WO2014062568A2

WO2014062568A2 - Amoxicillin formulation and method of using such formulation

Info

Publication number: WO2014062568A2
Application number: PCT/US2013/064835
Authority: WO
Inventors: Bharat Patel; JR. William Wade SMITH
Original assignee: Pathway Pharma, Llc
Priority date: 2012-10-15
Filing date: 2013-10-14
Publication date: 2014-04-24
Also published as: WO2014062568A3

Abstract

An antibiotic composition comprising amoxicillin in powder for suspension, and a pharmaceutically acceptable carrier. The composition can have a Cmax of 5.92 +/- 0.625 mcg/ml of the amoxicillin. The composition can have a Tmax range of 2.38 plus/minus 1.13 hours.

Description

AMOXICILLIN FORMULATION AND METHOD OF USING SUCH FORMULATION

PRIOR RELATED APPLICATION DATA

This application claims priority to U.S. Provisional Patent Application Ser. No. 61/714,141, filed October 15, 2012, which is incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to a method of treatment using amoxicillin and for formulations thereof, particularly powder for suspension formulations. This invention also relates to formulations of amoxicillin and to the use of such formulations to treat resistant bacterial infections.

BACKGROUND

Amoxicillin is a known β-lactam antibiotic and marketed under various tradenames, including the term "Amoxil." Amoxicillin is used to treat certain infections caused by bacteria, such as pneumonia; bronchitis; gonorrhea; and infections of the ears, nose, throat, urinary tract, and skin. Amoxicillin is an anti-infective indicated in treatment of infection due to susceptible strains of microorganisms:

Infections for the ear, nose and throat - due to Streptococcus spp (a- and β- hemolytic strains only), Streptococcus pneumoniae, Staphylococcus spp., or Haemophilus influenzae.

Infections of the genitourinary tract - due to Escherichia coli, Proteus mirabilis, or Enterococcus faecalis. Infections of the skin and skin structure - due to Streptococcus spp. (a- and β- hemolytic strains only), Staphylococcus spp., or Escherichia coli.

Infections of the lower respiratory tract - due to Streptococcus spp (a- and β- hemolytic strains only), Streptococcus pneumoniae, Staphylococcus spp., or Haemophilus influenzae.

Gonorrhea, acute uncomplicated (ano-genital and urethral infection) - due to Neisseria gonorrhoeae in male and female.

Duodenal ulcer recurrence in combination with other agents due to Helicobacter pylori

Infections of the ear, nose and throat are extremely common in children. Some of these infections may last only a few days and not require treatment. However, others may become severe and lead to subsequent medical issues.

Sinus and respiratory infections are common in elderly. Some of these infections may be viral in nature, are self-limiting and treated symptomatically. However, others may lead to secondary infections and/or become severe leading to subsequent medical issues.

There is always a need to provide new dosage regiments for amoxicillin providing optimized pharmacodynamic and pharmacokinetic profiles for amoxicillin, so that therapy is maximized. There also is need to provide higher dosage regimens for amoxicillin which are effective against increasingly drug-resistant bacteria, and can enable better compliance to national dosing guidelines through convenience of dosing.. It is to this need that this disclosure is directed.

DETAILED DESCRIPTION This application discloses a pharmaceutical composition in the form of an aqueous suspension, consisting essentially of (a) amoxicillin, (b) at least one additional agent selected from the group consisting of sweetening agents, flavoring agents, flavor enhancers, preservatives, antioxidants, co-solvents, and (c) water, is an optimal regiment for children. It is highly stable and provides a good compliance by children. In some embodiments, water can be added at the point of use in a ratio of about 1 part powder for suspension to about 2 parts water.

Some specific embodiments relate to a method of treating bacterial infections in humans which comprises administering thereto a therapeutically effective amount of amoxicillin such that the amount of amoxicillin is in the range of about 600 mg in a single dosage in about one teaspoon (e.g., 5 ml) or less. An infection caused by the organisms S. pneumoniae (including Drug Resistant and Penicillin Resistant S pneumoniae), H. influenzae and/or M. catarrhalis may be treated by this regiment.

Another embodiment includes a formulation suitable for killing or reducing the prevalence of drug resistant, S. pneumo, H. influenza and/or M. catarrhalis resistant to first line therapy.

Another embodiment relates to an immediate release pharmaceutical powder for suspension formulation when mixed with water comprising about 600 mg/5 mL of amoxicillin suspension in combination with pharmaceutically acceptable excipients or carriers. Another embodiment relates to an immediate release pharmaceutical suspension comprising about 600 mg of amoxicillin in combination with pharmaceutically acceptable excipients or carriers. Another embodiment includes an amoxicillin formulation including mannitol. Mannitol is a sweetening agent that is significantly sweeter than sucrose. Mannitol does not stimulate an increase in blood glucose levels, and is therefore a preferred sweetener for people with diabetes.

