower respiratory tract, sinusitis, skin and skin structure infections and urinary tract infections. These can be caused by caused by various bacteria both gram positive and gram negative. Among them are staphylococcus aureus, Enterobacter species in urinary tract infections, escherichia coli, H. influenzae, Moraxella catarrhalis, S. pneumoniae, Neisseria gonorrhoeae, Eikenella corrodens, Proteus mirabilis, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus saprophytics, Streptococcus pyogenes, viridans group streptococcus, Klebsiella species Bacteroides species, Fusobacterium species, and Peptostreptococcus species.

[0142] As discussed above there are various formulations and dispensing methods for methods and compositions of this invention. The appropriate dosages may be determined as discussed above within the bounds of this invention regarding initial and subsequent doses with regard to the relative amounts of the amoxicillin and clavulanate potassium. Delivery methods include but are not limited to liquid and oral suspensions. Dispensing systems include containers, syringes, spoons, straws and the like.

[0143] The method dosage containing the reduced amount of clavulanate potassium compared to conventional compositions should correspondingly reduce possible less common but severe side affects of jaundice and hepatitis, hemorrhagic/pseudomembranous colitis, angioedema, Stevens-Johnson syndrome, hypersensitivity vasculitis, tooth discoloration, and seizure , as well as the more common and disruptive side effects of diarrhea, vomiting or diaper rash, headache, mycosis, vaginitis and agitation, all while still maintaining the efficacy and benefits of the antibiotic treatment for acute otitis media and other illnesses. This should be seen whether the clavulanate potassium remains in a constant dosage throughout the about one to about fourteen day treatment regimen method, of about 10 mg/5 mL to about 45 mg/5 mL or less than about 21.5 mg/5 mL to about 28.5 mg/5 mL, or if the clavulanate potassium dosage is reduced through the respective about one day to about fourteen day dosage, being reduced either once, more than once or with each subsequent unit dose.

[0144] Besides amoxicillin and clavulanate potassium, other compositions may be used in the method of the present invention. For example, one

composition could be a cough suppressant and the other composition could be a fever reducer. Any combination of various cold, cough, fever, flu and other compositions could be included within the dispensing device or system of the present invention. For example, a four chamber dispensing device could include acetaminophen in the first chamber, antihistamine in the second chamber, expectorant in the third chamber, and a cough suppressant such as dextromethorphan in the fourth chamber. The patient could then vary the dosage of each chamber depending on symptoms of the cold or cough. For instance, the chambers could include compositions of aspirin, ibuprofen, acetaminophen, naproxen sodium, any pain or fever reducing composition, pseudoephedrine, phenylephrine, decongestants, antihistamines such as but not limited to brompheniramine, chlorpheniramine, dimenhydrinate, doxylamine,

diphenhydramine or any combinations thereof, guaifenesin or other expectorants, all alone or in combinations thereof. For instance, one chamber could contain a mixture of a decongestant and antihistamine. Many possible combinations could be within the dispensing device or system of the present invention.

[0145] Figure 1 is one embodiment of a dispensing system of the present invention. The container (10) has a partitioned internal chamber (20), a dispensing pump (30) and nozzle (40), and a cap (50, 60). The container (10, 100, 1 10) of Figures 1 -3 may be made of plastic, polymer, glass, metal and the like. In some embodiments the container (10, 100, 110) is opaque in order to maintain the potency of the liquid or powder medication held within due to changes based on exposure to light or oxidation. The container (10, 100, 1 10) may be single use or may be reusable and structured such that medication may be repeatedly filled for multiple sets of treatment regimen.

[0146] Figure 2 is another embodiment of a dispensing system of the present invention. The container (10) has dual internal chambers (70, 80), an adjustable valve (90) with preset ratios for delivering contents of internal chambers (70, 80), and metered dose dispensing pump (105) and a nozzle (1 10). In this embodiment the ratio of composition within the internal chambers (70, 80) may be either constant throughout the treatment regimen, or may vary over doses or days of the treatment regimen. Further, one chamber may be a constant dosage and the dosage dispensed from the other chamber may vary, either increasing or decreasing or a combination of both increased and then decreased dosages, over doses or days of the treatment regimen. Further embodiments of the present invention may include three or more chambers for compositions or medications. Again, each chamber may have a set and constant dosage throughout the treatment regimen, or may vary over doses or days of the treatment regimen.