Other suitable modified or immediate release formulations are described herein in greater detail.

One challenge in providing formulations of amoxicillin in which the drug release is effectively modified (and a ready explanation for the lack of success already referenced) is the relatively narrow window for absorption of the drug in the small intestine and the relatively short half life of the drug. Furthermore, the rapid elimination of amoxicillin (excretion half-life is 1.3 hours) makes it difficult to maintain serum levels as clearance from the body is very rapid.

The higher concentrated amoxicillin powder for suspension was unexpected and provides a treatment regiment for common diseases through one teaspoon as opposed to multiple plus fractions of about one teaspoon. Improved compliance by patients because of the easier use of the product and improved clinical outcomes are a result. Further there may be less bacterial resistance, which can lead to complete eradication of an infection from the patient. This eliminates current need to further treat with broader spectrum anti-infectives or combination anti- infectives which is thought to contribute to bacterial resistance.

As used herein, the term "amoxicillin" is used generically to refer to amoxicillin or an alkaline salt thereof, in particular amoxicillin trihydrate and (crystallized) sodium amoxicillin, without distinction and unless otherwise indicated. As used herein, the term "immediate release" refers to the release of the majority of the active material content within a relatively short time, for example within about 1 hour, preferably within about 30 minutes, after oral ingestion.

As used herein, the phrase "single dose" means a dose that is administered of about 600 mg. The dose may be administered in a single dosage form in the form of one teaspoonful (5ml) suspension. The single dose is effective within a regimen course of therapy at treating a bacterial infection.

The formulation provides an "Area Under the Curve" (AUC) value which creates an 85- 125% confidence interval that defines bioequivalence to greater volumes of lesser doses of amoxicillin (i.e. 5 mL 600mg, or 1 teaspoonful, to 7.5 mL 400mg, or 1.5 teaspoonful) thereby reducing drug administrations and enhancing patient compliance. Moreover, the formulation, when administered yields a T_max of 2.38 plus/minus 1.13 hours. In another embodiment, the formulation had a Cmax of 5.92 +/- 0.625 mcg/ml the amoxicillin in less than about Tmax range of 2.38 plus/minus 1.13 hours. In yet another embodiment, the formulation had a Cmax of 5.92 plus/minus 0.625 mcg/ml the amoxicillin in less than about Tmax range of 2.38 plus/minus 0.13 hours.

It will be appreciated that immediate release suspension comprising about 600 mg are novel. Accordingly, in a further aspect, one embodiment includes an immediate release pharmaceutical suspension formulation comprising about 600 mg (+/-25%) amoxicillin in combination with pharmaceutically acceptable excipients or carriers. In another embodiment, the immediate release pharmaceutical suspension formulation comprising about 600 mg (+/- 10%) amoxicillin in combination with pharmaceutically acceptable excipients or carriers.

Soluble pharmaceutically acceptable salts of amoxicillin include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium, and acid salts such as amoxicillin hydrochloride. Preferably, the salt is sodium amoxicillin, more preferably crystalline sodium amoxicillin.

As well as active material content, the powder for suspension may also include a pH modifying agent, such as a pH buffer, which may be contained in the suspension formulation. A suitable buffer includes calcium hydrogen phosphate. The composition may be adjusted by the addition of small amounts of inorganic and/or organic acids usually no more than about 1-2% by weight of the composition. In some examples, the pH of the suspension, having the power, was between 4 and 7. In one embodiment, the suspension can have a pH range of about 4.0 to about 8.5. In another embodiment, the suspension can have a pH range is about 5.0 to about 7.5. In some examples, the pH was about 4.8.

The components of the powder for suspension to achieve the expected drug benefits, should remain stable for preparation over time and under conditions normally encountered in consumer pharmaceutical applications to achieve benefit. The formulation powder for solution disclosed has been found stable and robust in a number of tests. For instance, the formulation powder for solution has been placed "on the shelf at room temperature for extended periods of time, and has remained true, without inactivation of the active ingredients. Moreover, the powder for solution has been subjected to alternating refrigeration and/or heat and/or room temperature conditions, and the active ingredients have remained stable.

The powder for suspension may be prepared through mixing of the ingredients. This mixing takes place at an elevated temperature and with applied shear. While the applied shear does not necessarily allow for greater solubility of any ingredient, it appears to provide better stability of the powder for solution during handling and storage. A mixture of the active ingredients and the excipients can be then mixed with water. The process may be carried out in whole or in part in a nitrogen or oxygen atmosphere.

One specific embodiment includes a kit of parts, as a rule, may consist of a bottle containing water, the other excipients such as the co solvent, and a bottle cap comprising a containment which represents housing for the active ingredient(s) and the solid components of the excipients. Before opening the bottle, the components contained in the bottle cap are released and admixed with the liquid components contained in the body of the bottle.

Another specific embodiment include a method of treating bacterial infections in children comprising the step of administering a single dose (5ml, or 1 teaspoonful) of amoxicillin in a suspension of about 600 mg of amoxicillin. In one example, the suspension is administered orally.

One advantage of specific formulations includes a daily dose that is compliant with the guidelines for treating ear, nose and throat infections produced by the Centers for Disease Control (CDC), which are well established and are generally followed in pediatric medicine. These guidelines call for the use of Amoxicillin 600 mg as a standalone agent, which hereto has not been available. Guidelines for treating sinus infections are also produced by the Centers for Disease Control (CDC) and are generally followed in geriatric medicine. These guidelines call for the use of Amoxicillin 600 mg as a standalone agent, which hereto has not been available.

Another advantage of specific embodiments is that patient compliance can be improved by providing a single dose formulation of amoxicillin. For example, 5 ml (one teaspoonful), or 5 ml. Compliance can be given to a child as in single dose administrations. The embodiment provides a method of treating infections, particularly resistant ear, nose and throat infections, in a human in need thereof by easily administered doses of administering single, high-dose amoxicillin. The patient may be an adult sixteen years of age or older, a child under sixteen years of age, or a young child twelve years of age or younger. As providing medicine to children is relatively difficult, a dose administered via 1 teaspoonful rather than more or fractions thereof can help improve regiment compliance.

The present disclosure also extends to formulations which are bioequivalent to the tablets of formulations, in terms of both rate and extent of absorption, for instance as defined by the US Food and Drug Administration.

Specific embodiments will now be described by way of example.

Example 1 - Illustrative Formulation

13.960 Amoxicillin trihydrate powder

18.7960 Pharmagrade sugar

0.170 Sodium CMC

0.510 Colloidal silicon dioxide

0.430 Flavors (bubble gum)

0.00268 Erythrosine

0.100 Mannitol IP

0.0255 Sodium methyl parabean 0.00428 Sodium propyl parabean

The pH is between 5.0 and 7.5, in the suspension

Example 2

Exemplary Excipients used and their impact on formulation

A. Pharmagrade sugar

• Increase stability

• Increase taste

• Provides bacteriolysis

• Sweeteners

• Acts as preservatives

B. Sodium carboxyl methyl cellulose

• Suspending agent

• Acts as surfactant(wetting agent)

• Increase physical stability

• Retards settling and agglomeration of the particles by functioning acts as an energy which minimizes the interparticle interactions.

C. Colloidal silicon dioxide

• Lubricants: Reduce friction.

• Antiadherants: Reduce sticking.

• Glidant: Increase flow property.

D. Mannitol · Sweetening agent (72% more sweeter than sucrose)

E. Sodium methyl parabean

• Preservatives (increases stability)

F. Sodium propyl parabean

• Preservatives (increases stability)

G. Erythrosine colorant · Coloring agent

H. Flavor (Bubble gum flavor)

• Flavoring agent

Example 3

After about six months, the amoxicillin oral suspension contained the equivalent of not less than 90.0 percent and not more than 120.0 percent of the labeled amount of amoxicillin. Example 4 - Preparation

A. Sample preparation

Weigh accurately about 60 mg of sample in dry 100 ml volumetric flasks dissolve and dilute to volume with solution A.

B. System suitability

Inject 20μ1 of the standard solution into the system and Measure the response of the same the relative standard deviation For the five replicate Injections should not be more than 2.0 % and Theoretical plates should not be less than 2000 for Amoxicillin Tryhydrate peak in reference solution and tailing factor is not more than 2.0.

C. Procedure

Inject 20μ1 of sample solution and record the response of the same.

D. Weight / ml

Select a clean and dry pycnometer weigh the empty Pycnometer, Filled with water. Adjust the temperature of filled Pycnometer at 25°C, remove any excess of water and weigh. Subtract the weight of empty Pycnometer from the weight of water filled Pycnometer and calculate weight of the water. Calculate the capacity of Pycnometer in ml by dividing the weight of quantity of Water which fills the Pycnometer at 25°C.by 0.99602. Fill the dried Pycnometer with sample solution. Adjust the temperature of the Pycnometer to 25°C, remove any excess of sample solution and weigh. Substract the weight of empty Pycnometer from the weight of filled Pycnometer and calculate the weight of the quantity of sample solution .Calculate the weight per ml of the sample solution by dividing the weight of the quantity of the sample solution which fills the Pycnometer at 25°C, by the capacity of the Pycnometer at the same temperature.