[0147] Figure 3 is a further embodiment of a dispensing system of the present invention in which a multi-compartment container (115) is shown including a single dispensing aperture (120) in a base (130) with a rotating top (140) for dispensing multiple, single unit doses of solid oral formulation, which may be preloaded with unit dose, having dose times and periods printed on top (150). In use, the solid oral formulation is dispensed either from the top or bottom of the container after the patient rotates the top (140). The top (140) may be rotated either manually or electrically via a button. The container may also include a rotating apparatus, not shown, and an electrical device to electrically rotate the top. Further, the container may also include electrical means for sound, such as an alarm, music or spoken word to remind the patient that the dosage is due to be administer, and taken by the patient. The container (1 10) may be used for only one treatment regiment or may be reusable and refillable for many treatment regimens.

[0148] Figure 4 is another embodiment of a dispensing system of the present invention including a blister style wallet package (200) having a base (210) with individual dosage units (220) containing unit doses of solid, powder or liquid formulations or sachets of liquid formulations. The dispensing system may include a cover (220). The dispensing system (200) may be made of paper, plastic, polymer, or metal, depending on the formulation within, and may include optional foils, plastics and other non-permeable barriers so as to protect the medication and compositions within.

[0149] Figure 5 is a further embodiment of a dispensing system of the present invention in which a multi-compartment container (300) is shown having dual internal chambers (310, 320), an adjustable valve (330) with preset ratios for delivering contents of internal chambers (310, 320), and metered dose

dispensing pumps on each chamber (340, 350) and a nozzle on each chamber (360, 370). In this embodiment the ratio of composition within the internal chambers (310, 320) may be either constant throughout the treatment regimen, or may vary over doses or days of the treatment regimen. Further, one chamber may be a constant dosage and the dosage dispensed from the other chamber may vary, either increasing or decreasing or a combination of both increased and then decreased dosages, over doses or days of the treatment regimen. Further embodiments of the present invention may include three or more chambers for compositions or medications. Again, each chamber may have a set and constant dosage throughout the treatment regimen, or may vary over doses or days of the treatment regimen.

[0150] Figure 6 is a further embodiment of a dispensing system of the present invention in which a multi-compartment container (400) is shown having dual internal chambers (410, 420) and a cap on each chamber (430). In this embodiment the ratio of composition within the internal chambers (410, 420) may be either constant throughout the treatment regimen, or may vary over doses or days of the treatment regimen. Further, one chamber may be a constant dosage and the dosage dispensed from the other chamber may vary, either increasing or decreasing or a combination of both increased and then decreased dosages, over doses or days of the treatment regimen. Further embodiments of the present invention may include three or more chambers for compositions or medications. Again, each chamber may have a set and constant dosage throughout the treatment regimen, or may vary over doses or days of the treatment regimen.

[0151] Figure 7 is a further embodiment of a dispensing system of the present invention in which a multi-compartment container (500) is shown having dual internal chambers (510, 520), and metered dose dispensing pumps on each chamber (540, 550) and a cap on each chamber (530). In this embodiment the ratio of composition within the internal chambers (510, 520) may be either constant throughout the treatment regimen, or may vary over doses or days of the treatment regimen with a combination of compositions in internal chambers (540, 550) on chamber 510, and another two internal chambers (560, 570) within the second chamber 520. Further, one chamber may be a constant dosage and the dosage dispensed from the other chamber may vary, either increasing or decreasing or a combination of both increased and then decreased dosages, over doses or days of the treatment regimen. Further embodiments of the present invention may include three or more chambers for compositions or medications. Again, each chamber may have a set and constant dosage throughout the treatment regimen, or may vary over doses or days of the treatment regimen.

[0152] Figures 8 and 9 are further embodiments of a dispensing system of the present invention. In Figure 8 a multi-compartment container (600) is shown having dual internal chambers (610, 620) and a cap on each chamber (630). In Figure 7 a multi-compartment container (700) is shown having dual internal chambers (710, 720) and a cap on each chamber (730). Other embodiments of the present invention may be envisioned for dispensing one or more

compositions.

[0 53] In a further embodiment of the present invention a dispensing system and method are disclosed wherein a container includes a mixture of clavulanate and amoxicillin (also referred to as amoxicillin/clavulanate) where the dose dispensed first contains more clavulanate than the doses dispensed thereafter. The system can deliver a minimum of two doses, or can deliver three or more multiple doses, as long as the first-provided dose contains more clavulanate than the second dose and any further subsequent doses thereafter contain a decreasing amount of clavulanate. The number of doses delivered depends on the length of the treatment and the frequency of administration. As few as two doses may be delivered, and as many as fifty doses, or more if dictated by the needs of treatment and the capacity of the dispensing system.

[0154] The dispensing system having a dispenser of this invention may include a container (10, 100) with a liquid suitable for reconstituting the compositions in the reservoirs or chambers (70, 80) to provide dosages in the form of suspensions. The liquid should be water, or another suitable solvent for a pharmaceutical suspension, as discussed above. The dispensing system may also include a vessel suitable for dispensing oral dosages of the compositions of this invention. An example is a cup or a straw, preferably with suitable

measuring marks to provide easy measurement of the required unit doses.

[0155] In a more preferred embodiment, the dispensing system contains a dispenser having two or more reservoirs or chambers (70, 80), such reservoirs containing the first and second pharmaceutically active compositions (or third and fourth, etc.) of this invention, and in one embodiment preferably amoxicillin and clavulanate. The composition in one reservoir or chamber contains a larger amount or concentration of clavulanate than the composition in the second reservoir. It is possible to add further pharmaceutically active compounds in differing amounts to these compositions. The dispensing system may include liquid carrier and dispensing vessel as well. See, for example, Figure 2.

[0156] A preferred dispensing system of this invention has two chambers, the first containing a composition of amoxicillin/clavulanate and the second containing a composition of amoxicillin/clavulanate with less clavulanate than the first. Preferably the compositions are suspensions, which may be dry for reconstitution (such as granules or powder). If so, the dispensing system may also have a container with a liquid suitable for reconstituting the compositions in the reservoirs to provide dosages in the form of suspensions. Such liquids have been discussed above. The container may conveniently hold an amount of liquid premeasured for this purpose.

[0 57] The dispensing system is preferably designed to dispense a premeasured amount of the first and second compositions from the chambers, for example through a nozzle (40, 90). Also included may be a vessel suitable for dispensing dosages for oral consumption such as a cup or a straw, which may be suitably marked for measurement. The dispensing system may be designed to dispense any convenient amount, but preferably the amount dispensed or measured is about 5 ml., more preferably 5 ml. The chambers may contain the same or different amounts of suspension.

[0158] In a preferred embodiment, the first chamber contains a suspension of from about 125 mg/5 ml to about 1200 mg/5 ml of amoxicillin and from about 1 mg/5 ml to about 125 mg/5 ml of clavulanate, and the second chamber contains a suspension of from about 125 mg/5 mi of amoxicillin and about 0 mg to about 120 mg/5 ml of clavulanate. More preferably the first chamber contains a suspension from about 125 mg/5 ml to about 1200 mg/5 ml of amoxicillin and from about 25 mg/5 mi to about 70 mg/5 ml of clavulanate and the second chamber contains a suspension comprising from about 125 mg/5 ml to about 1200 mg/5 ml of amoxicillin and from about 0 to 25 mg/5ml of clavulanate. Most preferably the first chamber contains a suspension comprising from about 125 mg/5 ml to about 600 mg/5 ml of amoxicillin and from about 21 mg/5 ml to about 45 mg/5 ml clavulanate and the second chamber contains a suspension from about 125 mg/5 ml to about 600 mg/5 ml amoxicillin and from about 1 to about 32.5 mg/5 ml of clavulanate. Within the ranges provided, the composition in the first chamber will most preferably contain more clavulanate than the composition in the second chamber. The amount of amoxicillin may be the same in both chambers or may be different within the ranges provided.

[0159] This invention is also directed to the dispenser of this invention discussed above with reservoirs, and adapted to provide the dosages in the form of aerosols, preferably for inhalation. The dispensing system may also contain tablets or sachets to provide unit doses, for example as a blister pack (200) as described in Figure 4. The dispensing system may be in the form of a rotating multi compartment case which dispenses unit doses of a solid oral dosage form such as a tablet (see for example Figure 3).

[0160] The dispensing systems of this invention may be provided as discussed with packaging materials and directions for use. The dispenser may be made of any suitable material, for example a rustproof metal, plastic, heavy cardboard, or other suitable materials. The reservoirs may be made of any suitable material such as glass or plastic.