Example 5

Accelerated Stability Study

Name of Product: Amoxicillin Oral Suspension Batch No.: TR-02

Each 5 ml after reconstitution contains D/M: 09-2010 Amoxicillin Trihydrate BP Equivalent to

Amoxicillin 600mg

Batch Size: 10 Liters D/E: 08-2012

Storage Condition: 40° + 2° C; 75% + 5% RH Started On: -2010

Packing: Packed in 100ml HDPE bottles Completed On: 03-24-201 1

Sample Quality: 12 HDPE bottles (100ml)

Conclusion: As per the testing reports product is found to be stable for 6 months when stored at accelerated conditions of temperature 40° + 2° C and RH 75% + 5%

Table 4

Claims

1. An antibiotic composition comprising

(a) amoxicillin in powder for suspension, and

(b) a pharmaceutically acceptable carrier

2. The composition as claimed in Claim 1, wherein the composition has a Cmax of 5.92 +/- 0.625 mcg/ml of the amoxicillin.

3. The composition as claimed in Claim 1, wherein the composition has a Tmax range of 2.38 plus/minus 1.13 hours

4. The composition as claimed in Claim 1, wherein composition comprising at least one excipient agent selected from the group consisting of sweetening agents, flavoring agents, flavor enhancers, preservatives, antioxidants, co-solvents.

5. The composition as claimed in Claim 1, further comprising manitol.

6. A antibiotic suspension comprising

(a) amoxicillin as a powder,

(b) a pharmaceutically acceptable carrier, and

(c) water,

wherein the amoxicillin from the composition Cmax of 5.92 plus/minus 0.625 mcg/mL is achieved in less than about Tmax range of 2.38 plus/minus 1.13 hours.

7. The suspension as claimed in Claim 6, wherein the concentration of amoxicillian is 600 mg per 5ml water.

8. The suspension as claimed in Claim 6, wherein the powder for suspension further comprises the addition of pharmaceutically acceptable sweeteners.

9. The suspension as claimed in Claim 6, wherein the suspension has a pH range of about 5.0 to about 7.5.

10. A process for preparing a powder for suspension of amoxicillin and mannitol comprising the steps of:

(a) dispensing of the materials of an antibiotic composition comprising (i) amoxicillin in powder for suspension, and a pharmaceutically acceptable carrier, wherein the composition has a Cmax of 5.92 +/- 0.625 mcg/ml of the amoxicillin.

(b) sifting of the materials by vibration,

(c) mixing of the materials for thirty minutes, and

(d) filling and packing of the material in bottles.

11. The process as claimed in Claim 10, carried out in controlled conditions of temperature 25°C and humidity NMT 50%.

12. The process as claimed in Claim 10, further comprising the step of adding acceptable sweeteners.

13. A method of treating human having β-lactam infection that comprises the step of administering to a human a suspension containing amoxicillin, wherein the Cmax of 5.92 +/- 0.625 mcg/ml the amoxicillin from the composition is achieved in less than about Tmax range of 2.38 plus/minus 1.13 hours.

14. The method as claimed in Claim 13, wherein the human is less than about 12 years of age.

15. The method of Claim 13, wherein the suspension further comprises about 450 mg to 750mg of amoxicillin and about 1 to about 10 mg of mannitol per 5 ml of water.

16. The method of Claim 13, wherein the suspension comprises about 600 mg amoxicillin and about 5mg mannitol per 5 ml.

17. A method of treating ear, nose or throat infections resistant to first line therapy in a human comprising administering to a human in need thereof a amoxicillin wherein the dose of amoxicillin wherein the dose(s) is/are about 600 mg per 5 mL, in a form of a suspension, and is a teaspoon.

18. The method of Claim 17, wherein the powder for suspension further comprises 500mg - 750mg amoxicillin per 5 ml.

19. The method of Claim 17, wherein the powder for suspension further comprises 500mg - 750mg amoxicillin and 1-lOmg mannitol per 5 mL

20. The method as claimed in Claim 17, wherein the humans are of age 12 or less.

21. The method as claimed in Claim 17, wherein the infection arises from at least bacterial selected from the group consisting of: S. pneumoniae, Drug Resistant and Penicillin Resistant S pneumoniae, H. influenzae M. catarrhalis, and combination therefor.