[0161 ] Dispensers of this invention may also include devices for injecting such as pen-injector type devices, in particular those with a dry or lyophilized compositions of this invention in the reservoirs (or cartridges). Dispensers may be suitable for providing aerosols, for example metered dose inhalers, nebulizers, dry powder generators, and sprayers. Nebulizers may be jet or ultrasonic. The dispensers of this invention have at least two reservoirs to contain the compositions of this invention in the form of doses having a first and second pharmaceutically active compound preferably amoxicillin and

clavulanate. The second pharmaceutically active compound is present in higher amounts in the first dosage than in subsequent doses. The aerosols provided may be aqueous or nonaqueous solutions or suspensions or solid particles such as granules or powders. See for example US 2009/0277441 and US

2011/00204545. Metered dose inhalers may require a propellant gas. Examples are Ventolin, Turbuhaler, Rotahaler, Diskus, Spiros, Spinhaler, and others. See for example WO 94/16970, WO 98/35888, WO 97/25086, EP 237507, U.S.

Patent No. 4,668,218, WO 94/08552 Dura, U.S. Patent. No. 5,458, 135 WO 94/06498. Nebulizers include AERx.TM. Aradigm, Ultravent.RTM.and Acorn II.RTM. (U.S. Pat. No. 5,404,871 , WO 97/22376), and may use solutions or generate particles preferably about 1 to 10 microns.

[0 62] An aerosol spray is made by forcing a liquid formulation through an opening. The size of the opening and the amount of force applied will affect to particle size and amount dosed at a time. The opening size and configuration, the applied pressure, and the liquid feed rate can be chosen to achieve the desired output and particle size. An electric field can be used to produce electrospray. A dispenser of this invention which is a metered dose inhaler includes pressurized canisters containing compositions of this invention with propellants as described above. The composition may be in solution or may be suspended powder. The metering valve measures dosages released as an aerosol, preferably with particle sizes in the 10 to 1 micron range.

[0163] Different modes of administration can be used to provide the compositions of this invention to patients, depending on dosage form as discussed above. Examples are suspensions, emulsions, solutions, colloids, powders, and tablets. The amount provided is determined by known methods depending on the condition, age, and weight of the patients as guided by dosing of compositions of this invention discussed above. [0164] The present invention thus is method including dosage of a composition having amoxicillin- clavulanate potassium of minimally sufficient quantity so as to maintain the efficacy of the composition in view of beta- lactamase mediated resistance H. influenzae and M. catarrhalis, without elevating the possibility of the severe side effects of jaundice and hepatitis and the more common and disruptive side effects of diarrhea, diaper rash and vomiting. The method allows the amoxicillin in the composition to be used as intended while reducing the side effects of the clavulanate potassium while further still maintaining the efficacy of the overall composition when dealing with various beta-lactamase medicated resistance issues.

[0165] Further, the reduced dosage treatment of the present invention may either be maintained throughout the treatment or further reduced throughout the treatments over subsequent days. Again, this reduced amount of clavulanate potassium in the total composition may be constant throughout the treatment regimen or preferably reduced throughout the treatment regimen, with the amount being of minimal sufficient quantity so as to maintain the efficacy of the total composition in view of beta-iactamase mediated resistance H. influenzae and M. catarrhalis.

[0 66] Having generally described the invention, the same will be more readily understood by reference to the following example, which is provided by way of illustration and are not intended as limiting.

Example

Formulations:

[0167] These formulations are provided as examples of possible oral suspension formulations within the dispensing device or system of the present invention. It will be apparent that these formulations and many variations of these formulations are available as compositions within the dispensing device or system of the present invention. Other types of formulations as discussed above such as aerosols, injectable solutions, capsules, topical formulations, and others may be included among these examples. Oral suspension (amounts in S ml)

200 mg Amoxicillin- trihydrate and 3.36 mg {0, 5mEc|) sodium

250 mg Amoxicillin trih^'ydrate and 3,39 mg (0.15 mEq) sodium

20 mg clavulanate potassium

10 mg clavulanate potassium

5 mg clavulanate potassium Oral suspension;

200, 250, 400 mg Amoxicillin trihydrate

20, 10, 5 mg clavulanate potassium

FD&C Red No 3

flavorings

silica gel

sodium benzoate

sodium citrate

sucrose

xanthan gum

These ingredients are sieved and milled separately and together, then blended and remilled, compacted by roller compaction, and screened with vibration to provide granules.

[0168] The invention has been described in terms of embodiments thereof, but is more broadly applicable as will be understood by those skilled in the art. The scope of the invention is only limited by the following claims.

Claims

1 . A method of treating bacterial infections which comprises providing at least two dosages of amoxicillin combined with clavulanate potassium wherein the initial dosage contains more clavulanate than subsequent dosages.

2. The method of claim 1 the clavulanate potassium is present in an amount about 0.1 mg/5 ml_ to about 65 mg/5 mL.

3. The method of claim 2 wherein the clavulanate potassium is present in an amount about 5 mg/5 mL to about 32.5 mg/5 mL.

4. The method of claim 3 wherein the clavulanate potassium is present in an amount about 10 mg/5 mL to about 32.5 mg/5 mL

5. The method of claim 1 wherein at least one subsequent dosage has no clavulanate potassium.

6. The method of claim 1 wherein the last dosage has no clavulanate potassium.

7. The method of claim 1 wherein the amount of clavulanate decreases over at least some subsequent dosages from the initial dosage.

8. The method of claim 1 wherein the dosages are given for up to fourteen consecutive days.

9. The method of claim 1 wherein the dosages are given for ten consecutive days.

10. The method of claim 1 wherein the dosages are given for seven consecutive days.

1 1. The method of claim 1 wherein the dosages are given for five consecutive days.

12. The method of claim 1 wherein the dosages are given for three consecutive days.

13. The method of claim 1 wherein the dosage is given twice a day.

14. The method of claim 1 wherein the composition is in the form of a liquid, gas or solid.

15. The method of claim 14 wherein the liquid is chosen from the class of liquids including but not limited to suspensions, emulsions, solutions, and colloids.

16. The method of claim 14 wherein the composition is a solid chosen from the class of solids including but not limited to tablets, capsules, and powders.

17. The method of claim 1 wherein the ratio of amoxicillin and clavulanate potassium is between about 28:1 to about 56:1.

18. The method of claim 1 wherein the ratio of amoxicillin and clavulanate potassium is about 35:1.

19. A method of treating pediatric bacterial infections which comprises providing at least two dosages per day, over a period of between three to fourteen consecutive days, of an oral suspension containing amoxicillin combined with clavulanate potassium wherein the clavulanate potassium is present in an amount no more than about 1 mg/5 mL to about 32.5 mg/5 mL.

20. The method of claim 19 wherein the initial dosage has more

clavulanate potassium than subsequent dosages.

21. The method of claim 19 wherein the dosages are given for up to fourteen consecutive days.

22. The method of claim 19 wherein the amount of amoxicillin in each dosage is from about 200 to about 600 mg/5 mL and the amount of clavulanate potassium in the first dosage is from about 21.5 mg/5 mL to about 28.5 mg/5 mL.

23. The method of claim 19 wherein the amount of clavulanate potassium in subsequent dosages is constant for all dosages.

24. The method of claim 19 wherein the amount of clavulanate potassium in subsequent dosages is less than the amount of clavulanate potassium in the initial dosage.

25. The method of claim 19 wherein the amount of clavulanate potassium in subsequent dosages is more than the amount of clavulanate potassium in the initial dosage.

26. The method of claim 19 wherein the bacterial infection is acute otitis media.

27. The method of claim 19 wherein the ratio of amoxicillin and

clavulanate potassium is between about 28: 1 to about 56:1.

28. The method of claim 27 wherein the ratio of amoxicillin and

clavulanate potassium is about 35: 1.

29. A method treating bacterial infections which comprises providing at least two dosages of a composition over a period of up to seven consecutive days and wherein the composition contains amoxicillin in an amount of from about 200 to about 600 mg/5 ml_ and clavulanate potassium in an amount of from about 21.5 mg/5 mL to about 28.5 mg/5 mL.

30. The method of claim 29 wherein the period is for up to five

consecutive days.

31 . The method of claim 29 wherein the ratio of amoxicillin and

clavulanate potassium is between about 28: 1 to about 56:1.

32. A dispensing system which comprises compositions including clavulanate and amoxicillin wherein the compositions contain different amounts of clavulanate from about 0.1 mg/5 mL to about 32.5 mg/5 mL.

33. The dispensing system of claim 32 wherein the ratio of amoxicillin and clavulanate potassium is between about 28:1 to about 56:1.